Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms

Positive and negative symptoms of psychosis may be common in patients with chronic post-traumatic stress disorder (PTSD), but few studies have investigated the use of antipsychotic agents in these patients. This preliminary study examined the potential efficacy of risperidone in treating psychotic symptoms associated with chronic PTSD. In a 5-week, prospective, randomized, double-blind, placebo-controlled trial, adjunctive risperidone treatment was assessed in 40 combat veterans with chronic PTSD and comorbid psychotic features. Most patients were receiving antidepressants and some other psychotics with doses of concurrent medications held constant for at least 1 month prior to and during the study. Thirty-seven patients completed at least 1 week of treatment with risperidone or placebo. The Positive and Negative Syndrome Scale (PANSS) and the Clinician Administered PTSD Scale (CAPS) were used to assess symptoms. The PANSS was the primary outcome measure. At treatment endpoint, risperidone-treated patients showed a significantly greater decrease from baseline, albeit modest, in psychotic symptoms (PANSS total scores) than placebo-treated patients (P < 0.05). CAPS ratings declined significantly in both groups but did not differ significantly between groups. However, CAPS re-experiencing subscale scores had greater improvement in the risperidone-treated patients at week 5 (P < 0.05, completer analysis) with a trend towards greater improvement versus placebo a endpoint (P < 0.1, LOCF). Risperidone was well tolerated with minimal extrapyramidal symptoms. These preliminary results support studying the potential efficacy of risperidone for treating global psychotic symptoms associated with chronic PTSD with a suggestion that core re-experiencing symptoms may also be responsive. Further research using randomized, controlled trial designs in larger patient groups are needed to define more adequately the role of risperidone and other atypical agents in PTSD.     

Oral risperidone with lorazepam versus oral zuclopenthixol with lorazepam in the treatment of acute psychosis in emergency psychiatry: a prospective, comparative, open-label study

Acutely psychotic patients presenting as psychiatric emergencies with aggression or agitation are often administered conventional antipsychotics intramuscularly. However, patients view intramuscular administration as coercive, and conventional antipsychotics are often associated with adverse events. In this open study, consecutive adult patients presenting with an acute exacerbation of schizophrenia or other psychotic disorder were assigned to oral risperidone 2-6 mg/day (n = 48) or oral zuclopenthixol 20-50 mg/day (n = 27) for 7-14 days. Lorazepam (either oral or intramuscular) was administered to both groups as needed. Patients were assessed regularly until day 14 or discharge. Mean Positive And Negative Syndrome Scale (PANSS) aggression scores (sum of item scores on excitement, poor impulse control, hostility and uncooperativeness) decreased steadily and similarly in both groups; the mean changes from baseline were statistically significant at days 10 and 14 and at study end-point. The mean decrease at study end-point in the PANSS component score for hostility was statistically significant in the risperidone group, but not in the zuclopenthixol group. Social Dysfunction and Aggression Scale aggression scores and Clinical Global Impression scores decreased significantly and similarly in both groups. Overall, 18.7% of patients showed minor extrapyramidal symptoms during the study, but only 16.7% of risperidone-treated patients, compared to 59.3% of zuclopenthixol-treated patients, received anti-parkinsonian medication (p < 0.001). Lorazepam was administered to all of the patients assigned to risperidone and to 89% of those assigned to zuclopenthixol. Oral risperidone plus lorazepam is a convenient, effective and well-tolerated alternative to conventional antipsychotics for the treatment of acute psychosis in emergency psychiatry.     

An open-label extension trial of risperidone monotherapy in the treatment of bipolar I disorder

The primary objective of this 9-week open-label extension trial was to assess the effects of risperidone monotherapy in patients with acute bipolar I disorder who completed treatment in two preceding 3-week double-blind trials. Patients with DSM-IV bipolar I disorder, experiencing an acute manic episode, received a flexible dose of risperidone (1-6 mg/day) or placebo in two independent double-blind, randomized, 3-week monotherapy trials. Completers who required ongoing treatment were eligible to enter this open-label 9-week extension trial during which all patients received risperidone. The primary efficacy measure was the mean change in the Young Mania Rating Scale (YMRS) total score. Secondary efficacy measures included the Clinical Global Impressions-Severity Scale, Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale and Global Assessment Scale. Safety assessments included adverse event reports, laboratory tests, and the Extrapyramidal Symptom Rating Scale (ESRS). Of the 283 patients who entered the extension study, 160 had previously received risperidone (RIS/RIS) in the acute treatment trial and 123 had received placebo (PLA/RIS). This study was completed by 71% of these patients. The mean+/-SE modal dose of risperidone was 4.6+/-1.5 mg/day. Patients in both the RIS/RIS and PLA/RIS groups improved significantly at the endpoint of the 9-week open-label study compared to their open-label baseline scores (-5.2+/-0.69, P<0.001 and -9.12+/-1.44, P<0.001, respectively) on the YMRS. Furthermore, changes from double-blind baseline to open-label endpoint were -29.4+/-1.0 in the RIS/RIS group and -23.9+/-1.4 in the PLA/RIS group. Significant improvements from both double-blind and open-label baseline were seen at week 1 of the open-label trial (P<0.001) and at each subsequent timepoint. A similar pattern was observed on the secondary measures of efficacy. Most frequent adverse events were extrapyramidal disorder (18%) and somnolence (12%). Most adverse events were mild or moderate in severity. The mean score for the Parkinsonism subscale of the ESRS was 1.1 at open-label baseline, and decreased by 0.1 at endpoint. Mean increase in body weight from open-label baseline was 0.6 kg in patients treated with placebo in the preceding double-blind trial and 1.2 kg in patients previously treated with risperidone. Risperidone treatment was well tolerated and resulted in further improvement during the 9-week extension, beyond the 3 weeks of acute treatment. Patients switched from placebo to risperidone improved markedly. Risperidone treatment did not induce depression.     

Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study

This double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 wk of risperidone augmentation of serotonin reuptake inhibitor (SRI) treatment in adult subjects with treatment-resistant obsessive-compulsive disorder (OCD) (failure of at least two SRI trials). Sixteen adult treatment-resistant OCD patients were randomly assigned to augmentation with 8 wk of either risperidone (n=10) (0.5-3.0 mg/d) or placebo (n=6) following at least 12 wk of SRI treatment. Four patients on risperidone (40%) and none (0%) on placebo were responders with both a Clinical Global Impression - Improvement (CGI-I) score of 1 or 2 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease >/=25%. Risperidone was generally well tolerated: there were 3 dropouts, 1 on risperidone and 2 on placebo. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation. Risperidone may be an effective and well-tolerated augmentation strategy in treatment-resistant OCD subjects, but larger sample size studies are required to demonstrate this.     

Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial

Background:Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms. Methods: Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating >/=4 despite >/=8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. Results: Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups. Conclusions: Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated.     

Patient-based and clinician-based support for the remission criteria in schizophrenia

This analysis characterizes patients with schizophrenia or schizoaffective disorder treated with risperidone who met remission criteria. In a 50-week, open-label trial, stable patients received long-acting injectable risperidone every 2 weeks. Remission criteria included severity (absent-mild ratings on core symptoms of the Positive and Negative Syndrome Scale) and duration (> or =6 months) components. The patients not remitted (severity component only) at baseline (n=394) are the subjects of this report. Measures applied included the PANSS, Clinical Global Impressions-Severity, patient-rated mental health status (Short Form-36), and Drug Attitude Inventory. Among patients who met remission criteria during the study (n=82), mean scores for all 30 PANSS items reflected absent-mild ratings at endpoint. The highest items represented an 'interpersonal' cluster, although mean ratings were still minimal to mild. Remitted patients experienced substantial improvements in Short Form-36 and Drug Attitude Inventory scores at endpoint. Although improvement occurred, it was less robust in patients who remained nonremitted (n=312). Logistic regression analysis found that remission (severity component only) was associated with a 97.1% probability of a 'not ill' rating on the Clinical Global Impressions-Severity. These remission criteria identified patients who differed from the nonremitted population on symptoms of psychopathology, medication attitude, health status, and overall clinical status, supporting the clinical validity of the remission criteria.     

Effects of risperidone on affective symptoms in patients with schizophrenia

The effects of risperidone on affective symptoms were determined by an analysis of pooled data from six double-blind trials of risperidone versus haloperidol in 1254 patients with chronic schizophrenia. Symptoms indicating mania were assessed by the Positive and Negative Syndrome Scale (PANSS) excitement and grandiosity items and by the excited cluster (excitement, hostility, uncooperativeness, and poor impulse control); anxious / depressive symptoms were assessed by the PANSS anxious / depressive cluster (somatic concern, anxiety, guilt feelings, and depression). Mean change scores from baseline to endpoint were compared in patients receiving risperidone, haloperidol or placebo by analysis of variance with factors for trial and baseline score included in the model. In all patients, change scores on excitement and grandiosity items and excited and anxious / depressive clusters were significantly greater for risperidone than for haloperidol or placebo. Dropouts due to inefficacy were less frequent with risperidone (5 of 59; 8%) than with haloperidol (7 of 38; 18%) or placebo (8 of 10; 80%). In patients with anxious / depressive symptoms at baseline (anxiety / depression cluster score > or = the median), anxiety / depression scores decreased significantly more with risperidone than with haloperidol, and symptom reduction occurred faster with risperidone. These results are consistent with previous reports and suggest that risperidone is more efficacious than haloperidol for affective symptoms in patients with schizophrenia.     

Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder

Increased aggressive behavior can occur in association with posttraumatic stress disorder (PTSD). This study tested the hypothesis that low-dose risperidone reduces aggression and other PTSD-related symptoms in combat veterans. Subjects were male combat veterans with PTSD who scored 20 or higher on cluster D (hyperarousal) of the Patient Checklist for PTSD-Military Version (PCL-M). Subjects were randomly assigned to either risperidone or placebo treatment groups. Drugs were administered over a 6-week treatment period in a double-blind manner. Subjects received either risperidone (0.5 mg/day; n = 7) or matched placebo (n = 8) tablets during the first 2 weeks of the treatment period. The dose of risperidone could then be increased up to 2.0 mg/day on the basis of response. Prerandomization psychotropic regimens were continued. Subjects were evaluated with the PCL-M and the Overt Aggression Scale-Modified for Outpatients (OAS-M). In comparison with placebo treatment, reductions in scores between baseline and the last week of treatment were significantly greater for OAS-M irritability and PCL-M cluster B (intrusive thoughts) subscales and on the PCL-M total scale. These results suggest that low-dose risperidone administration reduces irritability and intrusive thoughts in combat-related PTSD.     

Risperidone for the treatment of fecal smearing in a developmentally disabled adult.

PURPOSE: The use of risperidone in decreasing fecal smearing behavior as an expression of nonverbal aggression in a developmentally disabled adult is discussed. SUMMARY: A 36-year-old Caucasian man had a history of fecal smearing when he did not get his way or was upset. The patient had profound mental retardation, had an IQ in the range of less than 20 to 25, and was nonverbal. For this patient, fecal smearing was not only a behavioral issue but also a medical concern because he was hepatitis B positive with noncarrier status. Serology also confirmed previous infection with hepatitis A. Risperidone was started at 0.5 mg twice daily. Smearing frequencies during baseline and after risperidone intervention were tracked. During the course of treatment, the risperidone dosage was increased to a total daily dose of 4 mg. The mean +/- S.D. number of episodes per month decreased from 15.2 +/- 3 in the pretreatment period to 6.0 +/- 1.8 at 6 months and 6.7 +/- 1.2 at 12 months posttreatment with risperidone. On follow-up in October 2003, fecal smearing had further decreased to the point where it was no longer formally tracked. A diagnosis of mental retardation, developmental disability, or pervasive developmental disorder increases the possibility for emotional and behavioral problems. Previous medication classes tried in the management of aggressive behaviors have not produced consistent results. Risperidone has been used in the treatment of self-abuse, aggression toward others, and violent behaviors. CONCLUSION: Risperidone was effective in decreasing episodes of fecal smearing as an expression of nonverbal aggression in a developmentally disabled adult.     

Risperidone in acute and continuation treatment of mania

In a prospective study, we examined the efficacy of risperidone added-on to mood stabilizers in the acute and continuation treatment of mania over a 12-week period. Patients (n=108) with a DSM-IV diagnosis of bipolar disorder, manic or mixed episode requiring treatment with an antipsychotic were recruited. All subjects were on one or two mood stabilizers at the time of initiation of risperidone (range 0.5-4 mg). No other antipsychotic medication or ongoing benzodiazepine therapy was allowed. There was a significant decrease in mean Young Mania Rating Scale (YMRS) scores from baseline (27.5+/-7.5) to week 1 (-10.8, P<0.0001), week 3 (-17.7, P<0.0001) and to week 12(-22.6, P<0.0001). When response was defined as > or = 50% reduction in YMRS scores from baseline, 32%, 68% and 90% of patients met criteria at week 1, week 3 and week 12, respectively. Significant decreases in mean 21-item Hamilton Depression Rating Scale scores from baseline (12.2+/-7.7) to week 3 (-5.7, P<0.0001) and week 12 (-5.7, P<0.0001) were also observed. No significant changes in extrapyramidal symptoms were noted between baseline and endpoint. The mean daily dose of risperidone was 2 mg with a median of 1.8 mg. These findings support the results of the two previous double-blind, randomized trials and indicate that the addition of risperidone to mood stabilizers is a safe and effective treatment for acute and continuation treatment of mania. Risperidone add-on does not induce depressive symptoms and, furthermore, risperidone may have efficacy in treating comorbid depressive symptoms in bipolar patients.     

Paliperidone extended-release tablets in schizophrenia patients previously treated with risperidone

To assess the effect of paliperidone extended-release (ER) tablets in patients with acute symptoms who had previously received risperidone. Data for this post-hoc analysis were pooled from three 6-week, double-blind, placebo-controlled trials in patients treated with paliperidone ER 3-12 mg/day or placebo. Patients had to have received risperidone for > or =4 weeks within 2 weeks of study entry. Assessments were done using the Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Personal and Social Performance scale, the Simpson-Angus Scale , and adverse event (AE) reports. Altogether, 198 patients (paliperidone ER, n=142; placebo, n=56) met the established criteria. Mean (SD) duration of prior risperidone treatment and dose were 418.8 (572.8) days and 4.4 (2.5) mg/day for paliperidone ER and 527.0 (805.3) days and 4.1 (2.5) mg/day for placebo. Study completion rates were 61.3% for paliperidone ER versus 42.9% for placebo. At endpoint, paliperidone ER showed significant improvement versus placebo (P<0.05) in Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity, and Personal and Social Performance scores. Mean baseline Simpson-Angus Scale scores were low, with no significant changes at endpoint in either group. AEs > or =10% with paliperidone ER versus placebo were headache (16.2 vs. 16.1%), insomnia (14.1 vs. 16.1%), and agitation (8.5 vs. 10.7%). AE-related discontinuations were 2.1% with paliperidone ER and 5.4% with placebo. In patients who had received risperidone previously but remained sufficiently symptomatic for enrollment, paliperidone ER was significantly more effective than placebo in reducing symptoms and producing functional gains.     

Olanzapine versus risperidone. A prospective comparison of clinical and economic outcomes in schizophrenia

OBJECTIVE: To compare the clinical and economic outcomes associated with olanzapine and risperidone treatment for schizophrenia. DESIGN AND SETTING: An international, multicentre, double-blind, prospective study. To facilitate economic comparisons, our sample was restricted to patients enrolled in US sites. 150 patients with a Diagnostic and Statistical Manual of mental disorders, 4th edition (DSM-IV) diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder were randomised to therapy with either olanzapine 10 to 20 mg/day (n = 75) or risperidone 4 to 12 mg/day (n = 75) for a maximum of 28 weeks. In addition to tolerability and efficacy assessments, use of health services was assessed at baseline and prospectively, at 8-week intervals and at study completion. Clinically important response, defined as a 40% improvement in the Positive and Negative Syndrome Scale total score, maintenance of response and rates of treatment-emergent extrapyramidal symptoms were compared between groups. Direct medical costs were estimated by assigning standardised prices to resource units. Median total, inpatient/outpatient service and medication acquisition costs were compared between treatment groups. MAIN OUTCOME MEASURES AND RESULTS: The mean modal dosages for the olanzapine and risperidone treatment groups were 17.7 +/- 3.4 mg/day and 7.9 +/- 3.2 mg/day, respectively. Olanzapine-treated patients were more likely to maintain response compared with risperidone-treated patients (p = 0.048). In addition, a smaller proportion of olanzapine-treated patients required anticholinergic therapy compared with risperidone-treated patients (25.3 vs 45.3%; p = 0.016). Total per patient medical costs over the study interval were $US2843 (1997 values) [36%] lower in the olanzapine treatment group than in the risperidone treatment group (p = 0.342). Medication costs were significantly higher for olanzapine-treated patients ($US2513 vs $US1581; p < 0.001), but this difference was offset by a reduction of $US3774 (52%) in inpatient/outpatient service costs for olanzapine-treated patients in comparison with risperidone-treated patients ($US3516 vs $US7291, p = 0.083). Median cost findings were consistent with results observed using other robust measures of central tendency and provide conservative estimates of potential savings that may be obtained from olanzapine therapy. CONCLUSIONS: In this study, olanzapine-treated patients experienced clinical improvements that translated into savings in costs of care for both inpatient and outpatient services. These savings offset the difference in medication acquisition cost between olanzapine and risperidone.     

A comparison of the effects of olanzapine and risperidone versus placebo on eating behaviors

To thoroughly investigate the phenomenon of atypical antipsychotic associated weight gain, a feeding laboratory paradigm was developed. This study is a randomized, double-blind, parallel group trial comparing the tolerability and effects of a two-week exposure to olanzapine, risperidone or placebo on weight, resting energy expenditure (REE), and eating behaviors in 48 healthy human subjects. Subjects were randomized to receive olanzapine, risperidone, or placebo and titrated over four days to 10 mg/d, or 4 mg/d, respectively. The mean dose at endpoint was 8.75 mg/day for the olanzapine group and 2.88 mg/d risperidone group. Weight changes were significantly different between groups at midpoint (F = 5.477, df = 2, 44, P = .0001). The olanzapine group demonstrated a significant increase in weight at midpoint (1.59 + 1.80 kg, P = .002) and endpoint (2.25 + 1.62 kg, P = .0001) compared to placebo and at endpoint compared to risperidone (1.05 + 1.15 kg, P = .015). Resting energy expenditures corrected for fat free mass did not reveal any differences between groups. Olanzapine subjects demonstrated significantly more dry mouth and sedation versus placebo while risperidone subjects experienced significantly more sedation, dry mouth, dizziness stuffy nose and restlessness than placebo and more dizziness and stuffy nose versus olanzapine subjects. Thus, a human feeding lab paradigm utilizing a brief exposure to atypical antipsychotics functions as a method to investigate pharmacologically induced weight gain.     

A placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia.

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was -0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.     

Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol.

In a randomized, double-blind trial, patients with acute bipolar mania received 1-6 mg/day of risperidone, 2-12 mg/day of haloperidol, or placebo for 3 weeks, followed by double-blind risperidone or haloperidol for 9 weeks. Of 438 patients, 154 were randomized to risperidone, 144 to haloperidol, and 140 to placebo. The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period. At week 3, mean Young Mania Rating Scale (YMRS) score reductions from baseline were significantly greater in patients receiving risperidone than placebo (p<0.001). Differences between risperidone and haloperidol on this efficacy measure were not significant. Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks. No unexpected adverse events were reported. Extrapyramidal disorder and hyperkinesias, the most commonly reported adverse events with antipsychotic use, occurred less frequently with risperidone than haloperidol. We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term.     

Risperidone does not affect steady-state pharmacokinetics of divalproex sodium in patients with bipolar disorder

OBJECTIVE: Divalproex sodium can interact with many drugs in which combination treatments are used; it can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of other medications by displacing them from plasma proteins. The combination of risperidone and divalproex sodium is used to treat the manic phase of bipolar disorder. However, the effect of risperidone on the pharmacokinetics of valproate has not previously been systematically studied. The aims of this study were to determine the effect of repeated doses of oral risperidone on the pharmacokinetics of valproate in subjects stabilised on divalproex sodium and to document the safety of this combination. STUDY DESIGN: A multicentre, observational, randomised, parallel group, single-blind, placebo-controlled drug interaction study. PATIENTS: Twenty-two patients with bipolar disorder, in remission, were studied. METHODS: All subjects were treated with divalproex sodium 1000 mg/day monotherapy on days 1-14. Thereafter, subjects continued to take divalproex sodium for days 15-28; they also received adjunctive treatment with either placebo (n = 11) or risperidone (n = 11) 2mg once daily on days 15 and 16, and 4 mg once daily on days 17-28. Serial blood sampling was performed throughout to determine the plasma concentrations of valproate, risperidone and 9-hydroxy-risperidone. RESULTS: On analysis, steady-state pharmacokinetic parameters (peak plasma concentrations [C(max)], time to C(max,) area under the concentration-time curve) of valproate were of the same order of magnitude on day 14 (monotherapy) and day 28 (valproate plus risperidone or placebo), with no period effect. The parameters on day 28 were similar in the risperidone and placebo treatment groups, showing that risperidone, as adjunctive treatment, had no influence on the steady-state pharmacokinetics of valproate. Although there were more adverse events reported in the risperidone group compared with the placebo group (ten vs seven, respectively), none of them were serious or necessitated withdrawal. No clinically relevant changes in laboratory parameters, vital signs or ECG-tracings were observed in either group. CONCLUSION: These results indicate that adjunctive risperidone treatment had no influence on the steady-state pharmacokinetics of valproate and this combination was safe and well tolerated.     

Effects of risperidone on the peripheral noradrenegic system in patients with schizophrenia: a comparison with clozapine and placebo.

Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in risperidone-treated patients and compared their data with those from patients treated with clozapine or placebo. NE levels in risperidone patients were significantly higher than in placebo patients, but lower than in clozapine patients. Neither drug, however, had significant effect on plasma levels of the main neuronal metabolite of NE, dihydroxyphenylglycol (DHPG), suggesting that adrenoceptors blockade alone would not explain the NE findings. The rate of release of endogenous NE into the bloodstream (spillover) was elevated in both risperidone and clozapine patients in a manner that paralleled their NE levels; the NE clearance in both groups did not differ from placebo. Following 3H-NE infusion in risperidone-treated individuals, production of 3H-DHPG was normal, as it was in the clozapine group, suggesting that risperidone does not impede neuronal uptake or intraneuronal metabolism of NE by monoamine oxidase. Our data suggest that both risperidone and clozapine elevate plasma NE levels via enhanced neurotransmitter spillover, with risperidone producing a smaller effect.     

A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder

The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.     

Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study

This study compares the efficacy, safety, and tolerability of a partial dopamine agonist, aripiprazole, with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode. In total, 272 hospitalized patients were randomized to aripiprazole 30 mg/day or placebo in this 3-week, double-blind, placebo-controlled trial. Dosing could be reduced to 15 mg/day for tolerability and, subsequently, increased to 30 mg/day based on clinical response. Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score; response was defined as > or = 50% decrease from baseline YMRS score. Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3. A significantly higher response rate was observed in aripiprazole-treated patients (53% vs. 32% at endpoint). Aripiprazole produced significantly greater improvements from baseline on other efficacy assessments compared with placebo, including Clinical Global Impression - Bipolar Version Severity and Improvement scores. The 30 mg/day dose was maintained by 85% of aripiprazole-treated patients. Incidence of discontinuations due to adverse events was similar for aripiprazole (8.8%) and placebo (7.5%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation. In conclusion, aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes, and exhibited a favourable safety and tolerability profile.     

The relationship between early changes in the HAMD-17 anxiety/somatization factor items and treatment outcome among depressed outpatients

The 17-item Hamilton Rating Scale for Depression (HAMD-17) Anxiety/Somatization factor includes six items: Anxiety (psychic), Anxiety (somatic), Somatic Symptoms (gastrointestinal), Somatic Symptoms (general), Hypochondriasis and Insight. This study examines the relationship between early changes (defined as those observed between baseline and week 1) in these HAMD-17 Anxiety/Somatization Factor items and treatment outcome among major depressive disorder (MDD) patients who participated in a study comparing the antidepressant efficacy of a standardized extract of hypericum with both placebo and fluoxetine. Following a 1-week, single-blind washout, patients with MDD diagnosed by the Structured Clinical Interview for DSM-IV (SCID) were randomized to 12 weeks of double-blind treatment with hypericum extract (900 mg/day), fluoxetine (20 mg/day) or placebo. The relationship between early changes in HAMD-17 anxiety/somatization factor items and treatment outcome was assessed separately for patients who received study treatment (hypericum or fluoxetine) versus placebo with a logistic regression method. One hundred and thirty-five patients (female 57%, mean age=37.3+/-11.0 years; mean baseline HAMD-17=19.7+/-3.2 years) were randomized to double-blind treatment and were included in the intent-to-treat (ITT) analyses. After adjusting for baseline HAMD-17 scores and for multiple comparisons with the Bonferroni correction, patients who remitted (HAMD-17 score <8) after study treatment had significantly greater early improvement in Somatic Symptoms (General) scores than non-remitters. No other significant differences in early changes were noted for the remaining items between remitters versus non-remitters who received active treatment. For patients treated with placebo, early change was not predictive of remission for any of the items after Bonferroni correction. In conclusion, the presence of early improvement on the HAMD-17 item concerning fatigue and general somatic symptoms is significantly predictive of achieving remission at endpoint with active study treatment but not with placebo.