Alastair J. McKean

Reconciling the risk of QT interval prolongation in antidepressants

We discovered your article1 as a result of seeking answers to the myriad of theoretical and practical questions raised in response to a recent Food and Drug Administration (FDA) decision regarding citalopram. This decision is based in part on after-market case reports to the FDA and in part on a randomized, multi-center, double-blind, placebo-controlled, crossover study of 119 subjects receiving citalopram 20mg per day (Day 9), citalopram 60mg per day (Day 22), and placebo. At 20mg per day, the average QTc (the interval between the beginning of an electrocardiographic QRS complex and the peak of the subsequent T wave, corrected for heart rate) was increased by 8.5milliseconds and at 60mg daily by 18.5milliseconds. Based on this, the FDA advised against the use of citalopram above 40mg daily. To quote, “As a result of this thorough QT study, the FDA has determined that citalopram causes dosedependent QT (the interval between the beginning of a QRS complex and the peak of the subsequent T wave) interval prolongation and should no longer be used at doses above 40mg per day.”2 There are two assumptions on which the FDA based their decision. The first is that there is no antidepressant dose–response relationship or benefit to increasing antidepressant dose. We acknowledge that based on the relative lack of dose response from the research, there are real and significant questions related to the clinical practice of increasing the dose in patients who demonstrate no response. The second assumption, however, is that the dose-related changes in the QT interval are clinically relevant and that they directly lead to increased rates of torsades de pointes (TdP) and sudden cardiac death. Your findings identified “. . .4222 sudden cardiac death and ventricular arrhythmia outcomes for a rate of 3.3/1000 personyears” for all antidepressants and found no evidence of an increased hazard ratio for citalopram as compared to paroxetine (or ten other antidepressants). This would seem to argue strongly against the FDA decision. Your work is consistent with an older large-scale trial (1460 adult and elderly patients with major depression and/or dementia) in which the authors demonstrated that “there were no significant effects on. . .QTc intervals, indicating that citalopram has no effect on cardiac conduction and repolarization”3 and a more recent trial comparing venlafaxine’s effect on sudden cardiac death compared to fluoxetine, dusolepin, and citalopram.4 We would argue strongly that the FDA assumption that dose-related QT interval prolongation for citalopram leads to TdP and sudden death is not valid based on your research reflecting that there is no difference in rates of sudden death. There are other factors that your article considered, including genetic factors associated with drug metabolism, and medical comorbidity, which the FDA did not consider. Citalopram, a generic drug, is cautioned against, but the FDA remains silent regarding its still-proprietary enantiomer, escitalopram. Similarly odd is the decision to single out citalopram, ignoring a wide variety of antidepressants, despite large-scale trials—yours included—demonstrating its relative safety. Based on this and on clinical use of the drug over the past 14 years with a generally favorable safety profile, psychiatrists and other prescribers have met the FDA’s advisory with consternation, questioning the decision-making process. We recognize that QT prolongation can be potentially concerning but feel strongly that it must be considered in context. As the authors of a review of drug-induced arrhythmia stated, “it would be possible for regulatory bodies to reduce but not eliminate entirely the risk of TdP by declining to approve any drug with the potential to prolong the QTc interval, even to a modest degree. Although intuitively appealing, this approach inevitably would harm the public interest by denying patients access to many therapeutic agents whose proven clinical benefit far outweighs their arrhythmic risk (which in many instances is theoretical and based only on a modest potential for QTc prolongation).”5 This calls to attention the risk–benefit ratio of medications as a whole and cautions against the current FDA decision.

The Perils of Illegitimate Online Pharmacies: Substance-Induced Panic Attacks and Mood Instability Associated With Selegiline and Phenylethylamine

The recent rise in public access to illegitimate online pharmacies providing unrestricted access to psychotropic medications, in combination with the growing availability of substances that can produce legal highs, poses a significant risk to patients. This report describes a case of substance-induced depression and panic attacks associated with illegitimately obtained selegiline used in combination with the health supplement phenylethylamine (PEA).

Lack of rating scale normalization and a socioeconomically advantaged population limits the generalizability of preadolescent transgender findings

The article by Olson et al1 exploring the mental health of preadolescent transgender children residing in families that are supportive of their identity attempted to address questions Olson recently raised in a Clinical Perspectives piece published in the Journal of the American Academy of Child and Adolescent Psychiatry .2 We read the current article in Pediatrics with great interest, and their effort was laudable. An enhanced understanding of the symptoms and phenomenology of transgender preadolescents is critical, as this material could inform interventions for this marginalized population. Olson et al ambitiously examined symptoms of anxiety and depression in both … E-mail: mckean.alastair{at}mayo.edu

What Happens to Children Whose Parents Commit Suicide

Suicide remains one of the leading causes of death among 25- to 49-year-olds in the United States, and each year roughly 30,000 children are victims of parental suicide in the United States (Center for Disease Control and Prevention, 2005).1 We report a case of a young child who lost both of his parents to suicide.

Rehospitalization to a child and adolescent psychiatry unit: Role of trauma and bullying

OBJECTIVE Psychiatric rehospitalizations results in a significant burden to patients, families, and health care systems. Understanding psychiatric rehospitalizations offers an opportunity to identify weaknesses in current systems of care. The objective of this study was to test the hypothesis that a history of trauma or ongoing bullying increases the risk of psychiatric rehospitalization. METHOD Retrospective cohort study of 366 individual patients (71% female) admitted to a pediatric psychiatry unit between 1/1/2015 and 12/31/2015. The primary outcome measure was rehospitalization to the same psychiatric hospital unit within one year of first discharge. Trauma was defined as having a history of Post-Traumatic Stress Disorder, Reactive Attachment Disorder, or a filed Suspected Abuse and Neglect of a Child report by the end of first hospitalization. Ongoing bullying was identified by medical record review. RESULTS History of trauma (Odds Ratio (OR) = 3.2, 95% Confidence Interval (CI) = 1.8-5.6, p < 0.0001) and ongoing bullying (OR = 2.2, CI = 1.2-3.9, p = 0.009) were significantly associated with increased rates of rehospitalizations. We controlled for the following covariates: Patient Health Questionnaire-9 Modified (PHQ-9M) score, gender, age, relative age, initial length of stay, disrupted family system, and sexual orientation/identity. CONCLUSION History of trauma or ongoing bullying are important risk factors for pediatric psychiatric rehospitalization.