Is there a risk of adverse drug reaction if Risperdal (risperidone) is added to an ongoing therapy

Fråga: Is there a risk of adverse drug reaction if Risperdal (risperidone) is added to an ongoing therapy with Ritalina (methylphenidate) and Zoloft (sertraline)? The question concerns a 7-year-old boy with ADHD and Tourette´s disorder who is treated with methylphenidate 5 mg x3 and sertraline 75 mg x1. His symtoms have improved since starting this treatment, but he is still very obsessive and has severe emotional outbursts. His physician now wants to add risperidone to the other drugs.

Sammanfattning: No reports were found on the concomitant use of methylphenidate, risperidone and sertraline. There is a theoretical risk of drug interaction between methylphenidate and risperidone or sertraline and risperidone, leading to an increased plasma concentration of risperidone. This potential drug interaction can be handled by the use of therapeutic drug monitoring. If the drugs are to be used concomitantly, we recommend a low starting dose of risperidone and that the patient should be carefully observed for any adverse drug reactions. Also, there is a potential risk of drug interaction between methylphenidate and risperidone that could lead to attenuated or abolished therapeutic effect of methylphenidate.

Svar: No reports were found on the concomitant use of methylphenidate and risperidone. The mechanism of action of methylphenidate is not fully understood, but its therapeutic effect may be associated with its influence on multiple neurotransmittors, especially dopamine and noradrenaline (1). Several sources of evidence lead to the conclusion that effects on both noradrenaline and dopamine are important to the psychostimulant efficacy (1). The antipsychotic effect of risperidone is thought to be related to its ability to block dopamine (D2) receptors and serotonin (5-HT2) receptors (3). Considering the opposing pharmacological effects of the two drugs there is a theoretical risk for drug interaction resulting in attenuated or abolished effect of methylphenidate. This drug interaction has been described for methylphenidate and haloperidol, another D2-blocking drug (2).

Risperidone is extensively metabolised (3). The major metabolite, 9-hydroxyrisperidone, has a pharmacological profile similar to that of the parent drug. The 9-hydroxylation is catalysed by CYP2D6 and possibly also by CYP3A4 (4). The predominant metabolic pathway of methylphenidate is de-esterification to form ritalinic acid, which is pharmacologically inactive (5). In addition, there are minor pathways (less than 2 percent) involving among other things microsomal oxidation (5). Some studies indicate that methylphenidate inhibits the metabolism of imipramine (which is partly metabolised by CYP2D6) (2). Methylphenidate may thus have an inhibitory effect on CYP2D6 and this could lead to an increased plasma concentration of risperidone. The clinical significance of this is difficult to predict, but the situation can be managed by measuring the plasma concentration of risperidone.

Even though there are no actual interaction studies of sertraline and risperidone the combination has been used with good results in patients with obsessive-compulsive disorder who did not improve after an adequate trial with serotonin uptake inhibitors (6).

Sertraline is extensively metabolised by the cytochrome P450-system (7). In vitro studies suggest that there are several different CYP isoforms involved, but none is quantitatively dominant (7). In vivo studies have shown that coadministration of sertraline inhibits the metabolism of desipramine (mediated by CYP2D6) resulting in a 37 percent increase in the plasma concentration of desipramin (8). Coadminstration of sertraline and risperidone could thus result in a higher plasma concentration of risperidone than expected. Again, therapeutic drug monitoring of risperidone can be of interest.