Eur Arch Psychiatry Clin Neurosci (2008) 258[Suppl 1]:611

DOI 10.1007/s00406-007-1003-0

Yves Lecrubier

Refinement of diagnosis and disease classification in psychiatry

EAPCN 1003

j Abstract Knowledge concerning the classification

of mental disorders progressed substantially with the
use of DSM III-IV and IDCD 10 because it was based on
observed data, with precise definitions. These classifications a priori avoided to generate definitions related
to etiology or treatment response. They are based on a
categorical approach where diagnostic entities share
common phenomenological features. Modifications
proposed or discussed are related to the weak validity of
the classification strategy described above. (a) Disorders are supposed to be independent but the current
coexistence of two or more disorders is the rule; (b)
They also are supposed to have stability, however
anxiety disorders most of the time precede major
depression. For GAD age at onset, family history,
biology and symptomatology are close to those of
depression. As a consequence broader entities such as
depression-GAD spectrum, panic-phobias spectrum
and OCD spectrum including eating disorders and
pathological gambling are taken into consideration; (c)
Diagnostic categories use thresholds to delimitate a
border with normals. This creates subthreshold
conditions. The relevance of such conditions is well
documented. Measuring the presence and severity of
different dimensions, independent from a threshold,
will improve the relevance of the description of patients
pathology. In addition, this dimensional approach will
improve the problems posed by the mutually exclusive
diagnoses (depression and GAD, schizophrenia and
depression); (d) Some disorders are based on the
coexistence of different dimensions. Patients may
present only one set of symptoms and have different
characteristics, evolution and response to treatment.
Y. Lecrubier (&)
Directeur de Recherche INSERM U 302
Hopital de la Pitie-Salpetrie`re
INSERM U 302
Pav. Clerambault
47, bd de lHopital
75013 Paris, France
E-Mail: lecru@ext.jussieu.fr

An example would be negative symptoms in Schizophrenia; (e) Because no etiological model is available
and most measures are subjective, objective measures
(cognitive, biological) and genetics progresses created
important hopes. None of these measures is pathognomonic and most appear to be related to risk factors
especially at certain periods when associated with
environmental events. One of the major aims for a
classification of patients is to identify groups to whom a
best possible therapeutic strategy can be proposed.
Drugs may improve fear extinction while the genetic
and/or acquired avoidance may be called phobia. The
basic mechanism and or the corresponding phenotype
should appear in the classification. Progresses in early
identification of disturbances by taking into account all
the information available (prodromal symptoms, cognitive, biological, imaging, genetic, family information)
are crucial for the future therapeutic strategy: prevention.
j Key words diagnosis classification psychiatry
ICD DSM

Introduction
Our knowledge concerning the classification of mental disorders progressed substantially with the use of
DSM III-IV and IDCD 10 [2, 47]. The identification of
diagnostic entities was based on observed data with a
precise definition of criteria. The association of these
new diagnostic systems with well-defined and wellcontrolled strategies to collect the information in
relation with diagnostic criteria [24, 38, 42] produced
crucial data both for the organisation of mental health
care and for a better understanding of the diagnoses
as they are currently defined.
Both approaches (DSM or ICD) avoided introducing any etiological factor or treatment response
related data in the definition of a diagnosis or of a

clinical subtype. Diagnostic criteria are based on a

categorical approach where diagnostic entities share
common phenomenological features. Of course,
implicitly, each of these categories is probably produced by one or different specific etiological factors.
Mental disorders defined by DSM or ICD are of
major healthcare importance since at least one third
of the general population will suffer from one of
theses diagnoses in their lifetime [17, 35] with extremely disabling consequences (size and burden of
mental disorders in Europe, Eur. Neuropsychopharmacology [39]). Making sure that the current diagnostic criteria are valid and are fitting with effective
prevention and therapeutic strategies is therefore a
major health care problem. This paper will underline
the existence of contradictions and or inconsistencies
most often identified by the data produced when
using DSM or ICD criteria. It will also refer to some
proposals made to improve these difficulties.

Is the categorical approach valid?

The data produced when using the DSM/ICD, based
on the phenomenological features, are unfortunately
not consistent with the hypothesis of the existence of
independent nosological entities. In addition, biological and therapeutic data also challenge the validity of
the current classification.
If disorders are independent categories the coexistence of other disorders within a specific disorder
should be just by chance. In fact this is not the case.
The coexistence of two or more disorders during a
chosen period of time is much higher than by chance.
Actually this comorbidity is the rule: as an example
when exploring the presence of mental disorder lifetime, patients with a single disorder are only 1020%
[44], (Fig. 1). The existence of comorbidity is clinically very relevant; it impacts on functioning and also
on suicidal risk [22]

Fig. 1 Proportions of NCS-DSM-III-R disorders with

other lifetime mental disorders (derived from [44])

The independence between the different disorders

also implies the stability of diagnosis. Again, data
show that in the majority of patients who present a
lifetime comorbidity, anxiety disorders such as agoraphobia or social phobia precede the onset of major
depression (MDD) [35].
The exception to this sequence is for generalised
anxiety disorder (GAD): the age at onset, the symptomatology and family history are very close to those of
major depression. For these reasons grouping current
disorders into larger spectrum entities is proposed in
different areas of psychiatry [43] such as depression
and GAD spectrum, panic and phobia spectrum,
obsessive compulsive disorder spectrum including
eating disorders and pathological gambling [34].

What limits to define normality?

The DSM/ICD approach implies that diagnostic categories are limited by thresholds defining the border with
normality. The number of symptoms, their duration,
severity and some of their consequences on functionality should all reach a certain level. Subthreshold
conditions present with a smaller number of symptoms,
or a mildly shorter duration. As a consequence the
subjects are considered to be normal. Unfortunately
the clinical relevance of subthreshold conditions has
been shown repetitively [23]. Those patients with subthreshold depression [13] or with some residual
symptoms after an antidepressant treatment [32] will
develop a major depression on the short term (Fig. 2).
When assessing the diagnosis of patients who attempted
suicide the existence of subthrehold mental disorders
identifies more than 90% of attempters with a psychiatric disorder. It also confirms that most attempters
present with more than one psychiatric disorder
including subthreshold conditions [3].
As a consequence a good evaluation of all relevant
dimensions whether they reach the threshold pro-

74,1

Any anxiety disorder

81

PTSD

87,3

Agoraphobia

83,4

Simple Phobia

81

Social phobia

92,2

Panic disorder

89,8

Generalized anxiety

82,2

Any mood disorders

99

Mania/Hypomania
91,3

Dysthymia
83,1

Major depression
0

25

50
Proportions (%)

75

100

8
Residual or Subthreshold Depressive
Symptoms vs Recovery
Survival Distribution Function

1.0
Asymptomatic recovery (n=155)
Residual SSD recovery (n=82)

0.8
0.6
0.4
0.2
0.0
50

100

150 200 250 300 350 400

Weeks to First Prospective Relapse

450

500

Fig. 2 Subthreshold symptoms predict the onset of major depression [13]

100
80
60

threshold

40
20
0
Dim 1

Dim 2

Dim 3

Dim 4

ality, their evolution is not necessarily associated with

that of positive symptoms, their onset is often before
diagnostic criteria are met and they are the most
potent predictor for a poor long-term outcome. [19].
The therapeutic response to negative symptoms is
either mild for some antipsychotics or almost absent
[30]. Indeed they are a valid entity representing a
major therapeutic unmet need. Because they were not
recognised as a specific subtype for therapeutics, antipsychotics had all to be effective on positive symptoms before their effect or negative symptoms were
explored. Most of the biological correlations were
explored in the full group of schizophrenics while the
relevance may be only for those with NS or even a
subtype of NS (e.g. Chonicity and/or just a symptom
such as anhedonia present in only about half of
schizophrenics but possibly playing the role of a potent organiser of future pathology [45].
There is now a consensus to recognise NS as a
diagnostic subtype and as a justified therapeutic target (ECNP consensus meeting 2004 [30]). For any
dimension recognised as having face validity, identified with specificity on sensitivity a diagnostic subtype could be recognised, however this should remain
in the context of the current DSM/ICD diagnosis, e.g.
NS of schizophrenia.

Fig. 3 A dimensional approach is needed

Genetics and nosology

posed by criteria or not is certainly a better description of patients pathology (Fig. 3).
This dimensional approach also improves difficulties created by mutually exclusive diagnoses within
a categorical approach. Examples of this difficulty are
the exclusion of the diagnosis of GAD in patients with
MDD since anxiety is part of the criteria of MDD. A
similar exclusion is currently proposed for depression
when it is observed in the context of schizophrenia.
Still, in both cases the description of two symptomatologies is relevant for predicting the evolution and
to organise a therapeutic strategy [8].

Because no satisfactory etiological model was available

in psychiatry many hopes were created by the progresses in genetics. The initial expectations were that a
major breakthrough would be the consequence of
exploring specific genetic variables versus a disorder
(as a categorical entity). Data do not support this
linear approach. As pointed out by Kendler 2006 [16].

Are some dimensions or syndromes relevant?

There is evidence that one or several of the same genes

impact on the risk for developing different disorders
Familial aggregation of a single psychiatric syndrome
provides limited evidence for syndromic validity.
Gene discovery is not adequate for categorical psychiatric diagnoses.
In addition, genes are not necessarily discrete entities

The definition of some disorders is based on the

coexistence of several syndromic dimensions. Some
patients may present the symptoms of only one of these
dimensions with a specific impact on treatment and
outcome. The problem is therefore to decide whether
such a dimension is a relevant diagnosis or diagnostic
subtype. A crucial question when biological or genetic
information is associated with a pathological entity.
It has been suggested that this is the case for
negative symptoms (NS) in schizophrenia; 15% of
schizophrenics present with only NS. The identification of NS is specific and sensitive, they have face
validity (decrease or loss or a normal function), they
are responsible for a major impairment of function-

However, subjective assessment may be improved

by genetic foundations and, if the genetic approach
is not fitting with the nosological description it is
still very useful to clarify the role of genetic and
other factors in the etiology of psychiatric disorders.
Different trials show that only the combination of a
genetic subtype with specific events at a certain
point of time during development of an individual
creates a risk factor for developing a disorder. The
serotonin transporter (5HTT) presents with different
alleles able to modify the uptake function. The L
(long) or S (short) alleles are present in normal as
well as in depressed patients. However, if the individuals with the S allele are exposed to a large

9
Fig. 4 Schizophrenia: multiple genes of small effect
and specific events at a certain period

COMT

Neuregulin

Dysbidin

Disc 1

Mild congnitive &

Motor decits

Social & cognitive Pbs

Dierent reactivity & behaviour

Dopamine striatal dysfunction

Motivational salience
Prepsychotic feelings

Others

Birth trauma, hypoxia,

Low weight

Isolation, low
Hierarchical position

Cannabis

Migrants, urban area,

daily events

Onset of Psychosis

number of early stressful events the risk to develop

depression is much higher than in those who experience the same stressful events but have the L 5HTT
allele [6].
It is crucial to better understand whether preventing such a combination during the sensitive
period prevents the development of further pathology.
Clearly this information should be embodied in the
description and identification of patients if one wants
to progress in the prevention of mental disorders.
The multiplicity of gene-environment factors at
different stages of development may be illustrated by
the data available in schizophrenia.
We know that heritability is very high in schizophrenia; however, no single gene explains a substantial
increase of the risk for presenting schizophrenia
Multiple genes explain a small part of the increased risk and some of the genes overlap with an
increased risk for Bipolar disorder [5]. Worldwide
variations exist in the prevalence of schizophrenia
with an increase in urban areas (size of the town and
duration of exposure) especially for migrants [33,
40]. In addition, early events such as birth trauma,
hypoxia or low weight at birth also increase the
likelihood to develop schizophrenia [4]. Mild cognitive and motor deficits are observed very early
while later a different reactivity is observed in social
and emotional interactions. Therapeutic data (antipsychotics are dopamine receptors blockers), the
psychotic reactions induced by dopaminergic stimulants, and these social and emotional withdrawal
suggested some dopaminergic dysfunction which was
found repeatedly. In 1996, Laruelle et al. [21] already
had shown an excessive release of dopamine in
schizophrenia after an amphetamine challenge. Such
an increase could be related to positive symptoms
and in parallel may be responsible for impaired
prefrontalcortical functions which may be related to

negative symptoms and cognitive dysfunction [15].

As a consequence, in 2005 Kapur et al. [14] proposed
the concept of dopaminergic motivational salience
where reward is associated with attention and goal
directed behaviour. When an excessive salience is
induced by increased striatal dopaminergic functions
small daily events are given an excessive personal
significance, delusions may try to explain these
unjustified experiences.
Cannabis increases the risk to develop schizophrenia in individuals who present with these premorbid features but only in those who present with a
COMT enzyme responsible for a lower degradation
of dopamine [7]. A polymorphism of the COMT
gene (valine to methionine substitution at codon
158) produces an enzyme with reduced activity for
dopamine degradation. It is unclear whether this is a
susceptibility gene for schizophrenia, but the association with cannabis consumption increase very
substantially the risk for developing the disorder [7].
This is a clear example of a gene environment
interaction.
Figure 4 tries to summarize some of these findings
in order to underline how important it is to take these
data into account on one hand and how different this
approach is from the usual nosological approach.
In general, different phenotypes in conjunction
with specific events at certain periods during life appear to be relevant factors to develop (or to be protected from) one or several disorders [10]. Patients
with a diagnosis may present with different genetic/
environment combinations. When such combinations
are scientifically well established and are relevant for
treatment or prevention strategies it would be
important to consider this as a subtype within the
frame of a broader diagnosis (e.g., individuals with
some premorbid features of schizophrenia, the COMT
subtype and an important consumption of cannabis).

10

Does the classification describe appropriate

psychopharmacological targets?
Indeed if one of the major aims of classification is to
identify patients, in order to propose them the best
possible therapeutic strategy the current nosology do
not fit with psychopharmacological data. Antidepressants are the best treatment of most anxiety disorders
[37]. Some atypical antipsychotics are used in nonpsychotic patients. The difficulty is rather similar to
that described for genetic findings; nosology is not
necessarily the best target for a therapeutic effect. As an
example cycloserine facilitates fear extinction. It was
shown to be effective in acrophobia [36] and in social
phobia [12] but not yet in agoraphobia. Currently, the
indication could be restricted to acrophobia and social
phobia while in fact the only indication remains...
facilitation of fear extension whether this is useful in
different disorders and/or only in some patients within
a disorder. This is the challenge of introducing some
mechanisms of action or some biological subtypes as
relevant therapeutic targets. Another example would be
in the field of depression. Limbic-cortical connections
differentiate responders from non-responders to
treatment. Abnormalities are described in the limbic
pathway of non-responders [41]. In practice when
using deep brain stimulation adjacent to Broadman
area 25, a substantial proportion of patients, with
treatment resistant depression respond [26].

The future of surrogates

A total of 85% of patients with schizophrenia suffer
from a cognitive deficit, may be all of them [29].
These deficits (executive function, working memory,
verbal memory, attention) are a better predictor of
social functioning than even positive symptoms [27].
The new atypical antipsychotics may improve cognitive deficits in schizophrenia while the older antipsychotics did not [11]. This type of surrogate is more
likely to be associated with biological findings and
therapeutic interventions. It is therefore tempting to
use a range of cognitive tests to assess whether a
treatment improves schizophrenics cognition (see
ECNP consensus meeting 2004 [30]). The NIMH
MATRICS initiative identified potential tests to measure this broad area with a battery taking just about
one hour to administer. The specificity of the measure
and its clinical relevance are currently in an evaluation process. Surrogates of this nature are not yet
used in any classification; however, it is very likely
that they will be validated within some years.

Early identification of high-risk populations?

When biological, psychological and clinical features
evoke a prodromal stage indicating the existence of an

important risk for developing a disorder, a nosological entity should be available. Such patients do not
necessarily need any intervention on the short term
but we know that earlier interventions are the most
effective and in addition improve outcome [20, 28].
Prevention and/or postponing the onset of some
disorders such as schizophrenia are becoming very
relevant strategies with cognitive treatments [9, 31] or
with drug treatments [46].

Conclusion
During the last decades multiple possibilities for a
large number of heterogeneous therapeutic interventions developed. In order to match these possibilities
we need to create different heterogeneous set of
information to better describe the corresponding patients. All the relevant available information should be
used. Symptoms, cognitive surrogates, phenotypic
characteristics, environmental problems, genetic data
and family history may be associated for an early
identification, good prevention, and/or an appropriate therapeutic strategy.
All these additional information are currently relevant only in the context of the usual DSM/ICD categories especially if a dimensional approach improves
clinical description.
j Disclosure There is no conflict of interest. The corresponding
author assures that there is no association with a company
whose product is named in the article or a company that markets a competitive product. The presentation of the topic is
impartial and the representation of the contents are product
neutral.

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