Atypical Antipsychotics In Schizophrenia Research Articles

Paliperidone Extended Release Versus Olanzapine in Treatment-Resistant Schizophrenia: A Randomized, Double-Blind, Multicenter Study.

Paliperidone is an atypical antipsychotic as effective as other atypical antipsychotics for schizophrenia. However, few studies have explored the efficacy of paliperidone for treatment-resistant schizophrenia. This study aimed to compare the efficacy and safety of paliperidone extended release (ER) versus olanzapine in schizophrenia patients with either poor treatment response or intolerable adverse effects due to standardized antipsychotic therapy. This 12-week randomized, double-blind, multicenter study compared the treatment efficacy on psychotic symptoms, cognitive functions, and tolerance between paliperidone ER (6-15 mg/d, n = 45) and olanzapine (10-30 mg/d, n = 41) in treatment-resistant or treatment-intolerant patients with schizophrenia. The severity of psychotic symptoms was evaluated by the Positive and Negative Syndrome Scale and the Clinical Global Impression Severity of Illness Scale. The cognitive functions were assessed by the MATRICS Consensus Cognitive Battery. In addition, the metabolic impacts were evaluated by weight gain and waist circumference. Patients with either paliperidone ER or olanzapine treatment showed apparent improvement in psychotic symptoms, without significant intergroup difference. Twelve-week paliperidone ER or olanzapine treatment did not improve the cognitive functions. Both paliperidone ER and olanzapine treatment caused significant increase in weight and waist circumference, and olanzapine had a greater impact on waist circumference than paliperidone ER. In addition, both drugs were well tolerated. Paliperidone ER could be a safe alternative for treatment-resistant schizophrenia.

The prefrontal cortex as a target for atypical antipsychotics in schizophrenia, lessons of neurodevelopmental animal models.

Prefrontal cortex (PFC) inflammatory imbalance, oxidative/nitrosative stress (O/NS) and impaired neuroplasticity in schizophrenia are thought to have neurodevelopmental origins. Animal models are not only useful to test this hypothesis, they are also effective to establish a relationship among brain disturbances and behavior with the atypical antipsychotics (AAPs) effects. Here we review data of PFC post-mortem and in vivo neuroimaging, human induced pluripotent stem cells (hiPSC), and peripheral blood studies of inflammatory, O/NS, and neuroplasticity alterations in the disease as well as about their modulation by AAPs. Moreover, we reviewed the PFC alterations and the AAP mechanisms beyond their canonical antipsychotic action in four neurodevelopmental animal models relevant to the study of schizophrenia with a distinct approach in the generation of schizophrenia-like phenotypes, but all converge in O/NS and altered neuroplasticity in the PFC. These animal models not only reinforce the neurodevelopmental risk factor model of schizophrenia but also arouse some novel potential therapeutic targets for the disease including the reestablishment of the antioxidant response by the perineuronal nets (PNNs) and the nuclear factor erythroid 2-related factor (Nrf2) pathway, as well as the dendritic spine dynamics in the PFC pyramidal cells.

Therapy of Schizoaffective Disorder and Paranoid Schizophrenia with Episodic Course

Background. The use of atypical antipsychotics in schizophrenia contributes to the reduction of psychotic, affective, negative and cognitive disorders.Aims. To evaluate the effectiveness of ziprasidone therapy in patients with schizoaffective disorder and paranoid schizophrenia with episodic course.Materials and methods. In accordance with ICD-10 there were 14 (63.6 %) people with schizoaffective disorder (F25), 8 (36.4 %) people with paranoid schizophrenia, episodic course (F20.x1). Treatment with ziprasidone lasted 42 days. The dose of ziprasidone in 6 patients (27.3 %) was 80 mg, in 10 patients (45.5 %) – 120 mg, in 6 patients (27.3 %) – 160 mg. Evaluation of the effectiveness of ziprasidone therapy was carried out using psychometric scales (PANSS, General clinical impression scale to assess the effectiveness of therapy – CGI-S, CGI-I), adverse events were registered with the UKU scale.Results. The number of respondents was 19 (86.3 %) (reduction of the total score on the PANSS scale > 20 % of the pre-treatment level). Ziprasidone was effective in patients with schizoaffective disorder with a significant decrease in total score on PANSS subscales to the 14 th day of therapy (p < 0.05), with paranoid schizophrenia with episodic course – by the 21st day (p < 0.01). According to the CGI-S scale at the end of therapy, “borderline condition” was observed in 10 patients (52.6 %), mild severity – in 3 (15.8 %), normal condition – in 6 (31.6 %). CGI-I scale showed a significant improvement in 10 patients (52.6 %), marked improvement – in 9 patients (47.4 %). Among the mild adverse events that do not require discontinuation of the drug, we noted: weakness – in 3 patients (15.8 %), drowsiness – in 3 (15.8 %), impaired concentration – in 2 (10.5 %), orthostatic dizziness – in 2 (10.5 %), galactorrhea – in 1 (5.3 %).Conclusions. Ziprasidone is an effective antipsychotic drug that has a safe tolerability profile. It can be used in patients with schizoaffective disorders and paranoid schizophrenia with episodic course.

Long-acting atypical antipsychotics in schizophrenia: A systematic review and meta-analyses of effects on functional outcome.

Impairment in psychosocial function is common in schizophrenia. Long-acting injectable atypical antipsychotics are thought to enhance psychosocial function by boosting adherence. However, no systematic review has examined the effects of long-acting injectable atypical antipsychotics on psychosocial function in clinical trials. We searched major databases including Medline/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Central Register of Controlled Trials and Clinical Trial Registries for randomised controlled trials that compared long-acting injectable atypical antipsychotics to placebo, oral antipsychotic medications or long-acting injectable atypical antipsychotics for all years till 2018, with no language limits. We performed a systematic review of findings on change in psychosocial function and its predictors in the included reports. Data on change in psychosocial functioning were meta-analysed using a random-effects model. A total of 26 studies were included in systematic review, and 19 studies with 8616 adults, 68.1% males were meta-analysed. Long-acting injectable atypical antipsychotics were superior to placebo (standardised mean difference = 0.39; 95% confidence interval = [0.32, 0.47]; p < 0.001; I2 = 0%; 9 studies) and oral antipsychotic medications (standardised mean difference = 0.16; 95% confidence interval = [0.01, 0.31]; p = 0.04; I2 = 77%; 10 studies) for improved psychosocial function and superiority was maintained in short- and long trials. Poor psychosocial function was predicted by longer treatment duration, severe symptoms, poor cognition and poor insight. Functioning was assessed by either a single or a combination of measures, but was not the primary outcome in most studies. Other sources of bias include poor blinding and reporting of randomisation. Long-acting injectable atypical antipsychotics are beneficial for recovery of psychosocial function in comparison with placebo, but the magnitude of superiority over oral antipsychotic treatment was small. Severe psychopathology at baseline predicted poor psychosocial function. Future effectiveness trials in which post-randomisation involvement is kept to a minimum, and psychosocial function is included as primary outcome a priori, are needed to capture the real-world impact of long-acting injectable atypical antipsychotics and to address methodological biases.

Pharmacoeconomic analysis of using typical and atypical antipsychotics in schizophrenia

The aim: to provide a comprehensive pharmacoeconomic evaluation of the maintenance therapy with antipsychotics in outpatients diagnosed with schizophrenia.Materials and methods. The analysis was conducted by two mutually complementary steps: an epidemiological study on outpatients with schizophrenia, and a subsequent pharmacoeconomic modeling. Two medical technologies were evaluated and compared: treatment with classical antipsychotics (kA) and treatment with atypical antipsychotics (AA). For the clinical and economic analysis of these treatments, we used a number of indices derived from our retrospective study of patients’ medical records. The cost-effectiveness analysis, incremental analysis, and «budget impact» analysis were performed taking into account the direct and indirect costs of the treatments.Results. We determined the costs of managing outpatients with schizophrenia from the perspective of the healthcare budget and the social burdens; we also looked into the relevance and effectiveness of the current costs at various time intervals – 6, 12 and 24 months. As shown, the treatment strategies involving AA were more budget-consumptive than the kA treatments. even if the treatments were switched to the reproduced AA (up to 100% replacement), the costs would remain to be higher than those for the kA. The «cost-effectiveness» analysis related to «the proportion of stable patients» for the horizons of 6 and 12 months indicated that the reproduced AA would be more economically effective than the kA. However, when the observation period was increased to 24 months, this economic advantage of AA diminished, and the kA drugs had a lower CeR instead. For the «number of hospitalization-free days per year», the use of AA was more cost-effective only versus the 100% use of reproduced AA at the simulated horizon of 12 months. When the use of 100% reference AA or the combined use of reference + reproduced AA was simulated, the treatment with kA remained more economically effective, regardless of the simulated period.Conclusion. The pharmacoeconomic simulation of the antipsychotic therapy in outpatients with schizophrenia suggests the ways to optimize the treatment. Among them, (a) using AA for the treatment of at least 15.6% of patients (those who are employed); keeping the ≥60% use of kA to ensure the optimal resource-saving effect of the treatment; (b) using reproduced AA at the level of ≥70% (instead of the reference AA similar in efficacy and safety) to keep the treatment economically feasible.

Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia

BackgroundThere are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia.MethodsIn total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method.ResultsFor aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier–rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642–rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582).ConclusionWe suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.

Unresolved Issues for Utilization of Atypical Antipsychotics in Schizophrenia: Antipsychotic Polypharmacy and Metabolic Syndrome.

Atypical antipsychotics (AAP) are the prevailing form of schizophrenia treatment today due to their low side effects and superior efficacy. Nevertheless, some issues still need to be addressed. First, there are still a large number of patients with treatment-resistant schizophrenia (TRS), which has led to a growing trend to resort to AAP polypharmacy with few side effects. Most clinical treatment guidelines recommend clozapine monotherapy in TRS, but around one third of schizophrenic patients fail to respond to clozapine. For these patients, with clozapine-resistant schizophrenia AAP polypharmacy is a common strategy with a continually growing evidence base. Second, AAP generally have great risks for developing metabolic syndrome, such as weight gain, abnormality in glucose, and lipid metabolism. These metabolic side effects have become huge stumbling blocks in today’s schizophrenia treatment that aims to improve patients’ quality of life as well as symptoms. The exact reasons why this particular syndrome occurs in patients treated with AAP is as yet unclear though factors such as interaction of AAP with neurotransmitter receptors, genetic pholymorphisms, type of AAPs, length of AAP use, and life style of schizophrenic patients that may contribute to its development. The present article aimed to review the evidence underlying these key issues and provide the most reasonable interpretations to expand the overall scope of antipsychotics usage.

Comparison of Hematologic Variability between Clozapine Monotherapy and Augmentation Therapy with Atypical Antipsychotics for Schizophrenia: Results from a 6-Month Retrospective Follow-Up Study

Comparison of Hematologic Variability between Clozapine Monotherapy and Augmentation Therapy with Atypical Antipsychotics for Schizophrenia: Results from a 6-Month Retrospective Follow-Up Study

Clinical and Cost Consequences of Metabolic Effects of Lurasidone Versus Other Atypical Antipsychotics in Schizophrenia

Objective: To estimate the economic burden of hyperglycemia and diabetes associated with lurasidone versus other atypical antipsychotics in schizophrenia. Methods: A discrete event simulation model was developed to conduct the analysis from both US payer and societal perspectives over a 3-year timeframe. The model, based on the values of metabolic parameters at 1 year of treatment, identified patients with hyperglycemia at that point and predicted incident cases of diabetes over 3 years using a risk equation from the Framingham Heart Study. Direct and indirect costs of diabetes and hyperglycemia were estimated, according to patients’ disease status over time. Data on metabolic changes at 1 year were mainly from 4 clinical studies of lurasidone, supplemented with published data for other atypical antipsychotics. Cost inputs (2012 US dollars) were obtained from published sources. Results: Compared with olanzapine, risperidone, and quetiapine XR, lurasidone was predicted to result in 2,785,351, and 847 fewer hyperglycemia cases and 1,142,153, and 67 fewer incident diabetes cases per 10,000 patients over 3 years, respectively. Consequently, there was a reduction in the economic burden of diabetes and hyperglycemia by approximately $23 million, $2.9 million, and $3.4 million from a US payer perspective, and $28 million, $3.6 million, and $3.7 million from a societal perspective. Conclusion: Adverse metabolic effects of atypical antipsychotics could have substantial unfavorable clinical and economic consequences. Lurasidone may reduce these burdens and may be a treatment alternative for patients with schizophrenia.

Contribution of baseline body mass index and leptin serum level to the prediction of early weight gain with atypical antipsychotics in schizophrenia

This study investigated whether biochemical parameters add predictive information concerning risk for weight gain associated with treatment with atypical antipsychotics (AP) to that provided by baseline weight. Weight changes were assessed in 25 patients with schizophrenia after 3-6 months of treatment. These patients were started on AP monotherapy owing to a first psychotic episode or resumed treatment after at least a 6-month period of abandonment. Anthropometric and biochemical data were collected and analyzed as predictors of early weight change. The baseline biochemical and anthropometric data were not significantly higher in the patients than in the healthy participants. During follow up, the patients had significant increases in body mass index and total cholesterol and apolipoprotein B level. The baseline weight and leptin level were predictive of weight gain during follow up, with an inverse association in both cases. Baseline weight and leptin level may help to assess the risk of early weight gain with AP.

PMH58 - Atypical antipsychotics for schizophrenia in Brazil: A descriptive analysis of acquisition costs

PMH58 - Atypical antipsychotics for schizophrenia in Brazil: A descriptive analysis of acquisition costs

Economic Burden Associated with Extrapyramidal Symptoms in a Medicaid Population with Schizophrenia

No studies have assessed the economic impact of extrapyramidal symptoms due to atypical antipsychotics in schizophrenia. To assess healthcare resource use and medical costs associated with extrapyramidal symptoms in patients with schizophrenia. A retrospective analysis of Marketscan® Medicaid Multi-State Database (2004–2009) was conducted. Patients with schizophrenia and newly initiated on an AAP were included. Patients with and without extrapyramidal symptoms were matched using propensity-score matching. Healthcare utilization and costs were assessed in the 12-month follow-up period using logistic and two-part (gamma) regression models. Of 4,621 patients, 583 (12.6 %) had extrapyramidal symptoms. Patients with extrapyramidal symptoms had significantly more schizophrenia-related and all-cause hospitalizations and schizophrenia-related emergency room visits, as well as significantly higher schizophrenia-specific and all-cause total healthcare, inpatient, and prescription drug costs compared to patients without extrapyramidal symptoms. Extrapyramidal symptoms in patients with schizophrenia is associated with increased healthcare resource utilization and higher medical costs.

Comparative Effectiveness of Atypical Antipsychotics in Schizophrenia

Real-world, effectiveness studies add an important new dimension to the evaluation of the benefits of individual antipsychotics. Efficacy studies have already shown the unique effectiveness of clozapine, and suggested improved outcomes for olanzapine compared with some atypical antipsychotics and a reduced tendency to produce acute and chronic movement disorders for atypical compared with typical drugs. Recent effectiveness studies largely confirm these prior observations. The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) and SOHO (Schizophrenia Outpatient Health Outcomes) programmes confirmed the superiority of clozapine over other antipsychotics; CATIE and SOHO also confirmed olanzapine as probably the second most effective antipsychotic. Effectiveness studies have confirmed the high incidence of adverse metabolic effects with clozapine, olanzapine and (with less certainty) quetiapine but the ZODIAC (Ziprasidone Observational Study of Cardiac Outcomes) study found no excess cardiovascular events or deaths for olanzapine compared with ziprasidone. Prior observations on reduced frequency of movement disorders for second-generation versus first-generation antipsychotics were also largely (but not uniformly) supported. Overall, recent real-world studies have done much to confirm prior observations from efficacy-based randomized, controlled trials.

The α2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats

Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine). We assessed the effects of idazoxan (an α(2)-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats. In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed. Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment. These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their α(2)-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia.

Optimized voxel brain morphometry: association between brain volumes and the response to atypical antipsychotics

To date, few studies have addressed the relationship between brain structure alterations and responses to atypical antipsychotics in schizophrenia. To this end, in this study, magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to assess the relationship between the brain volumes of gray (GM) and white (WM) matters and the clinical response to risperidone or olanzapine in 30 schizophrenia patients. In comparison with healthy controls, the patients in this study showed a bilateral decrease in the anteromedial cerebellar hemispheres, the rectal gyrus and the insula, together with bilateral increases in GM in the basal ganglia. Both patient groups had a significantly smaller volume of WM in a region encompassing the internal and external capsules as compared to the controls. We found an inverse association between striatal size and the degree of clinical improvement, and a direct association between the degree of insular volume deficit and its improvement. The non-responder patient group showed a significant decrease in their left rectal gyrus as compared with the responder group. This study reveals a pattern of structural alterations in schizophrenia associated with the response to risperidone or olanzapine.

Efficacy and tolerability of paliperidone ER and other oral atypical antipsychotics in schizophrenia

Atypical antipsychotics are widely used in the pharmacologic management of schizophrenia. Information to guide evidence-based clinical decision making must be continually updated, particularly as new clinical trial data and new antipsychotic agents become available. This meta-analysis of oral atypical antipsychotics assessed the relative effectiveness and tolerability profile of a recently introduced agent, paliperidone extended-release (ER), to determine its place within the efficacy and tolerability spectrum of the labeled dose ranges of other oral atypical antipsychotics. Randomized placebo-controlled studies of risperidone, olanzapine, quetiapine, and aripiprazole were identified via database search (MEDLINE, EMBASE, Cochrane Library, PsycInfo, and Cumulative Index to Nursing & Allied Health Literature). Baseline demographic, efficacy, and safety data were extracted and combined in meta-analysis. Random effects meta-regression assessed potential confounding by patient mean age, gender ratio, and duration of therapy on variability in efficacy and safety. Within the spectrum of efficacy and safety of the class, paliperidone ER demonstrated a novel efficacy-tolerability profile versus the other oral atypical antipsychotics, including lower odds of withdrawal for any reason and less weight gain. Odds of withdrawal due to adverse events were lower with paliperidone ER compared with risperidone and with atypical antipsychotics as a class. Paliperidone ER was associated with lower odds of somnolence and agitation than the atypical class as a whole and with lower odds of weight gain than all of the atypical antipsychotics, including risperidone. The main factor in the observed variability in efficacy results between studies was the antipsychotic, rather than patient-related factors or duration of therapy. Paliperidone ER is an effective and well-tolerated oral atypical antipsychotic that provides an important new treatment option for patients with schizophrenia. Owing to the heterogeneity within the class, information on individual benefit/risk profiles of antipsychotics is necessary for selecting an appropriate treatment for each patient.

Association of adiponectin and metabolic syndrome among patients taking atypical antipsychotics for schizophrenia: A cohort study

Introduction Adiponectin, an adipocyte-derived hormone controlling lipid and carbohydrate metabolism, has been suggested to be a biomarker for metabolic syndrome in the general population. This study investigated the association between adiponectin levels and metabolic syndrome in patients treated with atypical antipsychotics. Methods Anthropometric and metabolic parameters and serum adiponectin levels were assessed in hospitalized patients with schizophrenia who had used the same atypical antipsychotic for at least 3 months. Retrospective reviews of the patients' medical records were conducted to obtain demographic data and pretreatment characteristics. Results The study included 567 schizophrenia patients treated with clozapine ( n = 231), olanzapine ( n = 94) and risperidone ( n = 242), for an average of 45.8 ± 27.8 months. The prevalence of metabolic syndrome among all subjects was 23.8%. The clozapine group had a higher prevalence of metabolic syndrome (28.7%) than did the olanzapine (24.2%) and risperidone groups (19.5%) ( P = 0.039), and the clozapine group had lower levels of adiponectin (8.46 ± 6.02 mg/mL) than did the olanzapine (10.26 ± 4. 9 mg/mL) and risperidone groups (10.69 ± 7.43 mg/mL) ( P = 0.001). Adiponectin level was negatively correlated with body mass index (BMI) increase after initiation of antipsychotic treatment. Cross-sectional regression analysis showed that age (OR, = 1.042, P = 0.001), BMI (OR = 1.404, P < 0.0001), and adiponectin level (OR = 0.862, P < 0.0001) were significant factors in the presence of metabolic syndrome. Significant predictors of metabolic syndrome were age at initiation of antipsychotic treatment (OR = 1.04, P = .007), BMI at initiation of antipsychotic treatment (OR = 1.44, P < 0.0001), BMI increase after initiation of antipsychotic treatment (OR = 1.40, P < 0.0001), and adiponectin level (OR = 0.86, P < 0.0001). Conclusion Lower levels of adiponectin and weight gain after taking antipsychotics are associated with higher risk of metabolic syndrome in patients taking atypical antipsychotics.

Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia

The serotonin (5-HT) 1A receptor has been found to be dysregulated in prefrontal cortex and other brain regions in schizophrenia, and 5-HT1A receptor levels in the amygdala have been related to negative schizophrenia symptoms. We have assessed the impact of the functional C-1019G variant of the 5-HT1A receptor on the response to risperidone or haloperidol in a prospective, randomized, double-blind study. Patients were treated for 4 weeks and negative symptoms assessed weekly. The variant influenced the response to risperidone: improvement of negative symptoms by 4.38 points for carriers of the C allele, compared with the GG genotype (1.22 points, P=0.046). In a second independent study of 130 schizophrenia patients treated with atypical antipsychotics, this effect was confirmed (P=0.003). The functional variant of the 5-HT1A receptor thus influences the response of schizophrenia patients to atypical antipsychotics and may be useful in the future to predict the pharmacogenetics of negative symptoms.

The Lesser of 2 Evils: The Ethics of Placebo-Controlled Trials

Abbreviations used in this article ADR adverse drug reaction ES effect size RCT randomized controlled trial TAU treatment as usual Can J Psychiatry 2008;53(7):430-432 It is widely accepted that the most powerful research design to assess the efficacy and effectiveness of a novel intervention is the RCT, in which one group of eligible patients is randomly assigned to receive the new drug and the other group receives something else. The question is, What should constitute that comparator condition? In situations where there is no effective treatment or where the existing treatment has many undesirable side effects, the answer is relatively straightforward: the comparison group should be a placebo. A much more difficult situation arises when an effective treatment does exist, such as selective serotonin reuptake inhibitors for depression or the atypical antipsychotics for schizophrenia. More than a decade ago, Rothman and Michels1 argued very cogently that under such circumstances, it is a violation of the Declaration of Helsinki to have a placebo arm in the trial, as that would deny patients available treatment, and that the comparison should be against TAU. However, the sheer number of letters to the editor in response to that article is an indication that the issue is neither clear-cut nor settled. At first glance, Rothman and Michels' points are very compelling. If a drug already exists, how can we refuse to give it to some patients? From a scientific point of view, why would we even consider using a placebo? Aside from the pecuniary reason of pharmaceutical companies wanting to introduce their me too version of a drug, it would seem reasonable that the correct scientific question should not be, Does this new drug also work for this condition? but rather, Does this new drug work better or have fewer ADRs than the existing treatment(s)? My position is that this argument would be unassailable if this were le meilleur des mondes possibles. However, despite Dr Pangloss' unwavering belief, this is not the best of all possible worlds. In light of that, placebo-controlled trials are a necessary evil, even when effective drugs exist. My arguments are 2-fold: first, the results of studies with 2 active drugs may be ambiguous and impossible to interpret; and second, more people are potentially left untreated or harmed in trials with active controls, compared with placebo controls. Regarding the first point, there are 2 possible outcomes in any clinical trial: the study finds a statistically significant (and ideally, clinically important) difference between the drugs in one direction or the other, or it does not. If the first situation is obtained, then there is no ambiguity: the new drug was either superior or inferior in comparison to TAU, and should or should not be adopted. The problem arises when the study finds no significant difference. This can occur for 1 of 2 reasons: both drugs were equally effective, or in this trial, both drugs were equally ineffective. However, if TAU has been shown to work in earlier studies, how can it occur that it was ineffective in the current trial? This is not merely a theoretical question. One metaanalysis found that, among 52 trials, only 48% of antidepressant arms showed superiority over a placebo; and the same proportion was seen in 13 trials of anxiolytics.2 Let us go through the steps of executing an RCT with a new drug. First, patients are assessed to determine whether they meet the inclusion criteria. second, those who satisfy the criteria are randomly assigned to one of the 2 groups. Third, therapeutic dosages of both drugs are given in a doubleblinded manner to all patients for a time sufficient for them to show an effect. Fourth, relevant outcomes are measured in an unbiased and blinded manner for all patients who entered the trial. Finally, the data are accurately and competently analyzed to see if the new drug is superior, or equivalent in effect but has fewer ADRs. …

Placebo-controlled clinical trials of new atypical antipsychotics in schizophrenia

Placebo-controlled clinical trials of new atypical antipsychotics in schizophrenia