Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind, controlled trial. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone.
A detailed analysis of the results of a multi-centre clinical trial shows that, while the relapse rate following recovery from an operationally defined depressive illness was smaller among patients subsequently treated with either amitryptiline or lithium than with a placebo, there was no clinically significant difference between the prophylactic efficacy of the 2 antidepressants. An account is given of the relative adverse effects of the treatments, and the implications of the findings are discussed. In a double-blind, long-term follow-up study, 117 bipolar patients received lithium carbonate, imipramine hydrochloride, or both and 150 unipolar patients received lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo. With bipolar patients, lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes. The combination treatment provided no advantage over lithium carbonate alone. With unipolar patients, imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences. The combination treatment provided no advantage over imipramine alone. The lithium carbonate-treated group had fewer manic episodes than the other groups. Treatment outcome, which was evaluated primarily in terms of the occurrence of major depression or manic episodes, was significantly related to characteristics of the index episode, ie, the episode that brought the patient into the study. The authors compared the efficacy of olanzapine and lithium in the prevention of mood episode relapse/recurrence.
                Patients with a diagnosis of bipolar disorder (manic/mixed), a history of two or more manic or mixed episodes within 6 years, and a Young Mania Rating Scale total score > or =20 entered the study and received open-label co-treatment with olanzapine and lithium for 6-12 weeks. Those meeting symptomatic remission criteria (Young Mania Rating Scale score < or =12; 21-item Hamilton depression scale score < or =8) were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5-20 mg/day (N=217), or lithium (target blood level: 0.6-1.2 meq/liter) (N=214).
                Symptomatic relapse/recurrence (score > or =15 on either the Young Mania Rating Scale or Hamilton depression scale) occurred in 30.0% of olanzapine-treated and 38.8% of lithium-treated patients. The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (-0.1% to 17.8%) exceeded the predefined noninferiority margin (-7.3%). Secondary results showed that compared with lithium, olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence. Depression relapse/recurrence occurred in 15.7% of olanzapine-treated and 10.7% of lithium-treated patients. Mean weight gain during open-label co-treatment was 2.7 kg; during double-blind monotherapy, weight gain was significantly greater with olanzapine (1.8 kg) than with lithium (-1.4 kg).
                These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment. Both agents were comparable in preventing depression relapse/recurrence. Recently, the therapeutic benefit of lithium augmentation in old age has come into question. These data, in light of the documented high incidence of side effects after lithium use in elderly patients, resulted in the design of a prospective, placebo-controlled lithium augmentation withdrawal study in elderly patients with unipolar depression. Twelve eligible geriatric patients (10 women and 2 men; mean [+/-SD] age, 76.2 +/- 5.7 years) with DSM-III-R unipolar depression receiving adjunct lithium therapy were randomized to receive continued lithium augmentation or matching placebo (withdrawal rate 150 mg/day/wk). At each clinic visit, patients were assessed for depression (Montgomery-Asberg Depression Rating Scale and Geriatric Depression Rating Scale) and lithium-induced toxicities (a 21-item side-effect checklist, renal and thyroid biochemistry). Over the 2-year observation period, the placebo group reported a decrease in composite 21-item side-effect score and specific lithium toxicities (e.g., urinary urgency, hand tremor, and renal/thyroid abnormalities). Two patients in the lithium maintenance group had a recurrence of depression at 61 and 96 weeks, respectively, immediately after a stressful life event (cerebrovascular accident [CVA] or death of spouse), and two patients had a recurrence in the placebo group at 7 and 92 weeks, respectively, without any apparent changes in life stresses. No other prognostic risk factors for recurrence were identified. Depression that recurred in patients who were receiving placebo was relatively resistant to reinstitution of lithium augmentation therapy. In otherwise stable geriatric patients with unipolar depression, the documented benefits of reduced side effects should be weighed against the risk of recurrence and subsequent lithium resistance before withdrawal of lithium augmentation. Twenty-seven patients with recurrent unipolar depression and 22 with bipolar II illness in remission for at least six months were randomly assigned on a double-blind basis to treatment regimens using lithium carbonate, imipramine hydrochloride, lithium carbonate plus imipramine, or placebo. Lithium carbonate was found to help prevent depressive relapse among patients with unipolar disease, and relapse of any type among those with bipolar II disease. No effect or interaction of imipramine was found in either group. These results add to a growing body of data that suggest the usefulness of lithium carbonate in the prophylaxis of unipolar depressive illness. The relative usefulness of lithium carbonate and imipramine requires further study. Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone.
                Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months.
                The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023).
                Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.
There was adequate efficacy evidence for lithium or antidepressants preventing relapse in unipolar affective disorder, however their relative efficacy was unknown. When considering lithium or antidepressant long-term therapy, patients and clinicians should take into account the patient's clinical history, the side-effects and the individual's likely adherence to the recommended treatment regime. Large-scale, long-term randomised trials in unselected groups of subjects with unipolar affective disorder are needed.