A Double-Blind Randomized Comparison of Nortriptyline Plus Perphenazine Versus Nortriptyline Plus Placebo in the Treatment of Psychotic Depression in Late Life

Objective: To conduct the first randomized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression.

Method: The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features (DSM-III-R criteria). Patients were started openly on nortriptyline treatment titrated to therapeutic levels. They were then randomly assigned under double-blind conditions to addition of perphenazine or placebo. Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression (HAM-D) and the Brief Psychiatric Rating Scale (BPRS); side effects were assessed with the Geriatric Movement Disorder Assessment.

Results: Both treatments were well tolerated. Of the 36 randomly assigned patients, 2 (1 in each group) dropped out due to treatment-related adverse effects. Four additional patients dropped out for administrative reasons. Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine (N = 14) or placebo (N = 16) for at least 2 weeks (median = 9 weeks). There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D, the BPRS, its psychoticism subscale, or any side effects measure. Rates of response (defined as resolution of both depression and psychosis) did not differ significantly in the 2 groups (nortriptyline-plus-perphenazine group, 50% vs. nortriptyline-plus-placebo group, 44%).

Conclusion: When treating older patients with psychotic depression, the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy. This finding supports existing data suggesting that the pathophysiology (and thus the required treatment) of psychotic depression may be different early and late in life.