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Biological Boundaries Between Bipolar I Disorder, Schizoaffective Disorder, and Schizophrenia Victoria E Cosgrove1,2 and Trisha Suppes1,2*

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Biological Boundaries Between Bipolar I Disorder, Schizoaffective Disorder, and Schizophrenia Victoria E Cosgrove1,2 and Trisha Suppes1,2* Cosgrove and Suppes BMC Medicine 2013, 11:127 http://www.biomedcentral.com/1741-7015/11/127 $VSSFOU$POUSPWFSTJFTJO1TZDIJBUSZ DEBATE Open Access Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia Victoria E Cosgrove1,2 and Trisha Suppes1,2* Abstract Background: The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate. Discussion: Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research. Summary: For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis. Keywords: Bipolar disorder, Hallucinations, Delusions, Schizoaffective disorder, Schizophrenia, DSM- 5, Genes, Psychiatric medication, Brain function Background distinguishing psychotic disorders [2] and, more broadly, Development of the fifth version of the Diagnostic and all psychiatric disorders [3-5]. On a phenotypic level, the Statistical Manual of Mental Disorders (DSM-5), slated lines of demarcation are concretely outlined in the current for publication in mid-2013, included a reconsideration version of the DSM (DSM-IV-TR; see Figure 1), but the of the relationship between psychosis occurring during clinical features that distinguish disorders are often un- major mental illness, specifically bipolar I disorder (BD I), clear or overlapping at the level of the presenting patient. schizoaffective disorder and schizophrenia. These dis- Further, the DSM’s precise nosology [6] is often incompat- cussions emerged before formal work on DSM-5 began ible with first person experiences of mental illness [7]. based on critical review of the emerging data on the bio- Schizophrenia, which occurs in approximately 1% of logical overlap between disorders seen particularly in the population, may be characterized by dramatic symp- genetics studies [1]. Historically, there has not been toms of delusions and hallucinations, affective flattening agreement about how biological research should best be and amotivation, or negative symptoms. While individuals interpreted to inform nosological boundaries specifically with schizophrenia may need ongoing support to main- tain themselves independently, recovery initiatives have * Correspondence: [email protected] demonstrated that achievement of personal or profes- 1Bipolar and Depression Research Program, VA Palo Alto Health Care System, sional goals and expansion of self-concept are attainable 3801 Miranda Avenue (151T), Palo Alto, CA 94304, USA 2Department of Psychiatry and Behavioral Sciences, Stanford University for individuals with schizophrenia [8,9]. By comparison, School of Medicine, Stanford, CA, USA BD I occurs in about 1% of the population and is © 2013 Cosgrove and Suppes; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cosgrove and Suppes BMC Medicine 2013, 11:127 Page 2 of 7 http://www.biomedcentral.com/1741-7015/11/127 Figure 1 DSM-IV-TR features of bipolar I disorder, schizoaffective disorder, and schizophrenia. notable for its episodic nature with severe but periodic body of research has focused on the genetic and neuro- symptoms of mania and depression. A common manic scientific etiological mechanisms of psychosis given presentation includes reports of minimal sleep accom- that symptoms occur in schizophrenia in addition to panied by increased energy, changes in mood and judg- schizoaffective disorder and BD I, among other psychi- ment, and impulsivity. About 50% of manic episodes atric illnesses (major depression not being considered contain psychotic elements such as grandiosity, frank here) [13-15]. The argument in favor of merging diag- delusions and hallucinations, or paranoia [10]. Even in nostic entities is based, in part, on the idea that cases where manic episodes manifest psychotic content, schizoaffective disorder has proven to be a challenging many individuals may be responsive to medications and differential diagnosis in clinical realms. Its diagnostic essentially return to full functioning with ongoing treat- reliability across both clinicians and treatment settings ment. Schizoaffective disorder, estimated to occur in is poor, and data promoting effective schizoaffective less than 1% of the population, appears to represent a disorder-specific treatments are very limited [16]. midpoint on the pathologic spectrum between BD I and Our aim in this paper is to first briefly and concisely re- schizophrenia with psychotic symptoms predominant view existing lines of biological evidence from behavioral and mood symptoms of mania and depression less evi- and molecular genetics, neuroscience, and psychopharma- dent (see Figure 1) [11,12]. Individuals meeting criteria cotherapeutics in order to determine whether they support for this diagnosis report at least a two-week period or refute the idea of merging diagnoses involving psych- without evidence of mood instability and persistent osis in DSM-5. Given that DSM-5 has chosen to retain psychotic symptoms. In the DSM-IV TR categorization DSM-IV-TR’s operative criteria for BD I, schizoaffective scheme, schizoaffective disorder includes both psychotic disorder, and schizophrenia, the subsequent discussion symptoms and severe mood episodes; however, by defin- willinpartemphasizesomeofthekeyfactorsthatmay ition, there must be periods of psychosis without any have informed the decision to sustain separation of no- disturbance in mood. sologic and diagnostic criteria for BD I, schizoaffective Hallucinations and delusions are typically considered disorder, and schizophrenia. Revisions in DSM-5 to all the hallmark of schizophrenia and mood fluctuations cen- psychiatric diagnoses were made only after balancing tral to BD I; however, psychotic symptoms may be present tensions in creating a manual of psychiatric nosology in both. Although bipolar mood episodes may have an that both adheres to the medical model of psychiatry [4] inherent episodic rhythm, schizophrenia, schizoaffective and is at once accurate, useful, and contemporary [17-20]. disorder, and BD I can all be chronic, lifelong conditions that cause significant functional impairment. Discussion Since both psychosis and mood disturbance may It is helpful to consider competing nosological models constitute core features of schizophrenia, BD I, and involving mood and psychotic disorders before attempting schizoaffective disorder, a debate arose during the early to critically evaluate biological evidence. Kraepelin’s pre-DSM-5 development process about the idea of dichotomous classification of psychosis into dementia merging diagnoses in the revised manual [1]. A substantial praecox and manic-depressive insanity has informed Cosgrove and Suppes BMC Medicine 2013, 11:127 Page 3 of 7 http://www.biomedcentral.com/1741-7015/11/127 earlier iterations of the DSM [21]. However, the National bridge categorical and dimensional classification strategies Institute of Mental Health’s(NIMH’s) Research Domain by including additional intermediate ‘spectra’ diagnoses Criteria, or RDoC, may be a more useful lens through [24,25]. Biological evidence from the domains of behav- which to examine data linking biology and behavior in ioral and molecular genetics and brain morphology and psychosis [22]. The RDoC framework purports a full functioning were considered. Additionally, psychopharma- spectrum, neurodevelopmentally continuous model for cotherapeutics, or differential response patterns to psychi- understanding psychiatric illness that is dimensional in atric medications for psychosis (that is, mood stabilizers, nature and encourages assessment of behavior at genetic, antipsychotics), were interpreted within the broader molecular, cellular, and physiological levels. In other framework of biological mediators and moderators of words, RDoC is a way to digest the relatively common treatment response (Tables 1 and 2). findings that risk genes for one psychiatric disorder are associated with risk for many psychiatric disorders or that Genetic evidence similar changes in brain structure or function are observed Genetic investigations offer a unique vantage point from in many psychiatric disorders [23]. which to consider
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