Rexulti (Brexpiprazole) & Weight Gain: Will It Make You Fat?

Rexulti (Brexpiprazole), is an atypical antipsychotic that was jointly developed by pharmaceutical companies Otsuka and Lundbeck.  In 2015, the FDA approved Rexulti for the treatment of schizophrenia and major depressive disorder (as an adjunct).  Rexulti functions as a “serotonin-dopamine activity modulator” (SDAM) and is intended to be a superior successor to the antipsychotic Abilify (Aripiprazole) in terms of effectiveness and tolerability.

More specifically, Rexulti acts as a partial agonist at 5-HT1A (serotonin), D2 (dopamine), and D3 (dopamine) receptors.  If compared to Abilify, it exerts greater receptor blockade and lower receptor stimulation whereby risk of side effects such as agitation and restlessness is decreased.  Although many individuals derive substantial therapeutic benefit from Rexulti in the treatment of schizophrenia and/or major depressive disorder, some are concerned with side effects, including weight change (e.g. weight gain, weight loss, etc.).

Rexulti (Brexpiprazole) & Weight Gain: Why It Might Occur…

In the event that you experience weight gain as a result of taking Rexulti, below are some possible causes.  Realize that the specific causes of weight gain among Rexulti users will be subject to significant individual variation, however, Rexulti’s action at the 5-HT2C and H1 receptors may play be most implicated.  That said, reasons as to why someone might gain weight from Rexulti include: appetite increase, hormone changes, slowed metabolism, and lower motivation to exercise.

• Appetite increase: While using Rexulti, you may notice a significant appetite increase, such that you’re far hungrier than usual. Even if you try to restrict your calories while using Rexulti, it may be a matter of time before you give in to your voracious appetite and consume more food than usual.  Consistently consuming more food (i.e. calories) than usual as a result of your elevated appetite will cause weight gain.
• Bloating: Certain Rexulti users may notice that they experience bloating or increased water retention during treatment. The bloating may occur throughout your entire body, or may seem most noticeable in one specific area such as the stomach.  In any regard, if you end up with bloating as a side effect, this might account for some of your weight gain.
• Blood sugar changes: For some individuals, antipsychotics can affect blood sugar levels and insulin secretion. If Rexulti causes low blood sugar (hypoglycemia), you may feel hungrier than usual or crave certain foods (e.g. carbohydrates), possibly resulting in weight gain.  Additionally, if Rexulti impairs insulin sensitivity, your body may have trouble properly storing nutrients and signaling to the brain when adequate food has been consumed; this could lead to overeating and weight gain.
• Constipation: For some individuals, constipation as a side effect of Rexulti may account for some weight gain. If a Rexulti user is regularly constipated throughout treatment, it means they’re unable to pass a bowel movement.  Inability to effectively pass a bowel movement means that digested foods are retained in the body for longer periods of time, causing the body to weigh more than usual.
• Cravings: While using Rexulti, you may experience increased food cravings – especially for unhealthy (hyperpalatable) foods. If you are constantly craving unhealthy foods such as candies, pastries, cookies, etc. – it’ll probably only be a matter of time before you cave into your urges and treat yourself.  If you cannot get your cravings under control, you may end up eating more high-calorie (calorically-dense) foods than usual, ultimately explaining your weight gain.
• Fat storage: Rexulti may induce weight gain by causing the body to store more fat than usual. It is believed that antagonism of H1 receptors could modulate activity within hypothalamus-brainstem circuits to promote body fat storage.  For this reason, some individuals may observe increased fat accumulation and in their midsection, hips, buttocks, and/or chest – and corresponding weight gain during Rexulti treatment.
• Fatigue or sedation: The neurochemical effects exerted by Rexulti are largely inhibitory. As a result, approximately 5%-8% of all users will experience sedation, somnolence, and/or fatigue.  If you end up with fatigue or sedation from Rexulti, there’s a good chance that you’ll exercise less than usual or become sedentary.  Reduced physical activity due to fatigue will result in fewer calories being burned and lower metabolic rate – each of which could cause weight gain.
• Gut bacteria: There’s a chance that Rexulti might alter concentrations of bacteria in the gut to cause weight gain. Gut bacteria have a tridirectional relationship with the brain and peripheral nervous system.  If Rexulti increases numbers of pathogenic bacteria and/or depletes healthy gut bacteria, this could send signals to the brain that would increase appetite – or signals to the peripheral nervous system to secrete certain hormones that might cause fat gain.
• Hormone changes: Antipsychotics like Rexulti are understood to induce hormone changes, each of which might alter body fat storage and metabolism in ways that unfavorably alter body composition and cause weight gain. Specifically, Rexulti has been noted to significantly increase levels of the hormone prolactin.  Elevated prolactin levels lead to weight gain for a subset of individuals.  Other sex hormones such as testosterone and estrogen could also be unfavorably modulated by Rexulti in ways that promote weight gain.
• Lower motivation: Because Rexulti exerts an inhibitory effect on neurotransmission to prevent positive symptoms of schizophrenia, some individuals will experience decreased motivation while under its influenced. If you feel less motivated than usual, it may be difficult to stay physically active or exercise throughout the day.  If you end up exercising less than usual because of reduced motivation – you’ll burn fewer calories, your metabolic rate will slow – and weight gain will ensue.
• Social eating: Untreated major depression and/or schizophrenia may result in social isolation and inadequate food intake. Assuming Rexulti effectively treats depression and/or schizophrenia, persons who are treated may become more socially engaged (rather than isolated).  Social engagement might lead to increased social eating (e.g. going out to eat), which may increase risk of weight gain (due to larger caloric loads).
• Slowed metabolism: Research suggests that antipsychotic medications can reduce resting metabolic rate (RMR). A reduction in resting metabolic rate means that the body is burning fewer calories at rest – while under the influence of an antipsychotic.  If Rexulti is slowing your resting metabolic rate (RMR), you might end up gaining weight even if you consume the same number of calories as before treatment.
• Taste enhancement: It is known that unmanaged depression and/or schizophrenia can sometimes blunt our sense of taste and pleasure associated with food consumption. When depression and/or schizophrenia are adequately treated with a medication like Rexulti, taste may improve and pleasure associated with food consumption may return.  If your taste improves and you derive more pleasure from food consumption, you might end up eating more than usual – thus explaining your weight gain.

Rexulti (Brexpiprazole) and Weight Gain (Research)

Included below are data from research and/or trials in which the effect of Rexulti (brexpiprazole) on body weight was documented.  Based on the available data, it seems as though most Rexulti users will experience modest weight gain over the short-term, and moderate weight gain over the long-term.

2016: Spotlight on brexpiprazole and its potential in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression.

A paper by Bruijnzeel and Tandon assessed the preliminary usefulness of brexpiprazole (Rexulti) in the treatment of schizophrenia and major depressive disorder.  In this paper, incidence of side effects and adverse reactions associated with Rexulti like weight gain was discussed.  Authors of the report noted that Rexulti’s affinity for the H1 and 5-HT2C receptors suggests that it may cause modest weight gain plus metabolic side effects.

When compared to its predecessor, Abilify, Rexulti exerted dose-dependent increases in prolactin concentrations – whereas Abilify reduced prolactin.  However, modestly greater weight gain was associated with Rexulti as a side effect compared to Abilify.  Favorably though, Rexulti didn’t seem to significantly affect serum glucose or lipids.

Authors highlighted that modest weight gain is a short-term side effect of Rexulti, and moderate weight gain is a primary long-term adverse effect of Rexulti.

• Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869657/

2015: Efficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Trial.

Correll, Skuban, Ouyang, et al. conducted a randomized, double-blinded, placebo-controlled trial to determine the safety and efficacy of Rexulti for the treatment of schizophrenia.  A total of 630 patients were recruited to participate in the study, all of whom were formally diagnosed with schizophrenia.  Patients were randomized to receive Rexulti at dosages of 0.25 mg; 2 mg; or 4 mg per day – or a placebo – for 6 weeks.

In addition to tracking the effectiveness of Rexulti via scales like the PANSS and CGI, researchers also evaluated tolerability and noted the incidence of side effects such as weight gain.  Results of the study indicated that Rexulti users exhibited moderate weight gain of 1.45 kg (at the 2 mg dose) and 1.28 kg (at the 4 mg dose), whereas placebo users gained just 0.42 kg.  In other words, 2 mg Rexulti users gained ~3.19 lbs. and 4 mg Rexulti users gained ~2.82 lbs. – over 6 weeks of treatment, whereas placebo users gained just 0.92 lbs.

• Source: https://www.ncbi.nlm.nih.gov/pubmed/25882325

2015: A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia.

Kane, Skuban, Ouyang, et al. conducted a trial to assess the effectiveness, safety, and tolerability of Rexulti in 674 adults with schizophrenia over a 6-week span.  Patients were randomized to receive Rexulti at dosages of 1 mg, 2 mg, or 4 mg – or a placebo – once daily.  In addition to measuring symptoms of schizophrenia with scales like the PANSS and CGI, researchers also documented weight changes of participants.

At the end of the 6-week trial, it was noted that Rexulti treatment was associated with moderate weight gain 1.23-1.89 kg (2.7-4.16 lbs.) compared to the placebo (0.35 kg).  More specifically, clinically relevant weight gain (defined as 7% increase in body weight from baseline) was observed in 10%-12.2% of Rexulti recipients.  This indicates that at least 1 out of 10 Rexulti recipients is likely to gain a clinically significant amount of weight – even after a relatively short-term (6 weeks) of treatment.

• Source: https://www.ncbi.nlm.nih.gov/pubmed/25682550/

2015: Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study.

Thase, Youakim, Skuban, et al. conducted a trial in which the effectiveness of 1 mg and 3 mg of Rexulti was tested among patients with refractory major depressive disorder.  A total of 669 patients were recruited for trial participation and were randomized to receive either: Rexulti (1 mg or 3 mg per day) or a placebo – for 6 weeks.  Researchers measured change in depressive symptoms via the MADRS, but also recorded participants’ body weight changes.

One of the most frequent adverse effects of Rexulti after the 6 weeks was weight gain (occurring in 6.6% (1 mg/day) and 5.7% (3 mg/day) of Rexulti users – compared to just 0.9% of placebo users.  In other words, more than 5% of Rexulti users experienced clinically-significant weight gain (defined as 7% increased body weight compared to baseline).

• Source: https://www.ncbi.nlm.nih.gov/pubmed/26301771

2015: Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants.

Thase, Youakim, Skuban, et al. sought to determine the effectiveness and tolerability of Rexulti among patients with refractory major depressive disorder.  Patients with major depressive disorder were randomly assigned to receive Rexulti at 2 mg/day (175 patients) or a placebo for 6 weeks (178 patients) – as adjuncts to an antidepressant medication.  Researchers monitored changes in depressive symptoms among the patients using the MADRS, and also recorded participants’ body weight changes – over the 6-week span.

Results indicated that clinically significant weight gain was the most common adverse effect of Rexulti, occurring in 8% of users.  In other words, 8% of Rexulti users experienced a body weight increase of at least 7% – compared to their baseline weights.  By comparison, significant weight gain occurred in just 3.1% of placebo users.

• Source: https://www.ncbi.nlm.nih.gov/pubmed/26301701

Based on the research, how much weight gain will Rexulti cause?

A modest-to-moderate amount.  Data from short-term and longer-term trials in which Rexulti (brexpiprazole) was evaluated for the treatment of schizophrenia or major depressive disorder (as an adjunct) reported weight gain as one of the most common adverse reactions.  Considering all available data, it seems as though clinically significant weight gain occurs in 5.7%-12.2% of users – and the amount of weight gained ranges from 2.82 lbs. to 4.16 lbs. – over a 6-week span.

• Schizophrenia: One large-scale short-term trial of Rexulti (2 mg and 4 mg) for schizophrenia reported weight gains of 3.19 lbs. (2 mg) and 2.82 lbs. (4 mg) after 6 weeks. Another large-scale short-term trial of Rexulti (1-4 mg) for schizophrenia reported clinically-significant weight gain in 10-12.2% of users over 6 weeks; the amount of weight gained ranged from 2.7 lbs. to 4.16 lbs.
• Major depression: One large-scale trial of adjunct Rexulti (2 mg) for the treatment of major depression reported significant weight gain in 8% of users. Another large-scale trial of adjunct Rexulti (1 mg and 3 mg) for the treatment of major depression reported significant weight gain in 6.6% (1 mg) and 5.7% (3 mg) users.

Because longer-term trials Rexulti haven’t been conducted, it remains unclear as to whether body weight might increase to a significantly greater extent over a long-term – compared to the short-term.  Most researchers speculate that weight gain is likely to be modest (fairly minimal) over the short-term, and moderate (more noticeable) over a long-term.  Nevertheless, while it’s possible that very long-term treatment (e.g. several years) might yield more significant weight gain than the short-term, this hypothesis isn’t substantiated by research.

Could Rexulti ever cause weight loss or remain weight neutral?

Yes. According to available data, although weight gain is among the most common Rexulti side effects, it only occurs in 5.7%-12.2% of all users.  In other words, more than 87% of all Rexulti users won’t end up gaining a clinically significant amount of weight (defined as at least 7% body weight increase from baseline) – at least over the short-term (6 weeks).  For most users, Rexulti will be a “weight neutral” antipsychotic such that it won’t induce major increases or decreases in body weight.

Based on the research, there’s no evidence to suggest that Rexulti is likely to cause weight loss.  However, weight loss could occur in a small percentage of users who end up transitioning to Rexulti from a different antipsychotic that’s associated with more substantial weight gain (e.g. Zyprexa).  For example, if you transition from Zyprexa to Rexulti, you might lose weight because you’re no longer dealing with the more substantial weight gain induction by Zyprexa.

It’s also possible that you might notice modest weight loss as a result of certain Rexulti side effects such as diarrhea, nausea, and/or vomiting (whereby you are less interested in consuming food).  Moreover, if you are already obese or overweight as a result of untreated depression or schizophrenia, getting your symptoms under control with Rexulti might improve your self-control and self-esteem, leading you to eat less and/or make healthier food choices – each of which could cause some weight loss.

Variables that influence Rexulti (Brexpiprazole) weight gain

There are a myriad of variables that might influence the amount of weight gain (or weight change) that you experience while using Rexulti.  These variables include things like: prior medication use; individual genetics; lifestyle habits; concurrent substance use; treatment duration; and Rexulti dosage.  It is a unique combination of these variables that likely determines which specific Rexulti users gain weight, remain weight neutral, or lose weight – as well as the overall degree of weight change.

1. Previous medication(s): Anyone who used a psychiatric medication before Rexulti may have experienced weight change as a result of that specific medication. For example, if you were taking an antipsychotic like Zyprexa, you may have gained a significant amount of weight – such that when you switch to Rexulti – you actually lose weight.  On the other hand, you might’ve previously using a drug that caused you to lose weight, such that when you switch to Rexulti you gain weight.  In these cases, some of the weight change that occurs while using Rexulti may be related to homeostatic rebound effects (opposite of what was experienced on the previous medications).
2. Genetics: Not everyone will experience weight change on Rexulti. Among persons who gain a significant amount of weight, it is thought that polymorphisms of the 5-HT2C receptor may be to blame.  Certain 5-HT2C polymorphisms put a subset of antipsychotic users at greater risk of weight gain than others.  User-differences in the expressions of genes implicated neurotransmission, hormone secretion, and/or fat storage – might also determine who gains weight, loses weight, and/or remains weight neutral on Rexulti.
3. Lifestyle: Your lifestyle may determine whether you’re likely to gain weight (or experience weight change) while using Rexulti. Someone who is getting proper sleep, keeping stress as low as possible, staying physically active, and eating a balanced diet (without junk food) will be at lower risk of weight gain during treatment than someone who makes poor or suboptimal lifestyle choices.
4. Concurrent substances: Anyone who takes other medications and/or substances (e.g. supplements) with Rexulti should realize that concurrent substances could explain weight change on Rexulti. In some cases, the other substances that you’re using might be fully responsible for your weight change, or more responsible for your weight change than Rexulti.  That said, concurrently used substances could (synergistically or antagonistically) interact with Rexulti via neurotransmitter systems, hormones, and/or hepatic metabolism (CYP450 enzymes) to promote weight change.
5. Duration of Rexulti use: Certain individuals will exhibit weight change after short-term Rexulti use, followed by weight stabilization (e.g. no further weight increase), yet others might experience no major weight change after a short-term, but significant weight gain after a long-term. Others might even gain weight over a short-term, and continue to pack on even more pounds over a long-term.  Nevertheless, the total duration over which you’ve been taking Rexulti could influence your weight gain (or change).
6. Rexulti dosage: There isn’t really much evidence to suggest dose-dependent effects of Rexulti on weight. It appears as though over a short-term, slightly more weight gain may occur among lower-dose users than higher dose users, however, these differences are not statistically significant.  That said, there might be individual variation in responses to Rexulti dose in terms of weight gain or loss.  Perhaps a subset of Rexulti users may notice that they gain more weight on a higher dose than a lower one; or vice-versa.

Possible ways to minimize likelihood of Rexulti-induced weight gain

Up to 12.2% of individuals may experience significant weight gain while using Rexulti over a short-term (6 weeks), and possibly a greater number of users could experience weight gain over a longer-term.  If you want to minimize the total amount of weight that you gain while taking Rexulti, below are some strategies to consider.  Understand that you should never utilize any of these strategies without first consulting a medical professional (e.g. psychiatrist) to ensure that they’re safe.

1. Track calories & activity: While taking Rexulti, you may benefit from tracking your caloric intake and activity level each day. If your caloric intake and activity level remain the same as they were before using Rexulti – you’ll be less likely to gain weight than if your caloric intake increases and/or activity level drops.  Monitoring your calories and activity level can also help psychiatrists to determine how much Rexulti is likely responsible for your weight gain (versus your lifestyle).
2. Evaluate & manage Rexulti side effects: If you experience side effects from Rexulti that are causing you to gain weight such as food cravings (which causes overeating) and/or lethargy (which makes it difficult to exercise) – you could ask your psychiatrist if there are any ways to minimize these side effects. If you can minimize certain Rexulti side effects that lead to weight gain, you may be able to prevent weight gain altogether.
3. Concurrent medication analysis: If you end up gaining weight on Rexulti, you may want to analyze the other medications and/or supplements that you’re taking along with it. If you’re using other substances, you may want to avoid using all concurrent substances that are deemed medically-unnecessary.  In some cases, eliminating substances from your regimen could decrease weight gain.  In other cases, you may want to ask your psychiatrist about adding another substance to your medication regimen that might help reduce the weight gain you’re experiencing on Rexulti.
4. Longer-term use: Some individuals may gain weight over a short-term with Rexulti, but experience minimal additional weight gain with longer-term use. If you’re upset about short-term weight gain, you may want to continue using Rexulti in hopes that your weight eventually stabilizes (or stops increasing).
5. Dosage modification: It’s possible that there are dose-dependent weight changes exhibited by a subset of Rexulti users. If you are experiencing weight gain at a high dose, you might want to ask your psychiatrist about trying a lower dose or the “minimal effective dose” necessary for symptom control (as this may help reduce your weight).  If you’re experiencing weight gain at a low dose, you may want to ask your psychiatrist about increasing the dose (as this might help with the weight gain).

Note: If you’re dissatisfied with Rexulti weight gain and/or other Rexulti side effects, it is recommended that you express this dissatisfaction to your doctor.  Some individuals might want to undergo Rexulti withdrawal and/or switch to another medication if the weight gain is of significant detriment to their health and/or becomes problematic.

Have you experienced weight gain from Rexulti?

If you’ve taken Rexulti and experienced weight gain, share a comment below documenting the amount of weight that you gained.  Mention how quickly you gained the weight after starting Rexulti, as well as reasons as to why you think the drug caused you to gain weight such as: it increased your appetite; decreased your motivation; and/or altered your hormone levels.  To help others get a better understanding of your situation, provide details such as: your Rexulti dosage; how long you’ve been using Rexulti; whether you use other medications (or supplements) with Rexulti; and mention whether you’ve tracked your calories and/or physical activity throughout treatment.

Lastly, if you haven’t noticed any major weight change on Rexulti (i.e. stayed weight neutral) or ended up with weight loss from Rexulti – be sure to share your experience as well.  In your experience, do the therapeutic benefits of Rexulti “outweigh” the weight gain?  Or is the weight gain so significant that it’s jeopardizing your health and/or wellbeing?

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