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Background: The olanzapine/fluoxetine combination has demonstrated effectiveness in treatment-resistant depression (TRD). Although this combination is being used by prescribers, this is the first study to examine long-term use. Long-term efficacy and safety were therefore investigated in a group of patients with major depressive disorder (MDD) with and without TRD., Method: 560 patients who met DSM-IV diagnostic criteria for MDD were enrolled in this 76-week, open-label study (Feb. 2000-July 2002). The Montgomery-Asberg Depression Rating Scale (MADRS) total score was the primary efficacy measure. Safety was assessed via adverse events, vital signs, laboratory analytes, electrocardiography, and extrapyramidal symptom measures., Results: MADRS mean total scores decreased 7 points from baseline (31.6 [N = 552]) at 1/2 week of treatment, 11 points at 1 week of treatment, and 18 points at 8 weeks of treatment. This effect was maintained to endpoint with a mean decrease of 22 points at 76 weeks. Response and remission rates for the total sample were high (62% and 56%, respectively), and the relapse rate was low (15%). Response, remission, and relapse rates for TRD patients (N = 145) were 53%, 44%, and 25%, respectively. The most frequently reported adverse events were somnolence, weight gain, dry mouth, increased appetite, and headache. At endpoint, there were no clinically meaningful changes in vital signs, laboratory analytes, or electrocardiography. There were no significant increases on any measure of extrapyramidal symptoms., Conclusions: The olanzapine/fluoxetine combination showed rapid, robust, and sustained improvement in depressive symptoms in patients with MDD, including patients with TRD. The long-term safety profile of the combination was similar to that of its component monotherapies.

Background: This study evaluates whether high-dose olanzapine is associated with elevation of serum prolactin levels., Method: Twenty-four patients taking daily doses of olanzapine of 20, 25, 30, and 40 mg for DSM-IV schizophrenia or schizoaffective disorder had serum prolactin levels measured. The patients were all from one author's (J.L.K.'s) clinical practice. The mean duration of olanzapine therapy was 15.3 months at a dose of at least 20 mg/day. Data were gathered in 2000 and 2001., Results: There was no significant correlation between olanzapine dose and prolactin level (Pearson product moment correlation coefficient = 0.09). No significant differences were found between mean prolactin values in each dose group., Conclusion: There was no significant elevation of prolactin with higher doses of olanzapine. Thus, preliminary evidence suggests that using higher doses of olanzapine is generally safe with regard to prolactin levels.

Background: The effectiveness of olanzapine in treating challenging behaviors in the intellectually disabled and its ability to substitute for conventional antipsychotic drugs were evaluated., Method: A total of 20 institutionalized adults with a mean age of 42.7 years (range, 18-55 years) with intellectual disability and aggression, self-injurious behavior, destructive/disruptive behavior, or combinations of these behaviors were studied. These individuals were receiving multiple psychotropic medications at baseline and were given additional treatment with the atypical antipsychotic agent olanzapine. The mean dose of olanzapine was 9.1 mg/day (range, 2.5-22.5 mg/day). Effectiveness was determined by retrospective review of the summaries of quarterly neuropsychiatric behavioral reviews and retrospective review of longitudinal behavioral graphs of target symptoms. Data were collected from 1995 to 2000., Results: A significant decrease in global challenging behaviors and specific target behaviors (i.e., aggression, self-injurious behaviors, destructive/disruptive behaviors) occurred (p <.05). A numerical decrease in the dosage of concurrent conventional antipsychotic medications occurred over the course of the first 6 months of olanzapine therapy, and a statistically significant (p <.005) decrease from the start of olanzapine therapy occurred in those subjects who received olanzapine for longer than 6 months (mean = 20.3 months). A significant increase in weight occurred in the subject group during the first 6 months of olanzapine treatment (p <.006), and sedation and constipation were the other common side effects noted., Conclusions: Olanzapine was found to be effective in the treatment of challenging behaviors in the intellectually disabled and in part could be substituted for administration of conventional antipsychotic drugs.

Background: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex., Method: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo., Results: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters., Conclusion: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

Background: Patients with chronic schizophrenia (DSM-IV criteria) often receive depot antipsychotic medications to assure longer administration and better compliance with their treatment regimen. This study evaluated whether patients stabilized on depot antipsychotic medication could be successfully transitioned to oral olanzapine., Method: In a 3-month open-label study, 26 clinically stable patients with schizophrenia taking depot antipsychotics for over 3 years were randomly assigned to continue on their current depot dose or to switch to oral olanzapine. Clinical ratings (Positive and Negative Syndrome Scale [PANSS], Global Assessment of Functioning [GAF] scale, and Clinical Global Impressions [CGI] scale) and side effect parameters (Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia Scale, AMDP-5 scale, vital signs, and weight) were obtained monthly., Results: Oral olanzapine patients (N = 13) demonstrated significant clinical improvement over the depot control group (N = 13) from baseline to 3-month endpoint (PANSS total, p =.012; PANSS general, p =.068; PANSS negative, p =.098; CGI-Improvement, p =.007; CGI-Severity, p =.026; GAF, p =.015). Side effect rating scales showed no statistical differences between the 2 groups (AIMS, Barnes Akathisia Scale, AMDP-5, vital signs). The depot control group showed no statistical superiority in any measure except weight change (p =.0005). After 3 months, all olanzapine patients preferred olanzapine to their previous depot medications and chose to continue on olanzapine treatment., Conclusion: Clinicians may expect clinical improvement when switching chronically psychotic patients from traditional depot antipsychotic drugs to oral olanzapine. Switching may be completed within a 4-week period with relative compliance being maintained and patients preferring oral olanzapine to their previous depot medications.

Background: Thus far, only selective serotonin reuptake inhibitors have been systematically studied in the treatment of trichotillomania, and the results are conflicting. This open-label study is the first to systematically evaluate an atypical neuroleptic, olanzapine, as a monotherapy in the treatment of trichotillomania., Method: Twenty-one patients were screened and 18 patients were enrolled in a 3-month open-label study of olanzapine for trichotillomania (diagnosis based on modified DSM-IV criteria). Patients with comorbid psychiatric disorders or on treatment with psychoactive medication were excluded. Olanzapine was titrated gradually in 2.5-mg/week increments up to a maximum dose of 10 mg/day., Results: Seventeen patients who completed at least 1 week of olanzapine treatment were evaluated. Hair pulling, as measured by the Massachusetts General Hospital Hairpulling Scale, decreased by 66% from baseline (p < or =.001), and mean scores on the Hamilton Rating Scale for Anxiety decreased by 63% (p < or =.05). Clinical Global Impressions scale scores also revealed significant improvement as a whole (p < or =.001), with 4 patients having complete symptom remission at the end of the study period., Conclusion: Findings suggest that olanzapine may be an effective monotherapy for trichotillomania.

Background: Although atypical antipsychotic agents are commonly used in the treatment of psychotic depression, there are no published prospective studies on their use in this condition. The aim of this study was to assess, by interim analyses, the efficacy of the atypical antipsychotic agent olanzapine in combination with the selective serotonin reuptake inhibitor antidepressant agent fluoxetine., Method: We enrolled 27 patients (17 women [63.0%] and 10 men [37.0%]; mean +/- SD age: 41.2 +/- 14.7 years) with DSM-IV-defined major depressive disorder with psychotic features into an open trial of olanzapine, 5 to 20 mg/day, plus fluoxetine, 20 to 80 mg/day. Patients were assessed at each visit with the 17-item Hamilton Rating Scale for Depression and both the psychotic and mood modules of the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition. We are reporting the results of the first 6 weeks of treatment., Results: Twenty-two (81.5%) of the 27 enrolled patients completed the 6-week open trial, and 5 (18.5%) dropped out, with only 2 (7.4%) dropping out due to side effects. Of the 27 patients, 74.1% (N = 20) met criteria for melancholic features, 14.8% (N = 4) had delusions alone, 18.5% (N = 5) had hallucinations alone, and 66.7% (N = 18) reported both delusions and hallucinations. In addition, the overall rates of response for the intent-to-treat group were as follows: depression response rate, 66.7% (N = 18); psychosis response rate, 59.3% (N = 16); psychotic depression response rate, 55.6% (N = 15); and psychotic depression remission rate, 40.7% (N = 11)., Conclusion: The combination of olanzapine and fluoxetine appears to be a promising, safe, and effective treatment for psychotic depression. Double-blind studies are needed to confirm this impression.

Background: This open-label, multicenter, randomized study compared the efficacy and safety of switching moderately ill Asian patients with schizophrenia from their current regimen of antipsychotic medication to the atypical antipsychotic olanzapine using either a direct switch method or a start-taper switch method., Method: Asian inpatients and outpatients with DSM-IV schizophrenia (N = 108) currently treated with predominantly typical antipsychotics were switched to olanzapine (initial dose of 10 mg/day) for 6 weeks. Patients were randomly assigned to 1 of 2 groups: the direct switch group (N = 54) received only olanzapine, while the start-taper switch group (N = 54) received olanzapine and their usual antipsychotic in decreasing doses for the first 2 weeks. A successful switch was defined as completing 6 weeks of therapy without worsening of symptoms (Clinical Global Impressions-Severity of Illness scale [CGI-S]) or extrapyramidal side effects (Simpson-Angus Scale). Overall efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and safety was assessed by recording adverse events and measuring vital signs., Results: Statistically significant (p < .001) improvements from baseline to endpoint occurred in both switch groups in the CGI-S score and the PANSS total score and subscores. However, no significant differences were observed between the switch groups for any efficacy measure. Both techniques had comparable rates of successful switching (direct switch, 74.1% vs. start-taper switch, 67.9%). The frequency of treatment-emergent adverse events was similar between switch groups with no clinically significant differences in any laboratory value or vital sign. Weight gain occurred in both switch groups (p < .001), but the groups were not statistically different from each other. Both switch groups showed statistically significant (p < .01) improvements from baseline to endpoint on the Simpson-Angus Scale and Barnes Akathisia Scale., Conclusion: Moderately ill Asian patients with schizophrenia may experience a decrease in symptom severity and improvement in extrapyramidal symptoms when switched from their current medication to olanzapine therapy.

Background: We report a clinical trial of olanzapine in the treatment of prominent apathy in the absence of depression in patients on long-term treatment with selective serotonin reuptake inhibitors (SSRIs) for nonpsychotic major depression., Method: Participants were 21 men and women who met DSM-IV criteria for major depressive disorder in full remission (Montgomery-Asberg Depression Rating Scale [MADRS] score < or = 12) who had been taking an SSRI for at least 3 months. Data are presented (last observation carried forward) based on 20 enrolled participants who completed at least 1 follow-up visit. Participants had significant symptoms of apathy, defined as a Clinical Global Impressions-Severity of Illness scale (CGI-S) score > or = 3, an Apathy Evaluation Scale (AES) score > 30, and a MADRS item 8 (inability to feel) score > or = 2. Participants with a personal or family history of psychosis were excluded. Olanzapine was titrated in 2.5-mg increments at weekly intervals, until CGI-S score improved > or = 2 points from baseline or > or = 1 point with dose-limiting side effects, and participants continued in the protocol for 8 weeks at a stable dose following this improvement., Results: Improvement was clinically evident and demonstrable on all symptom assessments: AES (mean +/- SD change in score = -21.3 +/- 8.7; p < .0001), CGI-S (-2.7 +/- 0.9; p < .0001), MADRS (-5.6 +/- 5.9; p = .001), and MADRS item 8 (-2.2 +/- 1.4; p < .0001). The mean dose of olanzapine was 5.4 +/- 2.8 mg/day., Conclusion: These preliminary data suggest that olanzapine may be effective in treating apathy syndrome in nonpsychotic patients taking SSRIs.

Background: Typical antipsychotics are commonly used in combination with mood stabilizers for acute mania. Although typical antipsychotics are effective, they have undesirable side effects such as induction of depressive symptoms and tardive dyskinesia. Atypical antipsychotics have more favorable side effect profiles, and recent evidence shows their efficacy in treating mania. Apart from a previous small study that compared risperidone with typical neuroleptics as add-on therapy to mood stabilizers, no studies to date have directly compared atypical antipsychotics with typical antipsychotics as add-on therapy to mood stabilizers in a clinically relevant, naturalistic setting., Method: This study is a chart review of all patients with DSM-IV-defined bipolar disorder, current episode mania (N = 204), admitted to the University of British Columbia Hospital during a 30-month period. Patients were separated into 3 groups according to the medications used: (1) mood stabilizer and typical antipsychotic, (2) mood stabilizer and atypical antipsychotic, and (3) combination: mood stabilizer plus a typical antipsychotic, then switched to mood stabilizer plus risperidone or olanzapine within I week. The atypical group was further subdivided into risperidone and olanzapine subgroups. Outcome was measured using Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) ratings generated by review of clinical information in the chart., Results: Patients treated with typical antipsychotics were more severely ill at admission and at discharge than those treated with atypical antipsychotics. Patients in the atypical (p < .005) and combination (p < .05) groups showed significantly greater clinical improvement at discharge than patients treated with typical antipsychotics. This difference was also significant in the subset of patients with psychotic features (p < .03). Risperidone and olanzapine were associated with fewer extrapyramidal side effects than were typical antipsychotics (risperidone vs. typical antipsychotics, chi2 = 8.72, p < .01; olanzapine vs. typical antipsychotics, chi2 = 16.9, p < .001)., Conclusion: Due to their superior effectiveness and side effect profile when compared with typical antipsychotics. atypical antipsychotics are an excellent choice as add-on therapy to mood stabilizers for the treatment of patients with mania.

Background: We performed a retrospective analysis of data involving 121 inpatients to examine the rate of weight gain during antipsychotic-free periods and during treatment with various antipsychotic drugs., Method: Data were analyzed to determine differences in weekly weight change during antipsychotic-free (N = 65), typical antipsychotic (N = 51), or atypical antipsychotic (N = 130) treatment periods. Atypical antipsychotic treatment periods were further subdivided into olanzapine (N = 45), clozapine (N = 47), or risperidone (N = 36) treatment periods. A paired comparison was conducted on 65 patients who had an antipsychotic-free treatment period preceding or following a neuroleptic drug treatment period. In addition, patients were classified as either non-obese (with a body mass index [BMI] < or = 29.9 kg/ml) or obese (BMI > or = 30.0 kg/m2) to test whether the rate of weight gain during treatment periods was related to initial BMI., Results: Across all treatment periods, weekly weight gain was as follows: 0.89 lb/wk (0.40 kg/wk) on atypical antipsychotic medication, 0.61 lb/wk (0.27 kg/wk) on typical antipsychotic medication, and 0.21 lb/wk (0.09 kg/wk) on no antipsychotic medications. The atypical antipsychotic versus antipsychotic-free comparison was significant (F = 3.51; df = 2,231; p = .031), while the typical antipsychotic versus antipsychotic-free comparison was not. Among the individual atypical antipsychotic medications, significantly more weight gain occurred during olanzapine treatment (1.70 lb/wk) (0.76 kg/wk) than with either clozapine (0.50 lb/wk) (0.22 kg/wk) or risperidone (0.34 lb/wk) (0.15 kg/wk) treatments (F = 7.77; df = 2,117; p = .001). In the paired analysis with patients serving as their own controls, the difference between weekly weight gain during atypical antipsychotic treatment and antipsychotic-free treatment was significant (t = -3.91; df = 44; p = .001), while the difference between weight gain during typical antipsychotic treatment and antipsychotic-free treatment was not significant. With the individual drugs. treatment with both olanzapine and clozapine caused significantly higher weekly weight gain than antipsychotic-free treatment (p = .001 and p = .036, respectively). while treatment with risperidone did not. Non-obese patients (BMI < 29.9 kg/m2) and obese patients (BMI > 30.0 kg/m2) did not differ significantly in their weight gain during typical or atypical antipsychotic treatment., Conclusion: Treatment with atypical antipsychotics was associated with more weight gain than treatment with typical antipsychotics. Among the atypical drugs, olanzapine was associated with more weight gain than either clozapine or risperidone. The patient's admission BMI was not associated with the amount of weight gained during subsequent antipsychotic treatment.

Background: An open-label trial was performed to explore efficacy and safety of olanzapine, an atypical neuroleptic with diverse receptor activity including both dopamine-2 and serotonin-2A and -2C antagonism, for treatment of Tourette's disorder., Method: Ten adult patients aged 20 to 44 years with Tourette's disorder were treated using an open-label, flexible dosing schedule for 8 weeks. Three patients who continued olanzapine were reevaluated after 6 months. Three subjects were psychotropic medication naive, 5 patients experienced intolerable side effects with conventional neuroleptics, and 2 patients had remote (> or = 10 years) successful response to conventional neuroleptics. Tic severity was rated by the Yale Global Tic Severity Scale; weight, vital signs, and adverse effects were assessed weekly. Electrocardiogram, laboratory studies, and comorbid symptoms, assessed by the Yale-Brown Obsessive Compulsive Scale and ADHD Behavior Checklist for Adults, were measured at baseline and at week 8., Results: Two of 10 patients prematurely discontinued olanzapine owing to excessive sedation. Of 8 patients who completed the 8-week trial, 4 (50%) demonstrated reduction of global tic severity scores by > or = 20 points, and 6 (75%) demonstrated reductions by > or = 10 points. No significant changes in comorbid symptoms were demonstrated. Sedation, weight gain, increased appetite, dry mouth, and transient asymptomatic hypoglycemia were the most common side effects. Tic improvements were maintained in 3 patients reassessed 6 months later. Final olanzapine dosages ranged from 2.5 mg to 20 mg daily (mean = 10.9 mg/day)., Conclusion: This open-label study suggests that olanzapine should be explored as a potential alternative to conventional neuroleptic medications for treatment of motor tics and Tourette's disorder.

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.

Rapid tranquilization of acutely psychotic patients with schizophrenia is usually carried out using typical antipsychotic agents. The objective of such treatment is to control agitation, not to treat psychosis, which usually responds only after a few weeks of treatment. An intramuscular formulation of the atypical antipsychotic olanzapine was developed for treatment of agitation in acutely psychotic patients. Studies conducted to assess control of agitation in schizophrenia also investigated the positive symptom efficacy of olanzapine when used to provide rapid tranquilization. This article summarizes the results of 3 clinical trials with intramuscular olanzapine with regard to positive symptom efficacy as measured by the Brief Psychiatric Rating Scale (BPRS; 0-6 scale) positive subscale. In 2 open-label trials, patients treated with intramuscular olanzapine experienced a mean decrease from baseline in BPRS positive subscale score. In 1 double-blind clinical trial of intramuscular olanzapine versus intramuscular haloperidol and intramuscular placebo, the mean decrease from baseline in BPRS positive subscale score for patients treated with intramuscular olanzapine was statistically significant (p < .05). In all 3 studies, positive symptom improvement continued following transition to oral olanzapine. These results suggest that intramuscular olanzapine has positive symptom efficacy early in the course of treatment and may provide a smooth transition to maintenance therapy with oral olanzapine.

Schizophrenic patients who have been prescribed atypical antipsychotics have a potential risk of gaining weight. The implications of weight gain for clinical care may differ depending on whether a patient is underweight or overweight at baseline. The exact mechanism for weight gain is not known, but several factors have been identified that can help predict which patients are at risk for gaining weight. These factors include better clinical outcome, increased appetite, and low baseline body mass index. In patients treated with olanzapine for up to 3 years, weight gain trended toward a plateau at approximately 36 weeks. Weight gain interventions, including behavioral modifications, show promise in controlling or reducing weight in patients treated with antipsychotics.

Acute, high-dose loading strategies (rapid neuroleptization) with the first-generation antipsychotics administered orally or parenterally, alone or combined with benzodiazepines, have been a commonly used treatment paradigm for controlling acutely agitated psychotic patients. The rationale was to achieve high plasma levels of drug within a shorter time period, resulting in rapid symptom mitigation. However, studies have shown that rapid neuroleptization with first-generation antipsychotics is associated with a greater incidence of side effects. To our knowledge, loading strategies with second-generation antipsychotics have not been investigated, primarily owing to a need for dose titration. Olanzapine, a second-generation antipsychotic, is well tolerated in doses ranging from 5 to 20 mg. The objective of this report was to determine experience with the use of up to 20 mg of an oral loading dose of olanzapine administered within 4 hours in the treatment of patients early in an acute psychotic phase of their illness. In the reported case series of 57 patients, olanzapine initiated at 15 to 20 mg/day was a safe and effective medication for rapidly calming the agitation of acutely agitated psychotic patients (rapid tranquilization). Furthermore, dose reduction over 2 to 3 weeks was achieved in a number of patients without appreciable loss of efficacy.

Background: Clozapine is an atypical antipsychotic indicated for the management of severely ill patients with schizophrenia who have failed to respond adequately to standard drug treatment. The significant risk of agranulocytosis and seizure associated with clozapine has led to the restrictions in its use. Additionally, drug-induced sedation, sialorrhea, enuresis, and weight gain are often cited as problematic consequences of clozapine treatment. Our primary objective was to determine the effectiveness and safety of a method of slow cross-titration from clozapine to olanzapine among patients responsive to clozapine treatment but experiencing medication-induced adverse events., Method: Changes in symptomatology, mood, subjective response, and safety were examined in 20 outpatients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder who converted from clozapine to olanzapine. Patients were considered clozapine-responsive as evidenced by improved social function and decreased symptoms with clozapine therapy; however, they were interested in alternative pharmacologic treatment because of clozapine-related side effects., Results: Equivalent efficacy of olanzapine to clozapine was found in 90% of the patients (18/20) in the study group, without rehospitalization or suicidal behavior in any of the patients. Also notable was a reduction in drug-induced side effects and improved subjective response to pharmacotherapy., Conclusion: The successful conversion from clozapine to olanzapine has the potential to provide great benefits for the patient, including reducing drug-induced side effects while maintaining symptom control. These preliminary results suggest that further research on converting clozapine responders to olanzapine is warranted.

Background: This study compared the efficacy and safety of 4 therapeutically relevant strategies for switching clinically stable patients from a conventional antipsychotic drug or risperidone to olanzapine., Method: Two hundred nine outpatients with a DSM-IV diagnosis of schizophrenia or schizo-affective disorder who were clinically stable while being treated with a conventional antipsychotic drug or risperidone were openly randomly assigned to either abrupt or gradual discontinuation of their prior antipsychotic drug. Patients were further randomly assigned in a double-blind fashion to immediate olanzapine initiation (olanzapine, 10 mg q.d. for 3 weeks) or stepwise initiation (a sequence of 1 week each on placebo; olanzapine, 5 mg q.d.; and olanzapine, 10 mg q.d.). The efficacy of these 4 switching paradigms was assessed using the Clinical Global Impressions (CGI)-Improvement scale, Patient's Global Impressions (PGI)-Improvement scale, and Positive and Negative Syndrome Scale (PANSS). Safety assessments included ratings for extrapyramidal symptoms, cognitive impairment, adverse events, laboratory parameters, weight change, and vital signs., Results: The paradigm of gradual antipsychotic drug discontinuation combined with an initial full dose of olanzapine, 10 mg/day, had the most favorable efficacy and tolerability profile overall. By week 3, the majority of completing patients on all 4 switching paradigms were either improved or clinically unchanged (> 90%). No clinically significant differences between switching paradigms were seen in laboratory values or vital signs., Conclusion: In this study, switching clinically stable outpatients with a diagnosis of schizophrenia or schizoaffective disorder to olanzapine was most successful when a full therapeutic dose of olanzapine was immediately initiated while gradually discontinuing prior conventional antipsychotic drug or risperidone treatment. Overall, switching was achieved without increased vulnerability to relapse or to occurrence of clinically burdensome antipsychotic drug withdrawal symptoms in the majority of patients.

Background: Adding the atypical neuroleptic risperidone to a serotonin reuptake inhibitor (SRI) has benefited patients with treatment-refractory obsessive-compulsive disorder (OCD). Since olanzapine and risperidone have similar serotonergic and dopaminergic receptor binding profiles, we tested the hypothesis that olanzapine augmentation would be beneficial in treatment-unresponsive OCD., Method: For this 8-week trial, we recruited 10 adult OCD patients (DSM-IV criteria) unresponsive to fluoxetine (> or =60 mg/day) for > or =10 weeks, which was continued throughout the trial. Other psychotropic medications were discontinued. Subjects had OCD for > or =1 year, a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of > or =18, and no organic, psychotic, or other primary Axis I disorder. Two weeks after olanzapine, 2.5 mg/day, was added, and in the absence of responder status (Y-BOCS score decrease > or =25%) and limiting side effects, we increased the dose to 5 mg/day, and after 2 more weeks, to 10 mg/day for 4 weeks., Results: The subjects had failed a mean of 3.3 SRI trials (range, 1-5) and had a mean +/- SD baseline Y-BOCS score of 29.0 +/- 4.9. Nine patients completed the trial. The subjects' mean +/- SD endpoint Y-BOCS score was 24.4 +/- 8.0 (a 16% decrease). The 3 responders' Y-BOCS scores dropped 68%, 30%, and 29%, but only 1 patient was rated "much improved." He maintained this improvement during a 6-month follow-up period taking olanzapine, 5 mg/day. Improvement in OCD was independent of improvement in mood symptoms. Six patients (60%) experienced significant weight gain., Conclusion: Olanzapine augmentation may benefit treatment-unresponsive OCD. Double-blind, placebo-controlled trials are warranted along with trials comparing risperidone and olanzapine augmentation.

Atypical neuroleptic agents are an excellent, safer, and more effective alternative to the widespread practice of maintenance adjunctive treatment with traditional neuroleptic agents in patients with bipolar disorder. Currently, a number of prospective studies are available with clozapine, risperidone, olanzapine, and quetiapine in the treatment of bipolar disorder. Most are short-term studies, although longer-term data are becoming available. Four double-blind studies of acute mania have been conducted with risperidone and olanzapine, leading to recent Food and Drug Administration approval for olanzapine in the indication of acute mania. Given the limited longer-term data, and the evidence for mostly adjunctive benefits with these agents, it seems unlikely that these agents will prove to be primary mood stabilizers in their own right. Nonetheless, they serve an important role as adjunctive treatments along with standard mood stabilizers in the rational polypharmacy of bipolar disorder. To date, differences in efficacy have not been established. However, differences in the side effect of weight gain may be even more relevant in bipolar disorder than in schizophrenia due to the need to use standard mood stabilizers that often potentiate such weight gain.

For patients hospitalized with acute episodes of psychosis, rapid stabilization of intense positive symptoms, hostility, and agitation is typically a preeminent therapeutic goal. These goals often differ from those of the nonhospitalized patient with psychosis for whom long-term treatment goals such as improvement of negative symptoms, cognitive function, compliance, and reduction in side effect burden may be paramount. Therefore, when selecting an antipsychotic treatment for hospitalized patients, efficacy against positive symptoms and hostility as well as speed of therapeutic onset should strongly be considered. At the same time, selection of antipsychotic treatment in the inpatient setting should establish a definitive treatment that will address long-term goals effectively after discharge. This article presents the rationale and practical guidelines for selection of treatment regimens for patients hospitalized due to acute psychosis.

Background: Previous studies have suggested that clozapine is associated with increases in both weight and serum triglyceride (but not cholesterol) levels. Because of the pharmacologic similarities between clozapine and olanzapine, we decided to evaluate if olanzapine use was associated with an increase in triglycerides., Method: Twenty-five inpatients (21 men, 4 women) were treated with olanzapine, and their outcomes were tracked prospectively in a medication utilization evaluation study., Results: After 12 weeks on a mean +/- SD dose of 13.8+/-4.4 mg/day, weight increased a mean of 12 lb (5.4 kg; from 190+/-37 lb [85.5+/-16.7 kg] to 202+/-30 lb [90.9+/-13.5 kg]), while fasting triglycerides increased a mean of 60 mg/dL (from 162+/-121 mg/dL to 222+/-135 mg/dL). Both increases were significant at p < .05. Fasting total cholesterol did not increase. The triglyceride increase was even larger when we excluded 8 patients who received various interventions to lower lipid levels (e.g., pravastatin, low-fat diet) during the olanzapine trial. There was a strong association between weight change and triglyceride change (p < .02); after controlling for weight, analysis of covariance showed no independent increase in triglycerides., Conclusion: These results suggest olanzapine has significant effects on weight and serum triglyceride levels. Clinical implications are discussed.

Background: Risperidone and olanzapine have each been demonstrated to be efficacious and safe in the treatment of patients with chronic schizophrenia. To evaluate their relative effectiveness, and to better understand the advantages and limitations of each neuroleptic during actual clinical use, we compared one directly against the other., Method: Forty-two subjects with DSM-IV schizophrenia had received open-label treatment with either risperidone or olanzapine. Symptoms, global functioning, and extrapyramidal side effects before and after acute treatment were compared within and across groups. At 6-month follow-up, the relative effectiveness of these 2 atypical neuroleptics on symptoms and quality of life were further evaluated., Results: Following an average of 4 weeks of acute treatment, both risperidone and olanzapine were effective in reducing negative, psychotic, and disorganized symptoms. Although both neuroleptics were associated with low occurrence of treatment-emergent parkinsonism, risperidone was more likely to induce akathisia. The measures for parkinsonism were no different across treatment groups, even after taking into account the higher rate of anticholinergic use in the risperidone group. Following 6 months of treatment with these 2 atypical neuroleptics, there was a significantly greater reduction in psychotic symptoms among risperidone-treated subjects. Otherwise, risperidone and olanzapine appear to be equally effective in reducing disorganized and negative symptoms and in improving the quality of life., Conclusion: Risperidone and olanzapine were equally effective as acute treatments. Risperidone was more effective for treatment of psychotic symptoms at 6 months, but otherwise the 2 medications were equally effective in the routine clinical care of patients with schizophrenia. If low (<6 mg/day) doses of risperidone are used, the 2 medications have comparable rates of parkinsonian side effects.

Background: In our experience, many of our schizophrenic patients treated with clozapine request the newer atypical antipsychotic agents in order to eliminate the weekly blood monitoring. However, there are few guidelines available to clinicians interested in switching patients successfully treated with clozapine to olanzapine., Method: The goal of this study was to collect preliminary data on the safety, clinical effectiveness, and predictors of response of switching clozapine patients to olanzapine. In an open trial, 19 patients receiving clozapine were switched to olanzapine., Results: Eight (42%) of 19 patients were considered responders. Seven patients decompensated seriously enough to require hospitalization. All 7 of these patients were restabilized on clozapine treatment in the hospital, and olanzapine was discontinued. In an additional 4 patients, clinical status worsened, and clozapine doses were titrated upwards and olanzapine was slowly discontinued. Overall, mean total Brief Psychiatric Rating Scale (BPRS) scores increased significantly from baseline to final assessment (p = .02). Responders had been treated for a significantly shorter period of time with clozapine prior to the switch compared to nonresponders (p = .04) and were receiving a lower dose of clozapine (p = .05). The final olanzapine dose did not differ between responders and nonresponders. All responders have remained on olanzapine treatment and are stable., Conclusion: In this open trial, the crossover from clozapine to olanzapine was generally well tolerated and resulted in a successful transition for 8 of the 19 patients. However, mean scores on the total BPRS and negative symptom and depressive symptom subscales significantly increased. Caution must be taken in determining which patients may benefit from the switch to olanzapine because of the risk of decompensation and hospitalization. Because this was an open trial, these findings require replication in a controlled trial.

The author reviews the evolution of emergency psychiatric practice over the past 20 years--from the concept of high-dose antipsychotic medication to the more rational treatment approach for acute psychosis made possible by modern pharmacodynamic insight and the availability of new pharmacotherapeutic agents. A decision tree for current practice in the rapid tranquilization of agitated, apparently psychotic patients is described.

Background: Clozapine is currently the treatment of choice for neuroleptic-resistant schizophrenia. Olanzapine is a new antipsychotic drug that has shown efficacy against positive and negative symptoms of schizophrenia, with minimal extrapyramidal side effects. However, the effectiveness of olanzapine has not yet been reported among treatment-refractory schizophrenic patients., Method: A total of 25 schizophrenic patients (DSM-IV criteria) with documented lack of response to two conventional antipsychotic drugs entered this 6-week prospective, open-label treatment trial with olanzapine 15 to 25 mg/day. An optional extension up to 6 months was provided., Results: As a group, the olanzapine-treated patients showed statistically significant improvement (p < .05) in both positive and negative symptoms by the end of 6 weeks of therapy. Overall, 9 of the patients (36%) met the a priori criteria for treatment-response (> or = 35% decrease in Brief Psychiatric Rating Scale [BPRS] total score, plus posttreatment Clinical Global Impression-Severity < or = 3 or BPRS total < 18). Only one patient discontinued treatment because of an adverse event during the study. Despite the relatively high dosages of olanzapine used, there were no reports of parkinsonism, akathisia, or dystonia, and no patients required anticholinergic medication., Conclusion: This open study suggests that olanzapine may be effective and well tolerated for a substantial number of neuroleptic-resistant schizophrenic patients. Further blinded, controlled trials are needed to confirm our results.

Compared with conventional antipsychotics, the so-called "atypical" antipsychotics promise improved side effect profiles and better control of the symptoms of schizophrenia. Therefore, most patients currently taking conventional antipsychotics could potentially benefit from a switch to an atypical antipsychotic. Often, the key issue in deciding whether to switch is the presence of countervailing factors that mitigate against the change. This paper discusses the indications and contraindications for switching antipsychotics, plus issues that require consideration before a switch is made. Also, the advantages and disadvantages of various switching techniques are discussed, with a particular focus on the newer antipsychotic olanzapine.

Olanzapine is a new antipsychotic agent with serotonin/dopamine antagonism action. Efficacy in treating overall psychopathology in acute schizophrenia as measured by the BPRS0-6 total score was demonstrated at 10 mg/day versus placebo; at doses in a 5-20 mg/day range, olanzapine was comparable or superior to haloperidol. Superior efficacy for negative and depressive symptoms was shown in comparison to haloperidol. Olanzapine has a favorable acute and tardive extrapyramidal symptom profile relative to haloperidol and caused substantially less elevation of serum prolactin. Dose-related weight gain and asymptomatic mild transaminase elevations occurred in olanzapine-treated patients.