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 paper1 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. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Pharmacological Treatments" is the third of six sections of the 2016 guidelines. With little new information on older medications, treatment recommendations focus on second-generation antidepressants. RESULTS: Evidence-informed responses are given for 21 questions under 4 broad categories: 1) principles of pharmacological management, including individualized assessment of patient and medication factors for antidepressant selection, regular and frequent monitoring, and assessing clinical and functional outcomes with measurement-based care; 2) comparative aspects of antidepressant medications based on efficacy, tolerability, and safety, including summaries of newly approved drugs since 2009; 3) practical approaches to pharmacological management, including drug-drug interactions and maintenance recommendations; and 4) managing inadequate response and treatment resistance, with a focus on switching antidepressants, applying adjunctive treatments, and new and emerging agents. CONCLUSIONS: Evidence-based pharmacological treatments are available for first-line treatment of MDD and for management of inadequate response. However, given the limitations of the evidence base, pharmacological management of MDD still depends on tailoring treatments to the patient.

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. METHODS AND RESULTS: In a critical evaluation of case reports, we found 29 cases: 22 women and 7 men (age range 18-95 years). With both oral and intravenous erythromycin administration, there was no significant relationship between dose and QTc interval duration in these cases. Notably, all patients had severe illness. Other risk factors included female sex, older age, presence of heart disease, concomitant administration of either other QTc prolonging drugs or agents that were substrates for or inhibitors of CYP3A4. Most patients had at least two risk factors. CONCLUSIONS: On the basis of case report evaluation, we believe that major risk factors for erythromycin-associated TdP are female sex, heart disease and old age, particularly against a background of severe illness. Coadministration of erythromycin with other drugs that inhibit or are metabolized by CYP3A4 or with QTc prolonging drugs should be avoided in this setting.

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. They only showed that the drugs reviewed caused varying degrees of QTc interval prolongation, and even that information was not clear and consistent enough to stratify individual drugs for this risk. The few toxicology studies provided valuable information but their findings are pertinent only to situations of drug overdose. Case reports were most informative about the drug-QTc interval prolongation-TdP link. At least one additional well established risk factor for QTc prolongation was present in 92.2 % of case reports. Of the 28 cases of TdP, six (21.4 %) experienced it with QTc interval <500 ms; 75 % of TdP cases occurred at therapeutic doses. There is little evidence that drug-associated QTc interval prolongation by itself is sufficient to predict TdP. Future research needs to improve its precision and broaden its scope to better understand the factors that facilitate or attenuate progression of drug-associated QTc interval prolongation to TdP.

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. Among the 12 case reports risk factors included female sex (nine cases), coadministration of a drug associated with QTc interval prolongation (eight cases), hypokalemia or hypomagnesemia (six cases) quetiapine overdose (five cases), cardiac problems (four cases), and coadministration of cytochrome P450 3A4 inhibitors (two cases). There were four cases of TdP. As drug-induced TdP is a rare event, prospective studies to evaluate the risk factors associated with QTc prolongation and TdP are difficult to design, would be very costly, and would require very large samples to capture TdP rather than its surrogate markers. Furthermore, conventional statistical methods may not apply to studies of TdP, which is rare and an 'outlier' manifestation of QTc prolongation. We urge drug manufacturers and regulatory agencies to periodically publish full case reports of psychotropic drug-induced QTc interval prolongation, TdP, and SCD so that clinicians and investigators may better understand the clinical implications of prescribing such drugs as quetiapine.

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. Hypertension during midlife is also associated with dementia later in life and the association is stronger for untreated hypertension. Calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin-1 receptor-blockers may be particularly beneficial in diminishing the risk of dementia associated with hypertension. Studies have fairly consistently shown that type 2 diabetes is a risk factor for dementia. Episodes of hypoglycemia add to this risk. Regular physical exercise during any point in the lifespan protects against cognitive decline and dementia. Most benefit is realized with physical exercise during early and midlife. Dyslipidemia also increases the risk of dementia but the findings are less consistent. Findings on the possible benefit of lipid-lowering agents (statins) are conflicting. Earlier studies identified smoking as protective of dementia but recent better designed studies have consistently shown that smoking increases the risk of dementia. The association of vascular risk factors with dementia is more robust for vascular dementia than Alzheimer's disease. Heterogeneity of studies and lack of trials specifically designed to assess cognition as an endpoint make firm conclusions difficult. But considering the expected global burden of dementia and projected attributable risk of vascular risk factors to it, there is sufficient evidence to promote vascular risk factor reduction strategies as dementia prevention interventions.

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. This case is an example of acquired long QT syndrome; a disorder that can be precipitated by macrolide antibiotics such as clarithromycin. Additional risk factors present in this case include: female gender, old age, heart disease, hypokalemia and hypomagnesemia. In this manuscript we comprehensively review past cases of clarithromycin-induced long QT syndrome (LQTS) and discuss them within the context of this case.

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. For second-generation antidepressants, there may be modest weight loss with bupropion and modest weight gain with mirtazapine and paroxetine. Other second-generation antidepressants are weight neutral but individual variations can occur. If significant change in weight occurs, switching to or adding a low-risk second-generation antidepressant should be considered. Mood stabilizers include lithium, valproate, carbamazepine, lamotrigine, oxcarbazepine, and most second-generation antipsychotics. Risk of weight gain is high with lithium and valproate and low with carbamazepine, lamotrigine, and oxcarbazepine. Given the complexity of bipolar disorder and its management, a switch of a mood stabilizer would be best done by a psychiatrist. Benzodiazepines, non-benzodiazepine and melatonergic hypnotics, doxepin, and trazodone are weight neutral. Diphenhydramine may cause weight-gain and can be switched to a weight-neutral hypnotic if needed. Stimulants can cause varying degrees of weight loss and switching to atomoxetine or bupropion may reverse this problem. If that fails, switching to clonidine or guanfacine can be tried. Switching must be evidence-based and take into account status of the condition being treated, efficacy, side effect profile, potential drug-drug interactions, required laboratory monitoring and cost of the drug(s) being considered, and patient's pregnancy status or plan. Non-pharmacological interventions both for mental disorders and overweight/obesity must be fully availed.

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. We report risk factors for methadone-associated QTc interval prolongation and TdP based on review of published case reports. We believe both drug manufacturers and the FDA would better serve our patients and inform clinicians if they more readily reported drug-induced outliers such as methadone-associated TdP using a case report format.

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. METHOD: We identify case reports using PubMed, Medline, EMBASE, and Cochrane. RESULTS: Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, "elderly", 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n = 10), older age (n = 4), heart disease (n = 3), hypokalemia (n = 2), bradycardia (n = 1), liver disease (n = 1), QTc interval prolonging drugs other than risperidone (n = 8), and metabolic inhibitors (n = 2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP. CONCLUSION: Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.

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. CONCLUSION: Applying conventional statistics as the FDA does may not be the best tool to study this phenomenon because SSRI-associated TdP is a very rare event and hence best understood as an 'extreme outlier'. Despite the limitations inherent in case report material, case reports on drug-associated QTc interval prolongation and TdP provide valuable information that should be considered along with other sources of information for clinical guidance.

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. METHODS AND RESULTS: In a detailed literature search, we found 15 women, five men, and one boy meeting our search criteria. Among the 17 adults with reported clarithromycin dose and concurrent QTc interval measurement, we found no statistically significant relationship between clarithromycin dose and QTc interval duration. This did not change for the adults who developed TdP. Among adults, major risk factors were female sex (15), old age (11) and heart disease (17). A total of eight adult subjects had all three major risk factors and 14 of the 20 adults had at least two major risk factors. All adult subjects had at least two risk factors besides clarithromycin. A total of four of the 20 adults received cisapride and three received disopyramide. Three adults were considered to suffer from some aspect of the congenital long QT syndrome. CONCLUSIONS: We believe that the risk factor description for this drug should be refined to emphasize the major risk factors of (1) female sex, (2) old age and (3) heart disease.

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. We found 12 cases: seven female and five male. Of the nine adults with reported azithromycin doses, concurrent QTc interval measurement, and without congenital long QT syndrome, we found no significant relationship between dose and QTc interval duration. Additional risk factors were female sex, older age, heart disease, QTc interval prolonging drugs and metabolic inhibitors, hypokalemia, and bradycardia. All 12 subjects had at least two additional risk factors. Elderly women with heart disease appear to be at particularly risk for drug-related QTc interval prolongation and torsade de pointes.