Pharmacological augmentation during disorder-specific psychotherapy for chronic and treatment-resistant depression: a retrospective cohort study

Background

Chronic and treatment-resistant depression (CD/ TRD) remain major clinical challenges and are associated with substantial functional impairment, poor long-term outcomes, and limited response to standard treatments. Although combined pharmacotherapy and psychotherapy is generally superior to monotherapy, it remains unclear which augmentation agent is most beneficial when combined with disorder-specific psychotherapy. Existing pharmacological trials rarely account for psychotherapy, while psychotherapy studies typically do not compare augmentation strategies. This represents a critical gap for treatment personalization. We aimed to explore whether depressive symptom trajectories differ between pharmacological augmentation strategies administered alongside the Cognitive Behavioural Analysis System of Psychotherapy (CBASP), a disorder-specific psychotherapy for CD.

Methods

We are conducting a retrospective cohort analysis of approximately 400 individuals with CD/ TRD treated with CBASP in a naturalistic inpatient setting over ten weeks. Patients receiving augmentation with aripiprazole, quetiapine, lithium, esketamine, or no pharmacological augmentation are being compared. Depressive symptoms were assessed pre- and post-treatment using the Beck Depression Inventory (BDI) and Montgomery–Åsberg Depression Rating Scale (MADRS) as well as weekly with the BDI. Primary outcomes include change in symptom severity, response (≥50% reduction), and remission. Group comparisons are adjusted for clinically relevant confounders, including baseline depression severity, illness chronicity, comorbidity, number of prior treatment failures, and demographic variables. To address confounding by indication, propensity score-based methods are applied.

Results

Preliminary data in n = 39 patients indicate clinically relevant symptom reductions during CBASP with heterogeneous symptom trajectories across augmentation strategies. Larger average reductions were observed for aripiprazole (Δ BDI = -10.91 vs. -4.57 without) and esketamine (Δ BDI = -10.67 vs. -8.00 without), as well as for quetiapine (Δ BDI = -12.00 vs. -8.00 without). In contrast, lithium-treated patients showed smaller reductions (Δ BDI = -3.00 vs. -8.76 without). Findings were consistent across BDI and MADRS (data not shown). While these preliminary observations suggest potential differences between augmentation strategies, subgroup sizes were small and effect estimates imprecise. Final analyses in the full cohort (≈400 patients) will allow more robust estimation of between-group differences and adjustment for confounding factors.

Discussion

With a final sample of approximately 400 individuals with CD/ TRD, this study will provide naturalistic, hypothesis-generating evidence on clinical outcomes associated with different pharmacological augmentation strategies during CBASP in CD/ TRD. The findings address a clinically relevant gap, as current treatment decisions are largely based on trial-and-error approaches rather than comparative evidence. The observed heterogeneity in symptom trajectories may indicate differential interactions between pharmacological mechanisms and psychotherapeutic processes. Given the retrospective, non-randomized design, results cannot be interpreted as causal and may be influenced by residual confounding, however, results may inform future prospective and randomized studies to directly compare augmentation strategies within standardized psychotherapeutic frameworks. Ultimately, such approaches may contribute to precision treatment strategies for optimizing combined pharmacotherapy and psychotherapy in CD/ TRD.

References

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