David J. Castle - Schizophrenia and Psychiatric Comorbidities: Recognition Management (Oxford Psychiatry Library Series)

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DOI: 10.1093/med/9780198870333.001.0001

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This scholarly volume is a very timely and welcome contribution to our field. It addresses and dissects the clinically critical issue of multiple comorbidities in schizophrenia. In addition, it integrates and synthesizes many lines of evidence for the extensive aetiological and clinical overlap among major psychiatric conditions that are currently regarded as free-standing DSM diagnostic categories. The implications for this scholarly scientific review and discourse should ultimately lead to a paradigm shift in conceptualizing the nosology, epidemiology, aetiology, and treatment of major psychiatric disorders including schizophrenia, depression, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), anxiety, OCD, PTSD and substance use.

For a long time, and prior to the neuroscience revolution that enabled probing the human brain and exploring the neurobiology of psychiatric disorders, the field of psychiatry was descriptive and simplistic. It categorized psychiatric disorders essentially as silos, defined by a set of signs and symptoms. If one or more psychiatric conditions co-occurred with a primary diagnosis, they were labelled as comorbidities, with no implications of a shared aetiology or biology. Amazingly, despite the rapid accrual of evidence of shared developmental or genetic aetiopathogenesis, dysplasia of the same brain regions on neuroimaging and a shared benefit from the same class of medications, DSM-5 and its traditional out-date schema, remains the diagnostic Bible of Psychiatry.

This archaic model is ripe for change.

The following are highlights of recent advances in re-conceptualizing the nosology of schizophrenia and other DSM diagnostic entities re-interpreting the comorbidities as evidence of the substantial clinical and biological overlap and inter-connectivity of psychiatric brain disorders.

Neurodevelopmental Pathology: Disruption of brain development during fetal life has been well established across the schizophrenia syndrome and practically all the so-called comorbidities (Beauchaine et al. 2018; Huttunen and Mednick 2018; Krueger and Eaton 2015).

Genetic Pleiotropy: About 50% of the 22,000 protein-coding genes in the human chromosomes are expressed in the brain during development. Schizophrenia and most psychiatric disorders are heavily genetic. Genetic pleiotropy has been identified across several psychiatric syndromes (Nasrallah 2013; Smoller and Cross-Disorder Group of the Psychiatric Genomics Consortium 2019). For example, the calcium channel A1 gene is shared by schizophrenia, autism, bipolar disorder, major depression and ADHD (Gudmundsson et al. 2019). This indicates that the DSM separation of those disorders is artificial and based on specific symptoms without integrating what is regarded as comorbid conditions into a unified model. Copy number variants have also been found in schizophrenia, ADHD, and autism spectrum disorders (Doernberg and Hollender 2016; Smoller and Cross-Disorder Group of the Psychiatric Genomics Consortium 2019).

Neuroimaging Concordance: Three brain regionsthe dorsal anterior cingulate, left insula, and right insulahave been reported to be abnormal across schizophrenia, bipolar disorder, major depression, OCD and anxiety. Those shared brain structural abnormalities are associated with various degrees of hypoplasia or atrophy (Goodkind 2015).

Intermediate phenotypes have been redefined to accommodate transdiagnostic vulnerabilities and aetiological complexity (Etkin and Cuthbert 2014; Beauchaine and Constantino 2017; Hyman 2019).

Shared symptoms have long been observed across various psychiatric disorders, including delusions, hallucinations, depression, anxiety, impulsivity, and autistic and cognitive symptoms (Kessler et al. 2011; Nasrallah 2017, 2019; Grisanzio et al. 2018).

Response to Pharmacotherapy: It is well recognized that the same class of psychotropic medications exert therapeutic efficacy across a variety of DSM disorders (Maher and Theodore 2012). The SSRIs and atypical antipsychotic exert efficacy in many psychiatric disorders beyond their original indication, which was approved by the FDA based on a specific DSM diagnosis.

Connectomics and neural circuits are now regarded as the neurobiological underpinnings of schizophrenia and other psychiatric disorders, and that may be a key reason for the transdiagnostic overlap (Elliott et al. 2018; Xia et al. 2018; Marshal 2020).

Similar neurobiological pathologies have been found to exist in several major psychiatric disorders including neuro-progression, white matter pathology, neuroinflammation, oxidative stress, mitochondrial dysfunction, glutamate pathways disruptions and shortened telomeres (Nasrallah 2017).

Familial Clustering: Various psychiatric disorders have been found to have significantly increased odds ratios (OR) among the first-degree relatives of patients with schizophrenia including bipolar 1 (4.27), bulimia (3.81), GAD (3.49), separation anxiety (3.10), drug abuse (2.83), conduct disorder (2.53), dysphasia (2.51), PTSD (2.30), alcohol abuse (2.27), major depression (2.18) and social phobia (2.0) (Plana-Ripoll et al. 2019).