Diagnosis of schizophrenia: a 19th Century concept not fit for 21st Century science

‘...certain genetic constitutions, together with mild neuropsychological impairment, confer a general vulnerability to all forms of serious psychiatric disorder.‘

Current approaches to psychiatric classification were developed during the 20th Century, mostly by American researchers who were attempting to refine clinical concepts developed by German investigators in the 19th Century [1]. The concept of ‘schizophrenia‘ is conventionally traced to the work of Emil Kraepelin [2], whose classificatory system evolved through successive editions of his Compendium of Psychiatry. He brought together a number of conditions previously considered to be separate under the label ‘dementia precox‘, which he contrasted with ‘manic depressive illness‘, mainly on the grounds that a poor outcome was evident in the former condition, but not the latter. Eugen Bleuler subsequently objected to Kraepelin‘s label on the grounds that the illness was neither a dementia (deterioration, although common, was not inevitable) nor ‘precox‘ (onset was commonly late in adolescence but could occur at any point during adult life) [3]. Bleuler‘s concept evolved into our present conception of schizophrenia, mainly as a consequence of the work of Kurt Schneider [4]. He proposed that the condition could be most easily identified on the basis of a collection of ‘first-rank‘ symptoms, which were mainly specific types of hallucinations and delusions. Hence, not only did the label for this illness change over time, but also its essential characteristics. For Kraepelin, cognitive deterioration was the core of the condition, whereas for Bleuler a   number of subtle emotional and psychological characteristics were more fundamental. Although Schneider denied that his first-rank symptoms were the most important in the condition (he was a clinical pragmatist and chose them because they were easy to spot), his work led to modern definitions that emphasize positive symptoms. In a historical account, Mary Boyle has argued that many of Kraepelin‘s patients may not have met modern criteria for schizophrenia, speculating that they were instead suffering from viral encephalitis [5].

The concept of schizophrenia has played a central role in the struggles to devise a universally acceptable system of psychiatric classification that is fit for the purpose. For example, it was the discovery that American psychiatrists were more willing to use this diagnosis than their UK colleagues [6], together with concerns regarding the alarming extent to which different psychiatrists in the same hospital would give different diagnoses to the same patients [7], which led to attempts to develop an approach that met formal criteria for reliability. The authors of the third edition of the American Psychiatric Association‘s Diagnostic and Statistical manual (DSM-III) [8] that used a Chinese-menu style checklist of symptoms, believed that they had solved this problem. This approach is therefore adopted in current diagnostic criteria, such as those in DSM-IV [9] and the International Statistical Classification of Diseases and Health Related Problems 10th Revision [10].

Much of this work has been driven by the assumption that psychiatric disorders are brain diseases, similar to those studied by neurologists. Therefore, in parallel with these developments, there have been attempts to define the underlying pathology of the condition and hence refute the arguments of the infamous American critic of psychiatry, Thomas Szasz [11]. He suggested that schizophrenia could not be a disease as there was no neuropathology associated with it. However, the apparent successes of these endeavors have created as many problems as they have solved.

Kety famously argued that, “If schizophrenia is a myth, it is a myth with a strong genetic component” [12], and genetic investigations have consistently yielded high hereditability estimates for the disorder [13]. In adult patients, the presence of numerous but difficult to define structural brain abnormalities [14], and the fact that many patients respond to dopamine-blocking medication, seem to confirm that schizophrenia is a brain disease. Studies have also shown that schizophrenia patients, however defined, perform poorly on a variety of neuropsychological tasks, for example measures of selective and sustained attention [15–17]. Genetic high-risk [18], birth-cohort [19] and population-based studies [20] have revealed that mild intellectual impairment and delayed developmental milestones are present before the onset of the disorder. The observed associations between schizophrenia and season of birth [21], maternal malnutrition [22] and obstetric birth complications [23] all suggest that early, and perhaps even fetal, brain damage can confer risk of the disorder. Hence, there appears to be ample evidence that schizophrenia is caused by a combination of genetic risk and early neuropsychological impairment.

‘If the 19th Century concept of schizophrenia is to be abandoned, what will replace it in the 21st Century?‘

The problem is that few of these findings are specific to schizophrenia. For example, molecular genetic studies implicate numerous genes, each with a small effect, most of which also confer vulnerability to bipolar disorders [24]. Whenever schizophrenia and affective psychosis patients have been compared on neuropsychological tests, similarities have been more evident than differences [25–28]. Furthermore, the severity of neuropsychological impairment, while predicting impairments in social functioning, does not predict the severity of positive symptoms, such as hallucinations and delusions [17]. Early developmental impairment has also been detected in individuals destined to develop an affective disorder [29], which is also associated with a season of birth effect and maternal malnutrition [30]. Dopamine-blocking drugs seem to be at least as effective in patients suffering from mania as those patients suffering from schizophrenia, and the only study to randomly assign psychotic patients to mood stabilizers and antipsychotics found that diagnosis did not predict a response to treatment [31]. Viewed in this light, the claim that schizophrenia is a specific brain disease seems highly tenuous and it seems more likely that certain genetic constitutions, together with mild neuropsychological impairment, confer a general vulnerability to all forms of serious psychiatric disorder. This hypothesis can be squared with the observation of a peak risk for psychosis in late adolescence, if it is assumed that this is a highly stressful time of life and neuropsychological impairment diminishes individuals‘ capacities for coping.

The lack of specificity in the research findings seems less than surprising when the concept of schizophrenia is itself placed under scrutiny. Although the authors of the DSM have boasted that that modern diagnostic systems are highly reliable (as indicated by the interclinician agreement regarding which patients merit which diagnoses), there has really been a ‘revolution in rhetoric rather than reliability‘ [32]. Even when specially trained clinicians are allowed a considerable time to diagnose each patient, problems regarding reliability persist [33]. These become more severe when raters are allowed to use different methods of collecting clinical information or when competing diagnostic criteria are compared [34]. In one recent study, for example, the number of patients out of 706 who suffered from schizophrenia varied between 268 and 387 according to the precise criteria used [35]. More tellingly, numerous statistical studies, carried out over many years, have never found that symptoms cluster together in a way that concords with Kraepelin‘s theory or any subsequent conception of the disorder [1]. In fact, once arbitrary exclusion rules (which define that patients cannot meet one diagnosis if they simultaneously meet the criteria for another) are removed from the diagnostic systems, it becomes clear that the majority of psychiatric patients meet the criteria for several disorders at the same time [36].

If the 19th Century concept of schizophrenia is to be abandoned, what will replace it in the 21st Century? Some have argued that categorical classifications can be replaced by dimensional conceptions, with patients rated on a series of different continua. For example, patients can be rated according to the severity of their positive symptoms, negative symptoms and formal thought disorder [35]. This approach squares well with recent epidemiological data that show that subclinical psychotic phenomena are surprisingly common in the general population [37–39].

Another approach advocated by the present author is to abandon the pretence that the complexity of psychiatric problems will be adequately captured by any simple method of classification, and instead try to explain the actual complaints (symptoms) experienced by psychiatric patients [1]. On this account, once we have successfully explained why people have hallucinations, delusions, thought disorders and so on, there will be no such schizophrenia left over to explain.

In the last 20 years or so, research motivated by this idea has made considerable progress in delineating the cognitive processes involved in particular complaints. For example, hallucinations seem to be a consequence of a breakdown in the process of ‘source monitoring‘, whereby we distinguish between our verbal thoughts and the speech of others [40]. However, paranoid delusions appear to be the consequence of biases in the way in which individuals gather and make sense of information regarding negative life experiences [41]. One virtue of this approach is that it has generated new hypotheses regarding the biology of mental illness. For example, neuroimaging studies confirm that auditory hallucinations are associated with the activation of the brain centers involved in the generation of speech [42] and recent elecrophysiological studies have begun to trace the neural pathways involved in our ability to discriminate between our own thoughts and what other people say [43]. The effect of dopamine-blocking medications on mania and positive symptoms becomes less mysterious once it is recognized that dopamine neurones are involved in motivational processes and not cognition, and that these drugs abolish the conditioned avoidance response in animals [44]. Consistent with these observations, a recent study found that, in the first-degree relatives of schizophrenia patients, an abnormal dopamine response to an experimental stressor predicted extreme emotional reactions to everyday events, but did not correlate at all with neuropsychological functioning [45].

It is to be hoped that, by further studying the actual experiences of patients, rather than by grouping patients into arbitrary and heterogeneous groups, a new generation of interventions will be developed that target specific complaints. Already, some novel psychological treatments seem to offer some promise both for patients with chronic or acute psychosis [46–50] and for individuals who are highly vulnerable to developing a psychotic disorder [51].