Psychopharmacology Clinical Trials Research Articles

\u201cInclude me if you can\u201d\u2014reasons for low enrollment of pediatric patients in a psychopharmacological trial

BackgroundLow recruitment in clinical trials is a common and costly problem which undermines medical research. This study aimed to investigate the challenges faced in recruiting children and adolescents with obsessive-compulsive disorder and autism spectrum disorder for a randomized, double-blind, placebo-controlled clinical trial and to analyze reasons for non-participation. The trial was part of the EU FP7 project TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes).MethodsDemographic data on pre-screening patients were collected systematically, including documented reasons for non-participation. Findings were grouped according to content, and descriptive statistical analyses of the data were performed.ResultsIn total, n = 173 patients were pre-screened for potential participation in the clinical trial. Of these, only five (2.9%) were eventually enrolled. The main reasons for non-inclusion were as follows: failure to meet all inclusion criteria/meeting one or more of the exclusion criteria (n = 73; 42.2%), no interest in the trial or trials in general (n = 40; 23.1%), and not wanting changes to current therapy/medication (n = 14; 8.1%).ConclusionsThe findings from this study add valuable information to the existing knowledge on reasons for low clinical trial recruitment rates in pediatric psychiatric populations. Low enrollment and high exclusion rates raise the question of whether such selective study populations are representative of clinical patient cohorts. Consequently, the generalizability of the results of such trials may be limited. The present findings will be useful in the development of improved recruitment strategies and may guide future research in establishing the measurement of representativeness to ensure enhanced external validity in psychopharmacological clinical trials in pediatric populations.Trial registrationEudraCT 2014-003080-38. Registered on 14 July 2014.

A Review of Methods for Monitoring Adverse Events in Pediatric Psychopharmacology Clinical Trials.

Pediatric psychotropic prescription rates are rising, emphasizing the need for careful monitoring of drug safety in this population. Currently, no standardized assessments are used in clinical trials for adverse event (AE) elicitation focused on long-term drug treatment in pediatric patients. Despite a lack of standardized AE elicitation methods in psychiatric clinical trials, it is clear that psychiatric medications have developmentally dependent AEs that differ from those observed in adults. In this review, we discuss the use of general inquiry elicitation, drug-specific checklists, and systematic elicitation scales for AE reporting in pediatric psychopharmacology trials. The checklists evaluated include the Barkley Side Effect Rating Scales (SERS), the Pittsburg side effect rating scale, and the Systematic Monitoring of Adverse events Related to TreatmentS (SMARTS) checklist. The systematic assessment scales discussed include the Systematic Assessment for Treatment of Emergent Events (SAFTEE) and the Safety Monitoring Uniform Report Form (SMURF). We review the advantages and disadvantages of each method and discuss the need for optimal assessment of AEs. AE instruments that are created and utilized for pediatric psychiatric trials must begin to incorporate symptoms that are relevant to this population and account for the nature of the disorders to better characterize treatment-emergent AEs and monitor long-term safety.

Comparative Mortality Risk in Adult Patients With Schizophrenia, Depression, Bipolar Disorder, Anxiety Disorders, and Attention-Deficit/Hyperactivity Disorder Participating in Psychopharmacology Clinical Trials

There is concern that increased mortality risk among patients with psychiatric illness may be worsened by psychopharmacological agents. To assess mortality risk among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies for US Food and Drug Administration (FDA) approval to market and to evaluate if psychopharmacological agents worsen this risk. The FDA Summary Basis of Approval (SBA) reports of new drug applications and supplemental applications for 28 psychopharmacological agents approved between 1990 and 2011. The FDA SBA reports detailing exposure data from acute placebo-controlled trials and safety extension studies including 92,542 patients from 47 adult drug approval programs for treatment of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder and SBA reports on combination and maintenance therapy programs for treatments of bipolar disorder. We reviewed and synthesized mortality data from SBA reports that combined mortality rates across the clinical trials, including information on patient exposure years (PEY) for active treatments and placebo for individual indications. Overall mortality rate per 100,000 PEY in relation to the psychiatric diagnosis of the patients participating in psychopharmacology clinical trials. Also, the overall mortality rates using PEY technique among patients assigned to psychopharmacological agents or placebo were evaluated. Overall, mortality risk was high and significantly associated with psychiatric diagnosis (χ²₄ = 1760; P < .001). Compared with the general adult population, patients with schizophrenia had the highest mortality risk (3.8-fold increase), followed by patients with depression (3.15-fold increase) and bipolar disorder (3.0-fold increase). The mortality risk was not increased when patients were assigned to psychotropic agents rather than placebo except for heterocyclic antidepressants. Suicide accounted for 109 of all 265 deaths (41.1%). These data suggest that increased mortality rates reported in population studies are detectable among adult patients with psychiatric illnesses participating in psychopharmacological trials. Furthermore, 3- to 4-month exposure to modern psychotropic agents, such as atypical antipsychotic agents, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors does not worsen this risk. Given the inherent limitations of the FDA SBA reports, further research is needed to support firm conclusions.

Challenges in Child and Adolescent Psychopharmacology Clinical Trials

Challenges in Child and Adolescent Psychopharmacology Clinical Trials

Plea to Establish a Registry of Clinical Trials on Cognitive-Behavioural Therapies and Cognitive Remediation

Dear Editor: In a 2009 article' published in The CJP reviewing treatment of obsessive-compulsive disorder, the authors noted that in the few available efficacy trials comparing medication and psychotherapy, cognitive-behavioural therapy (CBT) and (or) behavioural therapy has shown comparable or superior efficacy to medication. For a long time, psychopharmacological clinical trials, being mostly sponsored by the pharmaceutical industry, had been criticized for their lack of negative results concerning the medications being tested in these said trials. The scientific community has mobilized itself to solve this issue and over the last few years, it has become mandatory for psychopharmacological clinical trials to be listed in national and international registries, some of which are accessible online. 2^4 In Canada, there is no federal regulation that require researchers to register trials, though Health Canada is exploring that option: trial sponsors are encouraged to register trials in existing registers. Since 2004, the Canadian Institutes of Health Research (CIHR) has required that clinical trials it funds be registered in the United Kingdom Register. For instance, in 2008/09, 91 trials were obliged to register because of CIHR funding. Using these registries, researchers and clinicians can easily access all of the data concerning a molecule that has been studied in an observational or controlled trial. Further, these registries facilitate the elaboration of meta-analyses that must include negative, as well as positive, results to gain greater scientific meaning. Today, most of the internationally recognized scientific journals require a proof of subscription to one of these registries before accepting the results of a study for publication, which we believe is a self-evident and necessary change in an era of medicine that claims to be evidence-based. Recently, clinical trials involving approaches other than pure pharmacotherapy, such as CBT and cognitive remediation, have been carried out by our research group. A few of our studies produced negative end results; however, this allowed us to ascertain the difficulty in publishing such results as well as how their negative impact can influence our research team's desire to see them published.5 We believe the same thing happens in many other research teams and we worry that an important amount of information may be lost as negative results go unpublished and are not tallied up in any registry. We have recently consulted a large number of our colleagues studying CBT and cognitive remediation and realized that none of them ever felt an obligation to subscribe to any registry while carrying out large controlled studies involving these kinds of treatments. Thus this unavailability of negative results represents a significant inadequacy for these fields of research, as such results could definitely be useful to actual physicians and researchers. Moreover, advocates of registration are very satisfied with a recent aspect of the United States mandatory registration law (referred to as FDAAA 801). Clinical investigators must now submit basic results to a public database. This is the reason why we are now arguing on behalf of mandatory subscription to registries for all trials involving CBTs and cognitive remediation, as is already the case for psychopharmacological studies. Such registries would enable the scientific community to access negative results and conduct meta-analyses, as well as to structure and strengthen the knowledge we are developing in these fields of research. References 1 . Ravindran AV, da Silva TL, Ravindran LN, et al. Obsessive-compulsive spectrum disorders: a review of the evidence-based treatments. Can J Psychiatry. 2009;54(5):33 1-343. 2. US National Library of Medicine, US National Institutes of Health. Clinicaltrials.gov [Internet]. Bethesda (MD): US National Library of Medicine, US National Institutes of Health; 1997. …

Changes in Clinical Trials Methodology Over Time: A Systematic Review of Six Decades of Research in Psychopharmacology

BackgroundThere have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years.Methodology/Principal FindingsWe performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time.Conclusions/SignificanceClinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials.

The Clinical Global Impressions scale: errors in understanding and use

Objective The Clinical Global Impressions Severity and Improvement scales (CGI-S and CGI-I) are widely included as efficacy data in psychopharmacology new drug application submissions. This study was conducted to determine the extent to which clinical trials investigators included information unrelated to efficacy in their CGI ratings. Method Forty-five principal investigators provided CGI-S and CGI-I ratings of narratives of patients with major depressive disorder or generalized anxiety disorder. Investigators were blindly randomized to receive narratives that either did (experimental) or did not (control) contain indication-unrelated medical or psychiatric adverse events. Investigators then completed a survey assessing CGI-S and CGI-I rating patterns. Results CGI-S and CGI-I ratings were significantly more severe and less improved when the narratives contained medical and psychiatric adverse events unrelated to the diseases under study (major depressive disorder and generalized anxiety disorder) than when the narratives did not ( Ps < .04). In response to the survey, 46% and 56% of investigators reported that a psychiatric adverse event unrelated to the disease under study would not affect their CGI-S and CGI-I ratings, respectively. Although 87% of investigators reported that their CGI-S and CGI-I ratings would not be affected by a medical adverse event, actual CGI-S ratings were significantly more severe when an unrelated medical adverse event was described as occurring than when it was not ( P < .03). Conclusion Clinical trials investigators' inclusion of indication-irrelevant adverse events threatens the validity of the CGI as an efficacy measure and may contribute to failure to detect efficacy signals in psychopharmacology clinical trials.

Psychiatric Diagnosis and Clinical Trial Completion Rates: Analysis of the FDA SBA Reports

Completion rates may affect the safety and efficacy evaluations of psychotropics. We assessed completion rates in clinical trials evaluating psychotropics for five psychiatric disorders. We also examined differences in completion rates between psychotropics and placebo in each diagnostic category. We reviewed clinical data in the Food and Drug Administration summary basis of approval reports for 20 psychotropics evaluated for the treatment of depression, schizophrenia, obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), or panic disorder, consisting of 19 710 patients. Patients with OCD had the highest completion rates (78.0%), followed by patients with panic disorder (74.4%), GAD (69.2%), depression (64.7%) and schizophrenia (49.0%). Patients assigned to placebo had significantly lower completion rates in antipsychotic clinical trials. Patients assigned to psychotropics in OCD trials had significantly lower completion rates compared to the placebo group. A greater number of early terminations relating to a lack of efficacy was seen among patients assigned to placebo (17.4%) compared with patients assigned to psychotropics (12.2%). A greater number of early terminations relating to adverse events was seen among patients assigned to psychotropics (10.4%) compared with patients assigned to placebo (4.8%). Our findings suggest that psychiatric diagnosis and treatment assignment (placebo vs psychotropic) were associated with completion rates in clinical trials. These findings may help in the design of future psychopharmacology clinical trials.

Seizure Incidence in Psychopharmacological Clinical Trials: An Analysis of Food and Drug Administration (FDA) Summary Basis of Approval Reports

Clinical trial data provide an approach to the investigation of the effects of psychopharmacological agents, and psychiatric disorders themselves, on seizure threshold. We accessed public domain data from Food and Drug Administration (FDA) Phase II and III clinical trials as Summary Basis of Approval (SBA) reports that noted seizure incidence in trials of psychotropic drugs approved in the United States between 1985 and 2004, involving a total of 75,873 patients. We compared seizure incidence among active drug and placebo groups in psychopharmacological clinical trials and the published rates of unprovoked seizures in the general population. Increased seizure incidence was observed with antipsychotics that was accounted for by clozapine and olanzapine, and with drugs indicated for the treatment of OCD that was accounted for by clomipramine. Alprazolam, bupropion immediate release (IR) form, and quetiapine were also associated with higher seizure incidence. The incidence of seizures was significantly lower among patients assigned to antidepressants compared to placebo (standardized incidence ratio = .48; 95% CI, .36- .61). In patients assigned to placebo, seizure incidence was greater than the published incidence of unprovoked seizures in community nonpatient samples. Proconvulsant effects are associated with a subgroup of psychotropic drugs. Second-generation antidepressants other than bupropion have an apparent anticonvulsant effect. Depression, psychotic disorders, and OCD are associated with reduced seizure threshold.

Pretreatment attrition and childhood social phobia: Parental concerns about medication

Pretreatment attrition, the systematic self-exclusion of potential participants during the recruitment phase of a study, poses a significant threat to the external validity of randomized clinical trials. Very little is known about the factors that contribute to pretreatment attrition, especially among families seeking treatment for a child. The current study assessed pretreatment attrition in a randomized clinical trial of behavior therapy, fluoxetine, and placebo for child and adolescent social phobia. Reluctance toward medication treatment accounted for 44.7% of study refusals and was disproportionately common among ethnic minority families. Parents were particularly worried about the potential for side effects or physical/psychological dependency upon the medication. Results are discussed in terms of the implications for external validity in future psychopharmacological clinical trials.

The psychometric properties of the MASC in a pediatric psychiatric sample

The goals of this study were twofold: to examine the psychometric properties of the Multidimensional Anxiety Scale for Children (MASC) in a clinical sample of 193 children and adolescents who had received a diagnosis of major depressive or anxiety disorder, and to discriminate between these two groups of patients. Participants had volunteered in randomized psychopharmacological clinical trials. The MASC four-factor structure was confirmed and its subscales were found to be reliable. The MASC correlated well with other self-report measures of anxiety, and less so with measures of depressive symptoms. The MASC subscales and two MASC items as well as age differentiated between anxious and depressed pediatric patients. If these results are replicated in an independent study, those items could be used by clinicians to discriminate between these two disorders. The MASC is a clinically useful measure to discriminate between anxious and depressed pediatric patients. Limitations due to the highly selective sample are noted.

Atypical antipsychotics in the treatment of the persistently aggressive psychotic patient: methodological concerns

Aggressive behavior of psychotic patients impacts all aspects of their clinical care. Better treatments to address this problem are needed, and atypical antipsychotics, such as clozapine, risperidone, and perhaps quetiapine, have shown promise. However, studying the psychopharmacology of aggression is difficult because of the many methodological problems that arise in the design of appropriate clinical trials. These include imprecise definitions of aggression, the difficulty of measuring outcome because of the relative rarity of aggressive events, bias in the selection of patients for study, inadequate and inappropriate control groups, and inattention to comorbidities and concomitant medications in analyzing results. Since the usual outcome measure is the aggressive event rate, a large sample size and lengthy baseline and trial periods are required when this rate is low. Furthermore, formidable practical and ethical obstacles interfere with the many sound techniques (e.g. randomization) used in typical designs of psychopharmacological clinical trials. Current research methods should be modified and new ones developed in order to progress in assessing the antiaggressive effects of treatments.

Use of placebos in clinical trials involving children and adolescents.

Medications are commonly prescribed to treat child and adolescent psychiatric disorders, despite limited research about the safety and efficacy of their use in this population (1). The lack of data on medication treatment creates a dilemma for the physician. Added to this dilemma are pressures on the physician to treat patients quickly and with the least costly intervention, a circumstance that is often interpreted to mean that medication should be prescribed early in the treatment process. Clearly, additional data are needed to improve our database on the safety and efficacy of psychopharmacologic agents for children and adolescents and to serve as a rational guide for clinical treatment. At the same time, controversy has developed about the use of placebos in psychopharmacological clinical trials involving children and adolescents as subjects. Some investigators have proposed that the use of placebo treatment is unnecessary and unethical, serving only to deprive subjects of active treatment; a version of this position has been outlined by Rothman and Michels (2). In fact, some have proposed that it would be preferable to use an active placebo, that is, a medication or a medication dosage thought to be ineffective in the treatment of the study condition. Unfortunately, child and adolescent psychiatric disorders are not well understood, particularly because of the lack of data on the course and the outcome of these disorders. As such, it is impossible to predict changes in symptoms for individuals or groups of individuals within any sample, much as is the case in research on adult psychiatric disorders (3). Therefore, without a placebo control within the study, researchers have no basis for judging whether a given study medication was associated with improvement or worsening of symptoms. Furthermore, subjects in child and adolescent trials often have a high rate of response to placebo. This paper summarizes the findings of two recent studies—one part of a controlled trial and the other a naturalistic study. The findings highlight the need for clinicians to exercise caution in prescribing medication early in the course of assessment and emphasize the need for placebo in clinical trials.

Measuring disability in subjects with anxiety disorders

Subjects with anxiety disorders display substantial disabilities in health-related quality of life. The Sheehan Disability Scale (SDS) and SF-36 Questionnaire (SF-36) have been administered to subjects with anxiety disorders participating in psychopharmacology clinical trials and observational studies to evaluate their impaired functioning. The SDS does not address and does not include all the disabilities important to subjects with anxiety disorders and susceptible to being affected by drugs with anxiolytic effects, all of which are associated with significant problems. As a single-state-in-time rating, the SDS is often inadequate to discern subtle, but important,changes which may occur between measurements. The SF-36 as a measure of health status can, on the other hand, assess only the patient's behavior most directly affected by the disorder and treatment. As a result, the SF-36 enables the differentiation of functioning and well-being of subjects with anxiety disorders from diverse populations. There is little documentary evidence that demonstrates the value and actual performance of the SDS and SF-36 for the intended purpose. In the absence of a general consensus concerning operational definition, the measurement of disability in this patient population with these scales may be obsolete. There is the need for more specific and simple instruments capable to assess the distinct pattern of impairment associated with subjects with anxiety disorders.