We reviewed "treatment-resistant" bipolar disorder especially treatment-resistant bipolar depression and rapid-cycling bipolar disorder. Encouraging results have been reported by randomized controlled trials on inositol, ketamine, lamotrigine, modafinil and pramipexole administration during resistant depressive phases. In particular, ketamine demonstrated significant improvement compared with the placebo. Rapid-cycling bipolar disorder refers to the presence of at least 4 mood episodes in the previous 12 months that meet the criteria for manic, hypomanic or major depressive episodes in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). Rapid-cycling bipolar disorder has been reported to have a poorer outcome than non-rapid-cycling bipolar disorder. In addition, rapid cycling is associated with depression, substance abuse and suicide risk. Thus, clinicians need to pay closer attention when diagnosing and treating patients with rapid-cycling bipolar disorder. Quetiapine demonstrated significant improvement in double-blind placebo-controlled studies on rapid cycling. Hypothyroidism and antidepressants have been reported as risk factors for rapid-cycling bipolar disorder. Therefore, recent guidelines recommend that antidepressants be avoided and to administer quetiapine, especially during acute depressive episodes in rapid-cycling patients.
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