The impact of classification on psychopharmacology and biological psychiatry

Abstract

Nosological classification in psychiatry, as it is currently applied, does not facilitate biological and psychopharmacological research.

• Syndromal acuity has disappeared. Consequently, it is impossible to determine: (i) vi/hether a particular drug affects a particular symptom configuration; (ii) what exactly the behavioral correlate of a particular biological disturbance is. The problem of unfocused diagnoses is greatly magnified by the phenomenon called comorbidity.

• The boundary between distress and disorder is illdefined.

• Symptom configuration and certain nonsymptomatological variables such as duration and severity are prematurely linked, so as to conceptualize categorical entities. The validity of those constructs has not been sufficiently demonstrated. This undermines the validity of biological studies and leads to “nosologomania,” ie, an ever-growing series of undervalidated psychiatric “disorders.”

• Symptoms are grouped horizontally as if they all had the same diagnostic “valence.” This, however, is highly unlikely.

• The nosological disease model is unconditionally and uncritically accepted. Alternative models are ignored, particularly the reaction-form model, though it has substantial heuristic value, and deserves to be thoroughly scrutinized.

(Research) strategies to remedy this situation are pointed out.

Premises of the nosological disease model

The nosological disease model has dominated psychiatry ever since its introduction in 1863 by Kahlbaum.¹ However, this model is not an empirical one, based as it is on the core premise that disturbances of the “psychic apparatus” manifest themselves as discrete entities. In actual fact, this core premise itself rests on two “subpremises.”

The first “subpremise” is that psychiatric disorders are characterized by a particular symptomatology, course, outcome, treatment response, and, in principle, pathophysiology. The words “in principle” are important to stress that little is known, so far, about the neurobiological basis of mental disorders. The word “particular” implies that mental disorders are intrinsically stable, so that recognizing a particular type of syndrome allows reliable predictions to be made concerning course, outcome, treatment response, and (in principle) pathophysiology, and, conversely, that if the pathophysiology is known, then predictions can be made relative to possible type(s) of resulting syndrome(s), course, outcome, and treatment response.

The second “subpremise” postulates that each disease entity can be distinguished and individualized with respect to neighboring diagnostic constructs. It is therefore based on this core premise and its two attendant “subpremises” that mental diseases have been conceived of as discrete entities, and that, accordingly, diverse taxonomic classifications of mental disorders have been put forward.

Antinosology and neonosology

The nosological disease model encountered its first serious opponent with the advent of psychoanalytical philosophy during the first half of the 20th century. This school of thought regarded (deviant) psychological development and related inner conflicts as the decisive generators of abnormal behavior, and set itself the task of analyzing and diagnosing them. Phenomenology was deemed of subordinate importance, and pathophysiology inconsequential. By definition, an individual's life course and inner conflicts are essentially unique, making generalizations about mental disorders well-nigh impossible, and a taxonomy of mental disorders virtually meaningless. Of particular note is the fact that psychoanalytic schools remained mostly outside mainstream academic psychiatric centers in Europe, whereas in the USA they were to dominate academic psychiatry for many years.

During the 70s, a nosological revival set in, heralded by the publication of Feighner's Research Diagnostic Criteria (1972) ,² which reached its pinnacle in 1980 with the publication of the 3rd edition of the Diagnostic and Statistical .Manual of Mental Disorders (DSM-III).The taxonomy of DSM-IIT was constructed on nosological principles and defined a large number of discrete disorders based on symptomatological and some nonsymptomatological criteria, such as duration, severity, and course. The DSM system was based on consensus opinion and reviews of the literature rather than on systematic empirical studies. This was inevitable inasmuch as doing otherwise would have set back for years the publication of the first operationalized and standardized psychiatric taxonomy. Since DSM-III there have been two revisions (DSM-III-R and DSM-IV), yet without confirmation of the numerous diagnostic constructs that had been introduced. Validating studies were unable to keep pace with the rate of publication of new versions, and the field studies carried out toward this end were simply insufficient.

The International Classification of Diseases (I CD), drawn up by the World Health Organization (WHO), followed a similar fate. The 10th edition of the ICD (ICD-10), completed in the 80s, operationalized the diagnostic criteria for mental diseases and formulated decision trees to arrive at particular diagnoses. ICD-10 was likewise based on expert opinion and reviews of the literature. Experts from some 40 countries were involved in the project. A steering committee coordinated the activities of the different working groups, and the revision was finally put before and approved by a combined WHO/Adamha conference in 1985. For both DSM-IV and ICD-10, primary care versions are available, in which diagnostic criteria are simplified, several subtypes eliminated, and emphasis is placed on conditions encountered in everyday practice. Only in the case of ICD-1 0 was a version for researchers published, in which diagnostic criteria were defined in greater detail (DCR10). Like the DSM, the ICD system has a multiaxial structure, but the axes differ in both publications.

Sustained efforts are being made to homogenize the two classification systems where possible. DSM is far more used in psychiatric research than the ICD system, which explains why the following analysis is DSM-oriented. Nevertheless, most of the considerations presented here are applicable to the ICD taxonomy as well.

Psychiatric diagnosing; past and present

Some 40 years ago, the framework of psychiatric diagnoses was profoundly different from the way it looks today. On the one hand we gained, on the other hand we lost.

Then, psychiatric diagnoses were chaotic, in that standardized and generally accepted diagnostic criteria were lacking. Without too much exaggeration one could claim that every “school” of some renown had established its own taxonomy. Hence diagnoses were poorly comparable. Methods to assess abnormal human behavior were nonexistent. This situation was rather disastrous for research, particularly biological research, dependent as it is on a precise and valid definition of the object of study. Diagnoses at that time were inaccurate, but refined, at least in Rurope, due to the two dominant philosophies in psychiatry back in those days: phenomenology and psychoanalysis. In order to make a diagnosis, one was required:

• to provide a detailed account of the symptomatology of a given patient;

• to pay due attention to the experiential consequences of the symptoms;

• to describe in detail the psychogenesis of the disorder, ie, the alleged relationship between the complex: psychological development/personality structure/psychotraumatic event on the one hand, and the present psychopathology on the other.

In 1980, the third edition of the DSM appeared and the changes it brought about were profound. In a way they signified immense progress. A standardized and operationalized taxonomy was introduced that gained worldwide acceptance almost overnight by the psychiatric community, clinicians, and researchers alike.

However, the price that had to be paid for those benefits was high, in that the diagnostic process coarsened and markedly lost out in terms of sophistication, a statement that will be clarified in the next section. Is this accusation a fair one? Can a classification system be blamed for shortcomings in the way we make a diagnosis? After all, classification of psychiatric disorders is, or rather ought to be, the end point of the diagnostic process, in which all data concerning symptomatology, causation, and course of a psych opathologi cal condition crystallize in a single construct. In actual practice, however, classification is much more than that. To a considerable degree classification systems steer the diagnostic process. Psychopathological data tend to be viewed and interpreted in such a way as to fit as far as possible the diagnostic categories available.

The impact of classification on the diagnostic process is more profound the stricter and more detailed a taxonomic system spells out the diagnostic criteria. The influence that the DSM has exerted on the diagnostic process from the third edition onwards is a case in point.

Our trainees learn, as it were, to diagnose with a copy of the DSM in their hand or at least at the back of their mind. That which is not included in the DSM seems to have become almost irrelevant.

Since classification impacts on the making of a diagnosis, and since precise and valid diagnoses form the very bedrock of clinical psychopharmacology and biological psychiatry, classification has had and continues to have a profound influence on the development of those disciplines. Progress is slowed down if the definition of a diagnostic category is loose, if its validity is in doubt, or if available diagnostic categories do not fit clinical observations.

In the following sections, I shall endeavor to show to what extent the current diagnostic system has furthered or impeded progress. The group of mood disorders, in particular the construct of major depression, will be used as a paradigm, but the same reasoning can be applied to most of the diagnostic constructs currently distinguished.

Problems of validity

Predictive validity is the basic quality any diagnostic construct should possess. A diagnosis, once made, should allow reliable prognostication of symptoms, cause, course, outcome, and response to treatment. This is clearly not the case as far as the diagnostic construct of major depression is concerned:

• The diagnosis of major depression is based on evidencing X out of a scries of Y symptoms, irrespective of which ones. This construct therefore encompasses a wide range of syndromes without providing any information on the type of depressive syndrome thus observed.

• Major depression can be precipitated by a variety of etiological factors, psychological, biological, or related to living conditions. In some instances, no precipitating factors are demonstrable.

• With regard to pathophysiology, current hypotheses postulate a causal role of serotonergic dysfunction and hypothalamo-pituitary-adrenocortical (HPA) axis disturbances. These have indeed been found to be associated with major depression in some patients, but not in others, without these patient subgroups coinciding with any of the currently distinguished depression subtypes. Furthermore, disturbances of these systems are not specific to depression, but occur in other diagnostic categories as well.³-⁴

• Course and outcome also fail to show a characteristic pattern.^5,6 Some patients only develop a single episode, whereas the majority of them experience several. One patient may recover completely, another will suffer from residual symptoms, and in another still chronicity will set in.^7,8

• Treatment response, finally, is difficult to predict. Antidepressants may achieve complete recovery, partial response, or no response at all. Psychological interventions will be helpful in some patients, or totally useless in others.

The construct of major depression therefore shows great variability at almost every diagnostic level. Hence there is no question of any predictability being associated with the diagnostic characteristics: no single characteristic is reliably predictive of any other. In other words, the predictive validity of this construct is all but null.

Not only does the construct of major depression encompass a wide range of syndromes, but in the majority of cases it is also associated with other disorders, most notably personality and anxiety disorders.^10-13

Thus it appears that major depression is not so much a diagnostic entity as a diagnostic multiplicity. What we have is an aggregate of disorders, which although they do share some symptoms, are by no means congruent and, in addition, differ in terms of course, outcome, treatment response, and, one has to assume, pathophysiology as well.

“Coarsening” of diagnosis

As mentioned above, over the past two decades diagnoses have become more reliable but less sophisticated. The reasons for this will now be clarified, taking the groups of mood disorders as a paradigm.

The eclipse ofsyndromal exactitude

Syndromal differentiation has disappeared from the diagnosis of depression. The major depression constructs distinguished by the DSM - major depression and dysthymia - cover a variety of syndromes. Moreover, the two lists of symptoms one can choose from arc, for the most part, similar. Symptomatologically, the constructs resemble two unfocused and largely overlapping slides. I believe that this is detrimental to psychiatric research, particularly biological research. Study of the biological determinants of abnormal behavior requires above all precise definition of the object of study. It is highly unlikely that the search for the pathophysiology of vaguely defined constructs - unclearly demarcated from adjacent entities, probably being repositories for a variety of pathological conditions - stands much chance of success. Likewise, psych opharmacology is poorly served by the way depression is currently diagnosed. The syndromal heterogeneity of diagnostic constructs makes it impossible to demonstrate potential syndromal or symptomatological specificity of a given compound. Since a variety of new antidepressants are under development, several with high biological specificity and thus possibly higher psychopathological specificity than the drugs presently available, the current diagnostic system is a hindrance to psychopharmacological progress.

Do syndromes matter in biological psychiatry and psych opharmacology? They do indeed, and there is sufficient evidence to justify this statement. The syndrome of vital (or endogenous) depression, for instance, is a better candidate for tricyclic antidepressants than the syndrome of personal (or neurotic) depression.^14,15 Vital depression, moreover, is much less placebo-responsive than personal depression.¹⁶ An example of syndromal importance for biological psychiatry is the concept of SeCA depression (stressor-precipitated, cortisolinduced, serotonin-related, anxiety/aggression-driven depression), which I recently introduced. It is a new (hypothetical) depression type characterized biologically by specific serotonergic dysfunctions and psychopathologically by disturbed regulation of anxiety and aggression, both of which are precursor symptoms of the depression and which are considered to be the core features of the depressive syndrome.³

Precise syndromal differentiation seems to me the indispensable counterpart of both biological and pharmacological research in psychiatry.

The comorbidity maze

Comorbidity is very widespread in psychiatry and seriously undermines the validity of research efforts.¹⁷ For example, a depressed patient is included in a depression protocol and also qualifies for the diagnoses of generalized anxiety disorder with occasional panic attacks, alcoholism, and two or three personality disorders. A finding - biological, psychopharmacological, epidemiological, or otherwise - is made. Is this finding related to depression, to one of the other diagnoses, or to components of the syndromes covered by these diagnostic labels? Answers are not on hand. The problem is most often ignored, thus disqualifying most conclusions.

A sensible way to avoid the morass of comorbidity in experimental psychiatry and more particularly in biological psychiatry, is the strategy I have called funclionalization of diagnoses.¹⁸ Diagnosing in psychiatry is generally confined to two tiers: characterization of the prevailing syndrome(s), and a decision as to the best fitting categorical diagnosis or diagnoses. The diagnosticprocess in psychiatry can be widened using a third tier, that of functional psychopathology. This is achieved by dissecting the syndrome into what may be considered the elementary units of psychopathology, ie, the psychological dysfunctions underlying psychiatric symptoms. In a case of depression, for instance, these dysfunctions include disturbances in the regulation of mood, anxiety, and aggression, motoricity, information processing, memory, hedonic functioning, concentration, and others. Psychiatric symptoms are the manifestations of psychological dysfunctions. For example, hearing voices is a symptom; a particular perceptual disturbance is the underlying psychological dysfunction. Functional analysis of a psychiatric syndrome is, thus, fundamentally different from symptom analysis.

“Functionalization” of psychiatric diagnoses is important for several reasons. First, the problem of comorbidly occurring disorders is bypassed (not resolved) by relinquishing the concept of discrete and separate disorders and studying primarily the biology and psychopharmacology of abnormally functioning psychological domains. Second, this approach provides insight into the functional abilities of the patient, ie, which psychological domains are deranged and which are still functioning within normal limits. Third, psychological dysfunctions are measurable, many of them quantitatively This is in contrast to psychiatric syndromes or disorders, which permit, at best, a qualitative estimate of presence and severity. Functionalization is the obvious way to provide psychiatric diagnoses with a sound scientific foundation. If systematically carried through, functional psychopathology will ultimately lead to the equivalent of what pathophysiology is to somatic medicine: the discipline providing an understanding of the deflections in the psychological apparatus that underlie a particular psychiatric disorder.

Horizontal instead of vertical grouping of psychopathological phenomena

In present-day psychiatry, symptoms tend to be grouped horizontally, as if each carried equal diagnostic weight - we just count symptoms. Mood disorders are no exception to this rule. This approach resembles that of the internist who, in a case of pneumonia, would attach the same diagnostic valence to the symptom of fatigue as to the symptom of shortness of breath. In medicine, such an approach would be labeled malpractice. In psychiatry it is officially sanctioned.

A mental disorder can be considered as a composite of psychological dysfunctions, mutually interacting in a complex way. The diagnostic weight of the various components is presumably unequal. Some of them arc primary, ie, the direct consequence of the underlying cerebral substratum; others are secondary, ie, derivatives of the pathophysiological processes. Primary symptoms should be the prime target of research into the biology of the disorder and of therapeutic interventions, given their availability.

Since the work of Rugen Bleuler, the fundamental distinction between primary and secondary symptoms has received hardly any attention. The reason is not difficult to guess: because there were no methods to study the brain, it was virtually impossible to validate the primary/secondary distinction. As a result of advances in biological psychiatry and psychopathology, that argument no longer holds good. Our studies in mood disorders are a case in point. They led us, as mentioned above, to the hypothesis that a subgroup of depression exists in which: (i) serotonergic functioning is demonstrably disturbed; (ii) anxiety and/or aggression dysregulation are the primary psychopathological features and mood-lowering the subsidiary ones; and (III) serotonergic dysfunction and affective vulnerability are causally linked. If true, the proper treatment of such serotonin -related, anxiety/aggression-driven forms of depression would be a compound that ameliorates anxiety and/or aggression via regulation of serotonergic circuits.³ Verticalization of psychiatric diagnoses could fundamentally change the strategy for developing novel psychopharmacological principles. Instead of finding drugs to fight disorders such as schizophrenia or major depression, the goal would shift towards the development of drugs that regulate core types of psychological dysfunction underlying a particular psychopathological state.

Verticalization studies presuppose careful dissection of the prevailing syndrome into its component parts: the psychological dysfunctions. This is another reason why the functional approach should be an integral part of making a psychiatric diagnosis.

Neglect of psychogenesis

A fundamental shortcoming of the prevailing psychiatric taxonomy is the lack of an etiological axis. The rationale for this is the wish to be atheoretical. With today's methodologies, however, it is possible to put forward an etiological hypothesis that is as reliable as any on the presence or absence and severity of particular psychopathological symptoms.

What is most particularly missing is the requirement to formulate a hypothesis on the relationship between axis I and axis II diagnoses. In this context, is the frequent cooccurrence of depression and the complex stressors/personality imperfections a mere coincidence or is it of causal significance in that the latter complex is the pacemaker of the depression? If a causal relationship is probable, biological research into depression (or a particular type of depression) should focus primarily on the determinants of personality disorder rather than on those of depression.

This issue is of no less practical importance. If personality disorder constitutes the primary pathology, its treatment should be a integral part of the management of (certain types) of depression. Consequently, a refined diagnosis of depression should encompass diagnostic scrutiny of personality structure, its possible frailties, and the corresponding life events.

In summary, the practice of judging axes I, II, and IV independently ignores the possibility - probability even - that in depression these three domains broadly overlap, and does not lend itself to the formulation of hypotheses or the carrying out of corresponding research. In psychodynamic psychiatry, relationships between mood, personality, and life events arc taken for granted. In experimental psychiatry, belief in the selfevident has been lost, but with the diagnostic approach that it champions, the remedy could become as serious as the disease.

Categories and clinical realities

Finally, the question should be raised as to what extent the multiplicity of available diagnoses adequately covers the real situation of the individuals who attend our clinics and therapeutic units.

Proliferation of diagnostic categories

From the third edition onwards, the DSM has standardized diagnoses and operationalized diagnostic criteria. Precise syndromal definition has been abandoned, and the diagnosis of depression is tied to a fixed number of symptoms from a given series, regardless of the actual symptoms. Various depression types are distinguished, not on the basis of symptoms, but on their severity and duration. Major depression is defined as severe (at least more severe than dysthymia), time-limited, and of at least 2 weeks' duration, while dysthymia is defined as a less severe, long-lasting mood anomaly. In this way, the DSM system creates “disorders,” characterized by a compilation of nonsymptomatological and (crude) symptomatological criteria.

The dangers of this system are substantial. The number of symptoms necessary to qualify for a particular diagnosis has been determined arbitrarily. A considerable number of syndromes qualify for the same diagnosis. Moreover, much evidence indicates that the diagnostic constructs thus defined have little predictive validity as to their course, outcome, or treatment response.¹⁴ For instance, major depression can occur once in a lifetime or be recurrent; it may remit completely or partially; antidepressants may be efficacious or inactive; and psychological interventions effective or to no avail.

The rigidity of the system and the discrepancies between diagnostic constructs and clinical realities have fueled the need for novel categories of depression. Thus, if instead of showing 5 out of the 9 symptoms listed under the heading major depression the patient has only 2 to 4, the diagnosis changes from major depression to subsyndromal depressive disorder.¹⁹ Individuals with only one depressive syndrome are also included in depression studies, though to date they arc so far diagnostically unclassified:²⁰ If the severity is less than that required for major depression and the duration less than that required for dysthymia, the diagnosis changes to minor depression. Severity criteria, however, arc not specified. If episodes are recurrent and brief (less than 2 weeks), brief recurrent depression is diagnosed.²¹ Brief episodes not rapidly recurrent have so far not received a categorical position. Entities such as those mentioned are currently studied epidemiologically, psychopharmacologically, and otherwise as if they were discrete and separable entities, or discrete and separable subforms of one overarching entity (sec, for example, reference 22). Are those diagnostic constructs true categories, or artefacts generated by a diagnostic system based on nosological premises that prematurely and erroneously conceptualize diagnostic “packages,” which, however, lack clinical relevance? This is still a moot question, but before accepting these packages as valid diagnoses, one should consider and exclude other explanations for the wide spectrum of mood disturbances encountered in clinical practice, besides the DSM-defined categories. I will briefly discuss three alternative explanations for nosological diversity that deserve serious scientific attention.

Worrying is mistaken for depression

People may go through difficult periods and may complain in the face of severe problems once in a lifetime, repeatedly, or chronically. At what point does worrying cease to be worrying and turn into depression? The answer is not known. Psychiatry has failed to study these gray areas systematically. Hence the need to define ever more categories of mood anomalies, particularly with respect to milder forms. Boundary setting, however, is lacking. Is one symptom enough to qualify for the diagnosis of depression or are two enough or should there be a fixed minimum? Is symptom severity a critical feature, and, if so, how should it be defined: in terms of disruption of social and occupational life, decreasing work performance, subjective experience, or observer ratings? Is duration decisive and, if so, what should be the cutoff time? Due to the lack of answers, diagnostic categories have proliferated.

This state of affairs seriously undermines the validity of research data. How can we have confidence in the outcome of epidemiological studies if distress and depression are not clearly distinguishable, but are nevertheless distinguished? TTiis is all the more relevant if the study has been carried out by lay interviewers, with only a brief training and without psychiatric experience, using highly structured, standard interviews of modest clinical sophistication and with only two answers allowed per question: affirmative or negative. I am alluding to instruments such as the Diagnostic Interview Schedule (DIS)²³ and the Composite International Diagnostic Interview (CIDI).²⁴ They have been used in several large-scale epidemiological studies, though poor agreement has been demonstrated between diagnoses based on interviews conducted by lay persons and diagnoses made by psychiatrists.^25,26

How can one explore the biological determinants of depression or the clinical effects of antidepressants if the study group is composed of dépressives and worriers? The pathological substrate of pneumonia and the efficacy of penicillin would not have been clarified if patients with pneumonia and those with a common cold had been confused.

Boundary problems should thus have high priority in depression research, but regretfully they have not. The fact that ever more depression categories are being proposed does not provide much solace.

Partial response is held to be a new depression type

It is generally held that in 60% to 70% of cases depression responds favorably to antidepressants, and this seems to be true for all types of antidepressants. Response to antidepressants is generally defined in terms of ratingscale scores. For instance, a reduction in the Hamilton score of at least 50% identifies someone as a responder. However, more often than not, symptoms attenuate, but do not disappear, or some symptoms disappear but others persist.²⁷ This might have led to proposals for new, socalled subsyndromal depression categories.

Another diagnostic riposte to partial response (a euphemism for partial failure) is the postulate of two depression types occurring together, one responding to the prescribed antidepressant while the other one docs not. I am alluding to the concept of double depression, ie, major depression superimposed on dysthymia.²² Symptomatologically, however, major depression and dysthymia are virtually indistinguishable, differing principally only in severity and duration. How then can one decide whether residual depressive symptoms are the remnants of major depression or continuing dysthymia? Incomplete response is, I believe, a more plausible explanation for residual symptoms than the assumption of new depression types, especially since those novel constructs have, in no time, become the subject of study in their own right.

Unsuitability of nosology for ordering menial pathology

Since its inception as a scientific discipline by Kraepelin, psychiatry has been wedded to nosology as the classificatory principle of mental pathology. Research in psychiatry is disorder-oriented, particularly in biological psychiatry, where the search for markers and possible causes of true disorders, like schizophrenia, major depression, or panic disorder is the major goal. As I have argued elsewhere, abnormal psychic states can be conceived of in a different way, ie, as reaction patterns to noxious stimuli.²⁸ Noxious stimuli will disturb a variety of neuronal circuits and, hence, a variety of psychological systems. The extent to which neuronal disruption will be induced by a noxious stimulus is variable, because it is influenced by personality strength and neuronal adaptability. Psychiatric conditions will therefore lack symptomatological consistency and predictability. For instance, mood lowering is blended with fluctuating measures of anxiety, anger, obsessional thoughts, addictive behavior, cognitive impairment, and psychotic features. These features will vary in intensity and prominence between subjects and, over time, within the same individual. The need to demarcate depression categories is thus never-ending and in essence futile.

The reaction-form model provides an explanation for several other urgent questions facing psychiatry. First, the question as to why most psychiatric patients seem to suffer from a multitude of disorders. According to this model, the co-occurrence of various discrete mental disorders is mainly appearance. In fact, we are dealing with ever-changing composites of psychopathological features. Secondly, the reaction-form model offers an explanation for why, in spite of more than 35 years of intense efforts, no biological markers of categorical entities have been established, whereas the search for correlations between psychological and biological dysfunctions has been quite successful.

The reaction-form model, if valid, would have profound consequences for biological psychiatry The search for markers and, eventually, causes of discrete mental disorders would be largely futile. The most one could do would be to group the multitude of reaction patterns in a limited number of diagnostic “basins,” such as the group of the psychotic, dementia!, and affective reaction forms, each of which, however, would show considerable heterogeneity. Just as it is futile to search for the antecedents and characteristics of, for example, the group of abdominal disorders, so it would equally be foolhardy to hope for the discovery of, eg, the pathophysiology of the “basin” of affective reaction forms. Within the scope of this model, the focus of biological psychiatric research has to shift from the alleged mental “disorders” to disordered psychological domains. It is not schizophrenia, panic disorder, or major depression as such that will be studied, but disturbances in perception, information processing, mood regulation, anxiety regulation, and impulse control, to name but a few. A biology of psychological dysfunctions as they occur in dysfunctional mental states would thus be the ultimate goal of biological psychiatric research. Adopting the three-tier diagnostic approach in psychiatry (adding the “functional” level) would offer the opportunity to explore the relative merits of both diagnostic viewpoints - the nosological and the reactionform model - for experimental psychiatry.

Discussion

Depression research

Before the publication of the third edition of the DSM, the diagnosis of depression was weak in that terminology was not standardized and criteria were not operationalized, but it was strong in that symptomatological analysis was refined (at least in Europe, where phenomenology was in vogue) and etiological analysis prominent (particularly psychogenesis, officered by psychodynamic thinking). At the current time, the diagnosis of depression is strong in that standards are systematized and defined, but is weak in that syndromal specification has been relinquished and axis I, II, and IV data are left unconnected.

Research, and particularly biological research, is greatly hampered by these shortcomings. The depression constructs we study are symptomatologically ill-defined and heterogenous. It is unlikely that they can be considered as “entities” whose features such as biology, genetics, epidemiology, or treatment responses can be properly studied. Moreover, clinical practice indicates that depression, (some) personality deviations, and stressor susceptibility are so tightly interwoven that a hypothesis about their possible interrelationship seems indispensable, not only in terms of treatment, but for the sake of research as well. If it was shown to be plausible that (certain types of) depression (are) is the consequence of personality frailties and corresponding life events, research into the origin of depression would have to shift from depression per se to the underlying personality disorder.

Overlap of disorders

What severely hampers depression research is the fact that depression rarely occurs in isolation. The overlap between mood, anxiety, and personality disorders is so fundamental that discussion of any depression study should include whether the observed phenomena relate to depression, to coexisting anxiety or personality disorders, or to components of these conditions. Generally, this question is carefully avoided - avoidance behavior, however, does not promote progress.

Horizontal vs vertical approach

The diagnosis of depression has regressed to a horizontal level. Symptoms are simply counted, and if a certain number from a given series are present, depression is considered to exist. The essence of making a diagnosis, however, involves a vertical approach ranking symptoms according to their relationship to the pathophysiological substratum underlying a particular psychopathological condition. Symptoms directly related to the substratum should be the prime target of treatment efforts and pathogenetic research.

A prerequisite for the verticalization of diagnosis is functionalization of diagnosis, ie, dissection of the prevailing syndrome(s) into its (their) component parts - in other words, a series of psychological dysfunctions. Those dysfunctions should be charted and measured, whenever possible quantitavely. Functionalization of diagnoses would raise psychopathology to a true scientific level.

New diagnostic categories

Present-day psychiatric taxonomy is based on nosological premises. Mental disorders are considered as discrete entities. For the diagnosis of depression, this philosophy has acted as a straitjacket, for two reasons. First, many mood disorders could not be accommodated in the available categories, and second, the boundary between distress and depression appeared hard to identify. Consequently, there was a need to propose ever more new depression categories, each viewed as an entity in its own right and studied as such. Validity research has, however, not kept pace. This is why this “nosologomania”²⁹ has brought about a strong inflationary trend in depression diagnosis. Moreover, the proliferation of ever more diagnostic categories has magnified the problems caused by comorbidity.

Validity of the nosological disease model

The considerable overlap between mood, anxiety, and (certain) personality disorders raises a question of a fundamental nature, that of the validity of the nosological disease model for depression diagnosis. Can the pathology of affect regulation indeed be subdivided into discrete entities, or is an alternative disease model, ie, the reaction-form model, more appropriate and of greater heuristic value? According to the latter model, affect pathology does not crystallize into discrete “packages,” but manifests itself in inter- and intra-individually everchanging combinations of mood, anxiety, and aggression pathologies. This model provides answers for burning questions where the nosological model remains silent. Why do most patients with affective pathologies qualify for a host of disorders? Why, after searching for more than 35 years, has not a single biological marker for any disease entity been found?

The answer, according to the reaction-form model, is that the so-called “disorders” are artefacts of a categorical classification philosophy and not real disease entities. Disordered psychological domains (and in particular those that are directly correlated with the brain dysfunction underlying a particular state of psychological disorganization) should take center stage in biological psychiatry and psychopharmacology. Functional psychopharmacology, ie, treatment of psychological dysfunctions rather than (pseudo)disordcrs would be the “therapeutic arm” of the reaction-form disease model.

The heuristic value of the reaction-form model is such that it should be studied comparatively as a possible counterpart to the nosological model.²⁹

Guidelines for diagnosis of depression

To avoid the pitfalls discussed here, the diagnosis of depression has to be based on the following pillars: (i) refined syndromal characterization; (ii) introduction of a third (functional) tier in the diagnostic process; (iii) formulation of hypotheses regarding the relation between axis I and II diagnoses; and (iv) systematic study of the “vertical position” of the various psychological dysfunctions constituting the depressive syndrome.

Conclusion

The present discussion has focused on the diagnosis of depression. Much of what has been said is valid for psychiatric diagnoses in general. Hence I believe that serious investigation of the very foundations of our discipline, ie, diagnosis, is indicated.⁴

Based on lectures given at the Congress of the Association of European Psychiatrists held in Copenhagen, September 20-25, 1998 and at the Annual Meeting of the Royal Australian and New Zealand College of Psychiatrists, Christchurch, New Zealand, September 3-7, 1997.