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Combination of citalopram and nortriptyline in the treatment of severe major depression: a double-blind, placebo-controlled trial

Firoozeh Raisi, Nastaran Habibi, Abbas Ali Nasehi and Shahin Akhondzadeh1

Objective: Depression is a major health problem and is not only under-recognized and undertreated but is associated with significant morbidity and mortality. It has been suggested that combination therapy rapidly reduces depressive symptoms in patients with moderate-to-severe depression more effectively than monotherapy; however, this is controversial. Serotonergic and noradrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in the management of depression. The objective of this double-blind, placebo-controlled study was to investigate the efficacy and tolerability of the combination of citalopram and nortriptyline for the treatment of moderate-to-severe major depression.

Methods: A total of 45 patients, who met the Diagnostics and Statistical Manual of Mental Disorders-IV criteria for major depressive disorder based on the clinical interview were included in the study. Patients had a baseline Hamilton Depression Rating Scale score of at least 20. In this trial, patients were randomly assigned to receive nortriptyline 50 mg/day plus citalopram 40 mg/day (group 1) or placebo plus citalopram 40 mg/day (group 2), for the 8-week, double-blind, placebo-controlled trial.

Results: Both protocols significantly decreased the Hamilton Depression Rating Scale score over the trial period, but the combination of nortriptyline and citalopram showed significant superiority over citalopram alone in the treatment of moderate-to-severe major depressive disorder (t = 3.34; degrees of freedom = 36; p = 0.001). The difference between the two groups in the frequency of side effects was not significant.

Conclusions: The results of this study suggest that the combination of nortriptyline and citalopram is more effective than citalopram alone in the treatment of depression. This advantage probably results from serotonin and noradrenergic reuptake inhibition. Major depressive disorder (MDD) is one of the most common psychiatric disorders. Patients with this disorder show depressed mood or loss of interest as a key symptom, accompanied by five or more of the following symptoms: • Changes in weight or appetite • Insomnia or hypersomnia • Psychomotor agitation or retardation • Fatigue or loss of energy • Feeling of guilt or worthlessness • Difficulty in concentration or indecisiveness • Thoughts of death or suicide This disorder virtually always results in impaired interpersonal, social and occupational functioning. Lifetime prevalence of MDD is approximately 15%, and can be as high as 25% for women [1,2]. Forecasts suggest that by the year 2020, unipolar major depression could increase in world rank order from the fourth to the second leading cause of disabling-adjusted life years [3]. The main neurochemical theories regarding the pathogenesis of depression involve dysfunction of either norepinephrine