Does schizophrenia exist?
Criteria- based international classificatory systems like the ICD and DSM have ensured greater reliability for the diagnosis of schizophrenia. These, however, are an index of reliability, rather than validity.
There is an accumulating evidence for shared genetic/ environmental risk factors and neurobiological abnormalities between schizophrenia and bipolar disorder. Much of the evidence accumulated over the past twenty years points to a significant overlap and commonality of genetic heritage between schizophrenia and bipolar disorder. This article attempts to present an overview of the problems in delineating schizophrenia from bipolar affective disorder and suggest some alternatives
Key words: Schizophrenia, Diagnosis, International classification of diseases (ICD), Diagnostic and statistical manual (DSM).
“No experienced psychiatrist will deny that there is an alarmingly large number of cases in which, despite the most careful observation, it seems impossible to arrive at a reliable diagnosis.
“We therefore will have to get used to the fact that the symptoms we have used so far are not sufficient to always reliably distinguish between manic depressive insanity and schizophrenia, but there are overlaps based on the origin of these symptoms from given preconditions.”
Emil Kraeplin (1920). Die Ersheinungsformen des Irreseins. (‘The Manifestation Types of Insanity’)
The question sounds rather strange, one hundred years after Kraeplin teased out dementia praecox (renamed Schizophrenia by Eugene Bleuler) and manic depressive insanity (since christened bipolar disorder) from the common matrix of madness. Yet the title, borrowed from a recent Maudsley Discussion Paper1, is more than mere rhetoric. As Kraeplin himself soon realised, the differentiation was a nosological artefact rather than a naturalistic entity, but it was hoped that once the specific neuropathological constellation underlying the disorder was found, the concept would become more concrete. More than a hundred years on, this has unfortunately not happened.
Over this period the scope of the syndrome waxed and waned, till the advent of the more rigorous, criteriabased international classificatory systems like the ICD and DSM ensured greater reliability of the diagnosis. This was reflected most explicitly in the International Pilot Study of Schizophrenia (IPSS), launched by the WHO in 1967 in nine countries, which demonstrated the cross-cultural comparability of epidemiological data2, as well as a remarkably stable clinical picture3 and lifetime prevalence rates of around 1% across national boundaries4,5. These data, however, are an index of reliability, rather than validity. Irreverent critics6 have compared this to McDonald’s hamburgers, which taste the same regardless of where you buy them, Delhi or Detroit. The same holds good for the Burger King product which, though different in taste from the Macburger, is as reliable. This leaves the crucial issue of validity open and he consumer has only the vendors’ word that the product contains meat. Does it, really? Substitute MacDonald with DSM and Burger King with ICD and the picture becomes clearer. The diagnosis of schizophrenia in both systems identifies individuals who are seriously unwell but who have little else in common: ‘as no symptom is pathognomic or necessary, but variable subsets of symptoms can be sufficient for the diagnosis, patients may be allocated to the diagnostic category of schizophrenia without having a single symptom in common’7. Many patients have significant mood as well as psychotic symptoms8, with the former often posing higher risk and requiring greater therapeutic effort9. Clinical features show a high degree of variability between individuals and within the same patient at different points of time7. The course and outcome of the disorder varies widely, and the consistently observed better prognosis, on five out of six course and outcome dimensions regardless of the acuity of onset, in developing countries3 has not been satisfactorily explained, though several contextual, primarily psychosocial factors have been proposed10.
There is accumulating evidence for shared genetic/ environmental risk factors and neurobiological abnormalities between schizophrenia and bipolar disorder11. Imaging studies have failed to reveal any consistent patterns of brain pathology and while a recent computational morphometry study flagged some grey matter changes specific to schizophrenia, this finding was undermined by white matter abnormalities common to both schizophrenia and bipolar disorder12.
Evidence from molecular genetics
Potentially the most lethal blow to a unitary concept of schizophrenia comes from recent work on molecular genetics. Extensive genetic research, involving numerous candidate genes and multiple loci, has failed to identify any specific gene variance or combination specifically associated with schizophrenia13,14. Much of the evidence accumulated over the past twenty years points to a significant overlap and commonality of genetic heritage between schizophrenia and bipolar disorder. In an editorial in the British Journal of Psychiatry, Craddock and Owen summarise some of its main elements:
(a) Family studies indicate co-aggregation between schizophrenia and bipolar disorder, and between schizoaffective disorder and schizophrenia/bipolar disorder.
(b) Recent evidence from an appropriately designed twin study15 suggests that certain genes confer susceptibility across the spectrum of schizoaffective disorder, schizophrenia and bipolar disorder.
(c) Systematic whole-genome linkage studies of schizophrenia and bipolar disorder implicate some chromosomal regions in common, consistent with shared susceptibility genes.
(d) Variations in some recently identified genes, like the G72/G30 locus on chromosome 13q and DISC1, are associated with risk of both schizophrenia and bipolar disorder, and, in the case of the latter gene, schizoaffective disorder.
Reviewing the vast volume of literature on the subject, Jablensky7 attempts to articulate a rational point of view which merits verbatim citation: “The overview of evidence suggests that phenotypic variability has been confounding the search for the causes of schizophrenia since the inception of the diagnostic category. Attempts at redefining its boundaries by either ‘lumping’ or ‘splitting’ strategies have been undertaken over decades, with limited success. Most such attempts, based on various rearrangements of clinical symptoms and syndromes have ended in a failure to find natural boundaries between proposed clinical subtypes, either by locating a ‘zone of rarity’ between them, or by demonstrating a nonlinear relationship between the symptom profiles and a validating variable. The inconsistent and poorly replicated results of genetic linkage and association studies using the diagnostic category as the sole schizophrenia phenotype are kindling discontent with the current nosology of schizophrenia, based on the recognition that ‘current nosology, now embedded in DSM-IV, although useful for other purposes, does not define phenotypes for genetic study. It is now almost certain that the current broad diagnostic concept of schizophrenia does not demarcate a specific genetic entity”.
Search for a way out
This climate of discontent has had several sequelae. At the level of clinical practice it has created confusion and a search for pragmatic alternatives. There is a general reluctance to diagnose schizophrenia except in the most severe cases and, in consequence, its use has declined more than 100% since the 1960s16-18. At another level, the concept of schizophrenia spectrum disorders has gained ground19, based on the observation reported by Bleuler himself way back in 1920 and subsequently reinforced by the findings of the Danish-US adoptive study20,21 that the genetic legacy of schizophrenia is shared with vulnerability to other related syndromes. The schizotypal disorder in ICD-1022 lies at the core of this concept.
However, the most intriguing and promising concept to emerge from the ongoing dialectic has been that of the endophenotypes: measurable components along the pathophysiological pathway between aetiology and psychopathology23. Though associated with the clinical disorder, these may not be part of the diagnostic criteria, are detectible before the onset of the active illness/during remissions, and have a genetic basis, being present amongst ‘normal’ family members with frequency higher than that for the general population24. The large number of candidate endophenotype markers identified and under investigation include following:
1. Cognitive (continuous performance tests, attention/ vigilance based subtype, verbal dysmnesic subtype, verbal memory deficitcortical/ subcortical, dysexecutive type, prefrontal executive/working memory, frontal/ abstraction deficit profile, spatial working memory).
2. Neurophysiological (electrodermal deviance, prepulse inhibition of startle response, deficient gating of auditory evoked response, P300 amplitude reduction/latency delay, N400 amplitude reduction, mismatch negativity, SPEM).
3. Neurological (soft signs, composite laterality phenotype, nailfold plexus visibility) and,
4. Neuroimaging (fronto-thalamic grey matter deficit, fronto-stratal grey matter deficit, hypofrontality, MRI-derived 3 factor and whole brain nonlinear pattern phenotypes)7 .
It is conceivable that at some point in the not too distant future, the validation of some of these endophenotype markers may provide simple and inexpensive tests to facilitate early identification and targeted intervention in serious mental disorders8.
Where do we go from here?
Where then do we stand today? Does schizophrenia exist? Probably not. At least not as a homogenous diagnostic monolith initially visualised by Kraeplin. This will have major implications for treatment and the need for care model proposed by Jim van Os offers significant advantages25. A major spin-off may be in the vexed realm of stigma reduction and might render redundant calls for renaming schizophrenia, to which Japanese mental health professionals acquiesced in Aug 82, substituting the term with togo byo, ‘integration disorder’26. The time to jettison the concept finally is, however, still some distance away in the future and the situation was best summed up by McKenna, while concluding his robust defence of schizophrenia, “as a good working hypothesis, useful until genuine aetiological groupings are discovered, at which time no one will be very surprised that it ultimately turned out to be more than one disorder”27.
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4. World Health Organisation. International Pilot Study of Schizophrenia, Vol 1. Geneva: World Health
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9. Hogarty GE, McEvoy JP, Ulrich RF, DiBarry AL, Bartone P, Cooley S, et al. Pharmacotherapy of impaired affect in recovering schizophrenic patients. Arch Gen Psychiatry 1995; 52: 29-33.
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21. Kety SS, Wender PH, Jacobson B, Ingraham LJ, Jansson L, Faber B. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Arch Gen Psychiatry 1994; 51: 442-55.
22. World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. Geneva: World Health Organisation, 1992: 95-7.
23. Weiser M, Van OS J, Davidson M. Time for a shift of focus in schizophrenia: from narrow phenotypes to broad endophenotypes. Br J Psychiatry 2005; 187: 203-5.
24. Gottesman Il, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636-45.
25. Van Os J. A diagnosis of schizophrenia? In: Does Schizophrenia Exist? Maudsley Discussion Paper No 12. Institute of Psychiatry, Kings College,London 2003:7-13.
26. Sato M. Renaming schizophrenia: a Japanese perspective. World Psychiatry 2006; 5: 53-5.
27. McKenna P. Schizophrenia is a valid concept. In: Does Schizophrenia Exist? Maudsley Discussion Paper No 12. Institute of Psychiatry, Kings College, London 2003: 14-27.