What is the current documentation on methylphenidate (Concerta) treatment and anxiety as an adverse

Fråga: What is the current documentation on methylphenidate (Concerta) treatment and anxiety as an adverse drug reaction? This is a general question.

Sammanfattning: Overall, when taking the literature, clinical trials and additional information into account there are indications that methylphenidate could cause anxiety. However, it could be that it occurs in a lower frequency than according to the SPC. Another explanation could be that anxiety rather is an expression of the underlying disorder.

Svar: In Sweden, methylphenidate comes as Concerta (extended-release) and Ritalin (immediate-release, extended-release). Their therapeutic indication is attention-deficit hyperactivity disorder among children (>6 years) and teenagers (1, 2).

According to the SPC (1) anxiety is a common adverse drug reaction (ADR), occurring in 1/10-1/100. This is partly based on evaluations of 2772 subjects with attention-deficit hyperactivity disorder (ADHD), participating in seven open-label clinical trials, regarding safety of Concerta reported a 1.1% frequency of anxiety. The majority of ADRs were mild to moderate in severity (3). Anxiety as an ADR is mentioned in some literature (4) but absent in other.

The WHO adverse drug reaction-monitoring centre has received 113 reports (of a total of 5106) of cases regarding anxiety. These reports are not evaluated as to the causal relationship (5). In the Swedish adverse drug reactions register there are seven reports (of a total of 74) on anxiety disorders. All of them being assessed having a possible or probable relation to treatment. Symptoms presented within days to weeks after initiated treatment (6).

A double-blind placebo-controlled crossover trial concerning 32 pre-school children, aged 4-6 years, with ADHD assessed the frequency of ADR among methylphenidate users. Each subject received 7-10 days of treatment with either placebo, 0.3 mg/kg methylphenidate or 0.5 mg/kg of methylphenidate. Subjects were randomly assigned to start either methylphenidate or placebo. The statistically significant medication effect indicates that the proportion of children experiencing anxiety decreased (7).

Another randomized double-blind placebo-controlled crossover trial, concerning 206 children aged 5-15 years, compared 0.3 mg/kg and 0.5 mg/kg of methylphenidate (Ritalin) respectively to placebo in separate two-week trials addressing the frequency of ADR. The frequency of anxiety significantly decreased with both doses of methylphenidate treatment compared to placebo (8).

According to these studies decreased frequency of anxiety upon treatment combined with high-baseline rates suggest that anxiety might not be an ADR but rather an expression associated with ADHD disorder itself (7, 8).

An additional study on 30 adults evaluated changes in symptoms and efficacy of two different dosages, 30mg and 45mg methylphenidate per day respectively, but also compared with placebo. Each dosage was given for two weeks and subjects were randomly assigned to start either methylphenidate or placebo. This double-blind crossover trial included subjects with childhood and current ADHD symptoms. There was a reduction in anxiety with both placebo and methylphenidate. However, methylphenidate was significantly superior to placebo in reducing anxiety (9).