Seminar

Depressive illness
Alan Doris, Klaus Ebmeier, Polash Shajahan
WHO estimate that by the beginning of the next century major unipolar depression will be one of the most important
causes of ill health overall. Whereas the cause of depression is still obscure, it is becoming clear that a number of
diverse factors are likely to be implicated, both genetic and environmental. Effective treatment of depression
similarly involves a variety of methods, from electro-convulsive therapy to inter-personal psychotherapy. The
pathophysiology of depression is gradually becoming accessible through research strategies, such as functional
neuroimaging paired with mood altering interventions.
Depressive symptoms, such as unhappiness and
disappointment, are common. They affect up to a third of
the population.1 When symptoms become qualitatively
different, pervasive, or interfere with normal function, they
are considered to be pathological. The clinical syndrome
or illness is also known as depressive disorder, clinical
depression, or major depression. A subtype of depression,
characterised by loss of pleasure in almost all activities,
loss of reactivity to usually pleasurable stimuli, a distinct
quality of depressed mood, with symptoms worse in the
morning, early morning wakening, marked psychomotor
slowing or agitation, significant loss of appetite or weight
loss and excessive or inappropriate guilt is known as
melancholia. Episodes of major depression and at least
one episode of mania define bipolar affective disorder.
Dysthymia is characterised by intermittent depressive
symptoms not fulfilling the criteria for major depression,
but of at least 2 years duration. Major depressive episodes
can be superimposed upon dysthymia, resulting in double
depression.2 In this case, dysthymia can be conceptualised
as incomplete recovery from a major depressive episode.
Recurrent brief depression is recognised as a separate
category by DMS-IV and ICD-10; its symptoms are less
severe than major depression and shorter lasting than
dysthymia. Finally, the differences between major and
minor depression are in the degree of severity and
duration, rather than categorical.3

Epidemiology
Major depressive illness is common in the general
population (table); it reduces patients productivity and
quality of life and also increases their mortality. WHO
estimate that by the beginning of the next century major
unipolar depression will be one of the most important
causes of ill health overall.4 The introduction of agreed
operational diagnostic criteria and the use of standardised
interview techniques have allowed advances in the
prevalence estimation of various psychiatric disorders,
including major depression.

Lancet 1999; 354: 136975

MRC Brain Metabolism Unit and Department of Psychiatry,
University of Edinburgh, Royal Edinburgh Hospital, Morningside
Park, Edinburgh EH10 5HF, UK (A Doris MRCPsych ,
Prof K Ebmeier MRCPsych, P Shajahan MRCPsych)
Correspondence to: Prof K P Ebmeier

Prevalence

Depressive
symptoms

Bipolar
disorder

Major
depression

Dysthymia

Up to third of
population*

13%

161%

36%

Females: 7 to 32
per 100 000)
Males: 9 to 15
(per 100 000)
1/1
Female: 19
Male: 18

Females: 198%
Males: 11%

Incidence1,78

Female/male
Age at onset

17/1

2/1
Female: 23
Male: 26
Increasing rates in
younger age groups

23/1
Continues
to increase
up to age
65 years

*point.1 lifetime.77

Summary of prevalence and incidence estimates of depressive

syndromes

Trends in the epidemiology of depression

Major depression affects up to one sixth of the population,
perhaps more. Evidence from studies with diverse designs,
sampling, and measurement strategies, suggest that there
may be an increase in depressive disorders overall,
especially among the most recent birth cohorts.5 The scale
of this increase is uncertain. The Cross-National
Collaborative
Group
(CNCG)
analysed
nine
epidemiological studies and three family studies derived
independently from geographical locations in North
America, Western Europe, Middle East, Asia, and the
Pacific Rim.6 The studies had similar diagnostic
instruments, ie DSM-III, Schedule for Affective
Disorders, and Schizophrenia and the Diagnostic
Interview Schedule. Major depression was increasing over
time and occurred earlier for successively younger age
cohorts in many different locations. This phenomenon has
major public-health implications, in terms of the resulting
levels of morbidity and mortality associated with
depression. To the extent that the observed increases are
not artefactual (eg, due to increased help-seeking or
differential ascertainment),7 but due to real changes in
incidence and prevalence, they may be the result of
increasing stresses and reduction of social support
associated with modern living, particularly in younger
people. Women experience higher rates of depression than
men.810 Surveys suggest that this imbalance may be
normalising,11,12 although there are contradictory reports,
for example from Ireland.13 Significant environmental
changes have occurred over the past few decades. Male
unemployment is rising; together with increased
employment of women this may lead to a reversal of

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Panel 1: Tryptophan depletion

The depletion of cerebral tryptophan by a tryptophan-poor diet and a
high-concentration amino-acid drink not containing tryptophan has
been employed as an experimental model of clinical depression.
Depressive mood swings are provoked hours after the drink, due to
systemic tryptophan depletion and competition for active uptake into
the brain, in recovered depressed patients, as well as first-degree
relatives of depressed patients. The paradigm is used in a variety of
patient groups serving as a vulnerability marker for depression.

traditional roles. On the other hand, major depression, as

sole diagnosis or comorbid with other conditions (such as
substance abuse), may be diagnosed more readily. Both
factors help to explain the apparent increase in depressive
disorders among young men. Such secular changes may
also underlie the rising levels of male suicides.14

Cause and pathophysiology

Our present knowledge of the causes of depressive illness
is more sophisticated, but not necessarily clearer, than it
was a decade ago. Population genetic studies suggest that
there is an increased risk of bipolar illness in the relatives
of bipolar patients and an increased risk of unipolar
depressive illness in the relatives in both bipolar and
unipolar
patients.
Interesting
across-diagnosis
relationships exist with anxiety disorder and alcohol
problems, but are outside the remit of this seminar. The
contributions of genetic and environmental factors can be
quantified. For example, in a recent major study, 50% of
the variance in liability to suffer major depression at

follow-up was accounted for by stressful life events,

genetic factors, a previous depressive episode, and the
personality trait neuroticism.15 However, the distinction
between nature and nurture is increasingly blurred. Genes
appear to influence our liability to suffer life events,16 our
mating behaviour clearly affects our childrens genes.1719
Linkage and association studies with a variety of genetic
markers on chromosomes 11, 4, 18, 6, 13, 15, and others
have been disappointing, in that results have been difficult
to replicate. Statistically robust effects are usually very
small, and the respective genes are likely to work in
combination with others. Similar small effects have been
identified in a number of association studies of the
serotonin transporter gene,20 one within intron 2,21 and a
second close to the promoter region, upstream of the
transcription-start site.22
Monoamines
Because of the success of antidepressant medication, in
particular those drugs acting selectively on 5HT reuptake,
monoamines still have a prominent place in etiological
theories of depression. This is reinforced by the
observation that depressed patients in remission, but also
vulnerable healthy volunteers, develop depressive
symptoms after dietary depletion of tryptophan (panel
1).23,24 Neuroendocrine markers and receptor-ligand
studies at necropsy contribute to the evidence.25 For
example, endocrine responses to indirect (L-tryptophan,
clomipramine, fenfluramine) or direct (buspirone, mchlorophenyl piperazine) serotonin agonists are often
blunted in depressed patients, suggesting an abnormality

Figure 1: Z-map of regions with significantly reduced (p<001) grey-matter density in 20 treatment-resistant chronically depressed
patients compared with 20 age-matched and sex-matched controls
Note that there is reduced grey-matter density bilaterally in medial temporal cortex (figure modified from reference 35, with permission).

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Panel 2: Repetitive trans-cranial magnetic

stimulation (rTMS)
Induction of small electrical currents in cortical
neurons by localised magnetic-field changes can
cause stimulation or inhibition of neuronal pathways.
The effect has been used for some time to map a
variety of brain functions on the cortical surface with
non-repetitive, single stimuli. In the past 4 years
investigators have provided preliminary evidence that
rTMS over the dominant dorso-lateral pre-frontal
cortex improves the mood of patients. This has led to
the investigation of rTMS as an antidepressant
treatment. If confirmed as an effective treatment,
rTMS may offer an opportunity to influence specific
neuronal pathways implicated in the pathophysiology
of depressive illness in a selective way not possible
with other somatic treatments, such as drugs or ECT
(figure 2).

Figure 2: Left prefrontal rTMS motor threshold is

determined previously by electromyography, at the
maximum stimulation point for the abuctor pollicis brevis

of serotonergic transmission. Similarly, there is some

evidence from necropsy that particularly violent suicides
are associated with an increase in 5HT2 receptors in
frontal cortex, implying a secondary upregulation afterreduced serotonergic transmission.25 In-vivo imaging
studies of the relevant transmitter systems are in their
infancy, but first preliminary evidence of positive results is
encouraging.26 The serotonin theory of depression explains
the mechanisms of the illness only in part. Functional
changes during recovery from depression are found in
areas of the brain intimately linked to ascending
dopaminergic pathways, such as the basal ganglia and
medial prefrontal cortex.27 In addition, new evidence from
in-vivo receptor labelling studies suggests that
dopaminergic
underactivity
is
associated
with
psychomotor slowing.28 From a theoretical point of view, it
is interesting that total sleep deprivation, which is said
among other things to have an amphetamine-like effect,29
is an effective short-term antidepressant in about 60% of
patients.30
Hypercortisolaemia
Hypercortisolaemia is found during depressive episodes;
its clinical significance is not established, but theories
abound that implicate cortisol in the course of depression
or explain its increase as a regulatory antidepressant
mechanism. In parallel with hypercortisolaemia, an
increase in size of the adrenal glands can be observed,
which is reversible with clinical recovery from depression.31
Reduced bone density has been noted in depressed elderly
women, consistent with the effects of hypercortisolaemia.32
Other endocrine changes, reduced activity and medication
may confound the issue.33 Increased cortisol levels have
toxic effects on hippocampal neurons. The hippocampus,
in turn, exerts inhibitory control over the hypothalamicpituitary axis (HPA). A number of authors have
postulated on the basis of animal studies that chronically
increased cortisol initiates a vicious circle of hippocampal
damage with further HPA-overactivity.34 Evidence of

hippocampal atrophy has, in fact, been found in

conditions associated with chronic or severe stress, such as
post-traumatic stress disorder in combat veterans,
borderline personality disorder with a history of sexual
abuse, or chronic treatment resistant depression (figure
1).35 Atrophy may then represent the end state of the
vicious circle predicted by animal studies.
Functional anatomy
Our knowledge about the location of brain structures
associated with mood has increased over the past decade
through longitudinal functional-imaging studies of
patients.36 Mood changes have also been imaged in
patients and healthy volunteers during short-term changes
due to pharmacological3 and physical interventions, such
as transcranial magnetic stimulation38 and electroconvulsive treatment, after sleep deprivation, and
psychological mood induction. Significant diurnal
variations in mood occur spontaneously in some patients
with major depression and can be used for imaging
studies.39 In spite of the diversity of experimental designs,
most studies have implicated medial limbic structures,
such as orbito-frontal and cingulate cortex, and basal
ganglia. Additionally, some authors find hyperactivity of
the amygdala, and hippocampus, and parts of the temporal
lobes in the depressed state, which is reversible after
successful therapy. The amygdala-hippocampal complex
has been of intense interest because of its possible
involvement in the neuroanatomy of depression, its role in
memory (known to be impaired in depression), and
because it may be a structure vulnerable to the effects of
corticosteroids. An initial number of volumetric studies by
magnetic resonance imaging (MRI) in unipolar patients
have been negative.40,41 However, a reduction in
hippocampal volume has been described in a small sample
of elderly women with recurrent unipolar depression.42
Similarly, grey-matter changes in hippocampus were found
in middle-aged, chronic, treatment-resistant patients.35
The hippocampal changes were associated with poor

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Panel 3: Cognitive-behavioural therapy (CBT)

CBT is a psychological treatment shown among others to be useful in
depression. It is based on the theory that depressive symptoms may
arise from or be perpetrated by, dysfunctional patterns of thinking and
behaviour. A particular cognitive triad of dysfunctional patterns is
often present in those suffering from depression. Sufferers display a
negative view of themselves, a negative view of their current situation
and of the future. This negative thinking in depression may arise from
experiences particular to the individual in early life, which have formed
the assumptions and attitudes they hold about the world. In CBT the
patient and therapist work together to identify abnormal patterns of
thinking and behaviour contributing to the current illness, and also to
identify the assumptions about the world that underlie such patterns.
Patients are asked to keep a diary and learn to become more aware
of thoughts and behaviour. Links between thoughts, behaviour and
mood are highlighted with the therapists help. Once identified,
weighing up the evidence for and against challenges irrational
thinking. At a more advanced stage therapy aims to identify and
challenge underlying dysfunctional assumptions that may predispose
to becoming depressed. Behavioural strategies to complement the
cognitive approach may include activity setting or arranging
experiments designed to test the validity of irrational beliefs.

verbal memory performance. A likely explanation of the

discrepancy between publications is that the spatial
resolution of MRI sequences may have been insufficient to
detect changes in hippocampus in the earlier studies
(typical slice thickness 5 mm).
Seasonal affective disorder
A simple, therefore attractive and widely researched idea,
is that there is an inverse relationship between the duration
of the local daylight period and the incidence of recurrent
wintertime depression.43 This correlation is not always
replicable, and possible confounds, such as wintertime
unemployment, need to be considered.44 There is some
evidence for the effectiveness of light therapy in seasonal
affective disorder.45 However, the usual irradiation at 10
000 lux is not without side effects. About half the patients
suffer from headaches, and eye or vision problems early in
treatment.46 There have also been reports of emerging
suicidal tendencies during light therapy,47 so that this
treatment should not be given without prior and
continuing expert assessment. Proof that wintertime
depression is in any way different from major depressive
illness is still lacking. Its symptom patterns seems to be
consistent with (atypical) depression, with hypersomnia,
hyperphagia, and tiredness. Similar to other types of
depressive illness, symptoms can be provoked during
remission by tryptophan depletion48 and respond to
standard antidepressant therapy, such as fluoxetine.49
Treatment
Unfortunately, many depressed patients will not present to
medical services. Of those that do, as much as 50% may
not be recognised in primary care.50 Initial treatment is
therefore dependent on thorough assessment. Patient
management often requires a combination of physical or
psychological methods. The clinican has to be guided in
the choice of treatment by evidence of efficacy, patient
acceptability, and availability. Interventions that are
effective in psychiatric populations tend also to be effective
in primary care. Pharmacotherapy is the commonest
treatment in primary care with response rates between
50% and 60%, and is often used in addition to supportive
counselling. In mild to moderate illness, psychotherapy
(eg, cognitive-behavioural therapy [CBT], see panel 2) can

be effective. Severe symptoms, suicide risk, comorbid

medical illness, other psychiatric illness, substance abuse,
and failure to respond to treatment trigger referral to
specialists. Whether the individual is treated as an
outpatient, day-patient, or inpatient is determined by the
risk of self-harm, the treatment method proposed, social
support, and local resources. There is a measurable
discrepancy between current clinical practice and the lay
expectations for management. Even after the Defeat
Depression campaign of the Royal College of General
Practitioners and the Royal College of Psychiatrists, the
public seems to hold greatest store by counselling and
psychotherapy, whereas antidepressant drugs are thought
to be addictive.51
Pharmacotherapy
There is much evidence to support the effectiveness of
antidepressant drugs. Meta-analyses have consistently
found that both tricyclic antidepressants (TCA) and newer
more selective agents are superior to placebo, with an effect
size of about 05. This effect size increased if studies with
objective diagnostic criteria were the only ones included.52
An effect size of this magnitude is still remarkably small,
but can be explained by the relatively high rate of placebo
responders, particularly in outpatients. Although
marginally more efficacious,52 the clinical use of TCAs is
limited by the presence of side-effects, which can impair
compliance and may prevent the achievement of adequate
doses. The introduction of more selective antidepressants
has increased the choice, and the cost, of treatment. Lower
drop-out rates in drug trials and lower toxicity in overdose
are benefits.53 In more severe illness, TCAs may be more
effective.54 The effectiveness of some of the newer agents
may be obscured in meta-analyses that group them with
less potent drugs from the same family.55 Cost-effectiveness
analyses comparing TCAs and newer antidepressants need
to balance increased compliance and lower fatalities from
antidepressant overdose with the financial cost. The
monoamine oxidase inhibitors (MAOI) have been found
less effective than TCAs in major depressive illness, but
doses were comparatively low.56 However, they are said to
be the treatment of choice in illness with atypical features
(reactive mood, weight gain or increased apetite,
hypersomnia, heavy, leaden feelings in arms and legs,
longstanding sensitivity to rejection). In patients
unresponsive to other agents, MAOIs have a role as second
line agents.57 Whichever medication is chosen initially, an
assessment of response should be made after 46 weeks to
decide whether to continue with the strategy or to change.
Electro-convulsive therapy (ECT)
ECT remains the treatment of choice in severe,
life-threatening depressive illness. A number of controlled
trials over the past 40 years have shown the effectivness of
ECT, particularly in severe illnesses characterised by
biological features, retardation, or delusions. The main
side-effects of ECT are cognitive. A post-ictal confusional
state may occur, and memory impairment, which resolves
over a few weeks, is common. These can be minimised
by using brief pulse stimuli, or unilateral rather than
bilateral electrode placement. Several studies have
found no evidence that ECT causes changes to cerebral
anatomy despite commonly held fears that it may do.58
Despite its efficacy, ECT is most often used after
failure of pharmacotherapy, because of its poor public
image.

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Panel 4: Interpersonal psychotherapy (IPT)

IPT is a manual-based, time-limited treatment, particularly effective
for patients with depression. The focus for treatment are current
social context and relationships of the individual, and how
interpersonal problems may be connected to the onset or
maintenance of depressive symptoms. After confirming and
acknowledging the diagnosis and the need for other (eg, drug)
treatments, the therapist focuses on four key areas: grief and loss,
interpersonal role disputes, role transitions, and interpersonal skill
deficits. The therapist takes an active role and employs systematic
problem-solving strategies to address the identified issues.

Repetitive trans-cranial magnetic stimulation (rTMS)

rTMS is a new experimental treatment for depression and
other disorders (panel 3). Few controlled studies have
been completed thus far although initial results are
encouraging. Beneficial results have been reported in
controlled trials involving both patients with treatmentresistant depression and with less severe disorders.59,60
Currently, studies are investigating which combinations of
treatment factors (stimulus frequency, stimulus site,
duration of stimulus, and frequency of treatments) are
most effective in different subgroups of patients). The
dropout rate from trials has been low, and the safety
record of the treatment seems to be good, if patients with
reduced seizure threshold are excluded.
Alternative physical therapies
The use of unconventional therapies in the treatment of
depression is common, particularly in self-treatment. A
broad range of remedies claim to be effective, although
substantial evidence exists for very few. A meta-analysis of
randomised controlled trials found evidence for the
effectiveness of St Johns Wort (Hypericum perforatum) in
moderate depressive illness.61 It was found to have an
efficacy similar to conventional antidepressants with low
dropout rates and few patients complaining of side-effects.
The effect of exercise on depression has been studied
repeatedly, with reports of a moderate benefit.62 Further
studies are needed before the value of many alternative
therapies can be scientifically evaluated.
Psychological treatments
Effectiveness has been claimed for a variety of
psychological therapies. Non-specific benefits are likely to
result from contact with a supportive partner. Consistent
with the large placebo response in the treatment of
depressed patients, many different psychological therapies
have shown beneficial results when compared with no
treatment or waiting list. However, in contrast to somatic
treatments, there are few well-controlled studies of
psychological therapies of acute depressive illness, and few
studies comparing psychological treatments with drug
treatments. The best evidence to date favours the use of
CBT (panel 2), and interpersonal psychotherapy (IPT, see
panel 4), with psychodynamically oriented treatments
having little to support their specific rationale. In primary
care, the effectiveness of both CBT and IPT has been
demonstrated. Schulberg reported that 46% of primary
care patients treated with IPT in an intent-to-treat sample
had recovered at 8 months. This compares well with
nortriptyline treatment, which showed 48% recovery in the
same study. In the collaborative study of depression in 250
outpatients by National Institute of Mental Health, the
number of imipramine responders was greater than that in
IPT and CBT responders. Both were superior to

placebo.63 In more severe illness, combination of

psychotherapy with pharmacotherapy may be more
effective than psychotherapy alone.57 Such combination
therapy may also be more effective in patients with chronic
illness, comorbid personality disorder, or complex
psychosocial problems. As the rate of response to
psychotherapy appears to be slower than that for
pharmacotherapy a longer period is needed to decide
whether treatment is effective, before deciding a change in
management, perhaps 810 weeks.
Psychotherapeutic approaches have the advantage of
being acceptable to some patients who chose not to have
pharmacotherapy. There is evidence of efficacy across a
fairly broad range of illness severity. A major limitation is
the need for suitably skilled therapists to provide treatment.
Continuation therapy
After symptomatic recovery there is a period during which
the individual is at high risk of relapse, should the
treatment be discontinued. After remission from the first
episode of a depressive illness, it is necessary to continue
on antidepressant medication at full therapeutic dose for
1620 weeks.64 Individuals treated with ECT need the
introduction of an antidepressant towards the end of a
course to reduce the risk of relapse.
Maintenance therapy
Increasingly depression is recognised as an illness that has
a high chance of recurring, with as much as 80% of
patients suffering a further illness within 10 years.65,66
Patients who have had more than one bout of illness in
23 years should be considered for long-term maintenance
treatment. For individuals with frequent relapses,
continuing the agent that has brought about remission at
the same dose and indefinitely is the ideal for maintenance
therapy, as the benefits continue. However, this may not
be acceptable to the patient. A reduction in dose to
minimise side-effects may be necessary, as may a gradual
tapering of medication after 23 years. A 3-year follow-up
of individuals in the National Institute of Mental Health
Treatment of Depression Collaborative Research Program
found maintenance imipramine plus IPT to be effective in
preventing relapse (mean time to recurrence=131 weeks).67
Time to recurrence was 124 weeks for imipramine alone,
82 weeks for IPT alone, 74 weeks for IPT plus drug
placebo, and 45 weeks for placebo alone. The effectiveness
of other antidepressants in continuation and maintenance
therapy has also been shown.68,69 Few studies have assessed
the efficacy of CBT in preventing recurrence, though some
studies have found patients treated with CBT during the
acute phase to have less chance of relapse at follow-up.70,71
A study of CBT in the treatment of residual symptoms
after recovery from a depressive episode with
pharmacotherapy found a much reduced relapse rate over
the 2-year follow-up period.72
Lithium carbonate, either as monotherapy, or added to
antidepressant medication, has been shown to be effective
in reducing the risk of recurrence and may be particularly
useful in patients with frequent and severe relapses.73 Some
individuals respond only to ECT and require maintenance
ECT usually given at a rate of one treatment per month to
prevent recurrence.74
Treatment resistance
Response to medication is usually assessed as a 50%
reduction in the Hamilton Depression Rating Scale

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(HDRS), and occurs in 6070% of patients treated with

active medication. A large number of patients (2030% in
some studies) remain unresponsive or only partly
responsive to treatment, despite an adequate dose of
treatment given for enough time. This group therefore can
be regarded as treatment resistant. There is substantial
evidence that depression is under-treated.75 It is necessary
therefore to review previous treatment to ensure that a
high enough dose was given for a long enough period. Reevaluation of the diagnosis may show underlying comorbid organic disease or substance abuse. Various
strategies have been tried in treatment resistant cases.
Most often change to another antidepressant of a different
drug class is indicated, or a course of ECT. Augmentation
of a primary antidepressant with lithium or thyroid
hormones may be effective in resistant cases. In psychotic
depression the addition of antipsychotic medication is
often necessary to bring about improvement in symptoms.
An augmentation of serotonergic antidepressants with the
5HT1A antagonist pindolol would theoretically be of
value. The empirical evidence is, however, not convincing
at the moment.76
The Medical Research Council and the Royal College of Physicians
(Edinburgh) for financial support, Michael Glabus for generating the
statistical parametric maps, Charles Sidey for posing for the photograph.

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