Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind, controlled trial. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. Lithium combined with carbamazepine or haloperidol in the treatment of mania. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. A double-blind comparison of valproate and lithium in the treatment of acute mania. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a controlled clinical trial. A report by the Medical Research Council Drug Trials Subcommittee. Lithium addition to neuroleptic treatment in chronic schizophrenia: a randomized, double-blind, placebo-controlled, cross-over study. 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.
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. 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. Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy.
                A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores.
                The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores.
                The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures. Maintenance studies in bipolar disorder have received increased attention in recent years. The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies, as well as interest in a new group of drugs with mood-stabilizing properties. The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder. We present the methodology of a recently completed randomized, double-blind, placebo-controlled, parallel-group comparison of divalproex and lithium. We examine the consequences of salient design features, along with their implications for future studies. A fundamental conclusion is that such maintenance studies should be designed and executed to emphasize enrollment of patients with relatively active, severe forms of the illness. This goal is not achieved simply, as inherent features of long-term, placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder. Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies designed to achieve adequate statistical power. 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. Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were randomized to double-blind treatment with carbamazepine plus lithium [CBZ-Li] or haloperidol plus lithium [HAL-Li] with benztropine. Unit dosages of Li 300 mg, CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks. No rescue medications were permitted after 3 weeks. Standard ratings of psychopathology and side effects were accomplished weekly. Sixty patients entered the study but only 33 remained for randomization after drug washout. By 8 weeks both groups were improved from baseline without statistically reliable differences between them. However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout, whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications. We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects. 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. This study was carried out to compare the efficacy of lithium carbonate with that of valproate in acute mania and to determine whether pretreatment clinical characteristics, such as the presence of a mixed affective state, might predict a differential response to the two drugs.
                Twenty-seven patients meeting DSM-III-R criteria for acute manic episodes underwent a 3-week, randomized, double-blind, parallel-groups trial of treatment with lithium carbonate or valproate. Symptom severity was measured by using the Schedule for Affective Disorders and Schizophrenia, change version (SADS-C), the Global Assessment Scale (GAS), and the Brief Psychiatric Rating Scale (BPRS). Drug effects were compared by using repeated measures analysis of variance (ANOVA).
                At the end of the study, nine of 14 patients treated with valproate and 12 of 13 patients treated with lithium had responded favorably, as measured by changes in the SADS-C mania, BPRS, and GAS scores. Elevated pretreatment SADS-C depression scores were associated with good response to valproate. ANOVA revealed a significant interaction between drug and mixed affective state with respect to treatment response.
                Lithium and valproate were both effective in improving manic symptoms, and lithium was slightly more efficacious overall. Unlike the case with lithium, favorable response to valproate was associated with high pretreatment depression scores. Therefore, treatment with valproate alone may be particularly effective in manic patients with mixed affective states. nan We studied the effect of lithium addition to neuroleptic treatment in chronic schizophrenia, for which contradictory results have been produced in previous studies. Twenty-one chronic schizophrenic inpatients received lithium in a study with randomized, double-blind, placebo-controlled, cross-over design consisting of 8 weeks each of treatment with lithium capsules and identical placebo capsules. The total Brief Psychiatric Rating Scale (BPRS) scores at week 8 of the lithium treatment were improved significantly compared with those at week 8 of the placebo treatment. Of the BPRS subscales, however, only anxiety-depression improved, whereas none of the subscales for anergia, thought disturbance, activation and hostile-suspiciousness improved. There was no significant difference between the total Scale for the Assessment of Negative Symptoms (SANS) scores at any time during lithium and placebo treatment. These results suggest that the addition of lithium to neuroleptic treatment improves anxiety-depression in chronic schizophrenia. 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.
This systematic review indicates that lithium is an efficacious maintenance treatment for bipolar disorder. In unipolar disorder the evidence of efficacy is less robust. This review does not cover the relative efficacy of lithium compared with other maintenance treatments, which is at present unclear. There is no definitive evidence from this review as to whether or not lithium has an anti-suicidal effect. Systematic reviews and large scale randomised studies comparing lithium with other maintenance treatments (e.g. anti-convulsants, antidepressants) are necessary. Outcomes relating to death and suicidal behaviour should be included in all future maintenance studies of mood disorder.