Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study.

BACKGROUND: Olanzapine has demonstrated efficacy in the treatment of acute mania in 2 double-blind, placebo-controlled trials. We describe the results of the open-label extension from one of these trials. METHOD: In a 3-week, double-blind study of patients with DSM-IV bipolar I disorder, olanzapine was superior to placebo for the treatment of acute manic symptoms. Of the 139 patients who entered the double-blind phase of the 3-week study, 113 patients continued into the 49-week open-label extension. Efficacy measurements including the Young Mania Rating Scale (YMRS), the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Clinical Global Impressions scale-Bipolar Version, and the Positive and Negative Syndrome Scale and safety measurements including the Simpson-Angus scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale were completed throughout. The analysis considered all treatment results, starting with the first olanzapine dose. Adjunctive lithium and fluoxetine were allowed during the open-label extension. RESULTS: The mean length of olanzapine treatment was 6.6 months, with a mean modal dose of 13.9 mg/day. A significant mean improvement in the YMRS total score, baseline to endpoint (-18.01, p < .001), was observed. During treatment, 88.3% of patients experienced a remission of manic symptoms (YMRS total score < or =12), and only 25.5% subsequently relapsed (YMRS total score > or = 15). Significant improvement in HAM-D-21 scores was observed (p < .001). Forty-one percent of patients were maintained on olanzapine monotherapy. The most common treatment-emergent adverse events reported were somnolence (46.0%), depression (38.9%), and weight gain (36.3%). CONCLUSION: During up to 1 year of olanzapine therapy, either as monotherapy or in combination with lithium and/or fluoxetine, patients with bipolar disorder demonstrated significant improvement in mania and depression symptoms with a favorable safety profile. Further double-blind, controlled studies are needed to confirm these results.

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.

Response to placebo among bipolar I disorder patients experiencing their first manic episode.

BACKGROUND: The first episode of an illness may respond differently to any treatment compared to multiple episodes of the same illness. This study details the treatment response of six first-episode manic patients who participated in a previously reported study of 139 subjects comparing olanzapine to placebo in bipolar I mania (Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KNR, Daniel DG. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry 1999; 156: 702-709). METHODS: Six first-episode subjects participated in a 3-week double-blind, random assignment, parallel group, placebo-controlled study of olanzapine for bipolar mania. The Young Mania Rating Scale (Y-MRS), Clinical Global Impression, and Hamilton Depression ratings were administered weekly. Lorazepam as rescue medication was permitted for the first 10 days. RESULTS: Five subjects were randomized to placebo and one to olanzapine. Two subjects (40%) with psychotic mania (who also had their first-illness episode) were assigned to placebo and responded with greater than 50% reduction in the Y-MRS score and also remitted in 3 weeks. Another placebo-assigned subject had a 46% reduction in the Y-MRS scores, and two placebo-assigned subjects worsened. The olanzapine-assigned subject had a 44% reduction in the Y-MRS score. In contrast, 34 of 69 (48.6%) multiple-episode olanzapine subjects responded and 14 of 61 (23.0%) of placebo-treated subjects did. CONCLUSIONS: This preliminary data set suggest there may be differences in treatment response between first-illness episode versus multi-episode bipolar manic subjects. Larger numbers of subjects with these illness characteristics are needed to either confirm or refute this suggestion.

Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group.

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

Olanzapine versus haloperidol in the treatment of schizoaffective disorder. Acute and long-term therapy.

BACKGROUND: The effectiveness of antipsychotic monotherapy in schizoaffective disorder is limited, and further constrained by safety concerns. AIMS: We aimed to compare the efficacy, tolerability and safety profile of the new pharmaceutical, olanzapine, with haloperidol. METHOD: Data were assessed from 300 DSM-III-R schizoaffective subjects from a larger double-blind prospective international study. Subjects were randomly allocated to six weeks of olanzapine (5-20 mg) or haloperidol (5-20 mg) treatment; responders were followed for up to one year of double-blind, long-term maintenance therapy. RESULTS: Olanzapine-treated patients achieved a statistically significant greater improvement than haloperidol treated patients on overall measures of efficacy, including clinical response. Significantly fewer olanzapine patients left the study early, and fewer adverse events were observed among those receiving olanzapine. During maintenance, olanzapine-treated patients continued to experience additional improvement, with fewer EPS but more weight gain than those on haloperidol. CONCLUSIONS: Olanzapine demonstrated substantial advantages over the conventional antipsychotic haloperidol in the management of schizoaffective disorder.

Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy?

Schizophrenia patients frequently manifest concurrent anxiety and depressive symptoms. Such features exhibit prognostic relevance (i.e. patient morbidity and mortality). Despite this, they remain relatively unstudied and are not universally viewed as therapeutic targets. Conventional neuroleptic agents may not improve these symptoms and may actually worsen them. However, with the introduction of novel pharmacological agents for the treatment of schizophrenia, there is reason to believe that a wider spectrum of symptomatology may be treatment responsive. In this post hoc analysis of the Brief Psychiatric Rating Scale anxiety-depression cluster, olanzapine therapy was associated with a significantly greater baseline-to-end-point improvement in the cluster compared with haloperidol therapy among 1996 randomized, double-blind subjects. Moreover, the olanzapine treatment-effect advantage included both direct (mood symptoms) and indirect (positive, negative, and extrapyramidal symptoms) elements. This study concluded that the novel pharmacology of olanzapine delivered greater therapeutic activity in anxious and depressive symptoms accompanying schizophrenia than did the conventional dopamine D2 antagonist haloperidol.

Olanzapine versus haloperidol treatment in first-episode psychosis.

OBJECTIVE: It has been hypothesized that the morbidity and mortality associated with schizophrenia can be prevented by providing effective treatment during the first episode of psychosis. Hence, the authors examined patients with first-episode psychosis to determine the efficacy and safety of olanzapine and haloperidol treatment. METHOD: A subpopulation of first-episode patients (N=83) from a large prospective, multicenter, international, double-blind, 6-week acute treatment study was evaluated. These patients were selected from a pool of 1,996 patients who had a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder and who also met the following criteria: 1) the length of their current psychotic episode had to be 5 or fewer years, and 2) patients had to be 45 years of age or younger at onset of first psychotic symptoms. RESULTS: Compared to haloperidol, olanzapine showed a statistically significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) total and negative scores and in the Positive and Negative Syndrome Scale total and positive scores. Clinical response (defined as 40% or greater improvement in BPRS total score from baseline) was also statistically significantly higher in olanzapine-treated patients (67.2%) than in haloperidol-treated patients (29.2%). Olanzapine-treated patients further showed statistically significant improvements in the Simpson-Angus scale and Barnes Akathisia Scale scores, while haloperidol-treated patients showed a worsening on both measures. Compared to olanzapine-treated multiple-episode patients in the parent study, olanzapine-treated first-episode patients achieved an even statistically significantly higher response. Haloperidol-treated first-episode patients experienced statistically significantly more extrapyramidal symptoms than haloperidol-treated multiple-episode patients. CONCLUSIONS: In patients experiencing first-episode psychosis, olanzapine had a risk-benefit profile significantly superior to that of haloperidol. The study results suggest that novel antipsychotic agents such as olanzapine should be considered as a preferred option in first-episode psychosis, on the basis of both safety and efficacy advantages.

A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia.

BACKGROUND: Depressive symptoms are a common feature of schizophrenia and may represent a core part of the illness. Where present, it has been associated with greater overall morbidity and mortality. Monotherapy with conventional dopamine antagonists may either worsen or bestow a limited therapeutic benefit. Accordingly the use of adjunctive thymoleptics has been explored. In contrast, olanzapine (OLZ), an atypical antipsychotic agent, offers a distinctive and pleotropic pharmacology suggestive of a broader efficacy profile than conventional neuroleptic agents. METHODS: In a 6-week placebo- and haloperidol (HAL)-controlled trial with 335 randomized subjects with chronic schizophrenia in an acute exacerbation, three fixed dose ranges of OLZ (5, 10, or 15 +/- 2.5 mg) were evaluated versus HAL (10-20 mg) or placebo. RESULTS: Baseline to endpoint change in the Brief Psychiatric Rating Scale including the anxiety-depression cluster (items 1, 2, 5, 9) was analyzed. Two dose ranges of OLZ (10 +/- 2.5, 15 +/- 2.5) were superior to placebo (p < 05) in improving mood status, whereas HAL was not. CONCLUSION: Contributions from a more selective mesolimbic dopaminergic profile, D1 or D4 activity, the release of dopamine/norepinephrine in the prefrontal cortex, and/or serotonin 5-HT2A,C antagonism may explain the differential benefit seen with OLZ in the treatment of comorbid anxious and depressive symptoms in schizophrenia.

Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol.

BACKGROUND: Depressive signs and symptoms during the course of schizophrenia are common and have been associated with impaired recovery and a higher risk of self-harm. Novel antipsychotic agents introduce new pharmacological avenues that may differentially affect schizophrenic signs and symptoms, including depression. METHODS: This was a 17-country investigation of 1996 patients with schizophrenia or a related diagnosis randomly assigned to a blinded, comparative trial of the novel antipsychotic agent olanzapine (5-20 mg/d) or the conventional D2 antagonist haloperidol (5-20 mg/d). Patients were evaluated with the Positive and Negative Syndrome Scale, the Montgomery-Asberg Depression Rating Scale, and the Simpson-Angus Rating Scale. The trial consisted of a 6-week and a 46-week masked responder maintenance period. RESULTS: At least moderate depressive signs and symptoms (Montgomery-Asberg Depression Rating Scale score, > or =16) were seen in slightly more than half of this sample. Although both treatments were associated with short-term baseline-to-end point improvement on the Montgomery-Asberg Depression Rating Scale, olanzapine-associated improvements were significantly superior to those observed with haloperidol (P=.001). Furthermore, the response rate for the group receiving olanzapine (> or =50% improvement on the Montgomery-Asberg Depression Rating Scale after at least 3 weeks of treatment) was also significantly higher (P=.008). Analysis demonstrated that improvement in positive, negative, and/or extrapyramidal symptoms was associated with mood improvement (indirect effect); however, most of the olanzapine treatment effect on mood was a primary direct effect (57%) that alone was significantly greater than that seen with haloperidol treatment (P<.001). CONCLUSIONS: Depressive signs and symptoms in schizophrenia are responsive to treatment. The pleotrophic pharmacological features of olanzapine, through 1 or more non-D2-mediated pathways, likely contribute to its superior treatment effect. Better control of the mood disorders accompanying schizophrenia holds the possibility for improved patient outcomes.

Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine.

OBJECTIVE: The authors investigated whether primary negative symptoms of schizophrenia are enduring or treatment-responsive. METHODS: Previously, a double-blind, random-assignment trial of the novel antipsychotic olanzapine (in low, medium, and high dose ranges), placebo, or haloperidol (10-20 mg/day) for 335 schizophrenic inpatients was conducted for up to 52 weeks. Changes in the treatment groups from baseline to endpoint in summary scores on the Scale for the Assessment of Negative Symptoms (SANS) and several secondary measures were compared. This article describes a path analysis to determine to what extent the total treatment effect on negative symptoms was direct or indirect (i.e., mediated by differential effects on positive symptoms, extrapyramidal symptoms, or mood). RESULTS: Significantly greater improvement was achieved with high-dose olanzapine than with placebo or haloperidol. Olanzapine had a significantly greater direct effect than placebo on all SANS dimensions except anhedonia-asociality. Olanzapine also demonstrated a significantly greater direct effect than haloperidol on negative symptoms, especially on the dimensions of affective flattening and avolition-apathy. Olanzapine's superior effects were replicated in a subgroup with SANS-defined prominent negative symptoms (N = 116) and a subgroup with a BPRS-defined cross-sectional proxy for the deficit state (N = 117). CONCLUSIONS: These results suggest that the negative symptoms of schizophrenia are directly responsive to treatment. The significantly greater direct and indirect effects of olanzapine than of haloperidol on negative symptoms are likely related to olanzapine's pleotrophic pharmacology, which includes dopaminergic, serotonergic, muscarinic, and adrenergic activities. The results contribute to the hypothesis that negative symptoms may be under the influence of several neurotransmitters within one or more neuroanatomic circuits.