Aripiprazole

What it is

Aripiprazole is a second-generation antipsychotic. It treats schizophrenia in adults and in young people from the age of 15, and mania in bipolar disorder.¹ It also comes as a long-acting injection: see long-acting injections (opens in a new tab).

How it works

Most antipsychotics block the dopamine D2 receptor. Aripiprazole works differently. It binds firmly to D2 receptors and activates them, but only partly, so it is called a partial agonist.² In animal studies, it dampened dopamine activity where it was too high, and raised it where it was too low. It also partly activates the serotonin 5-HT1A receptor, blocks the 5-HT2A receptor, and has almost no effect on receptors for acetylcholine.¹

Many antipsychotics raise prolactin, a hormone. Aripiprazole does not; in trials, it lowered prolactin more often than placebo did.³

History

When it was described in 2002, aripiprazole was presented as the first antipsychotic to work by partly activating dopamine D2 receptors rather than blocking them.² It was approved across the European Union in June 2004.⁴ A monthly long-acting injection was tested in a trial that ran from 2008 to 2011.⁵

How well it works

Outcome	Aripiprazole	Placebo
Relapsed	34	57

In this trial, people whose symptoms were stable were randomly assigned to aripiprazole or to placebo.¹ A Cochrane review also found fewer relapses with aripiprazole than with placebo, and fewer people leaving the trials early, though many trials lost a large share of their participants.³

In a year-long comparison with haloperidol, about as many people stayed well: 77 in 100 on aripiprazole against 73 in 100 on haloperidol. More people completed the year on aripiprazole: 43 in 100 against 30 in 100.¹

For preventing relapse, trials found no clear difference between antipsychotics, so the choice depends mainly on side effects.⁶ When clozapine has not helped enough, adding aripiprazole is one of the better-supported options, though most of the trials were small.⁷

Side effects

The side effects above are from the European product information.¹ Three need particular attention:

• Restlessness. In schizophrenia trials, akathisia, an inner restlessness that makes it hard to sit still, affected 6.2 in 100 people on aripiprazole against 3.0 in 100 on placebo. In a year-long trial, movement side effects of all kinds were less common than with haloperidol: 25.8 in 100 against 57.3 in 100.¹
• Weight. In a 26-week trial, 13 in 100 people gained at least 7 in 100 of their body weight on aripiprazole, against 33 in 100 on olanzapine.¹ Among 18 antipsychotics, aripiprazole was one of those with the mildest effects on weight, blood sugar and blood fats.⁸
• New urges. Some people develop strong urges they cannot control, especially to gamble, but also to have sex, shop or eat. In some cases, the urges stopped when the dose was lowered or the medicine was stopped. Prescribers are advised to ask about such urges directly.¹

Get medical help straight away for high fever with stiff muscles, sweating or confusion; signs of very high blood sugar, such as great thirst, passing a lot of urine and weakness; thoughts of harming yourself; or signs of a blood clot.¹

Side effects can be reported to Lareb, the Dutch side-effects centre, to the FAMHP in Belgium, or to the manufacturer.

Administration

Aripiprazole tablets are taken once a day, with or without food. The prescriber sets the dose. Higher doses did not work better for most people, though some may benefit. Smoking does not change its level in the blood.¹ The long-acting injection is given every month, or every 2 months.^5,9

People with diabetes or its risk factors have their blood sugar checked regularly, and everyone is watched for signs of high blood sugar.¹

Contraindications and cautions

The only reason not to use aripiprazole at all is an allergy to it or to an ingredient.¹

It is not used for psychosis in dementia. In trials in older people with Alzheimer’s disease, deaths were about twice as common as on placebo: 3.5 in 100 against 1.7 in 100.¹

Care is needed in people with heart or blood vessel disease, low or high blood pressure, seizures, swallowing problems, a family history of heart rhythm problems, or a risk of blood clots. Suicidal behaviour is part of psychotic illness and has sometimes occurred soon after starting or switching antipsychotics, so people at high risk are watched closely.¹

Some antidepressants, such as fluoxetine and paroxetine, and some antifungal medicines raise the level of aripiprazole, so the dose is lowered. Carbamazepine, an epilepsy medicine, and St John’s wort lower it, so the dose is raised. Serotonin syndrome has been reported when it was combined with antidepressants that act on serotonin. Alcohol adds to the sleepiness.¹

There is too little information on pregnancy, so aripiprazole is used only if the benefit clearly justifies the risk, and babies exposed late in pregnancy are watched after birth. It passes into breast milk, so breastfeeding is weighed with the prescriber. It can affect driving. It is not recommended for schizophrenia in children under 15.¹

Check the patient leaflet, and ask the prescriber about your own situation.

Stopping

Across 30 trials with 4,249 people, 24 in 100 people who stayed on an antipsychotic relapsed within 7 to 12 months, against 61 in 100 who switched to placebo.¹⁰ Changes are best planned with the prescriber.

Alternatives

When restlessness or other movement side effects appear, the prescriber may lower the dose.¹ Other antipsychotics have different side effects: olanzapine (opens in a new tab), for example, causes much more weight gain.⁸ When two antipsychotics have not helped enough, the next step is clozapine (opens in a new tab). Alongside medicine, NICE recommends CBT for psychosis (opens in a new tab) and family intervention (opens in a new tab).¹¹

What we don’t know yet

• Why some people develop impulse-control problems on aripiprazole.
• Whether its milder effect on weight holds over many years.
• Who does better on a partial agonist than on a medicine that blocks dopamine.