David M. Gardner

International Consensus Study of Antipsychotic Dosing

OBJECTIVE Potency equivalents for anti-psychotic drugs are required to guide clinical dosing and for designing and interpreting research studies. Available dosing guidelines are limited by the methods and data from which they were generated. METHOD With a two-step Delphi method, the authors surveyed a diverse group of international clinical and research experts, seeking consensus regarding antipsychotic dosing. The authors determined median clinical dosing equivalents and recommended starting, target range, and maximum doses for 61 drugs, adjusted for selected clinical circumstances. RESULTS Participants (N=43) from 18 countries provided dosing recommendations regarding treatment of psychotic disorders for 37 oral agents and 14 short-acting and 10 long-acting parenteral agents. With olanzapine 20 mg/day as reference, estimated clinical equivalency ratios of oral agents ranged from 0.025 for sulpiride to 10.0 for trifluperidol. Seventeen patient and treatment characteristics, including age, hepatic and renal function, illness stage and severity, sex, and diagnosis, were associated with dosing modifications. CONCLUSIONS In the absence of adequate prospective, randomized drug-drug comparisons, the present findings provide broad, international, expert consensus-based recommendations for most clinically employed antipsychotic drugs. They can support clinical practice, trial design, and interpretation of comparative antipsychotic trials.

Modern antipsychotic drugs: a critical overview

CONVENTIONAL ANTIPSYCHOTIC DRUGS, used for a half century to treat a range of major psychiatric disorders, are being replaced in clinical practice by modern “atypical” antipsychotics, including aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone among others. As a class, the newer drugs have been promoted as being broadly clinically superior, but the evidence for this is problematic. In this brief critical overview, we consider the pharmacology, therapeutic effectiveness, tolerability, adverse effects and costs of individual modern agents versus older antipsychotic drugs. Because of typically minor differences between agents in clinical effectiveness and tolerability, and because of growing concerns about potential adverse long-term health consequences of some modern agents, it is reasonable to consider both older and newer drugs for clinical use, and it is important to inform patients of relative benefits, risks and costs of specific choices.

An open naturalistic trial of fluoxetine in adolescents and young adults with treatment-resistant major depression.

ABSTRACT Fifteen adolescents and young adults (ages 16-24) with a DSM-III-R diagnosis of major depression, who failed to respond to prior treatment with tricyclic antidepressants, were treated in an open trial using fluoxetine. Of the 11 patients who completed a 6-7 week trial, 64% showed a therapeutic response (>/=50% change) on the Hamilton Depression Rating Scale (HDRS), and 73% showed a positive response when rated by the Clinical Global Impression Scale (CGI). Side effects generally were mild, and the most common were tremor, dry mouth, nausea, sweating, and decreased appetite. Sweating, drowsiness, dry mouth, tremor, and alopecia appeared more commonly than in adult studies. One patient became manic, and none showed an increase in suicidal ideation. A starting dose of 20 mg daily often was tolerated poorly, and patients generally did better with 5-10 mg daily for the first week. Some patients appeared to exhibit antidepressant responses on 5-10 mg daily. These preliminary data suggest that fluoxetine, in doses ranging from 5 to 40 mg daily, when used in combination with psychosocial treatments, may be an effective antidepressant in adolescents or young adults who have not previously responded to adequate tricyclic therapy. Double-blind placebo-controlled studies are needed to evaluate the potential efficacy of fluoxetine in treating major depression in adolescents and young adults.

Effectiveness of contact-based education for reducing mental illness-related stigma in pharmacy students

BackgroundA strategy for reducing mental illness-related stigma in health-profession students is to include contact-based sessions in their educational curricula. In such sessions students are able to interact socially with a person that has a mental illness. We sought to evaluate the effectiveness of this strategy in a multi-centre study of pharmacy students.MethodsThe study was a randomized controlled trial conducted at three sites. Because it was necessary that all students receive the contact-based sessions, the students were randomized either to an early or late intervention, with the late intervention group not having participated in the contact-based education at the time when the primary outcome was assessed. The primary outcome, stigma, was assessed using an attitudes scale called the Opening Minds Survey for Health Care Providers (OMS-HC).ResultsWe initially confirmed that outcomes were homogeneous across study centres, centre by group interaction, p = 0.76. The results were pooled across the three study centres. A significant reduction in stigma was observed in association with the contact-based sessions (mean change 4.3 versus 1.5, t=2.1, p=0.04). The effect size (Cohen’s d) was 0.45. A similar reduction was seen in the control group when they later received the intervention.ConclusionsContact-based education is an effective method of reducing stigma during pharmacy education. These results add to a growing literature confirming the effectiveness of contact-based strategies for stigma reduction in health profession trainees.

The relationship between bipolar disorder and type 2 diabetes: More than just co-morbid disorders

Abstract Type 2 diabetes mellitus (T2DM) rates are three times higher in patients with bipolar disorder (BD), compared to the general population. This is a major contributing factor to the elevated risk of cardiovascular mortality, the leading cause of death in bipolar patients. There may be shared pathophysiology linking the two disorders, including hypothalamic-pituitary-adrenal and mitochondrial dysfunction, common genetic links, and epigenetic interactions. Life-style, phenomenology of bipolar symptoms, and adverse effects of pharmacotherapy may be contributing factors. Patients with BD and T2DM have a more severe course of illness and are more refractory to treatment. Control of their diabetes is poorer when compared to diabetics without BD, and an existing disparity in medical care may be partly responsible. Glucose abnormalities in bipolar patients need to be screened for and treated. Metformin appears to have the best benefit/risk ratio, and the dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists and analogues also appear promising, although these agents have not been specifically studied in populations with mood disorders. Physicians need to be aware of the increased risk for T2DM and cardiovascular disease in bipolar patients, and appropriate prevention, screening, case finding, and treatment is recommended.

Hypertensive episode associated with phenelzine and tap beer : a reanalysis of the role of pressor amines in beer

A case report of a hypertensive crisis resulting from the ingestion of tap beer in a patient on an irreversible monamine oxidase inhibitor (MAOI; phenelzine) stimulated the investigation of different kinds of beer for tyramine concentration. The objective was to determine the tyramine concentration in tap and bottled beers. A total of 98 beer samples (79 different brands of beer) were analyzed by high-performance liquid chromatography for tyramine. Of these 98 beers, 49 were bottled or canned beers and 49 were beers on tap. All of the bottled beers analyzed had safe tyramine concentrations (< or = 10 mg/liter; range, 0 to 3.16 mg/liter) and, thus, do not require restriction in patients receiving MAOIs. Therefore, the consumption of canned or bottled beer, including dealcoholized beer, in moderation (fewer than four bottles or cans; 1.5 liters within a 4-hour period) appears to be safe and does not require restriction in patients receiving MAOIs. Only 4 of 98 beer samples studied were found to have a dangerous (> 10 mg/liter) tyramine concentration, one of which was the index beer. The tyramine concentration in these four beers ranged from 26.34 to 112.91 mg/liter. All four of these beers were tap beers produced by bottom fermentation (lagers) and brewed by a secondary fermentation process. Although we did not find any visible bacterial growth in the tap beers with high tyramine content, this finding does not preclude the possibility that bacterial contamination, bacterial growth, production of tyramine, and eventually bacterial death occurred at some earlier time. Therefore, to err on the side of caution, it is recommended that patients on irreversible MAOIs avoid beers on tap.

Evidence-based decision making—the six step approach

The basic concept of evidence-based medicine proposes to make health related decisions based on a synthesis of internal and external evidence. Internal evidence is composed of knowledge acquired through formal education and training, general experience accumulated from daily practice, and specific experience gained from an individual clinician-patient relationship. External evidence is accessible information from research. It is the explicit use of valid external evidence (eg, randomised controlled trials) combined with the prevailing internal evidence that defines a clinical decision as “evidence-based.” To realise this concept in day to day clinical practice, the Evidence-Based Medicine Working Group proposed a 5 step strategy,1 corresponding to step 1 and steps 3 to 6 shown in the left hand column of the table. In teaching this 5 step approach, we encountered several difficulties. We noticed a growing hesitance to accept this strategy as students advanced in their medical training. In the presence of well established methods of treatment or …

Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, or conduct disorder

Objective: To develop evidence-based guidelines on pharmacotherapy for severe disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), or conduct disorder (CD). The guidelines assume that psychosocial interventions have been pursued but did not achieve sufficient improvement. Method: A multidisciplinary consensus group used the Grading of Recommendations Assessment, Development and Evaluation approach for rating evidence quality and for grading recommendations. We conducted a systematic review of medications studied in placebo-controlled trials for treating disruptive and aggressive behaviour in children and adolescents with ADHD, ODD, or CD. We followed consensus procedures to make 1 of 4 recommendations for each medication: strong, in favour (↑↑); conditional, in favour (↑?); conditional, against (↓?); and strong, against (↓↓). Results: For children and adolescents with disruptive or aggressive behaviour associated with ADHD, psychostimulants received a strong recommendation in favour of use, while atomoxetine and alpha-2 agonists received a conditional recommendation in favour of use. If these patients do poorly with ADHD medications, the medication with the most evidence is risperidone. Risperidone also has the most evidence for treating disruptive or aggressive behaviour in the absence of ADHD. However, given risperidones major adverse effects, it received only a conditional recommendation in favour of use. We recommended against using quetiapine, haloperidol, lithium, or carbamazepine because of the poor quality of evidence and their major adverse effects. Conclusion: When severe disruptive or aggressive behaviour occurs with ADHD, medications for ADHD should be used first. Other medications have major adverse effects and, with the exception of risperidone, very limited evidence to support their use.

Olanzapine for patients with treatment-resistant schizophrenia : A naturalistic case-series outcome study

Objective: This prospective, consecutive case-series outcome investigation evaluates the effectiveness of olanzapine in 16 patients with treatment-resistant schizophrenia. Method: Treatment resistance was defined as nonresponsiveness to at least 3 antipsychotic drugs from at least 2 different chemical classes. A minimum baseline score on the Brief Psychiatric Rating Scale (BPRS) of 45 was required for enrolment. Outcome evaluation measures included the BPRS, Global Assessment Scale (GAS), and Abnormal Involuntary Movement Scale (AIMS). Results: Subjects (n = 16) had a mean age of 40 years and mean duration of illness of 16 years. Olanzapine treatment was initiated at 5 mg daily and was increased based on clinical judgement up to a maximum of 40 mg daily. Significant decreases in mean BPRS (P < 0.001) and GAS (P < 0.01) scores were observed at weeks 4, 8, 12, and 16, compared with baseline. Eight of 16 patients responded to olanzapine, as defined by a 20% decrease in BPRS score by week 16. Dyskinetic movements significantly increased at week 4 (P < 0.01) but did not differ from baseline at weeks 8 and 16. Conclusion: These results suggest that olanzapine at moderate to high doses may offer an effective treatment for a significant proportion of patients with schizophrenia nonresponsive to multiple trials of conventional antipsychotics. A randomized controlled trial is encouraged to validate these findings, and comparative trials are required to determine when clinicians should consider this approach.

Monitoring and management of metabolic risk factors in outpatients taking antipsychotic drugs: a controlled study.

Objective: To evaluate the screening, monitoring, and management of metabolic risk factors and diseases in long-term antipsychotic users in relation to current practice guidelines and current standards of care as represented by a control group from an HIV clinic. Methods: We undertook a retrospective chart review of mental health clinic outpatients taking antipsychotic drugs long-term (cases) and HIV outpatients prescribed highly active antiretroviral therapy (control subjects). Results: We included 99 mental health clinic patients and 98 HIV patients in the analysis. According to information available in the outpatient clinic chart, the 10-year coronary artery disease risk was computable for 28% of the mental health clinic patients (mean risk 11.9%) and for 90% of the HIV patients (mean risk 9.5%) (χ2 = 77.0, P < 0.001). Metabolic risk factors were less frequently documented in mental health clinic charts. All HIV clinic patients were screened for hypertension and diabetes, and 90% were screened for dyslipidemia, whereas this information was missing for 30%, 39%, and 60% of mental health clinic patients, respectively (P < 0.001 for all). Disease monitoring was also more comprehensive in HIV clinic charts (for example, 100% of HIV patients were monitored for lipids, compared with 71% of mental health clinic patients; P = 0.001). Conclusions: Improved efforts are needed in the somatic care of patients with bipolar disorder and schizophrenia who are taking antipsychotics, given that they typically have moderate-to-high risk for metabolic diseases.