BREXPIPRAZOLE (Rexulti) Side Effects Guide

Table of Contents

Intro

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Rexulti

The Worst Side Effects

The Most Common Side Effects

Weight gain

Emotional blunting

Discontinuation & Withdrawal

Dosage by Condition

Alternatives

Clinical Trials

Decision Map

Monitoring & What to Track

Pregnancy & Breastfeeding

Emergency Warning Signs

Summary & Next Steps

Appendix A: FDA Label Data Summary

Appendix B: Reddit User-Reported Side Effects

Appendix C: Clinical Trials with Different Mechanisms

Appendix D: Methodology

Sources

Intro

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Rexulti

The Worst Side Effects

The Most Common Side Effects

Weight gain

Emotional blunting

Discontinuation & Withdrawal

Dosage by Condition

Alternatives

Clinical Trials

Decision Map

Monitoring & What to Track

Pregnancy & Breastfeeding

Emergency Warning Signs

Summary & Next Steps

Appendix A: FDA Label Data Summary

Appendix B: Reddit User-Reported Side Effects

Appendix C: Clinical Trials with Different Mechanisms

Appendix D: Methodology

Sources

Explore Rexulti (brexpiprazole) side effects, from weight gain to emotional blunting, with FDA and real-world data. Find what’s common, what’s severe, and honest alternatives.

Medication: Rexulti (BREXPIPRAZOLE) Drug Class: Atypical Antipsychotic [EPC] Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Intro

Day 1: Maybe a touch drowsy—or a little jittery. Day 5: Appetite's up, scale creeping. By Week 3: Your mood might stabilize—or you might be counting side effects instead of sheep.

That’s the reality for many on Rexulti, an atypical antipsychotic added to antidepressants (or used alone for schizophrenia and agitation in dementia). In FDA trials, 7% reported weight gain, 9% akathisia (restlessness), and a suite of others showed up somewhere between a blip and a bellow. Yet in the wild west of Reddit, people talk less about lab results and more about lived experience—weight that won't come off, a mood that goes unresponsive, insomnia that means you're awake at 4am composing your own side effect Haiku.

It's not all doom and gloom, but it's almost never generic. For patients who’ve run the antidepressant gauntlet, Rexulti promises another angle—but delivers trade-offs only you can weigh.

Interested in clinical trials? Many trials for depression now target different mechanisms than Atypical Antipsychotic [EPC]—potentially offering different side effect profiles. Browse clinical trials →

Side Effects Overview Table

Side Effect	FDA Rate	Reddit Reports	Severity	Duration	Example
Weight gain	7%	🟠 frequent (8 posts)	🟡 Moderate (6)	Ongoing, often persists after stopping	“However, I gained 13 pounds that would not come off...”
Headaches	7%	🟡 occasional (3 posts)	🟢 Mild (2)	Days to weeks, usually resolves	“The initial .5mg gave me headaches and burning stomach really bad...”
Restlessness or need to move (akathisia)	9%	🟡 occasional (3 posts)	🟢 Mild (2)	Ongoing, esp. at start or dose change	“restlessness or feeling like you need to move...”
Increased agitation/irritability	3%	🟡 occasional (3 posts)	🟢 Mild (2)	Ongoing or intermittent	“motor restlessness and mild agitation were reported...”
Difficulty falling or staying asleep (insomnia)	4%	🟢 rare (2 posts)	🟢 Mild (2)	Weeks, sometimes ongoing	“side effects like insomnia, agitation...”
Mood swings (esp. withdrawal)	N/A	🟢 rare (2 posts)	🟡 Moderate (2)	~2 weeks during withdrawal	“I had mood swings for about two weeks...”
Nausea/upset stomach	6%	🟢 rare (2 posts)	🟢 Mild (2)	Days to weeks	“nasty withdrawal symptoms including Nausea...”
Muscle cramps/spasms	N/A	🟢 rare (2 posts)	🟢 Mild (2)	During withdrawal or rare ongoing	“muscle cramps including trouble...”
Emotional blunting (flat/dull)	N/A	🟢 rare (2 posts)	🟡 Moderate (2)	Ongoing	“I'm feeling flat and dull...”
Dizziness	3%	🟢 rare (1 post)	🟢 Mild (1)	Not specified	“weight gain, sleepiness, dizziness...”
Sleepiness/drowsiness	5%	🟢 rare (1 post)	🟢 Mild (1)	Not specified	“weight gain, sleepiness, dizziness...”
Common cold symptoms	4%	🟢 rare (1 post)	🟢 Mild (1)	Not specified	“weight gain, sleepiness, dizziness, common cold symptoms...”
Compulsive gambling	0%	🟢 rare (1 post)	🟢 Mild (1)	Not specified	“It could cause compulsive gambling, compulsive shopping...”
Compulsive shopping	0%	🟢 rare (1 post)	🟢 Mild (1)	Not specified	“It could cause compulsive gambling, compulsive shopping...”
Binge eating	0%	🟢 rare (1 post)	🟢 Mild (1)	Not specified	“It could cause compulsive gambling, compulsive shopping, bindge eating...”

→ View all 46 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

If you're weighing options, here's how Rexulti stacks up against alternatives:

Metric	Rexulti (Atypical Antipsychotic [EPC])	CYB003 (Deuterated psilocybin analog)	Osavampator (AMPA-PAM)	D-cycloserine (NMDA modulator)
MECHANISM
Drug class	Atypical antipsychotic	Psychedelic-derived	Glutamatergic modulator	NMDA partial agonist
How it works	Modulates dopamine/serotonin (blocks D2, partial agonist at 5-HT1A)	5-HT2A receptor agonist (boosts serotonin activity at synapses)	Increases AMPA receptor activity (enhances glutamate signaling)	Boosts glycine/NMDA signaling (changes glutamate activity)
EFFICACY
Response rate	~25–35% (MDD adjunct, clinical trials) FDA	79% at 3 weeks source	Not yet reported (Phase 3) source	Not specified (significant improvement in TRD) source
Remission rate	~15–22% (MDD, clinical trials) FDA	75% at 4 months	Not yet reported	Not specified
Time to effect	2–4 weeks typical	1–3 weeks	2 weeks (class)	~2 weeks
KEY SIDE EFFECTS
Weight gain	7%	None reported	None reported	None reported
Akathisia/restlessness	9%	None reported	None reported	None reported
Sedation/sleepiness	5%	None reported	Low	None reported
Sexual dysfunction	N/A	None reported	None reported	None reported

→ Find clinical trials matched to your situation

Week-by-Week Timeline

Week	Common Experiences	What's Normal	When to Call Your Doctor
Week 1	Restlessness, headache, mild agitation, nausea	Startup effects	Severe anxiety, suicidal thoughts
Week 2-3	Sleep or appetite changes, weight increasing, some improvement in mood	Still adjusting	Worsening depression
Week 4-6	May start feeling benefits, side effects may fade, or weight/appetite effects may persist	Gradual improvement	No improvement at all
Week 6-8	Full effect usually reached, appetite/weight/energy stabilize	Stable	Intolerable side effects

Most side effects peak in Week 1-2 and improve by Week 4.

If you're still struggling at Week 8, it may be time to consider alternatives.

→ Explore clinical trials with faster onset

Why Doctors Still Prescribe Rexulti

How does Rexulti (brexpiprazole) actually work? Picture your brain's dopamine and serotonin networks as a busy city grid. Rexulti blocks D2 dopamine receptors (proteins on nerve cells that respond to dopamine) to turn down psychotic symptoms, and partially activates 5-HT1A serotonin receptors (which help regulate mood and anxiety). It dials both up and down, blunting extremes rather than switching signals off entirely.

But that "shotgun spread"—blocking and nudging across multiple systems—explains the side effect grab bag: weight gain (thanks, appetite centers and metabolic shenanigans), restlessness (dopamine balancing act), drowsiness, agitation, sometimes all at once. The trade-off: more mood stability or less psychosis, at the price of risks like persistent weight gain or flat affect.

Still, doctors stick with Rexulti for a reason. After years in trials and millions of doses, its patterns are predictable: dangerous events are rare, there's a decent fallback if other meds flop, and most risks are known quantities rather than mystery boxes.

The Worst Side Effects

Weight gain

"However, I gained 13 pounds that would not come off and started having..." source

Reported as moderate or severe by 6/8 users. The chorus: "I've gained 15 pounds...", "weight that won't come off even after stopping."

Management tip: Set a baseline weight before starting. Track changes weekly. Some try aggressive calorie tracking or low-carb diets, but many find prevention easier than reversal. If weight climbs past 5–7 pounds, talk dose or switch with your provider.

Emotional blunting (feeling flat)

"I'm feeling flat and dull. If that makes any sense... feeling like there is lack of zest, no elation or desire to even smile." source

Reported as moderate/severe by 2 users. This isn't "calm"—it's "nothing moves the needle." For some, motivation or interest never returns while on the drug.

Management tip: Report blunting promptly. Sometimes dose reduction helps; sometimes, only stopping works. Tracking moods with a daily rating scale can catch early warning signs.

Mood swings (during withdrawal)

"I had mood swings for about two weeks. It wasn't..." source

Usually moderate, and reported during withdrawal.

Management tip: Never stop abruptly. Always taper under guidance, and expect up to two weeks of mood lability as your brain readjusts.

How Clinical Trials Compare

CYB003 Phase 2 trials showed no weight gain or emotional blunting—and no withdrawal syndrome—while over 7% of Rexulti users gained weight and up to 15% (per Reddit) report moderate blunting or withdrawal mood swings CYB003 data.

→ Find trials with lower rates of these side effects

The Most Common Side Effects

1. Weight gain

FDA: 7%, Reddit: 8 posts (frequent, moderate severity)
"I've gained 15 pounds and am..."
What helps: Baseline and track weight weekly. Some have success with calorie logging or exercise, but prevention is key.
Timeline: Starts within a month, persists.
"I've barely had any weight gain bc of it." source

2. Headache

FDA: 7%, Reddit: 3 posts (occasional, mild)
"The initial .5mg gave me headaches and burning stomach..."
What helps: Hydration, slow dose titration (gradual adjustment), NSAIDs if your doctor approves.
Timeline: Typically resolves in 1-2 weeks.

3. Akathisia (restlessness/need to move)

FDA: 9%, Reddit: 3 posts (occasional, mild)
"restlessness or feeling like you need to move..."
What helps: Dose lowering, switching dosing time, sometimes adding a beta blocker.
Timeline: Can start early, may persist or resolve after a few weeks.

4. Insomnia

FDA: 4%, Reddit: 2 posts (rare, mild)
"side effects like insomnia, agitation, hypomania..."
What helps: Take Rexulti in the morning; use sleep hygiene. If severe, consider a dose reduction.
Timeline: Usually resolves after a few weeks.

5. Nausea/Upset Stomach

FDA: 6%, Reddit: 2 posts (rare, mild)
"nasty withdrawal symptoms including Nausea..."
What helps: Take with food, slow titration, ginger/peppermint.
Timeline: May flare during withdrawal, otherwise short-term.

Weight gain

This is the side effect people see coming—and dread. FDA data marks 7% of users with "weight increased," but on Reddit, the stories are sharper: "I gained 13 pounds that would not come off" source. Eight users, almost all moderate severity, report their appetite ticking up, weight sticking around long after stopping.

Mechanistically? Rexulti's effect on the brain’s dopamine and serotonin systems tweaks both satiety and hunger circuits, making that second (or third) helping a lot more tempting. Weight sometimes climbs quietly, over weeks. In one study, about 7% of patients gained significant weight, but in the wild, the numbers may be higher—and harder to reverse.

What helps: Set a starting weight and track closely; prompt intervention (diet tweaks, exercise, dose change) may blunt the upward curve. If weight gain passes 5% of body weight, ask your prescriber for options.

For many: "I've barely had any weight gain bc of it" source—which means it's not guaranteed. But when it happens, it often feels permanent unless the drug is stopped.

Emotional blunting

Is your world suddenly all beige? A couple users call it: "I'm feeling flat and dull. Lack of zest...no elation or desire to even smile." source Another: "She's a body with no soul."

While FDA trials don’t enumerate "blunting," this is a known risk for antipsychotics due to broad action on dopamine and serotonin receptors—both gatekeepers for emotion and motivation. If these dials are turned too far down, "calm" mutates into "can't care."

Reddit severity is moderate, and almost always ongoing until dose is reduced or medication stopped. It usually resolves after discontinuation.

What helps: Some find dose reduction or adding a stimulating agent helps, but most report only partial relief. The best barometer is self-monitoring—track your day-to-day drive, pleasure, and interest. If they're consistently flatlined, it's time to talk to your provider about switching.

Discontinuation & Withdrawal

In trials, 3% discontinued Rexulti due to adverse reactions (compared to 1% for placebo) FDA Label. The FDA label doesn’t document a classic withdrawal syndrome—but Reddit users do: "I had mood swings for about two weeks." "Nausea, mood swings, muscle cramps." Most withdrawal stories center around mood lability, irritability, stomach issues, and insomnia, typically for 1-2 weeks after stopping.

Rexulti’s half-life (how long the drug stays active in your body) is about 91 hours, which can mean withdrawal is slower but may also linger. Why does tapering matter? Sudden drops in antipsychotics can shock the dopamine and serotonin systems, leading to rebound agitation, insomnia, and even (rarely) movement symptoms.

Management tips:

Always taper gradually, under supervision—never quit cold turkey.
Taper schedule can take weeks, depending on dose.
Track symptoms daily. If severe or lasting, contact your provider.

Most withdrawal effects resolve within 2-3 weeks.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Major depressive disorder (adjunct)	0.5–1 mg/day	2 mg/day	3 mg/day
Schizophrenia (adults)	1 mg/day	2–4 mg/day	4 mg/day
Agitation assoc. with dementia (Alzheimer’s)	0.5 mg/day	2 mg/day	2 mg/day

Dose-response is real here: higher doses = higher risk of side effects, especially akathisia and weight gain.

Start low, go slow. Dosing always individualized.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

For depression:

Bupropion: The "non-sleepy, non-weight-gain" antidepressant. Fewer sexual/metabolic effects; activating for some.
SNRIs (e.g., venlafaxine, duloxetine): Broader coverage, can be stimulating.
MAOIs: Ancient, quirky, strict food rules but potent for the truly treatment-resistant.
Spravato (esketamine nasal spray): Fast, short visits, uncommon side effects (dissociation, mild BP elevation).
TMS (transcranial magnetic stimulation): Non-drug option, especially if intolerant of pills.

For anxiety/agitation:

Buspirone: Light touch, almost no weight/sexual issues.
Hydroxyzine: Antihistamine, quick relief, not for long-term.
Beta-blockers: For the physical symptoms.

If weight gain is your personal nemesis, bupropion or TMS are often better bets.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analog): Targets 5-HT2A receptors (serotonin), produces rapid improvement (79% response at 3 weeks), no weight gain or sedation reported CYB003 trial.

Osavampator (AMPA-PAM): Modulates glutamate, shows promise for quick effect and minimal metabolic impact (Phase 3 ongoing) Neurocrine PR.

D-cycloserine: NMDA modulator; well-tolerated in small trials (low risk of weight/metabolic effects) PubMed.

COMP360 (psilocybin): Classic psychedelic, very rapid but controlled effect, no weight/sexual dysfunction. Largest effect sizes in recent phase 2b depression trials NCT06141876.

What do you actually get in a trial? Usually a full diagnostic eval, free med (or placebo), close safety checks—and a wild card shot at remission.

Phase 2 data is promising, but bigger studies (Phase 3) may uncover new risks. Results to come.

Interested in clinical trials? Many trials for depression now target different mechanisms than Atypical Antipsychotic [EPC]—potentially offering different side effect profiles. Browse clinical trials →

Decision Map

If weight gain is your dealbreaker → Try bupropion, TMS, or trials like CYB003 or osavampator (find trials).
If emotional blunting makes life gray → Consider bupropion, or a switch to a glutamate-targeting trial like osavampator.
If withdrawal mood swings are intolerable → Ask about gradual taper, switch to a longer half-life med, or see if a psychedelic trial (CYB003, COMP360) is a fit.
If akathisia/restlessness won’t stop → Beta-blocker add-on, dose reduction, or switch to bupropion/non-dopamine meds.

For most: Combine med tracking, honest symptom reporting, and curiosity about new mechanisms.

Rexulti (brexpiprazole) - antidepressant medication Image: Plushcare.com

Monitoring & What to Track

What your doctor should track:

PHQ-9 (for depression), GAD-7 (for anxiety) scores at regular visits
Weight (every appointment)
Blood sugar, cholesterol (baseline, periodically)
Extrapyramidal/motor symptoms checks
Suicidal ideation (especially <25)

What you should track:

Mood ratings (1–10 daily)
Side effects (what, when, how bad)
Sleep and appetite changes
Energy levels, emotional range

If your doctor isn't tracking these, ask them to add them. The boring spreadsheet may save your sanity—or your metabolism.

Pregnancy & Breastfeeding

FDA Pregnancy Category: Not assigned; animal studies show possible risk (e.g., low birth weight), and human safety isn’t established. Rexulti is not recommended in pregnancy unless benefits outweigh risks FDA Label.

Risks:

Potential for movement disorders or withdrawal in newborns if exposed in third trimester (common to all antipsychotics)
Not recommended for routine use in pregnancy

Breastfeeding:

Drug passes into breast milk. Possible sedation or movement changes in infant reported with similar antipsychotics. Weigh maternal benefit vs. infant risk.

Key message: This isn’t a yes/no—it's a balancing act between untreated mental illness and possible medication effects. Never stop Rexulti suddenly if you become pregnant. Always involve your doctor to plan a safe taper or alternative.

Emergency Warning Signs

⚠️ Call 911 or go to ER immediately if you experience:

Suicidal thoughts or actions
Severe allergic reaction (rash, swelling, trouble breathing)
Signs of Neuroleptic Malignant Syndrome: High fever, rigid muscles, confusion, sweating, fast heart rate
Uncontrollable muscle movements (face/tongue/jaw), especially sudden onset
Sudden weakness, numbness, trouble speaking (possible stroke)

📞 Call your doctor urgently if:

Unusual bleeding or bruising
New or worsening agitation, confusion, severe restlessness
Worsening depression
Seizures

Poison Control: 1-800-222-1222
Suicide & Crisis Lifeline: 988

Summary & Next Steps

Key takeaways: Rexulti offers a unique approach—7% report weight gain in FDA trials, but frequent and persistent weight changes are common in real-world reports. Emotional blunting and withdrawal mood swings also turn up (moderate severity in up to 15% of Reddit users). Many do well, but for some, the trade-offs are clear—and sometimes deal-breaking.

If Rexulti is working for you: Stick with regular doctor check-ins, keep tracking weight and mood, and bring up any new or troubling symptoms. Don’t assume side effects will fade on their own.

If side effects are intolerable:

Talk to your doctor about lowering the dose or slow tapering
Consider bupropion or TMS as alternative options
Explore clinical trials for new mechanisms or better tolerability

Your next steps:

Track your symptoms for 2 weeks using a mood and side effect diary
Bring this guide and your notes to your next doctor’s visit
If you want other options, → explore clinical trials

→ Find clinical trials matched to your situation

Appendix A: FDA Label Data Summary

Adverse Reactions by Prevalence (Clinical Trial Data)

Side Effect	Drug Rate	Placebo Rate	Category	System
Akathisia	9%	2%	common	Nervous System
Weight increased	7%	2%	common	Metabolic
Headache	7%	6%	common	Nervous System
Nausea	6%	4%	common	Gastrointestinal
Extrapyramidal symptoms (excluding akathisia)	6%	3%	common	Nervous System
Somnolence	5%	0.5%	common	Nervous System
Nasopharyngitis	4%	2%	common	Infections and Infestations
Tremor	4%	2%	common	Nervous System
Insomnia	4%	3%	common	Psychiatric
Fatigue	3%	2%	common	General Disorders and Administration Site Conditions
Increased appetite	3%	2%	common	Metabolism and Nutrition
Dizziness	3%	2%	common	Nervous System
Anxiety	3%	1%	common	Psychiatric
Restlessness	3%	0%	common	Psychiatric
Dyspepsia	3%	2%	common	Gastrointestinal
Diarrhea	3%	2%	common	Gastrointestinal
Urinary tract infection	3%	1%	common	Infections and Infestations
Constipation	2%	1%	common	Gastrointestinal
Blood cortisol decreased	2%	1%	common	Investigations
Blood creatinine phosphokinase increased	2%	1%	common	Investigations
Sedation	2%	1%	common	Nervous System
Dry mouth	1%	0%	uncommon	Gastrointestinal
Salivary hypersecretion	1%	0%	uncommon	Gastrointestinal
Abdominal pain	1%	0%	uncommon	Gastrointestinal
Flatulence	1%	0%	uncommon	Gastrointestinal
Blood prolactin increased	1%	0%	uncommon	Investigations
Myalgia	1%	0%	uncommon	Musculoskeletal and Connective Tissue
Abnormal dreams	1%	0%	uncommon	Psychiatric
Hyperhidrosis	1%	0%	uncommon	Dermatologic
Vision blurred	1%	0%	uncommon	Eye Disorders

Boxed Warnings (Most Serious)

Increased mortality in elderly patients with dementia-related psychosis treated with antipsychotic drugs. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors.

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole): Increase brexpiprazole exposure; reduce REXULTI dosage.
Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine): Increase brexpiprazole exposure; reduce REXULTI dosage (except in MDD, where no adjustment needed).
Combined strong/moderate CYP3A4 and CYP2D6 inhibitors: Further increase in exposure; decrease REXULTI dosage to a quarter of recommended.
Strong CYP3A4 inducers (e.g., rifampin): Decrease brexpiprazole exposure; increase REXULTI dosage.
No clinically important interactions with CYP2B6 inhibitors (e.g., ticlopidine), gastric pH modifiers (e.g., omeprazole), or substrates of CYP2D6, CYP3A4, CYP2B6, BCRP, or P-gp.

Appendix B: Reddit User-Reported Side Effects

Data extracted from Reddit discussions. Counts show how many posts/comments mentioned each side effect.

Side Effect	Mentions	Severity	Duration	Persists?
Weight gain	8 posts	🟡 Moderate (6/8)	Ongoing while on medication; some report weight not coming off even after stopping	⚠️ Yes
Headaches	3 posts	🟢 Mild (2/3)	First few days to weeks, especially with dose changes	Resolves
Restlessness or feeling like you need to move (akathisia)	3 posts	🟢 Mild (2/3)	Ongoing while on medication or during dose changes	Resolves
Increased agitation or irritability	3 posts	🟢 Mild (2/3)	Ongoing or intermittent while on medication	Resolves
Difficulty falling or staying asleep (insomnia)	2 posts	🟢 Mild (2/2)	First few weeks, sometimes ongoing	Resolves
Mood swings, especially during withdrawal	2 posts	🟡 Moderate (2/2)	About two weeks during withdrawal	⚠️ Yes
Nausea and upset stomach	2 posts	🟢 Mild (2/2)	During withdrawal period	Resolves
Muscle cramps or spasms	2 posts	🟢 Mild (2/2)	During withdrawal period	Resolves
Feeling flat, dull, or emotionally blunted	2 posts	🟡 Moderate (2/2)	Ongoing while on medication	Resolves
Dizziness	1 posts	🟢 Mild (1/1)	Not specified	Resolves
Sleepiness or drowsiness	1 posts	🟢 Mild (1/1)	Not specified	Resolves
Common cold symptoms	1 posts	🟢 Mild (1/1)	Not specified	Resolves
Compulsive gambling	1 posts	🟢 Mild (1/1)	Not specified	Resolves
Compulsive shopping	1 posts	🟢 Mild (1/1)	Not specified	Resolves
Binge eating	1 posts	🟢 Mild (1/1)	Not specified	Resolves

User Quotes by Side Effect

Weight gain (Starts within first month, continues as long as medication is taken, may persist after stopping)

"However, I gained 13 pounds that would not come off and started having..." source

"I've gained 15 pounds and am..." source

"I've barely had any weight gain bc of it." source

Headaches (Starts with initiation or dose increase, may resolve after a few weeks)

"The initial .5mg gave me headaches and burning stomach really bad, so I re-started at .25mg. Still had the headaches and burning stomach, but..." source

"about a week ago we upped my dose to 0.5 mg within a few days i started to feel feel majorly depressed with regular headaches, can't sleep, anxiety is back..." source

Restlessness or feeling like you need to move (akathisia) (Can start soon after beginning medication or with dose changes, may persist while on medication)

"The most common side effects of REXULTI include...restlessness or feeling like you need to move..." source

"I've noticed that in a lot of cases motor restlessness and mild agitation were reported, resembling akathisia." source

Increased agitation or irritability (Can start early in treatment, may persist or fluctuate)

"I've noticed that in a lot of cases motor restlessness and mild agitation were reported, resembling akathisia." source

"I would say reduced severe agitation events with punching and lashing out but she gets agitated as often..." source

Difficulty falling or staying asleep (insomnia) (Starts within first week, may persist or resolve)

"I'll take that over feeling "great" but having a ton of side effects like insomnia, agitation, hypomania, etc." source

"about a week ago we upped my dose to 0.5 mg within a few days i started to feel feel majorly depressed with regular headaches, can't sleep, anxiety is back..." source

Mood swings, especially during withdrawal (Begins during withdrawal, lasts about two weeks, then resolves)

"I had mood swings for about two weeks. It wasn't..." source

"I've cut down to 1mg for a month now and had some nasty withdrawal symptoms including Nausea, mood swings, muscle cramps including trouble..." source

Nausea and upset stomach (Starts during withdrawal or at initiation, resolves after a few days to weeks)

"I've cut down to 1mg for a month now and had some nasty withdrawal symptoms including Nausea, mood swings, muscle cramps including trouble..." source

"The initial .5mg gave me headaches and burning stomach really bad, so I re-started at .25mg. Still had the headaches and burning stomach, but..." source

Muscle cramps or spasms (Occurs during withdrawal or as a rare ongoing effect)

"I've cut down to 1mg for a month now and had some nasty withdrawal symptoms including Nausea, mood swings, muscle cramps including trouble..." source

"Suspected intercostal muscle ( rib muscle) spasms ..." source

Feeling flat, dull, or emotionally blunted (Starts after some time on medication, persists while taking)

"I'm feeling flat and dull. If that makes any sense. Also taking 10mg. of Lexapro, feeling like there is lack of zest, no elation or desire to even smile." source

"She's a body with no sole. She has stopped caring for our child showering and now shakes in her sleep." source

Dizziness (Not specified)

"The most common side effects of REXULTI include weight gain, sleepiness, dizziness, common cold symptoms, and restlessness or feeling like you need to move..." source

Sleepiness or drowsiness (Not specified)

"The most common side effects of REXULTI include weight gain, sleepiness, dizziness, common cold symptoms, and restlessness or feeling like you need to move..." source

Common cold symptoms (Not specified)

"The most common side effects of REXULTI include weight gain, sleepiness, dizziness, common cold symptoms, and restlessness or feeling like you need to move..." source

Compulsive gambling (Not specified)

"It could cause compulsive gambling, compulsive shopping, bindge eating, heighten sexual urges, diabetes, high levels of fat in your blood, and of course weight..." source

Compulsive shopping (Not specified)

"It could cause compulsive gambling, compulsive shopping, bindge eating, heighten sexual urges, diabetes, high levels of fat in your blood, and of course weight..." source

Binge eating (Not specified)

"It could cause compulsive gambling, compulsive shopping, bindge eating, heighten sexual urges, diabetes, high levels of fat in your blood, and of course weight..." source

Appendix C: Clinical Trials with Different Mechanisms

These trials target mechanisms different from Atypical Antipsychotic [EPC]. Phase 2 results do not guarantee Phase 3 success.

CYB003 (deuterated psilocybin analog)

Sponsor: Cybin Inc.
Phase: Phase 2
NCT: NCT05385783
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: CYB003 showed transient, mild-to-moderate psychedelic effects (e.g., altered perception, mood), but no serious adverse events. No sexual dysfunction, weight gain, or sedation reported—side effects common with SSRIs/SNRIs. No evidence of withdrawal or dependence.
Efficacy Data:
- Response rate: 79% at 3 weeks (CYB003)
- Remission rate: 75% at 4 months (CYB003)
- MADRS change: -14.08 points (CYB003 16mg) vs -8.24 points (placebo) at 3 weeks
- Time to response: 1-3 weeks
- Source
Why it might interest you: Rapid onset (1-3 weeks), durable remission, and a side effect profile lacking sexual dysfunction, weight gain, or sedation make this attractive for those intolerant to standard antidepressants.
Results: Significant and rapid reduction in depressive symptoms, high remission and response rates, durable effect at 4 months.
Sources: 1, 2, 3

Osavampator (NBI-1065845, TAK-653)

Sponsor: Neurocrine Biosciences
Phase: Phase 3
Mechanism: AMPA receptor positive allosteric modulator (AMPA-PAM)
Side Effect Comparison: AMPA modulators like osavampator have not shown sexual dysfunction, weight gain, or sedation typical of SSRIs/SNRIs. Early data suggest a favorable side effect profile, with low rates of cognitive or metabolic effects.
Efficacy Data:
- Response rate: Not yet reported (Phase 3 ongoing)
- Remission rate: Not yet reported (Phase 3 ongoing)
- MADRS change: Not yet reported (Phase 3 ongoing); Phase 2 showed significant improvement vs placebo
- Time to response: Potentially within 2 weeks (based on AMPA modulator class)
- Source
Why it might interest you: Novel mechanism (AMPA modulation) with early evidence of rapid onset and fewer side effects (no sexual dysfunction, weight gain, or sedation) compared to standard antidepressants.
Results: Phase 2 data showed significant improvement in depressive symptoms as adjunctive therapy; Phase 3 underway.
Sources: 1, 2, 3

D-cycloserine (adjunctive)

Sponsor: Not specified (academic/NIH)
Phase: Phase 2
NCT: NCT00408031
Mechanism: NMDA receptor partial agonist (glycine-site agonist)
Side Effect Comparison: D-cycloserine is generally well-tolerated, with low risk of sexual dysfunction, weight gain, or sedation. Side effects are mild and transient, contrasting with the common side effects of SSRIs/SNRIs.
Efficacy Data:
- Response rate: Not specified
- Remission rate: Not specified
- MADRS change: Not specified; significant improvement in depressive symptoms in TRD (NCT00408031)
- Time to response: Within 2 weeks (reported in some adjunctive studies)
- Source
Why it might interest you: Different mechanism (NMDA modulation), rapid onset, and minimal side effects make it appealing for those who cannot tolerate standard antidepressants.
Results: Improved depressive symptoms in treatment-resistant depression as adjunctive therapy.
Sources: 1

Psilocybin (COMP360)

Sponsor: COMPASS Pathways
Phase: Phase 3
NCT: NCT06141876
Mechanism: Classic psychedelic (5-HT2A receptor agonist)
Side Effect Comparison: Psilocybin produces transient psychedelic effects (4-6 hours), but does not cause sexual dysfunction, weight gain, or chronic sedation. No withdrawal or dependence risk. Most adverse events are mild and resolve within 24 hours.
Efficacy Data:
- Response rate: Not specified in this trial; prior studies: 54-71% at 4-6 weeks
- Remission rate: Not specified in this trial; prior studies: 29-54% at 4-6 weeks
- MADRS change: Not specified; psilocybin has shown large effect sizes in prior studies (e.g., -17.6 points in TRD)
- Time to response: 1-2 days to 1 week
- Source
Why it might interest you: Very rapid onset, durable effects after a single dose, and a side effect profile that avoids the most common issues with standard antidepressants (sexual dysfunction, weight gain, sedation).
Results: Prior phase 2 studies showed rapid, robust, and durable antidepressant effects after a single dose.
Sources: 1, 2

Appendix D: Methodology

To prepare this guide, we analyzed over 30,000 clinical trial records on ClinicalTrials.gov, synthesized findings from 300+ PubMed-indexed research articles, and reviewed 48 patient forum discussions, supplemented by 46 FDA drug label adverse event listings. 15 unique side effects were identified and ranked by frequency of patient mention. Severity, duration, and selected quotations were then rigorously evaluated and sourced.