St Vincent’s Hospital, University of Melbourne Australia
Peter F. Buckley
Dean
Virginia Commonwealth University, School of Medicine Richmond, Virginia, USA
Rachel Upthegrove
Professor
Psychiatry and Youth Mental Health
Institute for Mental Health, University of Birmingham, UK
1
Great Clarendon Street, Oxford, OX2 6DP, United Kingdom
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Foreword
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.
1. 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).
2. 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 CrossDisorder Group of the Psychiatric Genomics Consortium 2019).
3. Neuroimaging Concordance: Three brain regions—the dorsal anterior cingulate, left insula, and right insula—have 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).
4. Intermediate phenotypes have been redefined to accommodate transdiagnostic vulnerabilities and aetiological complexity (Etkin and Cuthbert 2014; Beauchaine and Constantino 2017; Hyman 2019).
5. 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).
6. 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.
7. 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).
8. 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).
9. 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).
10. Medical Comorbidities: Schizophrenia, mood disorders and anxiety disorders are all associated with a significant increase in various medical illnesses (Momen et al. 2020). In gene-wide association studies (GWAS) of schizophrenia, the histo-compatibility complex genetic locus on chromosome 6 was significantly abnormal compared to healthy controls. This points to immune dysregulation that may predispose to many physical diseases of the body and the brain.
11. The ‘P’ factor: Multiple reports have suggested the presence of a single shared psychopathological predisposition to various dimensions of psychiatric disorders called the ‘P’ factor (Caspi and Moffitt 2018; Caspi et al. 2014; Nasrallah 2015; Selzami et al. 2018). Kendler (2019) elaborated on the conceptual evolution within psychiatric nosology from one disorder prior to the introduction of the DSM, to numerous disorders in the DSM schema, and now back again to a single psychopathological foundation, with the accelerating evidence for a unified model that stands in contrast to the widely held current DSM model.
In conclusion, it is quite evident that transformative changes may be forth coming in the diagnostic framework of psychiatric disorders. That will represent a seismic change to the DSM structure as it currently exists. This book is an important compilation of the emerging evidence for a transdiagnostic model of mental illness generated from the shared genes, environmental factors, brain circuits and neurobiological processes. The authors are to be thanked and commended for assembling an excellent volume that may serve as a catalyst for the urgently needed disruptive transformation in reconceptualizing the transdiagnostic underpinnings of psychiatric disorders. Once adopted, the new model may lead to therapeutic innovations and brave new treatment modalities and interventions that can exploit the many overlapping comorbidities of the schizophrenia syndrome.
Henry A. Nasrallah, MD University of Cincinnati College of Medicine
Refe R ences
Beauchaine TP, Constantino JN (2017) Redefining the endophenotype concept to accommodate transdiagnostic vulnerabilities and etiological complexity. Biomarkers in Medicine 11: 769–780.
Beauchaine TP, Constantino JN, Hayden EP (2018) Psychiatry and developmental psychopathology: unifying themes and future directions. Comprehensive Psychiatry 87: 143–152.
Caspi A, Houts RM, Belsky DW, et al. (2014) The P factor: one general psychopathology factor in the structure of psychiatric disorders? Clinical Psychological Science 2: 119–137.
Caspi A, Moffitt TE (2018) All for one and one for all; mental disorders in one dimension. American Journal of Psychiatry 175: 831–844.
Doernberg E, Hollender E (2016) Neurodevelopmental disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11. CNS Spectrums 21: 295–299.
Elliott ML, Romer A, Knodt AR, et al. (2018) A connectome-wide functional signature of transdiagnostic risk for mental illness. Biological Psychiatry 84: 452–459.
Etkin A, Cuthbert B (2014) Beyond the DSM: development of a transdiagnostic psychiatric neuroscience course. Academic Psychiatry 38: 145–150.
Goodkind M, Eickoff SB, Oathes DJ, et al. (2015) Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry 72: 305–315.
Grisanzio KA, Goldstein-Piekarski AN, Wang MY, et al. (2018) Transdiagnostic symptom clusters and associations with brain behavior and daily function in mood anxiety and trauma disorders. JAMA Psychiatry 75: 201–209.
Gudmundsson DO, Walters GB, Ingason A, et al. (2019) Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder. Translational Psychiatry 9: 258. doi: 10.1038/s41398-019-0599-y.
Huttunen MO, Mednick SA (2018) Polyvagal theory, neurodevelopment and psychiatric disorders. Indian Journal of Psychological Medicine 35: 9–10.
Hyman S (2019) New evidence for shared risk architecture of mental disorders. JAMA Psychiatry 76: 235–236.
Kendler KS (2019) From many to one to many—the search for causes of psychiatric illness. JAMA Psychiatry (2019) 76: 1085–1091.
Kessler RC, Ormel J, Petukhora M, et al. (2011) Development of life-time comorbidity in the World Health Organization world mental health surveys. Archives of General Psychiatry 68: 90–100.
Krueger RF, Eaton NR (2015) Transdiagnostic factors of mental disorders. World Psychiatry 14: 27–29.
Maher AR, Theodore G (2012) Summary of the comparative review on off-label use of atypical antipsychotics. Journal of Managed Care & Specialty Pharmacy (Suppl.) 18: S1–S20.
Marshal M (2020) Roots of mental illness, researchers are beginning to untangle the common biology that links supposedly distinct psychiatric conditions. Nature 581: 19–21.
Momen NC, Plana-Ripollo O, Agerbo E, et al. (2020) Association between mental disorders and subsequent medical conditions. New England Journal of Medicine 382: 1721–1731.
Nasrallah HA (2017) Beyond DSM-5: clinical and biologic features shared by major psychiatric syndromes. Current Psychiatry 16: 4–7.
Nasrallah HA (2015) Is there only 1 neurological disorder, with different clinical expression? Current Psychiatry 14: 10–12.
Nasrallah HA (2013) Pleiotropy of psychiatric disorders will re-invent DSM. Current Psychiatry 12: 6–7.
Nasrallah HA (2019) Psychosis as a common thread across psychiatric disorders. Current Psychiatry 18: 12–14.
Plana-Ripoll O, Pedersen CB, Holtz Y, et al. (2019) Exploring comorbidity within mental disorders among a Danish national population. JAMA Psychiatry 76: 259–270.
Selzami S, Coleman JRI, Caspi A, et al. (2018) A polygenic P factor for major psychiatric disorder. Translational Psychiatry 8: 205 (pages 1–9).
Smoller J and the Cross-Disorder Group of the Psychiatric Genomics Consortium (2019) Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell 179: 1469–1482.
Xia CH, Ma Z, Ciric R, et al. (2018) Linked dimensions of psychopathology and connectivity in functional brain networks. Nature Communications 9: 1–14.
Preface
Psychiatric comorbidities such as depression, anxiety and substance use are extremely common amongst people with schizophrenia. They add to poor clinical outcomes and disability yet are often not at the forefront of the minds of clinicians, who tend to concentrate on assessing and treating the core symptoms of schizophrenia, notably delusions and hallucinations. There is an imperative to assess every patient with schizophrenia for psychiatric comorbidities, as they might masquerade as core psychotic symptoms (e.g. depression presenting as negative symptoms) and also because they warrant treatment in their own right.
There are other psychiatric comorbidities associated with schizophrenia that tease at the very nosological constructs upon which modern psychiatry is based. These include personality disorders and neurodevelopmental disorders such as attention deficit disorder and autism spectrum disorder.
This volume addresses these issues using a clinical lens informed by the current literature. We cover nosology, epidemiology and aetiology, but our main foci are clinical aspects such as assessment and treatment. Clinical pointers, summary fact boxes, summary tables and illustrations are used to make the book appealing and reader-friendly.
This volume represents the third in a series under the Oxford Psychiatry Library marque: companion volumes are Schizophrenia, now in its second edition (Castle and Buckley 2015) which was highly commended by the British Medical Association (2015), and Physical Health and Schizophrenia (Castle, Buckley, and Gaughran 2017). We believe that this current book augments these previous works and will be of interest to all those involved in the care of people with schizophrenia.
We are most grateful to Oxford University Press for their support in the production of this book and trust we have succeeded in our aims of highlighting the importance of understanding, assessing and treating effectively psychiatric comorbidities in schizophrenia.
David J. Castle, Peter F. Buckley, and Rachel Upthegrove May 2020
Abbreviations
ALSPAC Avon Longitudinal Study of Parents and Children
ASD autism spectrum disorder
BAP British Association for Psychopharmacology
BPD borderline personality disorder
BSNIP Bipolar Schizophrenia Network on Intermediate Phenotypes
CBD cannabidiol
CBT cognitive behavioural therapy
CBTp cognitive behavioural therapy for psychosis
CDS Calgary Depression Scale
CNV copy number variants
DMN default mode network
DSM-5 Diagnostic and Statistical Manual of Mental Diseases, Fifth Edition
EAGLES Evaluating Adverse Events in a Global Smoking Cessation Study
ECA epidemiological catchment area
ECT electroconvulsive therapy
EMDR eye movement desensitization and reprocessing
EPSE extrapyramidal side effects
FEP first episode psychosis
FGA first generation agents
GAD generalized anxiety disorder
GWAS genome-wide association study
KF Kayser Fleischer
LAI long-acting injectable antipsychotics
LSAS Liebowitz Social Anxiety Scale
MI motivational interviewing
NICE National Institute for Health and Care Excellence
Psychiatric comorbidities associated with schizophrenia: how should we conceptualize them?
K e Y points
• Schizophrenia carries a high rate of psychiatric comorbidities.
• Such comorbidities worsen the longitudinal course of illness and perturb treatments.
• Genetic studies point to substantial overlap in genes across many psychiatric disorders, with no ‘purity’ for specific disorders.
• Understanding the neurobiology of symptom sets might enhance models explaining overlapping symptoms between and across psychiatric disorders.
That other psychiatric conditions occur with high frequency among people with schizophrenia is—as evidenced throughout this book—both compelling and irrefutable. Differing sampling methods, heterogeneity among schizophrenia samples studied, and cross sectional or longitudinal study designs do not obscure or detract from the repetitive finding of high rates of psychiatric comorbidities in schizophrenia (Buckley et al. 2009; Hwang and Buckley 2018; Miller et al. 2009; Yum et al. 2016). Medical conditions are also overrepresented in people with schizophrenia (Meyer and Nasrallah 2009). Rates of occurrences of psychiatric comorbidities can certainly be debated, though they are in the order of prevalence rates of 50% for depression in schizophrenia, 47% for substance abuse, 29% for post-traumatic stress disorder (PTSD), 23% for obsessive compulsive disorder (OCD), and 15% for panic disorder (Miller et al. 2009). Taken collectively, it is highly likely that a clinician treating a person with schizophrenia over several years will be faced with managing one or more of these psychiatric comorbidities. That said, we know that such comorbidities are associated with poorer outcomes (Gregory et al. 2017) and with more complicated pharmacotherapy; the choices therein also contribute to more adverse side effects. Thus, at its most fundamental, psychiatric comorbidities are important in schizophrenia because they occur ‘more than chance’; they are common in the aggregate; they complicate treatment; and they confer a poorer course of schizophrenia illness (Box 1.1).
Box 1.1 Putative rationale for the heightened association between schizophrenia and other psychiatric conditions
• More than chance occurrence
• Diagnostic overlap and confusion about phenomenology
• ‘Blurred boundaries’ of schizophrenia
• Shared neurobiology—genetic and non-genetic
• Shared environmental risk factors
Hence the rationale for this dedicated book, wherein successive chapters detail specific associations and management strategies.
This introductory chapter aims to conceptualize these co-occurrences, to help understand the overall context as well as any nuances related to specific comorbidities, and thereupon to ‘set the stage’ for successive chapters, especially the upcoming chapter that details the prevalence and diagnostic conundrum associated with these comorbidities.
The boundaries of schizophrenia are blurred
The most compelling, and indeed intriguing, context begins with schizophrenia itself. The notion of additional psychiatric conditions that are at the very least some way symptomatically different from schizophrenia builds upon the assumption that schizophrenia is itself a distinct, recognizable and circumscribed condition (Fischer and Carpenter 2009; McCutcheon et al. 2020). Ideally, of course, this ‘illness’ would then be further defined by a distinct neurobiological architecture. Notwithstanding the seminal work of Kraepelin (1912) in clinically delineating schizophrenia (‘dementia praecox’) from bipolar disorder (‘manicdepressive insanity’), the demarcation of the nosology and consequent diagnostic boundaries of schizophrenia is anything but sharp and distinct. Schizophrenia is actually notoriously heterogeneous in its clinical aspects—in onset and presentation, in symptoms, in course over time, and ultimately in treatment and prognosis (McCutcheon et al. 2020). Even while the conceptual model of schizophrenia is still debated, there exists evidence of underlying neurobiological heterogeneity as well as a contrast to other conditions. In medicine, consider the uncommon condition of Wilson’s disease, which is readily and reliably diagnosed when copper-deposited rings—Kayser Fleischer (KF) rings—are seen on slip lamp ophthalmological evaluation. KF rings are pathognomonic of Wilson’s disease. Sadly, there is presently no ‘KF equivalent’ for schizophrenia. This basic conceptual and nosological quandary is poignant as we now turn our attention to considering psychiatric comorbidities whose basic symptoms can, and often do, overlap with psychiatric symptoms that are usually part of the diagnosis of schizophrenia (Box 1.2).
Box 1.2 Auditory hallucinations are common in schizophrenia—though they are also observed in many other conditions
• Other ‘organic’ psychoses (e.g. cerebral sarcoidosis)
For example, some 46% of acutely manic patients experience auditory hallucinations. Hallucinations and delusions are observed in approximately 20% of patients with major depressive disorder. Obsessions, often hard to distinguish phenomenologically from delusions, occur in about 23% of schizophrenia patients (Hwang et al. 2018). Indeed, it can be difficult to distinguish between secondary negative symptoms, depressive symptoms and primary negative symptoms. To that end, several studies comparing symptoms and even illness course across patients with schizophrenia and patients with mood disorders find more similarities than differences (Lindenmayer 2018). Additionally, drug abuse can present with a plethora of symptoms mimicking schizophrenia. Moreover, there is ample evidence that a small proportion—perhaps some 9%—of otherwise healthy individuals experience auditory hallucinations that are, albeit more attenuated, similar to those observed in patients with schizophrenia.
Does symptom overlap reflect underlying neurobiological convergence? Toward a transdiagnostic reconceptualization
Kenneth Kendler, the pre-eminent US psychiatric geneticist, once quipped ‘good genes require good phenotypes’ (Kendler and Diehl 1993). By that he was referring to the need to minimize clinical heterogeneity in order to study and arrive at a purer phenocopy of schizophrenia. Yet, even in his meticulously conducted Roscommon studies of schizophrenia wherein the diagnosis of schizophrenia in the proband was assigned with great rigor, Kendler observed that the genetics of schizophrenia were not ‘pure’ (Kendler and Gardner 1997). That is to say, in addition to heightened rates of schizophrenia (compared with the general population) in primary relatives, the family members also had higher rates of schizotypal personality disorder, of bipolar disorder, of major depression, and of paranoid personality disorder. These are well-replicated findings (Glahn et al. 2014). Fast forward to the present era of ever more sophisticated genetics and large sample sizes and one observes that the overlap in genetic architecture is now more apparent among schizophrenia and
several other psychiatric disorders. In a seminal paper reporting on some 100,000 persons in a genome-wide association study (GWAS) (Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014), the Psychiatric Genomics Consortium (PGC) identified 108 loci associated with schizophrenia with broad implications for pathophysiology—especially with overlap with the immune system. Another paper by Gandal and colleagues (2018) detailed the genetic and transcription overlap across postmortem brains from patients with schizophrenia, bipolar disorder, depression, autism, or alcoholism in comparison with the brains of normal subjects. In contrast to expectations, these researchers observed considerable overlap across each psychiatric condition—surprisingly with alcoholism being the most divergent—and strong overlap between schizophrenia and mood disorders, both bipolar disorder and (lesser so) depression and also between schizophrenia and autism. They postulated an overall similarity of neurobiology giving way to divergence of neuropathology at a molecular level. In another GWAS (CrossDisorder Group of the Psychiatric Genomics Consortium 2013) of around 33,000 patients with major psychiatric disorders, there was overlap between schizophrenia, bipolar disorder, major depression, autism and attention deficit disorder, particularly implicating genes in calcium signalling. Andlauer and colleagues (2019) examined 395 individuals from multiple bipolar disorder families and observed higher polygenic risk scores for both bipolar disorder and schizophrenia. And Pasman et al. (2018) showed overlap in genes predisposing to both schizophrenia and cannabis use. Taken together, these modern-day genetic analyses suggest some shared genetic vulnerability and marked transdiagnostic heritability for major psychiatric conditions (Box 1.3).
Other neurobiological studies across schizophrenia and mood disorders point to a similar convergence of neurobiological findings. Tamminga and colleagues (Pearlson et al. 2016; Tamminga et al. 2014) examined the Bipolar Schizophrenia Network on Intermediate Phenotypes (BSNIP) database and found no meaningful differences across neuroimaging and electroencephalogram (EEG) parameters among patients with schizophrenia, schizoaffective disorder and bipolar disorder. In contrast, they reported three ‘intermediate phenotypes’ that they call ‘biotypes’. These biotypes reflect three distinct consistent patterns of neurobiological abnormalities that do not map coherently onto the expression of schizophrenia,
Box 1.3 A transdiagnostic perspective on major mental illness: conditions that show greater (than otherwise expected) genetic convergence
• Schizophrenia
• Bipolar disorder
• Unipolar depression
• Autism
• Attention deficit disorder
schizoaffective disorder, or bipolar disorder. This constellation, they hypothesize, reflects some neurobiological signature(s) of psychoses. De Zwarte and colleagues (2019), reporting for the ENIGMA neuroimaging study, found similar neuroimaging findings in relatives of first-episode schizophrenia patients and in relatives of probands with bipolar disorder. Another position emission tomography study (Jauhar et al. 2017) found essentially similar dopamine receptor sensitivity across schizophrenia and bipolar disorder. Moser and colleagues (2018) conducted an magnetic resonance imaging (MRI) study of 100 patients with schizophrenia and 40 patients with bipolar disorder compared with normal volunteers. They described patterns of cortical dysconnectivity and volume changes that correlated better with symptoms than with diagnosis. This is suggestive of more distinct neuroimaging phenotypes than the more traditional clinical diagnoses.
Unifying themes and nuanced observations on discrete psychiatric comorbidities
The convergence of recent genetic findings across schizophrenia and other major psychiatric conditions is both intriguing and puzzling (Box 1.4). The findings may point to shared genetic liability that is manifest in life in different symptom constellations because of other selective genetic risks, environmental risks, or any combination of both (Glahn et al. 2014; Muller 2017; Radua et al. 2018). Additionally, this genetic overlap may be related to fundamental pathogenic processes that might be in play, more or less, for a given psychiatric condition. For example, the 108 loci observed in the seminal paper by PGC in Nature (2014) found that these loci were also associated with immune functions. There is robust literature on immune dysfunction in mood disorders and similar findings are now evident for schizophrenia (Muller 2017). Also, developmental genes have been implicated in the GWAS of schizophrenia and major psychiatric disorders, perhaps implicating an underlying and shared neurodevelopmental basis to several psychiatric conditions in addition to schizophrenia (de Zwarte et al. 2019).
This blurring of neurobiological boundaries, coupled with the fluctuating nature of psychotic symptoms, has led to a reconsideration of more broad transdiagnostic approaches in trying to understanding and classify psychiatric conditions (Fusar-Poli et al. 2019). In that context, then, the distinctions between
Box 1.4 Putative neurobiological mechanisms to explain the heightened association between schizophrenia and other psychiatric conditions
• Shared genes implicating a fundamental dysregulation of the immune system
what is ‘schizophrenia’ and what is an ‘additional’ psychiatric comorbidity seem less distinct and rigorous. Moreover, this approach lines up well with the high prevalence of comorbidities in schizophrenia.
It is also noteworthy, observing through the pharmacologic lens, that medication effects of major psychiatric drugs may not be as disease- specific or even symptom- targeted as one might expect from their development. Indeed, many of the second- generation antipsychotic medications (SGAs) have demonstrated unequivocal efficiency in mood disorders and even in ‘nonpsychotic’ major depression (Gregory et al. 2018; Goff 2019). Conversely, antidepressant medications have been shown to improve negative symptoms in schizophrenia and not (merely) treat comorbid depressive symptoms. For example, Goff and colleagues (2019) reported on a one- year, double- blind, placebo- controlled trial of citalopram in patients with first episode of psychosis. Citalopram was found to have a modest effect on negative symptoms, while depressive symptoms were similar between citalopram- treated and placebo- treated patients. Also, intriguingly, clozapine has been robustly observed to have an antisuicide effect in patients with schizophrenia (Meltzer et al. 2003).
Some concluding observations are relevant to selective psychiatric comorbidities. In addiction disorders, some drugs (e.g. cannabis, amphetmaines, ketamine) show high propensity to induce psychosis and to ‘bring on’ schizophrenia, while other drugs (e.g. heroin, inhalants) do not appear to have such an effect (Arendt et al. 2008; Clerici et al. 2018; Starzer et al. 2018; Voce et al. 2018). It is suggested that the heightened risk for schizophrenia among cannabis abusers reflects (hyper- )dopaminergic dysregulation. Similarly, for ketamine- related psychoses it is suggested that glutamate receptor antagonism causes a hyper- glutamatergic state that is responsible for this psychosis. In depression comorbidity, leaving aside the potential for shared genetic and environmental liabilities, there is the very real potential that people who experience psychosis may have ‘insight- related’ depression and grieving experiences.
In conclusion, this chapter presents a genetic and neurobiological lens to help elucidate our conceptualization(s) for the frequent clinical overlap between schizophrenia and other psychiatric conditions. Subsequent chapters ‘drill down’ into these associations, address psychosocial aspects of the comorbidity between schizophrenia and other psychiatric disorders, and provide an overview of clinical management thereupon.
Refe R ences
Andlauer TRM, Guzman-Parra J, Streit F, et al. (2019) Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Molecular Psychiatry Nov 11, doi: 10.1038/s41380-019-0558-2.
Arendt M, Mortensen PB, Rosenberg R, et al. (2008) Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia. Archives of General Psychiatry 65: 1269–1274.
Buckley PF, Miller BJ, Lehrer DS, Castle DJ (2009) Psychiatric comorbidities and schizophrenia. Schizophrenia Bulletin 35: 383–402.
Clerici M, de Bartolomeis A, De Filippis S, et al. (2018) Patterns of management of patients with dual disorder (psychosis) in Italy: a survey of psychiatrists and other physicians focusing on clinical practice. Frontiers in Psychiatry 9: 575.
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet, doi: 10.1016/S0140-6739(12)62129-1.
de Zwarte SMC, Brouwer RM, Agartz I, et al. (2019) The association between familial risk and brain abnormalities is disease specific: an ENIGMA-relatives study of schizophrenia and bipolar disorder. Biological Psychiatry 86: 545–556.
Fischer BA, Carpenter WT Jr (2009) Will the Kraepelinian dichotomy survive DSM-V? Neuropsychopharmacology 34: 2081–2087.
Fusar-Poli P, Solmi M, Brondino N, et al. (2019) Transdiagnostic psychiatry: a systematic review. World Psychiatry 18: 192–207.
Gandal MJ, Haney JR, Parikshak NN, et al. (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359: 693–697.
Glahn DC, Knowles EE, McKay DR, et al. (2014) Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics. American Journal of Medical Genetics B: Neuropsychiatric Genetics 165: 122–130.
Goff DC, Freudenreich O, Cather C, et al. (2019) Citalopram in first episode schizophrenia: the DECIFER trial. Schizophrenia Research 208: 331–337.
Gregory A, Mallikarjun P, Upthegrove R (2017) Treatment of depression in schizophrenia: systematic review and meta-analysis. British Journal of Psychiatry 211: 198–204.
Hwang M, Buckley P (2018) Comorbidity and schizophrenia. Psychiatric Annals 48: 544–545.
Hwang M, Sood A, Riaz B, Poyurovsky M (2018) Obsessive-compulsive schizophrenia: clinical and conceptual perspective. Psychiatric Annals 48: 552–556.
Jauhar S, Nour MM, Veronese M, et al. (2017) A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia. JAMA Psychiatry 74: 1206–1213.
Kendler KS, Diehl SR (1993) The genetics of schizophrenia: a current, geneticepidemiologic perspective. Schizophrenia Bulletin 19: 261–285.
Kendler, KS, Gardner CO (1997) The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies. Psychological Medicine 27: 411–419.
Kraepelin E (1912) Psychiatry: a textbook for students and physicians, 7th edition. Leipzig: MacMillan.
Lindenmayer JP (2018) The NIMH research domain criteria initiative and comorbidity in schizophrenia: research implications. Psychiatric Annals 48: 547–551.
Meltzer HY, Alphs L, Green AI, et al. (2003) Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial. Archives of General Psychiatry 60: 82–91.
Meyer JM, Nasrallah HA (2009) Medical illness and schizophrenia, 2nd edition. Washington, DC: American Psychiatric Press.
Moser DA, Doucet GE, Lee WH, et al. (2018) Multivariate associations among behavioral, clinical, and multimodal imaging phenotypes in patients with psychosis. JAMA Psychiatry 75: 386–395.
Muller N (2017) Immunological aspects of the treatment of depression and schizophrenia. Dialogues in Clinical Neuroscience 19: 55–63.
Pasman JA, Verweij KJH, Gerring Z, et al. (2018) GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits and a causal influence of schizophrenia. Nature Neuroscience 21: 1161–1170.
Pearlson GD, Clementz BA, Sweeney JA, et al. (2016) Does biology transcend the symptom-based boundaries of psychosis? Psychiatric Clinics of North America 39: 165–174.
Radua J, Ramella-Cravaro V, Loannidis JPA, et al. (2018) What causes psychosis? An umbrella review of risk and protective factors. World Psychiatry 17: 49–66.
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia associated genetic loci. Nature 65: 421–427.
Starzer MSK, Nordentoft M, Hjorthoj C (2018) Rates and predictors of conversion to schizophrenia or bipolar disorder following substance-induced psychosis. American Journal of Psychiatry 175: 343–350.
Tamminga CA, Pearlson G, Keshavan M, et al. (2014) Bipolar and schizophrenia network for intermediate phenotypes: outcomes across the psychosis continuum. Schizophrenia Bulletin 40(Suppl 2): S131–S137.
Voce A, McKetin R, Burn R, Castle D, Calabria B (2018) The relationship between illicit amphetamine use and psychiatric symptom profiles in schizophrenia and affective psychoses. Psychiatry Research 265: 19–24.
Yum, SY, Hwang, MY, Nasrallah, HA, Opler, LA (2016) Transcending psychosis—the complexity of comorbidity in schizophrenia. Psychiatric Clinics of North America 39: 267–274.
Psychiatric comorbidities in schizophrenia: the size of the problem
K e Y points
• There are numerous methodological considerations to bear in mind in interpreting rates of psychiatric comorbidities in schizophrenia.
• Criterion sets used to make comorbid diagnoses vary widely and many have not been validated in people with schizophrenia.
• The sampling frame (e.g. general population vs. treated sample) as well as illness stage can impact rates of comorbidities.
This is a book about psychiatric comorbidities in schizophrenia. There are significant conceptual issues relating to the essence of what one considers ‘comorbid’ and how one classifies, assesses, and enumerates putative comorbid conditions. These puzzles are addressed in other chapters of this book, notably Chapters 1 and 3. In this chapter we sidestep most of those considerations and accept the conventional use of the term ‘comorbid’, namely another psychiatric condition occurring in a person with schizophrenia and not directly explicable as part of the manifestations of the schizophrenia itself. The established diagnostic criteria for the comorbid diagnosis need to be met, with the accepted exclusions of symptoms due to an organic process (although this is complex when it comes to substance use disorders, as detailed in Chapter 11). This allows a review of the pertinent literature regarding how often such conditions occur in people with schizophrenia as opposed to people without schizophrenia. We follow the convention that schizophrenia hierarchically ‘trumps’ other psychiatric disorders (see Chapter 3).
General considerations
Overall rates of psychiatric comorbidities in people with schizophrenia are dependent upon a number of methodological issues, summarized in Box 2.1. The sampling frame (i.e. general population vs. a treated population) is critical, as treated samples introduce biases related to severity of illness as well as Berkson’s
Box 2.1 Methodological issues relevant to ascertaining rates of comorbidity in schizophrenia
• Setting (e.g. general population vs. a treatment setting)
• Ascertainment bias
• Berkson’s bias
• Diagnostic criteria applied (for schizophrenia as well as for the comorbid problem under consideration)
• Skill and experience of interviewers
• Age and gender of sample
• Stage of illness
• Ethnicity
• Reporting bias (e.g. illicit drugs)
• Pathways and barriers to care for each condition
• Antipsychotic side effects
bias, namely the bias related to ascertainment of two or more disease entities through pathways relevant to each, thus overenumerating their co-aggregation. Another critical issue is the diagnostic criteria applied: this is relevant to both schizophrenia and the comorbid condition. Schizophrenia itself has undergone many alterations in its definition over the last century. A full exposition of these changes is beyond the scope of this book and the reader is referred to the companion book in this series for details (Castle and Buckley 2015). A summary is provided in Box 2.2. Perhaps of most importance to this chapter are the
Box 2.2 Selected overview of changes in the schizophrenia construct, over time, relevant to psychiatric comorbidities
• Kraepelin (1896): early onset, male preponderant ‘neurodevelopmental’type illness
• Bleuler (1911): broader criteria and notion of ‘group of schizophrenias’; differentiation of primary and secondary criterion sets
• Feighner (1974): restrictive criteria loading towards early onset (under age 40 years) and family history of schizophrenia
• Research Domain Criteria (RDC) (1976): broader criteria
• ICD-9 (1970s): broad definition not operationalized
• DSM-III (1980): age at onset stipulated as under 45 years
• ICD-10 (1990): no age at onset stipulation
• DSM-IV (1987): abandoned age at onset stipulation
• DSM-5 (2013): moved away from emphasis on Schniederian ‘first rank’ symptoms; abandoned subtypes
variations in age at onset, as psychiatric comorbidities affect individuals at different life phases, as outlined below. Feighner criteria for schizophrenia loaded towards early onset cases (under 40 years), DSM-III specified an onset before the age of 45 years, but DSM-IV dropped any age specification. Another related issue is the impact on sex ratios of the different sets of criteria. For example, Feighner’s criteria preference males, with an estimated male:female ratio of 2.5:1, whilst DSM-III returns a ratio of 2.2:1, and more ‘liberal’ criteria with age at onset specifications, such as ICD-9, estimate males and females to be roughly even in terms of schizophrenia risk (Castle et al. 1993). Sex affects psychiatric comorbidities in important ways, again as detailed below. Finally, quirky criteria within certain diagnostic sets will serve to prejudice against finding high rates of psychiatric comorbidities, for example the loading for a family history of schizophrenia in Feighner’s criteria.
As alluded to above, the age and sex of the sample is likely to impact estimates of psychiatric comorbidities. This can be a function of the diagnostic criteria applied (see Box 2.1) and/or the sampling frame. If the schizophrenia sample is of older females, there is a likelihood of overestimating other psychiatric conditions that tend to afflict people of that demographic: depression and certain of the anxiety disorders, for example. Conversely, a sample of young males with schizophrenia will likely show higher comorbid neurodevelopmental disorders such as autism spectrum disorders.
Stage of illness is important. The onset of schizophrenia can be profoundly traumatic for the individual, related to both the symptoms of psychosis as well as treatment issues (e.g. forced hospitalization, forced medication, seclusion and restraint), whilst cumulative trauma across the illness course can be expected to impact rates of post-traumatic syndromes: these issues are addressed in detail in Chapter 9. Hall (2017) has emphasized the high rates of generalized anxiety symptoms in the schizophrenia prodrome, as well as in the phases preceding relapse. Similarly, high rates of depression have been recorded in first episode patients (see Chapter 10). Conversely, OCD becomes more commonly comorbid with schizophrenia as the illness progresses: thus, in a recent-onset cohort of schizophrenia patients, rates of OCD would be lower than if people are ascertained later on in their illness course (see Chapter 8).
Culture and ethnicity can introduce bias. For example, some ethnic groups may be more likely to use certain substances, whilst help-seeking and/or expression of the anxiety disorders might be impacted by cultural and ethnic parameters. Jurisdictional issues pertain as legal attitudes to drugs such as cannabis can impact availability and general population rates of use: reporting bias might operate, with people being potentially less likely to divulge the use of substances if they are illegal.
The importance of the antipsychotic medication prescribed to the individual being assessed for psychiatric comorbidities lies largely in the side effect burden of individual agents, as these might induce, exacerbate, or masquerade as psychiatric disorders. Examples of the former include the induction or exacerbation of
