Olanzapine: a review of its use in the management of bipolar I disorder

Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder, and for maintenance therapy to prevent recurrence in responders.Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics, such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders, and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated, and although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms (EPS). Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.     

Divalproex in the treatment of bipolar disorder

Valproate is commonly used as a first-line agent for the treatment of acute bipolar I mania. Its efficacy in the treatment of acute mania has been established in randomized, controlled trials versus placebo, lithium, haloperidol, and olanzapine. Only preliminary data regarding the efficacy of valproate in acute bipolar depression are currently available. The efficacy of valproate in the maintenance treatment of bipolar disorder has not been definitively established but most evidence from randomized, controlled trials suggests that it may have comparable efficacy to lithium and olanzapine. The results of randomized, controlled trials of valproate in the treatment of bipolar disorder are reviewed along with their implications for clinical practice.     

Acute dysphoric mania: treatment response to olanzapine versus placebo

A substantial number of patients with mania have significant concomitant depressive features, and they may respond differently to mood stabilizers than patients with pure mania. This post-hoc analysis explored the response characteristics of olanzapine versus placebo in bipolar I manic patients with dysphoric and nondysphoric mania (differentiated by baseline Hamilton Depression Rating Scale [HAM-D] score of >20). Two similar, double-blind, randomized trials comparing olanzapine, 5-20 mg, to placebo were pooled for these analyses (N = 246). Mean changes in Young-Mania Rating Scale (Y-MRS) and HAM-D scores during 3 weeks of treatment were examined. Twenty-eight percent of patients had dysphoric mania (olanzapine, n = 33; placebo, n = 35). Among these patients, olanzapine-treated patients had greater improvement within 1 week than did placebo-treated patients on both mania ratings (Y-MRS: -9.7 vs. -3.0 points; = 0.011) and depressive symptom ratings (HAM-D: -9.9 vs. -5.4 points; = 0.025). Among those manic subjects without prominent depressive symptoms (olanzapine, n = 91; placebo, n = 87), mean Y-MRS improvement from baseline to endpoint with olanzapine (-11.5 points) versus placebo (-6.13 points) was comparable to the improvement seen with olanzapine versus placebo in the dysphoric mania subgroup ( = 0.476, test of interaction). In acutely ill manic patients with significant depressive symptoms, olanzapine demonstrated a broad spectrum of efficacy, effectively treating both manic and depressive symptoms. The magnitude of the antimanic response appears similar, regardless of baseline depressive features. Additional experience with putative mood stabilizers and atypical agents in mixed mania should include an exploration of their efficacy in treating both manic and depressive mood symptoms.     

Spotlight on olanzapine in bipolar I disorder

Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder and for maintenance therapy to prevent recurrence in responders. Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated and, although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms. Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.     

A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania

There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder. In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of the atypical antipsychotic olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale-Excited Component subscale and two additional agitation scales. At 2 hours after the first injection, patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam. At 24 hours after the first injection, olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania, whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine. Furthermore, no significant differences among the three treatment groups were observed in safety measures, including treatment-emergent extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes. These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania.     

Switching from other agents to extended-release carbamazepine in acute mania

There is a dearth of available knowledge relating to the efficacy of switching from one psychotropic agent to another in treating patients with acute mania. Methods: This is a post hoc analysis of data from two randomized, placebo-controlled trials of carbamazepine extended-release capsules (CBZ-ERC) in the treatment of mania, to evaluate the efficacy of CBZ-ERC in patients previously nonresponsive to lithium (n 5 40), olanzapine (n 5 38), or valproate (VPA, n 5 77). Results: In patients previously on lithium, Young Mania Rating Scale (YMRS) scores improved significantly from baseline to end point (27.4 6 SD 3.5 vs. 15.8 6 11.1; P 5 .0002). In patients previously on VPA or olanzapine, YMRS scores significantly improved in both CBZ-ERC- and placebo-treated groups (VPA: CBZ-ERC, P , .0001; placebo, P 5 .0002; olanzapine: CBZ-ERC, P , .0001; placebo, P 5 .0054). Improvement in YMRS was significantly greater in CBZ-ERC-treated patients versus placebo in subjects previously nonresponsive to lithium (CBZ-ERC 11.6 6 10.3 vs. placebo 4.0 6 11.2, P 5 .03), or VPA (CBZ-ERC 10.8 6 11.9 vs. placebo 5.7 6 9.2; P 5 .04), and trending to be greater for those previously nonresponsive to olanzapine (olanzapine 13.2 6 9.3 vs. placebo 7.3 6 9.7, P 5 .06). Conclusions: CBZ-ERC is an effective therapy for bipolar patients previously nonresponsive to lithium or valproate. Medication switch is frequently associated with symptom improvement.     

Antipsychotic drugs in bipolar disorder

Antipsychotic drugs are useful in the treatment of acute mania and as maintenance treatment. While both typical and atypical antipsychotic drugs are able to diminish manic symptoms, agitation and aggression in acute mania, the atypical antipsychotic drugs enjoy a number of advantages, including significantly less extrapyramidal symptoms, diminished risk of tardive dyskinesia, lack of increase in serum prolactin levels (with the exception of risperidone), improvement in cognition, and possible decrease in suicidality. Most of the atypical antipsychotic drugs have been found to be effective as an add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients. Long-acting typical neuroleptic drugs may be useful in the treatment of non-compliant bipolar patients. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental. Side-effects of note with the atypical antipsychotic drugs are weight gain (most prominently with olanzapine and clozapine), sedation, and agranulocytosis (clozapine). Atypical antipsychotic drugs are recommended for use in bipolar disorder for acute treatment, maintenance treatment, and for treatment-resistant patients.     

Intramuscular olanzapine: a review of its use in the management of acute agitation

Intramuscular olanzapine (Zyprexa) is a rapid-acting atypical antipsychotic drug that is also indicated for use in patients with agitation associated with schizophrenia or bipolar mania, the focus of this review. Evidence from three well designed trials indicates that this formulation of olanzapine is at least as effective as intramuscular haloperidol or lorazepam in the treatment of patients with acute agitation associated with schizophrenia or bipolar mania, and has a faster onset of action. Although transient reductions in blood pressure and heart rate may occur in some patients administered intramuscular olanzapine, preliminary evidence of a general lack of clinical effect on the corrected QT (QTc) interval and a low incidence of extrapyramidal symptoms (EPS) is promising. The parenteral formulation of olanzapine appears to offer an effective, fast-acting and generally well tolerated alternative in the treatment of this significant behavioural problem.     

Predictors of response to treatment of acute bipolar manic episodes with divalproex sodium or placebo in 2 randomized, controlled, parallel-group trials

Identification and control of factors that are associated with placebo and drug response in acute mania may influence the design and analysis of future trials in this condition. We analyzed pooled data from 2 multicenter, placebo-controlled, randomized trials of divalproex sodium for the treatment of acute manic episodes, using linear and logistic regression to search for common and treatment-specific predictors of response. In both treatment groups, patients with greater numbers of prior hospitalizations, more severe baseline symptoms, or younger age at onset of illness were found to be significantly less likely to respond. The effect sizes associated with these factors were of comparable magnitude to the effect size associated with divalproex treatment. Stratification on the basis of these prognostic factors may improve the power of future trials for the treatment of acute mania and may help explain patient response to treatment.     

Novel treatments for bipolar disorder

Treatments other than lithium have recently emerged as equally important in the management of bipolar disorder. The spectrum of efficacy of newer treatments differs from lithium and among the novel drug treatments valproate, generally used as the better tolerated divalproex form, principally benefits manic symptomatology both acutely and in prophylaxis. Atypical antipsychotic drugs have demonstrated efficacy in reducing acute manic symptoms. No controlled evidence of efficacy in prophylaxis has been published. Lamotrigine has demonstrated efficacy in both acute bipolar depression and maintenance efficacy in rapid cycling bipolar patients, especially those patients with bipolar II disorder, which is principally manifested as depression. Randomised, double-blind, placebo- controlled studies provide good evidence that regimens of risperidone or olanzapine in combination with lithium or valproate provide greater improvement in acute mania than the mood stabilisers alone. Similarly, valproate combined with antipsychotics provided greater improvement in mania than antipsychotic medication alone and resulted in lower dosage of the antipsychotic medication. A positive but unclear placebo-controlled study of omega-3 fatty acids added to lithium in bipolar disorder needs confirmation in standard clinical trial paradigms. Several other drugs that were reported as beneficial in various facets of bipolar disorder in open trials have not differed from placebo when studied in randomised, placebo-controlled trials.     

Novel treatments for bipolar disorder

Treatments other than lithium have recently emerged as equally important in the management of bipolar disorder. The spectrum of efficacy of newer treatments differs from lithium and among the novel drug treatments valproate, generally used as the better tolerated divalproex form, principally benefits manic symptomatology both acutely and in prophylaxis. Atypical antipsychotic drugs have demonstrated efficacy in reducing acute manic symptoms. No controlled evidence of efficacy in prophylaxis has been published. Lamotrigine has demonstrated efficacy in both acute bipolar depression and maintenance efficacy in rapid cycling bipolar patients, especially those patients with bipolar II disorder, which is principally manifested as depression. Randomised, double-blind, placebo- controlled studies provide good evidence that regimens of risperidone or olanzapine in combination with lithium or valproate provide greater improvement in acute mania than the mood stabilisers alone. Similarly, valproate combined with antipsychotics provided greater improvement in mania than antipsychotic medication alone and resulted in lower dosage of the antipsychotic medication. A positive but unclear placebo-controlled study of omega-3 fatty acids added to lithium in bipolar disorder needs confirmation in standard clinical trial paradigms. Several other drugs that were reported as beneficial in various facets of bipolar disorder in open trials have not differed from placebo when studied in randomised, placebo-controlled trials.     

Olanzapine/fluoxetine: a review of its use in the treatment of acute bipolar depression

Olanzapine/fluoxetine (Symbyax) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.     

Spotlight on olanzapine/fluoxetine in acute bipolar depression

Olanzapine/fluoxetine (Symbyax((R))) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the SSRI fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.     

Quality of life outcomes of risperidone, olanzapine, and typical antipsychotics among schizophrenia patients treated in routine clinical practice: a naturalistic comparative study

Findings in previous studies investigating the beneficial effect of risperidone and olanzapine versus typical antipsychotics on quality of life (QOL) are controversial since they did not adjust for various factors contributing to QOL. To test this assumption in a naturalistic cross-sectional design, we evaluated general and domain-specific QOL scores for baseline data of schizophrenia outpatients stabilized on atypical (N = 78, risperidone or olanzapine) and typical (N = 55) agents. Self-report and observer-rated QOL outcomes of both risperidone and olanzapine with typical antipsychotic therapy were compared across demographic, illness-related, and treatment-related factors using analysis of variance, multivariate analysis of variance, and correlation analysis. No significant differences were found in QOL outcomes of risperidone-treated and olanzapine-treated patients. Both self-report and rater-observed QOL measures indicated superiority of atypical over typical antipsychotic agents after adjusting for daily doses, duration of treatment, subjective tolerability, and adjuvant antidepressants. Lower daily doses and longer antipsychotic treatment were associated with better QOL. Self-report and observer-rated QOL scores correlated positively (r = 0.64, P < 0.001). Gender, marital status, age, education, living arrangement and employment status, age of onset, illness duration, symptom severity, emotional distress, subtypes of schizophrenia, and side effects did not affect QOL outcomes in either group. Risperidone and olanzapine revealed an advantage over typical agents in terms of QOL. Findings suggest that when calculating the beneficial effects of atypical antipsychotic therapy on QOL outcomes, daily doses, duration of treatment, and subjective tolerability may be intervening variables and should be adjusted accordingly to clearly appreciate benefits of atypical antipsychotics.     

A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D(2) receptor antagonist in the treatment of acute exacerbation of schizophrenia

JNJ-37822681 is a novel, highly selective dopamine D(2) receptor antagonist characterized by a rapid dissociation rate from the dopamine D(2) receptor. This profile was hypothesized to confer antipsychotic efficacy and improved tolerability. In this 12-week study, the efficacy and safety of JNJ-37822681 were evaluated in patients with an acute exacerbation of schizophrenia, randomly assigned (1:1:1:1:1) to JNJ-37822681 (10-, 20- or 30-mg bid), olanzapine (15mg once-daily), or placebo (for 6weeks followed by olanzapine for 6weeks). Of 498 randomized patients, 298 (60%) completed the study. All JNJ-37822681 dose groups and the olanzapine group showed significantly greater reduction in PANSS total score from baseline to week 6 versus placebo (all p-values<0.001). Least-squares adjusted mean changes from baseline to week 6 in PANSS total score were: -6.4 (placebo); -18.4 (10mg JNJ-37822681), -17.7 (20mg JNJ-37822681), -20.0 (30mg JNJ-37822681) and -22.9 (olanzapine). All JNJ-37822681 groups showed significant improvement versus placebo from baseline to week 6 in the PANSS subscales, Marder factors, Clinical Global Impression of Severity, and in the Subjective Well-Being on Neuroleptics scale (all p-values<0.05). The most common treatment-emergent adverse events with JNJ-37822681 were insomnia (17%) and akathisia (13%). Incidences of extrapyramidal symptoms were dose-related and were comparable for JNJ-37822681 10mg bid and olanzapine groups. All JNJ-37822681 dose groups showed lesser weight gain compared with olanzapine. The efficacy and tolerability profile of the JNJ-37822681 10mg bid was consistent with the study hypothesis.     

Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Flexible-dose clinical trials: predictors and outcomes of antipsychotic dose adjustments

In a new approach to the interpretation of data from flexible-dose studies, we examined the safety and efficacy measurements that preceded and followed dose changes, to identify clinical factors that predict dose change as well as subsequent outcome of clinical status with dose change. This was a post hoc analysis of 3 flexible-dosed olanzapine studies: acutely ill bipolar I patients with an index manic episode (N = 452) who received olanzapine (5-20 mg/d) or haloperidol (3-15 mg/d); acutely ill patients with schizophrenia (N = 339) who received olanzapine (10-20 mg/d) or risperidone (4-12 mg/d) for 28 weeks; and remitted bipolar I patients (N = 361) who received olanzapine (5-20 mg/d) or placebo for 48 weeks. The major findings of this analysis were: an increase in dose was predicted by baseline illness severity in the acute studies, and a decrease in dose was predicted by illness symptom improvement or worsening of adverse events. Dose decrease was followed by significantly decreased efficacy for patients with acute mania treated with olanzapine or haloperidol, and olanzapine dose increases were followed by improved efficacy. Treatment-emergent extrapyramidal symptom adverse events and akathisia typically predicted dose decreases. Techniques used in this analysis may prove to be useful in assessing the relationship between dose change and safety and efficacy measures.     

Asenapine: a review of its use in the management of mania in adults with bipolar I disorder

Asenapine is an atypical antipsychotic agent available in sublingual formulations (5 or 10 mg) and indicated in the US (Saphris) for the acute treatment, as monotherapy or adjunctive therapy, of manic and mixed episodes and in the EU (Sycrest) for the treatment of moderate to severe manic episodes, in adult patients with bipolar I disorder. In two large (both n = 480), well designed, 3-week trials in adult patients with bipolar I disorder, asenapine monotherapy was significantly more effective than placebo at improving mania symptoms, as assessed using the Young Mania Rating Scale total score (YMRS; primary endpoint), with significant differences between the asenapine and placebo groups occurring after 2 days of treatment. In both trials, Clinical Global Impression for Bipolar Disorder (CGI-BP) scale mania severity scores exceeded those of placebo. In one trial, response and remission rates exceeded those of placebo. In a 9-week extension study that recruited completers from the monotherapy trials, there were no significant differences between asenapine and olanzapine groups in terms in Montgomery-?sberg Depression Rating Scale (MADRS) scores, CGI-BP mania severity scores, YMRS response rates or YMRS remission rates during the extension phase. In the extension study, the efficacy of asenapine monotherapy appeared to be maintained over 40 weeks (total treatment duration of 52 weeks). In a 12-week trial of asenapine as adjunctive therapy to lithium or valproate, asenapine was more effective than placebo in improving manic symptoms, based on the difference between groups in the YMRS total score at week 3 (primary endpoint). Most adverse events associated with asenapine were of mild to moderate severity, with <7% of asenapine recipients experiencing serious adverse events (vs 7% with placebo). In a pooled analysis of the monotherapy trials, the most common adverse events (occurring in ≥ 5% of patients and at twice the incidence of placebo) reported during acute phase asenapine monotherapy for bipolar mania were somnolence, dizziness, extrapyramidal symptoms (EPS, other than akathisia) and increased bodyweight, which were similar in nature to those occurring during longer-term monotherapy with asenapine. EPS did not worsen in severity during longer-term asenapine monotherapy. Asenapine had minimal effects on plasma glucose, lipid and prolactin levels over both short- and longer-term treatment periods, and had little pro-arrhythmogenic potential. Further active comparator trials and longer-term tolerability and safety data are required. In the meantime, asenapine is a further option for the management of manic and/or mixed symptoms in patients with bipolar I disorder and may be of particular value for patients who are at high risk for metabolic abnormalities.     

Open-label treatment with olanzapine for patients with borderline personality disorder

This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline-to-endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open-label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open-label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population.