The aim of this research, which represents an additional and longer follow-up to a previous trial, was to evaluate a 5-year follow-up study of a combined treatment (pharmacological + psychoeducational and cognitive-behavioral therapy) as compared with a standard pharmacological treatment in patients with refractory bipolar disorder.

Forty patients were randomly assigned to either an Experimental group–under combined treatment — or a Control group — under pharmacological treatment. Data were analyzed by analysis of variance (ANOVA), with repeated measures at different evaluation time points.

Between-group differences were significant at all evaluation time points after treatment. Experimental group had less hospitalization events than Control group in the 12-month evaluation (P = 0.015). The Experimental group showed lower depression and anxiety in the 6-month (P = 0.006; P = 0.019), 12-month (P = 0.001; P < 0.001) and 5-year (P < 0.001, P < 0.001) evaluation time points. Significant differences emerged in mania and misadjustment already in the post-treatment evaluation (P = 0.009; P < 0.001) and were sustained throughout the study (6-month: P = 0.006, P < 0.001; 12-month: P < 0.001, P < 0.001; 5-year: P = 0.004, P < 0.001). After 5-year follow-up, 88.9% of patients in the Control group and 20% of patients in the Experimental group showed persistent affective symptoms and/or difficulties in social-occupational functioning.

A combined therapy is long-term effective for patients with refractory bipolar disorder. Suggestions for future research are commented.