For most patients with major depressive disorder (MDD) the first-line treatment is one of the selective serotonin reuptake inhibitors (SSRIs). However, some practitioners prefer to utilize a serotonin norepinephrine reuptake inhibitor (SNRI) or the norepinephrine-dopamine reuptake inhibitor bupropion as their first-line antidepressant treatments (Slide 1). Differences of opinion regarding first, second, or third choice of antidepressant often stem from regional practices or individual training.

A basic standard of practice in MDD treatment is to initiate monotherapy trials with several first-line choices of antidepressants before moving on to alternate strategies. This basic strategy was evaluated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Only approximately one third of the patients remitted after being treated with the study's first-line treatment, a 12-week trial of citalopram in doses up to 60 mg/day. As in other contemporary treatment studies, remission was defined as virtually complete relief of depressive symptoms. This is defined as a Hamilton Rating Scale for Depression score of ≤7 or a score of ≤5 on the self-report version of the Quick Inventory of Depressive Symptomatology.

For those who did not obtain an adequate response to the initial course of citalopram therapy, the STAR*D study compared several alternate treatments, including switching to another antidepressant, adjunctive therapy with another type of medication (ie, a medication that is not an antidepressant), or combination treatment (ie, adding another antidepressant). At the end of four sequential treatment trials, only approximately two thirds of the patients remitted. Of those, 40% to 70% relapsed within the next year despite continued therapy.

For most patients with major depressive disorder (MDD) the first-line treatment is one of the selective serotonin reuptake inhibitors (SSRIs). However, some practitioners prefer to utilize a serotonin norepinephrine reuptake inhibitor (SNRI) or the norepinephrine-dopamine reuptake inhibitor bupropion as their first-line antidepressant treatments (Slide 1). Differences of opinion regarding first, second, or third choice of antidepressant often stem from regional practices or individual training.

A basic standard of practice in MDD treatment is to initiate monotherapy trials with several first-line choices of antidepressants before moving on to alternate strategies. This basic strategy was evaluated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Only approximately one third of the patients remitted after being treated with the study's first-line treatment, a 12-week trial of citalopram in doses up to 60 mg/day. As in other contemporary treatment studies, remission was defined as virtually complete relief of depressive symptoms. This is defined as a Hamilton Rating Scale for Depression score of ≤7 or a score of ≤5 on the self-report version of the Quick Inventory of Depressive Symptomatology.

For those who did not obtain an adequate response to the initial course of citalopram therapy, the STAR*D study compared several alternate treatments, including switching to another antidepressant, adjunctive therapy with another type of medication (ie, a medication that is not an antidepressant), or combination treatment (ie, adding another antidepressant). At the end of four sequential treatment trials, only approximately two thirds of the patients remitted. Of those, 40% to 70% relapsed within the next year despite continued therapy.

Conventional antipsychotics have a substantial literature of >30 placebo-controlled studies supporting their use in depression. Reports describing the use of antipsychotic treatment in depression appeared as early as 1959. In the 1970s, combination products of perphenazine and amitrip-tyline were quite popular. Antipsychotic agents were effective for selected symptoms or in selected patients; yet, these agents were not viewed as “true” antidepressants, perhaps because of their lack of effects on loss of interest. The use of antipsychotics in patients with nonpsychotic depression declined rapidly in the 1980s when tardive dyskinesia (TD) surfaced as a potential adverse effect of this class of medications. Depressed patients were thought to be at increased risk. Interest in the potential utility of antipsychotics in depression resurfaced with the availability of the second-generation antipsychotics (SGAs), which possess a considerably lower risk for TD.

Most of the SGAs are inhibitors of the serotonin (5-HT)2A receptor and the dopamine (D)2 receptor. In fact, the ratio of these effects has been considered one attribute of an SGA. The SGAs have a variety of other receptor actions that might contribute to antidepressant effects but which vary substantially among the drugs. These include agonist effects at the 5-HT1A serotonin receptor, inhibition of the 5-HT2C receptor, and partial D2 agonism of aripiprazole (Slide 1). In addition, ziprasidone blocks 5-HT and norepinephrine (NE) reuptake and the metabolite of quetiapine has NE reuptake blocking effects.