Psychopharmacological Trials Research Articles

The Science and Ethics of Placebo in Pediatric Psychopharmacology

Pediatric psychopharmacology is a relatively new science. Although the use of psychotropic medications in children has risen in the past decade, there are few standard treatments for serious psychiatric or developmental disorders of childhood. The relative absence of standard treatments is further complicated by the fact that many of the agents used in pediatric psychopharmacology have been adapted from other fields. Therefore, investigators have a responsibility to make incremental progress from concept through pilot studies and large-scale, multisite efficacy and safety trials. Thus, although there is a pressing need to conduct medication trials that can guide clinical practice, there are scientific and ethical considerations to bear in mind when designing clinical trials in pediatric psychopharmacology. This article reviews essential ethical and scientific issues that are relevant to designing clinical trials in children with psychiatric and developmental disorders. Using examples from recently published literature, the article describes the challenges and pitfalls of various clinical trial study designs. The application of sound ethical and scientific principles is necessary to ensure that clinical trials are properly conducted and to guard against ambiguous results that can not guide practice.

Ethics and science of placebo-controlled trials

Readers of this journal might not stop to categorize their responses as communitarian rather than individualistic, but there are probably very few readers from either the clinical or basic research domains who would quibble with the ethics of using a placebo or a control in experiments. Most would regard it as unethical to do an experiment in animals or humans that was not properly controlled so that sense could be made of the findings. That said, there are problems with the current use of placebo-controlled trials in psychopharmacology. The use of placebo in randomized-controlled trials (RCTs) was predicated in the first instance on creating a null hypothesis to test out claims that were made for treatments of uncertain efficacy. Neither placebo nor randomization is needed when a treatment unequivocally works, in the way for instance that activated charcoal does for strychnine poisoning or penicillin for bacterial endocarditis or insulin for a diabetic coma. Those who framed the first RCTs possibly never envisaged an intermediate situation between treatments that clearly work and a debunking of claimed efficacy. However, this is the situation we face with placebo-controlled studies of modern anti-depressants, which based on data from 100 000 subjects randomized to either active treatment or placebo, show that 5 out 10 subjects appear to respond to active treatment, while 4 out of 10 respond to placebo (Stone and Jones, 2006). These responses furthermore were obtained on rating scale rather than real life measures. If RCTs were undertaken on treatments that work like penicillin for bacterial endocarditis, we would expect more dead bodies in the placebo arm than in the active treatment arm and once demonstrated such a finding might pose an ethical problem to further studies. In the case of the anti-depressants, however, and probably the anti-psychotics and other psychotropic agents, there are more dead bodies in the active treatment arms of trials than in the placebo arms1 (Stone 2007). These figures indicate that the number needed to treat (NNT) with placebo is 2.5, whereas the NNT for a specific response to drugs is 10. Given these data, and the additional risks attendant on active treatment, if clinicians were to follow the evidence, those in primary care at least would not prescribe anti-depressants as rapidly as they apparently do. There seem to be two problems here. One is a failure of clinicians to understand what placebo-controlled trials in fact show. The second, as suggested by Kotzalidis et al., is a failure of the field, when faced with data like this, to build on the science. Where are the efforts to delineate those clinical populations who are responsive to specific agents, thereby producing assay systems in which there is a more substantial difference between active agent and placebo. After something close to 1000 published trials of anti-depressants in clinical populations, a majority of which stem from companies pursuing marketing indications, as well as hundreds of healthy volunteer trials, there is little clarity on what the precise psychotropic effect of agents specific to the serotonin system might be compared with agents specific to the noradrenergic system. The fact that when a patient walks into a clinic, their physician still has no means of determining whether they might do better on a serotonergic rather than another agent signals a clear failure in the science of therapeutics. Instead these treatments are prescribed close to indiscriminately because placebo controlled-trials have supposedly shown in a statistically significant fashion that the drugs ‘work’. It is not surprising that when data from over a 100 000 patients is pooled selected rating scale findings can be shown to be statistically significant. But of the trials designed and undertaken by companies, something like 50% failed to produce a positive result. Against this background, a comment by Fisher (1935) in the Design of Experiments should unsettle us: ‘No isolated experiment, however, significant in itself, can suffice for the experimental demonstration of any phenomenon . . . In relation to the test of significance, we may say that a phenomenon is experimentally demonstrable when we know how to conduct an experiment that will rarely fail to give us a statistically significant result.’ The bottom line is that we haven’t been doing good science. The studies that have been done have arguably led to a degradation of rather than an improvement in clinical practice. Recent Department of Health 2001 guidance on research, which states that research which duplicates other work unnecessarily or which is not of sufficient quality to contribute something useful to existing knowledge is in itself unethical, seems applicable in this instance. If the science of therapeutics were demonstrably making progress, there would be much less grounds for critics to question what is being done.

The Family Forum: Directions for the Implementation of Family Psychoeducation for Severe Mental Illness

The Family Forum: Directions for the Implementation of Family Psychoeducation for Severe Mental Illness

Keeping media in mind

Don DeLillo's novel, White Noise (1984), has a character called Doctor Winnie Richards who, being a cognitive neuroscientist, is likened to ‘some phenomenal subhuman like a yeti or sasquatch’. Her role is to discover the chemical components of a mysterious new designer-pill which the main character's wife is taking in a secret psychopharmacology trial. Winnie eventually discovers that the drug, known as Dylar, is designed to inhibit a neurotransmitter that generates fear of death; whereby DeLillo gives his readers a flavour of what neuroscientists get up to. A sign of the development and rapid expansion of a scientific discipline is its impact on popular culture. White Noise depicts neuroscience, albeit through a fantastically distorted lens, from the vantage point of the mid-1980s as a coming discipline, which of course it was. Just as the invention of the telescope and the discovery of mathematical physics had provided new ways of understanding the universe, so rapid advances in non-invasive brain imaging, together with ever-advancing molecular biology, developmental biology, Artificial Intelligence, pharmacology and genetics were revolutionizing the study of the brain and central nervous system. After a century in the doldrums, neuroscience was, in its own estimation, taking off; and the promise for medicine was as great as the promise for basic neurobiology, psychology and philosophy of mind. The drama of the discipline's bright future was summed up a trifle woodenly in the preface to Eric Kandel (of whom more later) and J. Schwarz's 1985 edition of Principles of Neural Science : ‘One of the last frontiers of science, perhaps its ultimate challenge, is to understand the biological basis of mentation.’ So fast-forward 20 years: and how is the discipline doing in the eyes of popular culture in the mid-first-decade of the 21st century? Take Tom Wolfe's best-selling 2004 offering, I Am …

Clinical Psychopharmacology of Pediatric Mood Stabilizer and Antipsychotic Treatment, Part 2: Methodological Considerations

Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.In last month's ASCP Corner, I discussed some of the challenges and recent developments regarding the available evidence base for the use of antipsychotics and mood stabilizers in children and adolescents. 1 In this month's column, I will focus on some of the pertinent clinical psychopharmacology trials design issues that are relevant to the collection of data in children and adolescents who are in need of antipsychotic or mood stabilizer treatment.While it is clear that studying psychotropic medication effects in children and adolescents is crucial, it is also a difficult task.†‹†‹

An abbreviated version of the Connor-Davidson Resilience Scale (CD-RISC), the CD-RISC2: Psychometric properties and applications in psychopharmacological trials

Resilience may be an important component of the prevention of neuropsychiatric disease. Resilience has proved to be quantifiable by scales such as the Connor-Davidson Resilience Scale (CD-RISC). Here, we introduce a two-item version of this scale, the CD-RISC2. We hypothesize that this shortened version of the scale has internal consistency, test-retest reliability, convergent validity, and divergent validity as well as significant correlation with the full scale. Additionally, we hypothesize that the CD-RISC2 can be used to assess pharmacological modification of resilience. We test these hypotheses by utilizing data from treatment trials of post-traumatic stress disorder, major depression, and generalized anxiety disorder with setraline, mirtazapine, fluoxetine, paroxetine, venlafaxine XR, and kava as well as data from the general population, psychiatric outpatients, and family medicine clinic patients.

Issues in Psychopharmacology

Although pharmacologic treatment remains a critical element in the short- and long-term management of schizophrenia, the past decade has been a challenging time in terms of real progress. Despite the introduction of several new medications as well as the conduct of larger and more diverse clinical trials, there remains considerable debate as to how far we have progressed in addressing some of the fundamental unmet needs in treating this disorder. A theme in this issue of Schizophrenia Bulletin addresses a number of topics in this context. Although the notion of careful, systematic, and critical summaries of all relevant randomized controlled trials is not a new one, the Cochrane Schizophrenia Group is relatively young. Clive Adams, one of its founders, and colleagues provide the rationale and history of the group as well as reviewing its methods and contributions. The Bulletin also carries a “Cochrane Corner” in each issue to alert the field to schizophrenia-related reviews. Systematic meta-analyses are playing an increasingly important role in informing both the research agenda and clinical practice. The work of the Cochrane collaboration has been enormously valuable in this process. In recent years, the field of schizophrenia research has benefited from the application of various clinical trial methodologies to enhance the study of treatment outcomes and determine generalizability. Large effectiveness trials have provided data to expand our knowledge base beyond that which is provided by traditional efficacy trials. Stroup and Geddes provide examples of each type of trial to illustrate their relative advantages and disadvantages. Within the context of different trial designs, Leucht et al provide an overview addressing critical aspects of trial design, potential population sampling bias, endpoint choices and definitions, quality of assessments, data analysis and reporting, as well as, other potential sources of bias or confounds relevant to the interpretation of clinical trials data in schizophrenia. One of the most difficult challenges in the design, conduct, analysis, and interpretation of clinical trials is the problem of dropouts—those individuals who do not complete the trial, often for unknown reasons. A variety of statistical techniques have been developed and applied in order to address this issue; however, none is entirely satisfactory. Rabinowitz and Davidov discuss the association of dropout and outcome in trials of antipsychotic medication and its implications for strategies to address missing data. Another strategy to minimize dropouts in acute treatment trials would be to shorten the length of the trial, particularly when placebo control groups are included. Addressing this issue and drawing on recent meta-analysis suggesting that a substantial proportion of antipsychotic drug response occurs within the first 2 weeks, McMahon and colleagues present an exploratory analysis from short-term placebo controlled clinical trial data suggesting the potential feasibility of reducing the duration of such trials. Much more work needs to be done to determine the benefits and risks of such an approach, but this is a very valuable first step. In the final article, we provide a review of unanswered questions in the pharmacologic treatment of schizophrenia. Despite numerous trials being conducted with antipsychotic medication, there are many clinical decisions that must be made on a day-to-day basis for which sufficient data are not available to provide an adequate evidence base. We hope that these articles will provide a snapshot of current challenges and opportunities for further progress in the design, conduct, and interpretation of psychopharmacologic trials in schizophrenia.

Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam

Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-D-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately. All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam. This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal.

Validating the bipolar spectrum in the French National EPIDEP Study: Overview of the phenomenology and relative prevalence of its clinical prototypes

Background Few studies have been undertaken to ascertain the feasibility of using the bipolar (BP) spectrum in clinical practice. The only systematic national study is the French EPIDEP Study of consecutive inpatients and outpatients presenting with major depressive episodes (MDE). The protocol was developed in 1994 and implemented in 1995; publication of its first data began in 1998. This report provides the complete data set of the EPIDEP. Methods Forty-eight psychiatrists, practicing in 15 sites in four regions of France (Paris, Besançon, Bordeaux and Marseille), were all trained on a common protocol based on DSM-IV criteria for MDE ( n = 537) subdivided into BP-I (history of mania), BP-II (history of hypomania), as well as extended definitions of the “softer spectrum” beyond BP-I and BP-II. Measures tapping into this spectrum included the Hypomania Checklist (HCA), the cyclothymic (CT), depressive (DT) and hyperthymic (HT) temperament scales. These measures and course permitted post-hoc assignment of MDE in the bipolar spectrum, based in part on the Akiskal, H.S., Pinto, O., 1999. [The evolving bipolar spectrum: Prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22, 517–534] proposal: depression with history of spontaneous hypomanic episodes (DSM-IV, BP-II), cyclothymic depressions (BP-II½), antidepressant-associated hypomania (BP-III) and hyperthymic depressions (BP-IV). «Strict UP» was thereby limited to an exclusion diagnosis for the remainder of MDE. Limitation In the clinical setting, psychiatrists cannot be entirely blind to the observations in the various clinical evaluations and instruments. However, the systematic multisite collection of such data tended to minimize any such biases. Results After excluding patients lost to follow-up, among 493 presenting with MDE with complete data files, the BP-II rate was estimated at index at 20%; 1 month later, systematic probing for hypomania doubled the rate of BP-II to 39%. The comparison between BP-II and UP showed differential phenomenology, such as hypersomnia, increased psychomotor activation, guilt feelings and suicidal thoughts in BP-II. Related data demonstrated the importance of CT in further qualifying of MDE to define a distinct, more severe (“darker”) BP-II½ variant of BP-II. Moreover, BP-III, arising from DT and associated with antidepressants, emerged as a valid soft bipolar variant on the basis of the phenomenology of hypomania and bipolar family history. Finally, we found preliminary evidence for the inclusion of BP-IV into the bipolar spectrum, its total hypomania score falling intermediate between BP-II and strict UP. Using this broader diagnostic framework, the bipolar spectrum (the combined “hard” BP-I phenotype, BP-II and the soft spectrum) accounted for 65% of MDE. Conclusion The EPIDEP study achieved its objectives by demonstrating the feasibility of identifying the bipolar spectrum at a national level, and refining its phenomenology through rigorous clinical characterization and validation of bipolar spectrum subtypes, including MDE with brief hypomanias, cyclothymia and hyperthymia. The spectrum accounted for two out of three MDE, making “strict UP” less prevalent than BP as redefined herein. Our findings were anticipated by Falret, who in 1854 had predicted that many melancholic patients in the community would 1 day be classified in his circular group. We also confirmed Baillarger's observation in the same year that episodes (in this study, hypomanic episodes) could last as short as 2 days. Our findings deriving from a systematic French national database a century and a half later invite major shifts in clinical and public health services, as well as in the future conduct of psychopharmacologic trials. In this respect, the systematic training of clinicians in four regions of France represents a national resource for affective disorders and can serve as a model to effect change in diagnostic practice in other countries.

Flying Almost Blind

Flying Almost Blind

Assessment of the Integrity of Study Blindness in a Pediatric Clinical Trial of Risperidone

Controlled clinical trials in pediatric psychopharmacology rely on blinded parents and clinical evaluators for outcome data, but little is known about the success of the masking procedures. The blindness of clinical evaluators and parents was examined in a clinical trial of risperidone in autism. Clinical evaluators and parents were asked to guess individual treatment assignments at the end of an 8-week placebo-controlled trial of risperidone in children (aged 5-17 years) with autism. Clinical evaluators did not have access to adverse event data. The rates of correctly guessing individual treatment assignment (risperidone or placebo) were significantly greater than chance for both clinical evaluators and parents (P < 0.001). Clinical evaluators associated improvement with attribution to risperidone, and lack of improvement with attribution to placebo, in both the risperidone and placebo treatment arms. Parents associated improvement with attribution to risperidone only in the placebo treatment arm. Parents reported that adverse events influenced their guesses, but presence of adverse events was not associated with correctness of guess. Improvement was associated with attribution to active treatment regardless of actual treatment assignment, and adverse events did not appear to be a threat to study blindness.

Design Features that Affect Psychopharmacology Trials

Design Features that Affect Psychopharmacology Trials

Prevention of postnatal depression

Postnatal depression is the most frequent psychiatric disorder seen after childbirth, with a prevalence rate of 10% to 15%. The women at risk need to be identified by a valid and reliable method, either using a screening instrument or an interview schedule. The preventive strategies need to have enough power to detect a clinically worthwhile effect to be considered useful in clinical practice. Many of the risk factors for developing postnatal depression are present during the pregnancy and immediate post-partum period. The risk factors for postnatal depression include depression or anxiety during pregnancy, experiencing stressful life events during pregnancy or the early puerperium, maternity blues, low levels of social support, past history of depression and poor marital adjustment. The antenatal and postnatal period provides an ideal opportunity to screen women for these risk factors. The women identified to be at risk can be identified, and preventive interventions can be implemented. Routine clinical practice can be improved to identify some of the women at risk by better communication between health professionals. There are no antenatal screening tools that have been shown to be of benefit in predicting postnatal depression. Edinburgh Postnatal Depression Scale is widely used in the postnatal period to screen for depression. The psychosocial interventions to prevent postnatal depression have not been shown to be beneficial and there is a dearth of psychopharmacological trials to make firm conclusions about their efficacy in preventing postnatal depression. Individualised psychosocial interventions aimed at the at-risk populations and initiated in the postnatal period appear to have some benefit in preventing postnatal depression. The focus of this article will be the risk factors associated with postnatal depression, screening methods and tools to identify those at risk of developing the disorder and the psychosocial, psychological and psychopharmacological interventions to prevent postnatal depression.

Supporting tools in psychiatric treatment decision-making: Sertraline outcome investigation with artificial neural network method

Controlled trials in clinical psychopharmacology may fail to provide reliable information about the benefit of treatment for the patient when considered in a real-life setting rather than as a part of a well-defined sampling procedure. Previously, we applied the mathematical model of an artificial neural network (ANN) to a pool of clinical information gathered through case descriptions provided by senior psychiatrists in clinical charts of patients receiving their first exposure to sertraline. In the present study, we applied the same mathematical model to a larger sample. The performance of the ANN model in forecasting successful and unsuccessful treatment showed an overall accuracy of classification of 97.12%. This result supports our previous finding about the potential application of this method as a reliable predictor of a given psychiatric patient's outcome during a specific psychopharmacological therapy.

Abatement of craving in recovering alcoholics: A descriptive analysis

Craving is an important concept in addiction but it has been somewhat mired down in controversies about definition and measurement. This article attempts to clarify the relationship between drinking and craving in recovering alcoholics.Data from two randomized clinical psychopharmacology trials were separately analyzed, a 12-week study of Nalmefene versus placebo (N = 105), and a 52-week maintenance study of Naltrexone versus placebo (N = 155).No evidence of a drug versus placebo difference in overall drinking or craving outcome was found. A simple visual analog craving score was highly correlated (p<0.001) at multiple time points both with a multi-item craving instrument and with drinking. Alcohol dependent individuals who quit drinking had greater reduction in craving than did individuals who moderate their drinking (p ≤ 0.001). For abstinent alcoholics who continued in the trial, craving decreased by 50% in the first few weeks, 75% after two months, and 95% after one year. Knowledge of the potential decrease in craving may be of therapeutic benefit to alcohol dependent individuals contemplating abstinence.

Psychotherapy in controlled psychopharmacology trials. Does it matter if we ignore it?

The controlled trial is now the standard for assessing efficacy of new treatments in Psychiatry, as it is in the rest of medicine. Psychiatric outcomes with treatment are influenced by concurrent psychosocial factors. Psychotherapy, alone or in combination with pharmacotherapy is an effective treatment. Thus, if concomitant receipt of psychotherapy is not controlled for in a psychopharmacology trial, outcome may be biased. In this study, all peer reviewed journal articles describing the results of randomized, controlled psychopharmacology trials in two separate years were carefully reviewed to assess the possible influence of control versus lack of explicit control for effect of concomitant psychotherapy on clinical outcome. One hundred sixteen articles, published in the years 1996 and 2000, were reviewed. Those with categorically positive or non-positive global outcome were assessed for description of concomitant receipt of psychotherapy by subjects randomized to different pharmacotherapy treatments. Description of comparability in potentially confounding demographic and clinical variables was present in all studies. Only 22% of 89 studies meeting inclusion criteria explicitly controlled for concomitant psychotherapy. Seventy five percent of 20 studies that did, and only 46% of 69 studies that did not, found different outcomes in groups randomized to different pharmacotherapy interventions ( p = .024). This result was not accounted for by other aspects of study design such as placebo-vs.-active control comparison, trial size, length, geographic location, number of sites or authors, source of funding, or diagnostic composition)-suggesting that uncontrolled receipt of psychotherapy may reduce likelihood of finding a difference between a new treatment and a control pharmacotherapy intervention. If confirmed by further investigation, the results may warrant adoption of relevant recommendations for controlled trial design in psychopharmacology research. The method used in this report may be useful in other areas of controlled trial research to assess influence of confounding variables.

The Treatment for Adolescents With Depression Study (TADS): Demographic and Clinical Characteristics

The Treatment for Adolescents With Depression Study is a multicenter, randomized clinical trial sponsored by the NIMH. This study is designed to evaluate the short- and long-term effectiveness of four treatments for adolescents with major depressive disorder: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. This report describes the demographic and clinical characteristics of the sample and addresses external validity. Participants are 439 adolescents, aged 12-17 years inclusively, with a primary DSM-IV diagnosis of current major depressive disorder. Baseline data are summarized and compared with those from national samples and previous trials. The sample composition is 54.4% girls, 73.8% white, 12.5% African American, and 8.9% Hispanic. The mean Child Depression Rating Scale-Revised total score is 60.1 (SD = 10.4, range 45-98) with 86.0% experiencing their first major depressive episode. The most common concurrent diagnoses are generalized anxiety disorder (15.3%), attention-deficit/hyperactivity disorder (13.7%), oppositional defiant disorder (13.2%), social phobia (10.7%), and dysthymia (10.5%). Demographic results are consistent with data from national samples and large psychopharmacology trials involving depressed adolescents. The Treatment for Adolescents With Depression Study provides a large, diverse, and representative sample of depressed adolescents that highlights the complexity of major depressive disorder in adolescents and provides a rich source for explicating the effects of moderator and mediator variables on baseline psychopathology and treatment outcome.

Multiplicity-Adjusted Sample Size Requirements

A researcher must carefully balance the risk of 2 undesirable outcomes when designing a clinical trial: false-positive results (type I error) and false-negative results (type II error). In planning the study, careful attention is routinely paid to statistical power (i.e., the complement of type II error) and corresponding sample size requirements. However, Bonferroni-type alpha adjustments to protect against type I error for multiple tests are often resisted. Here, a simple strategy is described that adjusts alpha for multiple primary efficacy measures, yet maintains statistical power for each test. To illustrate the approach, multiplicity-adjusted sample size requirements were estimated for effects of various magnitude with statistical power analyses for 2-tailed comparisons of 2 groups using chi2 tests and t tests. These analyses estimated the required sample size for hypothetical clinical trial protocols in which the prespecified number of primary efficacy measures ranged from 1 to 5. Corresponding Bonferroni-adjusted alpha levels were used for these calculations. Relative to that required for 1 test, the sample size increased by about 20% for 2 dependent variables and 30% for 3 dependent variables. The strategy described adjusts alpha for multiple primary efficacy measures and, in turn, modifies the sample size to maintain statistical power. Although the strategy is not novel, it is typically overlooked in psychopharmacology trials. The number of primary efficacy measures must be prespecified and carefully limited when a clinical trial protocol is prepared. If multiple tests are designated in the protocol, the alpha-level adjustment should be anticipated and incorporated in sample size calculations.

Magnitude of placebo response and drug–placebo differences across psychiatric disorders

Placebo response, drug response, and drug-placebo differences appear to vary among psychiatric conditions. We evaluated the Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports to compare the magnitude of placebo response, magnitude of psychotopic drug response, and drug placebo differences among various diagnostic groups such as depression, anxiety, and psychotic disorders. Six diagnostic groups (psychosis, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), depression, post-traumatic stress disorder, panic) varied in response to both placebo and active drug treatments. Response to placebo was high among patients participating in GAD, depression, and panic disorder clinical trials. Conversely, patients participating in psychotic disorder and OCD trials experienced low response to placebo. Our findings indicate that the magnitude of placebo response and drug response were heterogeneous and were statistically significantly different among various psychiatric disorders. Although a noticeable degree of heterogeneity was detected in the drug-placebo ratio among various disorders, the differences did not reach statistical significance. This finding suggests that placebo use should be continued for newer agents being tested for all of the psychiatric disorders. These findings may help in the development of psychopharmacology trial designs and in the deliberations of ethics committees.

Venlafaxine has modest effects in autistic children

Objectives: Few controlled psychopharmacologic trials have been conducted in autistic children to determine which agents may be effective at alleviating associated symptoms. Methods: Fourteen male children (7.1 ± 3.0 years) with autistic disorder, diagnosed by ICD-10 criteria, completed a placebo-controlled, double-blind crossover trial of venlafaxine (Effexord®, Wyeth ) administered at a dosage of 30 mg daily for 6 weeks. Subjects were included in the study if their eye contact and expressive language were inadequate for their developmental level. Subjects had not tolerated or responded to other psychopharmacologic treatments (neuroleptics, methylphenidate, clonidine or desipramine). Results: Teacher ratings on the Aberrant Behavior Checklist irritability, stereotype and inappropriate speech factors were lower during treatment with venlafaxine than during treatment with placebo. Clinician ratings (Children’s Psychiatric Rating Scale Autism, Anger and Speech Deviance factors; Children’s Global Assessment ...