Psychiatric Annals

CME Article 

The Neurobiology of Schizoaffective Disorder

Shreedhar Paudel, MD; Hannah Brown, MD; Oliver Freudenreich, MD, FACLP

Abstract

Despite ongoing controversies, schizoaffective disorder remains a separate diagnosis under schizophrenia spectrum disorders in the Diagnostic and Statistical Manual for Mental Disorders, fifth edition. Clinically, schizoaffective disorder has symptom overlap with both schizophrenia and bipolar disorder with psychosis. In this review, we discuss clinical features, brain structural changes, neurodevelopment, neurocircuits, and the genetics of schizoaffective disorder. We also address the similarities and differences in underlying neurobiology of schizoaffective disorder, schizophrenia, and bipolar disorder with psychosis. Finally, we discuss the schizoaffective disorder diagnosis in the context of a transdiagnostic approach to psychosis. [Psychiatr Ann. 2020;50(5):190–194.]

Abstract

Despite ongoing controversies, schizoaffective disorder remains a separate diagnosis under schizophrenia spectrum disorders in the Diagnostic and Statistical Manual for Mental Disorders, fifth edition. Clinically, schizoaffective disorder has symptom overlap with both schizophrenia and bipolar disorder with psychosis. In this review, we discuss clinical features, brain structural changes, neurodevelopment, neurocircuits, and the genetics of schizoaffective disorder. We also address the similarities and differences in underlying neurobiology of schizoaffective disorder, schizophrenia, and bipolar disorder with psychosis. Finally, we discuss the schizoaffective disorder diagnosis in the context of a transdiagnostic approach to psychosis. [Psychiatr Ann. 2020;50(5):190–194.]

Schizoaffective disorder is often considered a controversial diagnosis, but the consensus is that it is a chronic psychotic illness with significant affective symptoms leading to functional impairment. The Diagnostic and Statistical Manual for Mental Disorders, fifth edition, (DSM-5)1 has included schizoaffective disorder under schizophrenia spectrum disorders as an independent diagnosis. To meet criteria for schizoaffective disorder, the patient must have experienced delusions or hallucinations without any major mood episodes for at least 2 weeks, at least one major mood episode, and mood symptoms should be present for the majority of duration of illness.1 Using both a categorical and dimensional approach to diagnosis, schizoaffective disorder is situated between schizophrenia and bipolar disorder with psychotic features.2,3 Molecular and genetic studies reveal significant overlap between schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Moreover, neuroimaging and neuropsychiatric evaluations suggest that schizoaffective disorder is almost indistinguishable from schizophrenia but different than bipolar disorder with psychosis. Despite significant clinical and biological similarities, further studies are needed to conclude that schizoaffective disorder aligns with the neurodevelopmental model proposed for schizophrenia.4 In this selective review, we compare the clinical, neurobiologic, and genetic features of schizoaffective disorder, schizophrenia, and bipolar disorder with psychosis.

Clinical Features of Schizoaffective Disorder

By diagnostic criteria, schizoaffective disorder is a separate disorder; however, clinically, schizoaffective disorder is frequently indistinguishable from schizophrenia. As the diagnostic stability and reliability of schizoaffective disorder has been questioned, delineating the natural course of the disease can be challenging.5 A longitudinal follow-up study found schizoaffective disorder as the most unreliable psychiatric diagnosis, and a recent systematic review found only moderate reliability of the schizoaffective disorder diagnosis.6,7 Thus, diagnosing schizoaffective disorder can be difficult, and the epidemiology and natural course of the illness is unclear. Prior epidemiological studies suggest that schizoaffective disorder is more common in women than in men and highly heritable. Although clinical features suggest that schizoaffective disorder falls in between schizophrenia and bipolar disorder with psychosis,8,9 a longitudinal follow-up study found no differences between schizophrenia and schizoaffective disorder in terms of clinical outcome.10 Similarly, a recent study examining key cognitive functions and social cognitive measures concluded that schizophrenia and schizoaffective disorder are largely indistinguishable.11 A Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) study similarly suggested that clinical characteristics of schizoaffective disorder and schizophrenia were closely related, although there is much less overlap between schizoaffective disorder and bipolar disorder with psychosis.12 Another B-SNIP study used the Schizo-Bipolar scale to evaluate clinical features of schizophrenia, schizoaffective disorder, and bipolar with psychosis. The study included 762 people with DSM-IV diagnosis of schizophrenia, schizoaffective, or psychotic bipolar disorder from 6 different sites in the United States.13 The scale scores range from 0 (representing the most bipolar-like) to 9 (representing the most schizophrenia-like lifetime symptoms). In the study, psychotic symptoms and mania or depressive symptoms represented schizophrenia-like and bipolar-like symptoms, respectively. People with schizoaffective disorder had mid-range scores, representing a disease entity between schizophrenia and bipolar disorder with psychosis.14 A dimensional approach in psychiatry focuses on the extent of a specific symptom severity on a spectrum ranging from the least to the most severe. A subsequent B-SNIP study highlighted the importance of a dimensional approach to psychotic spectrum disorders and proposed a three-dimensional approach to strengthen our current diagnostic classification system for psychosis. This multicenter study included 933 people with DSM-IV diagnosis of schizophrenia, schizoaffective, or psychotic bipolar disorder. This dimensional approach consists of the dimensions of transdiagnostic psychosis, affective and nonaffective psychosis, and five specific psychotic symptoms.15 Other scholars have also advocated for a dimensional approach in nosology of schizoaffective disorder focusing on altered neurobehavioral functions including information processing and emotional regulation.8 Taken together, this evidence suggests a unitary psychosis model, with schizoaffective disorder lying between schizophrenia and bipolar with psychosis.

Brain Structural Changes in Schizoaffective Disorder

Significant changes in brain structures have been found in people with schizoaffective disorder and schizophrenia when compared to healthy controls. Notably, the B-SNIP investigators found similar brain structural biomarkers in schizophrenia and schizoaffective disorder but not in people with bipolar disorder with psychosis.16 Magnetic resonance imaging (MRI) was used to study the brain biomarkers in the study. People with schizoaffective disorder and schizophrenia, in comparison to healthy controls, had extensive and diffusely distributed gray matter density loss, with the largest effects in frontal, anterior/middle cingulate cortex, and temporal regions. These structural changes were not found in patients with bipolar with psychosis.16 Further, individuals with schizoaffective disorder, similar to those with schizophrenia, had extensive volume reductions in neocortical and subcortical gray matter, whereas people with bipolar disorder with psychosis had smaller volume reductions limited to frontotemporal regions.17 Significant reduction of corpus callosum volume in anterior and posterior splenial regions has been documented in all patients with chronic psychosis, but clinical implications of the callosal abnormalities are different in schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis.18 A recent systematic review of neuroimaging and neuropsychological functioning found no significant differences in cognitive deficits and gray matter volume loss between people with schizophrenia and schizoaffective disorder, unlike that in people with bipolar disorder with psychosis.19 Neuroimaging studies have consistently found significant volume reduction in hippocampus in patients with schizophrenia and schizoaffective disorder but not in patients with bipolar disorder with psychosis.20 In summary, current evidence suggests there is a neurobiologic basis for the symptom overlap between schizoaffective disorder and schizophrenia, but not with bipolar disorder with psychosis.

Neurodevelopment and Circuit Disorders in Schizoaffective Disorder

As discussed above, brain structural changes are similar in people with schizoaffective disorder and schizophrenia; hence, neurodevelopment might be similar as well. Neurodevelopment is influenced by both genes and the environment. Genetic and environmental risk factors can alter synaptogenesis in the prenatal period, impair appropriate synaptic pruning during childhood, and cause subcortical dopamine dysfunction and cortical excitatory, and inhibitory imbalance during adolescence, all factors contributing to development of schizophrenia.21

Clinically, schizoaffective disorder and schizophrenia have significant overlap, suggesting that the neurocircuits involved in both conditions might be similar. A neurocircuit is formed by a group of neurons interconnected by synapses to carry out a specific brain function. The neurocircuit dysfunction in schizoaffective disorder and schizophrenia may include an imbalance between neuronal excitation and inhibition, deficits in synaptic plasticity, disruptions in neuronal synchrony, and abnormalities in dopaminergic signaling.22

Functional imaging studies demonstrate a hypoconnectivity in frontal, postcentral, and cerebral cortices and hyperconnectivity in the thalamus and temporal cortices in people with schizoaffective disorder and schizophrenia.23 This multicenter study reported findings from functional MRI of the entire brain among 238 healthy controls and 385 people with schizophrenia, schizoaffective or psychotic bipolar disorder. Abnormal neuronal connectivity affecting cortical glutamatergic, GABAergic, and dopaminergic circuitry has been described in schizophrenia.24 Hippocampal-prefrontal-striatal neurocircuits have been found to play a prominent role in information processing, and the dysregulation of dopaminergic signaling in the neurocircuit might lead to psychosis in both schizoaffective disorder and schizophrenia.25 Further contributing to psychotic symptoms may be the dysregulation of the mesolimbic dopamine system altering prediction error and N-methyl-D-aspartate receptor hypofunctioning leading to inability of glutamate neurocircuitry to compensate the dysregulated dopamine system.26,27 Additionally, a cortical cholinergic neurocircuit is proposed to be responsible for attentional deficits in schizophrenia and altered gamma-aminobutyric acid (GABA) function in parvalbumin positive interneurons in the lateral prefrontal cortex is hypothesized to be associated with executive function deficits in schizophrenia.28,29 Similarly, neurocircuits responsible for regulating stress responses such as the hypothalamic-pituitary-adrenal axis and amygdala neurocircuits are dysregulated in schizophrenia and schizoaffective disorder.29 Thus, there is not only significant clinical overlap between schizophrenia and schizoaffective disorder, but also similar brain structural changes, and altered neurodevelopment and neurocircuitry.

The Genetics of Schizoaffective Disorder

Genome-wide association studies and molecular genetic studies reveal overlap of susceptibility genes for schizoaffective disorder, schizophrenia, and bipolar disorder.4,30 Moreover, family and twin studies have demonstrated very similar genetic backgrounds between the three illnesses.4,31,32 A review study by Cosgrove and Suppes4 reported a clear genetic link between the three disorders based on familial studies while not finding any etiological contributions from susceptibility genes based on genome-wide studies. Similarly, a registry based familial study in Sweden31 and an adoption study in Denmark32 revealed shared genetic causes for schizophrenia and bipolar disorder. As discussed above, GABA is necessary for prefrontal cortex functioning; glutamic acid decarboxylase (GAD) is a GABA synthesizing enzyme. People with both schizoaffective disorder and schizophrenia had lower levels of GABA synthesizing enzyme GAD67 in the prefrontal cortex, but only people with schizoaffective disorder had lower GAD65 in the prefrontal cortex.33 This difference in enzyme activity may be one of the reasons why cognitive function is better in people with schizoaffective disorder than in those with schizophrenia.33 Despite similarities in susceptibility genes, people with bipolar disorder have differences in brain structure compared to people with schizophrenia or schizoaffective disorder. Similarly, the underlying neurobiology of schizoaffective disorder overlaps with that of schizophrenia but clinical differences still exist between the two diseases. Taken together, there are likely quantitative differences in susceptibility genes; for example, copy number variants for schizoaffective disorder, schizophrenia, and bipolar disorder.34

Conclusion

Despite changing diagnostic criteria and variability in diagnostic stability, schizoaffective disorder has continued to occupy a position in between schizophrenia and bipolar disorder with psychosis in psychiatric nosology and in the clinic. Clinical characteristics of schizoaffective disorder suggest more overlap with schizophrenia than with bipolar disorder with psychosis, a finding supported by brain imaging studies. Neurodevelopmentally, schizoaffective disorder appears to be similar to schizophrenia and structural changes in the brain of people with schizoaffective disorder and schizophrenia are almost indistinguishable. Alteration in functional connectivity in neurocircuits and neurotransmitters in both schizoaffective disorder and schizophrenia are also similar. Genetically, schizoaffective disorder is not only similar to schizophrenia but is also comparable to bipolar disorder. Evolving transdiagnostic approaches in line with a unitary psychosis model might soon pave the way for a different psychiatric nosology that will no longer recognize schizoaffective disorder as a separate disorder as currently conceptualized in DSM-5.

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Authors

Shreedhar Paudel, MD, is a Psychiatrist, Department of Psychiatry, Massachusetts General Hospital; and an Instructor of Psychiatry, Harvard Medical School. Hannah Brown, MD, is the Director, Wellness and Recovery after Psychosis Program, Boston Medical Center; and an Assistant Professor of Psychiatry, Boston University School of Medicine. Oliver Freudenreich, MD, FACLP, is the Co-Director, Schizophrenia Clinical and Research Program, Massachusetts General Hospital; and an Associate Professor of Psychiatry, Harvard Medical School.

Disclosure: Oliver Freudenreich has been a consultant for Alkermes, Neurocrine, Janssen, Novartis, and Roche; has performed contracted research for Otsuka, Janssen, Avanir, and Alkermes; receives royalties from UpToDate, Wolters Kluwer, and Springer; and has received payments from Medscape, Elsevier, and Global Medical Education for writing. The remaining authors have no relevant financial relationships to disclose.

Address correspondence to Shreedhar Paudel, MD, Department of Psychiatry, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; email: spaudel2@mgh.harvard.edu.

10.3928/00485713-20200413-01

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