Rapid antipsychotic response with ziprasidone predicts subsequent acute manic/mixed episode remission

Objective

To assess rapid antipsychotic efficacy with oral ziprasidone monotherapy in bipolar acute manic/mixed episodes with psychotic features, and predictive value of rapid antipsychotic response for subsequent acute manic/mixed episode remission.

Methods

Pooled analysis of two 3-week, randomized, double-blind, placebo-controlled trials of ziprasidone (40-160 mg/d) in inpatients with bipolar I disorder, and a current manic or mixed episode, with (n = 152) or without (n = 246) psychotic features. Psychosis improvement was evaluated by change in SADS-C psychosis score (sum of delusions, hallucinations, and suspiciousness items). Rapid antipsychotic response (?50% decrease in SADS-C psychosis score by Day 4) and acute manic episode response and remission (endpoint ?50% MRS decrease, and a MRS score ? 12, respectively) were analyzed.

Results

Significantly greater antipsychotic effects were observed by Day 4 with ziprasidone treatment (vs. placebo) and the magnitude of improvement increased significantly with time, in all subjects, in the subgroup of all psychotic subjects, and psychotic subjects with low baseline agitation (p < 0.05). Rapid antipsychotic response predicted subsequent acute manic episode remission independent of ziprasidone or placebo treatment received (p < 0.001, ROC AUC = 0.71) with significant improvement in accuracy of MRS remission prediction when compared to models using early changes in MRS score alone (p = 0.01).

Limitations

Post hoc analysis, use of 3 SADS-C psychosis items to assess psychosis.

Conclusions

The predictive value of rapid (Day 4) improvement in psychotic symptoms for subsequent (Day 21) remission of acute manic/mixed symptoms may facilitate enhanced therapeutics, in view of the current practice of brief hospitalization for patients with acute manic/mixed episodes with psychotic features.     

The efficacy of a rapid-acting intramuscular formulation of olanzapine for positive symptoms

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

The utility of intramuscular ziprasidone in the management of acute psychotic agitation.

Many psychiatric illnesses, including chronic schizophrenia, bipolar disorder, and dementia, are characterized by episodes of acute agitation, making administration of oral agents difficult or impossible. Ziprasidone, the first atypical antipsychotic available in both intramuscular (IM) and oral formulations, has demonstrated significant control of acute agitation within 15 minutes, as seen in two 24-hour studies in patients with schizophrenia. Improvement was maintained for > or = 4 hours, and a low incidence of extrapyramidal symptoms, akathisia, and dystonia as well as no excessive sedation were observed Also, two 7-day studies (n = 132 and n = 306) and one 6-week study (n = 567) of sequential IM/oral ziprasidone versus IM/oral haloperidol in patients with psychotic disorders found IM ziprasidone more effective than IM haloperidol within 3 days of IM treatment; both drugs produced further comparable improvements in efficacy parameters after transition to oral therapy. IM ziprasidone was associated with a lower incidence of movement disorders than was haloperidol in all of these studies. Overall, discontinuations were similar for IM ziprasidone and haloperidol in the comparative trials, including the sequential IM/oral studies. However, in the 6-week sequential IM/oral trial, the rate of discontinuation due to adverse events was twice as high among haloperidol vs ziprasidone patients. This report focuses on the pharmacology, clinical efficacy, and tolerability of IM ziprasidone, and provides an overview of the utility of other commonly used antipsychotics in the management of acute psychotic agitation.     

A long-term, multicenter, open-label study of risperidone in elderly patients with psychosis. On behalf of the Risperidone Working Group

RATIONALE: Studies have shown that risperidone is safe and efficacious in young and middle-aged adults with chronic schizophrenia, but considerably fewer data are available on the treatment of elderly patients with schizophrenia or other psychotic disorders, particularly long-term outcomes. OBJECTIVE: A 12-month, open-label study was conducted to assess the effects of risperidone in elderly, chronically ill, psychotic patients. METHODS: This study enrolled 180 elderly, chronically ill, psychotic patients (median age, 72 years [range 54-89]), 97 of whom completed the 12-month study. At endpoint, the mean dose of risperidone was 3.7 mg/day. RESULTS: Clinical improvement (> or =20% reduction in Positive and Negative Syndrome Score [PANSS] total score) was achieved by 54% of patients at endpoint. There were significant reductions in PANSS total, subscale (positive, negative, and general psychopathology), and cognition cluster scores at endpoint (p<0.001). Clinical Global Impressions severity of illness scores showed continued improvement through month 12 (p<0.001). In contrast, PANSS data from a historical comparable control group of patients receiving conventional antipsychotic agents showed no symptom improvement over a 12-month treatment period. The severity of preexisting extrapyramidal symptoms (EPS) in patients treated with risperidone decreased significantly from baseline to endpoint (p<0.001), and the use of antiparkinsonian medication decreased from 41.1% of patients before the trial to 25.6% during the trial. There were no spontaneous reports of tardive dyskinesia (TD) and the incidence of assessed TD was 4.3% in contrast to the expected 26% reported in middle-aged and elderly patients receiving conventional antipsychotic agents for 1 year. CONCLUSIONS: Long-term treatment with risperidone was associated with continued symptom improvement, a decrease in the severity of preexising EPS, and a low incidence of TD in elderly psychotic patients.     

Refractory psychosis and prominent cognitive deficits in a patient with mega-cisterna magna

We present a case of refractory psychosis with prominent cognitive deficits in a patient with 'mega-cisterna magna', a congenital defect within the 'Dandy-Walker Complex' continuum. The 21-year-old female had a 3-year history of refractory psychotic symptoms despite adequate antipsychotic treatment. CT and MRI scans disclosed 'mega-cisterna magna'. Thorough neuropsychological testing recorded extensive deficits. Treatment with amisulpride 1200 mg/day resulted in a 30% decrease in PANSS score within 2 months. Then galantamine 8 mg/day was added and PANSS score decreased further by 27% within 2 weeks. Cognitive and social functioning was overall much improved. The effect was sustained in a 24 months follow-up. It is postulated that even a less extended cerebellar lesion, such as mega-cisterna magna, can be associated with psychosis, and in some cases with treatment refractoriness or cognitive dysfunction. Adjuvant galantamine may improve cognitive and psychosocial functioning in these patients.     

Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients

BACKGROUND: There is a clear need for effective, well-tolerated intramuscular (i.m.) agents for the acute control of agitated psychotic patients. Currently used agents, including conventional antipsychotics and/or benzodiazepines, may be associated with distressing side effects such as extrapyramidal side effects and excessive sedation. OBJECTIVE: The objective of this study was to evaluate the efficacy and tolerability of the rapid-acting i.m. formulation of the novel antipsychotic ziprasidone in the treatment of inpatients with psychosis and acute agitation (DSM-IV diagnoses). METHOD: In a 24-hour, double-blind, fixed-dose clinical trial, patients were randomly assigned to receive up to 4 injections (every 2 hours p.r.n.) of 2 mg (N = 54) or 10 mg (N = 63) of ziprasidone i.m. The Behavioral Activity Rating Scale measured behavioral symptoms at baseline and the response to treatment up to 4 hours after the first i.m. injection. RESULTS: Ziprasidone i.m., 10 mg, rapidly reduced symptoms of acute agitation and was significantly more effective (p < .01) than the 2-mg dose up to 4 hours after the first injection. Patients were calmed but not excessively sedated, and over half were classed as responders 2 hours after the 10-mg dose. No acute dystonia or behavioral disinhibition was reported. One patient who received the 10-mg dose experienced the extrapyramidal side effect akathisia. CONCLUSION: Ziprasidone i.m., 10 mg, is rapidly effective and well tolerated in the short-term management of the agitated psychotic patient. Comparison with a study of identical design comparing 2-mg with 20-mg doses in patients with similar levels of psychopathology suggests that efficacy with 10 mg or 20 mg of ziprasidone i.m. is significant and dose related.     

A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia

BACKGROUND: Ziprasidone is a novel antipsychotic with a unique pharmacologic profile. This study compared ziprasidone with the conventional antipsychotic haloperidol in outpatients with stable schizophrenia. METHOD: Three hundred one outpatients with stable chronic or subchronic schizophrenia (DSM-III-R) were randomized and participated in this double-blind, multicenter, parallel-group clinical study comparing flexible-dose oral ziprasidone, 80-160 mg/day (N = 148), with haloperidol, 5-15 mg/day (N = 153), over 28 weeks. Patients were assessed using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Severity of Illness scale, the Montgomery-Asberg Depression Rating Scale, the Simpson-Angus Scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale. RESULTS: Modal doses at endpoint were 80 mg/day for ziprasidone and 5 mg/day for haloperidol. Improvements in all mean efficacy variables with both ziprasidone and haloperidol were observed. Significantly more patients were categorized as negative symptom responders (> or = 20% reduction in PANSS negative subscale score) in the ziprasidone group (48%) compared with the haloperidol group (33%) (p < .05). Ziprasidone had clear advantages over haloperidol in all evaluations of movement disorders. Changes in body weight were negligible with both treatments. No pattern of laboratory or cardiovascular changes was observed. CONCLUSION: Ziprasidone and haloperidol were both effective in reducing overall psychopathology; ziprasidone demonstrated effective treatment of negative symptoms and was better tolerated than haloperidol. Ziprasidone appears to offer an effective alternative to haloperidol in the long-term treatment of stable outpatients with schizophrenia.     

Duration of untreated psychosis and outcome in first-episode psychosis. Perspective from a developing country

OBJECTIVE: To investigate the association between duration of untreated psychosis (DUP) and treatment outcome in a sample of subjects from a developing country. METHOD: Forty-eight subjects with a first episode of psychosis were evaluated prior to treatment and at 3-month intervals over a period of 24 months. We first examined correlations between DUP and symptom improvement as measured on the Positive and Negative Symptom Scale (PANSS), and then performed multivariate analysis to determine the validity of DUP as a predictor of outcome. RESULTS: DUP was significantly correlated with improvement in PANSS total and negative subscale scores as well as the PANSS depression factor at 21 and 24 months. Multivariate analysis found DUP to be the only significant predictor of improvement in negative symptoms at 24 months. CONCLUSION: DUP was a significant predictor of outcome in a cohort form a developing country. This study provides support for early detection and intervention strategies.     

Quetiapine improves psychotic symptoms and cognition in Parkinson's disease.

Twenty-nine elderly patients who failed treatment with clozapine, risperidone, or olanzapine entered this 24-week, single-center, open-label trial to assess the efficacy of quetiapine (12.5-400 mg/day) for psychosis in patients with Parkinson's disease (PD). Psychiatric, motor, and cognitive assessments were administered at baseline and at periodic intervals for 24 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NPI), Unified Parkinson's Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention, and memory. Repeated measures statistical analysis was used to assess change from baseline. The results revealed significant improvements in the 24-week BPRS total score and NPI psychosis subscale scores, with no decline in UPDRS total or motor subscale scores. There was also significant improvement in recall scores on cognitive measures. These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD, suggesting that quetiapine is an effective and well-tolerated antipsychotic in this population.     

Intramuscular ziprasidone treatment of acute psychotic agitation in elderly patients with schizophrenia.

OBJECTIVE: Intramuscular (i.m.) ziprasidone treatment has been shown to be effective and well tolerated in reducing the symptoms of acute psychosis in adults. Few data are available as to safety in the elderly. The growing utilization of health services by elderly psychiatric patients warrants an evaluation in this population. METHOD: Consecutive elderly patients (60 years of and older) admitted to a psychogeriatric ward in a large, university-affiliated tertiary psychiatric center were treated by i.m. ziprasidone for acute psychotic agitation. Patients received three days of flexible-dose i.m. ziprasidone. After an initial dose of 10-20 mg, a subsequent dose of 10-20 mg could be given after 12 hours if needed (maximum daily dose: 40 mg). RESULTS: All treatment emergent side effects and adverse events along with the investigators' assessments of severity were systematically recorded as the primary outcome. The Brief Psychiatric Rating Scale (BPRS) and the Behavioral Activity Rating Scale (BARS) were the secondary outcomes. Twenty-one patients, six male and 15 female, mean age 71.4 +/- 1.3 years (range: 60-81 years) were enrolled. All had completed the three days i.m. ziprasidone treatment. There was one adverse event in a patient with untreated benign prostatic hypertrophy who developed urinary retention. Two side effects of mild severity that resolved spontaneously were observed: blurred vision and sedation. The BPRS decreased by 26.8 points after three days of treatment (p = 0.001). The BARS score, reflecting agitation, decreased significantly after each injection, reaching maximal decrease of 2.14 points at completion of study (p = 0.001). CONCLUSION: Intramuscular ziprasidone in this series of elderly patients suggests acceptable safety and efficacy in the management of acute psychotic agitation among elderly patients with schizophrenia.     

Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam

BACKGROUND: Standard treatment for acute psychotic agitation often involves intramuscular administration of the benzodiazepine lorazepam and the antipsychotic haloperidol. This study compared the efficacy and safety of oral treatment with the atypical antipsychotic risperidone plus lorazepam with those of standard intramuscular treatment. We hypothesized that the efficacy and speed of action of both treatments would be similar. METHOD: In a prospective, parallel-group, randomized, rater-blinded noninferiority study conducted at 24 sites in the United States, 162 patients exhibiting agitation associated with active psychosis were randomly assigned to receive either oral treatment with 2 mg of risperidone plus 2 mg of lorazepam (N = 83) or intramuscular treatment with 5 mg of haloperidol plus 2 mg of lorazepam (N = 79). The change scores on a 5-item acute-agitation cluster from the Positive and Negative Syndrome Scale (hallucinatory behavior, excitement, hostility, uncooperativeness, and poor impulse control) were the main outcome measure. The study was conducted from January 8 to August 8, 2001. RESULTS: Mean acute-agitation cluster scores were similar in the 2 groups at baseline. Mean score improvements at 30, 60, and 120 minutes after dosing were significant at each timepoint in both groups (p <.0001) and were similar in both groups (p >.05). Both treatments were well tolerated. CONCLUSION: A single oral dose of risperidone plus lorazepam was as effective as parenterally administered haloperidol plus lorazepam for the rapid control of agitation and psychosis. These findings suggest that this oral regimen is an acceptable alternative to the current intramuscular treatment for acute psychotic agitation.     

Efficacy and tolerability of ziprasidone versus risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder: an 8-week, double-blind, multicenter trial

BACKGROUND: More head-to-head comparisons of antipsychotics are needed to discern the relative efficacy and safety profiles of these compounds. Thus, we compared ziprasidone and risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder. METHOD: Patients with DSM-III-R acute exacerbation of schizophrenia or schizoaffective disorder were randomly assigned to double-blind ziprasidone 40 to 80 mg b.i.d. (N = 149) or risperidone 3 to 5 mg b.i.d (N = 147) for 8 weeks. Primary efficacy measures included Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness scale (CGI-S) score; secondary measures included scores on the PANSS negative sub-scale, CGI-Improvement scale (CGI-I), and PANSS-derived Brief Psychiatric Rating Scale (BPRSd) total and core items. Safety assessments included movement disorder evaluations, laboratory tests, electrocardiography, vital signs, and body weight. Efficacy analyses employed a prospectively defined Evaluable Patients cohort. Treatment equivalence was conferred if the lower limit of the 95% confidence interval of the ziprasidone/risperidone ratio of least-squares mean change from baseline was > 0.60. Data were gathered from August 1995 to January 1997. RESULTS: Equivalence was demonstrated in PANSS total scores, CGI-S scores, PANSS negative subscale scores, BPRSd total and core item scores, and PANSS total and CGI-I responder rates. Both agents were well tolerated. Risperidone exhibited a significantly higher Movement Disorder Burden (MDB) score (p < .05) and higher incidences of prolactin elevation and clinically relevant weight gain. However, compared with current recommendations, study dosing may have been high for some risperidone-treated patients (mean dose = 7.4 mg/day) and low for some ziprasidone-treated patients (mean dose = 114.2 mg/day). CONCLUSION: Both agents equally improved psychotic symptoms, and both were generally well tolerated, with ziprasidone demonstrating a lower MDB score and less effect on prolactin and weight than risperidone.     

Risperidone in psychotic combat-related posttraumatic stress disorder: an open trial

RATIONALE: Psychotic symptoms that frequently occur in combat-related posttraumatic stress disorder (PTSD) complicate its pharmacotherapy. We hypothesized that war veterans with psychotic PTSD, resistant to prior antidepressant treatment, would respond well to 6 weeks of treatment with the atypical antipsychotic risperidone, given as a monotherapy. METHOD: Twenty-six male war veterans with psychotic PTSD (DSM-IV) completed the 6-week inpatient treatment with risperidone (2-4 mg/day) during the period from November 1999 through December 2002. The primary outcome measure was change from baseline to endpoint (6 weeks) in Positive and Negative Syndrome Scale (PANSS) total and subscale scores. Secondary outcome measures were changes in PTSD Interview (PTSD-I) and Clinical Global Impressions-Severity of Illness scale (CGI-S) total and subscale scores. Clinical improvement was assessed by CGI-S, CGI-Improvement scale, and Patient Global Impression of Improvement scale, while adverse events were recorded by Drug-Induced Extrapyramidal Symptoms Scale. RESULTS: Treatment with risperidone for either 3 or 6 weeks in an open trial significantly reduced total and subscales scores on the PANSS and on the PTSD-I and CGI-S when compared to baseline scores in patients with psychotic PTSD. CONCLUSION: Our preliminary data from the open trial indicate that risperidone decreased most of the psychotic and PTSD symptoms. Psychotic PTSD patients, unresponsive to antidepressant treatment, improved significantly after treatment for either 3 or 6 weeks with risperidone.     

The many faces of psychosis in the elderly

PURPOSE OF REVIEW: As the population ages, the number of older patients with psychosis will greatly rise. This review focuses on the etiology, biologic and clinical findings, and treatments of common causes of psychosis in the elderly. RECENT FINDINGS: Recent studies on psychosis related to Alzheimer's disease indicate that antipsychotic drugs have equivocal efficacy in improving psychotic symptoms and may have side effects or risks that outweigh their benefits. Behavioral interventions for agitation in dementia are showing some promise. In older adults with schizophrenia, intramuscular ziprasidone was found to be effective, and evidence is emerging for the use of hormone replacement therapy. For depression with psychosis, a recent study found that the combination of an antidepressant with an antipsychotic is no more effective than an antidepressant alone. SUMMARY: There is support for the use of antipsychotic drugs for all types of psychosis in the elderly. While the atypical antipsychotics have a 'black box warning' on risk of death in elderly patients with dementia, the typical antipsychotics carry an even higher risk of death and adverse effects. Weighing the potential risks and benefits of treatment options is essential. Please refer to your country's regulations regarding the use of antipsychotic drugs.     

Initial treatment of severe acute psychosis with fast orally disintegrating risperidone tablets

INTRODUCTION: Although the use of atypical antipsychotics is the standard of care in the maintenance treatment of psychosis, most clinicians still rely on conventional neuroleptics to treat acutely agitated psychotic patients. The objective of this study was to evaluate the effectiveness and safety of a fast orally disintegrating tablet formulation of risperidone in the initial treatment of a large sample of very acutely ill psychotic patients. METHODS: In this multi-center, prospective, open-label observational trial, 191 schizophrenic patients were treated upon admission to hospital with fast orally disintegrating risperidone tablets for up to seven days. Co-medication was per usual clinical practice and at physician's discretion. Psychopathology was rated at baseline, 2, 24 and 48 hours and 4 and 7 days after initiation of therapy. RESULTS: A mean PANSS total score of 114.3+/-23.4 at baseline reflected a severely exacerbated patient population. The PANSS total score was significantly reduced to 83.6+/-26.8 (p<0.0001) and the CGI from 5.6+/-0.7 to 4.5+/-1.1 (p<0.0001) after 7 days. The median time to calmness was 70 min and the associated PANSS item 4 (excitation) dropped two hours after the first intake of the study medication from 4.3+/-1.5 to 3.1+/-1.5 (p<0.0001). A total of 172 patients (90.1%) out of 191 completed the study. The median risperidone dose was 2 mg/d at the initiation of therapy and 4 mg/d after one week. CONCLUSION: Oral treatment of acutely exacerbated schizophrenic patients with fast orally disintegrating risperidone tablets, alone or in combination with benzodiazepines, was associated with a rapid onset of action and a significant and clinically relevant improvement of acute symptoms.     

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.     

Validation of the behavioural activity rating scale (BARS): a novel measure of activity in agitated patients.

We report psychometric results of the Behavioural Activity Rating Scale (BARS) using data from three Phase III clinical trials of intramuscular ziprasidone in acutely agitated patients with psychosis (Studies 1 and 2) or in stable psychotic patients (Study 3). Convergent validity and divergent validity were assessed with baseline data from Studies 1 and 2 in subjects with acute agitation. To investigate convergent validity, we sought Pearson and Spearman correlation of BARS scores with scores on the Clinical Global Impression of Severity (CGI-S) Scale and a predefined cluster of agitation-related items from the Positive and Negative Syndrome Scale (PANSS). For divergent validity, we sought Pearson and Spearman correlation between BARS scores and a predefined cluster of PANSS items measuring negative symptoms. Discriminant validity was investigated with the help of subjects with moderate psychopathology (Study 3). Wilcoxon rank-sum and two-sample t tests determined whether mean (or median) BARS scores differed between subjects with acute agitation (Studies 1 and 2) and moderate psychopathology (Study 3). Responsiveness to treatment effect and rater reliability were also evaluated. In Study 2, Pearson correlation coefficients of BARS scores with PANSS agitation items and CGI-S were moderate (convergent validity) and statistically significant (P<0.005). The correlation between BARS scores and PANSS negative component scores was low (divergent validity). Treatment effect size was larger for BARS than for PANSS agitation items and CGI-S (responsive to treatment differences). Virtually perfect inter- and intra-rater reliability was achieved. Study 1 produced similar results. BARS showed psychometrically valid properties for measurement of behavioral activity in acutely agitated patients with psychosis.     

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.     

Comparison of the density of gamma-aminobutyric acid in the ventromedial prefrontal cortex of patients with first-episode psychosis and healthy controls

Background

Abnormality in the concentration and functioning of gamma-aminobutyric acid (γ-aminobutyric acid, GABA) in the brain is not only an important hypothetical link to the cause of schizophrenia but it may also be correlated with the cognitive decline and negative symptoms of schizophrenia. Studies utilizing high field magnetic resonance spectroscopy (MRS) report abnormal density of GABA in the ventromedial prefrontal cortex (vmPFC) of patients with chronic schizophrenia, but these results may be confounded by study participants’ prior use of antipsychotic medications.

Aim

Compare the density of GABA in the vmPFC of patients with first-episode psychosis to that in healthy controls and assess the relationship of GABA density in the vmPFC to the severity of psychotic symptoms.

Methods

Single-voxel ¹H-MRS was used to assess the concentration of GABA and other metabolites in the vmPFC of 22 patients with first-episode psychosis (10 with schizophrenia and 12 with schizophreniform disorder) and 23 healthy controls. Thirteen of the 22 patients were drug-naïve and 9 had used antipsychotic medication for less than 3 days. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of psychotic symptoms in the patient group.

Results

The mean (sd) GABA density in the vmPFC was significantly higher in patients than in controls (2.28 [0.54] v. 1.93 [0.32] mM, t=2.62, p=0.012). The densities of other metabolites – including N-acetylaspartic acid (NAA), glutamic acid (GLU), and glutamine (GLN) – were not significantly different between patients and controls. Among the patients, GABA density in the vmPFC was not significantly correlated with PANSS total score or with any of the three PANSS subscale scores for positive symptoms, negative symptoms, and general psychopathology. GABA concentration was not associated with the duration of illness, but it was significantly correlated with patient age (r=0.47, p=0.026).

Conclusion

Elevation of GABA density in the vmPFC of patients with first-episode psychosis confirms that this abnormality is independent of medication use. The failure to find a correlation of GABA density in the vmPFC with the severity of psychotic symptoms needs to be confirmed in larger studies, but it suggests that there are several intervening steps between brain pathology and clinical symptoms.