risperidone

There is conflicting evidence of an interaction between risperidone and tobacco smoking. 

a) In a retrospective analysis of 693 patients (including 401 smokers), smokers were receiving significantly higher daily doses of risperidone compared to non-smokers. Additionally, smokers had significantly lower dose corrected concentrations of risperidone metabolite and active moiety. 

b) A retrospective study of 136 patients (including 42 smokers) found that smoking had no significant impact on the serum concentrations of oral risperidone.

It has been suggested that polycyclic aromatic hydrocarbons found in tobacco smoke may induce CYP3A4, but the evidence remains unclear. Risperidone is a CYP3A4 substrate. 

While the evidence is contradictory, there is not enough evidence to suggest that concomitant use of risperidone and tobacco may result in decreased therapeutic effect of risperidone. Thus, dose adjustments should not be necessary in cases of increased or decreased tobacco smoking.

a) Caffeine is unlikely to influence risperidone levels.

b) Risperidone may enhance the tachycardic effect of caffeine.

a) Risperidone is mainly metabolized via CYP2D6 and CYP3A4. Inhibition of CYP1A2 by caffeine is unlikely to influence risperidone levels.

b) As an anticholinergic, risperidone blocks muscarinic M2 receptors and causes tachycardia, potentially enhancing the sympathetic stimulation produced by caffeine.

a) Concomitant use of risperidone and caffeine should not alter the therapeutic effect of risperidone.

b) Patients should be monitored for increased sympathomimetic effects such as increased heart rate if these drugs are used concomitantly.

a) As a CNS depressant, risperidone has the potential to enhance the adverse or toxic effects of other CNS depressants, such as cannabis.

b) Risperidone may enhance the tachycardic effect of cannabis.

a) The exact mechanism of increased CNS depression is unknown, but it appears that the effects are mainly additive.

b) Cannabinoids are known to cause tachycardia independent of any effects of other anticholinergics. There is a potentially additive effect when cannabis is concomitantly used with risperidone. 

a) It is important to warn patients of the potential for a reduction in psychomotor function when these drugs are taken concurrently. They may or may not be aware of their deterioration in skill level and response will vary between individuals. They will likely experience a deterioration in their abilities to operate a vehicle and/or carry out tasks that require mental alertness.

b) It is recommended to monitor the cardiovascular status of patients who use cannabinoids concomitantly with anticholinergics.

a) Cocaine is a strong CYP2D6 inhibitor. Concomitant administration with risperidone, a CYP2D6 substrate, may result in decreased clearance of risperidone and increased serum levels. 

The potential for CYP2D6 inhibition puts patients who are co-administering these two drugs at increased risk of adverse or toxic effects associated with higher levels of risperidone; however, to what extent cocaine inhibits the metabolism of risperidone is unclear. 

b) QTc interval prolongation has been observed with risperidone. Concomitant use with cocaine may result in an arrhythmia with the potential to develop Torsades de Pointes.

c) Risperidone may enhance the tachycardic effect of cocaine.

a) This interaction appears to be due to CYP2D6 inhibition by cocaine. 

b) Both risperidone and cocaine can cause QTc interval prolongation. When used together, these effects may be additive.

c) As an anticholinergic, risperidone blocks muscarinic M2 receptors and causes tachycardia, potentially enhancing the sympathetic stimulation produced by cocaine.

a) Concomitant use of cocaine with CYP2D6-metabolized risperidone may enhance the adverse/toxic effects of the latter drug. Patients should be monitored for the appearance of adverse drug effects and counselled on avoidance of cocaine while taking risperidone. 

b) Due to increased risk of QTc interval prolongation, it is recommended to avoid concomitant use of cocaine and risperidone.

c) Patients should be monitored for increased sympathomimetic effects such as increased heart rate if these drugs are used concomitantly.

AMPHETAMINES/STIMULANTS: Risperidone may enhance the tachycardic effect of stimulants.

METHYLPHENIDATE: Concomitant use of antipsychotics and methylphenidate may enhance each other's adverse or toxic effects. 

a) A 7-year-old patient developed acute dyskinesia after risperidone was withdrawn and methylphenidate was started. There are case reports in which two girls, who were receiving combined treatment with risperidone and a central stimulant (methylphenidate or dextroamphetamine), developed dystonia following dosage adjustment of one or both of the agents. 

b) A 5-year-old boy became agitated, irritable, vigilant and violent after the sudden discontinuation of risperidone accompanied by the initiation of methylphenidate 15 mg daily 2 days later. These symptoms resolved upon the discontinuation of methylphenidate. Methylphenidate was re-introduced after a 6-week drug free period with no recurrence of the severe behavioral reaction. 

c) There are numerous other case reports describing similar reactions associated with the discontinuation of risperidone and the initiation of methylphenidate. 

d) Adverse effects have also been reported in patients stopping methylphenidate after concomitant use with risperidone. A 9-year-old boy on a regimen of methylphenidate 15 mg and risperidone 1.5 mg three times daily developed acute dystonia when methylphenidate was discontinued. 

e) Similarly, a 11-year-old mentally-handicapped girl with epilepsy taking methylphenidate 30 mg and risperidone 1.75 mg daily became increasingly aggressive after her risperidone dose was increased to 2 mg daily. After 4 days, it was advised to decrease the methylphenidate dose. However, instead of tapering, the methylphenidate was abruptly withdrawn, after which the patient developed generalized dystonia with torsion movements of her trunk and axial muscles, and torticollis. Her symptoms resolved following the administration of intramuscular diphenhydramine. 

f) A 13 year old boy being medicated with risperidone, oxcarbazepine, and methylphenidate began to taper off risperidone. During the tapering, he developed dystonia and dyskinesias, despite treatment with other medications. Risperidone was reinstated at the original dose and his symptoms resolved. 

g) In a prospective study of pediatric patients with a diagnosis of ADHD (per DSM-5 criteria), patients receiving combined therapy of methylphenidate and risperidone had significantly higher TpTe (i.e. T-peak to T-end interval on the ECG) and TpTe/QTc values compared to patients receiving single drug therapy (i.e. methylphenidate or risperidone). 

AMPHETAMINE: a) Amphetamine-induced stimulatory effects may be reduced by antipsychotics. 

i) A study in 8 healthy subjects found that pre-treatment with risperidone 1 mg attenuated the discriminative-stimulus effects of dextroamphetamine. 

ii) In contrast, another study in 18 subjects found that while co-administration of risperidone resulted in increased sedative effects, it did not appear to decrease the stimulant-like effects of methamphetamine. 

b) A 9-year-old girl with ADHD, anxiety and aggression was taking sertraline 25 mg daily (decreased from 50 mg daily due to an increase in angry outbursts) and methylphenidate. The methylphenidate was discontinued due to activation. Risperidone (0.25 mg in the morning and 0.5 mg at bedtime) was initiated; its addition resulted in a slight reduction in aggressive behaviour. Her therapy was then augmented with extended-release dextroamphetamine 5 mg resulting in a significant decrease in her aggression. The dose was increased to 10 mg daily, and 4 days later, her risperidone dose was also increased (to 0.5 mg twice daily). One week after the dose increases, the patient developed bilateral blepharospasm. Both dextroamphetamine and risperidone were decreased to their starting doses which resulted in the full resolution of the blepharospasm. Dystonic symptoms did not reappear with the gradual increase of dextroamphetamine to 15 mg daily.

AMPHETAMINES/STIMULANTS: As an anticholinergic, risperidone blocks muscarinic M2 receptors and causes tachycardia, potentially enhancing the sympathetic stimulation produced by stimulants.

The proposed mechanism is likely to be an interaction between supersensitive dopamine receptors (after the withdrawal of dopaminergic blockade) and acute exposure to methylphenidate, which is an indirect dopamine agonist. 

It has been suggested that the dystonia that resulted from abrupt discontinuation of methylphenidate may be due to decreased dopamine transmission. 

Patients should be monitored for changes in clinical response to either risperidone or methylphenidate when on concomitant therapy. 

There is potential for serious adverse events (e.g. dystonia, agitation and irritability) when starting methylphenidate shortly after discontinuing an antipsychotic agent. There is only limited data on the latter interaction, but caution is warranted. The variability in the potential for antipsychotics to cause this interaction may be due to differences in how each affects dopamine levels. 

Abrupt discontinuation of stimulant treatment may result in emergence of extrapyramidal side effects due to removal of the anticholinergic effects of the stimulant. Conversely, sudden discontinuation of risperidone can result in severe dyskinesias. When used concurrently, stimulant and antipsychotic dosages should be tapered gradually before discontinuation.

METHYLPHENIDATE: g) The exact mechanism is unknown, but appears to be additive pro-arrhythmogenic effects of methylphenidate and risperidone. 

When used concurrently, stimulant and antipsychotic dosages should be tapered gradually before discontinuation. 
 

AMPHETAMINES/STIMULANTS: Patients should be monitored for increased sympathomimetic effects such as increased heart rate if these drugs are used concomitantly.

METHYLPHENIDATE: Clinicians need to be aware of this potential side effect, and to use the combination of psychostimulants and neuroleptic drugs with caution. In addition, particular caution is needed when adjusting medications for patients receiving both stimulant and antipsychotic medication due to their complex dopaminergic pharmacodynamic interactions. 

g) The significance is unclear. TpTe has been proposed as a marker of drug-induced abnormal repolarization. Therefore, concomitant use of methylphenidate and risperidone may increase the risk of ventricular arrhythmias. 

AMPHETAMINE: a) The effectiveness of amphetamines may be diminished when risperidone is co-administered. Patients should be monitored upon initiation of one of these drugs and during dosage changes. 

b) The cause of the bilateral blepharospasm in the 9-year-old girl is unclear. Risperidone alone can cause dystonias, so it is unclear if the blepharospasm was due to risperidone alone or an interaction between risperidone and dextroamphetamine. This case is further complicated by the fact that methylphenidate was stopped shortly before the dose of risperidone was increased.

LSD/HALLUCINOGENS: Risperidone may enhance the tachycardic effect of LSD and psilocybin ("magic mushrooms").

MUSHROOMS: Novel antipsychotic agents such as risperidone may block the psychotomimetic effects of psilocybin.

LSD/HALLUCINOGENS: As an anticholinergic, risperidone blocks muscarinic M2 receptors and causes tachycardia, potentially enhancing the sympathetic stimulation produced by LSD and psilocybin.

MUSHROOMS: Psychotomimetic effects are blocked dose-dependently by serotonin-2A antagonists such as risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol.

LSD/HALLUCINOGENS: Patients should be monitored for increased sympathomimetic effects such as increased heart rate if these drugs are used concomitantly.

MUSHROOMS: Some people may have a milder 'high' with mushrooms, if they are also taking risperidone.