Selective acquired long QT syndrome (saLQTS) upon risperidone treatment

Abstract

BackgroundNumerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially.Case presentationWe report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes.ConclusionsOur observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

“…Among atypical agents, risperidone had a similar cardiac safety profile to olanzapine; whereas, quetiapine was associated with lower risk compared to olanzapine. A case report of low-dose risperidone-induced long QT, confirmed on three independent drug challenges, was described [ 124 ] (Table 4 ). There are no reported cases of lithium induced TdP.…”

QTc Interval Prolongation with Therapies Used to Treat Patients with Parkinson’s Disease Psychosis: A Narrative Review

“…The effect of clozapine on QTc interval was described in 1 systematic review, 59 13 studies, 33 , 45 , 50 , 51 , 55 , 61 , 67 , 77–82 and 6 case reports. 71 , 73 , 83–86 One study found no significant change from baseline in mean QTc interval or the incidence of QTc prolongation, 79 but this is inconsistent with findings from other researchers. Four studies of 4951 psychiatric inpatients have reported an increased risk of QTc prolongation with clozapine (odds ratios, 1.006 [95% CI, 1.003–1.008] and 2.4 [95% CI, 1.4–4.2]), with the magnitude of effect being dose dependent ( Table 3 ).…”

“…Aripiprazole discontinued and QTc normalized (450 ms) after 14 days Vieweg et al 2013 130 28–87 Male (n = 4)/female (n = 9) Various Various All cases had QTc prolongation with APs in the absence of overdose. Risk factors for QTc prolongation: risperidone, female sex, older age, heart disease, hypokalemia, bradycardia, liver disease, QTc-prolonging drugs (other than risperidone), and metabolic inhibitors Lazarczyk et al 2012 71 37 Female Schizophrenia Aripiprazole: 20 mg/d Haloperidol: 3 mg/d Escitalopram: 20 mg/d Benzodiazepines: dose NR Addition of risperidone 1–2 mg/d increased QTc interval from 458 to 508 ms. Prolongation remained despite discontinuation of potential QTc-prolonging drugs. Administration of other APs, including clozapine, did not affect QTc Cohen et al 2001 83 30 Male Schizophrenia Clozapine: 500 mg/d QTc with clozapine 500 mg/d (monotherapy): 624 ms. QTc with olanzapine 10 mg/d + valproic acid 1800 mg/d: 504 ms Aripiprazole Karz et al 2015 70 80 Female Schizoaffective disorder, bipolar type Aripiprazole: 10 mg/d Fluoxetine: 20 mg/d Lisinopril: 5 mg/d Simvastatin: 10 mg/d Aspirin: 81 mg/d Aripiprazole was discontinued post-MI.…”

“…A 37-year-old woman who experienced QTc prolongation (an increase from 458 to 508 ms) with risperidone 1–2 mg/day had no such response with clozapine (dose not specified; Table 4 ). 71 On the other hand, QTc intervals of 472–504 ms have been reported in men ages 30–45 years taking clozapine 100–400 mg/day. 73 , 84 , 86 In each case, QTc returned to baseline after switching to aripiprazole, quetiapine, or olanzapine.…”

Antipsychotics cardiotoxicity: What's known and what's next

“…Genetic susceptibility, namely, mutations in the genes encoding potassium ion channel proteins ( i.e. , KCNH2 , KCNQ1 , and SCN5A ) is also directly associated with an increased risk of malignant arrhythmias[ 94 ]. In addition to the inherited hERG mutations that are associated with congenital long QT syndrome, suppression of native I Kr by psychotropic therapy also predisposes individuals to polymorphic ventricular tachycardia of the TdP type[ 95 ].…”