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


The results of the present study may be summarized as follows. Eighteen studies (n = 6140 SZ patients) were included. The pooled estimate of the prevalence of MDD in stabilized SZ outpatients was 32.6% (95% CI = 27.9–37.6). No publication bias was observed according to Egger's test. There was high heterogeneity across studies. The following factors were significantly associated with the SZ-MDD prevalence: publication in or after 2015, the inclusion of nonselected patients, the assessment tools (structured interviews vs clinician-rated questionnaire vs self-reported questionnaire), the inclusion of patients with substance use disorder or somatic chronic diseases, older age, the percentage of patients with high education levels, the number of lifetime hospitalizations, and the percentage of patients treated with antidepressants. No significant association was found for the other variables analyzed herein. Two-thirds of the extracted variables could not be explored due to an insufficient number of studies reporting these items.

SZ-MDD was identified in almost one-third of SZ-stabilized outpatients, which is approximately 2–3 times higher than in the non-SZ population.[1,63] We also found that studies published in or after 2015 reported higher rates of SZ-MDD, which may suggest an increase in the prevalence of MDD in this population, similar to the increased prevalence of MDD in patients without SZ as reported by the World Health Organization.[64] Because MDD has been identified as a major prognostic factor of SZ, healthcare providers and public health officials should have an increased awareness of the burden of SZ-MDD. Our results highlight the need for the systematic screening and treatment of MDD in SZ outpatients.

Our results highlight the lack of consensus on the evaluation of SZ-MDD patients, as indicated by the discrepancies in the prevalence among studies using structured interviews, clinician-rated questionnaires, and self-reported questionnaires (even for assessments specifically designed to evaluate SZ-MDD). This lack of clear guidelines for diagnosing SZ-MDD is, thus, an important barrier for management and treatment based on current knowledge, evidence, and available treatments. The analysis of the effect of assessment tools showed that the prevalence of MDD was lower among patients evaluated by structured interviews than in those evaluated with a clinician-rated scale; there were similar rates between the CDSS and the MADRS (the CDSS was developed to specifically assess depressive symptoms in SZ). The prevalence was also higher among patients who were diagnosed using self-reported questionnaires. Self-reported tools and clinician-rated tools have shown high levels of agreement in patients without SZ.[65] This may be due to increased neuroticism in SZ, a personality trait that may induce a response bias with respect to self-reported depressive symptoms.[66] The interpretation of our results, thus, remains unclear: do SZ patients overestimate their depressive symptoms, or do clinicians miss depressive symptoms due to inadequate tools? The debate remains open and requires further investigations.

Among sociodemographic data, we have identified that studies carried out among older patients and patients with lower education levels reported higher rates of MDD. The older patients should be targeted; however, most of the samples had a mean age ranging from 28 to 42 years. Further studies should explore SZ-MDD in more specific age ranks (such as 18–25 and >50 years). In particular, MDD onset has been suggested to begin before SZ onset (even 4 years earlier),[67] which may explain the absence of an association between MDD prevalence and age at SZ onset or SZ duration in our results. It suggests that preventive interventions, such as psychoeducation, and lifestyle interventions, including tobacco cessation, dieting, and physical activity training, should also be carried out in younger patients to detect early depressive symptoms.[68] The lower prevalence of MDD in patients with higher education levels is consistent with studies in non-SZ populations.[69] Patients with higher education levels have more cognitive resources to cope with depressive symptoms. Higher education levels may also be a reflection of better care at home during childhood (eg, better diets, less abuse, and less neglect). This suggests that supplementary efforts should be made to prevent SZ-MDD in patients with lower levels of education. We had no data on patients' income level, and thus, we could not determine if this association was due to higher financial resources, which is a limitation of our study. One of the most striking results regarding the sociodemographic data is the absence of an effect of sex on the prevalence. In individuals without SZ, MDD is 2–3 times more common in women than in men.[70] This suggests that the mechanisms of MDD onset in SZ patients may be partly specific and not influenced by hormones and that the increased prevalence of SZ-MDD patients may be mostly due to its increased prevalence in men. This may be consistent with previous findings suggesting dehydroepiandrosterone metabolism dysfunction in patients with SZ.[71]

Among clinical and physical health variables, our results suggest that substance abuse and chronic somatic illnesses may play a role in the increased prevalence of SZ-MDD. These associations have been described for individuals without SZ,[72,73] yet addictions and physical health remain insufficiently documented in SZ studies. For example, none of the studies reported the rate of tobacco smoking, but tobacco has been associated with an increased risk of MDD in the general population.[74] More than half of SZ patients are smokers or heavy smokers.[75] We also found no data regarding alcohol use disorder, metabolic syndrome, chronic pain, sexual dysfunctions, peripheral inflammation, or hypovitaminosis D, despite recent findings suggesting that these factors were associated with MDD.[12,76–79] We found no associations of SZ-MDD prevalence with global psychotic symptomatology, negative symptomatology, or stabilization status. This suggests that MDD should be considered a comorbidity rather than a dimension of SZ that could be connected to other dimensions as currently presented in the PANSS 5-factor structure.[80] We found that studies including patients with a higher number of lifetime hospitalizations reported a higher prevalence of SZ-MDD. Hospitalizations may be a severity marker and induce social withdrawal and autonomy loss, thereby leading to MDD; however, these results were not adjusted for age, which may be a key confounding factor. Hospitalizations may also play a role in MDD onset via psychotrauma, especially for hospitalization under restraint.[81]


The number of participants (>6000 patients) and the large number of studies carried out in miscellaneous countries are strengths of the present article. No publication bias was detected, which strengthens the confidence in the findings. We have identified several sources of heterogeneity.

Limitations and Perspectives

Few studies have explored SZ-MDD, and they fail to answer very basic questions of real-life importance for SZ patients living with MDD. For example, why are there no sex differences in SZ-MDD, suggesting that male patients with SZ are at greater risk of MDD compared to women? Tobacco smoking is present in more than half of SZ patients, but is it a risk factor for SZ-MDD, and does smoking cessation improve MDD? How much do physical activity, diet, hypovitaminosis D, peripheral inflammation, folate deficiency, and metabolic syndrome participate in SZ-MDD onset and maintenance? We still do not know if the first MDD episode should be treated like the others in SZ, and the question is much more difficult given that the first MDD episode may occur far before SZ onset. Cognition, functioning, and quality of life are presumably impaired in SZ patients with MDD, yet the studies exploring these associations do not provide enough data to draw conclusions. Lifestyle factors (sleep, diet/nutrients/probiotics, and physical activity) may also have a strong impact on SZ-MDD and have not been reported in the included studies; these factors do have a strong impact on MDD in individuals without SZ.[82,84,85] Another external validity issue is that all studies recruited patients in the hospital or hospital-related ambulatory settings, which may induce a recruitment bias and limit the external validity of these findings to the whole population of patients with SZ. Our results also highlight the lack of data on MDD history (age at first MDD episode, lifetime number of MDD episodes, and the mean number of previous antidepressant treatments). Future studies should examine these factors. More studies should also be carried out in homeless SZ patients as homelessness is a probable risk factor for SZ-MDD.[86] The study with the highest prevalence (69%) used the PHQ, which has not been validated in SZ. Our results indicate that this study was an outlier, which suggests that the PHQ probably overestimates SZ-MDD prevalence and should not be used in future studies. Some studies may have presented depressive symptoms in a quantitative manner (without cutoff) and could be further analyzed, especially for studies presenting the PANSS depressive subscore (that has no cutoff).