SSRIs and SNRIs Boost Clozapine Treatment Response

TOPLINE:

Standard doses of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) reduced the risk for relapse when added to clozapine in treatment-resistant schizophrenia, unlike other antidepressants, according to a new study. Sertraline, duloxetine, and escitalopram were particularly effective, and high-dose antidepressant use increased both psychiatric and somatic hospital admission risks.

METHODOLOGY:

• Researchers analysed and then meta-analysed data from two register-based, nationwide cohort studies in Finland (1996-2017) and Sweden (2006-2023) and included 23,206 patients with schizophrenia (mean age, 41.3 years; 9531 women) who were followed up from first clozapine use until death or the end of data linkage.
• This study had a within-individual cohort design in which each person served as their own control and compared clozapine augmentation with specific antidepressants against clozapine use alone.
• Researchers categorised antidepressant use into four dose categories: low (< 0.6 defined daily doses [DDDs] per day), standard (0.6 to < 1.1 DDDs per day), medium-high (1.1 to < 2.1 DDDs per day), and high (≥ 2.1 DDDs per day), with specific milligrams per day ranges for each medication.
• The primary outcome was schizophrenia relapse, defined as hospital admission with psychotic disorder; the secondary outcome was somatic hospital admission.
• The mean follow-up duration was 12.1 years for the Finnish cohort and 11.4 years for the Swedish cohort.

TAKEAWAY:

• A total of 65.8% of patients in the Finnish cohort and 51.0% in the Swedish cohort had a relapse during follow-up. Additionally, 52.6% of patients in the Finnish cohort and 41.2% in the Swedish cohort experienced hospital admission because of somatic reasons during follow-up.
• The lowest risk for relapse was observed with sertraline (adjusted hazard ratio [aHR], 0.76), followed by duloxetine (aHR, 0.78) and escitalopram (aHR, 0.85; P < .001 for all). Antidepressants other than SSRIs and SNRIs were associated with an increased risk for relapse without achieving statistical significance.
• Standard doses showed optimal effectiveness, with sertraline 30-54 mg/d (aHR, 0.49; 95% CI, 0.27-0.89), escitalopram 6-10 mg/d (aHR, 0.57; 95% CI, 0.37-0.88), and duloxetine 18-32 mg/d (aHR, 0.59; 95% CI, 0.46-0.75) showing the lowest risk for relapse.
• Augmentation with antidepressants was not associated with an increased risk for somatic hospital admission at low or standard doses; however, high-dose use was linked to elevated risks for both relapse and somatic hospital admission.

IN PRACTICE:

“[The study] findings support the use of SSRIs and SNRIs as viable augmentation strategies for clozapine-treated patients with schizophrenia, particularly at standard doses,” the authors wrote. “The same finding was not observed with other, non-SSRI and non-SNRI antidepressants,” they added. “The findings have important clinical implications, emphasising the potential utility of antidepressant augmentation in specific subgroups of patients with TRS [treatment-resistant schizophrenia], such as those with persistent negative symptoms, comorbid depression, or suicidal ideation. Given the increased risks associated with high-dose antidepressant use, clinicians should carefully balance the potential benefits with the risk of adverse outcomes,” they concluded.

SOURCE:

This study was led by Heidi Taipale, PhD, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland. It was published online in the August 2025 issue of The Lancet Psychiatry.

LIMITATIONS:

This study was limited by its observational design, the lack of randomisation, and the low number of users for some exposures. This study lacked information on why antidepressants were started or stopped, symptom severity fluctuations, social support or non-pharmacologic interventions, and confirmation of treatment resistance. Additionally, dose categorisation on the basis of DDDs was not optimal for some drugs. Schizophrenia relapse was broadly defined as hospital admission with psychotic disorder without symptom specificity, and major depressive disorder was rarely recorded. Furthermore, the findings were limited to long-term risks in low-cost healthcare settings, and people with lived experience were not involved.

DISCLOSURES:

This study received funding from the Sigrid Jusélius Foundation and the Finnish Ministry of Social Affairs and Health. This project used data from the REWHARD consortium supported by the Swedish Research Council. Several authors reported having financial ties with various sources including pharmaceutical companies. Details are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.