Towards diagnostic markers for the psychoses

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From psychosis to psychoses: diagnosing psychotic disorders in the 21st century 2 Towards diagnostic markers for the psychoses Stephen M Lawrie, Michael C O’Donovan, Elyn Saks, Tom Burns, Jeffrey A Lieberman

Psychotic disorders are currently grouped under broad phenomenological diagnostic rubrics. Researchers hope that progress in identifying aetiological mechanisms will ultimately enable more precise division of heterogeneous diagnoses into specific and valid subgroups. This goal has been an aim of psychiatry since the 19th century, when patients with general paresis were thought to have “insanity” similar to dementia praecox and manic depressive illness. Nowadays, the constructs of organic-induced and substance-induced psychotic disorder show that our diagnostic classification system already reflects, in part, aetiological factors. Most recently, gene copy number variation and autoimmunity have been associated with schizophrenia. We suggest how, on the basis of recent scientific advances, we can progress the identification of further putative subgroups and make the most of currently available interventions. Prompt diagnosis and treatment, and a more routine search for causes, could preserve function and improve outcome, and therefore be more acceptable to patients and carers.

Introduction The DSM and ICD classification systems for psychotic disorders, although reliable, are often described as invalid and lacking an aetiological or pathological basis. These two criticisms are related but not the same; both are also overstated. There are many ways of validating a medical diagnosis (panel 1).1,2 We know that no psychotic symptoms are diagnostically specific and that no psychotic disorders breed entirely true; rather, they have a tendency to aggregate together in disorders and in families. Treatment response is a potential validator but there are few, if any, specific treatments in psychiatry and it is important to consider that individuals responding to the same treatment do not necessarily have the same disorder. All psychotic disorders seem to be responsive, at least partly, to treatment with antipsychotic drugs, although they do not necessarily respond in the same way to each and every drug. Classification on the basis of disease course or outcome is similarly restricted, because psychotic disorders can have a wide range of outcomes, as is seen in the rest of psychiatry and medicine.3 However, there is a tendency for acute onset psychoses to be brief, for schizophrenia to be more likely to cause long-term disability than are other psychotic disorders, and for the affective and delusional psychoses to be intermediate in terms of outcome. Kenneth Kendler4 elaborated upon this validation scheme, proposing a group of “antecedent validators” including premorbid personality and precipitating factors, and used these to distinguish delusional disorders from other psychotic disorders. The key classificatory goal in psychosis, as in psychiatry and medicine generally, is an aetiological subtyping based upon biological or other assay. Both DSM and ICD classifications have for several editions included aetiological judgments with respect to organic or somatic and the substance-induced psychotic disorders, which www.thelancet.com/psychiatry Vol 3 April 2016

require the clinician to judge whether the psychosis can be attributed to a particular cause. This judgment is often done on the basis of a temporal relation, but can also be informed by physical investigations such as brain imaging or drug screening. Furthermore, we now have evidence of several genetic and autoimmune contributions to schizophrenia. The key question is how to build on these advances to further improve the management of psychotic disorders. In the first paper in this two-part Series,5 we discussed the rationale for the existing diagnostic approach to psychotic disorders and proposed a hybrid categorical–continuous system using continuous variables such as intelligence and duration of psychotic symptoms. In this second part of the Series, we make some suggestions for subgrouping, on the basis of our existing classifications and recent scientific advances.

Lancet Psychiatry 2016; 3: 375–85 This is the second in a Series of two papers about diagnosis of psychotic disorders in the 21st century Department of Psychiatry, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh, UK (Prof S M Lawrie MD); MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK (Prof M C O’Donovan PhD); USC Gould School of Law, University of Southern California, Los Angela, CA, USA (Prof E Saks PhD); Department of Psychiatry, University of Oxford, Oxford, UK (Prof T Burns DSc); and Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY, USA (Prof J A Lieberman MD) Correspondence to: Prof Stephen M Lawrie, Department of Psychiatry, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK [email protected]

Organic and somatic psychosis What used to be called the organic psychoses—ie, dementia and delirium—are both clinical diagnoses that prompt a search for an underlying cause. The dementias are increasingly subdivided by neuropathological or neuroimaging findings and by rare genetic mutations, but there is no neat clinicopathological correlation. DSM-5 includes a section on “Psychotic disorder due to another medical condition” in the chapter on schizophrenia, and stresses endocrine, metabolic, autoimmune, and epileptic causes in particular.6 In ICD-10, codes for organic hallucinosis, catatonic disorder, delusional (schizophrenia-like) disorder, and affective disorder, depending upon the predominant symptoms, are included in the “Organic, including symptomatic, mental disorders” chapter.7 ICD-10 specifically mentions head trauma, intracranial and extracranial neoplasms, Huntington’s disease, vascular disorders, infections, and various drugs (antihypertensive drugs, dopa preparations, steroids, and antimalarial drugs). Neither DSM-5 nor 375

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Panel 1: Strategies for establishing the validity of a clinical syndrome1,2 Clinical description Symptoms and other clinical features are identified and tend to aggregate (internal criterion; content validity) Discrimination from other disorders Demonstration of boundaries from related syndromes (discriminant validity) Disease course Follow-up studies identify a distinctive course or outcome (external criterion; predictive validity) Treatment response Clinical trials establish a distinctive treatment response Family history Family studies establish that the syndrome “breeds true” Biological validation Association with some more fundamental abnormality, whether cognitive or laboratory based (external criterion; concurrent validity)

Panel 2: Neurological disorders associated with an increased prevalence of psychotic symptoms • • • • • • • • • •

Alzheimer’s disease (40%)8 Lewy body dementia Frontotemporal dementia (10%)9 Huntington’s disease Parkinson’s disease Epilepsy (7%)11 Multiple sclerosis (4%)12 Neurosyphilis HIV encephalopathy Head injury

If available, prevalence estimates from systematic reviews are given in parentheses.

ICD-10 cite dementia as a possible cause of psychotic disorder, but many people with dementia have psychotic symptoms.8–10 Several neurological disorders are associated with psychotic symptoms more than expected by chance (panel 2).13,14 Perhaps as many as half of patients with Parkinson’s disease or Lewy body dementia have psychotic symptoms, especially visual hallucinations and misidentifications.14 Roughly 5–10% of patients with Huntington’s disease have, and may present with, “a schizophrenia-like psychosis”.13,14 Findings from robust epidemiological surveys suggest an increased risk of a psychotic disorder with atypical features in people with epilepsy (prevalence in epilepsy: interictal psychosis, 5%; postictal psychosis, 2%),11 and an increased risk of a predominantly positive symptom psychotic disorder in people with multiple sclerosis.12 Also, with regard to neurosyphilis, WHO estimates that 10–12 million new syphilis infections occur every year worldwide and that 376

without treatment, 30% of affected individuals may develop tertiary syphilis and present with general paresis.15 Intriguingly, HIV encephalopathy typically manifests acutely and with mood disturbance.14 However, in terms of Bradford Hill criteria for causation,16 these associations tend to have strength and consistency, but temporal relations are variable and specificity or reversibility with treatment is rarely demonstrated.13,14 Head injury, for example, is probably a risk factor for many psychiatric disorders.17 The factors determining whether someone with dementia or a neurological disorder will or will not develop psychotic symptoms or disorder, or depression, might be similar to determinants in the general population. However, it is at least as likely that different risk factors and biological pathways are implicated in older populations, or in individuals with the physiological disruptions of brain disease. For example, a recent characterisation of frontotemporal dementia caused by mutations in C9orf72 showed that almost half of those patients had delusions or hallucinations, and about a third had parkinsonism, with a median age at onset of 52 years.18 ICD-8 had several codes for listing some organic and somatic psychotic disorders separately according to common underlying conditions, but these were abandoned in ICD-9. Such an approach would make sense if there were specific clinical phenotypes, as may be true of some symptom profiles or in treatment response. For example, repeated observations and trials suggest that the psychotic symptoms or behavioural disruption seen in Lewy body dementia respond best to quetiapine or clozapine, and that risperidone is best avoided.19 Furthermore, the only randomised controlled trial of psychosis seen in the context of systemic lupus erythematosus (known as lupus cerebritis) supports the use of cyclophosphamide.20 The division of organic hallucinosis, catatonic disorder, delusional disorder, and affective disorder in ICD-10 would make sense if it predicted disease course or treatment response. It is not clear how adding the proposed DSM-5 continuous measures of psychopathology will aid diagnosis and classification in an area where subgrouping seems to be progressing, but it might enable more awareness of psychotic symptoms in these patients. Regarding autoimmune psychotic disorder, there has been a substantial increase in interest in anti-N-methylD-aspartate (NMDA) receptor autoimmune encephalitis (DSM-5)6 and limbic encephalitis (ICD-10)7 in recent years. A systematic review of seven available studies reported that 115 (8%) of 1441 patients with schizophrenia or a related psychotic disorder were anti-NMDA receptor antibody positive.21 However, of these patients, only 21 (1·5% of the whole sample) were positive for IgG antibodies, the only (sub)class higher in cases than controls. There is also a remarkable degree of unexplained heterogeneity, particularly in the rates of seropositivity in www.thelancet.com/psychiatry Vol 3 April 2016

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controls, across the studies. Even provisionally accepting the hypothesis of an aetiological role (in patients without evidence of encephalopathy), it is unclear whether antibody-positive individuals differ from those without antibodies in terms of pathology and response to antipsychotic treatment. Nor is it yet clear whether immunomodulators are effective treatments for their psychotic symptoms. There is a more long-standing general interest in autoimmunity, infection, and psychotic disorder. With the notable exception of rheumatoid arthritis (which seems to be negatively associated), many autoimmune disorders are associated with increased risk of psychotic disorder,22 and possibly of schizophrenia in particular. Perinatal, childhood, and adult infections are also associated with increased risk of schizophrenia,23 for which the evidence is probably strongest for Toxoplasma gondii.24 There is also evidence for immune dysfunction in schizophrenia, such as reports of activated microglia in brain tissue and on neuroimaging,25 and altered concentrations of cytokines and other inflammatory markers in cerebrospinal fluid and blood.26,27 Excluding the possibility that these associations are driven by reverse causation or ascertainment bias is difficult,22,27 but recent findings of an enrichment of genetic associations at loci containing genes highly expressed in immune tissues provide support for an aetiological role for altered immune function in schizophrenia. Mechanistic links are, however, still to be made between the genetic variants and altered immune function.28 Nonetheless, several clinical trials have shown that a range of anti-inflammatory drugs can improve symptoms in schizophrenia.29 The use of inflammatory markers to classify psychotic disorder would be premature, because levels are also raised in depression and might simply index behavioural or other changes such as inactivity. Nonetheless, a stratification research agenda is worth pursuing—eg, testing whether anti-inflammatory agents reduce psychotic symptoms via inflammatory pathways or if raised concentrations of cytokines predict response, or both.

Substance-induced psychotic disorder Drugs such as cocaine, amphetamines, phencyclidine, ketamine, cannabis, and even alcohol and opiates have long been recognised to precipitate psychotic symptoms.30–35 Indeed, some of these drugs are sometimes described as hallucinogens or psychotomimetics. The justification of the term substanceinduced psychotic disorder is that psychotic symptoms come on shortly after drug consumption and resolve quickly after cessation, often without the need for treatment. However, with continuing use, stimulants, cannabis, and alcohol seem to be able to cause prolonged reactions resembling schizophrenia, albeit with some apparent differences in epidemiology and biology.33,35–37 The recent emergence and apparently escalating use of www.thelancet.com/psychiatry Vol 3 April 2016

so-called legal highs or novel psychoactive substances, many of which have been proven to be synthetic cathinones, have fuelled concerns about an epidemic of substance-induced psychotic disorder that does not yet seem to have arrived. The wide availability of urine and hair screens for various drugs provides an objective marker of recent drug exposure, and it is usually possible to distinguish intoxication and withdrawal states from a psychotic disorder, but this remains a difficult area to study. Patients with drug histories tend to be non-compliant and often use several drugs at different times. It is difficult to refute the possibility that some full-blown psychotic disorder is brought on by patients self-medicating pre-psychotic symptoms. To complicate matters further, about a quarter of patients with established schizophrenia have a substance use disorder, usually cannabis or alcohol.35–39 However, for the most commonly used drugs, progress has been made in our understanding. Several cohort studies have shown that about 25–50% of patients who continue to take drugs after a diagnosis of substance-induced psychotic disorder develop schizophrenia or a related disorder, whereas those that stop taking drugs will probably remain well.40,41 There are clear differences between the age at onset of some substance-induced psychotic disorders and schizophrenia—younger in cannabis-induced and older in alcohol-induced psychotic disorder. Furthermore, neuroimaging profiles of both cannabis-induced and alcohol-induced psychotic disorder can differ from those in schizophrenia.35 These differing associations might reflect differing biology. Most stimulant and hallucinogenic drugs exert their effects by prompting dopamine release in reward centres of the brain, perhaps especially in individuals with low dopamine states (and possibly exacerbating them). How then can substanceinduced psychotic disorders be associated with what is the usual dopamine overdrive of schizophrenia? The likely answer is that they are not.42 Two imaging studies concur in showing that cannabis-dependent individuals, like other drug-dependent groups, have reduced dopamine synthesis.43,44 This finding is in keeping with animal studies showing that chronic cannabinoid exposure induces a hypodopaminergic state resulting from altered presynaptic mechanisms controlling dopamine release, with the concurrent development of postsynaptic D2 and D3 receptor supersensitivity.45 Furthermore, this finding fits with some replicated evidence that genetic variation affecting postsynaptic D2 receptor signalling could render some individuals more vulnerable to cannabis-induced psychotic disorder.33 So, the critical abnormality in cannabis-induced psychotic disorder might be at, or downstream from, the D2 or D3 receptor rather than in dopamine release. Further replication of this hypodopaminergic state would provide a biological validation for classifying substance-induced psychotic disorders separately to schizophrenia. 377

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Schizophrenia Classification problems Schizophrenia remains idiopathic, in that most patients do not have known causes, although 5–10% of patients have organic brain disease or neuroimaging anomalies of possible clinical significance, or both.46,47 These possibilities are under-investigated in most services. This situation brings us back to a central paradox of our existing classifications. If, as we identify aetiological subgroups of schizophrenia, we classify them separately from the clinical diagnosis that is schizophrenia, then schizophrenia shall always remain idiopathic.

Polygenic risk One indisputable fact about the major psychotic disorder diagnoses is that genes contribute substantially to aetiology, with heritability of around 70–80% for schizophrenia and bipolar disorder, and, depending on severity, 40% for recurrent major depression.48,49 A recent study analysed genome-wide single-nucleotide polymorphism (SNP) data for these disorders.50 The results showed that common alleles make an important contribution to the overall variance in liability to schizophrenia, bipolar disorder, and major depression. This measure of SNP-based liability was highly correlated between schizophrenia and bipolar disorder, but also between schizophrenia and depression—two disorders not usually regarded as phenotypically similar.50 The identification of genetic variants that are associated with an array of disorders, and the fact that disorder results when a threshold of genetic liability is reached, parallels findings in the rest of medicine (eg, autoimmune disorders). The molecular underpinnings of schizophrenia might be more varied than the symptomatic diversity. In what is now a very fast-moving discipline, 108 independent loci have been identified for schizophrenia and eight loci for bipolar disorder type I.28 Risk-associated alleles can also be used to generate risk profile scores; although, thus far, these scores do not have useful diagnostic properties. When pleiotropy is added into this mix, a genetic approach to the diagnosis and classification of psychotic disorder through common variants seems unlikely,51 but this situation might change as more of the variance is captured, particularly when scores are embedded within algorithms including other genetic and non-genetic data. Such data might also be used to inform predictions about whether the approximately 25% of patients with acute or brief psychotic disorders, or an at-risk mental state will get schizophrenia, and to stratify patients for likely response to different therapies, perhaps even by specific mutations.

Copy number variations (CNVs) During the past decade, high-density genomic arrays have established that rare (<1% frequency in the population), submicroscopic chromosomal deletions and 378

duplications known as CNVs occur at higher frequencies in patients with schizophrenia than in healthy controls. About a dozen recurrent CNVs have been implicated in schizophrenia at strong levels of evidence, including deletions of the NRXN1 gene, and deletions and duplications at 1q21.1, 15q13.3, 16p11.2, and 22q11.2. Together, about 2–3% of schizophrenia cases carry one or more of the known risk CNVs between them, compared with about 0·5% of unaffected people.52,53 CNVs might be of more direct diagnostic use than SNPs because many confer large increments in risk (odds ratio 2–60). However, all of these known pathogenic CNVs also increase the risk of one or more other neurodevelopmental disorders such as autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epileptic phenotypes. For example, deletion at 22q11.2 increases risk of a psychosis, which is usually schizophrenia, but it also increases the risk of ADHD, intellectual disability, anxiety, and depression.54 CNVs have also been implicated in bipolar disorder, particularly in early onset cases, but the evidence is less consistent.54 The factors that determine which particular diagnoses are manifest in any one individual are unknown, but probably include the full range of factors that determine risk of these disorders in the non-CNV-carrying population (eg, environmental factors, polygene profiles, and even chance). Because of the relatively high rate by which the CNVs occur, and the high probability (in some cases approaching 100%)55 for one or other neurodevelopmental disorder in family members who also carry a CNV, as well as other non-psychiatric disorders such as cardiac or immune deficits, there is an increasingly strong case for considering CNV screening and genetic counselling for patients with a psychotic disorder who wish it, and have been informed about the possible implications for family members.

Other neurodevelopmental psychotic disorders Benjamin and colleagues56 describe no fewer than 60 congenital and acquired disorders that can present with psychotic symptoms in young people. However, these disorders are not all recognised causes of schizophrenia, but some (such as sex chromosome aneuploidies57) clearly increase the risk of schizophrenia and others might do so.58,59 Few of these disorders can be treated any more than symptomatically, but genetic testing and counselling might be beneficial. 18 (30%) of these disorders have distinct phenotypes (termed “doorway diagnoses”), but most are easily overlooked without a standard neurological and laboratory assessment, including examination for dysmorphic features. Another 30% are associated with intellectual disability. Even mild intellectual disability (intelligence quotient [IQ] 50–70) is associated with a four-fold increased risk of schizophrenia.60 Conversely, a disorder called “propfschizophrenie” has been proposed, in which early onset schizophrenia causes apparent intellectual www.thelancet.com/psychiatry Vol 3 April 2016

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disability.61 Both extremes of intelligence seem to be risk factors for psychosis, as may be an IQ decline in adolescence.62 General cognitive ability is reliably indexed with standard methods of measurement, stable over time in health, and associated with life outcomes ranging from academic and vocational success to health and mortality.63 These and other considerations5 provide strong arguments for the routine measurement of intelligence in psychosis. Intelligence could be a useful biomarker for identification of patients who need more support, including those that could benefit from particular drugs, neurostimulation techniques, or psychosocial approaches that might enhance cognitive function as and when available. Clinicians should also be alert to the possibility of comorbid autism spectrum disorder and ADHD traits and appropriate, tailored drug or social skills therapies.

Diagnostic biomarkers An objective diagnostic test for schizophrenia that is not (largely) explained by somatic disease, substance misuse, CNVs, or other genetic anomalies would be valuable and could serve to highlight other subgroups. The overlapping, polygenic, and multifactorial risk factors for the different psychotic and indeed other disorders, reduce the chances that any such marker will have the requisite effect size and specificity, at least not on its own.64 However, some candidates exist, although few have been assessed in a rigorous fashion.65,66 The most important of these potential biomarkers are some well replicated differences in brain structure and function between patients with schizophrenia, bipolar disorder, depression, and controls. Measures of structural and functional connectivity are perhaps more likely to be sensitive to disorders characterised by dysconnectivity at an imaging systems level and abnormal synaptic plasticity at the neuronal or molecular level,67,68 but these techniques are much less well standardised. These differences are probably quantitative rather than qualitative,69 but even a straightforward structural MRI sequence, when analysed with multivariate pattern classification approaches, can accurately distinguish schizophrenia from controls in about 80% of cases and distinguish patients with schizophrenia or bipolar disorder with similar accuracy.70,71 Many technical and practical issues remain, including the need to analyse and return results on an individual patient basis in a population sample.72 There is also an array of potential proteomic and transcriptomic markers of schizophrenia,73 but these are often subject to many lifestyle or treatment confounders. Even when tested, they tend to be diagnostically non-specific,74 and are yet to be related to dimensions such as psychopathology.

risk prediction is commonplace in medicine for diagnosis and prognosis, especially for the effect of treatment in reducing the risk of adverse outcomes, but is rare in psychiatry.75 However, there is consistent evidence that ultra-high-risk criteria for three clinical risk syndromes— mild or brief psychotic symptoms, or non-specific symptoms plus schizotypy or a family history—predict psychosis (usually schizophrenia) in about 25% of patients during the next 2–3 years.76,77 The inclusion of other symptoms or cognition, or both, in multivariate models increases predictive power, although the particular symptoms or tests to use is far from clear.65,78 Neuroimaging can predict who will or will not develop psychosis with quite impressive predictive properties with univariate,65,79 and especially multivariate, approaches.70,71 Some evidence even shows that early diagnosis and treatment is associated with better outcomes for patients.80 Higher positive psychotic symptom scores tend to predict response to antipsychotic drugs.81 There are as yet no clinically useful predictors of response, resistance, patients who need antipsychotics to avoid relapse, or patients who might benefit from clozapine,65,66,82,83 but research is seeking to explore a combination of neuroimaging, cognition, genetic, clinical, and demographic information. Genes and neuroimaging focused on glutamate biology could, for example, be able to identify non-responders to standard antipsychotic drugs,84 and conceivably patients who might require early introduction to clozapine. Similarly, attention and memory could predict progress in social skill training programmes, and composite measures may be associated with response to supported employment and other rehabilitation.85

Antecedent validators Simple clinical measures could still have predictive or therapeutic value. Indeed, Robins and Guze1 showed that a family history of affective disorder can predict a good outcome in schizophrenia, as did many older studies,86 but this research has not been systematically pursued. Auditory hallucinations that consist of commands as opposed to memories might denote a subgroup of “voices” in patients who have been maltreated as children.87 These individuals might benefit from tailored psychological interventions as well as (or even more than) antipsychotic medication. Subgrouping by psychosocial risk factors in this way is of course akin to a diagnostic formulation for management in traditional clinical practice. Ultimately, however, whatever refinements are made, phenomenologically based diagnoses will always have restricted precision.

Schizophrenia-related psychotic disorders Multivariate risk prediction

Acute and transient or brief psychotic disorder

For a diagnosis to be of value, over and above the simple objectification of the concept, it should ideally prompt management that will improve outcome. Multivariate

Disorders that could be grouped together as the acute psychoses are DSM-5 brief psychotic disorder (up to 1 month in duration), schizophreniform disorder

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(1–6 months), and the ICD-10 acute and transient disorders (up to 3 months). These disorders share an acute onset and quick resolution of symptoms that are often schizophrenia-like. They also often have an apparent psychosocial stressor as a precipitant, which was a diagnostic criterion of what used to be called brief reactive psychosis in DSM-III(R) and several European diagnostic terms before ICD-10. Resolution within 1, 3, or 6 months is a highly inconsistent means of subgrouping and has uncertain, if any, validity in predicting outcome, particularly because DSM-5 states that symptoms of schizophrenia can be present for less than 6 months if treated. The validity of schizophreniform disorder can be questioned on several counts,88 not least because most patients will meet criteria for schizophrenia.6 In general, however, there are notable differences in the epidemiology of the acute and transient or brief psychotic disorders from schizophrenia, including a preponderance of female individuals, older age at onset (usually 30–50 years), and better premorbid and social functioning.89 These findings provide at least some face validity for their distinction from schizophrenia. Most patients with psychotic disorders of less than 3 months’ duration can also be reassured that they are likely to have no further episodes or, at most, brief recurrences. The key risk to predict is that of transition to schizophrenia. The subsequent development of schizophrenia typically occurs in 10–20% of individuals and within 5 years, and is more likely if patients are young, male, with poor premorbid function, and have more schizophrenia-like presentations.90 The potential role of psychotic symptom duration, schizophrenia genotyping, neuroimaging, and perhaps peripheral markers of stress such as cortisol concentrations or glucocorticoid receptor gene methylation status in validating acute and transient or brief psychotic disorders or predicting transition has not been examined. However, these disorders are rare (incidence about five per 100 000 population per year), and therefore difficult to study, although they can be more common in developing countries.

Delusional disorders Delusional disorders also have some epidemiology that seems to differentiate them from schizophrenia and affective disorders—eg, they affect both sexes equally, usually when individuals are in their late 40s or early 50s— but share an association with disadvantage and immigration, and a tendency to chronicity.91 One or sometimes more, fairly discrete delusions dominate the clinical picture, but different delusions tend to have somewhat different sex and outcome associations.92 Indeed, there is no satisfactory definition of a delusion that fits all cases, presumably because there are many types of delusion that resist a common definition. Thus, delusional disorders are already subgrouped in both ICD-10 and DSM-5, and some work points to different aetiological or psychobiological underpinnings, or both.93 (The absence of 380

a similar group of hallucinatory disorders in DSM or ICD classifications might demonstrate the greater disability associated with disrupted thought compared with abnormal experiences.) For example, delusions of (morbid) jealousy can have an organic (epileptic or alcoholic) basis, whereas delusions of altered identity (such as Capgras syndrome) can be reactive to circumstance and short lived. However, both types of delusional disorder can be associated with lesions in the frontal lobes.47,93,94 Particular delusional disorders could therefore prompt a search for an organic cause. The rarity of these disorders is a barrier to research, but studies of organic delusional syndromes in dementia could have spin-offs in identifying biomarkers for delusional disorders.

Schizoaffective disorder Jacob Kasanin’s original description of schizoaffective disorder was of a rare, acute onset psychosis with a “blending of schizophrenic and affective symptoms”, notable “emotional turmoil”, resolution within weeks or months, and a good outcome.95 However, by the time the diagnosis was included in DSM-IIIR, schizoaffective disorder was defined by brief mood disturbance and the presence of psychotic symptoms for more than 2 weeks in the absence of mania or depression. The criteria have since been modified, but the distinction between schizoaffective disorder and schizophrenia or bipolar disorder remains a fine one. This distinction reduces diagnostic reliability and argues against the validity of schizoaffective disorder. Several clinical, family, and outcome studies have generally not shown a discrete “third psychosis”, but commentators have been divided as to whether this means that schizoaffective disorder is a subtype of schizophrenia or a psychotic mood disorder. Perhaps the relative time spent in a primarily psychotic or mood disrupted state would be the best way of making a diagnosis of either schizophrenia or bipolar disorder. A systematic review96 concluded that schizoaffective disorder occupies an intermediate position between schizophrenia and bipolar disorder in terms of demographics, symptomatology, other clinical data, dexamethasone suppression test, neuroimaging results, response to treatment, evolution, and family morbidity. However, neuroimaging, genetic, and therapeutic studies of schizophrenia usually include patients with schizoaffective disorder. Nonetheless, there is replicated evidence that the Research Diagnostic Criteria for schizoaffective disorder, bipolar subtype (which has a broader definition than DSM) is associated with gamma-aminobutyric acid (GABA)-A receptor gene markers that are not associated with schizophrenia or bipolar disorder.97,98 If confirmed in further studies, this evidence would argue against the disorder being a simple mixture of bipolar disorder and schizophrenia. Schizoaffective disorder could also have clinical use in predicting treatment response to mood stabilisers and to lithium in particular, because if lithium works at all for schizophrenia-related psychotic disorders, it is in patients with schizoaffective disorder.99 www.thelancet.com/psychiatry Vol 3 April 2016

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Catatonia Catatonia used to be regarded as a feature of severe schizophrenia but it is now a diagnosis in its own right and a specifier of all psychoses (apart from delusional disorders in DSM-5, and organic psychotic disorders or schizophrenia in ICD-10). Catatonia is now regarded as rare in practice, but subtle signs (panel 3) can be seen in about 10% of patients with a psychotic disorder. The importance of the diagnosis or specifier is in identifying treatable causes, such as folate deficiency, and in a possible preferentially good response to benzodiazepines. Ironically enough, catatonia may now be most common in mood disorder.100

Affective psychotic disorders Most patients with bipolar disorder type I will have delusions or hallucinations at one or more points in their lives, but this is true for only a few people with major depressive disorder or recurrent depression, and psychotic symptoms are not required for either diagnosis. There are, however, groups of patients with psychotic symptoms during most illness episodes; for example, individuals with post-partum psychotic disorder, whose symptoms are usually affective in nature.101 The boundary between schizophrenia and affective psychotic disorder, if there is one, is one of the most contested subjects in psychiatry. Clinically, the type of thought disorder and the content of delusions seem to differ qualitatively between schizophrenia, mania, and psychotic depression,6,7,101 but there is much symptomatic overlap, a lack of clear biological differentiation, and clear evidence of substantial overlap in common genetic antecedents, as indeed there is between schizophrenia and major depressive disorder.50 At the time of writing, the success in identifying risk alleles for schizophrenia relative to bipolar disorder might simply reflect the larger sample sizes in studies on schizophrenia, but this difference does not explain the general lack of robust results in major depressive disorder, which might reflect more extensive phenotypic heterogeneity or even smaller per-allele effect sizes. So far, studies of severe and early-onset major depressive disorder subtypes have been no more successful than those that examine undifferentiated major depressive disorder, but this finding could be because of a lack of power. Greater progress might be made with subgroups of psychotic depression or mania, and puerperal psychotic disorder, if large populations could be acquired. Neurobiologically, bipolar disorder and affective disorders generally are less strongly associated with developmental disturbance indicators such as large CNVs (although CNVs are clearly involved)53 or intellectual impairment. Qualitative differences between schizophrenia and bipolar disorder might exist in amygdala volume and activations in emotional centres of the brain.65,102,103 However, many factors affect these heterogeneous results, potentially including personality and substance misuse and www.thelancet.com/psychiatry Vol 3 April 2016

Panel 3: Catatonic signs (three or more are required for the diagnosis in DSM-5)6 • • • • • • • • • • • •

Stupor Catalepsy (passive posturing versus gravity) Waxy flexibility Mutism Negativism (opposition or no response) Posturing (active posturing versus gravity) Mannerism (caricature of normal actions) Stereotypy (non-goal directed moves) Agitation, not influenced by external stimuli Grimacing Echolalia Echopraxia

treatment, which might themselves differentiate the disorders. Indeed, the greatest difference between the disorders might be in environmental risk factors,48 such as migration, which are much more strongly implicated in schizophrenia. There is also no clear biological distinction between bipolar disorder with or without psychotic symptoms, or between major depressive disorder with or without psychotic symptoms. A history of psychotic symptoms is associated with greater severity of neuroimaging, cognitive, and hormonal alterations but these effects are modest.49,65,69,104 However, a clear distinction can be drawn between bipolar disorder and major depressive disorder in that bipolar disorder has a much younger age at onset, recurs more frequently, and is associated with sensation seeking or extraversion rather than intraversion.49 Even though symptoms of subthreshold mania (elevated or irritable mood, and increased activity) can be seen in up to half of cases with major depressive disorder,49 these probably mark an increased risk of bipolar disorder development in those with major depressive disorder,49,105 as well as an increased chance of recurrence, possible risks of prescribing antidepressant drugs, and perhaps a likely response to lithium. Indeed, genetic and epidemiological evidence suggests that mania and depression might represent orthogonal dimensions of psychomotor activity and mood, plus or minus psychotic symptoms.106 A family history of lithium response could potentially identify a clinically useful subtype of bipolar disorder. Furthermore, psychotic symptoms and obesity may associate with lithium non-response in affective disorder, and genomics or insulin resistance could provide biomarkers of treatment resistance.107,108 Ultimately, we need reliable, quantitative predictors of transition to bipolar disorder, recurrence in bipolar disorder or major depressive disorder, and the likelihood of greater benefit than harm from lithium and other treatments. As with schizophrenia and related psychotic disorders, whether these are diagnostic subgroups, symptom severity scales, or biological measures should be an empirical matter. 381

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Panel 4: A suggested research approach to subgrouping psychotic disorders Predominant symptom • Schizophrenia • Mania • Depression • Delusions • Catatonia Reliably measurable continua (which may be categorised) • Duration of psychosis (months or years) • Intelligence (continuous or 15-point subgroups) • Polygenic risk score Categorical measures (more than one may apply, some of which could be measured on continua) • Neurological (eg, epilepsy, head injury, autoimmune) • Genetic (eg, copy number variations, sex chromosome aneuploidy) • Infectious (eg, toxoplasmosis, syphilis, HIV) • Psychosocial (eg, adversity, migration) • Substance use (eg, alcohol, cannabis, stimulant) • Family history (eg, affective disorder, schizophrenia, developmental disorder) • Treatment response (eg, antipsychotic drug, lithium, clozapine)

Panel 5: A research agenda to improve the diagnosis and classification of psychotic disorder • Qualitative and other studies of the social, legal, and ethical implications of a diagnosis • Questionnaire and other studies of the levels of risk at which genetic, imaging, and other investigations for early diagnosis and treatment of psychotic symptoms would be seen as worthwhile • Biological studies that aim to subgroup the psychotic disorders, within and across diagnoses • Register-based and cohort studies of the potential value of combining continua (such as intelligence and duration of symptoms) to improve the clinical usefulness of diagnoses and prediction of outcome • Studies of the clinical and biological determinants of treatment response and outcome • Proactive development of biomarker methodologies and identification of endophenotypic features using available biomedical technologies

Conclusions The clinical constructs we still use in classifying psychotic disorders are often criticised as historical baggage, but they use the tried and tested route for medical advance—ie, subgrouping. Indeed, organic or somatic (0·21%) and substance-induced psychotic disorder (0·42%) together could already explain as much as a sixth of the lifetime risk of psychotic disorders (3·5%).109 The “group of schizophrenias” includes disorders that could be regarded as mainly neurodevelopmental, among which those with pathogenic CNVs, intellectual impairment, and a range of congenital and acquired disorders manifesting fairly early in life might be the most obvious members. Other disorders might be regarded as primarily substance misuse-related, even 382

though other factors (eg, genetic, environmental, and simple bad luck) are likely to be operating. We could also delineate people with psychotic disorders that are potentially attributable to autoimmunity to the group of schizophrenias (panel 4). The next aetiological-led subcategories are difficult to predict, but we might best focus on the presence of known antecedents with strong effects (such as childhood adversity and migration) and the prediction of clinically relevant outcomes such as treatment response to the range of effective remedies we already have at our disposal, especially for treatments such as lithium and clozapine, which have potentially high gains as well as risks. Much of the stratification of disease in general medicine has been driven by established differences in response to treatments. In the near future, rare genetic mutations or particular combinations of common alleles, or both, could define relatively distinct, but overlapping, subtypes of psychotic disorder or allow stratification by treatment response, which might cut across conventional diagnostic classifications. In this Series, we have proposed the novel use of objective continua-like intelligence and the duration of symptoms, along with putative subgroups of psychotic disorder based on our existing classification and recent scientific advances, in a pluralistic approach, by contrast with more agnostic, neuroscience-based classifications.110 The routine measurement of continua such as intelligence and duration of symptoms, both fairly quick and reliable, could further aid subgrouping in a hybrid model of diagnostic categories and continua. Intelligence testing may be controversial but premorbid to current decline or post-onset decline is likely to predict a poor prognosis and could motivate more active treatment and early rehabilitations plans. Eliciting social impairment before or after diagnosis could similarly help to inform management. The combination of genetic, neuroimaging, and perhaps other demographic, clinical, and biological information could allow the subdivision of broad syndromal diagnoses into more precise and homogeneous subgroups, and also guide treatment selection by predicting response in the context of acute and maintenance treatment. Indeed, what is likely to emerge from research that will elucidate genes and genetic mechanisms, the biomarkers characterising endophenotypic measures, and the tried and true historical and phenomenological features, are profiles that will define disorders and guide diagnosis into more precise and valid classifications. Such studies will also need to include considerations of ethical issues, such as willingness to be investigated or informed of results depending on various potential health and wider social scenarios. These approaches may or may not fundamentally change our diagnostic system, but they do at least suggest a research agenda that might help patients (panel 5). www.thelancet.com/psychiatry Vol 3 April 2016

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Search strategy and selection criteria We searched PubMed for systematic reviews and original articles published in English, using the search terms “psychosis” and “diagnosis”, and the specific terms “schizophrenia”, “schizo-affective disorder”, “delusional disorder”, “schizophreniform disorder”, “bipolar disorder”, and “psychotic depression”. We did not apply any restrictions on publication date to our searches and did our last search on Jan 15, 2015. We included qualitative studies, case-control studies, cohort studies, randomised controlled trials, systematic reviews, and meta-analyses. These were supplemented by articles from our collections.

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If, as seems probable, early diagnosis preserves insight and social function, reduces the chances of violence convictions, and aids treatment that improves outcome in other ways, it is likely to be seen as acceptable. Clinicians should be encouraged to recognise the importance of making diagnoses as early as possible when diagnostic criteria are met and not delay treatment and investigation because of concerns for potentially stigmatising terms such as schizophrenia. This delay can potentially worsen outcome. If genetic and imaging data identify subgroups with practical implications, they too might be seen as more worthwhile. Mental health workers must also work with patients and carers, and advocacy organisations and representatives, to try to make the process and communication of diagnoses more acceptable and aid clinical improvement. Ultimately, across all branches of medicine, patients who report good health-care experiences tend to adhere to and respond better to treatment.

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Contributors SML initiated the manuscript, circulated an outline for coauthors to comment on, did the electronic searches, and wrote the first draft. All coauthors edited and revised the first and subsequent drafts.

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Declaration of interests SML has received grants and personal fees from Roche, grants from Pfizer and AbbVie, and personal fees from Janssen and Sunovion. TB has received speaker fees from Janssen. Eli Lilly sponsored a seminar in psychiatric genetics at the Japanese Schizophrenia Society at which MCO’D spoke and for which his department received an honorarium. MCO’D has also received a consultancy fee from Roche, and ES has received a speaker’s fee from Alkermes. JAL serves on the Advisory Board of Bioline, Intracellular Therapies, and PsychoGenics. JAL does not receive direct financial compensation or salary support for participation in research, consulting, or advisory board activities. JAL receives support from Allon, Hoffman-La Roche, GlaxoSmithKline, Eli Lilly and Company, Merck, Novartis, Pfizer, PsychoGenics, Sepracor (Sunovion) and Targacept; and holds a patent from Repligen. Acknowledgments SML acknowledges support from the Dr Mortimer and Theresa Sackler Foundation, Medical Research Foundation, Medical Research Council, Wellcome Trust, and European Commission. References 1 Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 1970; 126: 983–87. 2 Kendell RE. Clinical validity. Psychol Med 1989; 19: 45–55. 3 Kendell RE. The role of diagnosis in psychiatry. Oxford: Blackwell, 1975.

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