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Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.

Background: In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic. Method: Subjects with schizophrenia (N = 444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5–30 mg/day [N = 66]; quetiapine, 200–800 mg/day [N = 63]; risperidone, 1.5–6.0 mg/day [N = 69]; or ziprasidone, 40–160 mg/day [N = 135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason. Results: The time to treatment dis...

Background: Whilestudieshaveincreasinglyinvestigateddeficitsinreactiontime(RT)andRTvariabilityin children with attention deficit/hyperactivity disorder (ADHD), few studies have examined the effectsof stimulant medication on these important neuropsychological outcome measures. Methods: 316children who participated in the Multimodal Treatment Study of Children with ADHD (MTA) completedthe Conners’ Continuous Performance Test (CPT) at the 24-month assessment point. Outcomemeasures included standard CPT outcomes (e.g., errors of commission, mean hit reaction time (RT))and RT indicators derived from an Ex-Gaussian distributional model (i.e., mu, sigma, andtau). Results: Analyses revealed significant effects of medication across all neuropsychological out-come measures. Results on the Ex-Gaussian outcome measures revealed that stimulant medicationslows RT and reduces RT variability. Conclusions: This demonstrates the importance of includinganalytic strategies that can accurately model the actual distributional pattern, including the positiveskew. Further, the results of the study relate to several theoretical models of ADHD. Key-words: ADHD/ADD, go/no-go test, stimulants, reaction time, distributions, neuropsychology, phar-macology.A significant body of literature has documented thebehavioral benefits of stimulant medications inchildren with attention deficit/hyperactivity disorder(ADHD; Swanson et al., 1995). A majority of thesestudies have used behavioral indices such as parentand teacher rating scales and interviews to docu-ment medication effects. A minority of these studieshave utilized neuropsychological indices to assessmedication effects (see Denney & Rapport, 2001 forreview). The most commonly used neuropsycholo-gical tests across studies have been tests of attentionand inhibition. Stimulant medications appear to re-duce inhibition errors. Medication also appears tosignificantly quicken reaction time (RT) and reduceRT variability, especially on continuous performancetests (see Riccio, Reynolds, & Lowe, 2001 for review).RT variability and to a lesser extent mean RT areincreasingly becoming an area of focus in neuro-psychological studies comparing the performance ofpatients with ADHD to a control group. Significantand reliable differences in RT variability betweenADHD and normal control groups have been docu-mented on response inhibition tests (Conners, Ep-stein, Angold, & Klaric, 2003), discrimination tests(Leth-Steenson, Elbaz, & Douglas, 2000), and con-tinuous performance tests (Riccio et al., 2001). Fur-ther, Epstein et al. (2003) have shown that RTvariability demonstrated the strongest and most re-liable relationship to actual ADHD symptomatologycompared to other outcome measures on a com-monly used neuropsychological test, the Conners’CPT. The general pattern of RT differences has beenthat ADHD patients have slower and more variableRTs than normal controls (Riccio et al., 2001). Fur-ther, ADHD medications appear to accelerate meanRT and reduce RT variability (Riccio et al., 2001).Innovative new analytic techniques have beenintroduced to more accurately examine RT patternsamong ADHD patients. As pointed out by Castell-anos and Tannock (2002), the intra-individual vari-ability or moment by moment process of taskperformance in which individuals with ADHD

Comorbid conditions in children with attention deficit hyperactivity disorder (ADHD) are frequent and can affect treatment response and life course. From the multimodal treatment study of ADHD (MTA), we examined the persistence or development of conditions other than ADHD, e.g. oppositional defiant disorder (ODD), conduct disorder (CD), anxiety, depression, and learning disorder (LD) in 576 children, age 7–9 years, diagnosed rigorously with ADHD, who were randomly assigned to four different treatments for 14 months. The treatment groups were medication management alone (MedMgt), behavioral treatment alone (Beh), the combination (Comb), and community comparison routine care (CC). For the sample as a whole, we found significant decreases from baseline to 14 months in diagnoses of ODD, CD, and anxiety disorder but not LD or mood disorder. The CC group developed significantly more new ODD and retained more baseline ODD than the Comb or MedMgt groups. There were no significant treatment group differences for specific other conditions. Only the Comb group was significantly better than the CC group in reducing total number of disorders and impairment at 14 months in subjects with multiple conditions at baseline. Well-titrated and monitored stimulant medication can decrease ODD and possibly prevent future CD. Combined treatment may be required for the most disturbed children with ADHD who have multiple disorders and severe impairment.

background The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P

Maintenance treatment in schizophrenia requires the integration of both medication and psychosocial treatment interventions for maximum effect. We review the recent evidence for strategies drawn from both domains. For the use of anti-psychotic medication we focus on studies of dose reduction using two strategies that differ in assumptions regarding the action of medication. They are: continuous low-dose and targeted, early intervention or intermittent treatment. For psychosocial interventions we focus on studies of family treatment. Regarding dose reduction, we conclude that both strategies are feasible but the targeted strategy incurs higher relapse and rehospitalization rates. Regarding family treatment, we conclude that family treatment provides benefits beyond other psychosocial interventions or usual care, but that there is no evidence for differences in efficacy among family treatments.

Context Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. Objective To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. Design and setting Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Participants Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Interventions Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Main outcome measures Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. Results On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. Conclusion This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.