Do we have any solid evidence of clinical utility about the pathophysiology of schizophrenia?

In everyday psychiatric practice, diagnoses are made by noting the constellation of a patient's symptoms, with little contribution from observable signs and virtually none from investigations. This places psychiatry in an unusual, but not unique, position compared to other medical disciplines 1,2. Diagnostic accuracy, prognostication, management plans, and treatment evaluation are dependent on relatively subjective clinician assessments, and thereby prey to undue cultural influences and value judgements 3,4. There is a pressing need for objective tests to improve the classification of psychiatric disorders, to stratify patients into more homogeneous groups, and to plan their treatment accordingly. The current research focus on genetic, protein-based and imaging-linked “biomarkers” could help move from syndromal diagnoses to an etiological and/or pathophysiological classification, as well as aiding research into the identification of therapeutic targets. In the 100 years or so since schizophrenia was first described 5 and named 6, the diagnostic criteria may have been refined, but the process in everyday practice has remained essentially the same. Psychiatrists rely on the patient's description of symptoms, mental state examinations and behavioural observations, in line with the categories listed in the DSM-IV and the ICD-10. In both manuals, the presence of one of Schneider's first rank symptoms (FRS) is usually sufficient to make a diagnosis of schizophrenia. These diagnostic criteria have facilitated research into the causes of schizophrenia, and definite advances in our understanding of its origins and development have been realized. Several risk factors for the subsequent development of schizophrenia are established beyond reasonable doubt 7,8, and an impressive array of genetic, anatomical, functional, neurophysiological and neuropsychological findings regarding the pathophysiology of schizophrenia are now well replicated 9,10. The key clinical question is, however, whether we have learned anything about the nature of schizophrenia that could be useful in the management of our patients. In this review, we address this question in terms of making a diagnosis or an early diagnosis and in predicting therapeutic response. We do this by identifying the most robust findings and discussing their potential applications in clinical practice, in the realms of clinical features, historical information, cognitive testing, serum biomarkers, structural and functional imaging, and electrophysiological indices. As we are interested here in clinical utility over and above statistical significance, we concentrate on studies which provide data in terms of the sensitivity and specificity of the variables as a diagnostic aid, the predictive power of a test result and/or the likelihood that a test result in an individual patient is indicative of schizophrenia. It is worth noting that sensitivity and specificity are generally constant properties of a test, which are useful in service planning but not in dealing with individual patients. The positive predictive value (PPV) or negative predictive value (NPV) of a test result gives the risk level for a particular patient, which is useful clinically, but PPVs and NPVs are prevalence-dependent measures, and performance can therefore vary markedly in different settings 11. Likelihood ratios are a means of using sensitivity and specificity data to calculate the implications of test results in a particular patient 12,13,14. As a rough rule of thumb, likelihood ratios of a positive test result (LR+) of more than 5, and preferably more than 10, increase the risk of disorder by about 30% or 45%, respectively. The latter would, for example, indicate a clear change from a pre-test probability of say 50% (maximal uncertainty) to a post-test probability of 95% (highly likely). This might at first appear to be an alien practice, but it is for example what underpins the use of the CAGE questionnaire in identifying alcohol problems and the Mini Mental State Examination in diagnosing dementia 15,16. The type of study we need for a diagnostic test is a cross-sectional one comparing a representative population of patients and non-cases (controls for diagnosis, other diagnoses for differential diagnosis) who have been evaluated with the gold standard and blindly assessed with the test. For early diagnosis and treatment response tests, we need a longitudinal and preferably prospective study of a cohort of patients evaluated before or after the onset of their condition and followed up until outcome is clear, with preferably less than 20% loss to follow-up. In this review, we sought to identify replicated evidence from systematic reviews for the diagnosis, early diagnosis and treatment response of schizophrenia, in terms of the reliability of the examination, the size of the difference between schizophrenia and controls, and the ability to discriminate versus bipolar disorder. In each of our specified domains, we particularly sought reviews with some consideration of measurement reliability, heterogeneity and publication bias. We favoured reviews reporting an effect size such as Cohen's d of 1 or more, as this roughly and generally corresponds to a 70% non-overlap of data distributions and an odds ratio (OR) of approximately 5 17. In everyday medical practice, history-taking identifies diagnostic “hypotheses”. Evidence for and against these is sought on physical examination and (ideally) confirmatory diagnostic testing. In psychiatry, a similar initial approach is followed by the mental state examination, which includes more explicit evaluation of appearance, behaviour and speech than in the rest of medicine, but also several questions that are just further history gathering and some cognitive testing often of dubious validity. We psychiatrists are curiously averse to physically examining our patients and surprisingly willing to accept “CNS grossly normal” in medical records when this probably means that no neurological exam has been attempted. We might consider possible “organic” explanations for “secondary schizophrenia” and contemplate referral for brain imaging in unusual cases, but that is about as far as investigation is usually taken. To provide some clinical background, and as a comparator for laboratory tests, we first consider the evidence base for key aspects of the clinical examination in making a diagnosis of schizophrenia. Although counter-intuitive, and despite the potential tautology, particular psychotic symptom types are not in themselves strong associates of schizophrenia. Bizarre delusions, for example, are less reliably elicited (mean kappa across studies 0.5 or “moderate”) than delusions in general (0.7 or “substantial agreement”) 18, and have a low specificity, despite a PPV as high as 0.82 in 214 consecutive admissions 19. Similarly, Schneider's FRS have been over-sold as pathognomic, as they are both too rare to be a generally useful diagnostic aid, especially if strictly defined, and too common in other psychotic disorders 20. Peralta and Cuesta 21 recruited 660 inpatients with “the full spectrum” of psychotic disorders and found that any individual FRS usually had a LR+ of 1–2 for schizophrenia, depending on the particular symptom and the diagnostic criteria examined, and no FRS had a LR+ more than 4. There is clear evidence that several variables increase the risk for schizophrenia to a statistically significant degree 7,8,22. Table 1 lists some of these. Indeed, many of these risk factors, and especially family and developmental history, are sometimes used as supportive evidence to make a diagnosis of schizophrenia, but in an informal and variable way. These factors rarely elevate the risk by more than 5x relative to the population risk of approximately that risk to approximately in the presence of a positive family history in a relative is not and reliably the might the presence of such risk factors might be is in differential diagnosis, particularly in settings is more as the may and and developmental may be more for schizophrenia than bipolar disorder the other the risk of schizophrenia is by the risk from any one is and increase the odds of a of one was to make clinical use of the between and schizophrenia, despite the heterogeneity one might into of use is a risk for schizophrenia but it is sometimes that this may not be a that with up use in a to it is clear from that for example, as for with increase the risk of about and delusions more than may therefore psychotic symptoms, and some or at use may be before schizophrenia the standard clinical practice of making a diagnosis of or in and to if schizophrenia is probably We are not however, of any studies examining this practice, or the relative of subjective versus objective of use in so It be clear that we do use risk factors in making a diagnosis of schizophrenia, but as this is our to our patients it is clear that are some physical signs which are risk factors for schizophrenia and of potential pathophysiological physical and however, too and the risk of schizophrenia are to signs are more as it has been that of patients with schizophrenia have observable in and as compared to about of In a systematic and found an effect size of to a between the this effect size is probably by the in such to patient and There however, statistical and evidence of publication to in reliably these named evaluation of may be particularly in patients with the most it is clear that these signs are not to it is to what they the nature of the pathophysiological of schizophrenia, as specificity has been rarely however, that may be more and that have been as clinical and functional outcome the for further research Table There may be value in the reliability and diagnostic specificity of individual signs the of and their and in more than just a cognitive in everyday psychiatric practice is usually with a tests of reliability and validity. cognitive performance is not a research but patients with schizophrenia have a of most of which are at first have in general aspects of and of It however, to whether are over and above general performance There is also heterogeneity between to the of mental state on performance and the that many patients can approach at as well as in the and in are and a pathophysiological of is also the that many of these cognitive appear to be to the onset of with some further in some at after probably by other risk factors, treatment and other aspects of the disorder studies in this have the potential diagnostic utility of are replicated that about of patients a clinical most also appear to be in patients with bipolar disorder and psychotic to 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patients with schizophrenia in the and the of in the which to There is evidence for a of of brain and and in patients with schizophrenia compared to Table for There are similar as with the studies about when these The imaging however, less evidence of heterogeneity across studies and evidence for specificity versus bipolar disorder. imaging is relatively and and the current as an objective diagnostic test for schizophrenia. 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