Short duration of clozapine treatment linked to increased hospitalization

Abstract

Adjunctive sodium nitroprusside fails to improve symptoms of schizophrenia Sodium nitroprusside, which activates N-methyl-D-aspartate receptors, has been investigated as a potential adjunctive treatment for patients with schizophrenia who have not responded to multiple antipsychotic trials. Early clinical trials of intravenous sodium nitroprusside have shown mixed results. A new double-blind, placebo-controlled study evaluated the efficacy and safety of a single dose of the drug in treating positive, negative, and cognitive symptoms in patients with schizophrenia. Outpatients ages 18 to 65 with a primary diagnosis of schizophrenia and a total score of 70 or more on the Positive and Negative Syndrome Scale (PANSS) and a score of 4 or more on the Clinical Global Impression-Severity scale were eligible for inclusion. They were required to have had ongoing antipsychotic treatment for at least 8 weeks, and to have failed to achieve a clinically significant reduction in symptoms after at least 8 weeks of antipsychotic treatment sometime in the past year. Among the exclusion criteria were a major medical illness, orthostatic hypotension, and a current substance use disorder. Participants were randomized to one of three treatment sequences: sodium nitroprusside given in two study phases covering a 28-day period, placebo and sodium nitroprusside, or placebo and placebo. The primary outcome was PANSS positive, negative, and total score across each two-week phase. Fifty-two of 60 randomized patients received a first infusion, and 50 completed the first phase. Thirty-two placebo nonresponders in phase one went on to phase two. No significant between-group differences were seen in change in PANSS scores. Safety outcomes also were similar between the two groups, with no serious adverse effects reported. The researchers cited as a limitation the inclusion of smokers in the study, as it is believed that nicotine use could diminish the efficacy of sodium nitroprusside. [Brown H, et al. JAMA Psychiatry 2019; published online March 27; doi: 10.1001/ jamapsychiatry.2019.0151] Numerous sleep problems linked to methylphenidate treatment Drug labeling for methylphenidate products includes information on the medication s effects on sleep-related adverse events, but the magnitude of its effects has not been quantified and the question of which sleep problems are most closely associated with the drug has remained unclear. A systematic review and meta-analysis examined methylphenidate trials reporting sleep-related adverse events, to determine in part whether risk varies by drug formulation and type of sleep problem. Studies included in the review were randomized, placebocontrolled trials involving children ages 6 to 18 and reporting on sleep, based either on spontaneous reports or solicited responses. The researchers extracted from each study a variety of potential confounding variables. Thirty-five studies encompassing 75 reports of sleep-related adverse events were included. Significantly increased relative risks were found for the adverse events of general insomnia, initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several variables were associated with relative risk for sleep-related adverse events and type of drug studied, such as mean age of sample, percentage of males in sample, and percentage of stimulant responders in sample. Also, a higher risk of sleep-related adverse events was associated with extended-release formulations of methylphenidate and with drugs dosed once daily. Regarding the latter finding, the authors wrote it “is probably due to patients’ taking their dose too late in the morning or to individual differences in pharmacokinetics, which extend the duration of action into the bedtime period.” The researchers also found that the placebo adverse event rate is associated with both relative risk and type of drug studied, a finding that confounds comparisons among drugs. “Given that insomnia occurs with all methylphenidate products, studies would be more informative if they reported results for different classes of insomnia rather than lumping all types of insomnia under one nonspecific term,” the authors wrote. [Faraone S, et al. J Clin Psychiatry 2019; published online Apr 30; doi: 10.4088/JCP.18r12210] No seizure increase from ADHD drugs in patients with epilepsy Risk of attention-deficit/hyperactivity disorder (ADHD) is increased in patients with epilepsy, but there is concern that medication treatments for ADHD could lead to increased seizure frequency in this group. Conversely, some studies have suggested a potential protective effect of ADHD treatment on the frequency of seizures in patients with epilepsy. A study examining data from Swedish population registers assessed risk of acute seizures associated with initiation of ADHD treatment and repeated medication periods. The study population consisted of residents born between 1995 and 2003 who had received at least two primary seizure discharge diagnoses as documented in records from the Swedish National Patient Register. ADHD medication initiation was defined as a dispensation preceded by at least 18 months without a dispensation, while repeated ADHD medication periods referred to at least two consecutive dispensations no more than 183 days apart. The primary outcome of acute seizure was defined as a seizure leading to an unplanned inpatient visit or outpatient specialist visit. The researchers found no evidence of increased seizure risk from baseline among patients with epilepsy in the 24 weeks following ADHD medication initiation. In regression analyses adjusted for age and sex, there was no difference in seizure rate during ADHD medication and nonmedication periods at the population level. Within-individual analyses showed a significantly decreased rate of seizures associated with ADHD medication periods. Sensitivity analyses were consistent with the main results. “Despite longstanding concerns regarding the safety of stimulant medication use in individuals with epilepsy, our results add to a growing body of research showing limited evidence for an exacerbated seizure risk associated with ADHD medications,” the study authors wrote. [Brikell I, et al. Epilepsia 2019; 60:284–293]