Use of Placebo in Clinical Trials of Psychotropic Medication.

This position paper has been substantially revised by the Canadian Psychiatric Association's Research Committee and approved for republication by the CPA's Board of Directors on March 31, 2017. The original position paper was developed by the Scientific and Research Council and approved by the Board of Directors on October 4, 1996.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments.

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals.

Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses.

QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review.

We comprehensively reviewed published literature to determine whether it supported the link between corrected QT (QTc) interval prolongation and torsade de pointes (TdP) for the 11 second-generation antipsychotics and seven second-generation antidepressants commonly implicated in these complications. Using PubMed and EMBASE, we identified four thorough QT studies (one each for iloperidone, ziprasidone, citalopram, and escitalopram), 40 studies specifically designed to assess QTc interval prolongation or TdP, 58 publications based on data from efficacy and safety trials, 18 toxicology studies, and 102 case reports. Thorough QT studies, QTc prolongation-specific studies, and studies based on efficacy and safety trials did not link drug-associated QTc interval prolongation with TdP.

Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity.

Objectives: Erythromycin is a macrolide antibiotic that is widely used for various infections of the upper respiratory tract, skin, and soft tissue. Similar to other macrolides (clarithromycin, azithromycin), erythromycin has been linked to QTc interval prolongation and torsade de pointes (TdP) arrhythmia. We sought to identify factors that link to erythromycin-induced/associated QTc interval prolongation and TdP.

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports.

Over the past year, three articles have appeared in the New England Journal of Medicine describing conflicting findings about azithromycin and cardiac safety, particular azithromycin-induced QTc interval prolongation and torsade de pointes. The FDA wants healthcare providers to consider azithromycin-induced fatal cardiac arrhythmias for patients already at risk for cardiac death and other potentially arrhythmogenic cardiovascular conditions. In a systematic review of case reports we sought to determine factors that link to azithromycin-induced/associated QTc interval prolongation and torsade de pointes.

Clarithromycin, QTc interval prolongation and torsades de pointes: the need to study case reports.

Background: The manufacturers of clarithromycin sought a drug similar in efficacy to erythromycin but with a superior side-effect profile. They generally achieved this outcome, but postmarketing findings identified a series of reports linking clarithromycin to QTc interval prolongation and torsades de pointes (TdP) ultimately leading to a Black Box Warning. We sought to clarify risk factors associated with TdP among case reports of patients receiving clarithromycin linked to QTc interval prolongation and TdP.

Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports.

Objective: In the light of the recent United States Food and Drug Administration (FDA) warning to clinicians on using previously approved doses of citalopram because of the purported higher risk of torsade de pointes (TdP), we pursued the broader question: are selective serotonin reuptake inhibitor (SSRI) antidepressant agents as a group unsafe because they might induce QTc interval prolongation and TdP?

Method: We reviewed the literature and found only 15 case reports (6 of fluoxetine, 1 of sertraline and 8 of citalopram) of SSRI-associated QTc interval prolongation linking to TdP.

Results: A total of 13 cases contained sufficient information for analysis. In the setting of TdP, QTc interval prolongation does not clearly relate to SSRI dose.

Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports.

Recently, both the manufacturer of quetiapine and the US Food and Drug Administration warned healthcare providers and patients about quetiapine-induced QTc interval prolongation and torsade de pointes (TdP) when using this drug within the approved labeling.  We reviewed the case-report literature and found 12 case reports of QTc interval prolongation in the setting of quetiapine administration. There were no cases of quetiapine-induced TdP or sudden cardiac death (SCD) among patients using quetiapine appropriately and free of additional risk factors for QTc interval prolongation and TdP.

Possible role of vascular risk factors in Alzheimer's disease and vascular dementia.

The contribution of vascular risk factors to Alzheimer-vascular spectrum dementias is increasingly being recognized. We provide an overview of recent literature on this subject. Overweight and obesity as well as underweight during midlife predict cognitive decline and dementia later in life.

Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem.

We reviewed the literature and found 31 adult cases and 1 newborn case of methadone-associated QTc interval prolongation and/or torsade de pointes (TdP). Parametric statistics may not be useful in studying this issue because methadone-associated TdP is a very rare event and, hence, "an extreme outlier" consistent with scalable randomness. We may have to rely upon narrative medicine in the form of case reports with all its limitations and hazards to provide our best understanding.

Torsades de pointes following clarithromycin treatment.

A 75-year-old woman presenting with pre-syncope, shortness of breath and nausea was admitted to the emergency department following treatment with clarithromycin. Shortly after admission she developed a prolonged QT interval leading to torsades de pointes (TdP) and cardiac arrest. She was successfully cardioverted and clarithromycin was discontinued resulting in restoration of her usual QT interval.

Weight considerations in psychotropic drug prescribing and switching.

Our review describes potential weight-altering effects of psychotropic medications (antipsychotics, antidepressants, anti-anxiety medications, mood stabilizers, sedative-hypnotics, medications for attention-deficit/hyperactivity disorder, and other psychotropic medications) and offers guidance on switching a medication if its weight-altering effect becomes problematic. For second-generation antipsychotics, the risk of weight gain is high with clozapine and olanzapine, low with amisulpride, aripiprazole, and ziprasidone, and medium with other second-generation antipsychotics. Switching from a high-risk antipsychotic to a low-risk antipsychotic usually mitigates or reverses weight gain.

Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports.

Rationale: A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced IKr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP).

Objectives: The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP.

Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians.

Second-generation antipsychotics (SGAPs) and second-generation antidepressants (SGADs) have multiple US Food and Drug Administration-approved indications and are frequently prescribed by primary care physicians. We review the relative potential of these drugs to cause weight gain and glucose dysregulation, and offer clinical guidance to minimize and manage this risk. Among SGAPs, clozapine and olanzapine have a high risk for causing weight gain and glucose dysregulation; iloperidone, paliperidone, quetiapine, and risperidone have a medium risk; and aripiprazole, asenapine, lurasidone, and ziprasidone have a low risk.

Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling?

Recently, both the manufacturer of citalopram and the US Food and Drug Administration have warned health care providers and patients about new information implicating drug-induced QTc interval prolongation and torsade de pointes when using citalopram in doses >40 mg/day. This warning is not placed in the context of either benefits or risks in real-world clinical practice, leaving clinicians with an untenable choice between depriving patients of high-dose citalopram or malpractice litigation. We reviewed the literature and found no cases of citalopram-induced sudden cardiac death among patients taking up to 60 mg/day of citalopram and free of risk factors for QTc interval prolongation and torsade de pointes.