Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Predicting a 'combined treatment outcome' in chronic schizophrenia: the role of demographics, symptomatology, functioning and subjective well-being.

OBJECTIVES: The aim of this study was to determine what variables predict a 'combined treatment outcome' (COMBOUT) in patients with chronic schizophrenia. METHODS: This analysis (n=522) was based on a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients diagnosed with schizophrenia or a related disorder. COMBOUT was assessed using the PANSS for symptoms, CGI-S for overall clinical status, MADRS for depressive symptoms, QLS for functioning/QOL, and SWN-K for subjective well-being. Possible predictors included demographics as well as baseline scores (Model I), and early change (week 2) scores (Model II). RESULTS: Model I: significantly better outcome (higher COMBOUT score) was observed in patients with lower MADRS (T= - 6.36; p<0.001) or higher QLS (T=5.05; p<0.001) scores at baseline. Model II: significantly better COMBOUT was observed in patients with early improvement of QLS (T=4.93; p<0.001), SWN-K (T=3.88; p<0.001), PANSS (T= - 2.32; p=0.021) and CGI-S scores (T= - 2.22; p=0.027). Changes in EPS were not predictors of COMBOUT in the models tested. CONCLUSION: COMBOUT at endpoint was predicted by lower depressive symptom score and higher QOL at baseline and by early improvement in psychopathology, quality of life and subjective well-being.

Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia.

The goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P<0.01; false discovery rate <0.2). Sixteen of these SNPs were located in the serotonin 2A receptor (HTR2A). Bioinformatic analyses identified a putative antisense nested gene in intron 2 of HTR2A in the region of the genetic markers associated with LY2140023 response. These data suggest a genetic association exists between SNPs in several genes, such as HTR2A, and response to LY2140023 treatment. Additional clinical trials are needed to establish replication of these results.

The heterogeneity of antipsychotic response in the treatment of schizophrenia.

BACKGROUND: Schizophrenia is a heterogeneous disorder in terms of patient response to antipsychotic treatment. Understanding the heterogeneity of treatment response may help to guide treatment decisions. This study was undertaken to capture inherent patterns of response to antipsychotic treatment in patients with schizophrenia, characterize the subgroups of patients with similar courses of response, and examine illness characteristics at baseline as possible predictors of response. METHOD: Growth mixture modeling (GMM) was applied to data from a randomized, double-blind, 12-week study of 628 patients with schizophrenia or schizo-affective disorder treated with risperidone or olanzapine. RESULTS: Four distinct response trajectories based on Positive and Negative Syndrome Scale (PANSS) total score over 12 weeks were identified: Class 1 (420 patients, 80.6%) with moderate average baseline PANSS total score showing gradual symptom improvement; Class 2 (65 patients, 12.5%) showing rapid symptom improvement; Class 3 (24 patients, 4.6%) with high average baseline PANSS total score showing gradual symptom improvement; and Class 4 (12 patients, 2.3%) showing unsustained symptom improvement. Latent class membership of early responders (ER) and early non-responders (ENR) was determined based on 20% symptom improvement criteria at 2 weeks and ultimate responders (UR) and ultimate non-responders (UNR) based on 40% symptom improvement criteria at 12 weeks. Baseline factors with potential influence on latent class membership were identified. CONCLUSIONS: This study identified four distinct treatment response patterns with predominant representation of responders or non-responders to treatment in these classes. This heterogeneity may represent discrete endophenotypes of response to treatment with different etiologic underpinnings.

The different trajectories of antipsychotic response: antipsychotics versus placebo.

BACKGROUND: It is generally accepted that antipsychotics are more effective than placebo. However, it remains unclear whether antipsychotics induce a pattern or trajectory of response that is distinct from placebo. We used a data-driven technique, called growth mixture modelling (GMM), to identify the different patterns of response observed in antipsychotic trials and to determine whether drug-treated and placebo-treated subjects show similar or distinct patterns of response. METHOD: We examined data on 420 patients with schizophrenia treated for 6 weeks in two double-blind placebo-controlled trials using haloperidol and olanzapine. We used GMM to identify the optimal number of response trajectories; to compare the trajectories in drug-treated versus placebo-treated patients; and to determine whether the trajectories for the different dimensions (positive versus negative symptoms) were identical or different. RESULTS: Positive symptoms were found to respond along four distinct trajectories, with the two most common trajectories ('Partial responder' and 'Responder') accounting for 70% of the patients and seen proportionally in both drug- and placebo-treated. The most striking drug-placebo difference was in the 'Dramatic responders', seen only among the drug-treated. The response of negative symptoms was more modest and did not show such distinct trajectories. CONCLUSIONS: Trajectory models of response, rather than the simple responder/non-responder dichotomy, provide a better statistical account of how antipsychotics work. The 'Dramatic responders' (those showing >70% response) were seen only among the drug-treated and make a significant contribution to the overall drug-placebo difference. Identifying and studying this subset may provide specific insight into antipsychotic action.

Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia.

Clinical trial data were evaluated for the association between 22 single-nucleotide polymorphisms (SNPs) and response in acutely ill patients diagnosed with schizophrenia, schizoaffective disorder or schizophreniform disorder, who were treated with oral risperidone. All patients in the exploratory (78 African Americans) and validation (65 whites) data sets received risperidone 2-6 mg per day over 2-12 weeks. Two SNPs were found to have significant associations with response to risperidone over 2-12 weeks in both African-American and white patients and had a consistent direction of effect in both cohorts. Metabotropic glutamate receptor (GRM3) SNP, rs724226, was associated with a change in the positive and negative syndrome scale (PANSS) total response. Catechol-O-methyltransferase (COMT) SNP, rs165599, was moderately associated with a change in the PANSS Negative score. The greater prevalence of poor-responder GRM3 and COMT alleles in white versus African-American patients might have a clinical significance in evaluating the ethnic-specific response to risperidone.

Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial.

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.

Elevated prolactin levels in patients with schizophrenia: mechanisms and related adverse effects.

The neurologic processes involved in schizophrenia are complex and diverse and the mechanisms through which antipsychotic agents exert their effects have been only partly elucidated. Hyperprolactinemia is a common side effect of treatment with many antipsychotics and is particularly associated with conventional ('typical') agents as well as the atypical antipsychotic risperidone. In contrast, other atypical agents introduced over the last decade do not elevate prolactin levels. This article discusses the regulatory mechanisms involved in prolactin secretion, the physiologic role of prolactin, and the etiology of hyperprolactinemia. Elevated prolactin levels may play important roles, both direct and indirect, in various pathologic states, including breast cancer, osteoporosis, cardiovascular disorders, and sexual disturbances. Antipsychotic-induced hyperprolactinemia may be associated with similar clinical manifestations; these are examined with particular reference to patients with schizophrenia.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

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.

Effective resolution with olanzapine of acute presentation of behavioral agitation and positive psychotic symptoms in schizophrenia.

Behavioral agitation and prominent positive psychotic symptoms often characterize the acute presentation of schizophrenia. The clinical treatment goal is a rapid control of these symptoms. The relative efficacy of olanzapine, a novel antipsychotic drug, was compared with that of the conventional antipsychotic drug haloperidol. A post hoc analysis conducted on a large multicenter, double-blind, 6-week study of acute-phase patients with DSM-III-R schizophrenia or schizophreniform or schizoaffective disorders treated with olanzapine (5-20 mg/day) or haloperidol (5-20 mg/day) assessed the treatment effects on agitation (Brief Psychiatric Rating Scale [BPRS] agitation score) and positive symptoms (BPRS positive symptom score). Overall, olanzapine-treated patients experienced significantly greater improvement in behavioral agitation than did haloperidol-treated patients (last observation carried forward [LOCF]; p < .0002). Both groups showed similar reductions in agitation scores during the first 3 weeks of therapy; olanzapine was associated with significantly greater improvements at weeks 4, 5, and 6 (observed cases [OC]). Similarly, patients with predominantly positive psychotic symptoms experienced significantly greater improvement in BPRS positive symptom scores with olanzapine compared with haloperidol (LOCF; p = .013). In olanzapine-treated patients, improvement in BPRS agitation and positive symptom scores was significantly greater at weeks 4, 5, and 6 (agitation scores, p < or = .01; positive symptom scores, p < .05) (OC). These data suggest that olanzapine may be considered a first-line treatment for the patient in an acute episode of schizophrenia.

Weight change and atypical antipsychotic treatment in patients with schizophrenia.

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.

Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia.

BACKGROUND: Weight change and the weight-related health factors of nonfasting serum glucose, serum cholesterol, and diastolic blood pressure levels were analyzed in patients with DSM-III-R schizophrenia and related disorders who received treatment with olanzapine for up to 3 years, and comparisons were made to patients treated with haloperidol. Baseline body mass index (BBMI; kg/m2) and dose (mg/day) were investigated as predictors of long-term weight change experienced during olanzapine treatment. METHOD: This analysis retrospectively examined 573 patients receiving olanzapine and 103 patients receiving haloperidol for 39 weeks or more from a study of 1,996 patients randomly assigned 2:1 to either olanzapine, 5 to 20 mg/day, or haloperidol, 5 to 20 mg/day. After 6 weeks of acute therapy, patients continued for 1 year or more with either double-blind or open-label olanzapine therapy or double-blind haloperidol therapy. RESULTS: Mean weight gain for olanzapine-treated patients observed for a median of 2.54 years trended toward a plateau after the first 39 weeks of treatment with a last-observation-carried-forward mean weight change of 6.26 kg (13.8 lb) and a median of 5.90 kg (13.0 lb). This was significantly higher than that for haloperidol-treated patients, whose mean weight gain was 0.69 kg (1.5 lb) after 1.15 years (p < .001). Patients with higher BBMI (> 27.6) gained significantly less weight during treatment with olanzapine than their lighter counterparts (BBMI < 27.6) (p < .001). The effect of olanzapine dose on weight was not significant (p > or = . 183). Median serum glucose at endpoint was not significantly associated (p = .096) with weight change for olanzapine. Median serum cholesterol and diastolic blood pressure for olanzapine-treated patients at endpoint showed a relationship with weight change that was statistically (p < or = .001) but not clinically significant. The difference in incidence of elevated serum glucose, cholesterol, or diastolic blood pressure between olanzapine and haloperidol therapy groups was not different (p > .05). CONCLUSION: Mean weight gain during olanzapine treatment trended toward a plateau after the initial 39 weeks of treatment with no further significant gain out to 3 years. Higher BBMI was predictive of a lower long-term weight gain, while dose was not a significant predictor of greater longer term weight change. The relationship between weight change and glucose was not statistically significant. The association between weight change and changes in cholesterol as well as changes in diastolic blood pressure was statistically significant but not considered clinically relevant based on the ranges observed.

Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine.

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.

The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia.

BACKGROUND: There is relatively little comparative information on elevations in plasma prolactin level (PRL) with conventional versus novel antipsychotic agents. OBJECTIVE: This paper examines the comparative effects on PRL of olanzapine, risperidone, and haloperidol based on data from 3 multicenter, double-blind, randomized clinical trials. Magnitude of response, dose dependency, time course, effects of sex and age, and response to switching from haloperidol to olanzapine are assessed. METHODS: The effects of olanzapine, risperidone, and haloperidol on PRL were assessed in patients with schizophrenia or related psychoses participating in 3 double-blind clinical trials: (1) a 6-week acute trial comparing olanzapine 5 to 20 mg/d (n = 1,336) and haloperidol 5 to 20 mg/d (n = 660), with a 1-year, open-label olanzapine extension for responders; (2) a 54-week study comparing olanzapine 5 to 20 mg/d (n = 21), risperidone 4 to 10 mg/d (n = 21), and haloperidol 5 to 20 mg/d (n = 23) in early illness; and (3) a 28-week study comparing olanzapine 10 to 20 mg/d (n = 172) and risperidone 4 to 12 mg/d (n = 167). RESULTS: PRL elevations were significantly greater with risperidone than with either olanzapine or haloperidol in study 2. and significantly greater than with olanzapine in study 3 (all, P < 0.001). PRL elevations were significantly greater with haloperidol than with olanzapine in study 1 (P < 0.001 ). A dose-response relationship was not consistently confirmed with any of the drug treatments. Risperidone-associated PRL elevations peaked relatively early in treatment. In haloperidol- and risperidone-treated patients, the mean change in PRL was greater in women than in men. PRL decreased significantly when treatment was switched from haloperidol to olanzapine. CONCLUSIONS: This side-by-side analysis of 3 independent studies suggests that with the 3 antipsychotic drugs studied, PRL is elevated moderately by olanzapine (mean change, 1-4 ng/mL), intermediately by haloperidol (mean change, approximately 17 ng/mL), and strongly by risperidone (mean change, 45-80 ng/mL). No consistent dose-response relationship was observed, and the time course and sex-dependency of the response differed between the 3 agents. Patients with haloperidol-induced hyperprolactinemia may benefit from a switch to olanzapine. Long-term studies examining the health consequences of chronic hyperprolactinemia during antipsychotic treatment are needed.

Designing naturalistic prospective studies of economic and effectiveness outcomes associated with novel antipsychotic therapies.

The cornerstone of recent pharmacoeconomic work in schizophrenia is the hypothesis that the improved efficacy of novel antipsychotic medications will lead to a reduction in medical services utilization, thereby reducing direct medical costs associated with treatment. Creating the most valid design to prospectively examine the effectiveness and costs of competing pharmacotherapies requires a dialectic of opposing research paradigms. The final protocol must represent a series of decisions that strike a careful balance between being scientifically sound (internal validity) and generalizable to the real world of clinical treatment (external validity). The results must be useful to decision-makers in determining to what extent reductions in healthcare expenditures can offset higher drug acquisition costs within their type of treatment environment. This article is a review of several methodological challenges in the design of medical effectiveness trials, including whether to blind the study, definition of the patient population, degree of physician discretion in treatment, and how to collect and analyze data for patients who discontinue their originally assigned medication. The article also provides a discussion of how clinical practices can inform decisions made to meet these challenges. The issues are illustrated through a prospective study designed to evaluate the cost-effectiveness of the newer antipsychotics in general and olanzapine in particular. Cost-effectiveness studies of novel antipsychotic medications, particularly those with naturalistic designs, will increase in importance as the use of these second-generation agents continues to expand.

Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group.

The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.

Effects of chronic treatment with typical and atypical antipsychotic drugs on the rat striatum.

Human MRI studies have demonstrated that treatment with typical antipsychotics may increase the volume of the caudate nucleus while clozapine treatment is associated with either no change or a reversal of the previous volume increase. In this study four groups of seven rats were treated for 8 months with either the typical antipsychotic haloperidol, the atypical antipsychotic clozapine, the D2/D3 receptor antagonist raclopride, or vehicle (plain drinking water). Striatal sections were prepared using D1-like and D2-like receptor ligand autoradiography. Images (4-6 sections per rat, per ligand) were digitized and the area of the striatum was measured on each section. Rats treated with haloperidol did not have a larger mean striatum area than the control group on either D1- or D2-like ligand autoradiograms. Using the D2-like ligand autoradiograms, the clozapine treated animals had a smaller mean striatum area than the control group. Mean left striatum area was larger than mean right striatum area in each treatment group and in the control group. In contrast to the MRI findings reported in schizophrenia, the area of the striatum was not increased in rats treated with typical antipsychotic agents, but the clozapine-associated area reduction may parallel the clinical studies.

The routine use of atypical antipsychotic agents: maintenance treatment.

Placebo-controlled maintenance studies of conventional antipsychotic agents demonstrate a significant reduction in the risk of schizophrenic relapse in neuroleptic-treated patients. Neuroleptic discontinuation even in patients who remained in remission for as long as 5 years results in a relapse rate comparable to that seen for patients initially assigned to placebo. Yet, patients maintained on conventional neuroleptics are exposed to the risk of tardive dyskinesia (approximately 5% per year for patients with up to 10 years of neuroleptic exposure). Attempts have been made to reduce neuroleptic exposure. A lower maintenance dose was associated with higher relapse rates, as was intermittent, targeted therapy. Psychoeducational treatment studies reaffirmed that the major influence on the rate of rehospitalization was the dose of conventional maintenance medication. Although data are scarce for maintenance treatment with atypical antipsychotic drugs, findings suggest that atypical agents are at least as efficacious and may be better tolerated. Olanzapine has demonstrated efficacy in maintenance treatment as well as a reduced risk of tardive dyskinesia compared with haloperidol.

Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity.

Existing pathophysiological models of schizophrenia are limited in their ability to account for all the clinical dimensions of the disorder. The purpose of this article is to describe a comprehensive hypothesis of the pathophysiology of schizophrenia and specifically how a deficit in neural regulation of developmental origin can lead to a pathologic form of neuroplasticity, i.e., neurochemical sensitization, which causes the onset and psychotic symptoms of the illness. We propose that the symptoms of schizophrenia may be caused by deficits in neural regulation resulting in a pathologic condition of neurochemical sensitization analogous to the preclinical model of pharmacologically-induced behavioral sensitization. This condition, if sustained, can lead to potential neurotoxic effects which produce structural neuronal alterations and persistent morbidity. Several lines of indirect and direct clinical evidence are consistent with this hypothesis. These include the ability of stimulant and psychotomimetic drugs to induce psychosis in normal subjects, the development of apparent sensitization to psychosis-inducing effects of stimulants in chronic stimulant abusers and the increased susceptibility of patients with schizophrenia to the psychotogenic effects of Dopamine (DA) agonists. This hypothesis integrates and extends the work of other investigators and is consistent with specific aspects of the longitudinal course of schizophrenia. The association of longer duration and more episodes of psychosis, with poor treatment response and outcome, are also consistent with this model. Form this hypothesis, specific predictions about the illness course, treatment interventions, and pathophysiologic features of schizophrenia can be derived and tested through clinical investigation.