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Objective: The authors assessed gender differences in the proportion of clinical visits spent depressed, manic, or euthymic in patients with bipolar disorder. Method: Data were analyzed from 711 patients with bipolar I or II disorder who were followed prospectively over 7 years (13,191 visits). The main outcome measures were the presence of symptoms of depression or of hypomania or mania, measured by the Inventory of Depressive Symptomatology and the Young Mania Rating Scale. Data were analyzed using three separate repeated-measures regressions with a logistic link function to model the probability that an individual was depressed, manic, or euthymic. The models controlled for bipolar I or bipolar II diagnosis, rapid cycling, age, time in the study, comorbid anxiety disorders, and comorbid substance use disorders. Results: In approximately half of visits, patients had depressive, manic, or hypomanic symptoms. The likelihood of having depressive symptoms was significantly greater for women than for men. This was accounted for by higher rates in women of rapid cycling and anxiety disorders, each of which was associated with increased rates of depression. All patient groups showed an increase in number of euthymic visits and a decrease in number of visits with depressive and manic symptoms with increased time in study. Conclusions: Bipolar patients spend a substantial proportion of their time ill. Significant gender differences exist, with women spending a greater proportion of their visits in the depressive pole. This finding appears to be related to the corresponding differences in rates of rapid cycling and anxiety disorders.

Objective: The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder. Method: A total of 1,953 patients received open-label quetiapine (400-800 mg/day in flexible, divided doses) with either lithium or divalproex (target serum concentrations 0.5-1.2 meq/liter and 50-125 [micro]g/ml, respectively) for up to 36 weeks. After at least 12 weeks of clinical stability, 628 patients were randomly assigned to double-blind treatment with quetiapine or placebo, in combination with lithium or divalproex, for up to 104 weeks. The primary efficacy measure was time to recurrence of any mood event (mania, depression, or a mixed episode). Results: Fewer patients in the quetiapine group experienced a mood event compared with the placebo group (20.3% versus 52.1%). The hazard ratio for time to recurrence of a mood event was 0.32. Hazard ratios were similar for mania and depression events (0.30 and 0.33, respectively). Sedation, weight increase, and hypothyroidism occurred more frequently in the quetiapine group, as did discontinuations due to adverse events. The incidence and incidence density of a single emergent blood glucose value [greater than or equal to] 126 mg/ dl were higher in the quetiapine group (12.6% versus 5.4%; 18.44 versus 9.56 patients per 100 patient-years). Adverse events were generally consistent with the known tolerability profile of quetiapine. Conclusions: In patients stabilized on quetiapine plus lithium or divalproex, continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex.

Objective: Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression. Method: A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N-85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom se verity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania. Results: Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder. Conclusions: These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.

Objective: The authors evaluated the efficacy and safety of adjunctive aripiprazole in bipolar I patients with mania partially nonresponsive to lithium/valproate monotherapy. Method: This multicenter, randomized, placebo-controlled study included outpatients experiencing a manic or mixed episode (with or without psychotic features). Patients with partial nonresponse to lithium/valproate monotherapy (defined as a Young Mania Rating Scale total score [greater than or equal to]16 at the end of phases 1 and 2, with a decrease of [less than or equal to] 25% between phases) with target serum concentrations of lithium (0.6-1.0 mmol/liter) or valproate (50-125 [micro]g/ ml) were randomly assigned in a 2:1 ratio to adjunctive aripiprazole (N=253; 15 or 30 mg/day) or placebo (N=131) for 6 weeks. Results: Mean improvement from baseline in Young Mania Rating Scale total score at week 6 (primary endpoint) was significantly greater with aripiprazole (-13.3) than with placebo (-10.7). Significant improvements in Young Mania Rating Scale total score with aripiprazole versus placebo occurred from week 1 on-ward. In addition, the mean improvement in Clinical Global Impression Bipolar Version (CGI-BP) severity of illness (mania) score from baseline to week 6 was significantly greater with aripiprazole (-1.9) than with placebo (-1.6). Discontinuation rates due to adverse events were higher with aripiprazole than with placebo (9% versus 5%, respectively). Akathisia was the most frequently reported extrapyramidal symptom-related adverse event and occurred significantly more frequently among those receiving aripiprazole (18.6%) than among those receiving placebo (5.4%). There were no significant differences between treatments in weight change from baseline to week 6 (+0.55 kg and +0.23 kg for aripiprazole and placebo, respectively; last observation carried forward). Conclusions: Adjunctive aripiprazole therapy showed significant improvements in mania symptoms as early as week 1 and demonstrated a tolerability profile similar to that of monotherapy studies.

Objective: Neuroimaging studies are promising components for a new diagnostic framework for bipolar disorder, but a major issue is the potential confound of psychotropic medication upon experimental measures. Withdrawing all individuals from medication and examining only unmedicated individuals may be clinically unfeasible, and examining only unmedicated individuals may render findings less generalizable. Method: The authors review structural and functional neuroimaging studies of medicated and unmedicated patients with bipolar disorder to discern the possible confounding effect of medication. Results: Findings from studies identified on MEDLINE that included medicated individuals with bipolar disorder indicated either no significant effect or ameliorative effects of psychotropic medications on abnormal structural and functional neuroimaging measures relevant to pathophysiologic mechanisms of the disorder. Different strategies for assessing medication effects are compared. Conclusions: Neuroimaging studies of bipolar disorder ideally should recruit both unmedicated and medicated individuals. Individuals who are unable to tolerate medication withdrawal likely have more severe illness and are especially informative for research examining biomarkers of illness and treatment response.

Objective: In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. Method: For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. Results: At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete I year of treatnlent. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N-402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. Conclusions: While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.

Objective: This study estimated the risk of recurrence of mood episodes among women with a history of bipolar disorder who continued or discontinued treatment with mood stabilizers during pregnancy. Method: In a prospective observational clinical cohort study, the authors determined recurrence risk and survival-analysis-based time to recurrence of a new episode in 89 pregnant women with DSM-IV bipolar disorder. Eligible subjects were euthymic at conception and continued mood stabilizer treatment or discontinued treatment proximate to conception. Results: The overall risk of at least one recurrence in pregnancy was 71%. Among women who discontinued versus continued mood stabilizer treatment, recurrence risk was twofold greater, median time to first recurrence was more than fourfold shorter, and the proportion of weeks ill during pregnancy was five times greater. Median recurrence latency was 11 times shorter after abrupt/rapid versus gradual discontinuation of mood stabilizer. Most recurrences were depressive or mixed (74%), and 47% occurred during the first trimester. Predictors of recurrence included bipolar II disorder diagnosis, earlier onset, more recurrences/year, recent illness, use of antidepressants, and use of anticonvulsants versus lithium. Conclusions: Discontinuation of mood stabilizer, particularly abruptly, during pregnancy carries a high risk for new morbidity in women with bipolar disorder, especially for early depressive and dysphoric states. However, this risk is reduced markedly by continued mood stabilizer treatment. Treatment planning for pregnant women with bipolar disorder should consider not only the relative risks of fetal exposure to mood stabilizers but also the high risk of recurrence and morbidity associated with stopping maintenance mood stabilizer treatment.

Objective: The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents. Method: A 3-week multicenter, parallel, double-blind, randomized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico. The participants were outpatient and inpatient male and female adolescents 13-17 years of age with an acute manic or mixed episode. Subjects received either olanzapine (2.5-20 mg/day [N=107]) or placebo (N=54). The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure. Results: The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo, and a greater proportion of olanzapine-treated patients met response and remission criteria (44.8% versus 18.5% and 35.2% versus 11.1%, respectively). The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain [greater than or equal to] 7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%). The mean baseline-to-endpoint changes in prolactin, fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo. Conclusions: Olanzapine was effective in the treatment of bipolar mania in adolescent patients. Patients treated with olanzapine, however, had significantly greater weight gain and increases in the levels of hepatic enzymes, prolactin, fasting glucose, fasting total cholesterol, and uric acid.

Objective: Psychosocial interventions are effective adjuncts to pharmacotherapy in delaying recurrences of bipolar disorder; however, to date their effects on life functioning have been given little attention. In a randomized trial, the authors examined the impact of intensive psychosocial treatment plus pharmacotherapy on the functional outcomes of patients with bipolar disorder over the 9 months following a depressive episode. Method: Participants were 152 depressed outpatients with bipolar I or bipolar II disorder in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. All patients received pharmacotherapy. Eightyfour patients were randomly assigned to intensive psychosocial intervention (30 sessions over 9 months of interpersonal and social rhythm therapy, cognitive behavior therapy [CBT], or family-focused therapy), and 68 patients were randomly assigned to collaborative care (a 3-session psychoeducational treatment). Independent evaluators rated the four subscales of the Longitudinal Interval Follow-Up Evaluation--Range of Impaired Functioning Tool (LIFE-RIFT) (relationships, satisfaction with activities, work/role functioning, and recreational activities) through structured interviews given at baseline and every 3 months over a 9-month period. Results: Patients in intensive psychotherapy had better total functioning, relationship functioning, and life satisfaction scores over 9 months than patients in collaborative care, even after pretreatment functioning and concurrent depression scores were covaried. No effects of psychosocial intervention were observed on work/role functioning or recreation scores during this 9-month period. Conclusions: Intensive psychosocial treatment enhances relationship functioning and life satisfaction among patients with bipolar disorder. Alternate interventions focused on the specific cognitive deficits of individuals with bipolar disorder may be necessary to enhance vocational functioning after a depressive episode.

Objective: Practice guidelines have advised against treating patients with antidepressants during bipolar mixed states or dysphoric manias. However, few studies have examined the outcomes of patients with co-occurring manic and depressive symptoms who are treated with antidepressants plus mood stabilizing drugs. Method: The authors compared outcomes in patients with bipolar disorder who received a mood stabilizing agent with versus without an antidepressant for a bipolar depressive episode accompanied by [greater than or equal to] 2 concurrent manic symptoms. The 335 participants were drawn from the first 2,000 enrollees in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Kaplan-Meier survival curves and Cox regression models were used to compare time to recovery. General linear models examined the relationship between antidepressant use or mania symptom load at the study entry and mania or depression symptom severity at the 3-month follow-up. Results: Adjunctive antidepressant use was associated with significantly higher mania symptom severity at the 3-month follow-up. The probability of recovery at 3 months was lower among patients with higher baseline depression severity. Antidepressant use neither hastened nor prolonged time to recovery once potential confounding factors were covaried in a Cox regression model. Conclusions: In bipolar depression accompanied by manic symptoms, antidepressants do not hasten time to recovery relative to treatment with mood stabilizers alone, and treatment with antidepressants may lead to greater manic symptom severity. These findings are consistent with those from the STEP-BD randomized trial for pure bipolar depression, in which adjunctive antidepressants did not yield higher recovery rates than did mood stabilizer monotherapy.

Objective: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. Method: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score [less than or equal to] 12 and 21-item Hamilton Depression Rating Scale [HAM-D] score [less than or equal to] 8) at two consecutive weekly visits following 6-12 weeks of open-label acute treatment with 5-20 mg/day of olanzapine were randomly assigned to double-blind maintenance treatment with olanzapine (N=225) or placebo (N=136) for up to 48 weeks. The primary measure of efficacy was time to symptomatic relapse into any mood episode (YMRS score [greater than or equal to]15, HAM-D score [greater than or equal to]15, or hospitalization). Results: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). Conclusions: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.

Objective: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. Method: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. Results: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. Conclusions: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.

Objective: The authors tested the hypothesis that divalproex would be more effective than lithium in the long-term management of patients with recently stabilized rapid-cycling bipolar disorder. Method: A 20-month, double-blind, parallel-group comparison was carried out in recently hypomanic/manic patients who had experienced a persistent bimodal response to combined treatment with lithium and divalproex. Sixty patients were randomly assigned to lithium or divalproex monotherapy in a balanced design after stratification for illness type (bipolar I versus bipolar II disorder). Results: Of the 254 patients enrolled in the open-label acute stabilization phase, 76% discontinued the study prematurely (poor adherence: 28%; nonresponse: 26% [of whom 74% remained depressed and 26% remained in a hypomanic/manic/ mixed episode], intolerable side effects: 19%). Of the 60 patients (24%) randomly assigned to double-blind maintenance monotherapy, 53% relapsed (59% into depression and 41% into a hypomanic/ manic/mixed episode), 22% completed the study, 10% had intolerable side effects, and 10% were poorly adherent. The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively; the rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/ mania relapse. There were no significant differences in time to relapse. The proportion discontinuing prematurely because of side effects was 16% for lithium and 4% for divalproex. Conclusions: The hypothesis that divalproex is more effective than lithium in the long-term management of rapid-cycling bipolar disorder is not supported by these data. Preliminary data suggest highly recurrent refractory depression may be the hallmark of rapid-cycling bipolar disorder.

Objective: Selective serotonin reuptake inhibitors may be effective for some patients with pathological gambling, but those with comorbid conditions, such as bipolar spectrum disorders, may relapse during treatment. To the authors' knowledge, this is the first placebo-controlled treatment study in pathological gamblers with bipolar spectrum disorders; it compares sustained-release lithium carbonate to placebo. Method: Forty pathological gambling patients with bipolar spectrum disorders entered a 10-week randomized, doubleblind, placebo-controlled treatment study of sustained-release lithium carbonate. Outcome measures included gambling severity, mood, anxiety, and impulsivity scales. Results: Pathological gambling patients with bipolar spectrum disorders significantly improved while taking sustained-release lithium carbonate compared to placebo on total pathological gambling scores on the Yale-Brown Obsessive Compulsive Scale, including both thoughts/ urges and behavior, as well as on the Clinical Global Impression severity of pathological gambling scale. Affective instability (the Clinician-Administered Rating Scale for Mania score) was also lower in the group treated with sustained-release lithium carbonate compared to placebo. Ten (83%) of 12 completers were rated as responders in the sustained-release lithium group versus five (29%) of 17 in the placebo group. Of note, improvement in gambling severity was significantly correlated with improvement in mania ratings. Conclusions: Sustained-released lithium may be an effective treatment in reducing both gambling behavior and affective instability in pathological gamblers with bipolar spectrum disorder. This study highlights the need to identify subgroups of pathological gambling patients with bipolar spectrum conditions because this may have important treatment implications.

Objective: This study reviewed the evidence from randomized, controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression. Method: The authors performed a systematic review and meta-analysis of randomized, controlled trials. They searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The main outcome measures were the proportion of patients who clinically responded to treatment and the rate of switching to mania. Results: Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. Antidepressants were more effective than placebo. Antidepressants did not induce more switching to mania (the event rate for antidepressants was 3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two antidepressants. The rate of switching for tricyclic antidepressants was 10%, and for all other antidepressants combined, it was 3.2%. Conclusions: Antidepressants are effective in the short-term treatment of bipolar depression. The trial data do not suggest that switching is a common early complication of treatment with antidepressants. It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment. Given the limited evidence, there is a compelling need for further studies with longer follow-up periods and careful definition and follow-up of emerging mania and partial remission.

Objective: Growing evidence suggests that abrupt lithium discontinuation increases the risk of recurrence for patients with bipolar disorder. To assess the effect of abrupt change in lithium dose, the authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder. Method: In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4-0.6 meq/liter) or a standard (0.8-1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium. Results: In a Cox proportional hazards model incorporating pre- and postrandomization lithium levels and the interaction of these factors, only the interaction term remained significantly associated with time to recurrence. Conclusions: The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study's finding of superiority for lithium levels [greater than or equal to] 0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder. (Am J Psychiatry 2002; 159:1155-1159)

Objective: The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania. Method: This 3-week randomized, double-blind, placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer (lithium or divalproex) and placebo, risperidone, or haloperidol. The primary efficacy measure was the Young Mania Rating Scale. Other assessments used the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and safety measures. Results: The trial was discontinued by 25 (49%) of the 51 placebo group patients, 18 (35%) of the 52 risperidone group patients, and 28 (53%) of the 53 haloperidol group patients. Mean modal doses were 3.8 mg/day (SD=1.8) of risperidone and 6.2 mg/day (SD=2.9) of haloperidol. Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group, compared with the placebo group. Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline. Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients. Antiparkinsonian medications were received by 8%, 17%, and 38% of patients in the placebo, risperidone, and haloperidol groups, respectively. Conclusions: Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone, and as efficacious as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was well tolerated. (Am J Psychiatry 2002; 159:1146-1154)

Objective: The efficacy of clozapine was examined in a group of patients with treatment-refractory bipolar disorder, manic type with psychotic features. Method: Twenty-two subjects with treatment-refractory bipolar disorder with active manic and psychotic symptoms participated in a 12-week open-label trial of clozapine. After a 2-10-day drug washout period, patients began treatment with clozapine at 25 mg/day; the dose was increased 25 mg/day (as tolerated) to a maximum level of 550 mg/day. Patients were evaluated longitudinally over the course of the study with the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale, and the Clinical Global Impressions (CGI) scale. Results: Fourteen of the 22 subjects in the study continued taking clozapine for at least 10 of the 12 weeks. Among the entire group, mean improvements of 56.7%, 56.6%, and 39.1% were seen on the BPRS, Young Mania Rating Scale, and CGI, respectively. Seventeen of the 22 subjects (77.3%) experienced at least a 20% improvement in scores on all three scales. Conclusions: The findings from this open-label study, which are consistent with previous retrospective studies, case reports, and one other open-label prospective study, suggest that clozapine is an effective agent for patients with treatment-refractory psychotic mania.

Objective: Given the adverse impact of anxiety on treatment outcome in unipolar depression and the paucity of data on the rote of anxiety in bipolar disorder, the authors sought to determine the effect of anxiety on the acute treatment response of patients with bipolar I disorder. Method: The authors examined the correlates of response to the acute treatment of 124 consecutively treated patients with bipolar I disorder. Measures of anxiety included history of panic attacks and a composite variable reflecting current or past anxiety symptoms. Results: History of panic attacks proved to be a significant correlate of nonremission. Anxiety, as assessed with the composite variable, was associated with longer time to remission, as was the treatment of depressive versus manic symptoms and mixed versus manic symptoms. Patients with anxiety as assessed with the composite variable and patients with a history of panic attacks reported more severe medication side effects. They also required a greater number of medications, either sequentially or in combination, in order to achieve remission. Conclusions: The findings suggest that anxiety is a clinically meaningful correlate of poor outcome in the acute treatment of bipolar I disorder.

Two case studies illustrate the use of treatment algorithms for treating bipolar disease, also called manic-depression. Until the 1990s, lithium was the only effective treatment for bipolar disease, but now other drugs are proving to be effective in patients who cannot take lithium or do not respond to it.

Objective: The most widely accepted hypothesis regarding the mechanism underlying lithium's therapeutic efficacy in manic-depressive illness (bipolar affective disorder) is the inositol depletion hypothesis, which posits that lithium produces a lowering of myo-inositol in critical areas of the brain and the effect is therapeutic. Lithium's effects on in vivo brain myo-inositol levels were investigated longitudinally in 12 adult depressed patients with manic-depressive illness. Method: Medication washout (minimum 2 weeks) and lithium administration were conducted in a blinded manner. Regional brain myo-inositol levels were measured by means of quantitative proton magnetic resonance spectroscopy at three time points: at baseline and after acute (5-7 days) and chronic (3-4 weeks) lithium administration. Results: Significant decreases (approximately 30%) in myo-inositol levels were observed in the right frontal lobe after short-term administration, and these decreases persisted with chronic treatment. The severity of depression measured by the Hamilton Depression Rating Scale also decreased significantly over the study. Conclusions: This study demonstrates that lithium administration does reduce myo-inositol levels in the right frontal lobe of patients with manic-depressive illness. However, the acute myo-inositol reduction occurs at a time when the patient's clinical state is clearly unchanged. Thus, the short-term reduction of myoinositol per se is not associated with therapeutic response and does not support the inositol depletion hypothesis as originally posited. The hypothesis that a short-term lowering of myoinositol results in a cascade of secondary signaling and gene expression changes in the CNS that are ultimately associated with lithium's therapeutic efficacy is under investigation.

Objective: The authors critically examine the evidence supporting the hypothesis that lithium's therapeutic effects in bipolar affective disorder are mediated by alterations in the expression of specific genes in critical neuronal circuits. Method: Using the heuristic 'initiation and adaptation paradigm,' the authors appraise the biological effects and underlying molecular and cellular mechanisms of lithium's action. The evidence is critically reviewed, with special attention to the reductive and integrative approaches necessary for identifying lithium's clinically relevant cellular and molecular targets. Results: Lithium's acute effects are mediated through inhibition of specific enzymes involved in two distinct but interacting signaling pathways - the protein kinase C and glycogen synthase kinase 3beta signaling cascades - that converge at the level of gene transcriptional regulation. The expression of different genes, including transcription factors, is markedly altered by chronic lithium administration. Chronic lithium treatment also robustly increases the expression of the neuroprotective protein Bcl-2, raising the intriguing possibility that some of lithium's effects are mediated through underappreciated neurotrophic/neuroprotective effects. The importance of lithium's effect on circadian rhythms and the related methodological problems in validating the role of specific genes in lithium's therapeutic effects are discussed. Conclusions: Despite the plethora of lithium effects at the genomic level, direct evidence that the genes identified thus far are responsible for phenotypic changes associated with chronic lithium treatment is still lacking. The combination of sensitive molecular technologies, appropriately designed paradigms, better behavioral analysis, and a chronobiologic approach seems necessary for the future identification of one or more clinically relevant lithium-target genes.

Objective: The authors' goal was to determine the extent and pattern of blood serum monitoring of mood stabilizers in Medicaid patients with bipolar disorder. Method: Data were drawn from a Medicaid medical claims data set from Pittsburgh and the surrounding region. The authors identified bipolar patients using lithium, valproate, and carbamazepine (N = 718) and then examined the patient demographic, diagnostic, and service use variables associated with therapeutic drug monitoring. Results: A substantial proportion of lithium users (36.5%), valproate users (42.4%), and carbamazepine users (42.2%) with bipolar disorder diagnoses did not receive therapeutic drug level testing during the 12-month study period. Carbamazepine users who were male or in the 30-49-year age range were significantly less likely to be tested for serum drug level. Lithium users who did not receive partial-hospitalization psychiatric services and valproate users who received mental health case management were also less likely to be tested for serum drug level. Over one-half of the lithium users (54.1%) did not receive thyroid function tests, and few (4.2%) received renal function tests. Patients who did receive tests for serum drug level were likely to receive the other recommended tests. Conclusions: Many Medicaid patients with bipolar disorder received no therapeutic drug monitoring. Patient sociodemographic characteristics contributed little to explaining this omission, although some types of service utilization were related to rates of serum drug level testing.

Objective: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy. Method: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N=60) or monotherapy (N=15) in patients presenting in depressed, hypomanic, manic, or mixed states. Results: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization. Conclusions: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.

Objective: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. Method: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks' duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N = 70) or placebo (N = 69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. Results: The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group. On the basis of the clinical response criteria, significantly more olanzapine-treated patients (48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine. There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group. Conclusions: The results from this study suggest that compared with placebo, olanzapine has superior efficacy for the symptoms of acute mania.

The purpose of this study was to evaluate the outcome of bipolar disorder in the context of maintenance pharmacotherapy. Method: Eighty-two bipolar outpatients were followed prospectively for a mean of 4.3 years (minimum of 2 years); symptom rating and psychosocial outcome scales were used, and pharmacotherapy was rated on a 5-point scale. Results: Despite continual maintenance treatment, survival analysis indicated a 5-year risk of relapse into mania or depression of 73%. Of those who relapsed, two-thirds had multiple relapses. Relapse could not be attributed to inadequate medication. Even for those who did not relapse, considerable affective morbidity was observed. A measure of cumulative affective morbidity appeared to be a more sensitive correlate of psychosocial functioning than was the number of relapses. Poor psychosocial outcome paralleled poor syndromal course. Poor psychosocial functioning, especially occupational disruption, predicted a shorter time to relapse. Depressions were most strongly related to social and family dysfunction. Conclusions: Even aggressive pharmacological maintenance treatment does not prevent relatively poor outcome in a significant number of bipolar patients.

Objective: The longitudinal course of 51 patients with treatment-refractory bipolar disorder was examined to assess possible effects of heterocyclic antidepressants on occurrence of manic episodes and cycle acceleration. Method: Using criteria established from life charts, investigators rated the patients' episodes of mania or cycle acceleration as likely or unlikely to have been induced by antidepressant therapy. Discriminant function analyses were performed to assess predictors of vulnerability to antidepressant-induced mania or cycle acceleration. Further, the likelihood of future antidepressant-induced episodes in persons who had one such episode was assessed. Results: Thirty-five percent of the patients had a manic episode rated as likely to have been antidepressant-induced. No variable was a predictor of vulnerability to antidepressant-induced mania. Cycle acceleration was likely to be associated with antidepressant treatment in 26% of the patients assessed. Younger age at first treatment was a predictor of vulnerability to antidepressant-induced cycle acceleration. Forty-six percent of patients with antidepressant-induced mania, but only 14% of those without, also showed antidepressant-induced cycle acceleration at some point in their illness. Conclusions: Mania is likely to be antidepressant-induced and not attributable to the expected course of illness in one-third of treatment-refractory bipolar patients, and rapid cycling is induced in one-fourth. Antidepressant-induced mania may be a marker for increased vulnerability to antidepressant-induced cycle acceleration. Antidepressant-induced cycle acceleration (but not antidepressant-induced mania) is associated with younger age at first treatment and may be more likely to occur in women and in bipolar II patients.

Of 39 patients consecutively admitted for the treatment of primary mania, 21 (53.8%) simultaneously met the Research Diagnostic Criteria for major depressive disorder ('mixed' or 'depressive' mania). Only nine (42.9%) of the 21 patients with depressive mania responded to antimanic agents. In contrast, 16 (88.9%) of the 18 patients with pure mania responded to these drugs. This finding is consistent with previous reports suggesting that the mixed state is a virulent form of mania.

Little has been written about the treatment of bipolar disorder (also called manic-depressive illness) in its acute, depressed phase; bipolar disorder involves periods of depression and excessive excitement. Often, depressed bipolar patients are treated as other depressives are, with tricyclic antidepressants. In some cases these are prescribed in addition to lithium, which is the treatment of choice for maintaining mood stability in bipolar patients. In recent years, there has been increased attention paid to monoamine oxidase inhibitors (MAOIs) as an alternate treatment for depression in bipolar disorder and in the treatment of atypical (psychotic) depression as well. Tranylcypromine, an MAOI, has been found to be useful either alone or combined with lithium in bipolar disorder, and particularly in the depressed phase of bipolar disorder. In a controlled comparison study of tranylcypromine and a standard tricyclic antidepressant, imipramine, for the treatment of bipolar depression, a total of 56 outpatients were divided into two treatment groups (one for each drug). Subjects were followed for a total of 16 weeks. A significantly greater number of patients in the imipramine group than in the tranylcypromine group (seven versus two) were withdrawn from the study due to side effects of the medication, and of the remaining patients, a significantly greater number responded to acute treatment in the tranylcypromine group than in the imipramine group (21 versus 10, respectively). Tranylcypromine was therefore more effective than imipramine in the treatment of depressed, bipolar patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Long-term maintenance therapy with lithium is frequently prescribed for individuals with manic depression. Lithium is known to increase the serum levels of thyrotropin and decrease the levels of thyroid hormone. Reports of thyroid abnormalities in patients receiving long-term lithium therapy have not been consistent. This study investigated the incidence of goiter, assessed thyroid function and measured thyroid size in a group of manic-depressive patients. The frequency of these thyroid conditions was analyzed in relation to duration of lithium treatment. Also, indications of thyroid autoimmunity were evaluated. Subjects were divided into three groups: 19 patients who never received lithium therapy, used as a control group; 25 patients who had been treated with lithium for one to five years; and 50 patients who had been receiving lithium for more than 10 years. In addition to laboratory and ultrasonic scanning procedures, all patients were assessed for use of other drugs, smoking and drinking habits, and other diseases, past and present. The results showed that goiter developed in 44 percent of the group treated for one to five years, in 50 percent of those treated for over 10 years, and in only 16 percent of the untreated patients. In the control group, both thyroid size and goiter were influenced by patient smoking habits; smokers had larger thyroids and more goiter than nonsmokers. But this difference was not observed in the groups of patients receiving lithium; no differences in thyroid size or incidence of goiter were observed between smokers and nonsmokers. An above-normal frequency of hypothyroidism (under-active thyroid) was seen in lithium-treated patients (4 percent in patients treated between one and five years and 21 percent in those treated for over 10 years). The majority of patients had normal serum thyrotropin levels, and no cases of autoimmunity were detected. It is concluded that lithium may have direct effects upon the thyroid gland. (Consumer Summary produced by Reliance Medical Information, Inc.)

It is estimated that 15 to 30 percent of individuals with bipolar illness have an episode of depression or mania before the age of 20 years. For this study, bipolar I illness was defined using the criteria in the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III); these criteria include the presence of manic disorder without psychosis. Thirty-seven adolescents with bipolar I illness were evaluated after their symptoms had been stabilized with lithium, the drug of choice in treating this disease. After the patients were released from the hospital, they were monitored every four to six weeks for 18 months. The frequency of depressive and manic relapses was observed in the subjects during this follow-up period. Of the total group, 24 patients (65 percent) continued lithium maintenance therapy throughout the follow-up period without interruption, and 13 patients (35 percent) discontinued their therapy against medical advise. There were no significant differences between these two groups with regard to sex, age, or medical history. More than half (57 percent) of the total group relapsed during follow-up, but the relapse rate among those who discontinued lithium was three times that of compliant patients. Twelve out of the 13 noncompliant patients relapsed, while only nine out of the 24 patients who continued to take their medication relapsed. Some of the clinical and theoretical implications of these findings are discussed. The relapse rate in these adolescents was similar to that which has been observed in comparable adult groups. In general, patients who experience early relapse run a higher risk of subsequent relapse. (Consumer Summary produced by Reliance Medical Information, Inc.)

The most prominent characteristic of bipolar affective disorder is one or more manic episodes which alternate with one or more depressive episodes. Lithium therapy is the treatment of choice for this condition, but as many as 40 percent of bipolar patients do not respond to or tolerate this drug well. Previous studies have indicated that patients with rapid-cycling bipolar disorder represent a significant proportion of those who are resistant to this treatment. Carbamazepine has been used as a substitute and, although it has shown success with manic symptoms, it is not as effective in relieving the symptoms of depression. A second alternative treatment that has been suggested is valproate, and the efficacy of this drug in 55 bipolar patients was assessed. The subjects were all diagnosed with rapid-cycling bipolar disorder and had been resistant to other treatments. The patients were given valproate in combination with other drugs (35 subjects) or alone (20 subjects) and were followed over a period of about eight months. In the 20 patients receiving valproate alone, 89 percent exhibited a marked improvement during acute manic episodes, while only 57 percent showed a marked response during depressive episodes. The results confirmed previous studies that indicated valproate was effective in relieving manic symptoms, but had only a moderate effect on the symptoms of depression. The best method of treating depressive symptoms associated with this disorder is still not clear; more research is needed to determine whether a single drug or a combination therapy is the best approach. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objectives: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. Method: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score [greater than or equal to] 3 (mildly ill). Results: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. Conclusions: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.

Objective: The authors compared the new extended-release and standard preparations of divalproex sodium. Method: Twelve patients with DSM-IV bipolar disorder or schizoaffective disorder who were clinically stable while taking the standard form of divalproex participated in the study. These patients were given a single daily dose of the extended-release preparation of divalproex in an open 6-week trial. Clinical symptoms and adverse effects were rated weekly. Doses were adjusted to maintain steady serum valproate concentrations. Results: The medication change was associated with negligible changes in clinical status and tolerability. To maintain serum drug levels, however, 21% higher doses of the extended-release preparation were required. Conclusions: Use of extended-release divalproex once a day was as well tolerated as the standard preparation, with no change in efficacy within 6 weeks, but the daily dose needed to maintain stable serum valproic acid concentration was 21% higher.

Objective: The authors' goal was to determine if there is an association between brain-to-serum lithium ratios and age. Method: Lithium-7 magnetic resonance spectroscopy was used to measure in vivo brain lithium levels in nine children and adolescents (mean age=13.4 years, SD=3.6) and 18 adults (mean age=37.3, SD=9.1) with bipolar disorder. Results: Serum and brain lithium concentrations were positively correlated. Younger subjects had lower brain-to-serum concentration ratios than adults: 0.58 (SD=0.24) versus 0.92 (SD=0.36). The brain-to-serum concentration ratio correlated positively with age. Conclusions: These observations suggest that children and adolescents may need higher maintenance serum lithium concentrations than adults to ensure that brain lithium concentrations reach therapeutic levels. (Am J Psychiatry 2002; 159:1240-1242)

Objective: Phenytoin, a classical anticonvulsant, shares with antimanic anticonvulsants the property of blockade of voltage-activated sodium channels. The authors therefore planned a trial of phenytoin for mania. Method: Patients with either bipolar I disorder, manic type, or schizoaffective disorder, manic type, entered a 5-week, double-blind controlled trial of haloperidol plus phenytoin versus haloperidol plus placebo. Of 39 patients, 30 completed at least 3 weeks and 25 completed 5 weeks. Results: Significantly more improvement was observed in the patients receiving phenytoin. Added improvement with phenytoin in scores on the Brief Psychiatric Rating Scale and Clinical Global Impression was seen in the patients with bipolar mania but not those with schizoaffective mania. Conclusions: Blockade of voltage-activated sodium channels may be a common therapeutic mechanism of many anticonvulsants given for mania, and phenytoin may be a therapeutic option for some manic patients.

Objective: This study's purpose was to clarify the appropriate treatment of bipolar depression by comparing the addition of an antidepressant versus a second mood stabilizer for inpatients being treated with lithium carbonate or divalproex sodium. Method: Twenty-seven patients were randomly assigned to groups that received double-blind treatment with paroxetine or a second mood stabilizer (lithium carbonate or divalproex sodium) for 6 weeks. Results: Both groups showed significant improvement in depressive symptoms during the 6-week trial. There were significantly more noncompleters in the group being treated with the two mood stabilizers than in the group being treated with a mood stabilizer and paroxetine. Conclusions: Both treatments appeared to be effective; however, the addition of an antidepressant may have greater clinical utility in the treatment of bipolar depression.

Objective: The purpose of this study was to determine the dopamine [D.sub.2] receptor occupancy induced by low-dose haloperidol treatment in a prospective trial. Method: Seven patients with schizophrenia were treated with 2 mg/day of haloperidol for 2 weeks, and [D.sub.2] receptor occupancy was measured by [11C]raclopride and positron emission tomography. Results: The patients showed high levels of [D.sub.2] occupancy (53%-74%); five of them showed substantial clinical improvement, and none showed important side effects. Conclusions: The findings demonstrate that low doses of haloperidol induce [D.sub.2] receptor occupancies that are in the putative therapeutic range. In combination with recent empirical trials, these findings should encourage clinicians to initiate treatment of psychotic episodes with low (2-4 mg haloperidol equivalent) doses of typical neuroleptics, particularly for first-episode patients.

Factors that have been associated with a good response to lithium treatment in patients with bipolar disorder include good recovery between episodes, a family history of bipolar disorder, and a high recurrence rate.l Poor treatment response has been associated with poor compliance with medication, rapid cycling, (four or more episodes of mania and depression a year), alcohol abuse, and episodes of mixed mania and depression. Four bipolar disorder subgroups have been proposed based on episode-interval sequence: mania or hypomania followed by depression and then normal mood; depression followed by mania; continuous cycling; and no regular sequence. Data from five studies using these criteria for sequence typing were obtained to determine the prevalence of each sequence and the associated treatment responses. Of 576 bipolar disorder cases reviewed, the order of prevalence was as follows: mania or hypomania-depression, depression-mania or hypomania, irregular, and continuous cycling. In terms of treatment response, the rank from best to worst was: mania or hypomania-depression, irregular, continuous cycling in long cycles, depression-mania or hypomania, and continuous cycling in rapid cycles. It is concluded that bipolar episode sequences can predict patient response to lithium. (Consumer Summary produced by Reliance Medical Information, Inc.)

The development of lithium therapy as a preventive or prophylactic treatment for bipolar disorders has been one of the most significant advances in the mental health field in recent years. Bipolar disorder, chronic depression combined with at least one manic episode, affects 0.8 percent of the adult population of the US according to the National Institute of Mental Health (NIMH). Difficulties with lithium treatment include undesirable side effects, often resulting in noncompliance by some patients with regard to treatment. Thus far, no comparable effective treatment has been devised, but alternative methods of therapy are being explored and show some promise. The use of long-term drug therapies which prevent or ameliorate manic or depressive episodes was examined. Most of the difficulties lie in the development and effective evaluation of trial studies which provide insight into the long-range effects of drugs used in the preventive maintenance bipolar episodes. Carbamazepine, an anticonvulsant which also exhibits antidepressant properties, is being examined as an alternative to lithium. The effectiveness of this drug requires more systematic examination; in particular, the authors recommended research into the effects of carbamazepine alone and carbamazepine used in conjunction with lithium. The development of additional experimental models is suggested to investigate the benefits of carbamazepine treatment as a backup to lithium or a primary treatment in itself. More clarification is also needed between the role of antipsychotic and antidepressant drugs in the long-term care of the bipolar patient.

Objective: The authors explored the prevalence and predictors of nonresponse to reinstituted lithium prophylaxis in bipolar patients who had relapsed after discontinuation of successful lithium treatment. Method: The study was conducted with 54 bipolar patients for whom lithium had been reintroduced after one or more recurrences following discontinuation of successful prophylaxis. They were followed up, through bimonthly personal interviews, for 1 year after recovery from the episode during which lithium treatment had been resumed, or up to the first recurrence with onset after lithium reinstitution. Results: During the follow-up period, 44 patients did not have any affective episodes, whereas 10 had at least one recurrence. The only significant difference between the two patient groups was the longer duration of prediscontinuation lithium treatment for the patients who relapsed. Conclusions: Nonresponse to reinstituted prophylaxis should be considered among the possible risks of the interruption of effective long-term lithium treatment.

Twenty acutely manic patients were studied in a double-blind randomized trial comparing verapamil with lithium. The Petterson Mania Scale, the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impression (CGI) were administered before treatment and weekly during 4 weeks of treatment to evaluate response to verapamil and lithium. Both treatment groups improved significantly, and there were no significant overall differences between treatments.