Chapter 1
Psychiatric comorbidities associated with schizophrenia: how should we conceptualize them?
KEY POINTS
• Schizophrenia carries a high rate of psychiatric comorbidities.
• Such comorbidities worsen the longitudinal course of illness and perturb treatments.
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). Hence the rationale for this dedicated book, wherein successive chapters detail specific associations and management strategies.
Box 1.1 Putative rationale for the heightened association between schizophrenia and other psychiatric conditions
• Diagnostic overlap and confusion about phenomenology
• ‘Blurred boundaries’ of schizophrenia
• Shared neurobiology—genetic and non-genetic
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 (‘manic-depressive 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
• Unipolar, major depression (~ 20%)
• Neurological conditions—stroke, Parkinson’s disease, brain tumors, cerebral trauma
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 (Cross-Disorder 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).
Box 1.3 A transdiagnostic perspective on major mental illness: conditions that show greater (than otherwise expected) genetic convergence
Related posts:
Generalized anxiety and panic disorder in schizophrenia
Personality disorders and schizophrenia
Post-traumatic stress disorder and schizophrenia
Schizophrenia and obsessive compulsive disorder
Understanding and assessing substance use in schizophrenia
Why are psychiatric comorbidities so common in schizophrenia and why are they so often missed in clinical practice?
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