Olanzapine versus placebo in the treatment of adolescents with bipolar mania

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 > or =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.     

Olanzapine versus divalproex in the treatment of acute mania

OBJECTIVE: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. METHOD: A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures. RESULTS: The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. CONCLUSIONS: The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.     

Olanzapine versus placebo in the treatment of borderline personality disorder

BACKGROUND: Atypical antipsychotics are increasingly used in clinical practice in the management of borderline personality disorder (BPD), and a small but growing body of literature supports their efficacy. Here, we report the results of a double-blind, placebo-controlled study of olanzapine as a treatment for BPD. METHOD: Forty BPD patients (25 female, 15 male) were randomly assigned in equal numbers to olanzapine and placebo. Diagnoses were made using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and the Mini-International Neuropsychiatric Interview. Patients with schizophrenia, bipolar disorder, or current major depression were excluded. Olanzapine dosage was flexible, and the dose range was 2.5 to 20 mg/day, with most patients receiving 5 to 10 mg/day. No concomitant psychotropic medications were allowed. Patients were assessed at baseline and at 2, 4, 8, and 12 weeks. The primary outcome was change in the total score for the 9 BPD criteria on a 1-to-7 Likert scale, the Clinical Global Impressions scale modified for borderline personality disorder (CGI-BPD), using an analysis of covariance model including baseline score as covariate. Data were collected from July 2000 to April 2002. RESULTS: Olanzapine was found to be significantly (p <.05) superior to placebo on the CGI-BPD at endpoint, with separation occurring as early as 4 weeks. Similar results were found for the single-item Clinical Global Impressions scale. Weight gain was significantly (p =.027) greater in the olanzapine group. CONCLUSIONS: This study supports the efficacy of olanzapine for symptoms of BPD in a mixed sample of women and men. Further studies with olanzapine and other atypical antipsychotics are needed.     

Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study

OBJECTIVE: Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex. METHOD: This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest. RESULTS: Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness. CONCLUSIONS: In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.     

Verapamil versus lithium in acute mania.

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.     

Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease

OBJECTIVES: Psychotic symptoms and behavioral disturbances are a concern in the care of elderly patients with Alzheimer's dementia (AD). This study was conducted to compare the efficacy of olanzapine versus placebo in patients with psychotic symptoms associated with AD in long-term or continuing-care settings. METHODS: Patients (n = 652) with AD and delusions or hallucinations were randomly assigned to 10 weeks of double-blind treatment with placebo or fixed-dose olanzapine (1.0, 2.5, 5.0, 7.5 mg/day). RESULTS: Mean age was 76.6+/-10.4 years. Repeated-measures analysis showed significant improvement from baseline in NPI/NH Psychosis Total scores (sum of Delusions, Hallucinations items-primary efficacy measure) in all five treatment groups (p<0.001), but no pairwise treatment differences were seen at the 10-week endpoint. However, under LOCF analysis, improvement in the 7.5 mg olanzapine group (-6.2 +/- 4.9) was significantly greater than with placebo (-5.0 +/- 6.1, p = 0.008), while endpoint CGI-C scores showed the greatest improvement in the Olz 2.5 olanzapine group (2.8 +/- 1.4, p = 0.030) relative to placebo (3.2 +/- 1.4). There were significant overall treatment-group differences in increased weight, anorexia, and urinary incontinence, with olanzapine showing numerically higher incidences. However, neither the incidence of any other individual events, including extrapyramidal symptoms, nor of total adverse events occurred with significantly higher frequency in any olanzapine group relative to placebo. No clinically relevant significant changes were seen across groups in cognition or any other vital sign or laboratory measure, including glucose, triglyceride, and cholesterol. CONCLUSIONS: While 1.0 mg olanzapine did not show significant differences from placebo, the 2.5 mg dose was a reasonable starting dose. Olanzapine at 7.5 mg/day significantly decreased psychosis and overall behavioral disturbances (NPI/NH, BPRS) and was well tolerated.     

Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome.

BACKGROUND: The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo. METHODS: This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites. Sixty patients met prodromal diagnostic criteria, including attenuated psychotic symptoms, as determined by structured interviews. Olanzapine 5-15 mg daily or placebo was prescribed for 8 weeks. RESULTS: In the mixed-effects, repeated-measures analysis, the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant, and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8. Ratings of extrapyramidal symptoms remained low in each group and were not significantly different. Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). CONCLUSIONS: This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients. Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo. Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment.     

Quetiapine in the treatment of acute mania

Quetiapine is an atypical antipsychotic that has shown efficacy in the treatment of positive and negative symptoms in schizophrenia without causing extrapyramidal symptoms (EPS). To date, there are two monotherapy and two combination therapy studies with a double blind, placebo-controlled design on the use of quetiapine in mania. Several open studies and case reports support the results of the controlled trials suggesting that quetiapine is effective in treating the broad spectrum of manic symptoms and is tolerated well.     

Verapamil treatment of acute mania

Six acutely manic patients were openly treated with verapamil, a calcium channel blocker, as part of their medication regimen in an inpatient setting. All patients had a prompt reduction in their manic symptoms and have been maintained on this medication. Further controlled trials of verapamil in acute mania seem warranted.     

A pilot study of loading versus titration of valproate in the treatment of acute mania

Objective:  This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania.
Method:  Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n=5; mean age=33.4) or slower titration dose (10 mg/kg/day; n=6, mean age=30.6) of valproate for 7 days without other psychotropic agents, with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale.
Results:  The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines.
Conclusion:  This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.     

Pharmacologic loading in the treatment of acute mania

The rapid and safe reduction of manic symptoms is an important initial goal of the pharmacologic treatment of acute mania. The pharmacokinetics and studies of pharmacologic loading of lithium, valproate, and carbamazepine were reviewed. In addition, the feasibility of administering other agents with potential efficacy in mania, e.g., atypical antipsychotics and new anticonvulsants, was discussed. Further double-blind, controlled studies with adequate sample sizes comparing loading strategies with more gradual titration schedules of candidate antimanic agents are needed.     

The impact of response to previous mood stabilizer therapy on response to olanzapine versus placebo for acute mania

Objectives: A clinically important question for any new treatment for bipolar disorder is whether its efficacy extends to patients who have both responded and failed to respond to other mood stabilizers. In this secondary analysis of a placebo-controlled trial demonstrating olanzapine's efficacy for acute mania, we explore whether its usefulness extends to those patients with a history of poor response to other mood stabilizers.

Methods: This 4-week, double-blind, placebo-controlled trial studied olanzapine monotherapy 5–20 mg/day for hospitalized patients in acute manic or mixed bipolar episodes. The primary outcome variable was beginning to endpoint change in the Young-Mania Rating Scale (Y-MRS) total score. We investigated whether prospectively identified history of recent failure to respond to other mood stabilizers predicted response to olanzapine.

Results: As previously reported, olanzapine-treated patients experienced significantly greater improvement in Y-MRS total score and higher remission rates relative to placebo-treated patients. The current analysis compared these outcome parameters in patients with known poor prior response to lithium and/or valproate with all other patients and found no significant group by treatment interactions, i.e., treatment effects were not significantly diminished in non-responders to older mood stabilizing agents.

Conclusions: Olanzapine has been shown to be superior to placebo for the treatment of mania. This secondary analysis suggests that olanzapine monotherapy is similarly effective for patients whether or not they previously have failed to respond to another mood stabilizer for mania. A study limitation is that response to lithium or valproate was determined retrospectively.     

Pharmacologic agents for the treatment of acute bipolar mania.

The knowledge base regarding the medical treatment of acute bipolar mania is rapidly expanding. Information about agents with established antimanic properties is increasing, and more agents with putative antimanic properties are being identified. We first review the controlled studies supporting the efficacy of the established antimanic agents lithium, valproate, and carbamazepine and standard antipsychotics. We then review available research on two important classes of drugs that are emerging as potential treatments for acute mania: the novel antipsychotics, which include clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and the new antiepileptics, which include gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide. We conclude that although controlled data are accumulating to support the efficacy of several atypical antipsychotics in the treatment of acute bipolar mania, particularly olanzapine, ziprasidone, and risperidone, the novel antiepileptics need more extensive study before it can be concluded that any of them possess specific antimanic properties. We also conclude that as the medical options for acute bipolar mania expand, treatment guidelines must remain both evidence based and flexible, so that they represent cutting edge medical science yet can be tailored to the specific needs of individual patients.     

Elation versus irritability in mania.

Can a diagnosis of mania be made if the patient does not show the symptom of elation? Slater and Roth¹ described the cardinal symptoms of mania as an elated mood, hyperactivity, a rapid stream of thought, and distractability. In m In making a diagnosis, a recent paper by Feighner et al.² gives irritability equal weight with elation as the mood state in mania. An important question is whether irritability should in fact have equal status and whether the diagnosis could be made in the absence of elation. This paper will examine the diagnosis of manic-depressive illness made with irritability as the major mood state versus those patients diagnosed manic where elation was noted.     

Decision model for the acute treatment of mania

Decision making in psychiatric diagnosis and treatment has not been evaluated systematically. The authors present a model for treatment of an acute manic episode using a decision analysis software program. Six treatment options were put into the model: lithium, valproate, carbamezepine, electroconvulsive therapy, clonazepam, and neuroleptics. Each treatment was evaluated on three factors, efficacy, tolerability, and cost, using data from the literature and pharmacy and billing information. Output from the computer program identified three top choices among the six options: valproate, carbamazepine, and lithium, with valproate emerging as the first choice using the data we inputted. Depression and Anxiety 4:289–293, 1996/1997.© 1997 Wiley-Liss, Inc.     

Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD₁₇), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD₁₇ total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.     

Official guidelines for the treatment of acute mania

There are several national and international practice guidelines on the treatment of acute mania. Their purpose is to assess the available evidence of efficacy for medication used in the treatment of bipolar mania and to grade it according to the quality of studies available. The World Federation of Societies of Biological Psychiatry (WFSBP) has developed such guidelines in 2003. They categorize the scientific quality of the studies into four levels of evidence (A-D) and provide an algorithm based on the degree of severity of the acute manic episode.