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This pilot study was undertaken to estimate the acute antipsychotic effect size and side effect propensity of risperidone and olanzapine in the pediatric population, in comparison to haloperidol, a conventional antipsychotic with established efficacy. Risperidone and olanzapine are widely used as first-line treatments to ameliorate psychotic symptoms in youth, but their abilities to specifically treat children and adolescents presenting due to psychotic symptoms have not been rigorously studied. Subjects, selected because of prominent positive psychotic symptoms, were randomly assigned to double-blind, parallel treatment with risperidone, olanzapine, or haloperidol for 8 weeks. The primary outcome was reduction in the Brief Psychiatric Rating Scale for Children total score from baseline to termination. An exploratory, descriptive analysis was done to compare the three treatments. A total of 50 patients, 8-19 years, participated. All treatments reduced symptoms significantly with p-values (corrected for multiple comparisons) of 0.0018 for each of the atypical agents and 0.012 for haloperidol. In all, 88% of subjects treated with olanzapine, 74% treated with risperidone, and 53% treated with haloperidol met response criteria. The primary side effects observed in all patients were mild to moderate sedation, extrapyramidal symptoms, and weight gain. Risperidone and olanzapine acutely reduced psychotic symptoms in this pediatric sample. Exploratory comparisons indicate the magnitude of the antipsychotic response with these atypical agents is comparable to that observed with haloperidol. However, youth treated with risperidone and olanzapine experienced weight gain and extrapyramidal effects that appear more prevalent and severe than reported in adults.

Background: This randomized controlled trial compares the efficacy and safety of olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania., Methods: The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of olanzapine (5-20 mg/d, n = 234) with haloperidol (3-15 mg/d, n = 219)., Results: Rates of remission (Young-Mania Rating Scale score of < or =12 and 21-item Hamilton Rating Scale for Depression score of < or =8 at week 6) were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P =.15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P =.04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated patients, respectively (P =.56). Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques (P =.04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group., Conclusions: These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain.

Context: Although olanzapine has been widely adopted as a treatment of choice for schizophrenia, its long-term effectiveness and costs have not been evaluated in a controlled trial in comparison with a standard antipsychotic drug., Objective: To evaluate the effectiveness and cost impact of olanzapine compared with haloperidol in the treatment of schizophrenia., Design and Setting: Double-blind, randomized controlled trial with randomization conducted between June 1998 and June 2000 at 17 US Department of Veterans Affairs medical centers., Participants: Three hundred nine patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder, serious symptoms, and serious dysfunction for the previous 2 years. Fifty-nine percent fully completed and 36% partially completed follow-up assessments., Interventions: Patients were randomly assigned to receive flexibly dosed olanzapine, 5 to 20 mg/d, with prophylactic benztropine, 1 to 4 mg/d (n = 159); or haloperidol, 5 to 20 mg/d (n = 150), for 12 months., Main Outcome Measures: Standardized measures of symptoms, quality of life, neurocognitive status, and adverse effects of medication. Veterans Affairs administrative data and interviews concerning non-VA service use were used to estimate costs from the perspective of the VA health care system and society as a whole (ie, consumption of all resources on behalf of these patients)., Results: There were no significant differences between groups in study retention; positive, negative, or total symptoms of schizophrenia; quality of life; or extrapyramidal symptoms. Olanzapine was associated with reduced akathisia in the intention-to-treat analysis (P<.001) and with lower symptoms of tardive dyskinesia in a secondary analysis including only observations during blinded treatment with study drug. Small but significant advantages were also observed on measures of memory and motor function. Olanzapine was also associated with more frequent reports of weight gain and significantly greater VA costs, ranging from 3000 dollars to 9000 dollars annually. Differences in societal costs were somewhat smaller and were not significant., Conclusion: Olanzapine does not demonstrate advantages compared with haloperidol (in combination with prophylactic benztropine) in compliance, symptoms, extrapyramidal symptoms, or overall quality of life, and its benefits in reducing akathisia and improving cognition must be balanced with the problems of weight gain and higher cost.

Objectives: To compare the six-week clinical response and safety profile of schizophrenia patients, age > or =60 years, receiving olanzapine (OLZ) vs haloperidol (HAL) in a double blind, randomized trial., Methods: Double-blind data on patients age > or =60 randomized to 5 mg/d OLZ (n=83) or 5 mg/d HAL (n=34) (Week 1) then flexibly dosed to 5-20 mg/d over six weeks, with a 48-week extension for responders, were analyzed post-hoc. Efficacy indices included the PANSS Total and PANSS Psychosis Core Total (PPCT). Safety measures included the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS), treatment-emergent adverse events, and laboratory values. Mixed model, repeated measures (MMRM) analyses were applied to all continuous data measured at each visit. Continuous data recorded only at phase completion or termination were analyzed with a fixed effect last observation carried forward (LOCF) model. Frequencies of categorical response data were analyzed using Fisher's exact methods. Differences were tested for significance at Week 6 using a two-sided alpha value of 0.05., Results: HAL group (n=34; age range 60-80) received a mean modal dose 9.4 mg/d while OLZ group (n=83; age range 60-86) received a mean modal dose 11.9 mg/d. At Week 6, OLZ was superior to HAL on both the PANSS Total (p=0.015) and PPCT (p=0.043). Considering safety, OLZ was superior to HAL for the SAS and BAS (p<0.001; p<0.001). No spontaneous adverse event occurred more frequently with OLZ than with HAL. In patients never receiving adjunct anticholinergic therapy, no significant differences were present for anticholinergic-like side effects including blurred vision, dry mouth, constipation, or urinary difficulties., Conclusions: In elderly schizophrenia patients, olanzapine was more efficacious and better tolerated for extrapyramidal signs than was haloperidol. Olanzapine was equivalent to haloperidol for anticholinergic-like side effects when corrected for anticholingergic agents., (Copyright 2003 John Wiley & Sons, Ltd.)

The QTc prolongation by antipsychotic drugs is of major concern, especially in light of the data indicating an increased risk of sudden death in psychiatric patients taking these drugs. Sudden death in psychiatric patients could be partially attributed to drug-induced torsades de pointes and for this reason careful evaluation of QTc prolonging properties of antipsychotic drugs is needed. Antipsychotic drugs prolong QT interval usually by blocking the potassium IKr current. Improved understanding of ion channel structure and kinetics and its role in repolarization has tremendous impact on understanding of the mechanisms of drug-induced QT prolongation and torsades de pointes. Proarrhythmia caused by a QT-prolonging drug occurs infrequently, and usually multiple factors need to operate to precipitate such an event including a combination of two or more drugs affecting the same pathway, hypokalemia, and possibly genetic predisposition. Currently prescribed antipsychotics might cause QT prolongation ranging from 4-6 ms for haloperidol and olanzapine to 35 ms for thioridazine. The response of a patient to a drug is very individual and therefore an individualized system of drug administration and monitoring needs to be developed which takes into account baseline QTc duration and its changes after a drug was introduced. A systematic approach while stratifying psychiatric patients as those with short QTc (QTc < or = 0.41 sec), borderline QTc (QTC = 0.42-0.44 sec), and prolonged QTc (0.45 sec) is being proposed to improve the safety of administering antipsychotic drugs and to decrease the risk of drug-related sudden death in psychiatric patients.

Objective: Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial., Method: Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase., Results: Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%)., Conclusions: As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia.

Objectives: The aim of this cross-sectional study, the EIRE study, was to assess the frequency of several side effects with antipsychotics in the clinical setting. This paper addresses the adverse effect of weight gain., Method: Outpatients diagnosed of schizophrenia according to DSM-IV criteria and receiving a single antipsychotic (risperidone, olanzapine, quetiapine or haloperidol) for at least 4 weeks were consecutively recruited. Data were collected in a single visit, including data on demographic, clinical and treatment characteristics. Mean weight change was evaluated retrospectively by means of clinical charts and the weight at the time of the visit; in addition, the corresponding item of a modified version of the UKU, a Scandinavian side-effect rating scale, was used. Chi-squared test and logistic regression methods were used to analyze frequency of weight gain between treatments., Results: Out of 669 recruited, 636 evaluable patients were assessed. The treatment with the highest number of patients with weight gain as an adverse reaction on the UKU scale was olanzapine (74.5%), followed by risperidone (53.4%) and haloperidol (40.0%). The proportion of patients with clinically relevant weight gain (>or=7% increase versus initial weight) was also higher with olanzapine (45.7%) than with risperidone (30.6%) and haloperidol (22.4%). Five patients (13.5%) treated with quetiapine had some degree of weight gain according to the UKU scale, although no patient showed a clinically relevant weight gain (>or=7%). Treatment with olanzapine and risperidone were identified as risk factors of weight gain versus haloperidol. The risk of weight gain was higher in women (OR: 4.4), overweight patients (OR: 3.0) and in patients with

Objective: To quantitatively examine the effects of haloperidol and olanzapine on spontaneous motor activity in normal subjects., Design: Randomized, double-blind, placebo-controlled medication study., Participants: Normal volunteers (n = 30)., Interventions: Subjects received 1 dose of either haloperidol 2 mg (n = 9), olanzapine 10 mg (n = 10) or placebo (n = 10) and were admitted to hospital for the next 24 hours., Outcome Measures: Subjects wore an actigraphic monitor, which recorded movement in 15-second epochs. The Simpson-Angus Extrapyramidal Side Effect Scale (SAS) and the Barnes Akathisia Scale (BAS) were administered before and 7 and 24 hours after medication was given., Results: Compared with placebo, total motor activity was decreased by 41% with olanzapine (p = 0.004) and by 12% with haloperidol (NS). There were significantly more epochs with zero movement with olanzapine than with haloperidol or placebo. For non-zero epochs, the mean activity count and the distribution of activity counts did not differ significantly among groups. There were no positive findings on the SAS or the BAS., Conclusions: Olanzapine decreased total motor activity by increasing the amount of time during which subjects were immobile, rather than by affecting the magnitude of movement during periods in which there was activity. This effect occurred at a dose of olanzapine low enough not to cause clinically observed extrapyramidal side effects. Our results suggest that actigraphy is useful as a sensitive, noninvasive tool for measuring the effect of antipsychotics on spontaneous motor activity.

The frequency of neuroleptic malignant syndrome (NMS) after clozapine or olanzapine is low and often of non-serious nature. A 49 year-old female patient developed NMS 12 days after olanzapine re-exposure. Olanzapine was stopped, the patient was transferred to an ICU and received a course of nine uni- and bilateral ECT treatments. This led to remission. 14 months earlier the patient had presented with a first severe NMS episode after haloperidol depot injection and 4 days after starting oral clozapine. Following the first NMS episode olanzapine (20 mg per day) was administered for 11 months without adverse effects.

Background: Acutely agitated patients with schizophrenia who receive intramuscular (IM) medications typically are switched to oral (PO) antipsychotic maintenance therapy., Objective: The goal of this study was to assess the efficacy and safety of olanzapine versus those of haloperidol during transition from IM to PO therapy. We used additional data from a previously reported trial to test the hypothesis that the reduction in agitation achieved by IM olanzapine 10 mg or IM haloperidol 7.5 mg would be maintained following transition to 4 days of PO olanzapine or PO haloperidol (5-20 mg/d for both). We also hypothesized that olanzapine would maintain its more favorable extrapyramidal symptom (EPS) safety profile., Methods: This was a multinational (hospitals in 13 countries), double-blind, randomized, controlled trial. Acutely agitated inpatients with schizophrenia were treated with 1 to 3 IM injections to olanzapine 10 mg or haloperidol 7.5 mg over 24 hours and were entered into a 4-day PO treatment period with the same medication (5-20 mg/d for both). The primary efficacy measurement was reduction in agitation, as measured by the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score. Adverse events and scores on EPS rating scales were assessed., Results: A total of 311 patients (204 men, 107 women; mean [SD] age, 38.2 [11.6] years) were enrolled (131, 126, and 54 patients in the olanzapine, haloperidol, and placebo groups, respectively). In all, 93.1% (122/131) of olanzapine-treated patients and 92.1% (116/126) of haloperidol-treated patients completed the IM period and entered the PO period; 85.5% (112/131) of olanzapine-treated patients and 84.1% (106/126) of haloperidol-treated patients completed the PO period. IM olanzapine and IM haloperidol effectively reduced agitation over 24 hours (mean [SD] PANSS-EC change, -7.1 [4.81 vs -6.7 [4.3], respectively). Reductions in agitation were sustained throughout the PO period with both study drugs (mean [SD] change from PO period baseline, -0.6 [4.8] vs -1.3 [4.4], respectively). During PO treatment, haloperidol-treated patients spontaneously reported significantly more acute dystonia than olanzapine-treated patients (4.3%[5/116] vs 0% [0/122], respectively; P = 0.026) and akathisia (5.2% [6/116] vs 0% [0/122], respectively; P = 0.013). Significantly more haloperidol-treated patients than olanzapine-treated patients met categorical criteria for treatment-emergent akathisia (18.5% [17/92] vs 6.5% [7/107], respectively; P = 0.015)., Conclusions: In the acutely agitated patients with schizophrenia in this study, both IM olanzapine 10 mg and IM haloperidol 7.5 mg effectively reduced agitation over 24 hours. This alleviation of agitation was sustained following transition from IM therapy to 4 days of PO treatment (5-20 mg/d for both). During the 4 days of PO treatment, olanzapine-treated patients did not spontaneously report any incidences of acute dystonia, and olanzapine had a superior EPS safety profile to that of haloperidol. The combination of IM and PO olanzapine may help improve the treatment of acutely agitated patients with schizophrenia.

The underlying pathophysiological basis of tardive dyskinesia (TD) remains speculative. Haloperidol (HP) inhibits neuronal nitric oxide (NO) synthase (NOS) activity in vitro, but has not to date been studied in an intact animal model. Recent animal studies have found that extrapyramidal dysfunction evoked by chronic HP is associated with suppression of striatal cyclic guanosine monophosphate (cGMP), as well as plasma nitrogen oxides. Striatal dopamine (DA) is central to motor control, while NO plays an important neuroregulatory role in striatal DA function. Recent case reports suggest that atypical antipsychotics, such as olanzapine (OLZ), may be effective in reversing TD. Here, rats treated with HP (1.5 mg/kg per day p.o.) for 28 days developed significant vacuous chewing movements (VCMs) together with significant suppression of striatal NOS activity. Acute challenge with OLZ (1 and 2 mg/kg i.p.) significantly reversed both HP-induced VCMs and suppression of striatal NOS activity. Therefore TD may involve attenuation of NO-mediated neuromodulation in the striatum. Reversal of VCMs and NOS suppression with OLZ suggests that disinhibition of striatal NOS activity may underlie the clinical benefit of OLZ in TD.

Objectives: To evaluate and compare the drug response and side effects of adolescents with schizophrenia treated with olanzapine, risperidone, and haloperidol., Methods: Forty-three patients were treated with olanzapine (n = 19), risperidone (n = 17) and haloperidol (n = 7) for 8 weeks in an open clinical trial. Clinical improvement was evaluated with the Positive and Negative Syndrome Scale (PANSS), and side effects with the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale., Results: Significant clinical improvement was observed by week 4 for all medications. Olanzapine and haloperidol induced fatigability more frequently than risperidone. Haloperidol was associated with a higher frequency of depression and more severe extrapyramidal symptoms., Conclusions: To the best of our knowledge this is the first study in adolescents to compare the efficacy and side effects of three most commonly prescribed antipsychotic medications. Olanzapine, risperidone and haloperidol appear to be equally effective for the treatment of schizophrenia in adolescent inpatients but have different side effect profiles.

Atypical antipsychotics seem to differ mainly in their tolerability profile. The aim of this cross-sectional study, the Estudio de Investigaci n de Resultados en Esquizofrenia (Outcomes Research Study in Schizophrenia; EIRE study), was to assess in a clinical setting the frequency of several side-effects related to haloperidol, risperidone, olanzapine, and quetiapine. This article addresses sexual dysfunction and other reproductive side-effects (gynecomastia, menorrhage, amenorrhea, and galactorrhea). We recruited outpatients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) criteria and who had received a single antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) for at least 4 weeks. During a single visit, we collected data, including demographic and clinical characteristics, current antipsychotic and concomitant treatment, and adverse effects listed in a modified version of the UKU Scale. We used a Chi-squared test to determine pairs comparisons of the frequency of adverse reactions between treatments. To estimate risk of a given adverse reaction with a given treatment, we used a logistic regression method. We assessed 636 evaluable patients out of 669 recruited. Frequency of sexual dysfunction was high with haloperidol (38.1%) and also with olanzapine (35.3%), quetiapine (18.2%), and risperidone (43.2%). We found the frequency of other reproductive side-effects to be relatively low with all four drugs: haloperidol (6.9%), olanzapine (6.4%), quetiapine (2.7%), and risperidone (11.7%). Sexual dysfunction appeared to be dose-related with haloperidol, risperidone, and olanzapine. Risperidone and olanzapine showed a higher risk of sexual dysfunction and other reproductive sideeffects than haloperidol. Quetiapine showed a lower risk of sexual dysfunction during short-term treatment (< 12 weeks). However, data on longer-term treatment (> 12 weeks) are lacking. Our results suggest that none of the atypical antipsychotics that we studied significantly improved sexual dysfunction and other reproductive side-effects of the conventional antipsychotic, haloperidol, in stabilized patients during long-term treatment. Quetiapine appears to improve this profile during short-term treatment; however, longterm data, with larger samples, are required with this latter drug.

The superiority of olanzapine to haloperidol with respect to a decreased incidence of treatment-emergent extrapyramidal syndromes (EPS) in patients with schizophrenia was demonstrated in studies conducted in both Japan and Western countries. EPS measurements used in Western countries included the Simpson-Angus, Barnes akathisia and the Abnormal Involuntary Movement Scale, while the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) was used in Japan. The aim of this study was to clarify how the DIEPSS captures EPS profiles. The baseline prevalence and treatment-emergent incidence of EPS in Japanese schizophrenic patients treated with olanzapine or haloperidol were retrospectively compared as assessed by the DIEPSS to the prevalence and incidence of EPS in primarily Caucasian schizophrenic patients who were treated with olanzapine or haloperidol. Specifically, the prevalence and incidence of dyskinesia, akathisia and parkinsonism were compared between the Japanese trial and an international trial to examine if appropriate definitions using the DIEPSS can be derived assuming that a comparable prevalence and incidence of the syndromes would be observed when any differences in residual antipsychotic exposure at the initiation of study treatment were accounted for. For the incidence of all EPS syndromes, odds ratios were observed to be similar between the two studies, indicating that appropriate criteria for the clinical diagnosis of the EPS syndromes could be established based on the DIEPSS. This preliminary and retrospective work suggests that the DIEPSS can be used to operationally define the presence or absence, and make the clinical diagnosis, of specific EPS syndromes.

Previous clinical trials have clearly shown the superiority of olanzapine to haloperidol in the improvement of extrapyramidal symptoms (EPS) in schizophrenic patients. The primary purpose of this study was to compare EPS profiles in Japanese schizophrenic patients treated with an atypical antipsychotic, olanzapine, or a typical antipsychotic, haloperidol, as measured by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The DIEPSS, which consists of eight individual parameters and one global assessment (overall severity), was used to evaluate 182 patients enrolled in this 8-week study. The primary safety analysis was maximum change (that could be either a decrease or increase) from baseline in DIEPSS total score. Secondary analyses included change from baseline to maximum in DIEPSS total score, change from baseline to endpoint (LOCF) in DIEPSS total score, and the rank sum of the maximum change (that could be either a decrease or increase) from baseline in the DIEPSS individual items. Incidence of treatment-emergent EPS adverse events using the DIEPSS scale was also analyzed. The olanzapine group showed statistically significant superiority to the haloperidol group on the primary analysis (p<0.001). Secondary analyses also demonstrated olanzapine's superiority in DIEPSS total, parkinsonism, akathisia and overall severity scores (all p< or =0.014). Categorical analysis of treatment-emergent akathisia and parkinsonism syndromes at endpoint showed improvement in the olanzapine group but worsening in the haloperidol group. The results from this study suggest that olanzapine, as in Caucasian populations, is a safe treatment in Japanese patients chronically ill with schizophrenia.

Objective: Most of the data supporting the use of atypical antipsychotics (AA) is based on studies in young adult patients. The present study is an open-label naturalistic follow-up study of olanzapine treatment vs. haloperidol for elderly chronic schizophrenia patients. MEHTOD: 20 patients (mean age 72.7+/-5.9 years, mean disease duration 33.1+/-12.0 years) who met the DSM-IV criteria for schizophrenia were randomly assigned to olanzapine (n=10) or haloperidol (n=10) treatment during acute exacerbation. Primary outcome measure was rating on the Clinical Global Impression (CGI) scale and the Positive and Negative Symptom Scale (PANSS)., Results: Between-group differences were computed using analysis of covariance. PANSS Total score decreased from 84 at baseline to 65 after treatment with olanzapine while decreased only from 79 to 74 with haloperidol treatment (F= 6.66, P=.02). PANSS Negative subscale decreased from 19 at baseline to 15 with olanzapine treatment while increased (deteriorated) from 18 to 20 with haloperidol treatment (F=23.37, P=.0003). CGI decreased from baseline with both olanzapine and haloperidol treatments (1.1 vs. 0.4) but the decrease in the olanzapine group was significantly greater (F=4.63, P=.05). Mean weight increased in both groups but without statistical difference between groups., Conclusions: In elderly chronic schizophrenia patients, olanzapine treatment is superior to haloperidol in reducing negative symptoms as well as less induction of extrapyramidal symptoms (EPS).

Tardive dyskinesia is a severe complication of neuroleptic treatment. It may develop weeks, even years after starting a neuroleptic treatment and the symptoms may be irreversible. Neuroleptic compounds are not only used in cases of schizophrenia, but also in cases of severe depression with delusional symptoms. We want to present the case of a 67 year old female patient who developed haloperidol induced dyskinesea and stress unto the successful treatment of this complication with olanzapine in combination with paroxetine. Under this regime not only the improvement of the depression, but also of the tardive dyskinesea was impressive.

Atypical neuroleptics share a common feature, showing higher affinity for 5-HT2 receptors than for D2 dopamine receptors, but show considerable differences in their clinical and pharmacological properties. In clinical doses, they occupy serotonergic receptors near saturation, but show considerable differences regarding the D2 receptor occupancies, with clozapine showing the lowest degree of occupation. We assessed serotonergic and dopaminergic receptor responsiveness in two groups of male schizophrenic patients, one treated with the atypical neuroleptic clozapine (14 patients, doses 200-600 mg/d) and the other treated with olanzapine (11 patients, doses 10-30 mg/d). We measured the prolactin responses to the acute administration of a serotonergic drug, clomipramine, and a dopaminergic one, haloperidol. Tests were first performed in the drug-free state, and were repeated after the patients had been treated with stable doses of either drug for six weeks. Clomipramine administration induced significant increases of prolactin in the drug-free state. These responses were eliminated after treatment of the patients with either drug, thereby indicating a high 5-HT receptor occupancy by both clozapine and olanzapine. The prolactin responses to haloperidol were not altered after treatment with clozapine, but were significantly reduced after the olanzapine treatment. The baseline prolactin levels were not influenced by clozapine treatment, and were moderately but significantly increased after treatment with olanzapine. The results indicate that there is a difference between the two drugs in their capacity to block dopamine receptors at the hypothalamus-pituitary level, and match the results obtained by SPECT receptor binding studies for striatal dopamine receptors.

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.

There is current disagreement over whether men and women respond differently to typical or atypical antipsychotic medications. This study reanalyzed a large international clinical trial of olanzapine (Olz) compared with haloperidol (Hal) to test for sex differences in treatment response, controlling for illness chronicity and menopausal status. We hypothesized that women would show a greater response to either medication than men, particularly among first admission, premenopausal women. DSM-III-R schizophrenia inpatients (700 women and 1295 men) were randomly assigned to a 6-week trial of Olz vs. Hal. Longitudinal random effect models were used to test for interactions of sex with medication, chronicity and menopausal status on treatment response. Findings showed that women on olanzapine had a greater drop in overall symptomatology by week 4 than any other group, and their level of symptomatology remained lower throughout the 6-week trial. The sex differences in treatment response in olanzapine compared with haloperidol were, in part, dependent on chronicity and, in women, menopausal status. That is, first episode women on haloperidol exhibited an increase in symptomatology over the 6-week trial compared to their male counterparts, while multiply hospitalized women had a better treatment response on haloperidol than their male counterparts. Women on olanzapine had a significantly better treatment response than men, regardless of chronicity. Finally, premenopausal women had a significantly better treatment response than postmenopausal women, regardless of treatment and chronicity.

Selective dopamine D(2) antogonists increase meal size and decrease the rate of feeding within a meal. Three experiments investigated the extent to which the atypical antipsychotics, clozapine and olanzapine, and the prototypical antipsychotic, haloperidol, affected meal size and feeding rate. Microstructural analyses of meal patterning were made over a range of drug doses administered to free feeding male Lister hooded rats. Haloperidol and clozapine produced a short-term increase in food intake. Haloperidol (0.05-0.2 mg/kg) enhanced meal size (maximal at 0.1 mg/kg) and reduced feeding rate (monotonic decrease with increasing dose). Neither clozapine (1-10 mg/kg) nor olanzapine (0.3-3 mg/kg) enhanced meal size, although both drugs produced similar reductions in feeding rate to haloperidol. These data suggest that enhancement of meal size may be correlated with a high level of extrapyramidal side effects in an antipsychotic drug. The absence of an increase in meal size by two atypical compounds suggests that the increase in body weight associated with clinical treatment with these drugs cannot be modelled by acute stimulation of meal size in the rat.

Objective: To compare the risk of extrapyramidal syndrome (EPS) between risperidone, olanzapine, and haloperidol, taking into account patients' past antipsychotic drug use and past EPS., Methods: Data were obtained from the PHARMO-database, containing filled prescriptions of 450,000 community-dwelling people in the Netherlands from 1986 through 1999. We defined cohorts of first-time users of haloperidol, risperidone, or olanzapine aged 15 to 54 years. In the first 90 days of treatment, we assessed the occurrence of EPS, defined as first use of any antiparkinsonian agent. We estimated relative risks of EPS for risperidone and olanzapine versus haloperidol using a Cox proportional hazards model. Patients were subdivided according to prior use of antipsychotic and antiparkinsonian drugs., Results: We identified 424 patients starting treatment with haloperidol, 243 with risperidone, and 181 with olanzapine. Prior use of antipsychotic plus antiparkinsonian medication was significantly more frequent among users of risperidone and olanzapine than in those using haloperidol (36.2%, 40.3%, and 4.5%, respectively; p < 0.001). Within most subgroups of comparable treatment history, patients using risperidone and olanzapine showed reduced risks of EPS compared with haloperidol, although some of these findings did not reach statistical significance (RR 0.03-0.22). However, this was not observed for patients using risperidone who had experienced EPS in the past (RR 1.30; 95% CI 0.24 to 7.18)., Conclusions: In general, we observed reduced risks of EPS for risperidone and olanzapine compared with haloperidol within subgroups of patients with a similar treatment history. However, the added value of risperidone in patients who have experienced EPS in the past needs further study.

Objectives: Conventional neuroleptics ameliorate symptoms in children with autistic disorder; however, they are known to cause dyskinesias. Atypical neuroleptics, including olanzapine, may have less risk for dyskinesia, but their efficacy in autistic disorder is not established. This study was designed to investigate the safety and effectiveness of open-label olanzapine as a treatment for children with autistic disorder by using haloperidol as a standard comparator treatment., Method: In a parallel groups design, 12 children with DSM-IV autistic disorder (mean age 7.8+/-2.1 years) were randomized to 6 weeks of open treatment with olanzapine or haloperidol. Mean final dosages were 7.9+/-2.5 mg/day for olanzapine and 1.4+/-0.7 mg/day for haloperidol. Outcome measures included the Clinical Global Impressions (CGI) and the Children's Psychiatric Rating Scale (CPRS)., Results: Both groups had symptom reduction. Five of six in the olanzapine group and three of six in the haloperidol group were rated as responders according to the CGI Improvement item. Subjects showed improvement on the CPRS Autism Factor (F1,9 = 24.4, p = .0008). Side effects included drowsiness and weight gain., Conclusions: The findings suggest that olanzapine is a promising treatment for children with autistic disorder. Further placebo-controlled and long-term studies of olanzapine in autistic disorder are required.

It has been proposed that new atypical antipsychotics cause minimal prolactin (PRL) elevation compared to traditional antipsychotic agents because they spare dopamine blockade within the brain's tuberoinfundibular tract. The aim of this study was to compare the effects of olanzapine and haloperidol on PRL secretion in male schizophrenic patients. Twenty-nine male schizophrenic inpatients were included in the study. Fifteen of them were given olanzapine in a fixed dose of 10 mg/day PO and 14 of them were given haloperidol in a fixed dose of 10 mg/day PO for 6 weeks after a 2-week drug washout period. Fifteen age-matched healthy control subjects were used as control group. PRL levels were measured both before and after the 6-week treatment period in the patients. At the end of the 6th week, the PRL values observed with olanzapine treatment were significantly less than those observed with haloperidol, but not different from those of the controls. There was a significant positive correlation between the PRL values and the severity of extrapyramidal side effects in only the haloperidol group after the six week's treatment period. Our data indicate that short-term olanzapine treatment at doses of 10 mg/day PO causes minimal elevations in PRL secretion in male schizophrenic patients in contrast to haloperidol. This finding is consistent with the previous reports and may be attributed to olanzapine's differential effects on dopamine neurotransmission.

Conventional antipsychotic agents can induce extrapyramidal symptoms (EPS) that may be alleviated by switching patients to novel agents such as olanzapine. Patients with schizophrenia and related disorders (ICD-10) who were taking haloperidol (N = 94; mean dose = 12.7 mg/day) and had EPS (Simpson-Angus Scale [SAS] > 3) were directly switched to 6 weeks of open-label olanzapine treatment (mean dose = 11.4 mg/day). There were significant mean improvements (p <0.001 for all measurements) from baseline to endpoint on the SAS (-9.69+/-5.33; percentage change, 87.2%), the Barnes Akathisia Scale (-1.00+/-1.19; percentage change, 82.5%), and the Abnormal Involuntary Movement Scale (-1.48+/-2.89; percentage change, 81.1%), and anticholinergic use decreased from 47.9% to 12.8% (mean baseline to endpoint change: -1.52+/-1.91-mg equivalents of benztropine; p < 0.001). Significant mean baseline to endpoint improvements (p < 0.001 for all measurements) were observed on the Positive and Negative Syndrome Scale (PANSS; -25.28+/-18.67; percentage change, 30.3%), the PANSS-extracted Brief Psychiatric Rating Scale (0-6 scale, -13.41+/-10.16; percentage change, 54.4%), and the Clinical Global Impressions Severity scale (-1.16+/-1.19; percentage change, 26.4%). Spontaneously reported treatment- emergent adverse events with a greater than 5% incidence were somnolence (16.0%), increased appetite (14.9%), weight gain (11.7%), headache (8.5%), anxiety (7.4%), dizziness (6.4%), and insomnia (5.3%). Criteria for a successful switch were met by 90.5% of patients. Psychotic symptom exacerbation was experienced by 30.9% of patients at any time during the study and by 11.7% of patients at endpoint. Results suggest that a direct switch to olanzapine is a therapeutic option when patients with haloperidol-induced EPS are unable to tolerate a more gradual switch.

This randomized double-blind trial was conducted to test the efficacy and safety of olanzapine in Japanese patients with schizophrenia. Importantly, this study also represents the first large clinical trial of olanzapine conducted in an Asian population. Patients (n = 182) were randomly assigned to treatment with olanzapine or haloperidol over a period of 8 weeks. The primary analyses included: (i) a test of non-inferiority of olanzapine compared with haloperidol in efficacy using the Final Global Improvement Rating (FGIR); and (ii) comparison between the treatment groups in extrapyramidal symptom severity using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Olanzapine was comparable to haloperidol in efficacy in treating positive symptoms and significantly superior in treating negative symptoms. Extrapyramidal symptom severity was significantly improved for olanzapine-treated patients versus haloperidol-treated patients. Olanzapine was shown to be more effective and better tolerated than haloperidol in the treatment of Japanese patients suffering from chronic schizophrenia.

Little controlled data exist on the treatment of substance induced psychotic disorders. In this study, 30 patients meeting DSM-IV criteria for cannabis induced psychotic disorder were randomly allocated to receive either olanzapine or haloperidol in a 4-week double-blind clinical trial. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (haloperidol 25.7; olanzapine 27.1; P = 0.70); Clinical Global Impression (CGI) severity scale (haloperidol 1.8, olanzapine 2.3; P = 0.21) or the CGI improvement scale (haloperidol 1.3, olanzapine 1.7; P = 0.16). The haloperidol group however, developed significantly more extrapyramidal side-effects as measured by the Simpson Angus Scale (haloperidol 11.4, olanzapine 2.5; P = 0.014). Significantly (P = 0.027) more biperidin was used for extrapyramidal side-effects in the haloperidol (7.143 mg) than in the olanzapine (0.357 mg) group. Olanzapine appears to be as effective as haloperidol in the treatment of cannabis induced psychotic disorder, but is associated with a lower rate of extrapyramidal side-effects.

Background: Tardive dyskinesia is important in the side-effect profile of antipsychotic medication., Aims: The development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years., Methods: Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD), it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated., Results: The relative risk of tardive dyskinesia for the overall follow up period for haloperidol (n = 522) v. olanzapine (n = 1192) was 2.66 (95% CI = 1.50-4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n = 513) and 7.45% with haloperidol (n = 114). The relative risk throughout this follow-up period was 11.37 (95% CI = 2.21-58.60)., Conclusion: Our results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.

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.

As part of systematic treatment trials of haloperidol, clozapine, and olanzapine with a total of 35 children and adolescents with early onset psychosis, prolactin was measured at baseline and week 6 of treatment. The National Institute of Mental Health patients--13 females, 22 males (mean age, 14.1+/-2.3 years; range, 9.1-19 years) with childhood onset schizophrenia (n = 32), or Psychotic Disorder not otherwise specified (NOS) (n = 3) with onset of psychosis before age 13--were recruited for open or double-blind trials of haloperidol, clozapine, or olanzapine. Baseline serum prolactin was measured after a 3-week washout period and after 6 weeks of treatment. Mean prolactin concentration after 6 weeks of treatment was significantly elevated on all three drugs; however, on clozapine, mean prolactin remained within the normal range. Prolactin was increased above the upper limit of normal for 100% of 10 patients on haloperidol, 70% of 10 patients on olanzapine, and 0% of 15 patients on clozapine (chi2 analyses: H > C, p = 0.004; O > C, p = 0.001). Given the potential endocrine and possible cardiac correlates of hyperprolactinemia, these more robust prolactin elevations in pediatric patients after short-term exposure to olanzapine than those reported for adults justify longer observation intervals with bigger samples to establish treatment safety of atypical antipsychotics in adolescents.

The neuroleptic malignant syndrome (NMS) consists in an idiosyncratic reaction to neuroleptic drugs, probably related to a blockage of dopamine receptors in basal ganglia. Research criteria for diagnosing NMS from DSM-IV require severe rigidity and fever accompanied by 2 of 10 minor features including diaphoresis, dysphagia, tremor, incontinence, altered mentation, mutism, tachycardia, elevated or labile blood pressure, leukocytosis and elevation of creatine phosphokinase. From a clinical point of view, the NMS may range a large spectrum of presentations. Haloperidol is the most frequent drug associated with this syndrome. We report the case of a 30 year-old man who developed NMS at two different occasions, the first related to haloperidol and chlorpromazine and the second related to olanzapine, to our knowledge without previous mention in the indexed literature.

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.

Atypical neuroleptics present a unique opportunity to examine confounding by neuroleptic-induced extrapyramidal symptoms (EPS) in the assessment of negative signs of schizophrenia. EPS, such as facial bradykinesia and akinesia, involve some of the same response systems and phenomena as emotional display channels. EPS are attributed to the blockade of dopamine receptors in the striatum by traditional neuroleptics. Newer atypical neuroleptics target primarily mesolimbic and mesocortical areas, and receptors for other transmitters such as serotonin. Olanzapine has been reported as less likely to cause EPS and may improve some negative signs. We investigated the relationship between measures of EPS and negative symptoms in patients with schizophrenia treated with haloperidol or olanzapine. Patients were rated with the Positive and Negative Syndrome Scale (PANSS) and the Simpson-Angus Scale EPS scale. Results show that the two agents have comparable efficacy but different safety outcomes. A positive correlation between EPS and PANSS negative score was detected in the haloperidol group only. Stepwise multiple regression analysis shows that a big proportion of variability in PANSS negative symptoms is predicted by EPS in the haloperidol group, but not in the olanzapine group, even though EPS increased in patients treated with haloperidol but not in olanzapine patients.

Objective: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors' goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol., Method: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N = 707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N = 197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia., Results: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients., Conclusions: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment.

Prolactin elevation is both a common and a persistent event with the currently marketed antipsychotics, excluding clozapine. Elevations have been associated with both acute (galactorrhea, amenorrhea) and chronic (predisposition to osteoporosis) treatment-emergent adverse events. One of the defining criteria for an atypical antipsychotic is the relative lack of persistent prolactinemia. A double-blind, placebo- (N = 68) and haloperidol- (Hal: 15 +/- 5 mg/day, N = 69) controlled trial of three dose ranges of olanzapine (Olz-L: 5 +/- 2.5 mg/day, N = 65; Olz-M: 10 +/- 2.5 mg/day, N = 64; Olz-H: 15 +/- 2.5 mg/day, N = 69) in the treatment of schizophrenia afforded the opportunity to assess the temporal course of the influence of olanzapine and haloperidol on serum prolactin concentration. Consistent with its potent D2 antagonism, haloperidol was associated with a statistically significantly higher incidence of treatment-emergent prolactin elevation (72%) than seen with placebo (8%; p < 0.001) at week 2 of therapy. Expectedly, this elevation was also persistent at weeks 4 and 6. In contrast, olanzapine-associated treatment-emergent prolactin elevations were both lower in magnitude and transient. At week 2, 38% of the Olz-H, 24% of the Olz-M, and 13% of the Olz-L treatment groups exhibited a treatment-emergent prolactin elevation, with a mean increase of 0.35, 0.52, and 0.61 nmol/l, respectively; for haloperidol the mean increase was 1.23 nmol/l. For only the Olz-M and the Olz-H treatment groups did the week 2 incidence of treatment-emergent prolactin elevations differ statistically significantly from placebo. Both the incidence of elevations and the mean increase, in prolactin concentration were less than that seen with haloperidol. Furthermore, by treatment week 6, all three olanzapine groups exhibited incidences of treatment-emergent prolactin elevation that were comparable to placebo and were statistically significantly less than observed with haloperidol. Rapid adaptation was observed in the temporal course of prolactin elevations associated with olanzapine based on both the categorical analysis of treatment-emergent high values and the analyses of temporal change in mean concentrations. In contrast to haloperidol, the magnitudes of the treatment-emergent elevations associated with olanzapine were minimal. The rates of elevation were approximately one-half to one-third those observed with haloperidol and were significantly more transient. Olanzapine, even at the highest doses (15 +/- 2.5 mg/day) used, was not associated with persistent elevations of prolactin, consistent with an 'atypical' pharmacologic profile.

Background: A relative lack of extrapyramidal symptoms (EPS, i.e., the syndromes of dystonia, parkinsonism, akathisia, dyskinesia) is one criterion used to determine whether an antipsychotic is "atypical." The extrapyramidal symptom profiles of the novel antipsychotic olanzapine and the conventional antipsychotic haloperidol were compared in a population of 2606 patients from three well-controlled prospective clinical trials., Method: Extrapyramidal symptom data were analyzed for 1796 patients treated with olanzapine (5 to 20 mg/day) and 810 patients treated with haloperidol (5 to 20 mg/day) for up to 6 weeks of therapy. Patients were monitored weekly by three methods of extrapyramidal symptom assessment: (1) detection of extrapyramidal adverse events (signs and symptoms) by casual observation, nonprobing inquiry, and spontaneous report; (2) objective rating scale scores: and (3) use of concomitant anticholinergic medications. Emergence of EPS was assessed by (1) analysis of the incidence of extrapyramidal syndrome categories based on adverse events, (2) the incidence of extrapyramidal syndromes based on categorical analysis of rating scale scores, (3) analysis of mean maximum change in rating scale scores, and (4) categorical analysis of anticholinergic medication use. Outcome of EPS was assessed by (1) analysis of mean change in rating scale scores at endpoint and (2) mean anticholinergic use at endpoint., Results: Olanzapine was statistically significantly (p = .014, p < .001) superior to haloperidol in all four analyses related to emergence of EPS and in the two analyses related to outcome. Furthermore, during acute treatment, statistically significantly fewer patients treated with olanzapine (0.3%) discontinued the study because of any extrapyramidal adverse event than patients treated with haloperidol (2.7%, p < .001)., Conclusion: Olanzapine exhibited a statistically significantly lower extrapyramidal symptom profile than the conventional antipsychotic haloperidol at comparably effective antipsychotic doses. The lower extrapyramidal symptom profile with olanzapine was evident despite statistically significantly more frequent use of anticholinergic drugs among haloperidol-treated patients. Fewer olanzapine-treated than haloperidol-treated patients discontinued because of EPS, suggesting that olanzapine should contribute to better compliance with longer term maintenance treatment, with minimal anticholinergic-associated events.

Objective: This international, multicenter double-blind trial was designed to compare the therapeutic profile of an atypical antipsychotic, olanzapine, with that of a conventional dopamine D2 antagonist, haloperidol., Method: A total of 1,996 patients at 174 sites in Europe and North America were randomly assigned to treatment with olanzapine (N = 1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis involved the mean change from baseline to endpoint in total scores on the Brief Psychiatric Rating Scale (BPRS). Secondary analyses included comparisons of the mean change in positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety., Results: Olanzapine demonstrated clinical results superior to those of haloperidol on overall improvement according to the BPRS and on every secondary measure, including depression. Olanzapine was also associated with significantly fewer discontinuations of treatment due to lack of drug efficacy or adverse events. Substantially more olanzapine-treated patients (66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of therapy. Statistically significant advantages of olanzapine treatment were related to 1) change in negative symptoms, 2) extrapyramidal symptom profile, 3) effect on prolactin levels, and 4) response rate., Conclusions: Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenic psychopathology, with a substantially more favorable safety profile, than haloperidol. It meets several of the criteria for a novel atypical antipsychotic agent.

Olanzapine is a potential new "atypical" antipsychotic agent. The double-blind acute phase of this study compared three dosage ranges of olanzapine (5 +/- 2.5 mg/day [Olz-L], 10 +/- 2.5 mg/day [Olz-M], 15 +/- 2.5 mg/day [Olz-H]) to a dosage range of haloperidol (15 +/- 5 mg/day [Hal]) and to placebo in the treatment of 335 patients who met the DSM-III-R criteria for schizophrenia. In overall symptomatology improvement (Brief Psychiatric Rating Scale [BPRS]-total), Olz-M, Olz-H, and Hal were significantly superior to placebo. In positive symptom improvement (BPRS-positive), Olz-M, Olz-H, and Hal were comparable and significantly superior to placebo. In negative symptom improvement (Scale for the Assessment of Negative Symptoms [SANS]-composite), Olz-L and Olz-H were significantly superior to placebo and Olz-H was also significantly superior to Hal. The most common treatment-emergent adverse events included somnolence, agitation, asthenia, and nervousness. No acute dystonia was observed with olanzapine. Treatment-emergent parkinsonism occurred with Olz-H at approximately one-third the rate of Hal, and akathisia occurred with Olz-H at approximately one-half the rate of Hal. Prolactin elevations associated with olanzapine were not significantly greater than those observed with placebo and were also significantly less than those seen with haloperidol.