Comorbid Major Depressive Disorder in Schizophrenia

A Systematic Review and Meta-Analysis

Damien Etchecopar-Etchart; Theo Korchia; Anderson Loundou; Pierre-Michel Llorca; Pascal Auquier; Christophe Lançon; Laurent Boyer; Guillaume Fond


Schizophr Bull. 2021;47(2):298-308. 

In This Article

Abstract and Introduction


Comorbid major depressive disorder (MDD) in schizophrenia (SZ; SZ-MDD) has been identified as a major prognostic factor. However, the prevalence and associated factors of SZ-MDD have never been explored in a meta-analysis. All studies assessing the prevalence of SZ-MDD in stabilized outpatients with a standardized scale or with structured interviews were included. The Medline, Web of Science, PsycINFO, and Google Scholar databases were searched. Using random effects models, we calculated the pooled estimate of the prevalence of SZ-MDD. We used meta-regression and subgroup analyses to evaluate the potential moderators of the prevalence estimates, and we used the leave-one-out method for sensitivity analyses. Of the 5633 potentially eligible studies identified, 18 studies (n = 6140 SZ stabilized outpatients) were retrieved in the systematic review and included in the meta-analysis. The pooled estimate of the prevalence of SZ-MDD was 32.6% (95% CI: 27.9–37.6); there was high heterogeneity (I 2 = 92.6%), and Egger's test did not reveal publication bias (P = .122). The following factors were found to be sources of heterogeneity: publication in or after 2015, the inclusion of patients from larger studies, the assessment tools, the inclusion of patients with substance use disorder or somatic chronic diseases, age, education level, the lifetime number of hospitalizations, and antidepressant use. Two-thirds of the extracted variables could not be explored due to an insufficient amount of published data. The prevalence of MDD is high among SZ individuals. Healthcare providers and public health officials should have an increased awareness of the burden of SZ-MDD.


Major depressive disorder (MDD) is the most frequent mental disorder, and its impact on the global burden of disease and quality of life is increasing, especially in the wealthiest countries.[1] The development of antidepressants and talk therapies have changed the lives of countless patients. However, there remains great room for improvement, especially in schizophrenia (SZ) patients, for whom MDD was identified as the most frequent psychiatric comorbidity more than 30 years ago.[2] At the time, it was hypothesized that MDD may occur in more than 50% of patients with SZ.

Thirty years later, we still do not know the exact prevalence of MDD in SZ (SZ-MDD), despite numerous studies showing that it plays a major role in the prognosis of SZ, increases suicidality, increases weight gain, impairs quality of life, and impairs daily functioning independent of psychotic symptomatology.[3–5] Numerous studies have also examined the genetic overlap between MDD and SZ.[6] Studies published in the last 3 decades have reported prevalences ranging from 16% to 69%,[7,8] and we recently identified MDD in approximately 30% of our national FondaMental Academic Center of Expertise for Schizophrenia (FACE-SZ) cohort.[9] Such high rates may be explained by several factors. We have found that less than half of SZ patients with MDD receive antidepressants, and almost half of the patients treated with antidepressants remain unremitted.[9] In other words, 3 out of 4 SZ patients with MDD do not receive successful treatment in contrast to the results of 3 meta-analyses indicating that antidepressants are effective for treating SZ-MDD patients.[10–12] This discrepancy may explain the high prevalences and is consistent with the lack of international consensus and guidelines for the diagnosis and treatment of SZ-MDD in the latest National Institute for Health and Care Excellence release.[13] Altogether, these data suggest the need to improve the treatment of MDD in patients with SZ, and the first step is to identify the exact prevalence and the sources of the heterogeneity between studies.

The heterogeneity may be due to the absence of consensus on the categorial definition of SZ-MDD and the lack of a gold standard for evaluation.[14] Some authors make no distinction between MDD with or without SZ and use structured clinical interviews, clinician-rated questionnaires, or self-reported questionnaires that have already been shown to contribute to heterogeneity when evaluating the prevalence of MDD. In an attempt to reduce this heterogeneity, the clinician-rated Calgary Depression Rating Scale for Schizophrenia (CDSS)[15] was developed in the 1990s to specifically identify SZ-MDD patients by excluding symptoms that may be confounded with negative symptoms or antipsychotic secondary side effects, such as blunted affect or avolition.[16–19] However, this scale was not used in all recent studies, and the cutoff score to identify MDD varies across studies.

Beyond the assessment tool, many factors have been found to influence the prevalence of MDD with or without SZ, including sociodemographic data (female sex,[20] older age,[20] and unemployment[21]), addictions (tobacco, alcohol, and substance abuse),[22,23] physical health and biological disturbances (hypovitaminosis D,[24] metabolic syndrome,[25] chronic peripheral inflammation,[26] chronic physical pain,[27,28] and sleep disorders[29]), treatments (first-generation antipsychotics,[30,31] lower adherence to treatment,[32] and higher insight into illness[33]).

In summary, as mentioned by Upthegrove et al,[14] the current lack of evidence for the treatment of SZ-MDD is the result of a lack of sufficient investigation, leading to wide-ranging consequences for the illness and its prevention. MDD may, thus, be considered an important health inequality among SZ patients.[34]

The primary objective of this systematic review and meta-analysis was to determine the prevalence of SZ-MDD in stabilized SZ community-dwelling/real-world outpatients. The secondary objective was to quantitatively evaluate associated factors, including assessment tools, sociodemographic data, clinical variables, treatments, physical health and biological variables, cognition, functioning, and quality of life that moderate estimates of SZ-MDD prevalence.