How Rexulti Helps With Depression: Benefits and Side Effects

Medically Reviewed by Cerris Chung, PharmD, BCACP on June 27, 2024
8 min read

Dealing with mental health conditions like depression can be challenging. Some people struggle to find the right treatment or combination of treatments for their condition. In major depression disorder (MDD), there are lower levels of chemicals in the brain, also called neurotransmitters. These neurotransmitters – serotonin, dopamine, and norepinephrine – play key roles in thinking or planning, focusing, finding pleasurable things, maintaining healthy sleep, and other social behaviors. Therefore, low levels likely cause symptoms of depression. 

The typical antidepressants used to treat depression interact with these neurotransmitters but in different ways. This means that the person will have some improvement in their depressive symptoms but still have symptoms that disrupt their daily functions. Some people may have a partial response to treatment for their depression, also called treat-resistant depression (TDR). Extra medicines, also known as adjunctive treatment, can help boost the levels of neurotransmitters and continue to improve symptoms. 

Antipsychotic medicines have been used for many years to treat mental health conditions but have a history of increased side effects, like tremors, rigid muscles, or weight gain. Some antipsychotic medications can be added to antidepressant therapy (ADT) to help

with difficult-to-treat symptoms of depression. The newer second-generation antipsychotics, like Rexulti (brexpiprazole), block chemicals in the brain in a different way to help improve symptoms but also reduce the risk of side effects. 

Rexulti is a second-generation antipsychotic medicine that works by increasing dopamine and serotonin levels in the brain. It may increase the activity of dopamine D2 receptors and block serotonin 5-HT2A receptors, both of which increase dopamine levels. Rexulti can also partially stimulate serotonin 5-HT1A receptors to help elevate mood and reduce symptoms of depression. 

Rexulti is an oral tablet that is taken once daily, with or without food. The starting dose is usually a half-milligram daily and is increased, depending on your response and other things, like drug interactions and liver or kidney function. The maximum dose for depression is 3 milligrams each day. 

Your health care provider will provide instructions on how to start and change doses. It is important to take Rexulti as prescribed by your health care provider. Taking the medication daily will help balance symptoms to improve daily functions. It can take several weeks to start to see any improvement in symptoms. Consistent use is the key to feeling improvement over time. 

Two studies (studies 1 and 2) were completed to see if Rexulti was safe and effective as an extra treatment for MDD, compared with a placebo. Placebo-controlled studies help researchers see differences in the benefit or harm of a medicine, compared with no treatment. 

Everyone had a diagnosis of MDD, was on ADT, and had continued symptoms while on current medicine(s). Most of the people were White females, with an average age of 45 years. Everyone started taking ADT with a placebo for 8 weeks. People that showed persistent symptoms were selected to take either Rexulti or a placebo with their ADT. Everyone taking Rexulti started at a half-milligram daily and increased to 1 milligram each day at week 2. The studies had the following dose at week 3 and stayed at that dose for the rest of the study.

  • Study 1: increased dose to 2 milligrams daily
  • Study 2: stayed at 1 milligram daily or increased to 3 milligrams daily

The effectiveness of Rexulti was measured using a depression rating scale. A higher score on the scale means more severe depression symptoms. A decrease on the scale score shows an improvement in symptoms. This rating scale was used at each weekly visit during the study.

At the end of 6 weeks, most people who added Rexulti to their ADT improved moderate symptoms to mild symptoms of their depression. 

Efficacy Scores in MDD Trials

 

STUDY 1

 

STUDY 2

 

Placebo

Rexulti 2 mg

 

Placebo

Rexulti 1 mg

Rexulti 3 mg

Beginning 

27.3

26.9

 

26.5

26.5

26.5

At Week 6

22.1

18.5

 

20.2

18.9

18.2

Total Change

-5.2

-8.4

 

-6.3

-7.6

-8.3

The studies also showed that people taking Rexulti with their ADT saw improvements in other scales used to evaluate daily functions, like family, social, and work/school life.

Your results may differ from what was seen in clinical studies. You and your provider should determine if the benefits outweigh any potential risks for your depression. 

After a few weeks to months, you should see improvements in symptoms related to your depression. This means that you may function better in daily activities, like the following. Your family or friends may also notice more engagement.

  • Improved mood
  • More energy or motivation
  • Better sleep
  • Interested in activities
  • Decreased anxiety or worry
  • Increased appetite
  • Better concentration

The changes can be gradual and take weeks to show, so it is important to track how your symptoms change over time. The length of treatment is different for each person. Some may see short-term use, while others find benefit in long-term therapy. Your health care provider will use appropriate scales/scores to check your symptom changes. 

Do not stop taking Rexulti without talking with your health care provider, even if your symptoms have improved. If you stop, your symptoms may worsen or require further treatment.

Tell your health care provider if you do not think that your symptoms are improving after a few months. 

The most common side effects on Rexulti are weight gain, sleepiness, dizziness, cold-like symptoms, and restlessness or fidgeting. 

Antipsychotics may lead to weight gain, high blood pressure, diabetes, or high cholesterol. Your health care provider will monitor your weight, blood pressure, cholesterol level, hemoglobin A1c (a measure of blood sugar over time), and waist circumference. Healthy lifestyle choices such as exercising; controlling portion sizes; eating more vegetables, fruits, and lean meats; and limiting unhealthy fats and salt may prevent weight gain. Short walks every day can be helpful for your weight and mental health. For more information on adopting a healthy lifestyle, visit the American Heart Association website at https://www.heart.org/en/

Dizziness or sleepiness may cause falls. If you get dizzy, you should avoid sudden head movements or getting up quickly from a sitting or lying position. If you feel sleepy, try taking your dose in the evening, before bedtime. Avoid driving or doing other tasks or actions that require alertness until you know how Rexulti affects you. 

You may have an inner feeling of restlessness (akathisia) that makes it hard to sit still or makes you fidget more. This is usually seen at the beginning of treatment and may decrease over time. Regular exercise, like walking, stretching, or doing light activities around the house, may help reduce this feeling. Find activities that calm your brain, like breathing exercises, meditation, light yoga, or spending time in nature. Caffeine may worsen jitteriness, so limit or avoid soda, tea, coffee, or other stimulants.

Rexulti may cause problems with body temperature, making it difficult for your body to cool down (heat intolerance). Heavy exercise, extreme heat, dehydration, and certain medicines may worsen heat intolerance. Wearing lightweight clothing, staying hydrated, avoiding extreme heat, and exercising in cooler weather are some ways to help prevent heat intolerance.

While not common with Rexulti, antipsychotics may lead to belly pain or indigestion, nausea, vomiting, constipation, or dry mouth. Eating smaller or lighter meals or taking Rexulti with food may help reduce these effects. If you have a dry mouth, try sipping water frequently, sucking on ice, chewing sugar-free gum, or sucking on sugar-free candy. If you get constipation, drink plenty of water throughout the day; include high-fiber foods in your diet, like wheat, corn, bran, beans, and prunes; and avoid foods and drinks like tea, cheese, chocolate, unripe bananas, and white rice. 

Talk with your health care provider if you have persistent or worsening side effects. 

These are not all of the possible side effects. Talk with your health care provider if you are having symptoms that bother you. In the U.S., you can report side effects to the FDA at www.fda.gov/medwatch or by calling 800-FDA-1088 (800-332-1088). In Canada, you can report side effects to Health Canada at www.health.gc.ca/medeffect or by calling 866-234-2345.

Your health care provider may perform lab tests to monitor your health and assess how your body responds to the medication. The following are key pieces of this monitoring.

  • Weight at the start and changes in your weight during treatment
  • Complete blood count (CBC), to monitor your red blood cells (RBCs), white blood count (WBC), and platelets, especially in people with a history of leukopenia, neutropenia, or agranulocytosis
  • Fasting blood checks of your cholesterol, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. 
  • Fasting blood glucose or hemoglobin A1c, especially if you have a history or a risk of diabetes
  • Blood pressure 
  • Magnesium levels
  • Abnormal involuntary movement scale (AIMS), which is a tool that detects any changes in your movement or fidgeting, such as tardive dyskinesia

Several medicines can affect the blood levels of Rexulti. This may increase the risk of side effects or can cause Rexulti to not work as well. 

Your health care provider may lower the dose of Rexulti if you take the medicines or other things listed below. 

  • Strong/moderate CYP3A4 inhibitors, which include ciprofloxacin (Cipro), clarithromycin (Biaxin), diltiazem (Cardizem), fluconazole (Diflucan), itraconazole (Sporanox, Tolsura), ketoconazole (Nizoral), and grapefruit juice.
  • Strong/moderate CYP2D6 inhibitors, which include bupropion (Wellbutrin, Zyban), cinacalcet (Sensipar), duloxetine (Cymbalta), fluoxetine (Prozac), mirabegron (Myrbetriq) paroxetine (Paxil), quinidine, and terbinafine (Lamisil).

Your health care provider may increase the dose of Rexulti if you take the medicines or other things listed below.

  • Strong CYP3A4 inducers, which include phenytoin (Dilantin, Phenytek, and others), rifampin, barbiturates (such as phenobarbital), or the supplement St. John’s wort.

This is not a complete list of interactions. Tell your pharmacist or health care provider about all the prescription or over-the-counter (OTC) medicines, vitamins/minerals, herbal products, or other supplements you take or have recently taken. This will help them determine if there are any interactions with Rexulti, or if you need a dosage adjustment.

There is a copay program from the drugmaker that may allow you to pay $0 for your prescription. Whether you are eligible depends on whether you have prescription insurance and what type of insurance you have. You can find out more at https://www.rexulti.com/savings-cost, texting “SAVE” to 96747, and by calling 844-415-0674.