A salience dysregulation syndrome

Revisions of DSM and ICD are forthcoming. Should the old categoriesof psychotic disorder, in particular the construct of schizophrenia,be retained or is a new system of representation of psychosisin order? It is argued that both scientific and societal developmentspoint to a system of classification combining categorical anddimensional representations of psychosis in DSM and ICD. Furthermore,it is proposed to introduce, analogous to the functional descriptiveterm `metabolic syndrome', the diagnosis of salience dysregulation syndrome. Within this syndrome, three sub-categories may beidentified, based on scientific evidence of relatively validand specific contrasts: with affective expression; with developmentalexpression; and not otherwise specified.

INTRODUCTION

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INTRODUCTION

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A diagnostic construct in psychiatry ideally should: (a) havesome link with a measurable phenotype that exists in nature;(b) be valid in the classic sense of combining aetiological,symptomatic, prognostic and treatment specificity, settingit apart from other disorders; and (c) be useful and acceptable.Previous authors have argued that these three elements in combinationdo not apply to the diagnostic construct of schizophrenia.^1,2 The question, therefore, arises whether anything has changedand, if it has not, whether schizophrenia should continue tofeature in DSM–V and ICD–11.

How does psychosis exist in nature and how does this relate to schizophrenia?

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How does psychosis exist...

The various definitions of schizophrenia and related disordersin DSM, ICD, Research Diagnostic Criteria (RDC) and other classificationsystems in practice combine a mix of positive, negative, cognitive,depressive and manic symptoms in the context of need for care(formal or informal). However, the symptoms that characterisepatients with psychosis seen in mental health clinics are alsoprevalent in the community. A recent meta-analysis reported prevalence rates (around 8%) and incidence rates (around 3%)of positive psychotic experiences that are around 10 (prevalence)and 100 (incidence) times greater than reported rates for psychotic disorder.³ Subclinical psychotic experiences are typicallyexpressed in adolescence and young adulthood and are usually transitory.⁴ Nevertheless, they show a degree of epidemiological,psychopathological, longitudinal, familial and aetiologicalcontinuity with psychotic disorders and even display some syndromalcontinuity with diagnostic constructs such as schizophrenia.³

What are the implications for diagnosis? First, psychotic disordersappear to be unclear in that they blur into normality. Second,when a `first episode' of psychotic illness is diagnosed, itmay in fact be more correct to regard this as the poor outcomeof a phenotype representing subclinical dimensions of psychosisthat is transitory in the great majority of cases.³ Third,if psychotic experiences are frequent, their diagnostic valuewill be low in relation to the rare disorder of schizophrenia.Research has shown that even if the follow-up period is extendedto more than 15 years, the probability of developing a psychoticdisorder does not exceed 25%.⁴ Therefore, understanding thediagnosis of psychotic disorder in part becomes understandingthe onset of need for care (formal or informal) in the context of subclinical psychotic experiences with variable frequency,distress, preoccupation and influence on behaviour.

Schizophrenia: validity?

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Schizophrenia: validity?

A recent study showed that the total lifetime prevalence ofpsychotic disorders is 3.5%, divided over 12 different diagnostic categories.⁵ This prevalence estimate is much higher thanany previous investigation has suggested. Thus, the myriaddiagnostic categories in DSM and ICD that remain without scientificvalidation may have blinded us to the true prevalence of psychoticdisorders, hampering scientific progress.¹

As argued before,^1,2 there is no consistent evidence for specificityin terms of symptoms, aetiology, treatment and prognosis betweendiagnostic categories of psychotic disorders. A traditionalmisunderstanding is to suggest that mean differences on somevariable between traditional categories have diagnostic relevance.For example, first-rank symptoms may be more common in schizophreniathan in bipolar disorder but their diagnostic value is toolow to be of diagnostic significance, as indicated by a diagnosticlikelihood ratio (the likelihood of being a true positive ratherthan a false positive) of less than 2.⁶ Similarly, differencesin cognitive impairment and level of negative symptoms do not translate to diagnostic significance.⁷ Research to date suggeststhat of all psychopathological domains, manic symptoms in particularhave the highest level of specificity and represent the greatestdiagnostic value.⁸ Outside psychopathology, `points of rarity'between diagnostic categories of psychotic disorders are alsorare, although some prominent differences are apparent. The problem, however, is that not all observed differences flowin the same direction. For example, in terms of genetics, itis increasingly clear that there is considerable overlap ingenetic susceptibility across the traditional binary classificationof psychosis.⁹ However, the environmental risk associatedwith growing up in an urban environment may be specific for schizophrenia.¹⁰ Translating these findings to diagnosis wouldmean that one aetiological factor favours `lumping' of categories,at least in part, whereas the other favours `splitting'. Recentmeta-analytic work¹¹ indicates that in both bipolar disorderand schizophrenia, patients and their first-degree relativesdisplay alterations in neurocognition, but in bipolar disorderto a much lesser degree than in schizophrenia. Similarly, the childhood developmental cognitive impairments preceding onsetof schizophrenia are not detectable in bipolar disorder.¹⁰

The challenge for DSM–V and ICD–11 is to make useof the evidence suggesting specificity, such as the relativespecificity of manic symptoms for bipolar disorder and (familial)developmental impairment for schizophrenia,¹⁰ while at thesame time acknowledging that in many other areas no specificity appears to exist. Also, better research evidence for diagnosticvalidity is needed, not just in terms of the classic singlediagnostic dissociation (e.g. variable 1 is associated withcategory A but not category B) or even the double diagnosticdissociation (e.g. single dissociation plus evidence that a second variable, variable 2, is associated with category Bbut not category A), but in terms of evidence that is trulylogically inconsistent with a single underlying process suchas the demonstration of non-monotonic or reversed associationsof validating variables across diagnostic categories.¹² For example, based on this method, Linscott et al showed that,given the assumption that a monotonic process leads to unipolardepressive morbidity in relatives of patients in differentdiagnostic classes, the notion that the same process couldpossibly lead to bipolar morbidity in relatives could be rejected.¹³

Schizophrenia: utility?

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Schizophrenia: utility?

Although the diagnostic constructs of DSM, ICD or RDC schizophreniado not appear to be valid, they may nevertheless be useful`by virtue of the information about outcome, treatment response,and aetiology that they convey'.² However, there may be roomfor improvement. First, a growing number of studies suggest that when dimensional representations (i.e. scoring patients'symptoms along continuous axes of positive, negative, disorganisation,depressive, manic and cognitive symptoms) and categorical representations(i.e. grouping patients in categories of schizophrenia, bipolardisorder, schizoaffective disorder, schizophreniform disorder,etc.) of samples of patients with a range of psychotic disordersare compared in terms of the utility criterion of how much informationabout aetiology, treatment needs and outcome they convey, the combination of categorical and dimensional representationsin these patients does better than either representation alone.¹⁴Second, although some patients and their relatives may findit useful to learn that their experiences can be reduced toa dichotomous medical diagnostic construct, others will feelvictimised by the label of a highly stigmatised medical diagnosisthat paradoxically cannot be validated scientifically.

Therefore, in terms of utility the following conclusions maybe drawn. First, although criticisms about the diagnostic constructof schizophrenia may be deflected with the argument that itis merely a syndrome (the association of several clinicallyrecognisable features that often occur together for which aspecific disorder may or may not be identified as the underlying cause), the problem is that its very name and the way mentalhealth professionals use and communicate about the term resultsin medical reification and validation through professionalbehaviour rather than scientific data, exposing psychiatryto ridicule and hampering scientific progress.¹ It may be argued,therefore, that if it is a syndrome, calling it as such mayserve to remind professionals (and downstream of these, therest of the world) of the relatively agnostic state of sciencein this regard. Second, given the fact that maximum utilityin terms of conveying clinical information may be obtainedby combining categorical with dimensional representations of psychopathology, DSM–V and ICD–11 may be best servedby creating separate categorical and dimensional axes of thepsychopathology of psychotic disorders.

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Fig. 1 Salience dysregulation syndrome. Six dimensions that tend to co-occur make up the salience dysregulation syndrome. Individuals may make the transition from `risk' to `need for care' if they pass the threshold on one or more dimensions, and accordingly may fit sub-categories `with affective expression', `with developmental expression' and `not otherwise specified'. Patient A: `typical' salience dysregulation syndrome with developmental expression; Patient B: `typical' salience dysregulation syndrome with affective expression; Patient C: salience dysregulation syndrome not otherwise specified. Position of subcategories and dimensions with respect to each other is arbitrary.

From schizophrenia to salience dysregulation syndrome?

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From schizophrenia to salience...

Many people with impaired glucose regulation also have severalother continuous cardiovascular risk factors – they havea tendency to occur together. This is referred to as the metabolicsyndrome. Analogous to the metabolic syndrome, although inneed of improving on the weaknesses that since its introductionhave become apparent, many people with positive psychotic experiences,that have been shown to constitute a fundamental alterationin salience attribution,¹⁵ also display evidence of alterationsin other dimensions of psychopathology such as mania, disorganisationand developmental cognitive deficit. This may be referred toas the salience dysregulation syndrome. If the values of the dimensional components in this syndrome rise above a certainthreshold, need for care (formal or informal) may arise. Dependingon which combinations of dimensional psychopathology are mostprominent in this salience dysregulation syndrome and takinginto account which elements have been shown to possess the bestdiagnostic specificity, as discussed above, the categorical representation of this dimensional psychopathology may be expressedusing three sub-categories: with affective expression (highin mania/depression dimension); with developmental expression(high in developmental cognitive deficit/negative symptoms);and not otherwise specified (Fig. 1). The first two sub-categoriesare based on evidence of specificity and the more agnostic categoryof `not otherwise specified' reflects the continuing gap in knowledge.

Research agenda

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Research agenda

It is proposed that the combination of categorical and dimensional representations presented in salience dysregulation syndromebe further investigated, particularly with regard to clinicalutility and patient acceptability, focusing on non-monotonicityrather than traditional single or double dissociations as supportiveevidence. Many issues need to be resolved. For example, researchdata are needed in order to determine whether or not to retain`psychotic depression', characterised by mood-congruent psychotic symptoms, within major depressive disorder. Conversely, researchshould determine whether or not mania without psychotic symptomsshould be classified under salience dysregulation syndrome.Other basic questions include: which symptoms are requiredfor a diagnosis of salience dysregulation syndrome? How toassess developmental cognitive deficits, given the fact thata cognitive measure separating premorbid and current levelof functioning that can be used worldwide for the purpose ofdiagnosis is not available yet? Indeed, which dimensions shouldbe included in this syndrome and which symptoms in each dimension?Should patients scoring highly on both mania and developmental cognitive deficit be retained in the `with affective symptoms'sub-category, using the simultaneous presence of dimensionalratings to show differences in the level of comorbid developmentalcognitive deficit?

Transforming these questions into researchable hypotheses willrequire a major effort but there are many suitable data-setsworldwide in which these and other questions can be addressedin order to develop a more evidence-based and less parochialsystem of diagnosis for patients with severe mental illness.¹¹

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

J.v.O. is a member of the APA DSM–V Psychotic DisordersWork Group. The views expressed are his own. Thanks to ProfessorsRobin Murray and Assen Jablensky, and Drs Judith Allardyceand Catherine van Zelst for critical comments on earlier versionsof this manuscript.

REFERENCES

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