OR WAIT null SECS
In recent years there has been an explosion of new investigations into the pathophysiology of bipolar disorder and its medication therapies. This article will review current, emerging, and controversial therapies for the treatment of bipolar disorder, specifically the mania aspect.
Bipolar disorder (BPD) is a recurrent psychiatric disorder characterized by episodes of mania and hypomania, depression, or mixed episodes. Individuals with BPD often experience anxiety and decreased cognitive performance and productivity. BPD has emerged as a major health concern, with lifelong social and occupational impairment and poor prognosis secondary to its substantially elevated morbidity and mortality rates, which are largely due to associated cardiovascular disease, metabolic syndrome, substance abuse or misuse, and potential for physical self-harm. The lifetime prevalence of bipolar spectrum disorders is approximately 3% to 7% of the population. Given the disease complexity, individuals with BPD often require lifelong pharmacological therapy to achieve desired treatment outcomes. In recent years there has been an explosion of new investigations into the pathophysiology of BPD and its medication therapies. This article will review current, emerging, and controversial therapies for the treatment of BPD, specifically the mania aspect. (Formulary. 2011;46:82–97.)
The lifetime prevalence of clinical bipolar spectrum disorders is approximately 3% to 7% of the population, and the average age of onset is 15 to 30 years.2,3 Bipolar treatment is divided into 3 phases: acute, continuation, and maintenance. The selected medication therapy is based upon patient-specific factors, such as psychotic features, previous response, history, side effects, and coexisting medical illnesses, and cost to patient in addition to the evidence and guidelines.4 Lifelong pharmacologic therapy is essential, in most cases, to achieve treatment goals. Many individuals require medication therapy coupled with nonpharmacologic treatments, such as electroconvulsive therapy, psychotherapy, interpersonal and group therapy, or cognitive-behavioral therapy, to achieve and maintain normalcy. Several pharmacologic discoveries, investigations, and advances have recently occurred in the management of BPD and expand beyond even the most recent guidelines. The focus of this article is to review current and emerging therapies for the treatment of BPD, specifically therapies used for the mania aspect of BPD, and to briefly discuss the emerging roles of pharmacists in the management of BPD.
MANIA TREATMENT OPTIONS
Lithium, the only mood stabilizer shown to reduce suicidality, has well-established acute antimanic effects, and given its FDA approval, is effective and recommended for the treatment of acute mania.5–9 It is often used as a comparator to other pharmacological therapies for studies of efficacy and safety measures. Most recently, however, data for its long-term efficacy, specifically as monotherapy and efficacy in mixed episodes and atypical symptoms, has been debated and is controversial.10,11 The results of a prospective, multicenter study evaluating lithium's response and morbidity for approximately 10 years showed the treatment response remained stable in individuals with typical and atypical BPD symptoms, suggesting long-term benefits.10
The Bipolar Affective disorder: Lithium/ANtiConvulsant Evaluation (BALANCE) study, a multicenter, open-label trial investigating the superiority of combination therapy with lithium and valproate to either agent as monotherapy, found the lithium-valproate combination and monotherapy lithium to be likely more effective than monotherapy valproate for relapse prevention.12 Prevention of relapse to mania was more apparent with combination therapy than with valproate monotherapy, and prevention of relapse to depression was more apparent with lithium monotherapy than valproate monotherapy.12
A 3-week, double-blinded, parallel-group study compared the change in the primary and secondary measure, Manic State Rating Scale and Clinical Global Impression-Severity of Illness Scale (CGI-S scores), respectively, induced by olanzapine and lithium in the management of acute mania among 40 female patients.13 The results showed that both olanzapine and lithium significantly improved the manic intensity and frequency by the end of the study (P<.05); however, the between-group analysis for reduction in frequency and improvement in symptoms showed statistically significant (P<.0002 and .003, respectively) superiority favoring lithium.13
Despite its efficacy data and true mood-stabilizing properties, the number of prescriptions for lithium therapy has decreased in the United States because of its adverse-event profile.12 Potential long-term complications with lithium therapy are renal impairment, cardiac rhythm disturbances, and hypothyroidism; thus, baseline assessment for pregnancy, potential cardiovascular diseases, renal and thyroid function, and hematologic and electrolyte status are recommended. Given its narrow therapeutic index and potential for fatal effects in toxic concentrations, patient education regarding lithium toxicity and appropriate monitoring (weekly for 4 weeks, monthly for 3 months, then every 3 months thereafter or as clinically indicated) is critical.14 For several years, pharmacists have been involved in lithium monitoring, pharmacokinetic dosing, and screening for risk of lithium toxicity.
Valproate, a first-line therapy option for the acute and maintenance phase of mania, is beneficial for acute mania and for reducing the frequency, duration, or intensity of recurrent episode and is considered to be as effective as lithium. Studies show valproate is beneficial for the acute treatment of mixed states.11 Only the extended-release formulation of divalproex is FDA-approved for both acute manic and mixed episodes.
A 12-week multicenter, international, open-label, parallel-group efficacy equivalency study comparing valproate with lithium randomly assigned 268 adult patients currently experiencing a bipolar I disorder (BPD1) manic or mixed episode to receive valproate 20 mg/kg/d or lithium 600 to 900 mg/d.15 Dose adjustments were allowed after 5 days to target concentrations of 0.8 to 1.2 mmol/L for lithium and 70 to 125 μg/mL for valproate. Sixty-nine percent of the randomly assigned participants completed the study as designed. The discontinuation rate was similar between both treatment arms, with respect to discontinuing the study for lack of efficacy (n=13 for each arm) and adverse events (approximately 6% for each arm). The primary efficacy outcome measure of mean change in the Young Mania Rating Scale (YMRS) score from baseline to study end point was decreased in both treatment groups; however, the reduction, although not significant, was greater in the valproate group than lithium group (17.3+9.4 vs 15.8+5.3). In analyzing the secondary measures of remission rates, defined as YMRS scores and Clinical Global Impression-Bipolar (CGI-BP) scale change scores, a significant difference in rates was observed (P<.025), suggesting that valproate (71.9%) appears to be superior to lithium (58.5%). The authors concluded that both valproate and lithium are effective and acceptably tolerated therapies for acute mania.15
Another 12-week, multicenter, randomized, open-label, parallel-group comparative study evaluating the efficacy and safety of valproate and lithium in patients with BPD1 mania found the treatments showed similar results, although remission rates were better overall for the valproate-treated group.16 For the primary efficacy measure, the proportion of patients in remission as defined by YMRS score <12 at the end of the study and a reduction of >2 on the CGI-BP severity scale, noninferiority of valproate was shown, as evidenced by remission rates (65.5% in the lithium group and 72.3% in the valproate group) and a between-group difference of 6.78%. The mean duration of sustained response was 44 days for lithium-treated patients and 46 days for valproate-treated patients.16
Treatment-emergent adverse events were reported in approximately 45% of the patients in both groups in these 2 studies. In both studies, the incidence of tremor was higher in the lithium-treated group, while weight gain was more prevalent in the valproate-treated group.15,16
Investigators examining 2 valproate dosing strategies (20 mg/kg/d loading dose or 10 mg/kg/d titrated slowly upward until desired outcome was achieved) found the loading dose was most likely safe and may produce a faster antimanic effect due to achieving blood levels faster.17
Side effects reported in studies included sedation, somnolence, fatigue, weight gain, tremors, nausea, vomiting, muscle weakness, diarrhea, constipation, and abdominal cramping.15–17 In addition, less common side effects of blood dyscrasias, hepatoxicity, pancreatitis, hyperammonemic encephalopathy, and Stevens-Johnson syndrome have been reported.6
Carbamazepine (CBZ) use in BPD is limited because of its boxed warning for hematologic disorders, side-effect profile, and treatment complexity, which includes its various drug interactions and need for routine monitoring, despite its efficacy. Although routine pharmacokinetic monitoring of CBZ generally is not required for mood disorders, the expertise of a pharmacist is particularly beneficial for avoiding or managing drug-drug interactions and subsequent side effects, including hematologic disorders.
A systematic review and meta-analysis of CBZ versus lithium trials showed CBZ to be as effective as lithium in the acute phase and in the maintenance phase for prevention of relapse and hospitalization, but with less overall tolerability.18 The results of this analysis showed congruence to those of previously published reviews.18
A 6-week, randomized, double-blind study assessing the efficacy and safety of olanzapine plus CBZ to CBZ alone in 118 patients with manic or mixed-episode BPD showed no significant difference between treatment groups in change in YMRS scores (primary outcome measure), CGI-BP scores, Montgomery-Asberg Depression Rating Scale score, or in response or remission rates at study conclusion.19 The 6-week trial was followed by a 20-week open-label phase of 85 individuals (n=66 CBZ responders, 19 nonresponders). A statistically significant (P<.001) mean decrease in YMRS total score from week 6 to study conclusion was observed. Overall, the combination therapy was not superior to CBZ monotherapy. Regarding the safety data, the addition of olanzapine therapy did not affect CBZ concentrations; however, CBZ reduced serum olanzapine concentrations. Statistically significant treatment-emergent adverse events were elevated alanine aminotransferase, constipation, hypertriglyceridemia, and decrease in platelet count.19
The LICAVAL (efficacy and tolerability of the combination of LIthium and CArbamazepine compared to lithium and VALproic acid in the treatment of young bipolar patients) trial is a randomized, parallel group, rater-blinded study, with an estimated completion date of August 2012, that is evaluating the efficacy of lithium in combination with CBZ versus lithium with valproic acid for acute and maintenance treatment of BPD.11
Oxcarbazepine, the 10-ketoanalog of CBZ, shows little interaction with the cytochrome P450 system, has minimal risk of agranulocytosis and neurotoxicity, has demonstrated efficacy in BPD, and may afford itself as an alternative to CBZ for BPD.20 It is currently reserved for those unable to tolerate or who have suboptimal response to first- or second-line therapies.5,9
In a study evaluating the short- and long-term efficacy of adjunctive oxcarbazepine therapy in patients with suboptimal lithium response, oxcarbazepine significantly improved (P=.000) the 8-week Clinical Global Impression-Improvement scale (primary outcome), Bech-Rafaelsen Mania-Meloncholia Scale, and the Brief Psychiatric Rating Scale (BPRS) total score.21 Approximately 60% of the participants were classified as 8-week oxcarbazepine responders; the response rate among those with manic or mixed episodes was 70%; and approximately 63% of the responders maintained remission during the entire period of follow-up (at least 4 months). None of the patients discontinued the short- or long-term study because of adverse effects.21
A randomized, double-blind, placebo-controlled trial evaluating the prophylactic efficacy and long-term tolerability (52 weeks) of oxcarbazepine as adjunctive therapy to lithium (n=55) showed benefit, although nonsignificant, favoring oxcarbazepine with improving the average time to a mood disturbance occurrence, improving functionality, and decreasing the incidence of depressive episodes.22 Impulsivity was significantly improved in the oxcarbazepine group (P=.0443). The authors concluded that adequately powered studies are needed to further investigate the prophylactic efficacy of oxcarbazepine on impulsivity and other mood episodes.22
An 8-week, randomized, single-blinded study comparing oxcarbazepine to divalproex therapy in 30 patients diagnosed with current hypomanic episode assessed, using a blinded rater, the primary outcome of change in YMRS scores.23 Both treatment groups had statistically significant decreases in baseline YMRS scores at the study end point (P<.001). There was no significant difference observed in comparing between-group differences; however, the mean percent reduction favored divalproex compared with oxcarbazepine (79% vs 63.8%, respectively). Both medications were well tolerated. Although not adequately powered, the results of this study suggest comparable efficacy between oxcarbazepine and divalproex for the treatment of hypomania.23
Lamotrigine, although FDA approved for BPD, is only cautiously recommended in a variety of guidelines because of a lack of reproducible efficacious results as well as lack of distinctiveness from placebo for mania prevention.7–9,24 Lamotrigine is not approved or recommended for the treatment of acute mania.2,7 It is currently a treatment option for maintenance therapy of BPD to delay the time to occurrence of mood episodes, in patients actively receiving standard therapy for acute mood episodes.7 Results of several studies prove that lamotrigine has more specificity toward prolonging time to depressive episodes than manic episodes.24
A multicenter, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and tolerability of lamotrigine as maintenance therapy in 184 BPD1 patients with a recent manic/hypomanic episode and who achieved clinical stability with 8 to 16 weeks of lamotrigine as monotherapy or adjunctive therapy were randomly assigned to lamotrigine, lithium, or placebo for up to 76 weeks.25 Both active-treatment groups demonstrated superiority over placebo on time-to-intervention/relapse, but did not statistically significantly differ from each other. The lamotrigine-treated group had more incidences of elevated mood than did the lithium group (71% vs 44%). Lamotrigine was not superior to placebo in delaying time to elevated mood episode (P=.28). Although not significantly different from the other groups, the most common side effect reported in the lamotrigine group was headache.25
An open-label, randomized, clinical-practice-mimicking trial comparing lamotrigine (100-400 mg/d) to lithium (dosed to achieve 0.5-1.0 mmol/L) investigated the time to any of the following: need for an additional psychotropic agent at or after 6-months postrandomization, or hospitalization at or after 6-months postrandomization.26 The baseline index of mania was approximately 50% and with minimal stratification differences between the lamotrigine and lithium groups. Approximately 35% of the patients in each group reached the end point of needing hospitalization or additional psychotropic medication after 6 months. When examined by polarity index, lithium performed better than lamotrigine for mania prevention (relapse rate of 7% and 17%, respectively) and lamotrigine performed better for depression (relapse rate of 30% and 31%, respectively). In this study, most of the treatment failures occurred before the completion of 1.5 years, and of those patients followed for at least 5 years, the majority required combination therapy. The most commonly reported adverse effects for lamotrigine in this study were headache, dizziness, acne, and weight gain.26
ANTIPSYCHOTIC OPTIONS IN BPD
Asenapine, a sublingual disintegrating tablet, received FDA approval in 2009 for adults for the acute treatment of manic or mixed BPD1 episodes with or without psychotic features.27 Although not addressed in all of the most recent guidelines, asenapine has demonstrated efficacy for BPD treatment.27–30
Two 3-week double-blind, placebo-controlled trials (n=976) that randomly assigned individuals with acute mania or mixed BPD1 episodes to asenapine 10 or 20 mg/d, olanzapine 5 to 20 mg/d, or placebo found the active-treatment arms were superior to placebo in reducing YMRS scores, with improvement observed as early as day 2.27,28 Individuals completing 1 of these 3-week studies were eligible to participate in a 9-week, double-blind extension, noninferiority trial comparing the efficacy and tolerability of asenapine to olanzapine.29 The blinded nature from the 3-week trials were maintained, and placebo-treated individuals were switched to asenapine therapy. The change in YMRS total score from baseline, the primary outcome measure, was -24.4+8.7 for asenapine and -23.9+7.9 for olanzapine, showing no significant difference between the 2 agents and no inferiority for asenapine.29 The rates of response and remission, the secondary measures, were 90% vs 92% and 88% vs 91% for asenapine and olanzapine, respectively. Study completion and discontinuation rates were similar within both groups and were not related to treatment-emergent adverse events.29
After completing the study, patients were eligible for a 40-week extension study evaluating safety and tolerability. A higher rate of adverse events was reported with asenapine compared with olanzapine (70.9% vs 61.7%), although it was not statistically significant.30 Compared to olanzapine, asenapine-treated individuals experienced more extrapyramidal symptoms and less hyperprolactinemia, weight gain, and metabolic disturbances. Asenapine appears to be safe and well tolerated.30 Additionally, the mean changes in YMRS scores remained similar for asenapine (-28.6+8.1) and olanzapine (-28.2+6.8).30
Aripiprazole is recommended as monotherapy or a combination option for hypomanic or manic and mixed episodes in either acute or maintenance phases.7 Additionally, aripiprazole is FDA approved for the treatment of BPD-related psychomotor agitation and may offer a safer option to benzodiazepine use pending adequately designed studies.
A 100-week study (26-week randomized, double-blind study with a 74-week double-blind extension phase) evaluated the efficacy and safety of aripiprazole for relapse prevention in BPD1 patients.31 The primary efficacy parameter was time to relapse for any mood disorder for the 100-week study.31 The hazard ratio for aripiprazole versus placebo was 0.52, implying an overall reduced risk of relapse of about 48% for the 26-week phase.32 Aripiprazole, at week 26, proved better than placebo in terms of time to manic relapse (P=.01), but not for time to depressive relapse. Aripiprazole was also significantly better in improving YMRS total score, Positive and Negative Syndrome Scale (PANSS) cognitive subscale score, and CGI-BP severity.32 Approximately 21% of the patients entered the 74-week extension phase.31 Of these, approximately 37% completed the study. At week 100, the time to relapse for any mood episode was significantly longer for the aripiprazole group (P=.011).31 A statistically significant secondary efficacy measure was time to relapse for mania. Aripiprazole was also significantly better in improving YMRS total score, PANSS cognitive subscale score, and CGI-BP severity. The proportion of patients experiencing relapse was 33% for aripiprazole and 52% for placebo (P=.02), and there were significantly fewer manic relapses in the aripiprazole group compared to placebo (P=.05).31
A randomized, double-blind, placebo-controlled trial compared the long-term efficacy and tolerability of aripiprazole to lithium monotherapy in the acute and maintenance treatment of BPD1.33 Patients with acute mania or mixed states requiring hospitalization were randomly assigned to receive aripiprazole 15 to 30 mg/d, lithium 900 to 1,500 mg/d, or placebo for 3 weeks. Thereafter the placebo group was blindly assigned to aripiprazole.33 Improvement in the mean YMRS total score was significantly greater with aripiprazole by day 2 (-4.3 vs -2.8, respectively, P=.003) and up to week 3 (-12.6 vs -9.0; P<.001). At week 12, the proportion of the aripiprazole, lithium, and placebo groups completing treatment were 27%, 34%, and 29%, respectively.33
Clozapine use is limited by the risk of life-threatening agranulocytosis, despite a landmark trial showing its effectiveness, particularly in treatment-resistant or refractory illness, and several case reports and studies documenting clozapine association with significant clinical improvement compared to usual treatment.2
Results of an open-label, 12-week, prospective study of clozapine monotherapy in patients with treatment-refractory mania with psychotic features showed clozapine statistically improved (P=.0001) Brief Psychiatric Rating Scale (BPRS), YMRS, and CGI scores in all patients (n=22), as well as in those (n=14) classified as trial completers (completing >10 study weeks).34 The mean improvement scores for trial completers were 72.2%, 75.3%, and 55.7% on the BPRS, YMRS, and CGI, respectively. These findings are consistent with those from previously published case studies and retrospective and prospective studies.34
Clozapine-induced agranulocytosis is reported in 1% to 2% of patients during the first 6 months of treatment and occurs less frequently thereafter. FDA requires white blood cell count and absolute neutrophil count monitoring weekly during the first 6 months of therapy, biweekly for months 6 to 12 of therapy, then every 4 weeks for the remainder of the duration of treatment.14 Pharmacists play a vital role in clozapine monitoring in the retail, hospital, and office setting.
Other commonly reported clozapine-related side effects that hinder adherence are orthostatic hypotension, tachycardia, weight gain, metabolic syndrome, sedation, and constipation. Seizures are a dose-related side effect of clozapine.14
Olanzapine is a viable treatment option for both the acute and maintenance phase of BPD; however, concerns regarding its side-effect profile, specifically weight gain, hyperglycemia, transient hyperprolactinemia, and hyperlipoproteinemia, may hinder its use as first-line therapy.9,35 Other adverse effects include somnolence, dry mouth, dizziness, headaches, dyspepsia, agitation, asthenia, tremor, and elevated hepatic enzymes.6,35 Several double-blind placebo-controlled and active-comparator studies demonstrate the efficacy, safety, and tolerability of olanzapine for treatment of acute mania or mixed episodes and for maintenance therapy or relapse prevention as either monotherapy or augmentation therapy for BPD1.
An 8-week, randomized, open-label study assessing the efficacy of olanzapine (7.5-15 mg/d) or valproate (500-1,500 mg/d; adjusted to obtain serum concentrations between 50 and 100 μg/mL) as add-on therapy in lithium-treated BPD patients experiencing manic relapse showed both treatments were effective, as evident by statistically significant and similar improvements in YMRS and CGI-S scores at the conclusion of the study (P<.001).36 The olanzapine-treated group obtained an earlier clinical response, as evident by statistically significantly greater YMRS scores (P=.004, P<.001, P=.001, and P=.007, at weeks 1 through 4, respectively).36
Compared to haloperidol for the treatment of acute mania, olanzapine improved 12-week YMRS scores. Regarding the reduction of manic symptoms, haloperidol produced a better 6-week response, while olanzapine produced a better response during weeks 6 to 12. Both groups were statistically comparable by week 12, with no statistically significant differences seen in response or remission rates; however, olanzapine was found to be more effective in patients without psychotic features (56.7% vs 41.6%).35
A 12-month, double-blind, placebo-controlled study compared the efficacy of olanzapine and lithium for mood relapse prevention rates in patients with a history of 2 or more manic or mixed episodes in 6 years.37 This study found olanzapine to be noninferior to lithium. Overall, there was no statistically significant difference between groups in preventing a mood episode recurrence, according to YMRS.37 Secondary results showed olanzapine had significantly lower risks of relapse of manic and mixed episodes, and higher risks for depressive episodes. Statistical significance favored olanzapine for preventing mania, mixed episode, or hospitalization.37 A post-hoc analysis of this study, investigating differences in time to relapse among patients, based on their disease classification, found the rate of relapse significantly less in the olanzapine-treated group than the lithium-treated group for individuals classified with early-stage disease (P=.008), and insignificant differences for intermediate-stage and advanced-stage disease.38 The authors concluded that early treatment with olanzapine may predict better response and outcomes.37,38
Additionally, the results of an efficacy-based meta-analysis found olanzapine may prevent future manic episodes only in patients whose disease responded to acute manic or mixed episode olanzapine therapy and who are not adequately controlled on lithium or valproate monotherapy.39
Paliperidone, although not FDA-approved for BPD, is recommended by the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines as a second-line option for the management of acute mania.7 Several placebo- and active-treatment-controlled studies demonstrate its effectiveness for acute mania and mixed episodes.
A 12-week, multicenter, multi-phase, randomized, double-blind, placebo- and quetiapine-controlled study investigating the efficacy and safety of paliperidone extended-release (ER) in BPD1 patients experiencing an acute manic or mixed episode randomly assigned 493 patients to paliperidone-ER (3-12 mg/d), quetiapine (400-800 mg/d), or placebo for the acute, 3-week phase.40 Placebo-treated patients were switched to paliperidone-ER during the 9-week maintenance phase (eliminated from the 12-week efficacy analysis). The primary and secondary efficacy criteria for the 3-week analysis, comparing paliperidone-ER to placebo, were changes from baseline in YMRS and Global Assessment of Functioning (GAF) scores, respectively. The secondary outcome of the study was the noninferiority analysis, based on the change in YMRS scores, of paliperidone-ER compared to quetiapine at 12 weeks.40
At the 3-week end point, paliperidone-ER showed superiority over placebo as evident by a statistically significant (P<.001) reduction in YMRS scores (-13.2 vs -7.4, respectively), with improvement as early as day 2 and which was sustained throughout the acute phase.40 Both active-treatment groups had statistically significant improvement (P<.001) in GAF scores compared with placebo-treated patients. There was statistically significant improvement (P<.05) in the 3-week PANSS and CGI-BP severity scores for both active-treatment groups. Additionally, the percentage of responders was significantly (P<.001) higher in paliperidone-ER-treated and quetiapine-treated patients (55.8% and 49%, respectively) compared to placebo (34.6%). At the 12-week end point, the least squares mean difference showed that quetiapine was not superior to paliperidone-ER. The rate of responders and remittance for the paliperidone-ER-treated and quetiapine-treated patients were 64.7% vs 57.8% and 62.1% vs 56.3%, respectively. Overall, adverse events occurred at a similar frequency in the placebo and paliperidone groups (63% vs 65% respectively); however, the frequency of adverse events was higher in the quetiapine group (77%). The most common adverse effects were headache, somnolence, akathisia, sedation, insomnia, dizziness, constipation, dry mouth, and dyspepsia. Paliperidone-ER-treated patients had a higher incidence of depression at the 3-week and 12-week end point. The authors concluded that for the treatment of acute mania, paliperidone was efficacious and tolerable.40
A 3-week, randomized, double-blind, placebo-controlled efficacy study evaluating 3, 6, or 12 mg/d paliperidone-ER against placebo in 469 BPD1 patients with a recent manic or mixed episode assessed change in YMRS and GAF scores, primary outcome, and the key secondary outcome measures, respectively, from baseline to end point.41 At the 3-week end point, all treatment arms of paliperidone-ER demonstrated improvement in YMRS and GAF scores; however, the mean change in YMRS score was only statistically significant for the 12-mg arm (P<.01).11 Despite dose-dependent improvements in YMRS score and percent of responders and remitters, the improvements from the active-treatment groups were not significantly different from the placebo group.41 The incidence of adverse events was, likewise, dose-dependent. The adverse-effect profile of paliperidone-ER was similar to those previously reported in other studies.40,41
Quetiapine is available in both immediate-release and extended-release oral formulations. Both formulations have demonstrated efficacy for the acute and maintenance phases of BPD; however, to date, the extended-release formulation is only recommended to be used as monotherapy for acute mania.7
Trial 127, a multicenter, randomized, double-blind, parallel-group study of 623 individuals comparing the long-term efficacy (up to 104 weeks) of quetiapine to placebo, as adjunctive therapy to lithium or divalproex, favored quetiapine in the primary outcome, the time to recurrence of any mood event, as well as the secondary outcome, time to recurrence of mania or depression.42 The quetiapine group experienced statistically significant (P<.0001) risk reductions of 68% (any event), 70% (mania), and 67% (depression) for the primary and secondary outcomes. Regarding safety and tolerability, only sedation, weight gain, and hypothyroidism were found to be significantly (P<.001) greater in the quetiapine group; however, all-cause premature discontinuation favored quetiapine, with a mean medication exposure time of 240 days compared with placebo at 178 days.42 The International Trial 126 was performed in parallel with Trial 127 and demonstrated similar results and outcomes.43 The authors of both trials concluded the improved reductions were independent of the polarity of the index episode and that quetiapine was an effective long-term treatment option for BPD1 patients.42,43
Risperidone, available as oral immediate-release tablets and most recently as risperidone long-acting injectable (RLAI), was one of the first atypical antipsychotic agents to exhibit efficacy in the treatment of BPD1.2 The RLAI formulation may improve medication persistence rates among a population challenged by nonadherence.
A randomized, double-blind, placebo-controlled, multicenter study assessing the effect of adjunctive RLAI on time to relapse in BPD1 patients who frequently relapse favored RLAI over placebo.44 Overall relapse rates for the RLAI and placebo group, 23.1% and 45.8%, respectively, were not statistically significantly different; however, when controlled for the most recent episode, the results were statistically significant (P<.009).44
The results of a randomized, double-blind, placebo-controlled phase of a multiphase study evaluating the long-term (up to 24 months) efficacy of RLAI showed a delay in time to mood recurrence (primary end point) (P<.001) with RLAI compared to placebo.45 The secondary analysis of the primary end point was statistically significantly different in time to relapse of elevated mood episode (P<.001), but not in time to relapse of depressed mood.45
An open-label, naturalistic study evaluating the benefit of adjunctive RLAI to standard therapy in 29 acutely manic patients over a mean of 2 years found improvement in a variety of clinical outcomes.46 Specifically, there was improvement in CGI in 48% of RLAI-treated patients and statistically significant improvement in patient hospitalization (P<.006), number of hospitalizations due to manic or mixed episodes (P<0.007), reduction in hospital length of stay (P<.001), prolongation of time to relapse (P<.001), and increased medication adherence rates (P<.0001).46
In studies, the most commonly reported side effects with RLAI use were extrapyramidal symptoms and weight gain. Others reported were hyperglycemia, hyperprolactinemia, and insomnia.44,45
Ziprasidone has favorable data for efficacy in hypomanic/manic and mixed acute BPD1 episodes and for relapse prevention; however, more long-term studies are needed for ziprasidone to be highly recommended for the latter.3,7
A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ziprasidone as adjunctive treatment to a mood stabilizer randomly assigned patients who achieved stability with 8 weeks of open-label ziprasidone (80-160 mg/d) and lithium or valproate to ziprasidone or placebo plus a mood stabilizer for 6 months, with time to intervention for a mood episode and time to discontinuation as the primary and secondary end points, respectively.47 Time to intervention for a mood disorder was significantly longer for ziprasidone than placebo (43.0 vs 26.5 days; P=.0104). Time to discontinuation for any reason was significantly longer for ziprasidone (P=.0047) than placebo. Among commonly occurring adverse events, only tremor occurred more frequently with ziprasidone than with placebo (6.3% vs 3.6%). It appears that ziprasidone was well-tolerated and is an effective, safe alternative as adjunct to a mood stabilizer for maintenance therapy.47
A multicenter, multiphasic, randomized, double-blind study comparing ziprasidone and placebo with haloperidol (active reference) evaluated the efficacy of ziprasidone for acute (over 3 weeks) and maintenance (weeks 4-12) therapy of BPD1.48 Patients were randomly assigned in a 2:2:1 ratio to ziprasidone (80-160 mg/d), haloperidol (8-30 mg/d), or placebo. For the primary outcome of the mean change in the Mania Rating Scale (MRS) score from baseline to week 3, ziprasidone showed superiority over placebo, with a statistically significant improvement as early as day 2 (P<.01) and sustained throughout the 3-week acute phase (P<.01) and the 9-week maintenance phase. Furthermore, 92.5% of the ziprasidone responders (as defined by at least a 50% decrease in MRS score) at 3 weeks continued to positively respond at week 12. Ziprasidone significantly improved CGI-S scores at all evaluations (P<.05), particularly at days 14 (P<.001) and 21 (P=.002).48
Other indices reaching statistically significant difference were: GAF scores, PANSS total and positive scores, and Behavior and Ideation and Manic Syndrome subscale scores of MRS (P<.05). Likewise, haloperidol was superior to placebo in all psychiatric measures evaluated (P<.05). Although not powered to compare the 2 active-treatment groups, the change in MRS favored haloperidol; however, more participants discontinued haloperidol by week 3 and week 12 (9.9% vs 3.9% and 21.1% vs 9.6%, respectively), and reported more treatment-related depression with haloperidol at 3 and 12 weeks (5.8% vs 1.1% and 8.2% vs 3.4%, respectively, for haloperidol vs ziprasidone). Based on the results of this study, it was concluded that ziprasidone monotherapy is effective for the treatment of acute BPD.48
Amisulpride. An open-label study investigating the long-term (3 to 24 months) efficacy of amisulpride (200 and 800 mg/d) as add-on therapy to standard therapy in 11 patients with BPD1 not responding to their current therapy assessed the relapse rates before (11.7+8.2 months) and after amisulpride therapy (5.2+2.7 months).49 The comparison of overall relapse rates showed a statistically significant difference between the 2 comparative time frames, with intervention of amisulpride therapy resulting in decreased relapse rates (P=.05). The relative relapse risk without amisulpride therapy was 3.1 (P<.05). The decrease in the overall relapse rate was statistically significant, in favor of amisulpride (P<.05). A reduction was observed for all mood types, but statistical significance was only reached for mania and mixed episodes (P=.02). Additionally, significant improvement in CGI-BP scores was observed during the amisulpride-treated time frame (P<.05). Commonly reported amisulpride-induced side effects were sedation, weight gain, and tremor. The authors concluded that long-term (up to 9 months) amisulpride therapy is beneficial in reducing rates of manic and mixed episodes and improving symptoms of BPD1; however, more appropriately powered clinical trials are needed.49
A 3-month, multicenter, randomized, open-label, parallel-group, phase 2 study enrolled 120 actively manic BPD1 patients to compare the efficacy of valproate and amisulpride (400-800 mg/d) combination (VAL-AMS) with that of valproate and haloperidol (5-15 mg/d) combination (VAL-HAL).50 Valproate was initiated at starting dosing per local prescribing recommendations and was adjusted as warranted to obtain serum concentrations between 40 and 100 μg/mL. For the primary outcome, there was a greater percent of responders, as defined by >50% reduction in YMRS score and completion of the study as intended, in the VAL-AMS group (72.6%) than the VAL-HAL group (65.5%); however, the between-group differences were not statistically significant. At the conclusion of the study, the secondary outcomes of remission rates, response rates, and mean change in YMRS scores favored VAL-HAL therapy, although this was not statistically significant. There was a trend toward lower risk of relapse, greater decrease of Montgomery-Asberg Depression Rating Scale scores at 12 weeks, better patient satisfaction, better adherence, and lower incidence of switching to depression in the VAL-AMS group. Adverse effects, including extrapyramidal symptoms, were reported more in the VAL-HAL group. The most frequently reported adverse effects in the VAL-AMS group were fatigue, somnolence, and amenorrhea. Although this study did not show superiority in favor of amisulpride therapy as hypothesized, the authors concluded it is as effective as haloperidol, with better safety and tolerability.50
Protein kinase C (PKC) inhibitors. The only FDA-approved PKC inhibitor, tamoxifen, is recommended by the CANMAT guidelines as a third-line treatment option for acute mania.7 Emerging evidence demonstrates a benefit from tamoxifen therapy. In a 3-week clinical trial, the efficacy of tamoxifen (80 mg/d) was evaluated in the treatment of acute mania or mixed BPD episodes with or without psychotic feature.51 The primary outcome measure of change in YMRS scores demonstrated superior antimanic properties for tamoxifen, which had a decrease of 5.84 YMRS points per week compared with a placebo increase of 1.50 (P<.001). For the secondary measures of change in CGI-Mania and PANSS total and positive subscale scores, efficacy significantly favored tamoxifen (P<.001). Additionally, for the tamoxifen-treated group, there was less use of lorazepam, with a rate of decrease 2.5 times greater than placebo. Treatment-responder rates at study end point were 44% and 4% (P=.002) for tamoxifen versus placebo, respectively. Reported side effects, other than weight loss, were dermatologic in nature.51
A 6-week, double-blind, parallel-group, placebo-controlled study investigating the efficacy and tolerability of tamoxifen (80 mg/d) as adjunctive therapy to lithium in 40 hospitalized acute mania BPD patients showed statistically significant improvement in YMRS scores from baseline (primary end point) in tamoxifen-treated patients compared with placebo (P=.002).52 Additionally, statistical significance was observed in favor of tamoxifen with the secondary outcome measure, PANSS (P=.01), but not with the Hamilton Depression Rating Scale-17 scores. The only clinically significant side effect reported was fatigue, which was more prevalent in tamoxifen-treated patients. Other side effects with a high incidence in both groups were morning/daytime drowsiness, restlessness, and tremor. Like the aforementioned study, antimanic properties with tamoxifen were observed.52
Psychopharmacotherapy is used to treat acute BPD exacerbation, abate relapse, and to maintain mental well-being. Lithium and valproate continue to be the mainstay therapies for the treatment of both the acute and maintenance phase of BPD. Given their slower onset of action compared to the antipsychotics, lithium and valproate may produce better outcomes when used in combination with antipsychotics, particularly in individuals with moderate-to-severe symptoms.2,6 Antipsychotics, with the exception of quetiapine, may be associated with a switch to depression. Olanzapine, valproate, aripiprazole, risperidone, and ziprasidone may have better outcomes specific to mixed episodes.2,9 Anticonvulsants, with the exception of valproate, are limited in their use because of intolerance, and limited or irreproducible data. Lamotrigine, which is reserved for maintenance therapy, appears to have the most benefit in preventing a switch to depression. Often medications initiated for acute treatment are continued for maintenance therapy. There is strong evidence for antipsychotics in the treatment of mania and in some cases prevention of relapse; however, consideration should be given to their effect on polarity index, side-effect profile, and drug-drug interactions when selecting an agent.
PHARMACISTS IN THE MANAGEMENT OF BPD
Pharmacists can make substantial contributions to the multidisciplinary team caring for individuals with BPD and their families. In addition to their medication dispensing role, pharmacists can establish therapeutic relationships with patients and provide social support by serving as medication information resources such as through providing medication counseling, counseling on lifestyle modifications to ensure optimal clinical response to therapies, and, when warranted, assisting with the acquisition of medication through assistance programs. Additionally, pharmacists can serve as advocates and resources for directing patients and their families to community-based and national programs such as the local and on-line support groups, the National Alliance for the Mentally Ill, the National Mental Health Association, the National Depressive and Manic-Depressive Association, and the National Institute of Mental Health.
In collaboration with the medical team, pharmacists can assist with medication selection, medication and therapeutic monitoring, managing and avoiding drug-drug interactions, and developing strategies to aid in medication adherence. Pharmacists can assist with managing medication-induced/medication-exacerbated metabolic disturbances and weight management. Furthermore, pharmacists can serve as study investigators and as committee members for the development of expert consensus statements, treatment algorithms, and guidelines.
Dr Williams is an assistant professor of pharmacy practice, Butler University College of Pharmacy and Health Sciences, clinical pharmacist, family medicine, Indiana University Health, Indianapolis. Dr Ruekert is an assistant professor of pharmacy practice, Butler University College of Pharmacy and Health Sciences, clinical pharmacist, behavioral care services, Community Hospital North, Indianapolis. Dr Lum is clinical pharmacist, behavioral care services, Community Hospital North, Indianapolis.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
1. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd edition. New York: Oxford University Press; 2007.
2. Malhi GS, Adams D, Cahill CM, Dodd S, Berk M. The management of individuals with bipolar disorder: a review of the evidence and its integration into clinical practice. Drugs. 2009;69:2063–2101.
3. Stovall J, Keck P, Solomon D. Bipolar disorder: epidemiology and diagnosis. Available at: http://www.uptodate.com/contents/bipolar-disorder-epidemiology-and-diagnosis. Accessed January 11, 2011.
4. Stovall J, Keck P, Solomon D. Bipolar disorder: pharmacotherapy for acute mania, mixed states, and hypomania in adults. Available at: http://www.uptodate.com/contents/bipolar-disorder-pharmacotherapy-for-acute-mania-mixed-states-and-hypomania-in-adults. Accessed January 11, 2011.
5. Hirschfeld RMA, Bowden CL, Gitlin MJ, et al; Work Group on Bipolar Disorder. American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder, 2nd ed. Am J Psychiatry. 2002;159(suppl 4):1–50.
6. Department of Veterans Affairs, Department of Defense, Management of Bipolar Disorders Working Group. VA/DoD Clinical Practice Guideline for Management of Bipolar Disorder in Adults. May 2010. Available at: http://www.healthquality.va.gov/bipolar/bd_305_full.pdf. Accessed February 15, 2011.
7. Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11:225–255.
8. Hirschfeld RMA. Guideline Watch: Practice Guideline for the Treatment of Patients with Bipolar Disorder. 2005. American Psychiatric Association, Arlington, VA. Available at: http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed on February 15, 2011.
9. Suppes T, Dennehy EB, Hirschfeld RMA, et al; for the Texas Consensus Conference Panel on Medication Treatment of Bipolar Disorder. The Texas Implementation of Medication Algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870–886.
10. Berghofer A, Adla M, Adli M, et al. Long-term effectiveness of lithium in bipolar disorder: a multicenter investigation of patients with typical and atypical features. J Clin Psychiatry. 2008;69:1860–1868.
11. Campos RN, Costa LF, Bio DS, et al. LICAVAL: combination therapy in acute and maintenance treatment of bipolar disorder. Trials. 2010;11:72.
12. Geddes JR, Goodwin GM, Rendell JR, et al; the BALANCE Investigators and Collaborators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomized open label trial. Lancet. 2010;375:385–395.
13. Shafti SS. Olanzapine vs. lithium in management of acute mania. J Affect Disord. 2010;122:273–276.
14. Jibson MD, Marder S, Hermann R. Antipsychotic medications: classification and pharmacology. 2011 UpToDate. Online Version 18.3. Accessed January 11, 2011.
15. Bowden CL, Moslov S, Hranov L, et al. Efficacy of valproate versus lithium in mania or mixed: a randomized, open 12-week trial. Int Clin Psychopharmacol. 2010;25:60–67.
16. Bowden C, Göşüş A, Grunze H, Häggström L, Rybakowski J, Vieta E. A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. Int Clin Psychopharmacol. 2008;23:254–262.
17. Oluboka OJ, Bird DC, Kutcher S, Kusumakar V. A pilot study of loading versus titration of valproate in the treatment of acute mania. Bipolar Disord. 2002;4:341–345.
18. Ceron-Litvoc D, Garcia Soares B, Geddes J, Litvoc J, Silva de Lima M. Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum Psychopharmacol Clin Exp. 2009;24:19–28.
19. Tohen M, Bowden CL, Smulevich AB, et al. Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes. Br J Psychiatry. 2008;192:135–143.
20. Hirschfeld RM, Kasper S. A review of the evidence for carbamazepine and oxcarbazepine in the treatment of bipolar disorder. Int J Neuropsychopharmacol. 2004;7:507–522.
21. Benedetti A, Lattanzi L, Pini S, Musetti L, Dell'Osso L, Cassano GB. Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode. J Affect Disord. 2004;79:273–277.
22. Vieta E, Cruz N, García-Campayo J, et al. A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol. 2008;11:445–452.
23. Suppes T, Kelly DI, Hynan LS, et al. Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder. Aust N Z J Psychiatry. 2007:41:397–402.
24. Amann B, Born C, Crespo JM. Lamotrigine: when and where does it act in affective disorders? A systematic review. J Psychopharmacol. 2010 Sept; doi:10.1177/0269881110376695.
25. Bowden CL, Calabrese JR, Sachs G, et al; for the Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392–400.
26. Licht RW, Nielsen JN, Gram LF, Vestergard P, Bendz H. Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6). Bipolar Disord. 2010;12:483–493.
27. McIntyre R, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2010;122:27–38.
28. McIntyre R, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord. 2009;11:673–686.
29. McIntyre R, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord. 2009;11:815–826.
30. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine for long-term treatment of bipolar disorder: A double-blind 40-week extension study. J Affect Disord. 2010;126:358–365.
31. Keck PE, Calabrese JR, McIntyre RS, et al; for the Aripiprazole Study Group. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry. 2007;68:1480–1491.
32. McIntyre RS. Aripiprazole for the maintenance treatment of bipolar I disorder: a review. Clin Ther. 2010; 32(suppl A):S32–S38.
33. Keck PE, Orsulak PJ, Cutler AJ, et al; the CN138-135 Study Group. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithum-controlled study. J Affect Disord. 2009;112:36–49.
34. Green AI, Tohen M, Patel JK, et al. Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry. 2000;157:982–986.
35. Narasimhan M, Bruce TO, Massand P. Review of olanzapine in the management of bipolar disorders. Neuropsychiatr Dis Treat. 2007;3:579–587.
36. Maina G, Albert U, Salvi V, Mancini M, Bogetto F. Valproate or olanzapine add-on to lithium: an 8-week, randomized, open-label study in Italian patients with a manic relapse. J Affect Disord. 2007;99:247–251.
37. Tohen M, Greil W, Calabrese JR, el al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month randomized, double-blind, controlled clinical trial. Am J Psychiatry. 2005;162:1281–1290.
38. Ketter TA, Houston JP, Adams DH, et al. Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. J Clin Psychiatry. 2006;67:95–101.
39. Cipriani A, Rendell J, Geddes JR. Olanzapine in the long-term treatment of bipolar disorder: a systematic review and meta-analysis. J Psychopharmacol. 2010;24(12):1729–1738.
40. Vieta E, Nuamah IF, Lim P, et al. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010;12:230–243.
41. Berwaerts J, Xu H, Nuamah I, Lim P, Hough D. Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: a randomized, double-blind, dose-response study. J Affect Disord. 2010; doi:10.1016/j.jad.2010.06.030.
42. Suppes T, Vieta E, Liu S, Brecher M, Paulsson B, Trial 127 Investigators. Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry. 2009;166:476–488.
43. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008;109:251–263.
44. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11:827–839.
45. Quiroz JA, Yatham LN, Palumbo JM, Karcher K, Kushner S, Kusumakar V. Risiperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry. 2010;68:156–162.
46. Vieta E, Nieto E, Autet A, et al. A long-term prospective study on the outcome of bipolar patients treated with long-acting injectable risperidone. World J Biol Psychiatry. 2008;9:219–224.
47. Bowden CL, Vieta E, Ice KS, et al. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry. 2010;71:130–137.
48. Vieta E, Ramey D, Keller PA, et al. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol. 2010:24:547–558.
49. Carta MG, Zairo F, Mellino G, Hardoy MC, Vieta E. An open label follow-up study on amisulpride in the add-on treatment of bipolar I patients. Clin Pract Epidemiol Ment Health. 2006;2:19.
50. Thomas P, Vieta E; for the SOLMANIA Study Group. Amisulpride plus valproate vs haloperidol plus valproate in the treatment of acute mania of bipolar I patients: a multicenter, open-label, randomized, comparative trial. Neuropsychiatr Dis Treat. 2008;4:675–686.
51. Yildiz A, Guleryuz S, Ankerst DP, et al. Protein kinase C inhibition in the treatment of mania. Arch Gen Psychiatry. 2008;65:255–263.
52. Amrollahi Z, Rezaei F, Salehi B, Öngűr D, Renshaw PF. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect Disord. 2011;129(1-3):327–331.