Schizophrenia and Bipolar Disorder
Dementia
Agitation
Impulse Control Disorders

Schizophrenia and Bipolar Disorder

Krakowsli MI, Czobor P, Citrome L, et al: Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry 2006; 63(6):622-629.

Randomized, double-blind, parallel-group, 12-week trial. Physically assaultive subjects with schizophrenia or schizoaffective disorder who were inpatients in state psychiatric facilities were randomly assigned to treatment with clozapine (n = 37), olanzapine (n = 37), or haloperidol (n = 36). Outcome measures were number and severity of physical assaults as measured by the Modified Overt Aggression Scale (MOAS) physical aggression score and the number and severity of all aggressive events as measured by the MOAS overall score. Psychiatric symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS).

Clozapine was superior to both olanzapine and haloperidol in reducing the number and severity of physical assaults as assessed by the Modified Overt Aggression Scale (MOAS). Olanzapine was superior to haloperidol on similar outcomes. There were no significant differences among the 3 medication groups in improvement of psychiatric symptoms as measured by the PANSS total score and PANSS subscales.

The authors concluded that clozapine shows greater efficacy than olanzapine and olanzapine greater efficacy than haloperidol in reducing aggressive behavior. This anti-aggressive effect appears to be separate from the antipsychotic and sedative action of these medications.

Breier A, Meehan K, Birkitt M, et al: A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Archives of General Psychiatry 2002; 59(5):441-48.

This study was sponsored by a pharmaceutical company and included recently hospitalized acutely agitated patients with schizophrenia (N = 270) randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component scores 2 hours after the first injection. Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection.

Olanzapine exhibited a dose-response relationship for reduction in agitation. Mean PANSS-EC reductions 2 hours after the first injection of olanzapine were superior to those with placebo but not with haloperidol. A dose of 5.0, 7.5, or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection. There were no differences between treatment groups for hypotension, the most frequently reported adverse event. There was also no difference in clinically relevant changes in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol (16.7%) than with  IM olanzapine (0%) or with placebo (0%).

The authors concluded that intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile.

Dementia

Devanand DP, Mintzer MD, Schultz SK, et al: Relapse Risk after Discontinuation of Risperidone in Alzheimer’s Disease. New England Journal of Medicine 2012; 367(16):1497-1506.

180 patients with psychosis or agitation with Alzheimer’s Disease who received open-label of risperidone (average dose 0.97mg per day) for 16 weeks. Those who had a response were randomly assigned to three groups: continued risperdone therapy for 32 weeks, risperdone for 16 weeks followed by placebo for 16 weeks, or placebo for sixteen weeks. Rates of adverse events and deaths did not differ significantly. However, relapse in the group who had discontinued active treatment relapsed at higher rates (hazard ratio 4.88).

Sultzer DL, Davis SM, Tariot PN, et al: Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. American Journal of Psychiatry 2008; 165(7):844-854.

The CATIE-AD effectiveness study included 421 outpatients with Alzheimer’s Disease and psychosis or agitation. Assigned randomly to masked flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks, patients could be re- randomized to a different medication treatment at the clinician’s discretion This ended the Phase 1 period. Psychiatric and behavioral symptoms, functional abilities, cognition, care needs, and quality of life were measured at regular intervals.

There was greater improvement in patients treated with olanzapine or risperidone on the Neuropsychiatric Inventory total score, with risperidone on the Clinical Global Impression of Change, with olanzapine or risperidone on the Brief Psychiatric Rating Scale (BPRS) Hostile Suspiciousness factor, and with risperidone on the BPRS Psychosis factor at the end of phase I. There was worsening with olanzapine on the BPRS Withdrawn Depression factor.

In this descriptive analysis of clinical outcomes in AD outpatients in usual care settings, some clinical symptoms improved with atypical antipsychotic treatment. The authors concluded that antipsychotic medications may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. Functional abilities, care needs, or quality of life did not appear to improve with antipsychotics.

Vigen CLP, Mack WJ, Keefe R, et al: Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD. American Journal of Psychiatry 2011; 168(6):831-39.

CATIE-AD included 421 Alzheimer’s disease patients with psychosis or agitated behavior, randomized to blinded flexible-dose olanzapine, quetiapine, risperidone or placebo. Based on clinician’s judgment, patients could discontinue originally assigned medication and be randomized to another medication. They were followed for 36 weeks. Cognitive assessments were obtained at baseline, 12 weeks, 24 weeks and 36 weeks. Outcomes were compared among 357 patients with baseline and at least one follow-up cognitive measure obtained while on their prescribed medication or placebo for at least 2 weeks before cognitive testing.

Patients showed steady, significant declines over time in most cognitive areas, Patients on antipsychotics declined more than patients on placebo for multiple cognitive measures.

Agitation

Battaglia J, Moss S, Rush J, et al: Haloperidol, Lorazepam or Both for Psychotic Agitation? A multi-center, prospective, double-blind emergency department study. American Journal of Emergency Medicine 1997; 15(4):335-340.

Ninety-eight psychotic, agitated, and aggressive patients were prospectively enrolled during an 18-month period in emergency departments in five university or general hospitals. Patients were randomly assigned to receive intramuscular injections of lorazepam (2 mg), haloperidol (5 mg), or both in combination. Patients in each treatment group received 1 to 6 injections of the same study drug within 12 hours, based on clinical need. They were evaluated hourly after the first injection until at least 12 hours after the last. Efficacy was assessed on the Agitated Behavior Scale, a modified Brief Psychiatric Rating Scale, Clinical Global impressions scale, and an Alertness Scale. Effective symptom reduction was achieved in each treatment group with significant (P < .01) mean decreases from baseline at every hourly ABS evaluation. Significant (P < .05) mean differences on the ABS (hour 1) and MBPRS (hours 2 and 3) suggest that tranquilization was most rapid in patients receiving the combination treatment. Side effects incidence did not differ significantly between treatment groups, although patients receiving haloperidol alone tended to have more extrapyramidal system symptoms. The authors conclude that superior results are produced by the combination treatment and support the use of lorazepam plus haloperidol as the treatment of choice for acute psychotic agitation.

Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV: Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disorders 2012; 14:31-40.

This randomized, double blind, placebo-controlled, multi-center study of 314 inpatients with agitation associated with with bipolar I disorder. Subjects were randomized to inhaled loxapine 5 mg or 10 mg, or inhaled placebo. Patients receiving Dose 1 were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline inthe Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The secondary endpoint was the Clinical GlobalImpression-Improvementscore two hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests.

For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications.

The authors concluded that inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Impulse Control Disorders

Coccaro EF, Lee RJ, Kavoussi RJ: A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder. Journal of Clinical Psychiatry 2009; 70(5):653-662.

A double-blind, randomized, placebo-controlled trial of fluoxetine conducted in 100 individuals with Intermittent Explosive Disorder (research diagnostic criteria) and current histories of impulsive aggressive behavior. The primary measure of efficacy was the aggression score from the Overt Aggression Scale-Modified (OAS-M) for Outpatient Use. Secondary efficacy measures included the irritability score from the OAS-M and the Clinical Global Impressions-Improvement scale (CGI-I) score. The study took place between July 1990 and July 1999.

Fluoxetine treatment resulted in a sustained reduction in OAS-M aggression, and OAS-M irritability scores, apparent as early as week 2 (p < .01 for aggression and p < .001 for irritability at endpoint). Fluoxetine was also superior to placebo in the proportion of responders on the CGI-I (p < .001). Closer examination of the data revealed that full or partial remission of impulsive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. Fluoxetine did not exert an antidepressant or antianxiety effect, and its effects on impulsive aggression were not influenced by presence of current symptoms of depression or anxiety. Fluoxetine can reduce aggressive behaviors in those diagnosed with intermittent explosive disorder.