Many patients with depression do not fully respond to their first trial of antidepressant medication. The first step is to revisit the diagnostic assessment considering alternatives, and assess medication adherence and substance abuse. Depressive symptoms in the context of bipolar disorder and schizophrenia have different treatment approaches from the ones discussed here. See this SMI Adviser tip for bipolar disorder. For schizophrenia, the first priority is to control the psychotic symptoms; this can result in improvement in depressive symptoms. For schizoaffective disorder, there is limited evidence and the approach is thought to depend on the subtype.
With regard to major depression, in the STAR*D trial, patients who failed one antidepressant SSRI medication were entered into a study of multiple sequential comparisons of different solo antidepressant medications or combination strategies. There were few significant differences in remission rates. The study established that worthwhile options include bupropion, buspirone and T3 (triiodothyronine) augmentation; nortriptyline; and combined mirtazapine venlafaxine. Remission rates were low with all options tried. In guidelines, first-line treatments for resistant depression include adding lithium, combined olanzapine fluoxetine, adding quetiapine, adding aripiprazole, SSRI antidepressant plus bupropion, and adding mirtazapine. Cognitive behavioral therapy should be offered, in addition to other treatments. Second-line treatments include adding ketamine, adding lamotrigine, SSRI plus buspirone, venlafaxine, TMS (transcranial magnetic stimulation), ECT (electroconvulsive therapy), adding T3, and adding risperidone. In major depression with psychosis, the combination of antipsychotic and antidepressant medications is superior to either alone. There is evidence for ECT in psychotic depression, and positive reports for ketamine.