Continuous theta burst stimulation for bipolar depression: A multicenter, double-blind randomized controlled study exploring treatment efficacy and predictive potential of kynurenine metabolites.

BACKGROUND: While theta burst stimulation (TBS) shows promise in Major Depressive Disorder (MDD), its effectiveness in bipolar depression (BD-D) remains uncertain. Optimizing treatment parameters is crucial in the pursuit of rapid symptom relief. Moreover, aligning with personalized treatment strategies and increased interest in immunopsychiatry, biomarker-based stratification of patients most likely to benefit from TBS might improve remission rates. We investigated treatment effectiveness of continuous TBS (cTBS) compared to sham in BD-D, and assessed the capacity of plasma kynurenine pathway metabolites to predict treatment outcome. METHODS: Thirty-seven patients with BD-D underwent accelerated active or sham cTBS treatment in a multicenter, double-blind, randomized controlled trial. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HDRS-17) before treatment (T0), 3-4 days posttreatment (T1) and 10-11 days posttreatment (T2). Plasma tryptophan, kynurenine, kynurenic acid and quinolinic acid concentrations were quantified with ELISA. Linear mixed models were used for statistical analyses. RESULTS: Although the total sample showed depressive symptom improvement, active cTBS did not demonstrate greater symptom alleviation compared to sham. However, higher baseline quinolinic acid significantly predicted symptom improvement in the active treatment group, not in sham-stimulated patients. LIMITATIONS: The modest sample size limited the power to detect significant differences with regard to treatment effect. Also, the follow-up period was 10-11 days, whereas similar studies usually follow up for at least one month. CONCLUSION: More research is required to optimize cTBS for BD-D and explore the involvement of quinolinic acid in treatment outcome.

Clinical correlates of seasonality in bipolar disorder: A specifier that needs specification?

OBJECTIVE: Seasonal pattern (SP) is a bipolar disorder (BD) specifier that indicates a tendency towards affective relapses during specific moments of the year. SP affects 15%-25% of BD patients. In the past, SP was applied only to depressive relapses while, in DSM-5, SP may be applied to both depressive and (hypo)manic episodes. We examined the association between different clinical correlates of BD and SP according to its current definition in a cohort of patients with BD type I (BDI) and II (BDII). METHODS: Patients were recruited from a specialized unit and assessed according to the season of relapse and type of episode per season. SP and non-SP patients were compared looking into sociodemographic and clinical correlates. Significant variables at univariate comparisons were included in multivariate logistic regression with SP as the dependent variable. RESULTS: 708 patients were enrolled (503 BDI, 205 BDII), and 117 (16.5%) fulfilled DSM-5 criteria for SP. The mean age was 45.3 years (SD = 14.18), and 389 were female (54.9%). The logistic regression model included a significant contribution of BDII (OR = 2.23, CI 1.4-3.55), family history of mood disorder (OR = 1.97, CI 1.29-3.01), undetermined predominant polarity (OR = 0.44, CI 0.28-0.70), and aggressive behavior (OR = 0.42, CI 0.23-0.75). CONCLUSION: Our results outline a novel positive association of SP with undetermined predominant polarity, BDII, family history of mood disorder, and with fewer aggressiveness-related symptoms. Seasonality is associated with a biphasic pattern with similar dominance of (hypo)mania and depression and is more frequent in BDII as compared to BDI. Seasonal episodes may be easier to predict, but difficult to prevent.