Вы находитесь на странице: 1из 36

Schizophrenia and related disorders 15

Stephen M Lawrie Jeremy Hall Eve C Johnstone

Schizophrenia has been described as the heartland of psychia- had described the syndrome of Katatonie, and 3 years later
try. Certainly, many psychiatrists spend a large proportion Hecker had described Hebephrenie. But it was Kraepelin who
of their time caring for those suffering from this disorder. went beyond straightforward clinical description and divided
It is a relatively common condition, which often torments the various forms of insanity into two main groupings on the
and cripples people from adolescence or early adulthood, basis of their long-term course. The first grouping, which he
yet leaves them exposed to discrimination – and has been called manic–depressive insanity, pursued a fluctuating course
described accordingly as the worst disease affecting mankind. with frequent relapses but full recovery after each. The sec-
It probably causes more suffering and distress and blights more ond, for which he used Morel’s term dementia praecox,
lives than any cancer, and certainly represents a major burden embraced Kahlbaum’s catatonia, Hecker’s hebephrenia and
for carers, health services and society as a whole. About his own dementia paranoides, was a progressive disease which
30 years ago, when most patients were hospitalised for most either pursued a steady downhill course to chronic invalidism
of their lives, schizophrenia was the single most expensive or, if improvement did occur, resulted only in partial recovery.
illness for the UK National Health Service to manage. In the Initially, Kraepelin was criticised for introducing yet another
USA, all costs have been estimated as 2% of the gross national classification without any aetiological or pathological basis,
product. Recent figures suggest the total societal costs are in but it was not long before the force and utility of his unifying
excess of £2.6 billion per year for England alone. concepts impressed themselves on his contemporaries and
they started to come into general use.
In 1911, however, before full acceptance of this new classi-
Historical introduction fication, the Swiss psychiatrist Eugen Bleuler published his
Dementia Praecox or the Group of Schizophrenias, which was
Although brief descriptions of an illness with some resem- to be at least as influential as Kraepelin’s Lehrbuch. Although
blance to schizophrenia are to be found in the Hindu Ayurveda Bleuler regarded himself as developing Kraepelin’s concept of
as long ago as 1400 BC, and in the writings of the Cappadocian dementia praecox, in fact he changed it fundamentally, and
physician Aretaeus in the second century AD, recognisable it was his term schizophrenia that eventually won universal
descriptions of schizophrenia are considerably less common, adoption. Bleuler, influenced by the writings of Sigmund
in historical medical texts or literature generally, than those Freud and psychoanalytic ideas generally, coined the term
of melancholia or mania. The earliest unambiguous descrip- schizophrenia, meaning ‘split mind’, because he believed that
tions date only from the end of the 18th century, and it was the disorder was due to a ‘loosening of associations’ between
a further 100 years before the syndrome was defined with different mental functions, affecting both the transition from
any clarity. one idea to the next in thought and speech and the coordina-
That crucial step was achieved by Emil Kraepelin, professor tion between emotional, volitional (cognative) and intellectual
of psychiatry at the University of Munich, in the fifth (1896) (cognitive) processes. He also drew a distinction between his
edition of his Psychiatrie, ein Lehrbuch für Studierende und ‘four As’ (Box 15.1), which he regarded as the ‘fundamental
Ärzte. Throughout the 19th century, psychiatrists had strug- symptoms’, and the more obvious hallucinations, delusions
gled to develop a satisfactory classification of insanity. In and catatonic phenomena which for him were secondary phe-
1856 Morel had coined the term démence précoce to describe nomena of less importance. Bleuler therefore considered that
an adolescent patient, once bright and active, who had slowly schizophrenia could develop and be diagnosed in the absence
lapsed into a state of silent withdrawal. In 1868 Kahlbaum of hallucinations and delusions, and so added a fourth type,

ã 2010, Elsevier Ltd.


DOI: 10.1016/B978-0-7020-3137-3.00015-2
Companion to Psychiatric Studies

The principal problem with Bleuler’s concept of schizophre-


Box 15.1 nia was its lack of clear boundaries. Although he provided little
empirical evidence to justify the idea that his ‘fundamental
Bleuler’s fundamental symptoms (‘the four As’) symptoms’ were indeed fundamental, his assumptions were
• Loosening of Associations (thought disorder) widely accepted, particularly in the USA, and as a result the
• Blunt or incongruous Affect diagnosis of schizophrenia came to be based on the presence
• Autism (social withdrawal) of one or more of the so-called ‘four As’ (Box 15.1), whether
• Ambivalence (apathy) or not the patient was psychotic. It is clear that these phe-
nomena are intangible qualities that can be detected in many
psychiatric patients as well as in some healthy people, particu-
simple schizophrenia, to the hebephrenic, catatonic and para- larly when under stress. Their use as diagnostic criteria led to a
noid forms recognised by Kraepelin. marked expansion of the concept of schizophrenia, to the
Although Bleuler’s term ‘schizophrenia’ eventually dis- point at which it was degenerating into a vague synonym for
placed Kraepelin’s ‘dementia praecox’, and his assumptions severe (and sometimes not so severe) mental illness. Indeed,
about the nature of the disorder became very influential, in 1950s USA, patients were diagnosed as having schizo-
particularly in the USA, Kraepelin’s original concept remained phrenia without having any characteristic features at all. An
dominant in most of Europe. The incompatibility of the krae- example of this diagnostic practice is the concept of ‘pseudo-
pelinian and bleulerian approaches and the ambiguities present neurotic schizophrenia’ (Hoch & Polatin 1949), where patients
in them both resulted in considerable confusion and was a had a wide range of neurotic symptoms, such as phobias,
hindrance to fruitful research. obsessions and depersonalisation, often associated with severe
The crucial characteristic of Kraepelin’s dementia praecox – anxiety and attacks of psychotic disturbance lasting days, hours
what distinguished it from manic–depressive insanity – was its or perhaps only minutes.
prognosis. The illness progressed to a state of permanent Between 1920 and 1960 the confusion steadily increased.
impairment, and any recovery was either temporary or incom- The term ‘schizophrenia’ was used throughout the world, but
plete. However, it became recognised that some patients with in a bewildering variety of different ways which were rarely
the typical clinical characteristics of the condition did recover, made explicit. Some authorities, such as Kleist and Leonhard
and remained well indefinitely without any detectable defect. in Germany and Langfeldt in Norway, insisted that the term
Kraepelin himself came to accept that this occurred in 13% of should be restricted to illnesses resulting in permanent damage
his own cases. Nonetheless, he and most of his contemporaries to the personality; others were prepared to use it freely regard-
assumed that dementia praecox was a ‘disease entity’ with its less of outcome. Some psychiatrists would only make the diag-
own characteristic symptomatology, aetiology, pathology and nosis in adolescents or young adults; others were willing to do
course. However, the aetiology and neuropathology remained so at any age. Some insisted on the presence of certain key
a mystery, and here was evidence that the course was variable. symptoms; others were prepared to make a confident diagno-
It was widely assumed that this variable prognosis was an sis on the basis of indefinable subjective impressions – the
artefact, occurring because patients with a superficially simi- so-called ‘praecox feeling’. In the USA Bleuler’s views pre-
lar psychosis of good prognosis were being confused with dominated, largely because his concept of schizophrenia as a
those suffering from real dementia praecox/schizophrenia. psychological, and possibly psychogenic, disease was readily
Determined efforts were therefore made to distinguish the compatible with the prevailing psychoanalytic orientation.
two, and for decades this was a major theme in schizophrenia The overuse of the term was therefore most marked in that
research. country. In most of Europe, on the other hand, Kraepelin’s
In Europe, the Norwegian psychiatrist Langfeldt tried concepts still held sway. In most of the German-speaking
to distinguish between schizophrenia and what he called world schizophrenia was regarded as an endogenous and hered-
‘schizophreniform psychosis’ on the basis of a detailed study itary psychosis and the diagnosis was restricted to patients
of the symptomatology of the illness. He presented evidence exhibiting certain cardinal symptoms, mainly hallucinations
to suggest that the two had quite different outcomes, and that and delusions of particular kinds. Kleist and Leonhard devel-
electroconvulsive therapy (ECT) and insulin coma therapy oped very detailed classifications of different forms of schizo-
were ineffective in schizophrenia itself (Langfeldt 1960). phrenia, mainly on the basis of a meticulous study of the
Although his methodology had clear limitations, his claim chronic stage of the illness.
was initially widely accepted because it was so welcome. In Of greater influence, however, were the teachings of Kurt
the USA, similar efforts were made by clinical psychologists, Schneider, who focused attention on the earlier acute stage
and a series of rating scales – the Elgin, Phillips and Kantor of the illness and described a number of ‘symptoms of the first
Scales – were developed to discriminate between what they rank’ (Box 15.2), which he considered to be diagnostic of
called process and non-process schizophrenia, mainly on the schizophrenia in the absence of overt brain disease (Schneider
basis of the premorbid personality and psychosexual adjust- 1959). Many of these hallucinations and delusions can be
ment. Both Langfeldt and these American workers assumed interpreted as the result of a failure to distinguish between
that true process schizophrenia was endogenous and here- ideas and impulses arising in the patient’s own mind and
ditary, and that schizophreniform or non-process (‘reactive’) perceptions arising in the external world – a so-called ‘loss of
psychoses were psychogenic, but neither succeeded in ego boundaries’. Schneider was less interested in the theoreti-
demonstrating a clear demarcation between the two. cal significance of these symptoms than in their practical

392
Schizophrenia and related disorders CHAPTER 15

Pilot Study of Schizophrenia confirmed that psychiatrists


Box 15.2 in Washington – and also, for rather different reasons, in
Moscow – had a considerably broader concept of schizophrenia
Kurt Schneider’s ‘symptoms of the first rank’ than their counterparts in the other seven countries involved,
1. Auditory hallucinations taking any one of three specific forms: namely Colombia, Czechoslovakia, Denmark, India, Nigeria,
a. Voices repeating the subject’s thoughts out loud Taiwan and the UK (WHO 1973).
(Gedankenlautwerden or écho de la pensée), or anticipating
Increasing awareness in the 1970s of the scale and conse-
his thoughts
quences of international differences of this kind, and of the
b. Two or more hallucinatory voices discussing the subject,
or arguing about him, referring to him in the third person
low reliability of psychiatric diagnoses generally, led to a wide-
c. Voices commenting on the subject’s thoughts or behaviour,
spread realisation that key terms such as schizophrenia must
often as a running commentary be operationally defined in order to make it quite clear what
2. The sensation of alien thoughts being put into the subject’s mind criteria had to be satisfied to establish the diagnosis. Because
by some external agency, or of his own thoughts being taken schizophrenia, like most other psychiatric disorders, is still
away (thought insertion or withdrawal) recognised by its syndrome and its aetiology is still obscure,
3. The sensation that the subject’s thinking is no longer confined it must be defined by the presence of particular symptoms
within his own mind, but is instead shared by, or accessible to, or combinations of symptoms, or by its course, or by some
others (thought broadcasting) combination of the two. In the last 20 years many different
4. The sensation of feelings, impulses or acts being experienced or operational definitions of schizophrenia have been proposed,
carried out under external control, so that the patient feels as if
and this has inevitably led to comparisons of their relative
he were being hypnotised, or had become a robot (passivity)
utility in predicting response to treatment or long-term course,
5. The experience of being a passive and reluctant recipient of
bodily sensation imposed by some external agency (somatic or which is likely to correspond most closely with the putative
passivity) biological abnormality underlying the disorder. Because the
6. Delusional perception – a delusion arising fully-fledged on the syndrome of schizophrenia appears to merge into related syn-
basis of a genuine perception which others would regard as dromes, because we have not yet identified the underlying
commonplace and unrelated biological abnormality, and because political considerations
are also involved, there is not yet any single agreed definition,
nor any immediate prospect of a global consensus.
utility, regarding them as diagnostic aids that were pathogno- Areas of agreement are, however, increasing. Bleuler’s fun-
monic of schizophrenia in the absence of evident brain disease. damental symptoms, and thought disorder in particular, have
He accepted that some patients with otherwise typical lost their former influence, mainly because they are too intan-
schizophrenic illnesses never exhibited any of these symptoms, gible and therefore incapable of being reliably identified.
and that all of them could occur at times in epileptic and other Schneider’s first-rank symptoms are still influential in Britain
organic psychoses, but nonetheless he regarded them as suffi- and Germany, partly because their presence can be reliably
ciently characteristic to be worth distinguishing from what rated, but several studies have demonstrated that they have
he called ‘second rank’ symptoms such as perplexity, emo- little significance for long-term prognosis. The presence of
tional blunting, and hallucinations and delusions of other kinds. first-rank symptoms in the acute illness does not predict either
incomplete recovery or the development of a schizophrenic
defect state (Kendell et al 1979), and it is not uncommon
Definitions for these symptoms to develop in the course of what are in
other respects typical manic illnesses (Brockington et al
The confusion caused by the unresolved differences between 1980). In fact, none of the symptoms of the acute illness is
Kraepelin’s and Bleuler’s concepts of schizophrenia was at its as good a predictor of the long-term course as the duration
worst in the 1950s, and the best-known and most extensively and mode of onset (and pre-morbid features such as IQ).
studied differences were Anglo-American. On the basis of If the initial illness starts insidiously and lasts for several
the observation that the first-admission rate for schizophrenia months, a poor long-term prognosis is much more likely than
was considerably higher in the USA than in England and if it starts acutely in association with obvious stress and lasts
Wales, and vice versa for manic–depressive illnesses, detailed only a few weeks, regardless of the detailed symptomatology.
studies were mounted of series of consecutive admissions to There are now only two widely used definitions of schizophre-
mental hospitals in the two countries, using identical inter- nia: the American Psychiatric Association’s DSM-IV (APA
viewing methods and diagnostic criteria (Cooper et al 1972). 1994) criteria, which remain as they were despite the text
These comparisons showed that the symptoms of patients revision in 2000 (DSM-IV-TR), and ICD-10 (WHO 1992)
admitted to public mental hospitals in New York and London (Table 15.1). Both require clear evidence of psychosis, either
were virtually identical, but the proportion of patients given a currently or in the recent past, and specify particular kinds of hal-
diagnosis of schizophrenia was nearly twice as high in New lucinatory experience or delusional ideation (among other possi-
York as in London. This was because the New York psy- ble symptoms). Both stipulate that affective symptoms must not
chiatrists’ concept of schizophrenia included many patients be prominent. Indeed, the principal difference is in the mini-
who in London would have been regarded as suffering from mum duration of illness, being 1 month for ICD-10 and 6 months
depressive or manic psychoses, or even from neurotic illnesses for DSM-IV. In the USA DSM-IV is used for both clinical
or personality disorders. Shortly after this the International and research purposes. ICD-10 has both clinical and research

393
Companion to Psychiatric Studies

traits most often described are those of solitariness and cold-


Table 15.1 A comparison of DSM-IV(-TR) and ICD-10 diagnostic ness of affect. Some are noted to have been inclined to suspi-
criteria
ciousness, or to have abnormal speech patterns. These are
DSM-IV ICD-10 often called schizoid/schizotypal traits. The relationship of
such premorbid traits to the development of schizophrenia is
Symptoms 1 of: Bizarre delusions/ 1 of: Schneiderian difficult to determine. In a review of early German studies
schneiderian hallucinations delusions/hallucinations of premorbid personality in schizophrenia, Cutting (1985)
or or concluded that the schizoid trait complex was described in
2 of: Delusions 2 of: Catatonic behaviour 25% of schizophrenic patients, and other personality variants
Hallucinations Hallucinations (e.g. paranoid) in a further 15%. Such data were obtained ret-
Disorganised speech/behaviour Disorganised speech rospectively and are therefore not blind, and in themselves
Negative features Negative features offer no information as to whether such traits occur more
Dysfunction Social/occupational Not specified often in those destined to develop schizophrenia than in their
peers who will remain well. They also do not allow us to deter-
Duration At least 6 months One month mine whether the schizoid/schizotypal trait complex is a risk
Exclusions Mood disorder Mood disorder factor that contributes independently to the disease or is in fact
Substance abuse Substance abuse a preclinical manifestation of the disorder itself. Subsequent
Pervasive developmental Organic brain disease studies, especially of those at high genetic risk because they
disorder come from multiply affected families, do, however, indicate
that schizotypy in particular approximately doubles the risk
of – but far from guarantees – subsequent schizophrenia
(Cannon & Jones 1996; Owens & Johnstone 2006).
criteria but the latter are rarely used, and DSM-IV is preferred
by researchers worldwide. The more restrictive DSM-IV criteria Development
have the merit of defining a group of patients with a poor long-
term prognosis akin to Kraepelin’s original dementia praecox, Over the past 10 years a number of prospective studies have
but diagnostic criteria for schizophrenia of less than 6 months’ addressed these issues. Done et al (1994) used data from the
duration are then required, even though such a ‘schizophreni- 1958 UK National Child Development Survey (a birth cohort
form disorder’ may have limited validity. study conducted on all children born in a particular week in
It is, of course, very confusing for everyone, not least for 1958 and followed up at specified intervals until adulthood),
students, to have alternative definitions of a single disorder, as this had included assessments of social behaviour at the ages
particularly when it is commonplace for a patient to fulfil of 7 and 11 years. Those who went on to develop schizophre-
one set of criteria but not another. Under present circum- nia in adult life were compared with those who developed
stances, however, this is inevitable; and it is better for differ- other psychiatric disorders and those who remained well.
ences of this kind to be overt and acknowledged. The At 7 and 11 years pre-schizophrenic boys showed signifi-
existence of a number of definitions also helps to emphasise cantly more anxiety, hostility and inconsequential behaviour
that all definitions are arbitrary, justified only by their useful- than those who would remain well, and at 11 years pre-
ness, and liable to change. schizophrenic girls were significantly more withdrawn than
those who did not become mentally ill. Those destined to
develop affective psychosis in later life differed little from nor-
Clinical presentation and mal controls. Jones et al (1994) conducted a similar study
symptomatology using the 1946 British National Survey of Health and Develop-
ment (an earlier birth study) and found delayed motor devel-
opment, especially walking, as well as speech problems and a
Clearly the symptoms and other characteristics of the condi-
preference for solitary play as early as the age of 4. Both stud-
tion will vary somewhat, according to the way in which the
ies found evidence of relatively low IQ, and all these findings
syndrome is defined. There is nonetheless a core group of
have since been replicated in other countries. Clearly, there-
patients who fulfil most definitions, and international compar-
fore, many years before illness develops, there are significant
isons using films or videotapes of diagnostic interviews confirm
excesses of abnormal neurodevelopment and social behaviour
that psychiatrists throughout the world will consistently iden-
in children destined to develop schizophrenia in adult life.
tify these as people suffering from schizophrenia.
Nonetheless, by no means all of those who go on to develop
schizophrenia have been considered abnormal in any way,
Premorbid characteristics and some have shown very high levels of social, academic
and occupational functioning.
Personality
Schizophrenia can develop in personalities of all kinds, but Prodromal symptoms
some adults with schizophrenia are said to have been ‘odd’ as Quite what marks the transition from such abnormalities to
children. Observations in support of this view have been made psychotic symptoms and frank psychosis is largely unknown,
since the time of Kraepelin, and the premorbid personality but a number of prospective studies of individuals at high risk

394
Schizophrenia and related disorders CHAPTER 15

of developing schizophrenia have given us an insight into the Delusions


timing of these events. McGhie and Chapman (1961) revisited
The delusions of the acute illness are very variable in type and
the psychotherapy notes of 26 patients who were subsequently
even more so in their detailed content. Table 15.2 shows the
diagnosed with ‘schizophrenia’. Subjective difficulties were
frequency of the most common delusions and hallucinations in
recorded in focusing attention on pertinent rather than irrele-
large samples of first-episode and chronic patients. Delusions
vant stimuli (e.g. in someone else’s speech) and thinking
of reference and persecutory, grandiose, religious and hypo-
clearly, accompanied by relatively minor perceptual distur-
chondriacal ideas of various kinds are all common, but the
bances, anxiety and perplexity, and a reduced sense of control.
most specifically characteristic of schizophrenia are a variety
Individual delusions or hallucinations may be evident for
of passivity phenomena. The subject feels that he is no longer
months or even years before someone would meet the diag-
in control of his own thoughts, feelings or will, and that he is
nostic criteria for schizophrenia, but the bulk of the available
being influenced or controlled by some mysterious, alien force.
evidence suggests that it is more common for anxiety, depres-
Thoughts which are not recognised as his own are put into his
sion and negative symptoms to precede psychosis (Owens &
mind (thought insertion), or his own thoughts are taken away
Johnstone 2006). These may gradually give way to delusional
(thought withdrawal) or have somehow become accessible to
mood – the experience that something non-specific about the
other people (thought broadcasting). Or he may be convinced
external world is unusual or even disturbing, and thence to
that someone is trying to hypnotise him or impose their will
frank hallucinations and delusions. Klosterkotter et al (2001)
on his. The subject’s interpretation of these phenomena,
examined 160 outpatients with ‘diagnostic problems’ from
which lie beyond the bounds of normal experience, depends
1987 to 1998, over which time 79 developed DSM-IV schizo-
on his cultural background. Previous generations here attri-
phrenia. Prodromal symptoms were sensitive predictors of
buted them to God or the Devil; some people from other
psychosis, whereas individual delusions and hallucinations
cultures attribute them to spirits or witchcraft; and the inhabi-
were more specific, but neither effect was sufficiently strong
tants of modern industrial countries tend to attribute them
to be useful clinically. The advent of early intervention services
to electricity, X-rays, television, laser beams and satellites.
for people with the ‘at-risk mental state’ has given rise to
several studies of which symptoms predict the transition to
schizophrenia in the 20–30% who do so in 6–12 months.
Consistent symptom predictors are, however, few and far Table 15.2 Frequency of specific psychotic symptoms by stage
between, and negative symptoms such as social withdrawal of illness
appear to be as strong predictors as positive symptoms
First episodes Chronic patients
(Cannon et al 2008). This is because 10–20% of the general
(n ¼ 242) (%) (n ¼ 354) (%)
population may experience individual psychotic symptoms at
some point in their lives, especially as adolescents, but do Delusions
not develop a psychotic illness (Verdoux & van Os 2002).
Delusional mood 86 25

The acute illness Delusions of reference 77 60

Delusions of misinterpretation 74 52
Onset
Delusions of persecution 70 50
Schizophrenia can occur at any age from 7 to 70, but the onset is
usually in adolescence or early adult life. It may develop insidi- Alien penetration 52 –
ously. A young man whose previous behaviour has been unre- Thoughts read 48 –
markable may become more withdrawn and introverted. He
may acquire a new interest in religion, psychology or the occult, Delusions of grandiose ability 40 31
and drift away from his friends. He may also lose his drive and Delusions of catastrophe – 24
determination, and fail to complete a university degree or an
apprenticeship that had previously seemed well within his Thought insertion – 22
grasp. His parents may be worried by his failures, his apparent Hallucinations
lack of interest in achievement and his progressive distance
from them, but they do not suspect that he is ill until one 2nd person hallucinations 48 28
day, months or even years later, it suddenly becomes apparent Non-verbal auditory hallucinations 34 15
that he is entertaining delusional ideas, or hearing voices.
In other cases the onset is acute. Sometimes in the aftermath Other (tactile, gustatory) 36 16
of some obvious stress, or in the unfamiliar environment of a
Third-person hallucinations 32 16
foreign country, or possibly in the context of taking illicit drugs,
the subject becomes obviously ill over the course of a few days. Olfactory hallucinations 27 13
He becomes convinced that he is being watched or followed,
Visual hallucinations 23 11
may attach great significance to neutral stimuli such as the col-
ours of clothes, talk of laser beams or hypnosis. He may even From Johnstone et al (1986, 1991).
suddenly be found, mute and inaccessible, kneeling on a floor.

395
Companion to Psychiatric Studies

In short, the subject endeavours to make an unintelligible Behaviour


(primary) experience intelligible by (secondarily) attributing
Finally, the patient’s general behaviour is affected. Again, the
it to some powerful, invisible force of which he has some
nature of the change is variable but characteristically involves
knowledge but does not fully understand.
withdrawal from contact with and interest in other people,
and actions that seem bizarre or inexplicable to the onlooker.
Hallucinations Occasionally, the patient displays the particular behavioural
The hallucinations are equally varied and may involve any of abnormalities of Kahlbaum’s catatonia, becoming mute, or
the five senses (see Table 15.2). Auditory hallucinations in stuporose, or adopting strange postures, possibly for hours on
the form of voices are the most common, however, and the end. Catatonic phenomena of this kind used to be common
visual, olfactory, gustatory and tactile hallucinations are all and figured prominently in Kraepelin’s original descriptions
rare in the absence of hallucinatory voices. Although Schneider of dementia praecox. They are rarely seen nowadays in acute
and others have drawn attention to particular types of hallu- states, but continue to occur to some degree in chronic
cinatory voice that are characteristic of schizophrenia (see patients. The reason for this change is unknown. The beha-
Box 15.2), it is commonplace for schizophrenics to hear voices vioural abnormalities prior to first admission for schizophrenia
talking to them as well as about them, and the content is very have been studied in over 250 cases (Johnstone et al 1986).
variable. Indeed, from a diagnostic point of view the duration In addition to bizarre behaviour like that already described,
is probably more important than the detailed perceptual property damage or behaviour that is potentially threatening
characteristics or the content, because in other psychoses to the life of the patient, or indeed to others, occurred in at
hallucinatory voices rarely continue all day long, week after least 25% of patients.
week. Schizophrenic hallucinations frequently have a quality
intermediate between that of a genuine auditory perception
and a thought. Although the subject speaks spontaneously of
The chronic stage
a ‘voice’, he will often admit on questioning that he does not
Sooner or later the hallucinations and delusions of the acute
really hear it out loud or with his ears. It is in the mind – a
illness become less intense (see Table 15.2). Often they dis-
‘silent voice’ – which is nonetheless insistent, troublesome
appear completely, and even if they do persist for months or
and sometimes frightening. Often, too, the subject has diffi-
years their influence on the patient’s behaviour usually wanes.
culty describing what it says. Doubtless this is often due to
Unfortunately, this rarely indicates a full-blown recovery, even
embarrassment, or a reluctance to divulge what the subject
temporarily. Recovery is often complete after one or two
suspects his questioner will regard as evidence of insanity,
short-lived episodes of illness, but the more episodes a patient
but it does sometimes seem that the patient has genuine diffi-
has had, and the more insidiously developing and longer last-
culty in describing the content of the hallucination, perhaps
ing these have been, the more likely it is that some residual
because the normal link between perception and memory is
damage will remain. This ‘defect state’ is much less conspicu-
only partly established.
ous than the florid symptoms of the acute illness, and may not
be apparent at all to those who did not know the patient well
Affect before his illness, but in the long run it is a far more serious
The patient’s affect during the acute illness is as variable as his handicap. In its mildest form it involves nothing more than
thought content but is nearly always disturbed in some way. a subtle loss of vivacity, enthusiasm and emotional respon-
Perplexity is a common and characteristic feature of acute siveness. More commonly, however, the patient’s drive and
schizophrenia. The subject suspects that something strange is determination are affected. He becomes apathetic, no longer
going on around him but is not sure what, and ideas may come strives, and no longer cares. At the same time, and perhaps
and go in rapid succession as he seeks to integrate his changing fundamentally for the same reason, he loses interest in other
perceptions and affective state with his premorbid experience. people. He talks much less (‘poverty of speech’), and his
At other times the subject may be depressed, elated or angry, capacity to form enduring emotional relationships is greatly
and it is sometimes difficult to tell whether the content of the reduced. He may no longer be capable of falling in love, or
delusions and hallucinatory voices is secondary to the prevail- even developing new friendships, and if unmarried is likely to
ing mood or vice versa. In more established cases a general remain so. It is this apathy and emotional loss that make
flattening or blunting of affective responses often occurs. This schizophrenia the terrible illness it is, because there are per-
term refers to a loss of the ability to feel – or at least to manent changes in the personality that handicap the subject
express – any deep or profound emotion, and a matching in every sphere: his ability to get and keep a job, to be an effec-
inability to evoke a sympathetic response in other people. tive husband, wife or parent, to achieve much, and even to
(Technically, flattening refers to a reduced range of emotional fully enjoy anything.
expression and blunting to a reduced sensitivity to others, Most patients with chronic schizophrenia have recurrent
but the distinction is unclear and probably of little clinical psychotic episodes with hallucinations and delusions, usually
relevance.) Incongruity of affect – a mismatch between the taking much the same form on each occasion, or faded rem-
subject’s emotional responses and the setting or the topic of nants of earlier delusional systems, as well as this characteristic
conversation – silly giggling while important or distressing apathy and emotional blunting. Depression is also a common
events are taking place being the most common example – and important feature of chronic schizophrenia. Indeed,
may occur in both acute and more chronic states. ICD-10 recognises post-schizophrenic depression as a distinct

396
Schizophrenia and related disorders CHAPTER 15

subtype of schizophrenia. Some patients become depressed in This pattern of segregation into three (or more) syndromes
the immediate aftermath of their original psychotic episode; has been replicated in many other studies employing factor
others make an apparently full recovery only to return weeks analysis of schizophrenic symptoms, including patients with
or months later with widespread depressive symptoms. It is illnesses of variable chronicity, although much of the vari-
sometimes suggested that this lowering of mood is induced ance in symptom aggregations is not explained in such studies
by antipsychotics, but there is no convincing evidence from and additional, possibly developmental, factors need to be
controlled trials that this is so. More likely, it is partly inherent considered (Smith et al 1998). This work has, however, been
to schizophrenia and partly an understandable psychological developed by studies which suggest that each syndrome is
reaction to its dire effects and implications. Although the characterised by a specific pattern of neuropsychological test
depression of chronic schizophrenia is rarely as severe, or performance (see Frith 1992 and below), and altered
accompanied by such widespread biological disturbance as in perfusion in different sites in the brain (Liddle et al 1992).
primary depressive disorders, it is nonetheless an important
cause of suffering and disability. Furthermore it is often
treatable (see below). A note on thought disorder

Suicide and homicide Thought disorder is a characteristic feature of schizophrenia.


It is, however, an unsatisfactory term that has traditionally
Many schizophrenics, at least in the early stages of their illness, been applied to a variety of ill-defined abnormalities of the
are well able to appreciate that it has deprived them of their subject’s speech and writing which are assumed – and it is an
capacity to enjoy or feel deeply about anything. Self-harm is assumption – to be secondary to a more fundamental distur-
common – 32% of a sample of 532 individuals with recurrent bance of thinking. (The term ‘formal thought disorder’ is
schizophrenia had harmed themselves at least once (Johnstone sometimes used to emphasise that it is an abnormality of the
et al 1991), and some 5–10% die by suicide, usually in the form rather than of the content of speech, i.e. thought dis-
early years of the illness and often around the time of admis- order does not embrace delusional ideation.) These abnormal-
sion or discharge. Homicide, despite all the media attention ities were first noted by Hecker in 1871 (‘a peculiar departure
it generates, is rare. Patients with schizophrenia do have an from normal logical sentence structure, with frequent changes
increased rate of violent and non-violent crime, but any mem- in direction that may or may not lose the train of thought’),
ber of the public is far more likely to be attacked by a member and then by Kraepelin, but they were studied and described
of their own family, and if one is assaulted by a stranger he is in much more detail by Bleuler, who regarded them as a
more likely to be well than mentally ill (Walsh et al 2001). direct consequence of the ‘loosening of associations’ which
he thought was the fundamental deficit of schizophrenia.
Symptoms or syndromes? It is therefore to Bleuler that we owe the long-lived assump-
tion that thought disorder was of cardinal importance both
Hughlings Jackson, a 19th-century neurologist, used to distin-
aetiologically and diagnostically, being exhibited by all schizo-
guish between positive and negative symptoms in neurological
phrenics and by no one else. These were unfortunate assump-
diseases – the former being based on some active disturbance
tions for several reasons. No one has ever succeeded in
of cerebral function, the latter reflecting a reduction or loss
producing a satisfactory definition of the term thought disor-
of normal function. Crow (1980) developed these concepts
der, or in identifying any fundamental psychological or linguis-
in relation to schizophrenia by proposing that there are two
tic deficit capable of accounting for the various observable
pathological processes in the disorder that can occur either
abnormalities of schizophrenic speech. Worse still, few of the
separately or together in an individual case. Crow’s type I syn-
abnormalities Bleuler and his successors identified have proved
drome was characterised by positive symptoms (delusions,
to be specific to schizophrenia, and none to be manifested by
hallucinations and thought disorder) and thought to be acute,
more than a proportion of patients with what in other respects
whereas the type II syndrome was characterised by negative
are typical schizophrenic illnesses. Indeed, large studies of the
symptoms (affective flattening, apathy and poverty of speech)
symptomatology of schizophrenia (for example Johnstone et al
and chronic. Problems with this formulation included the
1991) show them to be rare in comparison to delusions and
question of whether the important factor was the type of
hallucinations.
symptomatology or the chronicity, and the issue of whether
The most obvious abnormality in the early stages of the ill-
thought disorder should be considered as a positive or a negative
ness is the subject’s inability to give a straight answer to any
symptom. Liddle (1987) then developed these issues further by
but the simplest of questions, so that the interviewer suddenly
examining the pattern of correlation between schizophrenic
realises, after talking to the patient for 5 or 10 minutes, that
symptoms in a group of patients with illnesses of similar
he has not yet learned anything useful. Usually none of the
chronicity, and found that the symptoms segregated into not
patient’s statements or replies has been obviously nonsensical
two but three distinguishable syndromes:
or bizarre, but almost every one has been vague or irrelevant,
• psychomotor poverty (poverty of speech, flat affect, and as a result little useful information has been transmitted.
decreased spontaneous movement); This abnormality is sometimes referred to as ‘poverty of
• disorganisation (disorder of form of thought and thought content’.
inappropriate affect); It is sometimes said that thought disorder involves the
• reality distortion (delusions and hallucinations). semantic content rather than the syntactic structure of speech,

397
Companion to Psychiatric Studies

and that the latter remains intact until a very late stage. This is
not so. It has been demonstrated by detailed linguistic analysis
Box 15.3
that the syntactic structure of schizophrenics’ speech is quite
different from both that of manic and of normal controls Examples of types of thought disorder
(Morice & Ingram 1982), and also that these abnormalities • Derailment – spontaneous speech in which ideas slip off track
(cf. flight of ideas in pressured speech)
progress with the passage of time. Schizophrenic speech may
be harder to comprehend in the acute illness, partly because • Tangentiality – replying to a question in an oblique or irrelevant
manner
the patient is often excited and preoccupied with delusional
• Incoherence – incomprehensible speech (‘word salad’) due to
ideas, but its structure is more abnormal in the chronic stage. misuse of grammar or syntax and/or missing or substituted
Sentence structure becomes more primitive, with fewer and words
less deeply embedded subordinate clauses, and grammatical • Illogicality – false conclusions based on faulty premises or
errors of varied kinds become more frequent. Above all, the inductive inferences
total quantity of speech is reduced (‘poverty of speech’). • Clanging – word sounds rather than meaning appear to govern
Bleuler and Kretschmer regarded thought disorder as a use
result of a generalised ‘dissociation’ of mental functions. From Andreasen (1979).
Subsequently, Babcock suggested that it was simply due to a
slowing of all intellectual processes, but later work showed
that, although schizophrenics were indeed slower than nor-
who knew nothing of linguistics. It remains to be seen whether
mals, so too were depressives and psychotics in general.
modern linguistic analysis will be any more successful, but
In the 1940s Cameron suggested that ‘over-inclusiveness’ was
future research is more likely to illuminate the fundamental
the fundamental disability, by which he meant an inability to
nature of thought disorder if it is based on linguistic concepts
maintain conceptual boundaries because of a failure to exclude
such as lexical density and dysfluency rather than on clinical
irrelevant associations. This has some empirical support from
metaphors such as derailment.
object sorting tests, and has interesting parallels with the
psychophysiological evidence (and subjective accounts) that
schizophrenics have difficulty discriminating between relevant Varieties of schizophrenia
and irrelevant sensory information. Both, in other words,
might be due to the breakdown of some hypothetical filtering Kraepelin recognised three varieties of schizophrenia –
or attentional focusing mechanism. In the 1960s it was hebephrenic, catatonic and paranoid – and Bleuler added a
claimed – though never confirmed – that schizophrenic speech fourth – simple schizophrenia. Bleuler also said that, although
tended to be less ‘redundant’ (more ‘condensed’) than normal he assumed schizophrenia to be a group of allied conditions
speech, so that, if every fourth or fifth word was deleted rather than a single disease, he regarded these subdivisions
(the Cloze technique), naive readers were less successful at as purely provisional. It is ironical, therefore, that his four
guessing the identity of the missing words. It is established, varieties have figured in most classifications of schizophrenia
however, that schizophrenics tend to use a more restricted ever since. Although several additional varieties have often
range of words, and hence to have a lower ‘type:token ratio’ been added, no schema which attempted to supplant them
than normal people, and that this tendency to repetition has ever won more than local acceptance. The expansion of
applies to syllables as well as to words and phrases, indicating the concept of schizophrenia that took place in the 1940s
that the cause is something more fundamental than simply and 1950s was partly due to the emergence of a series of
having a limited vocabulary. It has also been shown that, in new concepts, such as residual schizophrenia, latent schizo-
terms of Kelly’s personal construct theory, schizophrenics’ phrenia and schizoaffective psychosis (Kasanin 1933), which
constructs are less stable and more idiosyncratic than those were added to the original four and had the effect of bringing
of other people. new types of patient under the schizophrenia rubric.
Unfortunately, none of these observations has yet proved to The tenth revision of the ICD (WHO 1992) recognises
be of much practical use, and none of these various hypotheses seven varieties: Bleuler’s original four (paranoid, hebephrenic,
has illuminated the fundamental nature of thought disorder. catatonic and simple) plus undifferentiated schizophrenia,
Andreasen (1979) attempted to define 20 of the terms most residual schizophrenia and post-schizophrenic depression.
widely used to describe different facets of thought disorder, Schizoaffective states (see below) are classified separately
including derailment, tangentiality, clanging and illogicality from both schizophrenic and affective disorders. Schizotypal
(Box 15.3). She succeeded in demonstrating that most of disorder, ‘a disorder characterised by eccentric behaviour
these terms can be defined and rated with reasonable reliabil- and anomalies of thinking and affect which resemble those
ity, and showed which were relatively specific to schizophrenia seen in schizophrenia, though no definite and characteristic
and which were found equally or more commonly in mania. schizophrenic anomalies have occurred at any stage’, is now
These are valuable achievements, but a more radical approach included. Although schizotypal disorder does sometimes
is needed. Seventy years of research into thought disorder has evolve into overt schizophrenia, it is more often a stable and
achieved little, not because Bleuler was wrong in believing that enduring personality disorder which is relatively common in
there was something very odd about the speech of many schi- the close relatives of schizophrenics and assumed to be part
zophrenics, but because that research was conducted, often of the genetic ‘spectrum’ of schizophrenia (Kendler et al
without adequate controls, by psychiatrists and psychologists 1991).

398
Schizophrenia and related disorders CHAPTER 15

The main findings of an even larger cross-cultural com-


Box 15.4 parison by the World Health Organization, based on nearly
1400 patients from 12 centres in 10 countries, have also been
Subtypes of schizophrenia reported (‘The Ten Country Study’, Sartorius et al 1986).
• Hebephrenic – the illness starts early and insidiously and is This study attempted to identify all schizophrenics making a
dominated by thought disorder and disturbance of affect
first contact with any treatment agency, including religious
• Catatonic – motor abnormalities like posturing or stupor are present institutions and traditional healers, within a defined geograph-
• Paranoid – hallucinations and delusions are prominent and the
ical area, and so was able to generate incidence or inception
personality relatively well preserved
rates. Although affective symptoms (mainly depressive) were
• Simple – progressive deterioration and increasing eccentricity
develop in the absence of overt psychotic symptoms
more common in the industrial countries, and visual and audi-
• Residual – the original psychotic symptoms have died away, tory hallucinations and catatonic symptoms more common in
leaving only the apathy, emotional blunting and eccentricity of the developing countries, the core symptoms of schizophrenia
the defect state were again remarkably similar in all centres. So too were the
inception rates, and also the reasons for admission or referral.
When the same operational definition (PSE Catego class Sþ,
which effectively identifies patients with schneiderian first-
In day-to-day clinical practice most psychiatrists content rank symptoms) was applied in all centres the inception rate
themselves with a plain diagnosis of schizophrenia and only use ranged from 7 per 100 000 population per year in Aarhus
the subcategories for the minority of patients whose symptom- (Denmark) to 14 in Nottingham, with Agra and both the
atology corresponds closely to one of the subcategory stereotypes urban and rural areas in Chandigarh (India), Cali (Columbia),
(Box 15.4). Although the hebephrenic and catatonic forms tend Dublin, Honolulu, Moscow, Nagasaki and Prague in between.
to have the worst prognosis and the paranoid form the best, there This suggests that the incidence of schizophrenia is fairly sta-
are no consistent differences in response to treatment or progno- ble across a wide range of cultures, climates and ethnic group-
sis between the various categories, and patients may show the ings. There was, however, more variation in the incidence of
characteristic symptoms of different varieties at different stages ICD-10 schizophrenia between the sites where this could be
in their course. Nor is there convincing evidence from family calculated (Murray et al 2003).
studies that the different varieties ‘breed true’. Partly for these It used to be thought – mainly on the strength of his-
reasons, contemporary interest is focused primarily on how torical studies – that the incidence of schizophrenia had not
schizophrenia should best be defined, rather than on how it changed since the first decades of the 19th century, despite
should be subdivided. The current American classification, the profound social and cultural changes since that time.
DSM-IV(-TR) (APA 1994), for example, recognises only five There have, however, been several reports of declining hos-
varieties – disorganised (hebephrenic), catatonic, paranoid, pital first-admission rates for schizophrenia in industrial
undifferentiated and residual – and emphasises that the distinc- countries in the last 25 years, although it seems likely that
tion between them is based only on ‘the predominant clinical the observed decline is due partly to either changing diagno-
picture that occasioned the most recent evaluation or admission stic criteria, an increasing reluctance to admit schizophrenics
to clinical care’ and may therefore change over time. to hospital, less availability of inpatient facilities, or a combi-
nation of these (Cannon & Jones 1996; Murray et al 2003).
What is clear is that the presentation of the illness has
Epidemiology changed, at least in Europe and North America, since the
beginning of the 20th century. The hebephrenic and catatonic
forms seem to have become much less common and the para-
Frequency noid form considerably more common since Kraepelin and
In most of the industrial countries in which population surveys Bleuler wrote their classic descriptions. These changes have
have been carried out the lifetime risk of schizophrenia is been accompanied by a rise in the average age of onset and
about 1%, with an incidence of approximately 10–15 new a gradual improvement in prognosis, at least prior to the
cases per 100 000 population per annum and a prevalence of introduction of more restrictive diagnostic criteria (Hegarty
2–4 per 1000. In the American Epidemiologic Catchment et al 1994).
Area (ECA) survey, for example, which was based on over
18 000 interviews with random population samples, the life-
time risk for schizophrenia using DSM-III criteria was 1.3% Onset
(Regier et al 1988). Studies in Africa and Asia are less numer- The onset of the disease is characteristically between the
ous and have tended to produce somewhat lower estimates. ages of 15 and 45 years, but it may be before puberty, or
The International Pilot Study of Schizophrenia established delayed until the seventh or eighth decades. Schizophrenia
that substantial numbers of schizophrenics were admitted to may actually be more common in men (Aleman et al 2003).
psychiatric hospitals in all the countries involved (Colombia, Male schizophrenics are also consistently admitted to hospital
Czechoslovakia, Denmark, India, Nigeria, Russia, Taiwan, the 4 or 5 years earlier than females, and this appears to reflect a
UK and the USA) and that their symptoms were remarkably genuine and unexplained difference in the age of onset
similar in all nine, despite major differences in language, between the two sexes (Häfner et al 1989). The incidence is
religion, culture and degree of urbanisation (WHO 1973). higher in the unmarried than the married in both sexes.

399
Companion to Psychiatric Studies

Fertility
Table 15.3 Risk factors for schizophrenia and their estimated
The fertility of schizophrenics has been studied many times, relative risks/odds ratios
and there is general agreement that they marry less often than
other people, remain childless more often even when they do Risk factor RR/OR
marry, and have fewer children than other people. In the past
Family history RR 5–50
this was usually attributed to their confinement in sexually
segregated asylums. However, it is now apparent that their Immigrant/ethic minority status OR ¼ 5
fertility is low even before admission to hospital, and that
Developmental delay/abnormality OR ¼ 3
patients with schizophrenia living in the community still have
fewer children than other people. It remains uncertain as to Chronic cannabis/stimulant use OR ¼ 3
whether social or biological factors are responsible.
Childhood solitariness OR ¼ 2

Urban birth/residence OR ¼ 2
Mortality
Schizophrenics also have a substantially raised early mortality. Obstetric complications OR ¼ 2
Studies in Europe and North America suggest that their rela- Ventriculomegaly/cerebral ‘atrophy’ OR ¼ 2
tive risk of early death is increased two- or threefold, and over-
all they die on average 10 years earlier than population norms Maternal flu/malnutrition OR ¼ 2
(Saha et al 2007). Some of the increased risk is attributable Others, e.g. winter birth OR < 2
to suicide, and is shared by other forms of mental illness, but
there are also increased rates of death by homicide, accidents After Cannon & Jones (1996)
and a range of physical illnesses. There have been repeated
claims of associations, both positive and negative, between
schizophrenia and specific physical illnesses. There is a nega- it is still unclear whether they are true risk factors rather than
tive, and as yet unexplained, association between schizophre- early expressions of the disease (or a genetic or environmental
nia and rheumatoid arthritis. Despite many conflicting liability to it). We will discuss those with known or likely
claims, it is not established that schizophrenics are either more biological effects in the next section, and those of unknown
or less likely to develop cancers in general, or any particular pathophysiological significance here.
form of cancer, than other people. Nor is the claimed associa-
tion between schizophrenia and coeliac disease supported by Urban residence
convincing evidence. There are, however, a number of reports
of an increased risk of death from respiratory disease, presum- The first-admission rate for schizophrenia is generally higher
ably related to smoking. In recent years it has increasingly been in urban than in rural areas, and much higher in the central
appreciated that people with schizophrenia have strikingly areas of large cities than in the surrounding suburbs. Faris
elevated rates of diabetes, coronary heart disease and stroke, and Dunham (1939) first drew attention to this striking
and these chronic disorders are the most common causes of phenomenon in Chicago, and it has since been confirmed in
death in schizophrenia (Marder et al 2004). These conditions several other American and European cities. The highest
can be traced to the unhealthy lifestyles of many patients, admission rates are consistently from the poor working-class
who are often overweight with poor dietary habits, and to areas and the lowest from the middle-class suburbs. This geo-
the fact that the physical and cardiometabolic aspects of their graphical gradient is accompanied by an equally impressive
care are relatively neglected by health services. It must, how- social class gradient, the admission rate of social classes IV
ever, also be acknowledged that antipsychotic medication and V (unskilled and semiskilled manual workers) being con-
increases the risk of sudden cardiac death, probably when sistently higher than that of other occupational groupings.
coincidental factors such as dehydration exacerbate potassium These findings were originally regarded as evidence that being
channel blockade and QT prolongation and cause torsades de brought up in a working-class family, or in the central slum
pointes (Ray et al 2009). areas of a big city, created a predisposition to develop schizo-
phrenia. Goldberg and Morrison (1963), however, were able
to show by examining the birth certificates of a series of 672
Risk factors young male schizophrenics, that although they themselves
were predominantly from social classes IV and V, their fathers’
Table 15.3 summarises the epidemiological evidence and gives social class had not differed from that of the general popula-
best estimates of the likely strength (as risk or odds ratios) of tion, and that the disparity between the two was due to a
the best-replicated risk factors for schizophrenia (adapted ‘downward drift’ of the sons a few months or years before
from Cannon & Jones 1996). The relative risk of developing their admission to hospital. This normal distribution of social
schizophrenia if one has an affected first-degree relative ranges class at birth and decline prior to onset has been well repli-
from about 5 (for parents of an affected child) to 10 (for chil- cated (Cannon & Jones 1996; Murray et al 2003), but an
dren or siblings) to 15 (two or more first-degree relatives), increasing number of studies also suggest an effect of urban
and on to about 50 times if one has an affected identical twin. as opposed to rural birth. Most notably, Mortensen et al (1999)
The other effects are comparatively weak, and in many cases linked the Danish birth and psychiatric registers and found a

400
Schizophrenia and related disorders CHAPTER 15

relative risk of 2.4 for those with an urban birth after controlling obstetric complications). Boydell et al (2001), for example,
for any (first-degree) family history of schizophrenia. This found that the incidence of schizophrenia increased in non-
effect could, however, be attributable to any number of factors, white people in Camberwell, South London, as the proportion
including selective migration. of such ethnic minorities in the local population fell. This issue
will, however, remain controversial and politically sensitive
until rigorous epidemiological comparisons have been carried
Ethnicity and migration out and adequate explanations for the very high hospital
Pockets of high prevalence have been reported in isolated parts admission rates offered at an individual level.
of Scandinavia, Ireland and the Balkans, but these are probably
artefactual. In the ECA study, black people had a slightly
higher prevalence than whites. Migration, on the other hand, Other factors
has long been associated with a substantially increased risk of One of the most important reasons for studying the epidemi-
schizophrenia. Odegaard (1932) found Norwegians who had ology of a disease is to obtain clues to its aetiology. At one time
immigrated to Minnesota had a higher risk of schizophrenic the striking relationships found between schizophrenia and the
breakdown than those who had remained in Norway, and central areas of big cities, low social class, being unmarried and
Malzberg and Lee (1956) showed that immigrants to New being a migrant all seemed capable of providing that vital clue.
York had a much higher hospital admission rate than native- But the reasons for the relationships with urban birth/upbring-
born Americans, with their children halfway between. More ing and migration are still unclear, and the other two have
recently, Cochrane (1977) showed that most immigrant turned out to be consequences rather than causes of the disor-
groups to England and Wales, particularly West Indians, Asians der. There are, however, other important associations that can-
and Poles, have higher hospital admission rates for schizophre- not be consequences: e.g. season of birth, and maternal
nia than the English and the Scots. Similar findings have been nutrition/infection. The relationship between schizophrenia
reported from several other countries (e.g. Mortensen et al and season of birth has been found in virtually every country
1999), but the relationship is not invariable. At times the in the temperate latitudes of the northern hemisphere. First
cause of this increased risk has had considerable political as admissions are more likely to have been born in the early
well as scientific significance, with the host country or com- months of the year than the rest of the population, and corre-
munity being tempted to attribute the phenomenon to a selec- spondingly less likely to have been born in July to September.
tive migration of unstable undesirables, and the immigrants This relationship is not shared by other diagnostic categories
themselves and their fellow countrymen back home attributing and, although the excess of births in January to March is only
it to the stresses of living in a foreign and sometimes hostile land. about 8%, it is consistent and highly significant statistically
Cantor-Graae and Selten (2005) systematically reviewed the (Bradbury & Miller 1985). The odds ratio may only be about
studies from 1977 to 2003 and reported that the mean weighted 1.1, but the population-attributable risk for such a relatively
relative risk for developing schizophrenia among first-generation common event may be as high as 10% (Mortensen et al
migrants (40 effect sizes) was 2.7, and among second-generation 1999). In Australia and South Africa the excess of births is
migrants (seven effect sizes) the relative risk was 4.5. Subgroup in July to September (i.e. the winter months, as in Europe),
comparisons yielded significantly greater effect sizes for migrants although the data are less conclusive. Preliminary evidence also
from developing versus developed countries, and for migrants indicates that the siblings of schizophrenics show the same
from areas where the majority of the population is black. Enough distribution of birth dates as the general population, and
studies have been conducted on both first psychiatric con- that the winter birth excess in schizophrenia is greater the
tacts, rather than hospital admissions, to exclude arguments that colder the winter. This suggests that the incidence of schizo-
‘institutional racism’ makes psychiatrically disturbed immigrants phrenia is influenced by some widely distributed seasonal
more likely to be admitted, and at greater risk of being labelled variable – probably infective or dietary – acting either in utero
as schizophrenic once there if their behaviour is unusual. or in the early months of life.
The differential risk pattern across subgroups suggests a role for Intrauterine viral infection is one such possibility, for many
psychosocial adversity in the aetiology of schizophrenia. viral infections have a well-defined seasonal variation, and
It has also been reported that the Afro-Caribbean popula- rubella demonstrates that an inconspicuous infection in a
tions of several English cities have extremely high hospital young woman may cause permanent damage to the fetal ner-
admission rates for schizophrenia – perhaps 10 times as high vous system if she is pregnant at the time. There are indeed
as that of their white neighbours, with possibly even higher intriguing but unreplicated reports of associations between
rates in their offspring (McGovern & Cope 1987). It seems schizophrenia and rubella, toxoplasmosis, and a range of other
unlikely that differences of this magnitude could be generated neurotropic infectious agents. There have been several reports
by racial biasing of diagnostic criteria, inaccurate demographic from Finland, Denmark, England and Scotland that fluctua-
assumptions or ethnic differences in contact rates with psy- tions in the birth dates of schizophrenics can be related to fluc-
chiatric services. The offspring effect and the fact that the tuations in the incidence of influenza in the preceding few
incidence of schizophrenia is not elevated among Afro- months (for example, see Sham et al 1992), such as the
Caribbeans in the Caribbean argue against selective migration 1957 influenza epidemic. However, given that it is not known
and for post-migration factors. Recent studies suggest that whether or not the mother contracted the infection, these
these are more likely to be social (such as discrimination or associations can only suggest that possible damage to the fetus
isolation) than biological (such as infection, cannabis abuse or at that time may be aetiologically important.

401
Companion to Psychiatric Studies

Another related issue of interest is severe maternal food Familiality and genetic factors
deprivation during pregnancy. This is of course by no means
It has long been known that schizophrenia aggregates in
rare, but is often associated with civil disorganisation and
families. Risk for the disorder increases with the degree of
a lack of organised records such as registration of births.
genetic relatedness (Fig. 15.1). Adoption studies confirm a
In northern Holland, at the end of the Second World War,
key role of genetic factors in the aetiology of schizophrenia,
the entire population was severely deprived of food during
with adopted-away children sharing the genetic risk of their
the winter of 1944–1945. The deprivation was relatively cir-
biological, not their adoptive, parents (Kety et al 1975).
cumscribed in time, and organised record keeping was main-
However, as monozygotic co-twins are only 50% concordant
tained. An increased rate of schizophrenia was found in the
for the disorder, environmental as well as genetic factors must
daughters of women who suffered severe food deprivation
play a role.
during the first trimester of pregnancy (Susser & Lin 1992).
There is considerable debate regarding the exact genetic
Rare though such circumstances may be, it has recently been
architecture of schizophrenia (Craddock et al 2007; McClellan
possible to address this issue again in a Chinese population
et al 2007). The main controversy has centred on whether
and similar findings were made (St Clair, et al 2005). These
the genetic risk is conferred by a number of common risk
and other suggestions of severe maternal ‘stress’ being asso-
alleles, each of which confers a small increase in risk (the
ciated with schizophrenia require independent replication.
‘common disease, common variants’ hypothesis), or whether
Further, until the mechanism involved is established, the
instead a larger number of rare but highly penetrant mutations
meaning of these potentially important findings will remain
contribute to illness (the ‘common disease, rare variants’
unclear.
model). Recent advances in genetics and molecular biology
have provided evidence that both common and rare variants
Aetiology and pathophysiology contribute to risk for schizophrenia.
Large-scale association studies, focused on chromosomal
It should be clear that the causes of schizophrenia are far from regions showing linkage to schizophrenia, have been successful
fully understood but that a number of aetiological factors are in identifying schizophrenia susceptibility genes. Common
now known to be relevant. We have moved a very long way variants in the genes Neuregulin-1, Dysbindin and D-amino
from the position outlined by Kraepelin in 1919: ‘the causes acid oxidase activator (DAOA) conferring a small increase in
of dementia praecox are at the present time still mapped in risk have been identified using this approach, supporting the
impenetrable darkness’. Indeed, Weinberger (1995) commen- ‘common variants’ model (Chumakov et al 2002; Straub et al
ted that ‘Twenty years ago, the principal challenge for schizo- 2002; Stefansson et al 2002). There is, however, evidence of
phrenia research was to gather objective scientific evidence
that would implicate the brain. This challenge no longer
General
exists’. Now that the role of the brain is accepted, the priority population 1%
is to explore the mechanisms by which the factors known to
be relevant to the aetiology interact and produce the clinical First cousins 2%
features of schizophrenia. 12.5%
3rd Uncles/aunts 2%
degree
relatives Nephews/nieces
Neurobiological factors 4%

Grandchildren 5%
The neurobiological factors known to be relevant to the
aetiology of schizophrenia may conveniently be considered 25%
Half siblings
2nd 6%
under the headings in Box 15.5. degree
relatives Parents 6%

Siblings 9%
Box 15.5 50%
1st Children 13%
degree
Biological factors relevant to the aetiology relatives Fraternal twins 17%
of schizophrenia
• Familiality and genetic factors Identical twins 48%
• Occurrence of ‘schizophrenia-like’ psychoses 100%
• Pharmacological mechanisms of antipsychotic drugs 0 10 20 30 30 50
• Substance use Genes Relationship to Risk of developing schizophrenia (%)
• Pregnancy and birth complications shared person with
• Deficits in intellectual function schizophrenia
• Structural brain changes
Fig. 15.1  The risk of schizophrenia according to the genetic
• Changes in regional cerebral blood flow on functional imaging
strength of the relationship with an affected patient (courtesy of Irving
I. Gottesman 1994 and used with permission).

402
Schizophrenia and related disorders CHAPTER 15

considerable variation between populations in susceptibility


genes and variants (Gardner et al 2006). Recent whole-genome Table 15.4 Organic diagnoses in Northwick Park study of 268 first
episodes
association analyses also suggest that multiple low-penetrance
common variants contribute risk for schizophrenia (Moskvina Organic diagnosis No. of
et al 2009). Common high-penetrance variants have not cases
generally been found by these studies (Sullivan et al 2008).
Rare variants conferring high risk for schizophrenia have, Alcohol excess/withdrawal 3
however, also been identified. Perhaps the most striking Drug abuse/withdrawal 2
example is the DISC1 (Disrupted in Schizophrenia 1) gene,
identified in a large Scottish family in which a chromosomal Syphilis 3
translocation was associated with a high frequency of schizo-
Carcinoma of the lung 1
phrenia and other disorders (St Clair et al 1990). Although
this translocation is rare – possibly unique to this single family – Autoimmune multisystem disease (systemic lupus erythematosus) 1
common variants in DISC1 conferring risk for schizophrenia
Thyrotoxicosis 1
have also been identified (Chubb et al 2007). Smaller chromo-
somal abnormalities, known as copy number variants (CNVs), Cerebrovascular accident 1
have also been shown to be more common in patients with
Sarcoidosis 2
schizophrenia than in controls (Walsh et al 2008; ISC 2008;
Stefansson et al 2008) and to confer increased risk for the dis- Cerebral cysticercosis with secondary epilepsy 1
order. One example is the 22q11 deletion known to occur in
From Johnstone et al (1987)
velocardial facial syndrome, which is associated with a greatly
increased risk of schizophrenia. Notably this genomic region
includes the COMT (Catechol-O-Methyl Transferase) gene,
involved in dopamine metabolism, which has also been investi-
gated as a potential risk gene for schizophrenia. It is likely that was found in 15 of 268 cases (6%), and some overlap was
rare mutations smaller than CNVs also contribute risk for the apparent (Table 15.4). The worrying possibility that other
disorder, but these are more difficult to identify by current organic cases are missed is obvious, but this cohort was
methods. followed up for a further 5 years and no additional relevant ill-
The field of schizophrenia genetics is rapidly advancing nesses were known to develop. A small number of subsequent
with the development of new technologies. It is highly likely reports continue to hint at (but not confirm) an association
that multiple further genetic risk variants will be identified with head injury, epilepsy and cerebral infections, particularly
over the coming years. However, major challenges remain. in children and adolescents. Clarification of these effects and
These include producing more rigorously defined phenotypes any mechanism by which those conditions produce ‘secondary
for genetic investigation, and understanding the functional schizophrenia’ could illuminate our understanding of the
impacts of risk-associated variation. pathogenesis of the illness in general.

‘Schizophrenia-like’ psychoses The effects of antipsychotic drugs


This term refers to primary cerebral disease or to systemic Chlorpromazine was introduced into psychiatric practice by
disease affecting the brain and causing ‘secondary’ schizophre- Delay and Deniker in 1952, and by the early 1960s it was clear
nia. In the great majority of patients the illness develops in the that phenothiazines relieved schizophrenic symptoms and
absence of demonstrable organic disease, but certain ‘organic’ were not simply strong sedatives. A large number of other anti-
diseases, which could not result from any of the social and psychotic agents were introduced, and it became evident that
environmental disadvantages secondary to the disorder, occur they all shared the property of blockade of D2 dopamine recep-
in association with schizophrenia more often than would be tors and that their antipsychotic efficacy was proportional to
expected by chance. Davison and Bagley (1969) reviewed the their ability to block these receptors. By the early 1970s a
early literature on CNS disorders and concluded that certain number of pieces of evidence led to the conclusion that anti-
tumours and head injuries, temporal lobe epilepsy, Hunting- psychotic drugs acted by blocking D2 receptors. This position
ton’s disease, Sydenham’s chorea and Wilson’s disease, as well was made much less clear by the demonstration that clozapine
as some infections (general paresis and rheumatic encephalitis) (a weak D2 antagonist with a wide range of other pharmaco-
were over-represented in people with schizophrenia. Notwith- logical effects) is generally more effective against psychotic
standing the effects of reporting bias, the conditions are so symptoms than traditional antipsychotics which are much
varied that it is difficult to see any common path by which more effective D2 blockers. The conclusion is that D2 blockade
they could all come to produce the same clinical picture, and some other pharmacological mechanism is more effective
although there is a tendency for them to affect the temporal in antipsychotic terms than D2 blockade alone. It used to
lobes and diencephalon. When the occurrence of these condi- be thought that 5HT2a blockade, and the ratio of this to D2
tions was studied in relation to a large defined cohort of first blockade in particular, was an important determinant of
schizophrenic episodes (Johnstone et al 1987), underlying ‘atypicality’ – and indeed may of the newer drugs were devel-
organic disease of at least possible aetiological significance oped with this in mind – but 5HT2a blockade is evident at

403
Companion to Psychiatric Studies

subtherapeutic doses. An alternative view is that clozapine cancer patients, which found a relative risk of approximately
and some newer ‘atypicals’ have a faster dissociation off the 6 for hallucinations and 9 for delusions. Recent studies, how-
dopamine receptor, making them more accommodating of ever, suggest that tetrahydrocannabinol may increase anxiety
physiological dopamine transmission. These and others con- and psychosis, whereas cannabidiol may have opposing effects.
ceptions of atypicality all include an attenuation of D2 receptor
antagonism in the striatum (Gründer et al 2009). Indeed, the
preferential extrastriatal binding of the novel antipsychotics, Pregnancy and birth complications
initially reported on clozapine by Pilowsky and colleagues, This evidence includes the well-documented tendency for
has now been shown for several of them. individuals who later develop schizophrenia to have been born
It is now clear from several in vivo and postmortem studies in the winter months of the year, and the possible effects of
that dopamine receptors are elevated in number and the dopa- maternal influenza or food deprivation in pregnancy described
minergic system is overactivated in schizophrenia, and this above. More generally, a large number of studies have examined
is not entirely attributable to therapeutic blockade. We have the frequency of a variety of obstetric complications in indivi-
in effect moved from an over-simplistic view about the distur- duals with schizophrenia compared to controls. Individual stud-
bance of neurotransmission involved – such as that various ies have produced variable findings, as one would expect, but
other transmitter systems are implicated (e.g. serotonin, gluta- a number of systematic reviews provide evidence that such
mate) – but dopamine almost certainly has a role. More gener- complications are associated with the later development of
ally, these neuropharmacological studies provide important schizophrenia.
evidence for disturbances at the synaptic level in schizophrenia Cannon et al (2002) have summarised this literature and
(Stephan et al 2006). conducted a meta-analysis on prospective studies. There is
good evidence that low birthweight (especially < 2 kg)
increases the risk of schizophrenia. It is unclear whether this
Substance use is attributable to genetic or environmental factors, but the
An association between various illicit drugs and psychotic increased rates of congenital malformations and ‘minor physi-
symptoms has been commonly observed. Psychotic ‘reactions’ cal anomalies’ in schizophrenia implicate the genetic control
to cannabis, LSD, amphetamines and more recently to Ecstasy of fetal growth and development. On the other hand, perinatal
and ketamine ingestion occur, but it can be difficult to distin- problems such as pre-eclampsia, uterine atony and emer-
guish them from delirious states or drug taking as a reaction to gency sections suggest possible hypoxic brain damage. Direct
psychosis. There is certainly no convincing evidence for specific evidence of birth asphyxia in neonates who go on to develop
cannabis or amphetamine psychoses. Although drug challenge schizophrenia is limited, but the hippocampus is very sensitive
with methylphenidate and ketamine can provoke psychotic to such effects, and a number of structural brain imaging
symptoms in schizophrenics, it can also do so in controls, and studies suggest that the hippocampus is small in schizophre-
has only transient effects in both groups. The mechanisms of nia and that this may be related to obstetric complications
such effects remain unclear, although cannabis and stimulants (Shenton et al 2001).
increase dopamine release and LSD is a 5HT2a agonist.
The prospective Swedish study of cannabis use and psycho-
sis in conscripts did provide good evidence that cannabis use Changes in brain structure
can precede the onset of psychosis. Andreasson et al (1987) Pneumoencephalographic studies conducted from the 1920s
linked information about drug use in approximately 50 000 indicated that there is a degree of ventricular enlargement
young men conscripted in 1969/70, to a national register of and a reduction of brain tissue in schizophrenia, but they were
psychiatric admissions up to 1983. They found that cannabis difficult to interpret because of the problems of conducting
use was associated with a 2.4-fold increased risk of a this investigation in control subjects. The introduction of
subsequent admission for schizophrenia, and that the relative non-invasive imaging allowed controlled studies to be carried
risk in more frequent users was 6, but could not exclude out, and the finding of enlarged ventricular spaces in schizo-
the possibility that other drugs were responsible or that the phrenia (Johnstone et al 1976) has been widely replicated.
‘pre-psychotic’ turned to cannabis after the development of A host of structural MRI studies suggest that schizophrenics
early symptoms but before the onset of psychosis. Zammit have reduced volumes of the whole brain, the prefrontal
et al (2002) recently updated the study, with linkage to admis- lobe and the thalamus, and parts of the temporal lobes in par-
sion data up until 1996, and were able to control for these and ticular (see Ch. 4). These findings are evident in first-episode
other potential confounders. They demonstrated that stimu- patients, and even in relatives and subjects at high risk (Lawrie
lant use was not responsible, and that the elevated risk of et al 1999), suggesting a developmental cause. There are also
admission for schizophrenia in cannabis users held in those an increasing number of studies showing changes in frontal
who were admitted more than 5 years after conscription. and temporal lobes as people at high risk develop schizophre-
A number of case–control studies also support the association nia (Pantelis et al 2003), and that these imaging investigations
between cannabis and schizophrenia, as do some more recent could have predictive utility if preventative treatments were
cohort studies (see, for example, Moore et al 2007). Further, available (Job et al 2006).
this observational evidence that cannabis is psychotomimetic Neuroimaging studies stimulated a resurgence of interest in
is strongly supported by a meta-analysis of randomised con- neuropathological work in schizophrenia that was first con-
trolled trials (RCTs) of cannabinoid antiemetics or placebo in ducted in the early part of this century. The whole brains,

404
Schizophrenia and related disorders CHAPTER 15

temporal lobes and the thalamus of patients with schizophre- General intelligence is reduced in patients with schizophre-
nia are consistently smaller and lighter than in controls. This nia, and to a lesser extent in their healthy siblings. This appears
appears to be due to smaller neurons and less neuropil rather to largely predate the illness, but there may also be further
than a loss of neurons (Harrison 1999). Reductions in the reductions around the time of onset. There does not appear
numbers of dendritic spines and the expression of synapto- to be any progressive dementia as such, even though some
physin mRNA (a marker of synaptic activity) support imaging patients with longstanding illnesses appear to be impaired to
findings suggesting that subtle differences in interregional such a level. Performance IQ is lower than verbal IQ, and
connectivity may underlie schizophrenia (Table 15.5). There there are notable deficits in reaction time and motor skills
is also a lack of gliosis, interpreted as indicative of a disorder (Heinrichs & Zakzanis 1998).
of neurodevelopment rather than degeneration (Weinberger There are also clear impairments in tests of attention,
1995). A variety of subtle cytoarchitectural abnormalities executive function and memory, although it is difficult to reli-
in the hippocampus and in the cerebral cortex have been ably demonstrate that these are greater than the global pro-
reported, but none has been convincingly replicated (Harrison blems already described. Frith (1992) deals with this by
1999). Indeed, neuropathology studies do not consistently find providing evidence for relationships between particular cogni-
reductions in the size of medial temporal lobe structures – tive disturbances and specific types of symptom (see below),
although it is difficult to obtain large numbers of well- each of which can be mapped onto regional abnormalities on
preserved brains, and most MRI studies therefore have much functional imaging. Several studies do, however, suggest that
more power to detect such differences. The postmortem and there may be particular problems with memory (Heinrichs &
MRI studies do, however, generally agree about the location Zakzanis 1998). Implicit memory and the ability to learn new
and extent of these macroscopic structural changes. information are relatively preserved, but working, episodic
and semantic memory are impaired – deficits that are, if any-
thing, improved by antipsychotic medication but exacerbated
Cognitive dysfunction by anticholinergics. There are, in particular, strong suggestions
In his original monograph Bleuler had maintained that intel- that hallucinations are related to difficulties in remembering
ligence, and cognitive function in general, was unimpaired in the source of episodic memories (cf. monitoring whether sti-
schizophrenia, and this view was generally accepted until muli are internally or externally generated), and that people
recently. It was well known, of course, that many schizo- with schizophrenia have difficulty organising the encoding and
phrenics performed poorly on formal tests of intelligence, retrieval of memories. The latter is another pointer to the
but it was assumed that this could usually be explained as a importance of disconnectivity in schizophrenia, as functional
secondary consequence of apathy, or of the subject’s preoccu- imaging in healthy volunteers reliably activates frontal and
pation with hallucinatory experiences or delusional ideas. This temporal lobes during such activity, and these activation
view was challenged by the demonstration of ventriculomegaly patterns are disturbed in schizophrenia (Stephan et al 2006).
on computed tomography (CT) scans (Johnstone et al 1976),
and members of the same research group at Northwick Park
soon showed that many chronic schizophrenics were disor- Changes in regional cerebral blood flow
iented in time and some did not even know how old they were In 1974, Ingvar and Franzen demonstrated that patients with
(Crow & Stevens 1978). When the cognitive abilities of schizophrenia had relatively reduced cerebral blood flow in
chronic schizophrenics were examined in detail, evidence of the frontal lobes. This ‘hypofrontality’ was confirmed in some
widespread impairments was found. subsequent studies but not in all, and some even found ‘hyper-
frontality’. Other studies compared activity during the per-
formance of certain neuropsychological tests and that in a
reference condition (‘cognitive challenge’ studies), with
Table 15.5 Evidence for cortical dysconnectivity in schizophrenia greater and more consistent hypofrontality being evident (after
Investigation Finding Weinberger et al 1986). A key consideration, however, is
whether or not the patients can or will actually do the test in
Structural MRI Interregional volume correlations reduced the scanner.
Greater success has been evident in establishing the neuro-
Diffusion tensor White matter tract integrity reduced
anatomical correlates of specific symptoms, such as mapping
imaging
auditory hallucinations to language areas of the brain (McGuire
Postmortem Reduced synaptophysin mRNA expression et al 1993, Fletcher & Frith 2009). There is also a remarkably
neurochemistry consistent body of evidence from various ligand studies that
presynaptic dopamine activity is increased (see Ch. 4). The cur-
Postmortem Reduced dendritic spines
rent focus of much functional imaging research in schizophrenia
microscopy
is on disconnectivity, and reduced frontotemporal connectivity
Cognitive Organisation of encoding and retrieval may be in particular (Friston & Frith 1995; Stephan et al 2006). A vari-
responsible for impaired memory ety of studies have been carried out and, taken together, they
suggest imbalances between neuronal activity at diverse
Functional imaging Altered relationships between frontal and temporal
interconnected brain sites rather than abnormal function at a
lobe activity on certain tasks
single location (see e.g. Lawrie et al 2002).

405
Companion to Psychiatric Studies

Social factors found evidence for various indices of thought disorder in


patients’ relatives, and probably therefore reflect a genetic
Although the twin and adoption studies prove beyond reason- liability to schizophrenia. Moreover, genetic studies suggest
able doubt that schizophrenia is genetically transmitted, this that environmental factors contributing to the aetiology of
evidence has also established that environmental influences schizophrenia are much more likely to be unique or ‘non-
must play a major role as well, as estimates of the concordance shared’ rather than familial.
rate in monozygotic twins are consistently 50% or lower. There is nowadays much more concern about the effects of
If someone whose genetically identical twin develops schizo- childhood trauma, and child sexual abuse in particular, on a
phrenia has less than a 50:50 chance of doing the same, range of psychiatric disorders. Both are thought to be increased
whether or not he does must depend on his past or present in patients with schizophrenia, and auditory hallucinations are
environment. sometimes described as the voice of the abuser. Such clinical
reports are, however, rare. Moreover, the effects of abuse are
likely to be non-specific and potentially related to many aspects
Abnormal family relations? of childhood adversity, including those already putatively
In the 1940s Fromm-Reichmann coined the phrase ‘schizo- linked to schizophrenia.
phrenogenic mother’ and later workers supported the concept,
with claims that the mothers of schizophrenics were both
overprotective and hostile to their children. A few years later Life events
Gregory Bateson suggested that schizophrenia was produced Events in the weeks or months immediately prior to the onset
by the constant reception of incongruent messages from a of illness have received less attention than events during child-
key relative – to take a trite example, the verbal message hood, but there is some evidence that they may be relevant.
‘You know that Mummy loves you’ accompanied by non- Steinberg and Durrell (1968) showed that the schizophrenic
verbal behaviour implying something quite different – and this breakdown rate of recruits to the US army was much higher
‘double-bind hypothesis’ remained in vogue for a decade or in their first month of military service than at any time in
more. Shortly afterwards, Lidz and his colleagues at Yale car- the next 2 years, suggesting that the transition from civilian
ried out a series of intensive studies of 17 upper middle-class life to recruiting barracks was a contributing factor. The effect
families with what they regarded as schizophrenic children. was the same in volunteers as in enlisted men, and they were
They described several highly abnormal relationships within able to produce fairly convincing evidence that the illnesses
these families that differed with the sex of the schizophrenic presenting in the first month of service were indeed new and
child, and which they suggested were associated with the not merely newly detected. Further evidence was provided
development of schizophrenia in this son or daughter. Their by Brown and Birley (1968), who obtained detailed infor-
work aroused great interest, and their terms ‘marital schism’ mation about the events of the previous 12 weeks from
and ‘marital skew’ obtained the same wide currency as 50 patients with schizophrenic illnesses of recent onset and
Bateson’s ‘double-bind’. Around the same time, and with a 400 controls from the same neighbourhood. They found that
similarly dramatic impact, RD Laing published his influential the schizophrenics had experienced significantly more life
book The Divided Self. Unfortunately, these studies all had events than the controls in the 3 weeks immediately prior to
serious methodological defects and owed their influence more the onset of illness, but only in those 3 weeks. The difference
to their catchphrases and the prevailing climate of opinion than between schizophrenics and controls remained, even when all
to objective evidence. They were not conducted blind, had no events that might have been a consequence of incipient illness
adequate control groups, involved a very diffuse concept of (e.g. losing a job by being sacked rather than by closure of
schizophrenia and were retrospective, so that it was difficult the firm) were eliminated. It has to be borne in mind, how-
to tell which of the observed abnormalities had preceded ever, that the concept of schizophrenia employed in both
the onset of schizophrenia in the child, and might therefore these studies was a broad one. In Brown and Birley’s study,
have some aetiological significance, and which were reactions 24 patients were only ‘probably schizophrenic’, and furthermore
to the child’s illness. only 24 of the 50 were first admissions.
Overall, there is some evidence that the parents of schizo- Subsequent work has been scanty and largely unable to
phrenics are emotionally disturbed more often than the par- overcome the major methodological problems of identify-
ents of normal children, and that more of the mothers and ing enough independent events in people with reliably diag-
fathers have schizoid or schizotypal personality traits. These nosed first-episode psychosis. This is not surprising, given
relatively well-substantiated parental abnormalities are, how- the findings already described that prodromal symptoms
ever, easily explicable in genetic terms. Alongside these global may precede psychosis by years. There is, however, a general
studies of parental personalities and family interactions a series consensus that major life events can precipitate symptoms in
of more limited and better-designed studies of communication the predisposed.
patterns in schizophrenic and non-schizophrenic families was
carried out. The most influential of these were by Singer and
Wynne (1965), who gave Rorschach tests to the parents of Expressed emotion
schizophrenics and claimed that they consistently produced More attention has been paid to the determinants of relapse in
more deviant responses (i.e. that they were more ‘thought dis- those who have already had one episode of schizophrenia,
ordered’) than control parents. Most subsequent studies also mainly because the comparatively high probability of a further

406
Schizophrenia and related disorders CHAPTER 15

episode makes it feasible to mount prospective studies. Brown reformulations of descriptive psychopathology, but do permit
et al (1972) showed that the relapse rate over the next scientific study of these experiences. This kind of approach
12 months in young men who had just recovered from a first has certainly been successful in understanding the Capgras
episode of schizophrenia was far higher (58% versus 16%) in delusion. Facial processing in Capgras subjects is normal, but
those who returned to live with a relative – usually a parent the emotional concomitants of familiar face perception appear
or wife – who was prone to make critical comments about to be somehow disconnected from it, leading to an anomalous
them than in those who lived with a relative who was more affectless experience that can be explained in the delusion
tolerant and accepting. Moreover, the ill-effects of what the (Halligan & David 2001).
authors called ‘high expressed emotion’, or high EE, were Frith (1992) suggested that it is possible to explain the
mitigated to some extent if the patient was receiving antipsy- symptoms and signs of schizophrenia in terms of abnormalities
chotic drugs, and also if patient and relative were in contact of three main cognitive processes:
with one another for less than 35 hours a week, i.e. social with- • Negative symptoms and some inappropriate behaviours
drawal seemed to be protective. These findings have since (e.g. perseverations) may be considered the result of
been widely – although not invariably – replicated: a system- inability to generate spontaneous (willed) actions.
atic review of 27 studies demonstrated a robust effect, espe- • Some positive symptoms, e.g. passivity experiences,
cially in chronic patients, albeit less than in affective and auditory and somatic hallucinations, may be considered
eating disorders (Butzlaff & Hooley 1998). the result of a lack of awareness of the prior intention
The origins of the behaviour measured by EE are, how- that accompanies a deliberate act. Being unaware of
ever, uncertain. It is possible that the EE measure is predic- their own intentions, patients will experience their
tive at least in part, because relatives respond in a particular own actions, thoughts and subvocal (and perhaps vocal)
way to sufferers whose illness in any case has a poor progno- speech as resulting from some source other than
sis. There is evidence that at least some components of high themselves.
EE are associated with a variety of abnormalities in the
• Delusions of persecution and reference may be understood
patient, and that high EE develops over time as part of the
as the result of an inability to correctly infer the intentions
coping style of relatives in response to the difficulty of living
of other people. Similarly, the patient’s inferences about
with someone with schizophrenia. The fact that high EE is
what other people are thinking may be incorrectly
less evident in relatives of first-episode patients than in
perceived as information coming from an external source.
those with subsequent admissions is used in support of this
This could provide an explanation for third-person auditory
argument.
hallucinations.
In terms of this theory, schizophrenia may be explained as a
Psychological factors defect of the mechanism (referred to as ‘meta-representation’
or ‘theory of mind’) that enables us to be aware of our goals
Innumerable psychological theories of both the aetiology and and our intentions, and to infer the beliefs and intentions of
the pathogenesis of schizophrenia have been proposed. Many others (Table 15.6).
were derived from psychoanalysis, others from behavioural Frith developed this work in relation to changes in regional
psychology. Apart from the defective filter theory of sensory cerebral blood flow in response to neuropsychological tests
overload, few were backed by any substantial empirical data, (see above). This led him to suggest that the failure of some
and most are now of only historical interest. Recently, however,
some new and more promising models have been propounded
from a cognitive neuropsychological perspective.
Table 15.6 Three principal abnormalities of cognitive process
A number of studies have examined psychotic symptoms in
thought to underlie schizophrenia
terms of what is known about the determinants of social inter-
action, sensory experience and belief formation. Delusional Process Associated symptoms
content, for example, may reflect everyday concerns about
being attacked or excluded, or people’s preoccupations with Inability to generate willed action Poverty of action
spiritual matters. People tend to have ‘attributional styles’, Perseveration
such as a tendency to egocentricity, externalising (attributing Inappropriate action (distractibility,
disorganised behaviour)
events to outside forces) or intentionalising (attributing inten-
tions to others’ behaviour). There is some evidence that those Inability to monitor willed action Delusions of passivity
with delusions are disposed to jump to conclusions and stick to Certain auditory hallucinations
them (‘reasoning biases’), despite limited information, espe- Thought insertion
cially if the material is emotionally salient. Thus, persecutory
Inability to monitor the beliefs and Delusions of reference
delusions could be related to some combination of personality
intentions of others Paranoid delusions
factors (e.g. pessimistic explanatory style), focusing on a spe-
Third-person hallucinations
cific stimulus (perceptual/attentional bias), misinterpreting it
Certain kinds of incoherence
and ignoring information that goes against that interpretation
(Kaney et al 1999, Blackwood et al 2001). These concepts From Frith (1992).
are rather vague and overlapping, and sound a little like simple

407
Companion to Psychiatric Studies

schizophrenic patients to distinguish between their own actions in particular (Moutoussis et al 2007; Smith et al 2007).
and intentions and internal events may be due to a functional Through computational modelling of neural networks that
disconnection between frontal brain areas concerned with have been trained on empirical data, putative pathologies can
action and more posterior areas concerned with perception be introduced into the system and the effects monitored. For
(Frith 1992; Friston & Frith 1995). Much of this model has example, it has been shown that ‘pruning’ modelled synaptic
since been independently replicated, particularly with regard connections in a speech system results in initial improvements
to some auditory hallucinations and negative symptoms (Lawrie in word detection, but that, after about 40% pruning, halluci-
et al 2002; Fletcher & Frith 2009). It has the additional appeal nations are simulated, as speech percepts with no input
of being compatible with much of what is known about the (McGlashan & Hoffman 2000). This approach offers great
biology of the disorder. potential for integrating what is known about schizophrenia
Dopamine neurons are sensitive to both the occurrence and and developing it by modelling various insults that could in
time of ‘reward’. Qualitatively, the dopamine phasic response turn refine empirical research in patients.
is increased if rewards occur without being fully predicted.
Quantitatively, dopamine activity conforms to a mathemati-
cal model, the temporal difference equation, and a number Summary
of fMRI studies have reported temporal difference activity in
dopamine-rich brain regions of humans engaged in various The most plausible synthesis of the genetic, neuropathological
tasks. Of relevance to schizophrenia research, a version of and epidemiological evidence described above is that schizo-
‘incentive salience’ theory proposes that dopamine release phrenia is a neurodevelopmental disorder, as Weinberger
assigns an incentive value (reward) to stimuli or behaviours. (1987, 1995) has suggested. The structure of the hippocampus
It has been argued that schizophrenia is a state of aberrant and other parts of the temporal lobe, and the connections
salience, in that patients attend to internal and external stimuli between these and the frontal lobes, are abnormal in at least
inappropriately, and that this explains symptoms such as hallu- a substantial proportion of schizophrenics. These abnormalities
cinations and delusions, from both a physiological and a phe- may either be genetically determined or produced by injury to
nomenological perspective (Kapur 2003). The implication is the developing brain (mediated perhaps by disruption of the
that phasic activity in dopamine-rich brain regions should be normal sequence of neuronal migrations), either in utero or
abnormal in schizophrenia, and there is supporting evidence at the time of birth. This would account for the changes in
(Murray et al 2007). Detailed temporal difference-based the brains of schizophrenics, found on structural imaging and
theories about aspects of psychosis have been proposed and at postmortem examination, and the subtle intellectual and
can be tested in humans, in animals and even in computer social disabilities of schizophrenic children before the overt
models (Moutoussis et al 2007; Smith et al 2007). onset of their illness.
The 20–30-year delay before the onset of the psychosis
could be explained in purely genetic or maturational terms,
Animal and computer models but could also be related to the precipitating effects of canna-
Animal models of serious mental disorders have obvious bis and/or stress on dopaminergic systems. Myelination and
problems and are less fashionable than they were. Latent inhi- synaptic pruning are not complete in the frontal lobes until
bition has, however, continued to be studied. It is a pheno- puberty or later, and it has been shown that the behaviour
menon, readily demonstrable in animals and man, whereby of infant monkeys with surgical lesions of their dorsolateral
repeated exposure to a stimulus without consequence retards prefrontal cortex does not become overtly abnormal until they
subsequent conditioning to that stimulus. (For example, a rat are adult (Weinberger 1987, 1995; McGlashan & Hoffman
repeatedly exposed to a particular odour will take longer to 2000). Alternatively – or in addition – the core pathology of
learn the significance of that odour if it is subsequently paired schizophrenia may be an ongoing impairment in the control
with a rewarding or punishing stimulus.) An early study found of synaptic plasticity, which is manifest as neural disconnectiv-
that although schizophrenics in remission displayed latent inhi- ity (Stephan et al 2006). A number of neuroimaging and
bition in the same way as normal controls, acutely ill schizo- electrophysiological studies have reported evidence of struc-
phrenics did not (Baruch et al 1988). Quite apart from the tural and functional brain disconnections in schizophrenia
intrinsic interest of a simple and widely applicable paradigm which appear to arise, or at least to worsen, around the time
in which schizophrenics perform ‘better’ (respond more) than of onset of the classic delusions and hallucinations. Such
normals, latent inhibition is known to be abolished in rats by ‘loosening of associations’ between brain regions and processes
amphetamine, and to be strengthened by antipsychotics. It has may disrupt the usual neural mechanisms thought to be crucial
the makings, therefore, of a possible animal model of schizophre- for distinguishing self- from non-self-generated actions, and in
nia. Work also continues on pre-pulse inhibition as an index of determining the significance of external events, leading to
‘sensorimotor gating’ and on the conditioned avoidance response characteristic symptoms (Fletcher & Frith 2009).
as a marker of antipsychotic efficacy, as do efforts to breed A multifactorial model of this kind can accommodate most
strains of animals and to knock out particular genes with specific of the established neurobiological and psychosocial facts about
performance patterns on these tests (Kilts 2001). schizophrenia. There are, of course, speculative elements in
The advent of artificial intelligence as a tool to understand the model, and the role of psychosocial factors remains poorly
information processing in the human brain has also led to specified, but it does at least provide a plausible conceptual
new approaches to psychosis, and delusions and hallucinations framework to guide future research.

408
Schizophrenia and related disorders CHAPTER 15

Course and prognosis Illnesses that develop acutely in response to stress have a much
better prognosis than those that develop insidiously for no
apparent reason. And if patients have prominent schizoid per-
Kraepelin’s original concept of dementia praecox was founded
sonality traits, particularly if they are also young, of low intel-
on the belief that such illnesses all progressed to a state of
ligence and have a poor work record, the outlook is much
global deterioration, or at least resulted in permanent damage
bleaker than if they are married, more mature and have a more
to the personality. The outcome of schizophrenic illnesses, as
‘normal’ personality. Several studies have also reported a
Kraepelin himself eventually came to realise, is, however, very
worse prognosis – at least where hospital discharge rates are
variable, regardless of how the syndrome is defined. Some
concerned – in men than in women. Social considerations
resolve completely, with or without treatment, and never
may be partly responsible for this difference, but the fact that
recur. Some recur repeatedly, with full recovery every time.
women also have a later age of onset than men suggests that
Others recur repeatedly but recovery is incomplete: that is,
there are intrinsic differences in the nature of the illness
there is a persistent defect state that does not improve or
between the sexes.
indeed tends to deteriorate with successive relapses. Finally,
some illnesses pursue a progressive downhill course from the
beginning. The relative frequency of these different outcomes Outcome frequencies
depends a great deal on how schizophrenia is defined. If it is
defined in such a way as to exclude those with prominent Numerous studies of outcome have been published over the
affective symptoms, the proportion of patients making a full years, many of which class patients in simple categories of
recovery is reduced; if the diagnosis is also restricted to outcome such as ‘recovered’, ‘improved’ and ‘not improved’.
patients with a 6-month history, the proportion recovering Interpretation of even such simple terms can vary: some
without permanent defect is reduced still further (Hegarty class patients as recovered when their delusions, although
et al 1994). present, are not readily revealed; and others class such indivi-
duals as having continuing symptoms. Notwithstanding these
limitations, most studies report that about 50% of people with
Outcome predictors schizophrenia will improve and 20% or so will recover
Predicting the type of course that the illness of individual (Hegarty et al 1994). A particularly large study of 532 patients
patients will take is an issue of great clinical importance. In discharged from inpatient care in a London borough between
the days before operational definitions for schizophrenia were 1975 and 1985 and followed up between 1987 and 1990 was
used, Vaillant (1964) and others carefully identified factors conducted by Johnstone et al (1991) and provides detailed
predictive of outcome, but these were features that were less information about various outcomes. The heterogeneity of
than central to the disorder (Box 15.6). outcome in schizophrenia was very evident in this study –
The development of more closely defined criteria for although there were some striking successes, unemployment,
schizophrenia might have been expected to improve the pre- social difficulties and a restricted lifestyle were common, and
diction of outcome, but this hope has not really been realised. many patients had continuing symptoms. A slightly more
Studies have been conducted in which more and less restric- encouraging picture emerged from a 13-year follow-up of a
tive criteria for the diagnoses have been applied to groups of representative cohort of 67 first-episode patients, of whom
patients who were then followed up for several years (e.g. approximately 40% had been employed over the previous
Hawk et al 1975; Kendell et al 1979). On the whole the cri- 2 years and 20% were living independently (Mason et al
teria were not very successful in identifying groups of patients 1995). Menezes et al (2006) have reviewed this first-episode
with a poor outcome, and in general what success there was lay literature and Table 15.7 gives summary estimates of the
in defining symptomatic rather than social outcome. frequency of outcomes based on these studies. Standardised
Outcome seems to be determined more by the circum- criteria for remission have now been drawn up by a panel of
stances under which the illness develops and the premorbid American experts, but have not yet been employed in many
personality than by the symptomatology of the illness itself. studies.

Box 15.6
Table 15.7 Frequency of desirable outcomes in first episode
Vaillant’s predictors of a good prognosis schizophrenia (estimates)
• Acute onset Outcome Frequency (%)
• A stressful precipitating event
• Family history of depressive illness Improvement 50
• No family history of schizophrenia
No further episodes 20
• Absence of schizoid traits in the premorbid personality
• Confusion or perplexity Employment / higher education 40
• Prominent affective symptoms
Live independently 20

409
Companion to Psychiatric Studies

Influences on outcome the prognosis of schizophrenia is rather better in so-called


‘underdeveloped’ countries, despite their meagre psychiatric
Illnesses do not have an outcome in vacuo, or even a pure
services. The most important evidence to this effect comes
‘natural history’. Outcome is always affected for good or ill
from the International Pilot Study of Schizophrenia. In that
by treatment and other environmental influences, and there
study a large series of psychotic patients, the majority of
is little doubt that the outcome of schizophrenia has improved
whom were schizophrenics, were studied in nine different
in the last 50 years. Hegarty et al (1994) have systematically
centres in different parts of the world. The same structured
reviewed this literature. Follow-up studies conducted in the
interviewing methods were used in all nine centres and the
1920s and 1930s, before any effective treatments were avail-
patients were re-interviewed at 2 years and 5 years, again using
able, only reported full recovery in about 10% of patients,
the same methods and criteria throughout. Quite unexpect-
and at least 60% were either unimproved or dead at the time
edly, the average outcome was considerably better in the
of assessment. Since the 1950s all comparable follow-up stud-
underdeveloped countries (Colombia, India and Nigeria) than
ies have shown much better results. To what extent this
in the industrialised countries (Czechoslovakia, Denmark, the
improvement was due to the phenothiazine drugs introduced
UK, the USA and Russia) (Sartorius et al 1977). The differ-
in 1952, and to what extent it was due to the changes in the
ence did not lie in the proportion of patients pursuing a steady
milieu of mental hospitals and in public attitudes to mental
downhill course: this was much the same throughout. Rather,
illness taking place simultaneously, is difficult to determine,
it lay in the proportion suffering recurrent relapses. Despite
but the combination certainly produced a substantial change.
the much more extensive follow-up treatment available in
In most industrial countries the number of mental hospital
the industrial countries, a high proportion of their patients
beds fell by at least 50% between 1950 and 1990, and although
had further psychotic episodes, whereas Colombian, Nigerian
financial and political considerations played an important
and Indian patients did not. The same finding had emerged
role in many places, the major cause of this massive reduc-
from an earlier comparison of the outcome of schizophrenia
tion was the changed outlook towards and management of
in London and Mauritius. Although careful comparisons of
schizophrenia.
the initial symptomatology and other characteristics of the
There is little doubt, though, that the effects of antipsy-
patients from the nine study centres did not reveal any impor-
chotics on the long-term prognosis of schizophrenia are less
tant differences between them, the possibility that these
impressive than the short-term effects. Although contempo-
differences in outcome were due to unrecognised differences
rary patients spend less time in hospital than their predeces-
in the types of patient admitted to hospital in the nine centres
sors, and are far less likely to end their days as permanent
obviously cannot be excluded. Certainly, people with acute
hospital invalids, a disturbingly high proportion still remain
behavioural disturbances are more likely to come to medical
chronically handicapped by defect states or recurring halluci-
attention in settings where psychiatric services are novel and
nations and delusions, and still require repeated admissions
thinly spread than are those with insidiously developing dis-
to hospital despite long-term drug therapy. The review by
orders that do not cause the same alarm; and the former are,
Menezes et al (2006) suggests that the availability of both
of course, likely to have a better prognosis than the latter.
pharmacotherapy and psychosocial treatments, including
Partly to elucidate these intriguing differences in outcome,
‘atypical’ drugs, improves outcome in first-episode cases, as
the WHO mounted a further international comparison involv-
does living in a developing country.
ing 12 centres in 10 countries, known as the Determinants of
These comparatively disappointing results have prompted
Outcome of Severe Mental Disorders Programme (or ‘Ten
great interest in the amount of time people have psychosis
Country Study’). The preliminary results of this major study
before getting treatment – the duration of untreated psychosis
confirm that, at follow-up 2 years after their initial inception
(DUP) – and the development of early intervention services to
into treatment, schizophrenic illnesses have a better prognosis
reduce this, especially in parts of the UK, USA and Australia.
in developing than in developed countries (Sartorius et al
Marshall et al (2005) have reviewed both the studies of corre-
1986). Part – but only part – of this difference is attributable
lational data and those comparing long and short DUP groups.
to a higher proportion of illnesses in the developed countries
Both types of study showed a statistically significant associa-
having a relatively insidious onset. It seems likely, there-
tion between DUP and positive symptoms, total symptoms,
fore, that there is something about the social organisation of
and overall functioning at 6 months. What studies there are
contemporary industrial societies, or their family structure or
suggest that the observed association between DUP and out-
attitude to mental illness, which has a deleterious effect on
come is not explained simply by premorbid adjustment, but
the course of schizophrenic disorders. Not only is the outcome
they do not rule out some effect of this, and it is difficult to
worse in industrial than in developing countries, it is probably
disentangle an insidious onset of schizophrenia in some people
worse in urban than in rural areas within industrial countries.
from a longer DUP. Moreover, many studies do not blindly
A comparison within the UK has shown that the functioning
assess DUP and outcome, and the variability in outcome
of schizophrenic patients in the rural district of Nithsdale in
attributable to DUP is likely to be as little as a few percent.
southwest Scotland was higher than that of similar patients
from south London (McCreadie et al 1997). To what extent
Cultural influences this is due to the much higher use of the psychiatric services
The vast majority of follow-up studies have been carried out in by the Nithsdale population is a matter for speculation.
the industrialised countries of Western Europe and North To summarise, schizophrenia used to be regarded as a
America. There is, however, fairly substantial evidence that steadily progressive disease with a poor prognosis. It is now

410
Schizophrenia and related disorders CHAPTER 15

clear that this is not necessarily so – or perhaps no longer so. clinicians should be comfortable accessing and using the
The long-term prognosis is rather better than we used to detailed information in the Cochrane Database of Systematic
believe, and the course of the illness is very variable. Further- Reviews. Even this secondary research and reporting does
more, at least in industrial countries its clinical presentation not, however, provide particularly good evidence on the
has changed from that at the beginning of the 20th century. harmful effects of treatment, which is probably most reliably
The catatonic and hebephrenic forms have become much less determined from large observational studies. In what follows
frequent, and paranoid forms more frequent. These changes we refer to key individual studies and systematic reviews
and differences are usually attributed to advances in treatment where possible.
and to the pathoplastic effects of cultural differences and
social changes. It is possible, however, that they are actually
due to a slowly progressive change in the nature of the disease, Treating acute symptoms
as occurred with scarlet fever in the 20th century. If such a The phenothiazines, butyrophenones and thioxanthenes were
change has indeed taken place, it is likely to be due to some initially used in schizophrenia for the purpose of treating the
change in the environmental factors contributing to the positive symptoms of acute episodes. In the 1960s several
aetiology of the condition; if so, identifying these could inform large-scale trials demonstrated that these drugs were highly
therapeutic and even preventative approaches. effective in combating such symptoms, and were not merely
supersedatives (Hollister et al 1960; National Institute of
Mental Health 1964). Nonetheless, about 30% of patients
Treatment show only limited effects in such trials (Davis 1976), and
about 10% of cases do not appear to show any response at
Before the 1930s there was no effective treatment for any of all, even to prolonged treatment (Johnstone et al 1986). The
the so-called functional psychoses, and the prime function Cochrane Review of chlorpromazine, for example, also
of mental hospitals was to keep their patients in tolerable describes many adverse effects, particularly sedation, parkin-
comfort and physical health in the hope that spontaneous sonism, hypotension and weight gain. Haloperidol is less
remission would take place. Regimens were essentially cus- sedative but also more likely to cause dystonia and akathisia.
todial, with whatever occupational, recreational and spiritual Pimozide and sulpiride were greeted with much enthusiasm
accompaniments local custom and resources allowed. The in the 1980s, but have relatively slight advantages and dis-
introduction of Sakel’s insulin therapy in 1933, Moniz’s pre- advantages (Cochrane Library 2009). It used to be thought
frontal leukotomy and von Meduna’s convulsive therapy in that non-specific and adverse effects had a more rapid onset
1935 and Cerletti’s ECT in 1938, and the possibilities of cure than therapeutic benefits, but a meta-analysis of trials that
these dramatic new therapies seemed to offer, had a profound reported results over the first 4 weeks of treatment has shown
effect on the atmosphere and morale of mental hospitals that total scores on the Brief Psychiatric Rating Scale and the
throughout the world. ECT and insulin coma therapy were Positive and Negative Syndrome Scale reduced by about 14%
both widely used throughout the 1940s, and thousands of during week one, 8% during week two, and 4–5% during weeks
patients were enthusiastically subjected to prefrontal leukot- four and five. This pattern of ‘early-onset’ improvement was
omy. The discovery of the calming effects of chlorpromazine present even after the estimated effect of placebo treat-
by Henri Laborit in the early 1950s had an even more pro- ment was removed and when results were restricted to the
found effect, and within a few years of the introduction of psychotic subscales of the scales (Agid et al 2003).
these new phenothiazine drugs the insulin coma regimen and Partly because of individual differences in absorption and
leukotomy both declined rapidly. ECT remained in widespread metabolism, the dose required to bring psychotic symptoms
use much longer, mainly in combination with phenothiazines under control varies considerably from one patient to another,
or as a second-line treatment for patients who had failed to from 150 mg/day in chlorpromazine equivalents to as much
respond to these drugs, but is now very rarely used. as 1000 mg/day. Baldessarini et al (1988) comprehensively
reviewed the published controlled trials of different anti-
psychotic dosages in the treatment of schizophrenia. They
Antipsychotic drugs concluded that, in the acute illness, moderate doses (chlor-
promazine 300–600 mg/day, or equivalent doses of other anti-
The various types and preparations of antipsychotic drugs are psychotics) are most effective. They also found evidence of a
now the mainstay of schizophrenia management. Most have biphasic or inverted-U dose–response relationship, suggesting
been evaluated in RCTs and shown to be of benefit. It is that if a patient does not respond to moderate doses of anti-
beyond doubt that they ameliorate acute episodes, such that psychotics it is as logical to reduce the dose as to increase it.
placebo-controlled trials in this situation would be unethical.
The RCTs are, however, generally small and short-lived, so
that potentially important benefits of antipsychotics or differ- The ‘atypical’ antipsychotics
ences between them are quite likely to be missed in individual Until the early 1980s the psychopharmacology of acute schizo-
studies (Thornley & Adams 1998). The Cochrane Library phrenia was dominated by the idea of the relevance of dopa-
(2009) includes more than 150 systematic reviews and meta- mine receptor blockade. This situation changed with the
analyses of pharmacological (and psychosocial) treatments. comeback of the ‘atypical’ antipsychotic clozapine. The con-
Space precludes them being individually cited here, but all cept of atypical antipsychotic drugs was originally derived

411
Companion to Psychiatric Studies

from the idea that the antipsychotic and extrapyramidal than traditional antipsychotics in first-episode patients, and
effects of such drugs are linked, so that in order for a drug relatively few studies demonstrating benefits in the medium
to be an effective antipsychotic it must necessarily produce to long term. The original NICE guidelines (2002) which sug-
extrapyramidal side effects (EPSE) in patients. Clozapine gested that they should be used as first-line treatments in
produces minimal extrapyramidal effects. It was introduced newly diagnosed patients now look biased – just as the new
in the 1970s but withdrawn from use in the USA, Great guidelines do in stating that all patients with schizophrenia
Britain and much of continental Europe after it was shown to should be offered CBT (NICE 2009).
be associated with agranulocytosis in a small percentage of The management of the positive symptoms of acute epi-
cases. However, Kane et al (1988) reported a large multicentre sodes is, however, only one aspect of the management of
trial in the USA concerning 268 patients with chronic schizo- schizophrenia, and it is not difficult to make the case that
phrenia who had failed to respond to at least three different the reduction of relapse rates and the treatment of the nega-
antipsychotics, and also to a 6-week trial of haloperidol tive symptoms of the defect state are at least as important.
60 mg/day. In this situation clozapine (in doses of up to
900 mg/day) was found to be more effective than chlorprom-
azine in doses up to 1800 mg/day; in a 6-week double-blind Relapse reduction
comparison, 30% of clozapine versus 4% chlorpromazine Many studies have focused on the role of antipsychotic drugs
patients achieved preset standards of improvement. Clozapine in reducing schizophrenic relapse. The benefits of both oral
has a wider-ranging pharmacological profile than most tradi- (Leff & Wing 1971) and depot medication (Hirsch et al
tional antipychotics. It has a relatively modest affinity for D1 1973) have been clearly demonstrated. Reviewing 24 con-
and D2 receptors and effects upon many other neurotransmit- trolled studies, Davis (1976) concluded that the evidence for
ter receptors, including other dopamine receptor subtypes, the efficacy of maintenance antipsychotic treatment was over-
serotonin and adrenergic receptors. Which, if any, of these whelming. The drugs do not, however, abolish the tendency to
effects is relevant is not currently established, but it seems relapse. In a 2-year follow-up study of oral antipsychotics
most likely that it is related to preferential dopamine blockade versus placebo, the rate of schizophrenic relapse in placebo-
in the mesolimbic systemc (Grunder et al 2009). The dis- treated patients was 80%, whereas that of patients on active
advantages of clozapine are its unnecessarily high cost, a ten- antipsychotics was 48% (Hogarty et al 1974). Gilbert et al
dency to cause hypersalivation and major weight gain, and that (1995) systematically reviewed studies comparing medica-
frequent neutrophil counts are necessary in order to detect tion maintenance and withdrawal, and found an overall 37%
incipient marrow depression and to prevent deaths from agran- reduction in relapses over an average of about 8 months in
ulocytosis. It is also associated with slightly increased rates of the continuation groups.
potentially life-threatening seizures, myocarditis, thromboem- Although a few trials suggest that oral haloperidol and chlor-
bolism and cardiomyopathy, but clozapine reduces overall promazine continue to reduce relapses in the long-term
mortality as it lowers suicide risk. (Cochrane Library 2009), there is no good reason to select
Other ‘atypical’ antipsychotics have been introduced. Indi- one drug over another. Compliance is, however, a major prob-
vidual trials suggest they may have benefits over ‘typical’ drugs lem. Patients with schizophrenia are often unreliable at taking
on overall efficacy, some side effects, compliance and various tablets once their acute symptoms have subsided and they have
aspects of functioning. The vast majority of these trials have, left hospital. There are several reasons for this. They may not
however, been sponsored by the pharmaceutical industry, accept that they have been ill in the first place, and even if they
and systematic reviews show much less dramatic benefits do they may not accept that there is any risk of the illness
(Geddes et al 2000; Cochrane Library 2009). Psychiatrists recurring. The drugs often cause unpleasant side effects which
have at last got around to conducting independent effective- are more obvious than their antipsychotic effect. For these rea-
ness studies. Of these, the Clinical Antipsychotic Trials in sons, ‘depot’ preparations capable of producing adequate serum
Intervention Effectiveness (CATIE) study is by far the most levels when administered at intervals of 2 weeks or more have
important. Lieberman et al (2005) randomised 1493 patients been developed. The introduction of these injectable depot pre-
with schizophrenia at 57 US sites to one of five treatments: parations over 30 years ago was hailed as a great advance, and
olanzapine (7.5–30 mg/day), perphenazine (8–32 mg/day), they are now widely used, often with special clinics and elabo-
quetiapine (200–800 mg/day), risperidone (1.5–6.0 mg/day) rate follow-up arrangements to ensure that patients do not miss
and ziprasidone (40–160 mg/day) for up to 18 months. The their regular injection every 2, 3 or 4 weeks. They are probably
primary outcome measure of continuation of medication was a significant advance, and underused since the marketing of the
evident in only 26% at 18 months. This rate was slightly higher ‘atypicals’, but it is important not to forget that no trial compar-
in patients allocated to olanzapine, but they also tended to suf- ing long-term relapse rates on daily tablets and fortnightly injec-
fer metabolic derangements and put on more weight. Overall, tions has demonstrated any clear advantage for the latter.
it is becoming increasingly clear that the beneficial and adverse For example, Hogarty et al (1979) conducted a further study
effects of the newer ‘atypicals’ are as different from each other comparing maintenance prophylaxis with oral and with depot
as those of traditional antipsychotics (Leucht et al 2009). In antipsychotics. There was no difference between the two
short, the newer atypicals have a different profile of adverse groups, and the 2-year relapse rate remained substantial. These
effects, the main problems being obesity and undesirable car- trials have, however, generally been so small that one cannot
diometabolic effects (Allison et al 1999). Allied to this, there rule out a clinically significant advantage (Cochrane Library
is virtually no evidence that these drugs are more effective 2009).

412
Schizophrenia and related disorders CHAPTER 15

Concern about the extrapyramidal side effects of antipsy- partially reflects the underlying brain disruption in schizophre-
chotics led to several attempts to maintain chronic patients nia. Certainly, it is well established that indistinguishable
on very small doses of antipsychotics, or to give these drugs involuntary movements are not uncommon in elderly schizo-
only at the first sign of impending relapse. The results have, phrenics who have never received antipsychotics of any kind
however, been disappointing. Johnson et al (1987), for exam- (for example, see Owens et al 1982), and that persistent
ple, found that if chronic schizophrenics who were well chewing movements and other dyskinesias were observed in
controlled on relatively low doses of flupentixol (up to chronic schizophrenics long before antipsychotics existed
40 mg i.m. fortnightly) were transferred double-blind to half (Farran-Ridge 1926). This interaction may explain why TD is
that dose, their relapse rate over the next 3 years was signifi- so difficult to treat: despite several trials of several different
cantly increased. Although Baldessarini et al (1988) found that interventions, the only (possibly) effective approach is to
quite low doses (chlorpromazine 50–100 mg/day or equiva- reduce the dose of antipsychotic (Cochrane Library 2009).
lent) provide adequate maintenance therapy in about 50% of On the other hand, it is also important to realise that stop-
patients, subsequent systematic reviews of RCTs have shown ping patients’ maintenance medication may, paradoxically,
that relapse rates are lower on doses of 200–500 mg (Barbui result in their receiving an increased rather than a reduced
et al 1996) or 166–375 mg (Bollini et al 1994). Higher doses total dose over the next year or two, because they may relapse
than this merely increase the side-effect burden, but reducing and then require a substantially larger dose to bring their psy-
medication doses towards this target range should be done chotic symptoms back under control (Johnson et al 1983).
cautiously and carefully. Only rarely is it appropriate to give patients two or more
different antipsychotics simultaneously. Sometimes there are
good reasons for temporarily increasing the effective dose in
Managing EPSE a patient on an injectable depot preparation by giving a second
Because they block the dopamine receptors of the nigrostriatal drug orally as well; and some patients cannot tolerate an ade-
system, all conventional antipsychotics tend to produce trouble- quate dose of one drug because of its hypotensive or sedative
some extrapyramidal side effects (EPSE). For this reason, some effects, or an adequate dose of another because of its extrapy-
clinicians prescribe antiparkinsonian drugs routinely whenever ramidal effects, but can tolerate a mixture of the two in lower
they want to use more than a small dose of an antipsychotic. This doses. Most polypharmacy, however, is simply a public display
is not good practice, for a variety of reasons. Akathisia and par- of pharmacological ignorance.
kinsonism are the most common and troublesome EPSE, and
there is little evidence that the routine prescribing of antiparkin-
sonian drugs reduces them to any worthwhile extent. There is Negative symptoms
also some evidence that the use of these drugs may impair the Clear benefits of antipsychotic medication have been demon-
efficacy of antipsychotics, particularly in controlling positive strated in the treatment of acute episodes and in the reduction
symptoms, and increase the incidence of tardive dyskinesia; of relapse rates, but there is no drug treatment that can reli-
and because they have mild stimulant properties some patients ably be recommended as relieving negative symptoms in the
abuse them or become dependent. What trial evidence there is same way that antipsychotic agents relieve positive symptoms.
suggests that short-term benzodiazepines, specifically clonaze- The effect of these drugs on negative symptoms is uncertain.
pam, may be the best treatment for akathisia (Cochrane Library Controlled trials have yielded conflicting evidence: traditional
2009). In general, therefore, antiparkinsonian drugs should only antipsychotics have been found to improve, to have no effect
be used if the patient actually develops an acute dystonia or trou- upon, or to exacerbate negative symptoms. The same is true
blesome parkinsonism and it is not feasible to reduce the dose of of both dopamine agonists and antidepressants.
antipsychotic. And even if this is necessary, and successful, an There may, however, be slightly more encouraging results
attempt should be made to withdraw the antiparkinsonian agent from RCTs of the ‘atypicals’, in particular clozapine and ami-
after a couple of months because it will often be possible to do so sulpiride, and possibly olanzapine. Clozapine reduced negative
without the extrapyramidal symptoms returning. symptoms in the original treatment resistance study (Kane
The case for giving antipsychotic drugs to chronic schizo- et al 1988), and all three drugs appear to do so in general
phrenics year in, year out is less compelling than the case for (Cochrane Library 2009; Leucht et al 2009). It is important
using them during acute episodes or exacerbations – about to note, however, that these improvements may be attributable
20% of patients will not have further episodes, and a sim- to reductions in negative symptoms secondary to positive
ilar percentage will relapse regardless. The disadvantages of symptoms or EPSE, rather than primary negative symptoms.
chronic medication are also substantial. Many patients are seri- Storosum et al (2002) have, however, reviewed the amisul-
ously distressed by akathisia or rigidity, sedation or weight piride trials from this perspective and found that these
gain, and others who are fortunate enough not to suffer in this explanations are unlikely, although they noted a relatively high
way are understandably reluctant to continue ‘taking drugs’ placebo response rate and suggest that there may be both
indefinitely. There is also the long-term risk of tardive dyski- enduring and non-enduring primary negative symptoms. There
nesia (TD) to consider; which, even though the patient may are also encouraging preliminary results, from a few small trials,
be unaware of it, is often all too obvious to the general public. that augmentation with the NMDA receptor co-agonists glycine
The incidence of TD may be as high as 5% per year on or D-serine is effective in reducing negative symptoms (Cochrane
medication, but such figures can give a distorted idea of the Library 2009). On the other hand, there appears to be no
frequency as some cases remit spontaneously. TD at least effective drug treatment for patients in the ‘defect state’.

413
Companion to Psychiatric Studies

Depressive symptoms prove to have a role in managing treatment-resistant patients,


but most of the trials to date have included both resistant
Tricyclic and other antidepressants are frequently given to
and intolerant patients. Clozapine remains the only proven
schizophrenics in an attempt to relieve their associated depres-
drug treatment in resistant cases, producing notable improve-
sive symptoms. The apathy and flattening of affect of the
ment in about one-third. There are suggestions that lamotri-
schizophrenic defect state can resemble depression but, in
gine augmentation, ECT and certain psychological approaches
addition to this, the occurrence of depressive symptoms in
may be valuable.
schizophrenic patients when they are not actively psychotic
(in what is sometimes called secondary or post-psychotic
depression) has increasingly been recognised (McGlashan & ECT
Carpenter 1976). The value of adjunctive antidepressant treat-
ment both on an acute (Siris et al 1987) and on a maintenance Although antipsychotics have been central to treatment of
basis (Siris et al 1994) has been demonstrated, although the acute schizophrenia for the past 40 years, ECT has been exten-
trials may have overestimated the therapeutic benefits sively used in some centres, albeit less so now than in the past.
(Cochrane Library 2009). In May’s (1968) pivotal trial, patients treated with ECT fared
significantly better than those who only received psychother-
Evidence-based prescribing apy, though less well than those receiving phenothiazines.
Subsequent trials, including those comparing both real and
The results of these clinical trials provide the basis of a rational dummy ECT under double-blind conditions, found it to have
prescribing policy (Box 15.7). Acute schizophrenic illnesses genuinely beneficial effects in acute schizophrenia, though
should almost invariably be treated with antipsychotic agents, these are no longer detectable 3–6 months later (Cochrane
and it is probably wise to try to keep most patients on a main- Library 2009). For this reason the principal indication for
tenance dose for at least a year or two thereafter, even if their using ECT in the treatment of schizophrenia nowadays is when
recovery is complete and rapid. With so many similar prepara- rapid improvement is desired, or for severe schizoaffective
tions to choose from, the choice of drug is largely a matter of illnesses (see below). The statement that ECT has value in
personal preference and relative costs. Many psychiatrists will the treatment of cases of catatonic stupor tends to be passed
use chlorpromazine in the acute phase, and if the patient down in editions of textbooks over the decades. The condi-
is overactive or frightened its sedative effects are valuable. tion is so vanishingly rare that there is little evidence one
However, the hypotensive effects of chlorpromazine may be way or another, but a placebo-controlled trial in the 1950s
dangerous in the elderly or in patients with a history of heart showed no advantage of active treatment. However, a recent
disease, and in them a drug such as trifluoperazine may be large trial of 114 patients with treatment-resistant schizophre-
preferable (see Ch. 11). Usually the drug can be given orally, nia, defined in the same way as by Kane et al (1988), found
but intramuscular injection (or liquid medication) may be that ECT and flupentixol led to remission in 58 cases, and
necessary initially if the patient is aggressive, refusing to take that the combination of weekly and then fortnightly contin-
tablets, or there are doubts about compliance. uation ECT with flupentixol kept the vast majority well
If EPSE are a particular problem and not improved by (Chanpattana et al 1999). The study requires replication, and
reducing antipsychotic dosage, it probably makes sense to the treatment may not be acceptable to many patients, but it
switch to a new ‘atypical’ drug. Some of these drugs may yet does at least suggest a therapeutic option in patients who do
not respond to or cannot tolerate clozapine.
Box 15.7
Social and psychological measures
An evidence-based prescribing policy for schizophrenia
Acute episode Although in the short run antipsychotics have a much more
dramatic effect on the symptoms of schizophrenia than any
Chlorpromazine equivalents 300–600 mg/day orally
other therapeutic measure, there is a great deal more to
—If acute dystonia, administer iv anticholinergic
—If akathisia, reduce antipsychotic dose/prescribe concurrent
the treatment of the disorder than prescribing antipsychotic
oral benzodiazepine agents. There is abundant evidence that the course of
—If parkinsonism, reduce antipsychotic dose/prescribe schizophrenic illnesses and the resulting social handicaps can
concurrent oral anticholinergic be affected, for good or ill, by the patient’s social environment,
If intolerant of side-effects, change to ‘newer’ (atypical) drug and it has been known for 30 years that many of the most
obvious behavioural abnormalities of chronic schizophrenics,
Maintenance
such as posturing and talking to themselves, are not intrinsic
Oral/im antipsychotic 150–500 mg chlorpromazine equivalents per
or inevitable, but are to a considerable extent the product
day years
of a monotonous, unstimulating environment. This was well
Treatment resistance illustrated by Wing and Brown’s (1961) comparison of three
Change to clozapine mental hospitals in southern England. In their hospital C,
Comorbid depression patients had few if any personal possessions, little liberty,
Concurrent antidepressants spent much of the time unoccupied in the wards, and were
generally treated as ‘inmates’, whereas in hospital A they had

414
Schizophrenia and related disorders CHAPTER 15

their own clothes and other personal possessions, spent most prior to discharge, with the involvement of patients and all their
of the day actively employed, and generally lived as free and carers, so that each professional involved has a specific remit.
normal a life as possible. A third hospital, B, was intermediate. One of the key goals of CPA is to maintain service contact with
The incidence of social withdrawal (underactivity, lack of con- patients, which it certainly does, but at the price of prolonging
versation, neglect of hygiene and personal appearance) and hospital stays and increasing readmissions without any obvious
socially embarrassing behaviour (incontinence, mannerisms, gains in clinical outcome (Cochrane Library 2009). CPA was
purposeless overactivity, threats of violence, talking to self) politically enforced in England and Wales in the 1990s and
was higher in hospital C than it was in A (B was intermediate probably just put further pressure on already stretched services.
in all respects), despite the fact that these patients’ initial type ACT, on the other hand, involves identifying the most appro-
and severity of illness appeared to have been the same, and priate key worker to coordinate a therapeutic package, with
there were no important differences in the prescribing and specific treatments being provided by particular staff. ACT
discharge policies of the two hospitals. certainly maintains patient contact better than standard care,
Too much stimulation, or stimulation of the wrong kind, and probably also reduces readmissions and their duration,
can also be harmful. There is, for example, the evidence that and homelessness, while increasing employment and indepen-
schizophrenic illnesses may be precipitated by events in the dent living (Cochrane Library 2009). The vast majority of
previous few weeks, both pleasant and unpleasant, which dis- the trials were, however, conducted in the USA, and studies
rupt the subject’s normal lifestyle (Brown & Birley 1968). that found the most impressive results were conducted on the
There is also the evidence that returning to live with a critical first tranche of patients to be de-institutionalised – who pre-
or hostile relative after a schizophrenic illness increases the sumably had the best prognoses. These studies also usually have
relapse rate over the next 12 months (Brown et al 1972). ACT teams with relatively high staff:patient ratios, although it
The overall management of schizophrenia is therefore based appears that this is less important than the frequency and aims
on an attempt to avoid both extremes. To this end, attempts of the patient contact. Both of these models of service delivery
are made to get the patient into an occupation and a domestic are compatible with the community mental health teams
setting in which they have some real but limited responsibil- (CMHTs) commonly employed in the UK and elsewhere,
ities, in which they have a daily routine which is ordered and which in themselves do little more than improve patient and
predictable without being too monotonous, and in which carer satisfaction (Cochrane Library 2009). The obvious danger
they are protected from emotional demands they cannot meet. is that CMHTs attempting to provide ACT ‘on the cheap’ can
This is often easier said than done. end up providing something more akin to the CPA. On the
other hand, Ziguras et al (2002) systematically reviewed both
RCTs and non-randomised controlled trials and found positive
Service organisation effects of the CPA on many aspects of patient functioning,
For the last 40 years, partly because of the realisation that although the improvements were still better for ACT. It is a
mental hospitals themselves could have detrimental effects moot point as to whether the RCTs higher internal validity or
on their patients if their stay was prolonged, and partly for the controlled trials’ possibly greater external validity should
straightforward financial reasons, intensive efforts have been guide service planners. In fact, it appears that intensive case
made to discharge schizophrenics as soon as their psychotic management, including ACT, is best reserved for patients who
symptoms have resolved and to keep them ‘in the community’ need to use psychiatric services frequently in any case, and
as much as possible thereafter. To be successful, or for the in them it may reduce hospitalisation (Burns et al 2007a). How-
patient to be better off, such a policy requires the provision ever, no study has yet randomised or otherwise allocated treat-
of a range of hostels, day centres, ‘half-way houses’ and occu- ment providers (rather than patients) to different approaches,
pational placements in the community. Unfortunately, these in an attempt to control for the likely ‘therapeutic zeal’ in a
facilities have not yet materialised in anything like adequate new or experimental service that would be less likely to be
numbers. For this reason many psychiatrists (though not maintained in long-term routine clinical practice.
hospital managers) are increasingly questioning whether early
discharge is always in the patient’s interests, and whether
mental hospitals have not been too eager to discard their Rehabilitation
traditional ‘asylum’ role. A back bedroom can be just as Some patients have a home and a job to return to, or succeed
deprived and harmful an environment as a back ward, and a in obtaining accommodation and employment without the aid
park bench even more so. There is in fact some evidence that of any formal rehabilitative measures. Most are too badly
between 1981 and 1996, in a representative sample of patients handicapped by the effects of illness on their drive, initiative
in Nithsdale, Scotland (Kelly et al 1998), these ‘innovations’ and demeanour, by the social stigma of having been mentally
were associated with an overall worsening of outcome, although ill, and often too by their previous lack of education and
wider socioeconomic changes are an alternative explanation. marketable skills, to be capable of obtaining a job without
Various approaches to organising community services have assistance. In the past it was one of the primary functions of
been implemented and examined over that time. The principal rehabilitation programmes to help people who had schizophre-
two – case management or the care programme approach nia to obtain suitable paid employment. However, this has
(CPA), and assertive community treatment (ACT) – seem to become increasingly difficult, mainly because fundamental
have surprisingly different effects (at least as evaluated in industrial changes have resulted in a substantial reduction in
RCTs). CPA mainly involves planning community management the need for unskilled or semiskilled workers. As a result,

415
Companion to Psychiatric Studies

rehabilitation programmes have also been developed to help adapt to the change that has come over the patient and
patients with defect states or recurring psychotic episodes to remains angry, frightened and critical. There are various ways
cook and shop for themselves, to obtain temporary or unpaid of trying to deal with this potentially hazardous situation.
employment and to use their leisure time productively. It may be possible to arrange for the patient to move into alter-
It remains possible, however, to train some patients for full- native accommodation, but this is not always available, and
time paid employment, but it is clear that supported employ- even if it is it may be impossible to persuade either the patient
ment is superior to pre-vocational training (Crowther et al or the relative that this is preferable to returning home.
2001). Sheltered workshops and work skills training have at Indeed, it is often the mothers who are most critical of their
most temporary benefits and do not increase the likelihood schizophrenic son’s or daughter’s behaviour who are least will-
of gaining competitive employment. Supported employment ing to be parted from them. An alternative strategy in such
places patients directly into competitive jobs, with support circumstance is to mitigate the ill-effects of the relative’s emo-
from trained ‘job coaches’, and several American RCTs have tional involvement by reducing the time the two spend in one
shown that in about a third of trial participants it leads to paid another’s company. A full-time job is, of course, the best way
employment. There is clearly a need to develop and evaluate of doing this, but if this is impossible, regular attendance at
such programmes outside the USA. Social skills and cognitive a day hospital or day centre of some kind may achieve the
abilities tend to predict successful vocational rehabilitation, same end.
and adding these elements into these treatments may enhance A further preventive strategy is to try to alter the attitudes
their efficacy. In a recent very impressive trial, Burns et al and behaviour of the relatives, and various forms of family
(2007b) randomised 312 patients in six European centres to therapy have been developed to this end. Several small-scale
receive individual work placement and support (IPS) or but important clinical trials have now been reported. In the
vocational services. At 18 months’ follow-up IPS was more first, 24 schizophrenics who were all living in a ‘high expressed
effective for every vocational outcome, with 85 (55%) patients emotion’ environment, and therefore at high risk of relapse,
assigned to IPS working for at least 1 day compared to were randomly allocated either to routine outpatient care or
43 (28%) patients assigned to vocational services. Patients to receive a special package of social interventions consisting
assigned to vocational services were also significantly more of factual talks to their relatives about schizophrenia, fort-
likely to drop out of the service and to be readmitted to hos- nightly group meetings for the relatives designed to help them
pital. Local unemployment rates and the degree to which share experiences, and regular family therapy sessions in the
benefits produced perverse incentives against employment patient’s home designed to reduce expressed emotion and
accounted for a substantial amount of the heterogeneity in face-to-face contact (Leff et al 1982). All 24 patients received
IPS effectiveness. depot antipsychotics throughout. After 9 months the relapse
Some people with schizophrenia have become homeless by rate was 50% in the controls but only 9% in the treatment
the time they are first admitted to hospital; others become so group, and the only patients in the treatment group to relapse
after a series of further relapses and readmissions. Many of were the two in whom no reduction in expressed emotion
them are unable to cope in ordinary rented accommodation (EE) or face-to-face contact was achieved. This trial therefore
even if landlords can be persuaded to take them. Other types adds to the evidence that high expressed emotion can provoke
of accommodation geared to their needs have to be provided. relapse and that reduced face-to-face contact is protective.
In the past, hostels were often provided by psychiatric It does not, of course, reveal which elements of the treatment
hospitals themselves, either on the hospital site or elsewhere, package were most important.
and supervised to varying extents by nurses. Now hostels, There are now at least 25 trials of various family interven-
group homes, flats and bedsits reserved for former psychiatric tions (and several systematic reviews of them). Each has
patients tend to be provided by local authority social work included education about the illness, but usually combined
departments and voluntary organisations. The amount and with one or more approaches described as crisis manage-
quality of supervision provided is very variable, and not all ment, problem solving or family therapy. There is no doubt
of it is supportive of the proven elements of psychiatric man- that these all tend to reduce relapse rates, but the effect
agement, but the greater quantity and variety of protected appears less strong than it once did (Pitschel-Walz et al
housing available increases the likelihood that individual 2001; Patterson & Leeuwenkamp 2008; Cochrane Library
patients will eventually find a suitable niche. It is, however, 2009). The mode of action, however, remains unclear. There
deeply regrettable that the provision of suitable supported is no good evidence that any one therapeutic model is better
accommodation remains insufficient. than another, and thus education may be the key component.
Medication compliance may be improved, and the general sup-
port given may be reassuring, but the ability of a family to
Family treatments ‘cope’ with patients does not seem to be affected (Cochrane
Discharging patients from hospital when adequate community Library 2009). Reducing EE does not appear to be crucial;
facilities are not available may also place a heavy burden on indeed, provided the patient intervention is comprehensive,
relatives, a burden that service providers may do little to the family need not necessarily be involved (Pitschel-Walz
relieve. A particular difficulty sometimes arises when the et al 2001).
patient is living with a relative, usually a spouse or parent, These uncertainties, and the time-consuming nature of the
who is willing to have him back, but it becomes clear while treatment, may explain why this successful intervention is
the patient is in hospital that this relative cannot accept and rarely implemented in clinical practice. Family interventions

416
Schizophrenia and related disorders CHAPTER 15

can, however, be successfully delivered in a group setting, chlorpromazine but only minimal contacts with a social
which may provide an additional source of information and worker; a third group received placebo tablets and ‘major role
reassurance. What effectiveness studies there are suggest that therapy’; and a fourth group received placebo tablets and
relatives feel they benefit most from education and support. minimal social contacts. As expected, the relapse rate was
Nonetheless, these approaches are by definition of no value much lower in patients on maintenance chlorpromazine than
to the many patients who no longer have contact with their in those on placebo (48% versus 80%). Overall, ‘major role
families or do not wish them to be involved in their treatment. therapy’ had no effect on the relapse rate, but more detailed
analysis showed that in patients who might have been
expected to have a good prognosis the relapse rate was
Education reduced by this treatment, and in those who might have been
Information about the illness and its management can of expected to have a relatively poor prognosis the relapse rate
course be provided to patients themselves. The early trials of was increased. In other words, some patients benefited but
what has sometimes been called psycho-education (sic) tended others were harmed, and the two tended to cancel each other
to provide other interventions as well, such that the specific out. What the mechanism of harm is we can only speculate,
effects of education are difficult to determine. More recent but it is easy to imagine how an intensive relationship with
studies have focused on education, usually given didactically a keen social worker might create something akin to a ‘high
to groups of both patients and families. Even relatively brief expressed emotion’ situation. The moral is clear: emotional
programmes, of ten sessions or fewer, seem to reduce relapse pressures, including those from well-meaning psychothera-
rates over the subsequent 9–18 months, with an effect compa- peutic interventions, may be positively harmful to those who
rable to that of lengthier treatment and that of family inter- have recently had a schizophrenic illness, and so should only
ventions (Cochrane Library 2009). Education also appears to be offered if it is quite clear that the patient is capable of
improve global functioning and, perhaps surprisingly, to reduce responding. Emotional withdrawal may be a valuable self-
relatives’ expressed emotion, but these results are derived protective strategy as well as a symptom.
from two or three small studies. Medication compliance may
also be improved, but behavioural techniques appear to be
more successful in this regard (see below). Behavioural and cognitive interventions
The clinical ‘bottom line’ is that a relatively brief series of As trials of the efficacy of psychotherapy have demonstrated
educational sessions may be as good as any psychosocial inter- in other settings, behavioural and cognitive approaches to psy-
vention in terms of reducing relapse rates. Patients and their chosis tend to be more valuable in general. Probably the first
families may, however, wish for a more flexible system that technique to be used and evaluated was the token economy,
they can use at times of particular difficulty. Regardless, it in which a desired behavioural change was fostered by giving
should be borne in mind that education could potentially have tokens as rewards for designated desirable behaviours. The
undesirable effects, perhaps particularly in newly diagnosed tokens could be exchanged for cigarettes, food etc. Token
patients hearing about the likelihood of poor outcomes, just economy programmes were widespread in the 1970s but
as family interventions can actually increase EE in low EE became restricted to long-stay wards, where socially appropri-
families. ate behaviours were rewarded in long-stay patients who were
preparing to be transferred to the community. They were
regarded as effective in reducing some psychotic behaviours,
Psychotherapy and improving personal care and work capabilities in hospital,
Some of the benefits of these interventions may be attribut- but early controlled trials did not adequately control for medi-
able to ‘supportive psychotherapy’, but it is clear that anything cation effects and lacked community follow-up data. Despite
resembling psychoanalysis is at best worthless and at worst this, it is not clear why the treatment fell out of favour, partic-
positively harmful in schizophrenia – a lesson that should be ularly as a small number of RCTs do suggest the token
borne in mind by early-intervention enthusiasts. The results economy may be one of the few effective treatments of
of May’s (1968) trial in California indicated quite unequivo- negative symptoms (Cochrane Library 2009).
cally that psychodynamic psychotherapy was valueless in the As enthusiasm for psychotherapy and the token economy as
active phase of the illness. The only detectable effects, treatments for schizophrenia waned, interest developed in
whether psychotherapy was given alone or in combination with social skills training. This involves various combinations of
a phenothiazine, were on the duration and cost of hospital instruction, modelling, rehearsal, feedback and homework,
treatment, both of which were substantially increased. usually with the main aim of improving communication skills
The effect of psychoanalytically oriented social casework on to enhance access to resources and reduce stresses. Early con-
patients recovering from an episode of their illness were trolled studies suggested benefits in reducing relapse rates, but
explored in a large American trial (Goldberg et al 1977) in often included other therapeutic elements. Recent systematic
which 400 newly discharged schizophrenics were randomly reviews and meta-analyses suggest benefits on symptoms,
allocated to one of four groups and followed for 2 years. The functionality and possibly even substance abuse at 1–2 years
first group received maintenance chlorpromazine plus what (Pilling et al 2002; Patterson & Leeuwenkamp 2008).
the authors called ‘major role therapy’ (a combination of inten- Other active therapies, in particular cognitive behavioural
sive psychoanalytically oriented social casework and voca- therapy (CBT), may offer greater benefits with less input.
tional rehabilitation); a second group received maintenance CBT involves challenging key beliefs, problem solving and

417
Companion to Psychiatric Studies

coping enhancement, and has been enthusiastically advocated controlled versus randomised trials (Cochrane Library 2009).
for patients with schizophrenia for more than a decade. Early It is also far from clear that improving compliance or reducing
RCTs suggested that relapse rates were reduced, but suffered abuse necessarily leads to improved outcomes. Clearly, much
from the perennial problems of not controlling for therapist more work is required on these neglected aspects of clinical
time, non-blinded outcome raters and not being able to iden- research.
tify which elements of the treatment were effective (see Cognitive remediation is a relatively new and developing
Cochrane Library 2009). Two more recent studies merit par- treatment for the increasingly recognised cognitive deficits in
ticular mention. Sensky et al (2000) randomised 90 patients, patients with schizophrenia. Typically, patients receive guided
who had responded to chlorpromazine at most only partially, practice on tests of attention, memory and/or higher functions
to an equal amount of manualised CBT or ‘empathic, non- such as planning. A number of controlled studies suggest – not
directive’ befriending. Blinded raters assessed the severity surprisingly, given patients’ preserved ability to learn – that
of positive and negative symptoms at baseline, at treatment performance improves with practice. However, these studies
termination and after 9 months’ follow-up. Both treatments and systematic reviews of the few available RCTs (Pilling
appeared effective on both measures at the end of treat- et al 2002; Cochrane Library 2009) suggest that this does
ment, but the group treated with CBT showed further not generalise to other tasks. Future studies might more prof-
improvements at follow-up, whereas the befriended group lost itably address the value of compensatory strategies such as
some of their earlier gains. This well-conducted trial demon- simple diary keeping and other memory aids.
strates that CBT may be effective for treatment resistance
and negative symptoms, but used experienced therapists to Evidence-based principles of psychosocial
provide lengthy and intensive treatment. It is not likely that management
this could be made available for anything more than a fraction
of the patients with schizophrenia in most health services. In summary, the best available evidence suggests that the man-
Turkington et al (2002) therefore conducted a pragmatic trial agement of schizophrenia after discharge from hospital is best
of brief CBT given by newly trained psychiatric nurses to a accomplished through assertive community treatment (ACT)
representative sample of patients in secondary care. The inter- in general and using additional therapies as indicated (see
vention led to a greater improvement in overall symptoms, Box 15.8). Illness education and family treatments appear to
insight and depression, and fewer treatment dropouts than be more or less equally effective at reducing relapse rates,
standard care. It remains to be seen whether this would hold and can be initiated during periods of inpatient care. Education
true in treatment-resistant patients, who may require more provided routinely to patients, and to their carers when
skilled treatment. There is also a concerning trend for more requested, may be the most cost-effective general approach.
recent, better-controlled studies – with, in particular, blinded Given financial constraints, CBT may be best reserved for
outcome raters – to find less substantial effects of CBT treatment-resistant patients who can use it. If patients have
(Wykes et al 2008). CBT may yet prove to be the single most a realistic wish to obtain paid employment, supported employ-
useful psychosocial intervention for schizophrenia, perhaps ment schemes are clearly preferable to pre-vocational training.
particularly for residual psychotic symptoms, but further eval- Dynamic psychotherapies appear to have no demonstrable
uation of its essential components and practicality is required place in the management of schizophrenia, although some
before it should be advocated for routine use. patients still want them and some practitioners (generally in
CBT techniques have also been adapted and integrated with the private sector) are prepared to provide them.
motivational interviewing principles for patients with poor
medication compliance or substance abuse comorbidity. These
are both very common clinical problems that worsen overall Box 15.8
outcome. Psychiatrists tend to underestimate their prevalence,
which may be as high as 50%, and have almost no treatments Evidence-based principles of psychosocial
of proven efficacy to deal with them. There are suggestions
interventions for schizophrenia
from systematic reviews that ACT, family interventions and
1. ACT is preferable to CPA
education may increase the amount of medication patients
2. Supported employment is better than pre-vocational training
say they take (Cochrane Library 2009). This is, however, an
3. Education may be as effective as other PSI for reducing relapse
obviously unreliable outcome measure (albeit perhaps the
rates
most practical one), and as a rule complex interventions, 4. Psychodynamic psychotherapy is of no general value
including involving patients in decisions, and addressing bar- 5. Token economy may reduce negative symptoms (in restricted
riers to adherence, reminders and rewards, are more effective ward settings)
than education alone in general medical patients (Cochrane 6. Social skills training improves functioning at 1–2 years
Library 2009). A few preliminary trials suggest that this holds 7. CBT may reduce positive symptoms and may be effective in
true in schizophrenia; certainly, focused treatments such as treatment resistance
compliance therapy have not lived up to their early promise. 8. Cognitive remediation by guided task practice does not appear
Similarly, integrated mental health and substance abuse to generalise
therapeutic programmes – or what might be called ‘comorbid ACT, assertive community treatment; CBT, cognitive behavioural therapy; CPA, care
substance abuse therapy’ – may reduce substance abuse, programme approach; PSI, psychosocial interventions
although there is a notable discrepancy between open and

418
Schizophrenia and related disorders CHAPTER 15

As the number and quality of RCTs evaluating these or placebo. Although the treatment reduced relapse rates at
interventions increases, it is more difficult to sustain the view 2 years, the most important determinant was whether or not
that their benefits are simply attributable to enhanced medi- patients had had a year or more of untreated psychosis prior
cation compliance and non-specific support (Patterson & to admission – but this did not hold if the DUP was set at
Leeuwenkamp 2008). More importantly, we need to know 3 months or 6 months. Very few of the subsequent studies sug-
whether, for example, optimised antipsychotic regimens and gesting the importance of DUP have been conducted in the
psychosocial therapies are complementary, and whether cloza- context of a trial, and the association of a long DUP with a
pine and CBT have additive effects in resistant patients or on poor outcome may simply reflect confounding due to the
negative symptoms, etc. A particularly comprehensive system- well-recognised tendency for illnesses with a gradual rather
atic review and meta-analysis has suggested that generic drug than an acute onset to be more severe.
and non-drug treatments do indeed have additive effects, par- True prevention remains the ultimate goal. The literature
ticularly in chronic patients (Mojtabai et al 1998). The meth- thus far, however, is enthusiastic and descriptive rather than
ods and results of that review can be criticised on several experimental, with very few exceptions. Building upon their
grounds – as it was based on controlled trials, found no specific innovative service for young adults presenting with psychotic
effects of different treatments, and there was some evidence symptoms in Melbourne, Australia, McGorry et al (2002)
of publication bias – but clinicians and patients are probably randomised 59 patients to ‘needs-based’ supportive psy-
right to want to use both approaches. Whatever else, we must chotherapy and case management with or without low-dose
now pay far more attention to the views and wishes of patients risperidone and CBT for 6 months. At the end of treatment,
and their families than in the past, and they clearly want and three (10%) of those receiving risperidone and CBT had
appreciate time being spent with them. That time should be developed psychosis, compared to 10 (33%) who did not.
used to provide treatments in line with the best available evi- However, a further three people in the experimental treat-
dence. Indeed, the careful implementation and evaluation of ment arm went on to develop psychosis in the following
this is likely to be the best way of refining the delivery of 6 months, rendering the difference non-significant. Whether
the most effective therapies in an integrated clinical service. this represents incidence reduction or delayed onset remains
to be seen and requires replication. It has to be said, however,
that the conversion rate to psychosis in Australia is substan-
Prevention tially higher than preliminary results suggest elsewhere (e.g.
Klosterkotter et al 2001). Why this may be is uncertain, but
We have already discussed some aspects of secondary and it is important that we do not let our enthusiasm for preven-
tertiary prevention, as well as ‘early intervention’. In one of tion of this most disabling disorder to lead us to instigate
the first studies of ‘relapse prevention’ Jolley et al (1990) incompletely evaluated new treatments. This is equally true
attempted to maintain schizophrenic outpatients in stable of exciting new approaches such as glutamate receptor agonists
remission off all medication, but to ensure that they received for both positive and negative symptoms (Patil et al 2007),
oral haloperidol at the first signs of relapse by warning both pharmacogenomic prediction of antipsychotic drug response
patients and their relatives what those signs were likely to and adverse effects (Arranz & Leon 2007), and a variety of
be, and providing both monthly follow-up appointments and approaches to improving the physical and general health of
a 24-hour telephone contact. Unfortunately, the experiment patients. Patients with schizophrenia have all too often been
failed, partly because only 50% of the relapses were preceded let down in the past by over-enthusiastic advocates of experi-
by any prodromal symptoms at all; and, although the drug-free mental interventions. After all, in any financially constrained
patients had fewer extrapyramidal symptoms than did con- service, every resource consumed by exciting innovations is
trols, this was not accompanied by any improvement in social one that could have been spent on interventions with a more
functioning. Subsequent studies have rarely taken such an rigorous evidence base.
ambitious approach, usually comparing the effects of various
doses or frequencies of medication with or without psychoso-
cial approaches. It does appear to be possible to reduce relapse Related disorders
rates on low-dose or intermittent medication with sufficiently
frequent relapse education and monitoring, perhaps particu- Disorders ‘related’ to schizophrenia include a variety of condi-
larly in first-episode rather than chronic patients, but much tions, described by a wide range of terms, that share some of
more evaluation of such interventions is required. the features of schizophrenia, but not all. In general they tend
Given the obvious limitations of currently available treat- to be characterised by psychotic symptoms but do not have
ments for schizophrenia, primary prevention or early inter- the chronicity, the lack of a mood-related component, or
vention in the first episode are extremely desirable goals. perhaps the poor prognosis. As noted above, the range of
This has been reinforced by several recent studies suggesting disorders given the diagnosis of schizophrenia has at times
that the duration of untreated psychosis (DUP) prior to initi- been very wide, and whether or not a psychotic episode will
ating treatment is associated with a variety of markers of a fulfil criteria for schizophrenia depends very much on the
poor outcome (see above). Ironically, however, the first dem- operational definition used. Definitions such as that in
onstration of such an effect does not stand up to close exami- DSM-IV(-TR), in which a 6-month duration is obligatory,
nation. Johnstone et al (1986) randomised 120 first-episode exclude many first-episode cases, and cases with a duration
patients, about to be discharged, to maintenance antipsychotics of at least 1 month and less than 6 months would be classed

419
Companion to Psychiatric Studies

as ‘schizophreniform’ disorder (APA 1994). This is the most


obviously arbitrary and probably invalid byproduct of opera- Table 15.8 Subtypes of delusional disorder
tional definitions in this area (and not to be confused with Subtype Related terms Relative
the term ‘schizophrenia-like’ disorder in ICD-10 (WHO frequency*
1992) to refer to conditions with features of schizophrenia
but which are due to brain damage and dysfunction or to sys- Persecutory Self-referential 39/71
temic physical disease). The other schizophrenia-related disor- Litigious (querulous paranoia)
ders in these classifications which are discussed below have a Grandiose 2/71
much longer pedigree and stronger evidence of distinctive
characteristics. Hypochondrial Monosymptomatic 4/71
(somatic) hypochondriacal psychosis
Delusional dysmorphophobia
Persistent delusional disorder Jealous Morbid jealousy 16/71
Othello ‘syndrome’
Persistent delusional disorder (PDD) is characterised by one
Delusional jealousy
or more non-bizarre delusions or a delusional system. Formerly
known as ‘paranoia’ or ‘paranoid psychosis’, Kahlbaum and Erotomanic De Clerambault’s ‘syndrome’ 2/71
Kraepelin distinguished it from schizophrenia, as do contem-
*From Opjordsmoen (1988)
porary classifications, although Bleuler and Schneider appear
to have viewed them as subtypes of schizophrenia with a good
prognosis. Both ICD-10 (WHO 1992) and DSM-IV(-TR)
(APA 1994) stress the importance of excluding subcultural
Patients with these disorders typically present to physicians,
beliefs and features of schizophrenia, depression or organic
requesting cosmetic surgery or treatment which is rarely bene-
brain disease. However, the duration criterion for ICD-10 is
ficial. Munro’s patients were in a wide age range, but Trabert
3 months, whereas that for DSM-IV(-TR) is only 1 month,
(1995), in a review of 1223 case reports of delusional infesta-
and ICD-10 recommends that delusions of less than 3 months’
tion, described a generally older age of onset. Rather confus-
duration should be coded as an ‘acute and transient psychotic
ingly, monosymptomatic hypochondriacal psychosis of the
disorder’ (see below). Paraphrenia is included as a persistent
dysmorphic type is sometimes referred to as delusional dys-
delusional disorder in ICD-10, but as schizophrenia in DSM-
morphophobia, whereas non-delusional dysmorphophobia or
IV(-TR) (in which patients over the age of 40 are regarded
body dysmorphic disorder is essentially a variant of hypochon-
as having paraphrenia and those over 60 as having late para-
driasis. The borderline between overvalued ideas and delusions
phrenia). However, most patients in these age groups who
in these areas is unclear, and both conditions may respond to
have delusions usually also have hallucinations and hence a
antidepressants in any case (Phillips et al 2002).
diagnosis of schizophrenia.
It is likely that dysmorphic ideas are on a continuum with
dysmorphic delusions, as is increasingly recognised for most
Subtypes psychotic phenomena. These difficulties are worsened when
Five subtypes of delusional disorder are described in DSM-IV psychiatrists loosely use terminology such as ‘Othello syn-
(-TR), according to the predominant delusional theme drome’ and de Clerambault’s syndrome (see Table 15.8) when
(Table 15.8). ICD-10 also includes the categories of self- they are actually referring to abnormal ideas of specific con-
referential and litigious, which are incorporated into the perse- tent. It should not be forgotten that most such ideas when
cutory subtype in DSM-IV(-TR). The latter is the classic and seen in clinical practice do indeed present as part of a
probably the most common form of PDD. It, and the jealous syndrome – but that syndrome is schizophrenia, depression,
variant, are often said to be most likely to be associated with or indeed an organic disorder. The same is equally true of
dangerous behaviour. This is, however, a recognised risk of the ‘delusional misidentification syndromes’ such as Capgras
other types if patients become angry or frustrated with the and Fregole.
attention or lack of it that they are receiving.
The hypochondriacal or somatic subtype merits particular Epidemiology and aetiology
consideration, both because of the number and variety of syno-
Until recently there were no population surveys of the preva-
nyms and because it has been said in the past (probably incor-
lence of delusional disorder. The best available evidence was
rectly) to respond specifically to pimozide (Munro 1988).
therefore from reviews of hospital admission data (Kendler
Munro popularised the term monosymptomatic hypochondria-
1982) or large case series (Opjordsmoen 1988). The preva-
cal psychosis, and in a case series of 50 patients described
lence of DSM-IV PDD in the general population has now been
three main types of delusion:
reliably estimated to be about 0.18% – about six times higher
• olfactory (in which the patient complained of extreme than hospital data would suggest – with a possible female
halitosis or body odour); excess (Perala et al 2007). Delusional jealousy (where it is in
• infestation (insect, worms or foreign bodies under the fact the idea of infidelity that is delusional) is probably more
skin); common in men and erotomania in women. The age at onset
• dysmorphic delusions (of ugliness or misshapenness). is typically later than in schizophrenia, and delusional jealousy

420
Schizophrenia and related disorders CHAPTER 15

tends to present at an older age than other subtypes. Hypo- effective. Antidepressants, particularly those with seroto-
chondriacal delusions can, however, occur in young people, ninergic effects, appear to be effective in treating obsessive
and may represent the prodrome to schizophrenia in up to and depressive symptomatology – and indeed the delusions
20% of cases. The course is quite variable – outcome is generally (Phillips et al 2002).
better than in schizophrenia (Opjordsmoen 1988) – but it is
often chronic, especially in the persecutory type (APA 1994).
The aetiology and pathophysiology of delusional disorder Acute and transient psychotic disorders
remain obscure, not least because of the difficulty of assem- (ATPD)/brief psychotic disorder (BPD)
bling a large enough cohort for meaningful studies. There is
no clear evidence that it is genetically inherited, and most If persistent delusional disorder is a ragbag of historical ‘syn-
studies suggest that the prevalence of schizophrenia is not dromes’, then acute and transient psychotic disorders are more
raised in the relatives of people with delusional disorder. so. Several early European psychiatrists described syndromes
There may, however, be a tendency for ‘feelings of inferiority’, with symptoms like those in schizophrenia but with an acute
paranoid personality traits and delusional disorder itself to run onset and usually a favourable outcome – including Legrain’s
in families (Kendler et al 1985). Although a number of organic bouffée délirante, Wimmer’s reactive psychosis, Leonard’s
brain conditions can lead to secondary delusions, there is no cycloid psychoses, etc. Many of these survived into ICD-9,
clear pattern in their lesions or location. Immigrants may be as did ‘hysterical psychosis’. ICD-10 has improved matters
at elevated risk. Hearing loss is, however, clearly associated slightly by subdividing the diagnostic categories into acute
with an increased risk of paranoid psychosis in the elderly polymorphic (i.e. changeable) psychotic disorder with or with-
(Cooper et al 1974). out symptoms of schizophrenia, and an acute schizophrenia-
The associations with immigrant status and hearing loss hint like psychotic disorder. The DSM-IV(-TR) criteria for ‘brief
at the relevance of psychosocial factors. A lack of sensory psychotic disorder’ are much clearer – albeit not necessarily
information and/or an unfamiliar environment may precipitate any more valid – in essentially defining it as schizophrenia
psychosis in those predisposed through personal cognitive of less than 1 month’s duration and with a full return to pre-
biases, leading to the formation of persecutory delusions. morbid functioning. ICD-10 demands an acute onset and a
These mechanisms are, of course, likely to be the same as in duration of less than 3 months, but makes no outcome restric-
the formation of delusions in schizophrenia (see psychological tions. Pillmann et al (2002) examined 1036 patients admitted
theories above), but there is in addition some specific evidence to a German hospital over a 5-year period with psychosis
that patients with delusional disorder may have a tendency to and found that 4% met the criteria for ATPD, of whom
make external attributions for negative events, a particular sen- 62% fulfilled criteria for BPD, the remainder mainly having
sitivity to threatening stimuli, a tendency to ‘jump to conclu- schizophreniform disorder.
sions’, and to be more likely to remember negative feelings The essential clinical features are perplexity, confusion,
than specific events (Kaney et al 1999). rapid shifts in intense affect, and disorganised behaviour.
Epidemiological information is extremely limited, but there
appears to be an association with pre-existing personality dis-
Management order, female gender and a relatively young age of onset
Paranoid delusions have little diagnostic value, and the diag- (APA 1994). There may also be strong cultural influences on
nosis of a delusional disorder requires organic, schizophrenic, presentation and duration. It has been suggested that ATPDs
affective and sometimes neurotic features to be excluded. may be particularly common in African Caribbeans living in
In the latter situation, as in paranoid personality disorder, the London – which may partly explain the increased rates of psy-
beliefs are not of delusional intensity nor held with absolute chosis and use of the Mental Health Act to detain them in hos-
conviction, i.e. patients may acknowledge alternative interpre- pital. In the Northwick Park functional psychosis study,
tations of their complaints. In induced delusional disorder researchers followed up patients with illnesses that did not
(‘folie à deux’) the symptoms are usually paranoid or grandiose fulfil the operational criteria for schizophrenia after 2 years
and arise within the confines of a close relationship in two (or and compared them with those who did. ‘Partial’ illnesses,
more) people who are otherwise socially isolated (Silveira & where delusions were not held with full conviction, had a
Seeman 1995), the treatment being separation or perhaps psy- similar prognosis to that of schizophrenia; whereas ‘transient’
chotherapy for the recipient and treatment of the underlying psychoses (with short-lived symptoms) had good symptom
condition in the dominant partner. and social outcomes, although they tended to recur (Johnstone
Separation of the patient from the focus of the delusions, et al 1996). Others, however, have reported diagnostic stabil-
where possible, and supportive psychotherapy are the princi- ity in most cases (Pillmann et al 2002) or only in women
ples of psychosocial management. It is often quite difficult to (Singh et al 2004).
establish a therapeutic relationship – these people do not usu- The differential diagnosis includes delirium and substance
ally view themselves as ill, often continue to function relatively intoxication, as well as factitious disorder and malingering.
well, and may wish to see a different type of doctor, if any. There is also some phenomenological overlap with the ‘Ganser
Suicidal and homicidal thoughts may be particularly likely in syndrome’. Management is as for an acute schizophrenic
delusional disorder and must be taken seriously. episode, although particular care may need to be taken to
Antipsychotic drugs are the mainstay of treatment. There ensure adequate hydration and nutrition, and there may be a
are no trial data to back up claims that pimozide is particularly particularly high risk of suicide.

421
Companion to Psychiatric Studies

Schizoaffective disorder mood stabilisers. However, a relatively recent systematic


review of controlled treatment studies of schizoaffective disor-
Following Kraepelin’s separation of dementia praecox and der suggests that antipsychotics alone may be just as effective,
manic–depressive disorder, it was soon recognised that a con- or even more so, for schizoaffective disorder currently
siderable proportion of patients with functional psychotic ill- depressed, with little evidence that lithium or anticonvulsants
nesses did not fit neatly into either category, having features were better than antipsychotics alone in the manic subtype
typical of both. The term schizoaffective psychosis was intro- (Levinson et al 1999). The evidence, such as it is, suggests a
duced by Kasanin (1933) and is still to be found in ICD-10 clear difference in the therapeutic responses of schizoaffective
and DSM-IV(-TR). Both classification systems stress that disorder and post-psychotic depression, and demonstrates the
there must be a period of 2 weeks with at least one typical importance of distinguishing between them.
symptom of schizophrenia and of affective disorder to be able
to make the diagnosis, but DSM-IV(-TR) demands that full
criteria for the two disorders be met. Both have manic/bipolar Concluding remarks
and depressive subtypes, and ICD-10 has an additional mixed
type subcategory. It is likely that these criteria have improved It is clear that there are several disorders related to schizo-
the reliability of the diagnosis and possibly even increased the phrenia that share some but not all features. Whether or not
notoriously low levels of agreement between various defini- they are sufficiently different to merit the distinction is a
tions of schizoaffective psychosis (Brockington & Leff 1979), matter of debate. Ideally, however, future studies need to
but it is difficult to know because the condition is so infre- examine the full range of these diagnoses to accurately define
quently studied. When it is, it is usually as an indistinguishable their similarities and differences. In particular, if we exclude
subgroup of people with schizophrenia. milder variants, a poor prognosis in schizophrenia becomes
Psychiatrists are still reluctant to make the diagnosis clini- a self-fulfilling tautology and aetiological research runs the
cally, as it smacks of ‘fence-sitting’, which may account for risk of telling us more about the influences on the severity of
the impression that the disorder is relatively rare. What evi- psychosis rather than schizophrenia per se. It is nonetheless
dence there is suggests that it is uncommon (Johnstone et al the case that the use of diagnostic criteria has facilitated an
1992), but this may be an artefact of psychiatric classification. exponential rise in our understanding of these disorders,
This is an important point, as rarity (or indeed distinctive sub- and indeed an increase in the array of effective treatments
types of psychosis more generally) would argue against the we have at our disposal. If one compares what we have learned
view that there may be a ‘continuum of psychosis’ and for in the past 100 years, 50 years, 25 years and even the last
the kraepelinian distinction between the functional psychoses. 10 years, increasing progress is clearly being made. It is there-
The family studies that have been conducted suggest that fore entirely reasonable to suggest that some important genes
there is an increased risk of both schizophrenia and mood dis- and pathophysiological mechanisms will be identified, newer
orders in the relatives of patients with schizoaffective disorder, and more effective treatments will be developed, and out-
and that the outcome is typically somewhere between that of comes over the next 10–20 years generally improved. The
affective disorder and schizophrenia. Management, similarly, ultimate goals of an aetiological classification, valid diagnostic
usually consists of treating psychotic symptoms with antipsy- tests and prevention are further off, but perhaps not too
chotics and mood disturbance with antidepressants and/or far behind.

References
Agid, O., Kapur, S., Arenovich, T., Zipursky, R.B., Andreasson, S., Allebeck, P., Engstrom, A., Baruch, I., Hemsley, D.R., Gray, J.A., 1988.
2003. Delayed-onset hypothesis of Rydberg, U., 1987. Cannabis and Differential performance of acute and
antipsychotic action: a hypothesis tested and schizophrenia: a longitudinal study of chronic schizophrenics in a latent inhibition
rejected. Arch. Gen. Psychiatry 60, 1228–1235. Swedish conscripts. Lancet ii, 1483–1486. task. J. Nerv. Ment. Dis. 176, 598–606.
Aleman, A., Kahn, R.S., Selten, J.P., 2003. Sex APA, 1994. Diagnostic and statistical manual of Blackwood, N.J., Howard, R.J., Bentall, R.P.,
differences in the risk of schizophrenia: mental disorders, fourth ed. American Murray, R.M., 2001. Cognitive
evidence from meta-analysis. Arch. Gen. Psychiatric Association, Washington, DC. neuropsychiatric models of persecutory
Psychiatry 60, 565–571. Arranz, M.J., de Leon, J., 2007. delusions. Am. J. Psychiatry 158, 527–539.
Allison, D.B., Mentore, J.L., Heo, M., et al., Pharmacogenetics and pharmacogenomics of Bleuler, E., 1911. Dementia praecox, or the
1999. Antipsychotic-induced weight gain: schizophrenia: a review of last decade of group of schizophrenias (J. Zinkin, Trans.
a comprehensive research synthesis. Am. J. research. Mol. Psychiatry 12, 707–747. 1950). International University, New York.
Psychiatry 156, 1686–1696. Baldessarini, R.J., Cohen, B.M., Teicher, M.H., Bollini, P., Pampallona, S., Orza, M.J., et al.,
Andreasen, N.C., 1979a. Thought, language, and 1988. Significance of neuroleptic dose and 1994. Antipsychotic drugs: is more worse?
communication disorders, I: Clinical plasma level in the pharmacological A meta-analysis of the published randomized
assessment, definition of terms, and treatment of psychoses. Arch. Gen. controlled trials. Psychol. Med. 24, 307–316.
evaluation of their reliability. Arch. Gen. Psychiatry 45, 79–91. Boydell, J., van Os, J., McKenzie, K., et al., 2001.
Psychiatry 36, 1315–1321. Barbui, C., Saraceno, B., Liberati, A., Incidence of schizophrenia in ethnic
Andreasen, N.C., 1979b. Thought, language, and Garattini, S., 1996. Low-dose neuroleptic minorities in London: ecological study into
communication disorders, II: Diagnostic therapy and relapse in schizophrenia: meta- interactions with environment. Br. Med. J.
significance. Arch. Gen. Psychiatry analysis of randomized controlled trials. Eur. 323, 1336–1338.
36, 1325–1330. Psychiatry 11, 306–313.

422
Schizophrenia and related disorders CHAPTER 15

Bradbury, T.N., Miller, G.A., 1985. Season of Cooper, A.F., Curry, A.R., Kay, D.W.K., et al., Goldberg, S.C., Schooler, N.R., Hogarty, G.E.,
birth in schizophrenia: a review of evidence, 1974. Hearing loss in paranoid and affective Roper, M., 1977. Prediction of relapse in
methodology, and etiology. Psychol. Bull psychoses of the elderly. Lancet ii, 851–857. schizophrenic outpatients treated by drug and
98, 569–594. Craddock, N., O’Donovan, M.C., Owen, M.J., sociotherapy. Arch. Gen. Psychiatry
Brockington, I.F., Leff, J.P., 1979. 2007. Phenotypic and genetic complexity of 34, 171–184.
Schizoaffective psychosis: definitions and psychosis: Invited commentary on Gründer, G., Hippius, H., Carlsson, A., 2009.
incidence. Psychol. Med. 9, 91–99. Schizophrenia: a common disease caused by The ‘atypicality’ of antipsychotics: a concept
Brockington, I.F., Wainwright, S., Kendell, R.E., multiple rare alleles. Br. J. Psychiatry re-examined and re-defined. Nat. Rev. Drug
1980. Manic patients with schizophrenic or 190, 200–203. Discov. 8, 197–202.
paranoid symptoms. Psychol. Med. Crow, T.J., 1980. Molecular pathology of Häfner, H., Recher, A., Maurer, K., et al., 1989.
10, 73–83. schizophrenia: more than one disease How does gender influence age at first
Brown, G.W., Birley, J.L., 1968. Crises and life process? Br. Med. J. 280, 66–68. hospitalization for schizophrenia? A
changes and the onset of schizophrenia. Crow, T.J., Stevens, M., 1978. Age transnational case register study. Psychol.
J. Health Soc. Behav. 9, 203–214. disorientation in chronic schizophrenia: the Med. 19, 903–918.
Brown, G.W., Birley, J.L., Wing, J.K., 1972. nature of the cognitive deficit. Br. J. Halligan, P.W., David, A.S., 2001. Cognitive
Influence of family life on the course of Psychiatry 133, 137–142. neuropsychiatry: towards a scientific
schizophrenic disorders: a replication. Br. J. Crowther, R.E., Marshall, M., Bond, G.R., psychopathology. Nat. Rev. Neurosci.
Psychiatry 121, 241–258. Huxley, P., 2001. Helping people with severe 2, 209–215.
Burns, T., Catty, J., Dash, M., Roberts, C., mental illness to obtain work: systematic Harrison, P.J., 1999. The neuropathology of
Lockwood, A., Marshall, M., 2007a. Use of review. Br. Med. J. 322, 204–208. schizophrenia: a critical review of the data
intensive case management to reduce time in Cutting, J., 1985. The psychology of and their interpretation. Brain 122, 593–624.
hospital in people with severe mental illness: schizophrenia. Churchill Livingstone, Hawk, A.B., Carpenter Jr., W.T., Strauss, J.S.,
systematic review and meta-regression. Edinburgh. 1975. Diagnostic criteria and five-year
Br. Med. J. 335, 336–340. Davis, J.M., 1976. Recent developments in the outcome in schizophrenia: a report from the
Burns, T., Catty, J., Becker, T., et al., 2007b. drug treatment of schizophrenia. Am. J. International Pilot Study of schizophrenia.
The effectiveness of supported employment Psychiatry 133, 208–214. Arch. Gen. Psychiatry 32, 343–347.
for people with severe mental illness: a Davison, K., Bagley, C.R., 1969. Schizophrenia- Hegarty, J.D., Baldessarini, R.J., Tohen, M.,
randomised controlled trial. Lancet like psychoses associated with organic et al., 1994. One hundred years of
370, 1146–1152. disorders of the central nervous system: a schizophrenia: a meta-analysis of the
Butzlaff, R.L., Hooley, J.M., 1998. Expressed review of the literature. In: Harrington, R.N. outcome literature. Am. J. Psychiatry
emotion and psychiatric relapse: a meta- (Ed.), Current problems in neuropsychiatry. 151, 1409–1416.
analysis. Arch. Gen. Psychiatry 55, 547–552. Headley Brothers, Kent. Heinrichs, R.W., Zakzanis, K.K., 1998.
Cannon, M., Jones, P., 1996. Schizophrenia. Done, D.J., Crow, T.J., Johnstone, E.C., Neurocognitive deficit in schizophrenia: a
J. Neurol. Neurosurg. Psychiatry Sacker, A., 1994. Childhood antecedents of quantitative review of the evidence.
61, 604–613. schizophrenia and affective illness: social Neuropsychology 12, 426–445.
Cannon, M., Jones, P.B., Murray, R.M., 2002. adjustment at ages 7 and 11. Br. Med. J. Hirsch, S.R., Gaind, R., Rohde, P.D., et al.,
Obstetric complications and schizophrenia: 309, 699–703. 1973. Outpatient maintenance of chronic
Historical and meta-analytic review. Am. J. Faris, R., Dunham, W., 1939 (reprinted 1960). schizophrenic patients with long-acting
Psychiatry 159, 1080–1092. Mental disorders in urban areas. Hafner, fluphenazine: double-blind placebo trial.
Cannon, T.D., Cadenhead, K., Cornblatt, B., New York. Report to the Medical Research Council
et al., 2008. Prediction of psychosis in youth Farran-Ridge, C., 1926. Dementia praecox and Committee on Clinical Trials in Psychiatry.
at high clinical risk: a multisite longitudinal epidemic encephalitis. J. Ment. Sci. Br. Med. J. 1, 633–637.
study in North America. Arch. Gen. 72, 513–523. Hoch, P., Polatin, P., 1949. Pseudoneurotic
Psychiatry 65, 28–37. Fletcher, P.C., Frith, C.D., 2009. Perceiving is forms of schizophrenia. Psychiatr. Q.
Cantor-Graae, E., Selten, J.P., 2005. believing: a Bayesian approach to explaining 23, 248–256.
Schizophrenia and migration: a meta-analysis the positive symptoms of schizophrenia. Hogarty, G.E., Goldberg, S.C., Schooler, N.R.,
and review. Am. J. Psychiatry 162, 12–24. Nat. Rev. Neurosci. 10, 48–58. Ulrich, R.F., 1974. Drug and sociotherapy in
Chanpattana, W., Chakrabhand, M.L., Friston, K.J., Frith, C.D., 1995. Schizophrenia: the aftercare of schizophrenic patients, II:
Sackeim, H.A., et al., 1999. Continuation a disconnection syndrome? Clin. Neurosci. Two-year relapse rates. Arch. Gen.
ECT in treatment-resistant schizophrenia: a 3, 89–97. Psychiatry 31, 603–608.
controlled study. J. ECT 15, 178–192. Frith, C.D., 1992. The cognitive Hogarty, G.E., Schooler, N.R., Ulrich, R., et al.,
Chubb, J.E., Bradshaw, N.J., Soares, D.C., neuropsychology of schizophrenia. Erlbaum, 1979. Fluphenazine and social therapy in the
Porteous, D.J., Millar, J.K., 2007. The DISC Hove. aftercare of schizophrenic patients: relapse
locus in psychiatric illness. Mol. Psychiatry analyses of a two-year controlled study of
Gardner, M., González-Neira, A., Lao, O.,
13, 36. fluphenazine decanoate and fluphenazine
Calafell, F., Bertranpetit, J., Comas, D.,
hydrochloride. Arch. Gen. Psychiatry
Chumakov, I., Blumenfield, M., 2006. Extreme population differences across
36, 1283–1294.
Guerassimenko, O., et al., 2002. Genetic and Neuregulin 1 gene, with implications for
physiological data implicating the new human association studies. Mol. Psychiatry Hollister, L.E., Trauts, L., Prusmack, J.T., 1960.
gene G72 and the gene for D-amino acid 11, 66–75. Use of thioridazine for intensive treatment of
oxidase in schizophrenia. PNAS schizophrenia refractory to other
Geddes, J., Freemantle, N., Harrison, P.,
99, 13675–13680. tranquillizing drugs. J. Neuropsychiatr. 1,
Bebbington, P., 2000. Atypical antipsychotics
200–204.
Cochrane Library, 2009. Update Software, in the treatment of schizophrenia: systematic
Oxford. overview and meta-regression analysis. Ingvar, D.H., Franzén, G., 1974. Abnormalities
Br. Med. J. 321, 1371–1376. of cerebral blood flow distribution in patients
Cochrane, R., 1977. Mental illness in immigrants
with chronic schizophrenia. Acta. Psychiatr.
to England and Wales: an analysis of mental Gilbert, P.L., Harris, M.J., McAdams, L.A.,
Scand. 50, 425–462.
hospital admissions, 1971. Soc. Psychiatry Jeste, D.V., 1995. Neuroleptic withdrawal
12, 25–35. in schizophrenic patients: a review of the International Schizophrenia Consortium, 2008.
literature. Arch. Gen. Psychiatry Rare chromosomal deletions and duplications
Cooper, J.E., Kendell, R.E., Gurland, B.J., et al.,
52, 173–188. increase risk of schizophrenia. Nature 455,
1972. Psychiatric diagnosis in New York and
237–241.
London. Maudsley Monograph 20. Oxford Goldberg, E.M., Morrison, S.L., 1963.
University Press, Oxford. Schizophrenia and social class. Br. J. Job, D.E., Whalley, H.C., McIntosh, A.M.,
Psychiatry 109, 785–802. Owens, D.G., Johnstone, E.C., Lawrie, S.M.,

423
Companion to Psychiatric Studies

2006. Grey matter changes can improve the Kendell, R.E., Brockington, I.F., Leff, J.P., 1979. Lieberman, J.A., Stroup, T.S., McEvoy, J.P.,
prediction of schizophrenia in subjects at high Prognostic implications of six alternative et al., 2005. Effectiveness of antipsychotic
risk. BMC Med. 7 (4), 29. definitions of schizophrenia. Arch. Gen. drugs in patients with chronic schizophrenia.
Johnson, D.A.W., Pasterski, G., Ludlow, J.M., Psychiatry 36, 25–31. N. Engl. J. Med. 353, 1209–1223.
Street, K., 1983. The discontinuance of Kendler, K.S., 1982. Demography of paranoid McClellan, J., Susser, E., King, M.C., 2007.
maintenance neuroleptic therapy in chronic psychosis (delusional disorder): a review and Schizophrenia: a common disease caused by
schizophrenic patients: drug and social comparison with schizophrenia and affective multiple rare alleles. Br. J. Psychiatry
consequences. Acta. Psychiatr. Scand. illness. Arch. Gen. Psychiatry 39, 890–902. 190, 194–199.
67, 339–352. Kendler, K.S., Masterson, C.C., Davis, K.L., McCreadie, R.G., Leese, M., Tilak-Singh, D.,
Johnson, D.A., Ludlow, J.M., Street, K., 1985. Psychiatric illness in first degree et al., 1997. Nithsdale, Nunhead and
Taylor, R.D., 1987. Double-blind comparison relatives of patients with paranoid psychosis, Norwood: similarities and differences in
of half-dose and standard-dose flupenthixol schizophrenia and medical illness. Br. J. prevalence of schizophrenias and utilisation
decanoate in the maintenance treatment of Psychiatry 147, 524–531. of services in urban and rural areas. Br. J.
stabilised out-patients with schizophrenia. Br. Kendler, K.S., Ochs, A.L., Gorman, A.M., et al., Psychiatry 170, 31–36.
J. Psychiatry 151, 634–638. 1991. The structure of schizotypy – a pilot McGhie, A., Chapman, J., 1961. Disorders of
Johnstone, E.C., Crow, T.J., Frith, C.D., et al., multitrait twin study. Psychiatry Res. attention and perception in early
1976. Cerebral ventricular size and cognitive 36, 19–36. schizophrenia. Br. J. Med. Psychol.
impairment in chronic schizophrenia. Lancet Kety, S.S., Rosenthal, D., Wender, P.H., 1975. 343, 103–116.
ii, 924–926. Mental illness in the biological and adoptive McGlashan, T.H., Carpenter Jr., W.T., 1976.
Johnstone, E.C., Crow, T.J., Johnson, A.L., families of adopted individuals who have Postpsychotic depression in schizophrenia.
MacMillan, J.F., 1986. The Northwick Park become schizophrenic: a preliminary report Arch. Gen. Psychiatry 33, 231–239.
Study of first episodes of schizophrenia, I: based on psychiatric interviews. Proc. Annu. McGlashan, T.H., Hoffman, R.E., 2000.
Presentation of the illness and problems Meet. Am. Psychopathol. Assoc. Schizophrenia as a disorder of
relating to admission. Br. J. Psychiatry 63, 147–165. developmentally reduced synaptic
148, 115–120. Kilts, C.D., 2001. The changing roles and targets connectivity. Arch. Gen. Psychiatry
Johnstone, E.C., Macmillan, J.F., Crow, T.J., for animal models of schizophrenia. Biol. 57, 637–648.
1987. The occurrence of organic disease of Psychiatry 50, 845–855. McGorry, P.D., Yung, A.R., Phillips, L.J., et al.,
possible or probable aetiological significance Klosterkotter, J., Hellmich, M., Steinmeyer, E.M., 2002. Randomized controlled trial of
in a population of 268 cases of first episode Schultze-Lutter, F., 2001. Diagnosing interventions designed to reduce the risk of
schizophrenia. Psychol. Med. 17, 371–379. schizophrenia in the initial prodromal phase. progression to first-episode psychosis in a
Johnstone, E.C., Leary, J., Frith, C.D., Arch. Gen. Psychiatry 58, 158–164. clinical sample with subthreshold symptoms.
Owens, D.G., 1991. Disabilities and Kraepelin, E., 1896. Lehrbuch der Psychiatrie. Arch. Gen. Psychiatry 59, 921–928.
circumstances of schizophrenic patients – a Barth, Leipzig. McGovern, D., Cope, R.V., 1987. First
follow-up study. Br. J. Psychiatry Kraepelin, E., 1919. Dementia praecox and psychiatric admission rates of first and
159 (Suppl.), 37–39, 44–46. paraphrenia (R.M. Barclay, Trans.). second generation Afro-Caribbeans. Soc.
Johnstone, E.C., Frith, C.D., Crow, T.J., et al., Livingstone, Edinburgh. Psychiatry 22, 139–149.
1992. The Northwick Park ‘Functional’ Langfeldt, G., 1960. Diagnosis and prognosis of McGuire, P.K., Shah, G.M., Murray, R.M.,
Psychosis Study: diagnosis and outcome. schizophrenia. Proc. R. Soc. Med. 1993. Increased blood flow in Broca’s area
Psychol. Med. 22, 331–346. 53, 1047–1052. during auditory hallucinations in
Johnstone, E.C., Connelly, J., Frith, C.D., et al., Lawrie, S.M., Whalley, H., Kestelman, J.N., schizophrenia. Lancet 342, 703–706.
1996. The nature of ‘transient’ and ‘partial’ et al., 1999. Magnetic resonance imaging of Malzberg, B., Lee, E.S., 1956. Migration and
psychoses: findings from the Northwick Park brain in people at high risk of developing mental disease: a study of first admission to
‘Functional’ Psychosis Study. Psychol. Med. schizophrenia. Lancet 353, 30–33. hospitals for mental disease, New York,
26, 361–369. 1939–1941. Social Science Research Council,
Lawrie, S.M., Buechel, C., Whalley, H.C., et al.,
Jolley, A.G., Hirsch, S.R., Morrison, E., et al., 2002. Reduced frontotemporal functional New York.
1990. Trial of brief intermittent neuroleptic connectivity in schizophrenia associated with Marder, S.R., Essock, S.M., Miller, A.L., et al.,
prophylaxis for selected schizophrenic auditory hallucinations. Biol. Psychiatry 2004. Physical health monitoring of patients
outpatients: clinical and social outcome at 51, 1008–1011. with schizophrenia. Am. J. Psychiatry
two years. Br. Med. J. 301, 837–842. 161, 1334–1349.
Leff, J.P., Wing, J.K., 1971. Trial of maintenance
Jones, P., Rodgers, B., Murray, R., Marmot, M., therapy in schizophrenia. Br. Med. J. Marshall, M., Lewis, S., Lockwood, A.,
1994. Child development risk factors for 3, 599–604. Drake, R., Jones, P., Croudace, T., 2005.
adult schizophrenia in the British 1946 birth Association between duration of untreated
Leff, J., Kuipers, L., Berkowitz, R., et al., 1982.
cohort. Lancet 344, 1398–1402. psychosis and outcome in cohorts of first-
A controlled trial of social intervention in the
Kane, J., Honigfeld, G., Singer, J., Meltzer, H., families of schizophrenic patients. Br. J. episode patients: a systematic review. Arch.
1988. Clozapine for the treatment-resistant Psychiatry 141, 121–134. Gen. Psychiatry 62, 975–983.
schizophrenic: a double-blind comparison Mason, P., Harrison, G., Glazebrook, C., et al.,
Leucht, S., Corves, C., Arbter, D., Engel, R.R.,
with chlorpromazine. Arch. Gen. Psychiatry 1995. Characteristics of outcome in
Li, C., Davis, J.M., 2009. Second-generation
45, 789–796. schizophrenia at 13 years. Br. J. Psychiatry
versus first-generation antipsychotic drugs for
Kaney, S., Bowen-Jones, K., Bentall, R.P., 1999. schizophrenia: a meta-analysis. Lancet 167, 596–603.
Persecutory delusions and autobiographical 373, 31–41. May, P.R.A., 1968. Treatment of schizophrenia.
memory. Br. J. Clin. Psychol. 38, 97–102. Science House, New York.
Levinson, D.F., Umapathy, C., Musthaq, M.,
Kapur, S., 2003. Psychosis as a state of aberrant 1999. Treatment of schizoaffective disorder Menezes, N.M., Arenovich, T., Zipursky, R.B.,
salience: a framework linking biology, and schizophrenia with mood symptoms. 2006. A systematic review of longitudinal
phenomenology, and pharmacology in Am. J. Psychiatry 156, 1138–1148. outcome studies of first-episode psychosis.
schizophrenia. Am. J. Psychiatry 160, 13–23. Psychol. Med. 36, 1349–1362.
Liddle, P.F., 1987. The symptoms of chronic
Kasanin, J., 1933. The acute schizoaffective schizophrenia: a reexamination of the Mojtabai, R., Nicholson, R.A., Carpenter, B.N.,
psychoses. Am. J. Psychiatry 90, 97–126. positive–negative dichotomy. Br. J. 1998. Role of psychosocial treatments in
Kelly, C., McCreadie, R.G., MacEwan, T., Psychiatry 151, 145–151. management of schizophrenia: a meta-
Carey, S., 1998. Nithsdale schizophrenia Liddle, P.F., Friston, K.J., Frith, C.D., et al., analytic review of controlled outcome
surveys 17: fifteen year review. Br. J. 1992. Patterns of cerebral blood flow in studies. Schizophr. Bull. 24, 569–587.
Psychiatry 172, 513–517. schizophrenia. Br. J. Psychiatry Moore, T.H., Zammit, S., Lingford-Hughes, A.,
160, 179–186. et al., 2007. Cannabis use and risk of

424
Schizophrenia and related disorders CHAPTER 15

psychotic or affective mental health approach to treat schizophrenia: a Silveira, J.M., Seeman, M.V., 1995. Shared
outcomes: a systematic review. Lancet randomized Phase 2 clinical trial. Nat. Med. psychotic disorder: a critical review of the
370, 319–328. 13, 1102–1107. literature. Can. J. Psychiatry 40, 389–395.
Morice, R.D., Ingram, J.C.L., 1982. Language Patterson, T.L., Leeuwenkamp, O.R., 2008. Singer, M.T., Wynne, L.D., 1965. Thought
analysis in schizophrenia: diagnostic Adjunctive psychosocial therapies for the disorder and family relations of
implications. Aust. N. Z. J. Psychiatry treatment of schizophrenia. Schizophr. Res. schizophrenics. Arch. Gen. Psychiatry
27, 11–21. 100, 108–119. 12, 187–212.
Mortensen, P.B., Pedersen, C.B., Perälä, J., Suvisaari, J., Saarni, S.I., et al., 2007. Singh, S.P., Burns, T., Amin, S., et al., 2004.
Westergaard, T., et al., 1999. Effects of Lifetime prevalence of psychotic and bipolar Acute and transient psychotic disorders:
family history and place and season of birth I disorders in a general population. Arch. precursors, epidemiology, course and
on the risk of schizophrenia. N. Engl. J. Med. Gen. Psychiatry 64, 19–28. outcome. Br. J. Psychiatry 185, 452–459.
340, 603–608. Phillips, K.A., Albertini, R.S., Rasmussen, S.A., Siris, S.G., Morgan, V., Fagerstrom, R., et al.,
Moskvina, V., Craddock, N., Holmans, P., et al., 2002. A randomized placebo-controlled trial 1987. Adjunctive imipramine in the
2009. Gene-wide analyses of genome-wide of fluoxetine in body dysmorphic disorder. treatment of postpsychotic depression:
association data sets: evidence for multiple Arch. Gen. Psychiatry 59, 381–388. A controlled trial. Arch. Gen. Psychiatry
common risk alleles for schizophrenia and Pilling, S., Bebbington, P., Kuipers, E., et al., 44, 533–539.
bipolar disorder and for overlap in genetic 2002. Psychological treatments in Siris, S.G., Bermanzohn, P.C., Mason, S.E.,
risk. Mol. Psychiatry 14, 252–260. schizophrenia, II: Meta-analyses of Shuwall, M.A., 1994. Maintenance
Moutoussis, M., Williams, J., Dayan, P., randomized controlled trials of social skills imipramine therapy for secondary depression
Bentall, R.P., 2007. Persecutory delusions training and cognitive remediation. Psychol. in schizophrenia. A controlled trial. Arch.
and the conditioned avoidance paradigm: Med. 32, 783–791. Gen. Psychiatry 51, 109–115.
towards an integration of the psychology and Pillmann, F., Haring, A., Balzuweit, S., et al., Smith, D.A., Mar, C.M., Turoff, B.K., 1998. The
biology of paranoia. Cognit. Neuropsychiatry 2002. The concordance of ICD-10 acute and structure of schizophrenic symptoms: a meta-
12, 495–510. transient psychosis and DSM-IV brief analytic confirmatory factor analysis.
Munro, A., 1988. Monosymptomatic psychotic disorder. Psychol. Med. Schizophr. Res. 31, 57–70.
hypochondriacal psychosis. Br. J. Psychiatry 32, 525–533. Smith, A.J., Li, M., Becker, S., Kapur, S., 2007.
(Suppl. 2), 37–40. Pitschel-Walz, G., Leucht, S., Bauml, J., et al., Linking animal models of psychosis to
Murray, R.M., Jones, P.B., Susser, E., van Oz, J., 2001. The effect of family interventions on computational models of dopamine function.
Cannon, M. (Eds.), 2003. The epidemiology relapse and rehospitalization in schizophrenia Neuropsychopharmacology 32, 54–66.
of schizophrenia. CUP, Cambridge. – a meta-analysis. Schizophr. Bull. 27, 73–92. St Clair, D., et al., 1990. Association within a
Murray, G.K., Corlett, P.R., Clark, L., et al., Ray, W.A., Chung, C.P., Murray, K.T., Hall, K., family of a balanced autosomal translocation
2007. Substantia nigra/ventral tegmental Stein, C.M., 2009. Atypical antipsychotic with major mental illness. Lancet 336, 13.
reward prediction error disruption in drugs and the risk of sudden cardiac death. St Clair, D., Xu, M., Wang, P., et al., 2005. Rates
psychosis. Mol. Psychiatry 12, 46–77. N. Engl. J. Med. 360, 225–235. of adult schizophrenia following prenatal
National Institute of Mental Health, 1964. Regier, D.A., Boyd, J.H., Burke, J.D., et al., exposure to the Chinese famine of 1959–
Psychopharmacology Service Center 1988. One-month prevalence of mental 1961. J. Am. Med. Assoc. 294, 557–562.
Collaborative Study Group. Phenothiazine disorders in the United States. Arch. Gen. Steinberg, H.R., Durrell, J., 1968. A stressful
treatment of acute schizophrenia. Arch. Gen. Psychiatry 45, 977–986. social situation as a precipitant of
Psychiatry 10, 246–261. Saha, S., Chant, D., McGrath, J., 2007. A schizophrenic symptoms: an epidemiological
NICE, 2002. Technology Appraisal Guidance systematic review of mortality in study. Br. J. Psychiatry 114, 1097–1105.
No. 43 – Guidance on the use of newer schizophrenia: is the differential mortality Storosum, J.G., Elferink, A.J.A., van Zwieten, B.J.,
(atypical) antipsychotic drugs for the gap worsening over time? Arch. Gen. 2002. Amisulpride: Is there a treatment for
treatment of schizophrenia. National Psychiatry 64, 1123–1131. negative symptoms in schizophrenia patients?
Institute for Clinical Excellence, London. Sartorius, N., Jablensky, A., Shapiro, R., 1977. Schizophr. Bull. 28, 193–201.
NICE 2009. Clinical Guideline No. 82 – Two-year follow-up of the patients included Straub R Jiang, Y., MacLean, C.J., et al., 2002.
Schizophrenia. National Institute for Clinical in the WHO international pilot study of Genetic variations in the 6p22.3 gene
Excellence, London. schizophrenia. Psychol. Med. 7, 529–541. DTNBP1, the human ortholog of the mouse
Odegaard, O., 1932. Emigration and insanity: a Sartorius, N., Jablensky, A., Korten, A., 1986. dysbindin gene, is associated with
study of mental disease among Norwegian- Early manifestations and first-contact schizophrenia. Am. J. Hum. Genet.
born population of Minnesota. Acta incidence of schizophrenia in different 71, 337–348.
Psychiatr. Neurol. Scand. (Suppl. 4). cultures. A preliminary report on the initial Stefansson, H., Sigurdsson, E.,
Opjordsmoen, S., 1988. Long-term course and evaluation phase of the WHO Collaborative Steinthorsdottir, V., et al., 2002. Neuregulin
outcome in delusional disorder. Acta Study on determinants of outcome of severe 1 and Susceptibility to Schizophrenia. Am. J.
Psychiatr. Scand. 78, 576–586. mental disorders. Psychol. Med. Hum. Genet. 71, 877–892.
Owens, D.G., Johnstone, E.C., Frith, C.D., 16, 909–928. Stefansson, H., Rujescu, D., Cichon, S., et al.,
1982. Spontaneous involuntary disorders of Schneider, K., 1959. Clinical Psychopathology. 2008. Large recurrent microdeletions
movement: their prevalence, severity, and Grune and Stratton, New York. associated with schizophrenia. Nature
distribution in chronic schizophrenics with Sensky, T., Turkington, D., Kingdon, D., et al., 455, 232–236.
and without treatment with neuroleptics. 2000. A randomized controlled trial of Stephan, K.E., Baldeweg, T., Friston, K.J., 2006.
Arch. Gen. Psychiatry 39, 452–461. cognitive-behavioral therapy for persistent Synaptic plasticity and dysconnection in
Owens, D.G., Johnstone, E.C., 2006. Precursors symptoms in schizophrenia resistant to schizophrenia. Biol. Psychiatry 59, 929–939.
and prodromata of schizophrenia: findings medication. Arch. Gen. Psychiatry Sullivan, P.F., Lin, D., Tzeng, J.Y., et al., 2008.
from the Edinburgh High Risk Study and 57, 165–172. Genomewide association for schizophrenia in
their literature context. Psychol. Med. Sham, P.C., O’Callaghan, E., Takei, N., et al., the CATIE study: results of stage 1. Mol.
36, 1501–1514. 1992. Schizophrenia following pre-natal Psychiatry 13, 570–584.
Pantelis, C., Velakoulis, D., McGorry, P.D., exposure to influenza epidemics between Susser, E.S., Lin, S.P., 1992. Schizophrenia after
et al., 2003. Neuroanatomical abnormalities 1939 and 1960. Br. J. Psychiatry prenatal exposure to the Dutch Hunger
before and after onset of psychosis: a cross- 160, 461–466. Winter of 1944–1945. Arch. Gen. Psychiatry
sectional and longitudinal MRI comparison. Shenton, M.E., Dickey, C.C., Frumin, M., 49, 983–988.
Lancet 361, 281–288. McCarley, R.W., 2001. A review of MRI Thornley, B., Adams, C., 1998. Content and
Patil, S.T., Zhang, L., Martenyi, F., et al., 2007. findings in schizophrenia. Schizophrenia quality of 2000 controlled trials in
Activation of mGlu2/3 receptors as a new Research 49, 1–52.

425
Companion to Psychiatric Studies

schizophrenia over 50 years. Br. Med. J. Walsh, T., et al., 2008. Rare structural variants descriptions and diagnostic guidelines. World
317, 1181–1184. disrupt multiple genes in Health Organization, Geneva.
Trabert, W., 1995. 100 years of delusional neurodevelopmental pathways in Wing, J.K., Brown, J.W., 1961. Social treatment
parasitosis: meta-analysis of 1,223 case schizophrenia. Science 320, 539–543. of chronic schizophrenia: a competitive study
reports. Psychopathology 28, 238–246. Weinberger, D.R., Berman, K.F., Zec, R.F., of three mental hospitals. The Journal of
Turkington, D., Kingdon, D., Turner, T., 2002. 1986. Physiologic dysfunction of dorsolateral Mental Science 107, 847–861.
Effectiveness of a brief cognitive-behavioural prefrontal cortex in schizophrenia. I. Regional Wykes, T., Steel, C., Everitt, B., Tarrier, N.,
therapy intervention in the treatment of cerebral blood flow evidence. Arch. Gen. 2008. Cognitive behavior therapy for
schizophrenia. Br. J. Psychiatry Psychiatry 43, 114–124. schizophrenia: effect sizes, clinical models,
180, 523–527. Weinberger, D.R., 1987. Implications of normal and methodological rigor. Schizophr. Bull.
Vaillant, G.E., 1964. Prospective prediction of brain development for the pathogenesis of 34, 523–537.
schizophrenic remission. Arch. Gen. schizophrenia. Arch. Gen. Psychiatry Zammit, S., Allebeck, P., Andreasson, S., et al.,
Psychiatry 11, 509–518. 44, 660–669. 2002. Self reported cannabis use as a risk
Verdoux, H., van Os, J., 2002. Psychotic Weinberger, D.R., 1995. From neuropathology factor for schizophrenia in Swedish
symptoms in non-clinical populations and the to neurodevelopment. Lancet 346, 552–557. conscripts of 1969: historical cohort study.
continuum of psychosis. Schizophr. Res. WHO, 1973. Report of the International Pilot Br. Med. J. 325, 1199.
54, 59–65. Study of Schizophrenia. World Health Ziguras, S.J., Stuart, G.W., Jackson, A.C., 2002.
Walsh, E., Buchanan, A., Fahy, T., 2001. Organization, Geneva. Assessing the evidence on case management.
Violence and schizophrenia: examining the WHO, 1992. ICD-10. The ICD-10 classification Br. J. Psychiatry 181, 17–21.
evidence. Br. J. Psychiatry 180, 490–495. of mental and behavioural disorders: clinical

426