Comorbidity in Schizophrenia: Conceptual Issues and Clinical Management

Schizophrenia is a complex and challenging psychiatric disorder that affects cognitive, perceptual, and emotional functioning, with current evidence indicating multiple biological and psychosocial pathogeneses. Clinical and research interests in the comorbidity issues of schizophrenia were borne out of the real-world challenge that patients often do not present with “pure” diagnoses but rather with multiple coexisting psychiatric and medical conditions. The DSM-5 has evolved in the past decade toward a “symptom dimension” perspective. In addition, the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) initiative has emerged to address the research needed by providing a platform for the systematic examination of biopsychosocial factors and their interface in pathogeneses of the complex and heterogenous psychopathology seen in schizophrenia (1). The position of the U.S. Food and Drug Administration that comorbidity is the norm rather than the exception has promoted a shift in clinical research and drug development that has facilitated a better understanding and treatment of comorbidity in schizophrenia. This is a significant shift from the long-held hierarchical Kraepelinian diagnostic concept that coexisting psychiatric conditions such as depression, panic, and obsessive-compulsive symptoms are part of the schizophrenic illness.

This conceptual shift in part is driven by biological research findings and pharmacological advances. The fact that multiple pharmacotherapeutic agents such as lithium, antidepressants, antipsychotics, and benzodiazepines are effective across conditions such as bipolar disorder, major depression, schizophrenia, and anxiety disorders validates a biological overlap between categorical diagnoses. There are hopes that emerging genetic and molecular neurobiological findings will allow syndromic illnesses to be subcategorized on the basis of etiopathogenesis (2).

In this clinical synthesis, we discuss the conceptual perspectives of comorbidity in schizophrenia, with a focus on depression and obsessive-compulsive disorder (OCD).

Depression in Schizophrenia

Historically, affective and psychotic illnesses were viewed as distinct entities, and the presence of comorbid mood symptoms in a psychotic illness poses a challenge to the Kraepelinian dichotomy (3). Conversely, affective and psychotic disorders can be viewed as two opposite ends of a continuum (4). Psychiatry is going through a transition period, in which current advancements in neurobiological and genetic studies have favored the utility of traditional categorical as well as symptom-based dimensional approaches.

Prevalence and Clinical Significance

Depressive symptoms have been long recognized as a distinct symptom domain in schizophrenia and may occur at any time during the course of illness (5). The prevalence of depression in schizophrenia ranges from 25% to 81%, depending on the patient population and treatment setting (6). Concurrent depression in a patient with schizophrenia was previously considered to be a favorable prognostic indicator (7); however, it is now believed to serve as a poor prognostic factor for recovery and reintegration into the community (8). The presence of depressive symptoms in patients with schizophrenia worsens quality of life (9) as well as increases risk of suicide (10), psychotic relapse, and psychiatric hospitalization (11). Also, depressive symptoms in schizophrenia are associated with greater disability, greater danger to self and others (violence, arrests, victimization, suicidality), greater substance-related problems, and poorer overall quality of life (12, 13). The characteristics associated with increased risk of progression from unipolar depression to schizophrenia include parental history of schizophrenia, male sex, younger age and history of substance use disorders (14).

Pathogenesis

The neural mechanisms underlying depressive symptoms in schizophrenia are not well understood. It has been suggested that depressive symptoms in schizophrenia could be psychological or may represent core symptomatology of the psychotic illness, which later transform into negative symptoms of schizophrenia (15).

Recent advances in imaging techniques have provided an opportunity to study the potential neurobiological differences between individual diagnostic categories of psychiatric illnesses. Neuroimaging studies have consistently reported cortical function deficits in depression and schizophrenia (16, 17). Functional connectivity (FC) within brain networks has been suggested to be globally decreased in schizophrenia (18). Chen et al. (19) reported increased orbitofrontal cortex FC density, implicated in abstract and reward reinforcement processing, as discerning for depression. Resting-state FC of the brain reflects self-referential processing: a function implicated to ventromedial prefrontal cortex reported to be hyperactive in depression and hypoactive in schizophrenia as compared with healthy control participants (20). There is limited literature on the neurobiological underpinnings of comorbid affective symptoms in psychotic illness. Frontoparietal control network activation is involved in higher order task processing, and within-network connectivity disruptions are implicated among participants with both depression and schizophrenia (18).

Diagnosis and Treatment

The relationship between depressive symptoms and negative symptoms of schizophrenia requires further clarification. The symptom overlap between depression and negative symptoms in schizophrenia, such as amotivation, avolition, and limitations in emotional and social responsiveness, has been frequently reported (21). Various screening tools, such as the Calgary Depression Rating Scale, have been utilized to attempt to differentiate symptoms of depression from negative psychotic symptoms of schizophrenia (22, 23).

There are limited data and no clear guidelines for the treatment of depressive symptoms that may present during various stages of the psychotic illness, such as acute, chronic persistent, and remission phases. Although numerous reports have indicated the use of tricyclic antidepressants, such as imipramine, to treat depression among patients with psychosis, their utility and response are patient dependent (24). Current treatment recommendations of depression in schizophrenia include decreasing the dose of first-generation antipsychotics and identifying and subsequently treating akinetic features of depression with anticholinergic medication. Adjunctive treatment with antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), followed by a switch to second-generation antipsychotics as well as cognitive-behavioral psychotherapy may be considered (15, 25).

In conclusion, concurrent depressive symptoms in schizophrenia are common and require careful evaluation and targeted treatment interventions. Because concurrent depressive symptoms are associated with significantly poorer long-term functional outcome in schizophrenia, active treatment intervention should be the standard of care.

Obsessive-Compulsive Symptoms in Schizophrenia

Obsessive-compulsive symptoms in schizophrenia have challenged clinicians over the years. Their clinical profile is similar to traditional nonpsychotic OCD, such as contamination as well as sexual, somatic, religious, and aggressive themes, with or without accompanying compulsions and intrusiveness (26). The presence of obsessive-compulsive symptoms in schizophrenia was frequently overlooked because they were previously regarded as a defense mechanism against psychotic decompensation by maintaining psychological integrity (27, 28). Yet, current clinical and research findings indicate a poorer clinical course and long-term outcome as well as greater neuropsychological and functional impairments (29).

Prevalence

The NIMH Epidemiologic Catchment Area study, and several subsequent studies, found high comorbidity rate ranging from 4% to 50%, with an average prevalence of 23% (29, 30). The wide range of prevalence is believed to be because of diverse study methodology, patient population, and type of antipsychotic medication treatment as well as varying demographic and clinical settings. Furthermore, evidence suggests more than one pathogenesis of obsessive-compulsive symptoms in schizophrenia (31–33). Obsessive-compulsive symptoms among patients with schizophrenia may manifest during the prodromal phase, as part of active psychotic illness, as obsessive ruminations during recovery or the remission phase, as concurrent independent OCD or as de novo obsessive-compulsive symptoms associated with second-generation antipsychotic treatment (34, 35). Current neurobiological evidence of obsessive-compulsive symptoms in schizophrenia suggests greater prefrontal cortex dysfunction as well as glutaminergic and serotonergic dysregulations (36).

Pathogenesis

The current neurobiological evidence in OCD and schizophrenia suggests that they constitute two distinct disorders with some overlap, which might explain shared commonality of clinical features. Current evidence suggests dorsolateral prefrontal cortical dysfunction in schizophrenia and corticostriatal-thalamic circuitry abnormality in OCD. Neuroimaging studies of patients with schizophrenia have shown significant degenerative changes in the cingulate and caudate nuclei as well as in the orbitofrontal cortex (37, 38). Although these areas are also implicated in OCD, no gross anatomical changes in these areas have been found in patients with OCD (39). Functional magnetic resonance imaging studies also revealed differences between OCD and schizophrenia: hyperactivity in the orbitofrontal cortex, caudate nucleus, and thalamus have been observed in OCD, whereas dorsolateral prefrontal cortical dysfunction is the predominant finding in schizophrenia (37, 38).

Neuropsychological studies have demonstrated greater prefrontal cortical functional impairment in the OCD subgroup compared with patients with only schizophrenia (40–43). Although OCD and schizophrenia share some epidemiological and clinical similarities, no clear familial relationship or shared genetic etiology has been found between OCD and schizophrenia (44). However, emerging epidemiological and genetic findings suggest that schizophrenia and obsessive-compulsive symptoms constitute multiple distinct subgroups, with a unique neurobiological pathogenesis.

Treatment

The efficacy of anti-OCD medication, such as SSRIs and second-generation antipsychotics, in the treatment of obsessive-compulsive symptoms in schizophrenia has been studied extensively in recent years, but the findings are variable. This variation may be attributable to study methodology, presence of multiple pathogeneses, and pharmacological profiles of antipsychotic treatment. For instance, clozapine is known to induce de novo obsessive-compulsive symptoms in schizophrenia; however, clozapine monotherapy has also been shown to successfully treat obsessive-compulsive symptoms as a part of its antipsychotic efficacy (45). Obsessive-compulsive symptoms that develop as a part of the psychotic process might be successfully treated with antipsychotic medication along with overall improvement in psychosis.

De novo obsessive-compulsive symptoms that develop with second-generation antipsychotic treatment are thought to be related to 5-HT2A antagonism, whereas D2 blockade is thought to be related to the antiobsessional effect of second-generation antipsychotics (46, 47). If obsessive-compulsive symptoms are exacerbated or newly develop with use of second-generation antipsychotics, a dosage adjustment (48, 49) or switching to an antipsychotic with strong antidopaminergic properties and a negligible 5HT2 receptor affinity should be considered (50). Current evidence suggests that use of antipsychotics with antidopaminergic (D2-D3) properties and minimal 5-HT2A affinity, such as amisulpride, offer a better therapeutic option for neuroleptic-induced obsessive-compulsive symptoms in schizophrenia.

Patients with OCSs before schizophrenia onset respond poorly to changes in antipsychotic regimen (50). In these patients, adjunctive SSRI treatment should be considered. Clinicians must be aware of potential pharmacokinetic and pharmacodynamic interactions of adjunctive anti-OCD agents, such as SSRIs and clomipramine, with antipsychotics. For instance, fluvoxamine blocks CYP1A2 enzyme and may increase plasma concentration of olanzapine up to 100%, and clozapine by up to 5–10 times (51–54). Therefore, SSRI augmentation to treat obsessive-compulsive symptoms may be avoided among patients taking clozapine with the dosage adjustment alone. However, adjunctive SSRI treatment may be needed for some patients.

Finally, individualized cognitive behavioral psychotherapy should be considered in a stabilized patient with obsessive-compulsive symptoms and schizophrenia (55, 56).

Discussion

Schizophrenia is a chronic debilitating disorder, and its management can be challenging, particularly in the presence of comorbid conditions such as depression and obsessive-compulsive symptoms. These coexisting symptoms in schizophrenia can affect the clinical course, treatment response, and outcome. To better understand the complex clinical heterogeneity of schizophrenia with comorbid disorders, clinicians have conceptualized various subtyping strategies that characterize the clinical, neuropsychological, and treatment profiles and facilitate better management of these patients.

Although limited data support the etiological hypotheses of affective symptom domains in psychotic illness, the current evidence suggests that morphology and FC may be unique and distinctive. The concept that affective symptoms have a distinct psychopathology can provide researchers and clinicians with an avenue to better understand schizophrenic illness.

A growing body of evidence from biological studies suggests possible genetic diathesis influencing multiple clinical phenotypic traits, and the intracellular signaling in response to neurotransmitter activity depends on the function of various ion and voltage-gated membrane channels. Recent research links the role of the calcium channel gene across major psychiatric and neurocognitive disorders, suggesting the need for further exploration of comorbidity in schizophrenia (57–59). Proponents of the concept of comorbidity in schizophrenia have argued that symptoms such as depression, dementia, social anxiety, and OCD may constitute distinct clinical conditions with a unique underlying pathogenesis. The traditional clinical subtypes with distinct clustering of symptoms predicting longitudinal clinical course have been proposed as a foundation to systematically understand the pathogeneses and treatment of schizophrenia (60). Furthermore, the delineation of phenotypes was viewed as fundamental to identifying candidate genes, or, alternatively, dissecting appropriate behavioral correlates was seen as a prerequisite for neurobiological underpinnings. Consequently, subtyping strategies have been proposed as phenomenological groundwork for a systematic biological understanding of schizophrenia.

Conclusions

Schizophrenia is a complex, heterogeneous, and disabling psychiatric disorder that disrupts cognitive, perceptual, and emotional functioning. The clinical, pharmacological, and neurobiological profiles of comorbid conditions in schizophrenia have been extensively explored in recent years. However, the diagnostic and treatment issues of coexisting or overlapping psychiatric symptoms and disorders in schizophrenia remain poorly understood and clinically challenging (61).

The concept of comorbidity in schizophrenia has posited that symptoms such as depression and OCD may constitute distinct schizophrenic subtypes with a unique underlying biological pathogenesis. The publication of the DSM-5 and the NIMH RDoC project may provide a meaningful platform for future studies as researchers and clinicians move beyond the DSM-5 to a more neurobiologically based “precision psychiatry” (62) that may pave the way for a better understanding and management of this complex disorder.

For now, schizophrenia with comorbid conditions will need to be looked at through the prism of combined categorical and dimensional perspectives. Researchers and clinicians need to be able to work with categorical systems such as the DSM-5 and ICD-10 while ensuring that all dimensions of psychopathology are attended to by providing individualized biopsychosocial treatment while also exploring new research approaches.