The mechanisms of tolerance in antidepressant action.
Fifty-seven highly recurrent unipolar patients, excluded from previous long-term studies with selective serotonin reuptake inhibitors (SSRIs) after they experienced a new recurrence, were acutely treated with the full dosage of the SSRIs they were on. Fifty-one of them (89.5%) had a sustained response and entered into the 4-month continuation therapy. During this phase, no relapse was observed. At the end of it, all patients gave their written informed consent to be enrolled in a 24-month long-term therapy, maintaining the same treatment dosage of fluvoxamine 300 mg/day, sertraline 150 mg/day, or paroxetine 40 mg/day. At the end of the study, 28 out of the 51 outpatients (54.9%) showed a further recurrence. Nevertheless, second recurrences observed during this second maintenance therapy were less severe than first recurrences, decreasing from 25.1+/-3.4 to 21.6+/-3.3 (P<0.0001), respectively. Considering the clinical characteristics of patients, we found that a high number of prior depressive episodes and an early age at onset of illness may predict a bad outcome. Moreover, patients with a longer duration of euthymia during a first maintenance period are less likely to have a new episode of depression.