Brexpiprazole Usage and Side Effects

The Full Story

Depression is one of the most common mental health problems in the US. It is estimated that 7.1% of adults and 13.3% of adolescents have experienced at least one episode of major depression. Major depression means that a person has suffered at least 2 weeks with depressed mood, loss of interest or pleasure in daily activities, and symptoms such as problems sleeping, eating, focusing, and having enough energy. There is a very good chance that most of us know someone with depression or maybe have experienced it ourselves.

There are many medications available to treat this common malady. Even so, a large survey in 2017 concluded that more than one-third of adults with major depression do not receive treatment. A selective serotonin reuptake inhibitor (SSRI) is usually the first drug prescribed. Examples of SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro).

If someone cannot take an SSRI due to side effects or individual preference, alternatives include drugs like bupropion (Wellbutrin), venlafaxine (Effexor), or mirtazapine (Remeron). The goal for antidepressant treatment is to relieve symptoms of depression. It usually takes a couple of weeks to start seeing improvement, and the greatest benefit will likely be felt in about 4-8 weeks after starting an antidepressant medication.

Brexpiprazole (Rexulti) was approved in the US in 2015 as an adjunctive (add-on) treatment for major depression in people who haven't had enough relief from taking one of the first-line medications. Brexpiprazole is added to an antidepressant with the goal of producing complete remission of depression symptoms. Brexpiprazole is also FDA-approved for schizophrenia treatment. It belongs to the category of drugs known as "second-generation" or "atypical" antipsychotics. Brexpiprazole interacts with serotonin and dopamine receptors in the brain, which regulate mood. Restoring the balance of serotonin and dopamine by affecting these receptors is how the drug is thought to work in depression and schizophrenia. It is not approved for use in children or adolescents.

What should someone taking brexpiprazole look for?

When brexpiprazole is advertised on television or other media, a lot of adverse effects are listed. Some of these warnings—such as serious adverse reactions like tardive dyskinesia, diabetes, and suicidal thoughts—are general precautions for all medications in the antipsychotic group, whether a particular drug has shown the effects or not. Fortunately, the incidence of side effects with brexpiprazole has been low since it was introduced in 2015. In clinical trials, side effects that occurred noticeably more with brexpiprazole than with a sugar pill (placebo) were restlessness/agitation (akathisia), drowsiness, and weight gain (2–4 pounds). Suicidal thoughts occurred more with brexpiprazole than with placebo in people under 18 years of age, so the medication is not approved for children and adolescents.

Once in a while, a reaction called dystonia can occur when someone is just starting to take a medication like brexpiprazole. It is not usually possible to predict who might have this reaction, but it is uncommon. Some examples of dystonia symptoms are: muscle spasms, jaw clenching, twisting movements, and rolling up of the eyes. If it happens, this reaction is readily treated with medications in an emergency room.

Is brexpiprazole habit-forming? The answer is that it has not been found to cause dependence in human or animal studies. If someone has been taking brexpiprazole and wants to stop, it should only be discontinued under a physician’s supervision. Otherwise, a person's original depression or schizophrenia symptoms can return. Brexpiprazole has a half-life of 91 hours, meaning it will take 19 days to be nearly 100% cleared from the body. The gradual reduction in drug concentrations over 19 days can help in preventing withdrawal symptoms.

If the drug is taken during the third trimester of pregnancy, a newborn can experience withdrawal symptoms, such as agitation, tremor, somnolence, and difficulty feeding. Decisions about using brexpiprazole in pregnancy should be made by a woman and her healthcare provider.

Brexpiprazole is broken down in the liver by two important enzymes, known as CYP3A4 and CYP2A6. The activity of these enzymes is affected by numerous other drugs. Because of this, brexpiprazole has many potential drug interactions. It’s best to discuss the possibility of interactions with your doctor and pharmacist, based on all of your prescription and non-prescription medications and supplements.

What if someone takes too much brexpiprazole?

Although brexpiprazole has been available in the US since 2015, until recently there were no published cases of overdose. Now there is a case report of a 16-month-old boy who was taken to the ER about 18 hours after getting into brexpiprazole. He took as many as 10 3-mg tablets. He developed moderate symptoms consistent with brexpiprazole's side effects, and he recovered after 3 days. (See "This Actually Happened")

The starting adult dose of brexpiprazole is 0.5–1 mg daily. To minimize adverse effects, a person's maximum dose should not exceed 4 mg daily. A national, evidence-based guideline from the American Association of Poison Control Centers has been used to decide when someone should seek medical help after taking more than a usual dose of brexpiprazole. If a child under 12 years of age unintentionally gets 4 times (or more) the usual adult starting dose, or if someone 12 years of age or older takes 5 times (or more) the adult starting dose, a trip to an emergency room will probably be advised. The child in the published case report had taken up to 30 mg brexpiprazole, which is 30 times the usual adult starting dose! Of course, a person will also be referred to an ER if they are already having symptoms or have taken the medicine in an attempt to harm themselves.

Leslie A. McCament-Mann, PhD, RPh
Clinical Toxicologist