Risperidone (Risperdal) Side Effects: What CYP2D6 Genetics Can and Can't Explain

Extrapyramidal symptoms (EPS) are movement side effects: stiffness, tremor and slowed movement (parkinsonism), inner restlessness (akathisia), and sudden muscle spasms (dystonia). In the label's adult schizophrenia trials at 2 to 8 mg a day, parkinsonism was reported by 14% of people on risperidone against 8% on placebo, and akathisia by 10% against 3%. In two fixed-dose trials, EPS became more common as the dose went up, from 7% at 1 mg a day to 20% at 16 mg a day in one of them.^[1]

Risperidone raises the hormone prolactin, the rise persists during long-term use, and the label says it is associated with higher prolactin elevation than other antipsychotics. High prolactin can cause breast enlargement or milk discharge, missed periods, and erectile problems, and over the long term it can lower bone density. In placebo-controlled trials in children and teenagers, 49% to 87% of those on risperidone had raised prolactin, depending on the condition treated, against 2% to 7% on placebo.^[1]

In short adult trials, 8.7% of people on 1 to 8 mg a day gained at least 7% of their body weight, against 2.9% on placebo. In longer studies, average weight gain was 4.3 kg at 24 weeks and 5.3 kg at 48 weeks. Children and teenagers gained more: 32.6% reached the 7% threshold in short trials, against 6.9% on placebo. The label also warns about raised blood sugar and blood fats, so weight, glucose and lipids are worth checking during treatment.^[1]

Sedation was reported by 10% of adults on 2 to 8 mg a day in the schizophrenia trials, against 2% on placebo, and the label describes sleepiness as dose-related. Risperidone can also drop blood pressure when you stand up, causing dizziness or a fast heartbeat, especially while the dose is being raised. Fainting was reported in 0.2% of adults in clinical studies.^[1]

Fluoxetine and paroxetine block CYP2D6 and raise the combined level of risperidone and its active metabolite. With either drug, the label advises lowering the risperidone dose and not going above 8 mg a day in adults. Carbamazepine works the other way: it roughly halves the combined level, and the label allows up to double the usual risperidone dose alongside it. A dose that suited you can stop suiting you when one of these drugs is started or stopped.^[1]

CYP2D6 is the main enzyme that clears risperidone, by turning it into 9-hydroxyrisperidone. Because the label says the metabolite has similar activity to risperidone, the effect on the brain comes from the two combined, often called the active moiety.^[1]

If you are a normal or intermediate metabolizer, the DPWG advises no change: usual dosing applies. For intermediate metabolizers it found little evidence of more side effects.^[3] If you are a poor metabolizer, the combined level is higher and more of it is risperidone. The DPWG reports that the share of patients with treatment failure rises from 16% to 26%, and it advises using 67% of the normal dose, reducing further to 50% if troublesome side effects from the central nervous system occur despite the lower dose.^[3] If you are an ultrarapid metabolizer, more of the drug is converted to the metabolite and the share with treatment failure rises from 16% to 37%. The DPWG advises choosing an alternative or adjusting the dose against the maximum dose of the metabolite, which is sold on its own as paliperidone.^[2] Here, "normal dose" means the dose the same person would get without the gene variant.

A CYP2D6 result is most useful when risperidone is being started or its dose is being set, and when side effects seem out of proportion to a modest dose. It is also worth having if you have had similar trouble with other drugs cleared by CYP2D6, such as haloperidol, aripiprazole or some antidepressants. The DPWG does not recommend testing everyone who starts an antipsychotic, but advises following its guideline when a genotype is already known, and suggests testing case by case, for example when someone takes several drugs cleared by CYP2D6.^[2]

The Gene2Rx Psychiatric ($35) and Full ($50) reports include risperidone and show the DPWG recommendation for your CYP2D6 result; the $5 Starter report does not. A few limits apply. Consumer DNA tests such as 23andMe and AncestryDNA are not clinical-grade, and their raw data is labeled not for medical use. And genetics is one factor among many: dose, age, other medicines and other conditions all shape how risperidone is tolerated.

No. Because CYP2D6 turns risperidone into a metabolite that works much like the drug itself, a slow converter has more risperidone and less metabolite, but the combined total shifts less than risperidone alone. Poor metabolizers do tend to reach higher combined levels, which is why the DPWG advises a lower dose for them, but dose, other medicines, age and individual sensitivity matter too.^[2] Raised prolactin and weight gain happen in many people with a typical CYP2D6 result.

Yes. The DPWG does not advise avoiding risperidone in poor metabolizers. It advises 67% of the normal dose, and 50% if troublesome side effects from the central nervous system still occur. Your prescriber decides how to apply that to you.

These long-acting injections contain the same drug, so CYP2D6 converts it in the same way. The DPWG states its recommendations for risperidone without separating tablets from injections, and each injection's label has its own dosing steps. With a long-acting injection a dose change takes effect slowly, so how to apply a genetic result to a particular product is a decision for your prescriber.

Paliperidone is 9-hydroxyrisperidone, the active metabolite CYP2D6 makes from risperidone, sold as a drug in its own right. It depends much less on CYP2D6, which is why the DPWG uses paliperidone's maximum doses as the reference when adjusting risperidone for ultrarapid metabolizers.