Albert Jan Schutte

It is increasingly recognized that depressive illness is associated with frequent recurrences. The National Institute for Mental Health Consensus Development Conference concluded that between 50% and 85% of patients will have at least one subsequent episode of depression.

 The natural history of a treated episode of depression typically comprises an amelioration of symptoms leading to remission (symptoms returned to pre-depression baseline). Most studies of antidepressant medications evaluate the response up to this point. After a further three to six months free of depression (during which time the patient may have continued to receive antidepressant medication), the patient is considered to have recovered. Episodes of depression manifest before recovery are termed relapses, whilst episodes after recovery are considered to be recurrences. However, the usage of this terminology is frequently imprecise in the published literature.

 Studies of the prophylaxis of depression using tricyclic antidepressants are surprisingly rare and mostly involve small patient groups. The results of these studies are generally positive, showing an advantage for amitriptyline (one-year study versus placebo in 13 patients), and imipramine (two-year study versus placebo in 100 patients). Maprotiline has also been shown to be more effective than placebo in a one-year study involving more than 370 patients in each group, although the absence of a "symptom-free" period made this a study of relapse, not recurrence prevention. There is one recent more convincing study which shows a clear and statistically significant reduction of recurrence in patients given imipramine in a three-year maintenance trial in 128 patients. These findings suggest that antidepressant treatment should not be withdrawn immediately after a patient has responded but should be continued as maintenance therapy.

 The anticholinergic effects, weight gain and cardiotoxicity associated with the tricyclic antidepressants, however, can result in high levels of withdrawal from treatment and the use of subtherapeutic doses. The selective serotonin re0uptake inhibitors (SSRIs) have a better safety profile than the tricyclic antidepressants and thus offer a more attractive alternative for long-term therapy.

 Although a number of SSRIs have shown some efficacy in studies assessing the prevention of relapse, there is little evidence available regarding their use in the prevention of recurrence. The only study conducted to date assessed the efficacy of fluoxetine in 456 patients with DSM-III major depression. Patients were treated openly with fluoxetine (40-80 mg/day) for 6 weeks and the responders were continued on open treatment for a further 18 weeks. The 220 patients who continued to respond entered a one-year, double-blind phase during which they received placebo or fluoxetine (40 mg/day). At the end of the study, 57.4% of patients given placebo had a recurrence of depression compared with 26.1% of those given fluoxetine (p<0.01). However, the dosage of fluoxetine used in this study was relatively high compared with the recommended daily dose.

 With fluvoxamine there is a double-blind, placebo-controlled, randomized, multicenter, parallel-group study to assess the efficacy of fluvoxamine in preventing recurrence of DSM-III-R major depression. Following six-months open treatment with fluvoxamine (up to 300 mg/day during months 1-4; 100 mg/day during months 5 and 6), patients who responded to treatment, assessed by Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI), were randomized to receive fluvoxamine 100 mg/day (n=110) or placebo (n=94) for a further 12 months. The incidence of recurrence was significantly higher with placebo than with fluvoxamine (35.5% vs. 12.7%; p<0.001). Moreover, the time to recurrence was significantly longer in the fluvoxamine group than in the placebo group (181 vs. 96 days; p<0.005). The benefits of fluvoxamine were also demonstrated by a significantly lower mean MADRS total score (7.8 vs. 12.5; p<0.001), CGI severity of illness score (1.8 vs. 2.4; p=0.01) and Covi anxiety scale total score (4.7 vs. 5.8; p=0.002) at the end of the study. There was no difference between the groups in the incidence of adverse events (35% with fluvoxamine, 37% with placebo). The results show that fluvoxamine has marked beneficial effects in preventing the recurrence of depression.