Handling of Missing Outcome Data in Acute Stroke Trials: Advantages of Multiple Imputation Using Baseline and Postbaseline Variables

Background

In acute stroke randomized trials, missingness of final functional outcome data reduces study power and potentially biases findings of treatment effect. Best methods for handling missing outcome data have not been well delineated for diseases with monophasic onset and subsequent improvement, like acute stroke.

Evidence Base for Using Atypical Antipsychotics for Psychosis in Adolescents

Atypical antipsychotic medications have been the first line of treatment for adolescents with psychosis in the past couple of decades. Till the late 90s, there were very few randomized controlled trials (RCTs) on the treatment of adolescents with psychosis, although a fifth of schizophrenia starts during adolescence. Most of the treatment guidelines for adolescents with psychosis were derived from data on adults. In the past 10 years, there has been increasing number of studies on adolescents with psychosis. The current paper summarizes the findings of trials on adolescents with psychosis in 4 groups: (a) atypical antipsychotic medications vs placebo, (b) atypical antipsychotic medication vs typical antipsychotic medications, (c) one atypical antipsychotic medication vs another atypical antipsychotic medication, and (d) Low dose vs standard dose of atypical antipsychotic medication. We included 13 RCTs, with a total of 1112 participants. Although our review suggest that atypical antipsychotic medications are as effective as typical antipsychotic medications as regards clinical efficacy, atypical antipsychotic medications have a preferred side effect profile and lesser drop-out rate from trials. Obviously, this is extremely important as treatment adherence is key to successful remission of psychotic symptoms and also in some case prevent relapse of illness. Treatment with olanzapine, risperidone, and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidemia. Adolescents may respond better to standard-dose as opposed to lower dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trial should be longer term and have uniform ways of reporting side effects.Key words: atypical antipsychotic, medications, adolescents, psychosis, systematic review, meta-analysis, young people, pharmacology, schizophrenia     

Pharmacological Strategies to Counteract Antipsychotic-Induced Weight Gain and Metabolic Adverse Effects in Schizophrenia: A Systematic Review and Meta-analysis

Background: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. Objective: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Data Sources: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Study Selection: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Data Extraction: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Data Synthesis: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to −3.17 kg (95% CI: −4.44 to −1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. Conclusion: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.Key words: antipsychotic, meta-analysis, metabolic, concomitant, PRISMA, schizophrenia     

Assessing and interpreting treatment effects in longitudinal clinical trials with missing data.

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure.     

Efficacy of atypical antipsychotic medication in the management of behaviour problems in children with intellectual disabilities and borderline intelligence: a systematic review

The use of medications to manage problem behaviours is widespread. However, robust evidence to support their use seems to be lacking. The aim was to review research evidence into the efficacy of atypical antipsychotic medication in managing problem behaviour in children with intellectual disabilities and borderline intelligence. A systematic review was conducted for placebo-controlled randomised double-blind trials. The included studies (N = 6) showed that risperidone was significantly more effective than placebo in managing problem behaviours. However, most studies highlighted adverse events primarily somnolence and weight gain. There is now some evidence in favour of the use of risperidone. However, because of possible adverse events, these medications have to be used with caution.     

Use of depot antipsychotic medications for medication nonadherence in schizophrenia

Objectives: To describe factors associated with initiation of depot antipsychotic medications in psychiatric outpatients with schizophrenia and recent medication nonadherence. Methods: A national sample of psychiatrists reported on adult outpatients with schizophrenia who were nonadherent with oral antipsychotic medications in the last year. Results: In total, 17.6% of psychiatrists initiated depot antipsychotic injections. Initiation was significantly and positively associated with public insurance, prior inpatient admission, proportion of time nonadherent, average or above average intellectual functioning, and living in a mental health residence. Use was inversely associated with using second-generation antipsychotics and other oral psychotropic medications prior to medication nonadherence. Psychiatrists who were male, nonwhite, and more optimistic about managing nonadherence were more likely to initiate depot injections. Conclusions: Initiation of depot injections is a joint function of patient, physician, treatment, and setting factors. Use of long-acting preparations in this population is uncommon despite clinical recommendations urging their use.     

Management of treatment resistance in schizophrenia.

A systematic approach to the evaluation and characterization of treatment resistance in schizophrenia has become increasingly important since the introduction of the second-generation antipsychotics. The need for accurate evaluation will increase further as other new antipsychotic medications are developed. Patients with schizophrenia may manifest poor response to therapy because of intolerance to medication, poor adherence, inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Criteria for treatment-resistance are presented to help in standardizing treatment and clinical trials. As clinicians face the decision of when to change or augment antipsychotic medications, a clear understanding of the appropriate length of a treatment trial and which target symptoms respond to antipsychotic therapy is critical for maximizing response in patients with treatment-resistant schizophrenia.     

Toward a model of memory enhancement in schizophrenia: glucose administration and hippocampal function

Recognition of the need to treat cognitive deficits in schizophrenia is compelling and well established, with empirical findings and conceptual arguments related to cognitive enhancement appearing regularly in the literature. Cognitive enhancement itself, however, remains at an early stage. Biological approaches have centered on the development of antipsychotic medications that also improve cognition, but the results have so far remained modest. As a way to facilitate the development of cognitive enhancers in schizophrenia, this article focuses on adjunctive pharmacological approaches to antipsychotic medications and highlights the need for systematic explorations of relevant brain mechanisms. While numerous conceptual criteria might be employed to guide the search, we will focus on 4 points that are especially likely to be useful and which have not yet been considered together. First, the discussion will focus on deficits in a particular cognitive domain, verbal declarative memory. Second, we will review the current status of preclinical and clinical efforts to improve declarative memory using antipsychotic medications, which is the main, existing mode of treatment. Third, we will examine an example of an adjunctive intervention-glucose administration-that improves memory in animals and humans, modulates function in brain regions related to verbal declarative memory, and is highly amenable to translational research. Finally, a heuristic model will be outlined to explore how the intervention maps on to the underlying neurobiology of schizophrenia. More generally, the discussion underlines the promise of cognitive improvement in schizophrenia and the need to approach the issue in a programmatic manner.     

A prospective, multicentre, open-label study to evaluate the effectiveness of aripiprazole in the treatment of a broad range of patients with schizophrenia

PurposeThe aim of this study is to evaluate the effectiveness of 12-week treatment with aripiprazole in a broad range of patients suffering from schizophrenia by using a variety of physicians, caregivers and patients scales.Subjects and methodsA total of 361 in- or outpatients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia received open-label aripiprazole (10–30 mg per day) in this 12-week, prospective, multicentre, uncontrolled study. The primary endpoint was the Clinical Global Impression-Improvement (CGI-I) scale which measured effectiveness of study medication, including efficacy, safety and tolerability. A variety of physician-, patient- and caregiver-rated parameters were measured to gain a complete view of the effectiveness of aripiprazole.ResultsThe effectiveness of aripiprazole treatment was demonstrated in a broad range of schizophrenia patients (CGI-I score of 3.0; 95% confidence interval: 2.8, 3.2: last observation carried forward [LOCF]) as the upper bound of the 95% CI was less than 4 (score of “no change”). Both patient and caregiver PGI-I scores (LOCF: 95% CI: 2.79, 3.09 and, 95% CI: 2.74, 3.17, respectively) corroborate this finding. Aripiprazole had a positive effect on disease severity by study end, as assessed by an increase of the (physician-rated) CGI-S scores, with 57.3% of patients having improved disease, one-third maintaining their condition (30.8%) and 11.3% with worsening symptoms (LOCF). The Investigator Assessment Questionnaire (IAQ) showed a great improvement (>50% of patients). Patients reported significantly improved quality of life and overall, 71% of patients and 67% of caregivers preferred aripiprazole to their previous antipsychotic medication (LOCF; P < 0.0001 over time).ConclusionAripiprazole was effective in a broad range of patients with schizophrenia.     

Comparative remission rates of schizophrenic patients using various remission criteria

Rationale

New standardized criteria for remission in schizophrenia were presented in 2005 which need to be examined in regard to their significance for clinical trials.

Objectives and methods

Data of six antipsychotic drug trials (n = 2463) were analyzed by evaluating the proportion of participants who meet the new remission criteria, their symptomatic components, other criteria for remission and simple response-measures (at least 50% Brief Psychiatric Rating Scale (BPRS) reduction and an at least 50% PANSS reduction or a CGI-severity score of “mild or better”).Results: A total of 23.3%/27.2% (last-observation-carried-forward (LOCF)/completer analysis (CO)) of the patients with positive symptoms at baseline met the severity criteria of remission at 4 weeks, 10.5%/20.3% (worst case/CO) met the severity and time criteria at 28 weeks (three studies) and 10.9%/32.4% (worst case/CO) met the severity and time criteria at 52 weeks (one study). At 4 weeks 4.5%/5.5% (LOCF/CO) met the severity criteria when a more stringent severity threshold of “very mild or better” was applied. Absence of symptoms was attained only sporadically. The psychotic symptoms component was met by fewer patients than the negative component. The criteria were more stringent than “at least 50% BPRS reduction” and “CGI-severity score not more than mild” and – for the long-term results – than “at least 50% PANSS reduction”. In the short-term analysis, the criteria were less stringent than “at least 50% PANSS reduction”.

Conclusions

The applicability of the severity component of the new criteria in clinical trials was confirmed. The time criterion remains difficult to evaluate.     

A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients Schizophrenia Trial of Aripiprazole: (STAR) study.

BACKGROUND: Naturalistic effectiveness trials of atypical antipsychotics are needed to provide broader information on efficacy, safety, and tolerability in patients with schizophrenia treated in a community practice setting. METHOD: In this 26-week, open-label, multicentre study, patients with schizophrenia requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled were randomized to receive aripiprazole or an atypical antipsychotic standard of care (SOC) treatment (i.e., olanzapine, quetiapine, or risperidone based on the investigator's judgment of the optimal treatment for the individual patient and the patient's prior response to antipsychotic medication). The primary objective was to compare the effectiveness of a 26-week treatment of aripiprazole versus SOC, as measured by the Investigator Assessment Questionnaire (IAQ) total score at Week 26 last observation carried forward (LOCF) (primary endpoint), a validated measure that monitors relief or worsening of 10 key symptoms associated with the psychopathology of schizophrenia and side effects of antipsychotic treatment. Secondary objectives were to further assess effectiveness using the Clinical Global Impression - Global Improvement (CGI-I) and Clinical Global Impression - Severity of Illness scale, to assess time to treatment discontinuation, patient preference of medication, quality of life, and the tolerability of aripiprazole compared with SOC. RESULTS: Aripiprazole treatment (n=268) resulted in significantly better effectiveness than SOC treatment (n=254; P<0.001; Week 26 LOCF) as evidenced by the IAQ total score beginning at Week 4 (the first assessment point) and sustained through Week 26. A similar relationship was demonstrated among patients who completed the study (observed cases analysis); aripiprazole was associated with significantly better effectiveness at all time points with a greater differential effect from SOC over time. Patients treated with aripiprazole also demonstrated significantly greater improvements on the CGI-I scale (responder rate, P=0.009 at Week 26 LOCF), as well as on quality of life (Quality of Life scale total score; P<0.001 at Week 26). Furthermore, a significantly higher proportion of patients receiving aripiprazole rated their study medication as "much better" on the Preference of Medication Questionnaire (POM) scale than their pre-study medication compared with SOC patients (P<0.001; Week 26). Time to treatment discontinuation and rates of discontinuation due to adverse events were similar in both treatment groups. The incidence of patients with one or more extrapyramidal symptom (e.g., akathisia, dystonia, parkinsonian events, and residual events) was higher in patients receiving aripiprazole compared with patients treated with SOC (13.5% vs. 5.6%); however, a higher proportion of patients in the SOC-treated group had clinically significant weight gain (21.2% vs. 7.3% for aripiprazole) and potentially clinically relevant elevated fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and serum prolactin compared with patients receiving aripiprazole. CONCLUSIONS: Aripiprazole is an effective atypical antipsychotic for the treatment of schizophrenia, demonstrating better effectiveness than SOC agents used in this study in patients for whom a switch in antipsychotic medication was warranted.     

The association of dropout and outcome in trials of antipsychotic medication and its implications for dealing with missing data

OBJECTIVE: The extent to which noncompletion of a clinical trial relates to outcomes has implications for choosing the most appropriate method for contending with missing data due to dropout. We examined whether dropout relates to outcome in clinical trials of antipsychotic medication. METHODS: Data from 5 large clinical trials of schizophrenia (n=3483) were examined separately. Patients were aggregated into groups based on their final study visit. Group mean Positive and Negative Syndrome Scale (PANSS) total scores for each visit were computed and graphed. Change from baseline to end point for each group was computed and examined using ANCOVA. Cox regression modeling was used to examine baseline PANSS total and change as predictors of time to dropout. RESULTS: In all 5 trials there was a statistically significantly relationship between time in trial and improvement. The longer the patients remained in the trial the more that they improved, with trial completers showing the most improvement at each time point. Higher baseline PANSS scores and symptom deterioration indicated by increased PANSS preceding the final study visit prior to dropout corresponded significantly with a greater likelihood of dropout. CONCLUSIONS: Dropout in clinical trials of antipsychotic medications corresponds with efficacy outcomes, the dynamics of symptom change and baseline symptom severity. Therefore, methods for statistical analysis should examine both efficacy and dropout and cannot assume that missing data due to dropout are completely at random.     

Low Dose vs Standard Dose of Antipsychotics for Relapse Prevention in Schizophrenia: Meta-analysis

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. Data source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). Data extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. Data synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low–dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.     

Interventions to reduce antipsychotic polypharmacy: A systematic review

BackgroundIt still remains unclear as to how to counteract antipsychotic polypharmacy that remains controversial but common. The objective of this study was to synthesize the clinical evidence to reduce antipsychotic polypharmacy (i.e. use of multiple antipsychotics) in schizophrenia.MethodsA literature search was performed to identify clinical trials that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia by any form of systematic intervention using PubMed as well as MEDLINE, EMBASE, and PsycINFO (last search: June 2012). The search terms included “antipsychotics” and “polypharmacy”. Cross-referencing was also performed.ResultsThe literature search identified 17 studies. Only 3 studies (1 randomized controlled trial and 2 open-label trials) were found that systematically switched antipsychotic polypharmacy to monotherapy. In two of them, more than two thirds of the subjects successfully completed the switch (40/58, 69.0%; 34/44, and 77.3%, respectively) while less than half the subjects tolerated it in the other study (6/14 and 42.9%) although the sample size was very small. On the other hand, 14 studies that examined impacts of interventions have physicians refrain from antipsychotic polypharmacy. While a modest intervention with educational approach alone was effective in three of the five articles, a more assertive intervention that directly cautioned physicians on the use of polypharmacy was effective in 10 of 12 articles.ConclusionThe literature search revealed the paucity of the data. Careful switching from polypharmacy to monotherapy seems feasible in a majority of patients with schizophrenia. Assertive interventions, rather than passive educational approaches alone, appear more effective in reducing antipsychotic polypharmacy.     

Arrêt et réduction du tabac chez le patient souffrant de schizophrénie

ObjectivesThis systematic review of the literature looked at data on pharmacological and non-pharmacological strategies of smoking cessation and reduction of consumption in patients with schizophrenia.MethodThe research was conducted on Medline for the period 1980–2018. We included randomized controlled trials, including preliminary studies of stable schizophrenic patients with no other severe psychiatric disorder and no other substance use than tobacco, treated with antipsychotic medications. Individual or group smoking cessation programs with or without pharmacological treatment, including a validation of abstinence, were included.ResultsPharmacotherapies for nicotine dependence—nicotine replacement therapy (n = 3), bupropion (n = 6), varenicline (n = 8), association of medications (n = 4)—were used in 23 studies combined with behavioral support. Compared to the placebo, bupropion and varenicline at the end of treatment were found to be the most effective pharmacotherapies to stop or reduce smoking and control craving. All the medications were well tolerated and did not lead to aggravation of psychosis or changes in symptoms. Non-pharmacological interventions: behavioral and cognitive therapies (n = 5) combined with pharmacological treatment facilitated the management of smoking risk situations and improved adherence to antipsychotics; other psychosocial interventions (n = 7) allowed the development of social skills; contigency management strategies with financial reinforcement can be used (n = 4); the practice of physical activity and the use of an electronic cigarette allowed reduction of tobacco consumption. The results of transcranial electromagnetic stimulation studies (n = 6) were discordant. Atypical antipsychotics appear to be associated with a better success of attempts to stop smoking.ConclusionSmoking cessation strategies for patients with schizophrenia appear to be effective and should combine (1) smoking cessation medications with sufficient duration, (2) diversified psychosocial approaches and (3) physical activity practice.     

A Study of the Impact of Cannabis on Doses of Discharge Antipsychotic Medication in Individuals with Schizophrenia or Schizoaffective Disorder

Patients with schizophrenia or schizoaffective disorder have a high prevalence of comorbid cannabis use disorder (CUD). CUD has been associated with poorer outcomes in patients. We compared doses of antipsychotic medications at the time of discharge from hospital among inpatients with schizophrenia or schizoaffective disorder with or without concurrent cannabis use. We reviewed the medical records of patients (N = 8157) with schizophrenia or schizoaffective disorder discharged from the hospital between 2008 and 2012. The patients were divided into two groups; those with urine drug tests positive for cannabis and those negative for cannabis. Doses of antipsychotic medications were converted to chlorpromazine equivalents. Bivariate analyses were done with Student’s t test for continuous variables and χ ² test for categorical variables. Linear regression was carried out to adjust for potential confounders. Unadjusted analysis revealed that the cannabis positive group was discharged on lower doses of antipsychotic medication compared with the cannabis negative group (geometric mean chlorpromazine equivalent doses 431.22 ± 2.20 vs 485.18 ± 2.21; P < 0.001). However, the difference in geometric mean chlorpromazine equivalent doses between the two groups was no longer significant after adjusting for sex, age, race, and length of stay (geometric mean difference 0.99; 95 % CI 0.92–1.10). Though limited by lack of information on duration, amount and severity of cannabis use, as well as inability to control for other non-antipsychotic medications, our study suggests that cannabis use did not significantly impact on doses of antipsychotics required during the periods of acute exacerbation in patients with schizophrenia or schizoaffective disorder.     

Impact of DSM-5 Changes on the Diagnosis and Acute Treatment of Schizophrenia

Objective:To examine the consequences and validity of changes in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnostic criteria for schizophrenia, eg, omission of subtypes, using a large dataset of double-blind, randomized, placebo-controlled schizophrenia trials.Methods:Data from 22 short-term efficacy registration trials of second generation antipsychotics for the treatment of acute psychotic episodes in patients with schizophrenia (N = 5233), submitted to the Dutch regulatory authority were analyzed. We examined whether patients in these pre-DSM-5 trials met the diagnostic criteria for schizophrenia according to DSM-5. Using linear regression, we examined differences in effect size between DSM-IV subtypes and between DSM-5 symptom dimensions.Results:Over 99.5% of the patients met DSM-5 diagnostic criteria for schizophrenia and no differences in effect size were found between schizophrenia subtypes (P = .65). Symptom dimensions that respond best to treatment with second generation antipsychotics were hallucinations, delusions, disorganized speech, and mania (Hedge’s g −0.23 to −0.31).Conclusions:Results of clinical trials in patients with pre-DSM-5 schizophrenia also apply to patients diagnosed with DSM-5 schizophrenia. Omission of the classic subtypes is justified as they are not predictive of response to treatment. The DSM-5 C-RDPSS scale adds valuable information to the categorical diagnosis of schizophrenia, which is relevant for antipsychotic response.Key words: antipsychotics, clinical trials, diagnostic criteria     

Impact of Antipsychotic Treatment on Attention and Motor Learning Systems in First-Episode Schizophrenia

Background: Antipsychotic medications have established clinical benefit, but there are few neuroimaging studies before and after initiating antipsychotic medication to assess drug influence on brain circuitry. Attention and motor learning tasks are promising approaches for examining treatment-related changes in frontostriatal systems. Methods: Twenty-one unmedicated first-episode schizophrenia patients (14 antipsychotic-naïve) participated in functional imaging studies while performing visual attention (prosaccades) and motor learning tasks (predictive saccades). Posttreatment testing was completed in 14 patients after 4–6 weeks of antipsychotic treatment. Matched healthy controls were studied in parallel. Results: Pretreatment, patients had reduced activation in the dorsal neocortical visual attention network. Activation deficits were significantly reduced posttreatment. Higher medication dose was associated with greater caudate activation at follow-up. For the motor learning task, patients’ dorsolateral prefrontal cortex (DLPFC) was unimpaired prior to treatment but showed significantly reduced activation after treatment. Conclusion: Impairments in dorsal cortical attention networks are present in untreated first-episode schizophrenia patients. These impairments are reduced after antipsychotic treatment, suggesting a beneficial effect on neural systems for attention. Treatment-emergent decreases in DLPFC activation observed for the motor learning task are consistent with other clinical and preclinical evidence suggesting that antipsychotics can have adverse effects on prefrontal function.Key words: fMRI, cognition, dorsolateral prefrontal cortex, saccades, caudate, risperidone     

Drug treatments for schizophrenia: pragmatism in trial design shows lack of progress in drug design

Aims.The introduction of second generation antipsychotic (SGA) medication over a decade ago led to changes in prescribing practices; these drugs have eclipsed their predecessors as treatments for schizophrenia. However, the metabolic side effects of these newer antipsychotics have been marked and there are increasing concerns as to whether these novel drugs really are superior to their predecessors in terms of the balance between risks and benefits. In this article, we review the literature regarding comparisons between first generation antipsychotic (FGA) and SGA in terms of clinical effectiveness.Methods.Large (n > 150) randomized-controlled trials (RCTs) comparing the effectiveness (efficacy and side effects) of FGA and SGA medications other than clozapine were reviewed, as were meta-analyses that included smaller studies.Results.The superiority in efficacy and reduced extrapyramidal side effects (EPSE) of SGAs is modest, especially when compared with low-dose FGAs. However, the high risk of weight gain and other metabolic disturbances associated with certain SGAs such as olanzapine is markedly higher than the risk with FGAs at the doses used in the trials.Conclusions.The efficacy profiles of various FGAs and SGAs are relatively similar, but their side effects vary between and within classes. Overall, large pragmatic trials of clinical effectiveness indicate that the care used in prescribing and managing drug treatments to ensure tolerability may be more important than the class of drug used.Key words: antipsychotic drugs, clinical effectiveness, schizophrenia, randomized controlled trials     

Fluphenazine (Oral) Versus Placebo for Schizophrenia

Fluphenazine, a phenothiazine derivative, was one of the first drugs to be classed as an “antipsychotic” and was approved by the Food and Drug Administration in 1959. In Britain, it was first used for the relief of anxiety. The American reports, however, were the first to indicate its value in psychotic illness. Fluphenazine is an inexpensive and widely accessible antipsychotic drug that has been available to treat people with schizophrenia for five decades. We updated our original search (from September 2006) using The Cochrane Schizophrenia Group Trials register (May 2012); we found no new relevant studies. Seven randomized controlled trials (RCTs) were included with a total of N = 439 participants. Results, based on this small selection of studies, suggested that there was no significant difference between oral fluphenazine and placebo for most outcomes, including global state and leaving the study early. Results did suggest a statistically significant effect favoring oral fluphenazine in the short term for levels of relapse (n = 38, 1 RCT, RR 0.25 CI 0.06–1.03) with levels of extrapyramidal adverse effects more frequent with oral fluphenazine. The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. In this review, for perhaps the first time, we objectively quantified the effects of oral administration of fluphenazine in comparison with placebo. It is indeed a potent antipsychotic but with considerable adverse effects. Other drugs may well be preferable.Key words: oral fluphenazine, systematic review, meta- analysis, schizophrenia