Augmentation of olanzapine in treatment-resistant schizophrenia

OBJECTIVE: Up to 40% of patients with schizophrenic psychoses have symptoms that are resistant to monotherapy with antipsychotic drugs. In consequence, combinations of drugs are often used, especially based on the antipsychotic agents clozapine and olanzapine because of their broad receptor-interaction profile. The aim of this review was to provide a critical overview of the published results of olanzapine augmentation. METHODS: A systematic database search was performed of MEDLINE and BIOSIS (Ovid), looking for publications on augmented therapeutic approaches involving olanzapine. The search terms used were "augmentation," "combination," "schizophrenia," "olanzapine," and the names of other antipsychotic drugs and non-antipsychotic agents, including brand names, spanning publications from 1966 until the end of December 2004. RESULTS: Of 14 reports dealing with 8 different antipsychotic augmentation strategies (83 patients), only 1 trial, of sulpiride-olanzapine therapy, was performed in a randomized manner. Based on clinical observation, a significant number of the treatments led to favourable results. In contrast to adjuvant therapy with antipsychotic drugs, augmentation of olanzapine with glycine, antidepressants or mood stabilizers was evaluated in well-designed clinical trials (8 publications, 989 patients), with distinct improvements of positive and/or negative symptoms reported. CONCLUSIONS: The combination of olanzapine with antidopaminergic atypical antipsychotic agents seems to follow a neurobiological rationale. The augmentation trials with non-antipsychotic agents, for example, mood stabilizers, were successful and showed that randomized and placebo-controlled trials are feasible. Therefore, systematic evaluations of antipsychotic agents as adjuvant therapy are possible as well as necessary to determine the benefits and risks of any new treatment strategy.     

奥氮平与利培酮治疗难治性精神分裂症的对照研究

目的 比较奥氮平与利培酮对难治性精神分裂症的疗效及安全性.方法 68例难治性精神分裂症患者按照排列表法随机分为奥氮平组[34例,(24.1±5.4)mg/d]和利培酮组[34例,(7.9±1.8)mg/d],疗程均为12周.采用阳性和阴性症状量表(PANSS)、临床总体印象量表(CGI)及治疗中需处理的不良反应症状量表(TESS),在治疗前及治疗第1,2,4,8,12周末分别评定疗效和不良反应.结果 (1)奥氮平组PANSS总分、阳性症状分、阴性症状分及一般病理分均从治疗第2周末起较治疗前下降(P<0.05～0.01);利培酮组PANSS总分、阳性症状分、一般病理分从治疗第2周末起,阴性症状分从第4周末起,较治疗前下降(P<0.05～0.01);奥氮平组从治疗第2周末起各时点PANSS总分、阴性症状分均低于利培酮组(P<0.05～0.01).(2)治疗第2周末起,2组临床总体印象量表-严重程度和改善程度(CGI-SI)总分均较治疗前下降(P<0.05～0.01);2组间各时点CGI-SI分的差异无统计学意义(P>0.05).(3)治疗第12周末,奥氮平组、利培酮组临床总有效率分别为65%、41%,差异有统计学意义(P<0.05).(4)奥氮平组、利培酮组不良反应发生率分别为53%(18/34)和59%(20/34),差异无统计学意义(P>0.05);奥氮平组体质量增加发生率高于利培酮组(P<0.05);利培酮组静坐不能、异常泌乳和(或)闭经、肌张力增高的发生率高于奥氮平组(P<0.05).结论 奥氮平对难治性精神分裂症有良好疗效,不良反应轻微.     

Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium

Objective

The objective of the study was to assess the efficacy and safety of second-generation antipsychotics olanzapine and risperidone vs. haloperidol in patients of delirium admitted to medical and surgical wards.

Methods

Prospective follow-up single-blind randomized controlled trials were performed. Consecutive patients with delirium referred to the consultation–liaison psychiatry team were eligible for the study. The study sample comprised 64 patients, with 20 subjects in the haloperidol group, 21 subjects in the risperidone group and 23 subjects in the olanzapine group. A flexible dose regimen (haloperidol −0.25 to 10 mg; risperidone −0.25 to 4 mg; olanzapine −1.25 to 20 mg) was used. Delirium Rating Scale-Revised-98 (DRS-R98) was used as the primary efficacy measure, and mini mental status examination (MMSE) was used as a secondary efficacy measure.

Results

There was no significant difference in mean baseline DRS-R98 severity scores and MMSE scores between the three groups. However, there were a significant reduction in DRS-R98 severity scores and a significant improvement in MMSE scores over the period of 6 days, but there was no difference between the three groups. Four patients in the haloperidol group, six subjects in the risperidone group and two subjects in the olanzapine group experienced some side effects.

Conclusions

Risperidone and olanzapine are as efficacious as haloperidol in the treatment of delirium.     

Extrapyramidal symptom profiles in Japanese patients with schizophrenia treated with olanzapine or haloperidol

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.     

Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.

OBJECTIVE: This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol. METHODS: A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). RESULTS: Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol. CONCLUSION: Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.     

One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia

Neurocognitive deficits in schizophrenia can reach 1 to 2 standard deviations below healthy controls. The comparative effect of typical and atypical antipsychotic medications on neurocognition is controversial, and based primarily on studies with small samples and large doses of typical comparator medications. The present study assessed neurocognitive efficacy. It was hypothesized that olanzapine treatment would improve neurocognitive deficits to a greater degree than either risperidone or haloperidol treatment. This was a double-blind, randomized, controlled, parallel study with neurocognition assessed at baseline, and 8, 24, and 52 weeks. Per protocol, the haloperidol arm was discontinued. Four hundred and fourteen inpatients or outpatients with schizophrenia and schizoaffective disorder were treated with oral olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Individual domains (executive function, learning and memory, processing speed, attention/vigilance, verbal working memory, verbal fluency, motor function, and visuospatial ability) were transformed into composite scores and compared between treatment groups. At the 52-week endpoint, neurocognition significantly improved in each group (p < 0.01 for olanzapine and risperidone, p = 0.04 for haloperidol), with no significant differences between groups. Olanzapine- and risperidone-treated patients significantly (p < 0.05) improved on domains of executive function, learning/memory, processing speed, attention/vigilance, verbal working memory, and motor functions. Additionally, risperidone-treated patients improved on domains of visuospatial memory. Haloperidol-treated patients improved only on domains of learning/memory. However, patients able to remain in treatment for the entire 52 weeks benefited more from olanzapine or risperidone treatment than haloperidol treatment.     

A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia.

BACKGROUND: Many studies have indicated that excess free radical formation may be involved in the pathogenesis of patients with schizophrenia. Some investigators suggested that the use of free radical scavengers might provide improvement in schizophrenia. The aim of this study was to determine the effectiveness and to evaluate the side effects of extract of Ginkgo biloba (EGb) plus haloperidol in chronic, treatment-resistant inpatients with schizophrenia. METHOD: One hundred nine patients meeting DSM-III-R criteria for schizophrenia completed a double-blind, placebo-controlled, parallel-group study of EGb plus haloperidol. Fifty-six of the patients were randomly assigned to receive a fixed dose of 360 mg/day of EGb plus a stable dose of haloperidol, 0.25 mg/kg/day, and 53 were assigned to receive placebo plus the same dose of haloperidol for 12 weeks. Patients were assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Scale for the Assessment of Positive Symptoms (SAPS) at baseline, week 6, and week 12 and the Treatment Emergent Symptom Scale (TESS) for side effects at week 12. RESULTS: There was a significant reduction in both groups in BPRS total score after 12 weeks of treatment (p < .05). However, a significant reduction in total SAPS and SANS scores was noted in the EGb group (p < .05), but not in the placebo group. There was a lower SAPS total score in the EGb group than in the placebo group at the end of 12 weeks of treatment (p < .05). Of those treated with EGb plus haloperidol, 57.1% were rated as responders as compared with only 37.7% of those receiving placebo plus haloperidol when assessed by the SAPS (chi2 = 4. 111, p = .043). After 12 weeks of treatment, TESS subscore 1 (behavioral toxicity) and subscore 3 (symptoms of nerve system) were significantly decreased in the EGb group compared with the placebo group (p < .05). CONCLUSION: EGb treatment may enhance the effectiveness of antipsychotic drugs and reduce their extrapyramidal side effects.     

Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone

OBJECTIVE: Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses. METHOD: Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared. RESULTS: In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain. CONCLUSION: This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.     

家族性与散发性难治性精神分裂症的对照研究

目的 探讨家族性与散发性难治性分裂症患者的临床特点。方法 在533例住院分裂症患者中有113例符合难治性分裂症的标准，其中根据有无精神病家族史分为家族性分裂症组(研究组)和散发性分裂症组(对照组)，对研究组与对照组的临床资料进行比较。结果 研究组与对照组相比，在首次发病年龄上差异有显著性意义；而在性别、病前性格、文化程度、有无诱因、起病形式、治疗前病程、总病程、病程特点、住院次数、服药依从性、社会支持、家庭经济水平、症状特点及诊断分型等方面差异均无显著性意义。结论 首次发病年龄对于分裂症遗传学研究具有重要意义。     

阿立哌唑与氟哌啶醇治疗难治性精神分裂症的对照研究

目的比较阿立哌唑与氟哌啶醇治疗难治性精神分裂症的疗效。方法78例符合入组条件的难治性精神分裂症病人,随机分2组,分别应用阿立哌唑或氟哌啶醇治疗12用,应用阳性和阴性症状量表（PANSS）和刮反应量表（TESS）评定疗效和副反应。结果阿立哌唑组总有效率为61．54％,明显高于氟哌啶醇组的43．59％。2组间在PANSS总分,阴性症状量表分及一般病理症状量表分值方面的差异具有显著性意义（P〈0．01）。结论阿立哌唑对难治性精神分裂症的疗效优于氟哌啶醇,对阴性症状的效果尤其明显。     

D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia.

BACKGROUND: D-serine, a selective full agonist at the glycine site of N-methyl-D-aspartate glutamate receptor, might presently be the compound of choice for counteracting the hypothesized dysfunction of this receptor class in schizophrenia. Studies performed with Taiwanese patients indicate that D-serine significantly improves schizophrenia symptoms when used as adjuvant to conventional neuroleptics but not to clozapine. We assessed the efficacy and safety of D-serine adjuvant treatment for Occidental schizophrenia patients treated with newer atypical antipsychotics. METHODS: Thirty-nine risperidone- or olanzapine-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover trial with 30 mg/kg/day D-serine added to their antipsychotic medication. Measures of clinical efficacy and side effects were determined biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. RESULTS: D-serine administration induced increased serine serum levels (p < .001) and resulted in significant (p < .001) improvements in negative, positive, cognitive, and depression symptoms, as measured by the Positive and Negative Syndrome Scale. For approximately one third of the sample, D-serine treatment resulted in significant (>20%) reductions in Brief Psychiatric Rating Scale total scores. D-serine was well tolerated, and no detrimental changes in clinical laboratory parameters were noted. CONCLUSIONS: These findings 1) indicate that risperidone and olanzapine efficacy might be augmented with D-serine adjuvant treatment; 2) confirm D-serine efficacy against main schizophrenia symptom domains; and 3) warrant the assessment of D-serine antipsychotic monotherapy for this illness.     

15例难治性精神分裂症患者由氯氮平换用喹硫平治疗的临床报告

虽然氯氮平是治疗精神分裂症的二线药物,并能够将其他抗精神病药物治疗无效的精神分裂症的疗效提高30％左右,但仍然有部分患者对氯氮平治疗无效,或不能耐受氯氮平的不良反应,此时就需要将氯氮平换为其他精神病药物。但由于撤药综合征的问题,氯氮平换用其他抗精神病药物被大部分精神科医生视为临床难题。本文就此总结了15例服用氯氮平的精神分裂症患者换用喹硫平的临床特点。     

Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol

BACKGROUND: Prolactin levels are elevated to varying degrees by antipsychotics. Prolactin elevations may result in sexual and other adverse effects, and they may be related to antipsychotic effects. We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level, to explore the relation between clinical effects and prolactin level, and to determine the relationship between plasma levels of antipsychotics and prolactin level. METHOD: Treatment-resistant patients (133 men, 24 women) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind, randomized, 14-week trial comparing clozapine (N = 40), olanzapine (N = 39), risperidone (N = 41), and haloperidol (N = 37). Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5, 8, 10, 12, and 14 during the trial. Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale. Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available. Data were gathered from June 1996 to December 1999. RESULTS: Risperidone caused significant elevation of prolactin levels (p <.05) that appeared to be dose-dependent. Clozapine and olanzapine were associated with decreases of prolactin, whereas haloperidol led to a minor, nonsignificant increase. Plasma olanzapine and prolactin levels were correlated. Prolactin levels were not related to clinical improvement or extrapyramidal side effects. CONCLUSION: Antipsychotics show major differences in their effects on prolactin, and risperidone has clearly the most robust effect.     

An efficacy analysis of olanzapine treatment data in schizophrenia patients with catatonic signs and symptoms

Thirty-five patients suffering from schizophrenia, as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were preselected from 7 clinical trials according to a priori criteria of catatonic signs and symptoms based on 3 Positive and Negative Syndrome Scale (PANSS) items: scores for PANSS item 19 (mannerism and posturing) and either item 4 (excitement) or item 21 (motor retardation) had to exceed or equal 4 at baseline. This particular patient population represents a severely psychotic sample: mean +/- SD PANSS total scores at baseline were 129.26 +/- 19.76. After I week of olanzapine treatment, mean PANSS total score was decreased significantly (-13.14; p < .001), as was mean PANSS total score after 6 weeks of olanzapine treatment (-45.16; p < .001); additionally, the positive subscale, negative subscale, and mood scores improved significantly. A significant improvement in the catatonic signs and symptoms composite score was also observed at week 6 (-4.96; p < .001). The mean +/- SD daily dose of olanzapine was 18.00 +/- 2.89 mg after 6 weeks of treatment. The present data analysis suggests the efficacy of olanzapine in the treatment of severely ill schizophrenic patients with nonspecified catatonic signs and symptoms.