LEVOMILNACIPRAN HYDROCHLORIDE (Fetzima) Side Effects Guide

Table of Contents

Fetzima (Levomilnacipran) Side Effects: The Real Patient Timeline

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Fetzima

The Worst Side Effects

The Most Common Side Effects

Sexual Dysfunction and Painful Orgasm

Severe Constipation and Anal Fissures

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

Fetzima (Levomilnacipran) Side Effects: The Real Patient Timeline

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Fetzima

The Worst Side Effects

The Most Common Side Effects

Sexual Dysfunction and Painful Orgasm

Severe Constipation and Anal Fissures

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

Fetzima (levomilnacipran): real-world and clinical side effects, how it works, user tips, FDA rates, timelines, and emerging alternatives for antidepressant therapy.

Medication: Fetzima (LEVOMILNACIPRAN HYDROCHLORIDE) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Fetzima (Levomilnacipran) Side Effects: The Real Patient Timeline

Day 1: That stomach-turning nausea. Day 4: The sweat kicks in, enough to make you eye antiperspirant on pharmacy shelves you didn't know existed. Week 2: Maybe your appetite has vanished—or you're nervously clocking your pulse after reading one too many forums. Welcome to the opening act of Fetzima (levomilnacipran), one of the newer kids on the antidepressant block, and the only SNRI (serotonin-norepinephrine reuptake inhibitor) designed to work more on norepinephrine (a brain chemical tied to motivation and alertness) than serotonin (the one everyone blames for mood).

Roughly 17% of clinical trial patients reported nausea on Fetzima, making it the side effect to beat—and the top reason for quitting (1.5%) FDA label. But "common" in clinical trials can sound clinical, until you hear from someone on Reddit who said, "I had really, really bad constipation/anal fissures for the first several weeks..." source.

Standard SSRIs and SNRIs? They're still the main event for depression, but for many people, the side effect trade-offs are getting old—and the arrival of trial drugs with less sexual dysfunction or withdrawal could upend the equation. Until then, here's how Fetzima actually lands in real life.

Interested in clinical trials? Many trials for depression now target different mechanisms than Antidepressant—potentially offering different side effect profiles. Browse clinical trials →

Side Effects Overview Table

Side Effect	FDA Rate	Reddit Reports	Severity	Duration	Example
Excessive sweating	9%	🟡 occasional (3 posts)	🟢 mild	First week or two	source
Nausea and upset stomach	17%	🟢 rare (2 posts)	🟢 mild	First week or two	source
Sexual dysfunction and painful orgasm	6% (male), <2% (female)	🟢 rare (2 posts)	🟡 moderate	Several weeks/ongoing	source
Severe constipation and anal fissures	9%	🟢 rare (2 posts)	🟡 moderate	Several weeks	source
Increased heart rate and palpitations	6%	🟢 rare (2 posts)	🟡 moderate	A few weeks	source
Headache in the first days	N/A	🟢 rare (1 post)	🟢 mild	First two days	source
Loss of appetite	3%	🟢 rare (1 post)	🟢 mild	Initial days	source
Shakiness or tremor	N/A	🟢 rare (1 post)	🟢 mild	Initial days	source
Scattered and racing thoughts	N/A	🟢 rare (1 post)	🟢 mild	Acute episodes	source
Withdrawal symptoms after stopping	N/A	🟢 rare (1 post)	🟢 mild	About 1 week	source
Vivid and unusual dreams	N/A	🟢 rare (1 post)	🟢 mild	Ongoing	source
Mild fatigue after taking medication	N/A	🟢 rare (1 post)	🟢 mild	First two days	source
Stomach pain after a few weeks	N/A	🟢 rare (1 post)	🟢 mild	A few weeks in	source
Urinary retention or hesitancy	4%	🟢 rare (1 post)	🟢 mild	First two weeks	source
Restless legs and aching at night	N/A	🟢 rare (1 post)	🟢 mild	Ongoing	source

→ View all 60 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

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

Metric	Fetzima (Antidepressant)	Bupropion (NDRI)	CYB003 (Psilocybin analogue)	Osavampator (AMPA-PAM)
MECHANISM
Drug class	SNRI (serotonin-norepinephrine reuptake inhibitor)	NDRI (norepinephrine-dopamine reuptake inhibitor)	Psychedelic-derived (5-HT2A receptor agonist)	AMPA receptor positive allosteric modulator
How it works	Inhibits reuptake (prevents brain from reabsorbing) of serotonin & norepinephrine	Inhibits reuptake of norepinephrine & dopamine	Activates serotonin 5-HT2A receptors	Enhances glutamatergic signaling via AMPA receptors
EFFICACY
Response rate	50-55% (MDD, typical for SNRIs) FDA	49-54% source	53.3% (16mg) at 3 weeks source	Phase 3 ongoing (Phase 2 significant improvement over placebo)
Remission rate	32-35%	28-33%	75% (4 months, 16mg dose)	Not yet published
Time to effect	2-8 weeks	2-4 weeks	1-3 weeks	1-2 weeks (early data)
KEY SIDE EFFECTS
Nausea	17%	2-4%	10-20% (transient)	4-8%
Sexual dysfunction	6% male, <2% female	<2%	None reported	None reported
Increased heart rate	6%	<1%	None reported	<1%

→ Find clinical trials matched to your situation

Week-by-Week Timeline

Week	Common Experiences	What's Normal	When to Call Your Doctor
Week 1	Nausea, headache, jitters, sweating	Startup effects	Severe anxiety, suicidal thoughts
Week 2-3	Constipation, appetite loss, sleep changes, racing heart	Still adjusting	Worsening depression, uncontrolled heart rate
Week 4-6	May start feeling benefits, sexual changes	Gradual improvement	No improvement at all
Week 6-8	Full effect usually reached, dreams may be vivid	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 Fetzima

Fetzima is an SNRI (serotonin-norepinephrine reuptake inhibitor): it prevents your brain from reabsorbing serotonin (affecting mood) and norepinephrine (affecting motivation and alertness), so more of both hang around in your synapses (the gaps between nerve cells where signals jump). This dual mechanism is supposed to help both "classic" depression and the motivational deadweight often untouched by SSRIs.

But boosting norepinephrine comes with side effects—not just mood, but also your gut (cue: nausea, constipation), heart (racing pulse, sweaty palms), and even your sex life. The upside: after decades and thousands of patients, most doctors can predict what’s going to show up and manage it.

Why keep using it? Reliability. For some, especially if SSRI fatigue or emotional flatness set in, a norepinephrine-heavy SNRI offers a shot at sharper motivation—with tolerable, time-limited startup annoyances. "It can be quite helpful for depression with fatigue and low motivation symptoms but can cause vasoconstriction and urinary hesitancy (and constipation)," one user shared source.

The Worst Side Effects

Sexual dysfunction and painful orgasm

"I also experienced pretty harsh sexual side effects, most notably, painful orgasm." source Reported as moderate/severe by 1/2 users. Management tip: Some patients find switching to a different antidepressant (like bupropion) or adding adjunct therapies (buspirone or sildenafil for men) helps. Open conversation with your prescriber is key, as sexual effects may persist as long as you stay on the drug.

Severe constipation and anal fissures

"I had really, really bad constipation/anal fissures for the first several weeks..." source Moderate/severe (1/2 users). Often the reason for discontinuation if severe. Management tip: Stay hydrated, up your fiber, and don't ignore the urge to go. If severe, stool softeners or a change in medication may be warranted.

Increased heart rate and palpitations

"I have constant sweating, high blood pressure, and high heart rate." source Moderate (2/2 users). Often resolves with time but can be distressing. Management tip: Monitor your pulse, avoid excess caffeine, and let your doctor know if it doesn’t settle by Week 3-4 or is severe at any time.

How Clinical Trials Compare

CYB003, in phase 2 trials, showed no sexual dysfunction or cognitive blunting, and only transient mild-to-moderate headache/nausea—no persistent constipation or tachycardia source.

→ Find trials with lower rates of these side effects

The Most Common Side Effects

1. Excessive sweating

FDA: 9% | Reddit: 3 (occasional), all mild source
What helps: Lightweight, breathable clothing; frequent showers; fans. Tends to resolve after first 2 weeks.

"I have constant sweating, high blood pressure, and high heart rate." source

2. Nausea and upset stomach

FDA: 17% | Reddit: 2 (rare), all mild source
What helps: Take with food; ginger chews. Most say this peaks in week 1-2, then fades.

"I experienced sweating and constant nausea for a week or two." source

3. Severe constipation

FDA: 9% | Reddit: 2 (rare), moderate severity source
What helps: Hydrate, high-fiber diet, gentle laxatives short-term. Can persist for several weeks but often resolves.

4. Sexual dysfunction (including painful orgasm)

FDA: 6% males (<2% females) | Reddit: 2 (rare), moderate severity source
What helps: Open discussion with doctor; adjunct treatments may help. Can persist as long as drug is taken; may resolve after stopping.

5. Increased heart rate and palpitations

FDA: 6% | Reddit: 2 (rare), moderate severity source
What helps: Monitor caffeine, report to doctor if ongoing past week 4. May resolve with time.

Most of these effects begin within the first days and fade by weeks 2-4—though sexual effects and constipation can stick around longer for some. If side effects persist beyond 4 weeks or worsen, talk to your doctor. → Find clinical trials that may avoid these side effects

Sexual Dysfunction and Painful Orgasm

You don't read about this on the bottle, but the reality for some is exactly what this Redditor described: "I also experienced pretty harsh sexual side effects, most notably, painful orgasm." source

In FDA trials, 6% of men reported some form of sexual dysfunction (from erectile issues to ejaculation disorder), with a dose-response relationship: 6% at 40mg, up to 10% at 120mg. Among female patients, sexual side effects were far less common (<2%). The spectrum ranges from "things are different, but tolerable" to—occasionally—pain with orgasm or just no desire at all.

Reddit tells both sides: one user noted, "I've been on fetzima for a couple years and it doesn't affect my sexuality. In fact it gives me a flush of full body goosebumps when I finish." source

Management tips:

Open the conversation. Urologists and psychiatrists increasingly recommend "drug holidays" (if safe) or adjunct therapies for sexual side effects. For some, switching to bupropion or adding low-dose sildenafil is effective.
Sexual side effects often linger as long as the drug is taken, but usually resolve within weeks after stopping.
Don’t be afraid to ask your prescriber directly—it’s more common than you think.

For most, the risk is real but not inevitable. And for a handful, things might even get better. Brains (and sex lives) are weird that way.

Severe Constipation and Anal Fissures

Nothing says "memorable side effect" like the phrase "anal fissures." One user laid it bare: "I had really, really bad constipation/anal fissures for the first several weeks..." source

FDA numbers: 9% developed constipation, though Reddit comments suggest the real-world severity can be a rude surprise. The timeline? Starts within the first week, lingers for several weeks, and—if you're lucky—fades with time.

"It can be quite helpful for depression with fatigue and low motivation symptoms but can cause vasoconstriction and urinary hesitancy (and constipation)." source

Management tips:

Start with hydration (actual water, not just coffee).
Add fiber gradually. Bulk-forming supplements help some.
If it gets severe, stool softeners or gentle laxatives (senna, polyethylene glycol) are sometimes needed.
And don't wait—address constipation early. If you develop bleeding or severe pain, see your provider.

Fetzima isn’t unique among SNRIs here, but for a few unlucky users, the GI toll is a dealbreaker. Listen to your gut—sometimes literally.

Discontinuation & Withdrawal

Withdrawal isn’t rare among SNRIs, and Fetzima can be abrupt for some. "The withdrawal sucked for about a week but it was manageable," one user noted source.

Clinical trials don't pin down a rate, but the FDA warns about classic symptoms: agitation, nausea, headache, fatigue, mood changes, irritability, insomnia, dizziness, and odd "electric zap" sensations. Fetzima's half-life (how long it stays active in your body) is around 12 hours—shorter than some SNRIs, so sudden stops can be abrupt.

Management tips:

Always taper slowly. A reduction every 1-2 weeks is typical, but your doctor may adjust this for your situation.
If withdrawal symptoms start, pause the taper or briefly increase dose, then resume more slowly. Never tough it out without your doctor.

Timeline: Symptoms typically begin 1-3 days after stopping, peak within a week, and resolve within 2-3 weeks for most.

Stopping suddenly is almost always a bad idea. If you need to stop—pregnancy, major side effect, or no benefit—ask for a supervised, gradual taper.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Major depressive disorder	20mg once daily (for 2 days), then increase to 40mg once daily	40-80mg once daily	120mg once daily

Dose increases should occur in increments of 40mg no more often than every 2 days.
Dose-response: Higher doses increase side effect risks, particularly sexual and cardiac effects.
Reduce dose for renal impairment.
For CYP3A4 inhibitor drug interactions, max is 80mg.

Reference: FDA label

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

Bupropion (Wellbutrin, NDRI): Wired and a little weird, but less sexual dysfunction and actually may boost libido for some. Activating and sometimes a touch anxiogenic.
SNRIs (venlafaxine, duloxetine): Similar risk of GI and sexual side effects, but a longer track record and more data for pain symptoms.
SSRIs (sertraline, escitalopram): More sexual side effects, but lower risk for high blood pressure or heart rate issues.
MAOIs: Last-resort, food restriction required, but still gold-standard for some treatment-resistant cases.
Spravato (esketamine): Fast-acting, nasal spray; clinical setting only; less sexual dysfunction but more dissociation and blood pressure spikes.
TMS (transcranial magnetic stimulation): Not a drug, but a device—no systemic side effects.

If you're dealing with intolerable sexual dysfunction, bupropion is usually first to try. For chronic constipation or blood pressure spikes, SSRIs may be milder.

→ Compare your options on WithPower

Clinical Trials

Several new drug mechanisms are in late-stage development for depression—targeting exactly the side effects that drive many patients off current meds:

CYB003 (deuterated psilocybin analogue): Aims for rapid effect (weeks, not months), with no sexual dysfunction, weight gain, or persistent cognitive issues. 75% remission at 4 months; transient headache/nausea most common. source, clinical trial
Osavampator (AMPA-PAM): Early phase 3. AMPA modulation offers fast-onset benefits without chronic GI or sexual side effects seen with SNRIs/SSRIs. Headache and GI symptoms most common, but typically mild. source
D-cycloserine (NMDA partial agonist): Shown to rapidly reduce depressive symptoms as an adjunct, with few side effects—primarily mild headache/dizziness, no withdrawal. source
Psilocybin (classic psychedelic): Single or few doses; no chronic GI or sexual side effects. Transient anxiety/headache, but high rates of rapid remission in TRD. source

Why consider a trial? Free treatment, intensive monitoring, and access to therapies not yet on the market—but uncertainty, possible placebo, and frequent clinic visits go with the territory. Results are promising, but phase 3 confirmation is always the kicker.

Interested in clinical trials? Many trials for depression now target different mechanisms than Antidepressant—potentially offering different side effect profiles. Browse clinical trials →

Decision Map

If sexual dysfunction/painful orgasm is the dealbreaker → Bupropion (NDRI) OR CYB003, Osavampator trials
If severe constipation ruins your routine → SSRIs (sertraline, escitalopram), or TMS if meds are intolerable OR CYB003, Osavampator trials
If palpitations/high heart rate is a red flag → SSRIs or Bupropion (but check with doc), OR D-cycloserine, Osavampator trials
If withdrawal risk scares you → Longer half-life meds (fluoxetine), non-drug options (TMS), OR Psilocybin trials
For GI startup side effects (nausea/sweating) → Bupropion or wait it out (often resolves), OR Psilocybin, CYB003 trials

Fetzima (levomilnacipran) - antidepressant medication Image: YouTube

Monitoring & What to Track

Your doctor should be tracking:

Mood: PHQ-9 or HAM-D score every visit
Blood pressure and pulse
Weight (if appetite changes or GI side effects)
Any signs of suicidal ideation (especially in first weeks and under age 25)
Renal function in patients with kidney issues

You should be tracking:

Daily mood score (1-10 scale)
Side effect log (with when and how severe)
Sleep duration and quality
Appetite, weight, and energy
Any unusual physical symptoms (palpitations, sweating, GI changes)

If your doctor isn't tracking these, ask them to. You’re the best source of real-world data for your own case.

Pregnancy & Breastfeeding

Fetzima is not recommended during pregnancy unless benefits clearly outweigh risks (FDA Pregnancy Category: not assigned; animal studies show risk at high doses). Like all antidepressants, the big scare is potential risk for newborn withdrawal/adaptation syndrome, especially if taken in the third trimester. There's also the theoretical risk of hypertension or cardiac issues in the baby, though this is rare.

Untreated depression during pregnancy also comes with major risks: poor prenatal care, prematurity, and higher suicide risk. For breastfeeding, Fetzima passes into breast milk, but levels in infants are low. Data are limited—if breastfeeding, watch for irritability, feeding changes, or withdrawal symptoms in the baby.

Key message: This is a risk/benefit calculation with your doctor—not an automatic stop or go. And if you become pregnant, don’t stop suddenly—taper with medical support.

Emergency Warning Signs

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

Suicidal thoughts, plans, or behaviors
Signs of serotonin syndrome: agitation, confusion, fever, sweating, shivering, muscle stiffness, diarrhea, tremors (especially if on other serotonergic drugs)
Severe allergic reaction: rash, swelling, difficulty breathing
Seizure or unexplained loss of consciousness

📞 Call your doctor urgently if:

Severe anxiety or new agitation
Worsening depression
Unusual bleeding or bruising
Severe constipation with abdominal pain, vomiting, or no bowel movement >3 days
Palpitations, chest pain, or persistent high blood pressure
Signs of urinary retention (inability to urinate)
New or worsening seizures

Poison Control: 1-800-222-1222 National Suicide Prevention Lifeline: 988

Summary & Next Steps

Key takeaways: About 17% of Fetzima users experience nausea, with excessive sweating (9%) and constipation (9%) also common. Most real-world side effects—like vivid dreams or mild fatigue—tend to resolve in the first few weeks, but sexual dysfunction and heart rate changes can persist for some.

If Fetzima is working for you: Stick with it, track your side effects, and don’t hesitate to flag anything new or alarming to your doctor. Most startup side effects fade by week 4.

If side effects are intolerable: Don't tough it out. Talk to your doctor about dose adjustments, possible switches (like bupropion for sexual dysfunction, SSRIs for less constipation), or participation in clinical trials with different mechanisms.

Your next steps:

Track your symptoms for 2 weeks using a mood diary
Discuss this guide with your doctor at your next appointment
If considering alternatives, → 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
nausea	17%	6%	very common	Gastrointestinal
constipation	9%	3%	common	Gastrointestinal
hyperhidrosis	9%	2%	common	Dermatologic
heart rate increased	6%	1%	common	Cardiovascular
erectile dysfunction	6%	1%	common	Reproductive/Sexual
tachycardia	6%	2%	common	Cardiovascular
ejaculation disorder	5%	0%	common	Reproductive/Sexual
vomiting	5%	1%	common	Gastrointestinal
palpitations	5%	1%	common	Cardiovascular
testicular pain	4%	0%	common	Reproductive/Sexual
urinary hesitation	4%	0%	common	Renal/Urinary
blood pressure increased	3%	1%	common	Cardiovascular
hot flush	3%	1%	common	Vascular
hypotension	3%	1%	common	Vascular
hypertension	3%	1%	common	Vascular
decreased appetite	3%	1%	common	Metabolic
rash	2%	0%	common	Dermatologic
angina pectoris	0%	0%	uncommon	Cardiovascular
supraventricular and ventricular extrasystoles	0%	0%	uncommon	Cardiovascular
dry eye	0%	0%	uncommon	Ophthalmologic
vision blurred	0%	0%	uncommon	Ophthalmologic
conjunctival hemorrhage	0%	0%	uncommon	Ophthalmologic
chest pain	0%	0%	uncommon	General
thirst	0%	0%	uncommon	General
abdominal pain	0%	0%	uncommon	Gastrointestinal
flatulence	0%	0%	uncommon	Gastrointestinal
blood cholesterol increased	0%	0%	uncommon	Metabolic
liver function test abnormal	0%	0%	uncommon	Hepatic
migraine	0%	0%	uncommon	Nervous System
paraesthesia	0%	0%	uncommon	Nervous System

Boxed Warnings (Most Serious)

Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. FETZIMA is not approved for use in pediatric patients.

Drug Interactions

Monoamine Oxidase Inhibitors (MAOIs): Concomitant use increases risk of serotonin syndrome. Contraindicated with MAOIs or within 7 days of stopping FETZIMA, or within 14 days of stopping an MAOI. Includes selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.
Other serotonergic drugs: Increased risk of serotonin syndrome. Includes other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, St. John's Wort.
Drugs that interfere with hemostasis: Increased risk of bleeding with antiplatelet or anticoagulant drugs (e.g., NSAIDs, aspirin, warfarin).
Strong CYP3A4 inhibitors: Increases levomilnacipran exposure. Maximum recommended FETZIMA dose is 80 mg once daily. Includes ketoconazole, itraconazole, clarithromycin.
Alcohol: May result in accelerated release of levomilnacipran. Avoid concomitant use.

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?
Excessive sweating	3 posts	🟢 Mild (3/3)	First week or two	Resolves
Nausea and upset stomach	2 posts	🟢 Mild (2/2)	First week or two	Resolves
Sexual dysfunction and painful orgasm	2 posts	🟡 Moderate (1/2)	Several weeks (painful orgasm); ongoing (altered sensation)	Resolves
Severe constipation and anal fissures	2 posts	🟡 Moderate (1/2)	First several weeks	Resolves
Increased heart rate and palpitations	2 posts	🟡 Moderate (2/2)	A few weeks	Resolves
Headache in the first days	1 posts	🟢 Mild (1/1)	First two days	Resolves
Loss of appetite	1 posts	🟢 Mild (1/1)	Initial days	Resolves
Shakiness or tremor	1 posts	🟢 Mild (1/1)	Initial days	Resolves
Scattered and racing thoughts under pressure	1 posts	🟢 Mild (1/1)	Not specified (acute episodes)	Resolves
Withdrawal symptoms after stopping	1 posts	🟢 Mild (1/1)	About a week after stopping	Resolves
Vivid and unusual dreams	1 posts	🟢 Mild (1/1)	Ongoing	Resolves
Mild fatigue after taking medication	1 posts	🟢 Mild (1/1)	First two days	Resolves
Stomach pain after a few weeks	1 posts	🟢 Mild (1/1)	A few weeks in	Resolves
Urinary retention or hesitancy	1 posts	🟢 Mild (1/1)	First two weeks	Resolves
Restless legs and aching at night	1 posts	🟢 Mild (1/1)	Ongoing while on medication	Resolves

User Quotes by Side Effect

Excessive sweating (Starts within first days, peaks in first week, often resolves by week 2)

"I experienced sweating and constant nausea for a week or two." source

"I have constant sweating, high blood pressure, and high heart rate." source

"Shaky, loss of appetite, thoughts scattered but then fast when put on the spot, a headache for the first 2 days that only started in the late afternoon, and sweating." source

Nausea and upset stomach (Starts within first days, peaks in first week, often resolves by week 2)

"I experienced sweating and constant nausea for a week or two." source

"I mostly just had side effects on Fetzima - I had really, really bad constipation/anal fissures for the first several weeks, would get nauseous..." source

Sexual dysfunction and painful orgasm (Starts early in treatment, may persist as long as medication is continued)

"I also experienced pretty harsh sexual side effects, most notably, painful orgasm." source

"I've been on fetzima for a couple years and it doesn't affect my sexuality. In fact it gives me a flush of full body goosebumps when I finish." source

Severe constipation and anal fissures (Starts within first week, persists for several weeks, may resolve with time)

"I had really, really bad constipation/anal fissures for the first several weeks..." source

"It can be quite helpful for depression with fatigue and low motivation symptoms but can cause vasoconstriction and urinary hesitancy (and constipation)." source

Increased heart rate and palpitations (May start early, can appear a few weeks in, may persist or resolve)

"I have constant sweating, high blood pressure, and high heart rate." source

"...then a few weeks in racing heart at night." source

Headache in the first days (Starts on day 1, resolves by day 3)

"...a headache for the first 2 days that only started in the late afternoon..." source

Loss of appetite (Starts in first days, may resolve quickly)

"Shaky, loss of appetite, thoughts scattered but then fast when put on the spot..." source

Shakiness or tremor (Starts in first days, may resolve quickly)

"Shaky, loss of appetite, thoughts scattered but then fast when put on the spot..." source

Scattered and racing thoughts under pressure (Occurs acutely, not described as persistent)

"...thoughts scattered but then fast when put on the spot..." source

Withdrawal symptoms after stopping (Begins after stopping, lasts about a week)

"The withdrawal sucked for about a week but it was manageable." source

Vivid and unusual dreams (Starts after beginning medication, persists as long as taking)

"The main side effect I get is vivid dreams they're a little weird sometimes but it's worth the quality of sleep I get in trade off." source

Mild fatigue after taking medication (Starts on first days, resolves quickly)

"I felt a little fatigued after taking it." source

Stomach pain after a few weeks (Begins a few weeks after starting, duration not specified)

"...then a few weeks in racing heart at night. Also, I had stomach pains." source

Urinary retention or hesitancy (Starts early, resolves by week 2)

"After 2 weeks, any urinary retention issues completely dissipated, unlike Effexor, Pristiq and even Cymbalta." source

Restless legs and aching at night (Develops after starting medication, persists as long as taking)

"I've recently developed aching and pain in my legs at night. Sounds like restless leg syndrome. Today I found out that can be connected to the medication." source

Appendix C: Clinical Trials with Different Mechanisms

These trials target mechanisms different from Antidepressant. Phase 2 results do not guarantee Phase 3 success.

CYB003 (deuterated psilocybin analog)

Sponsor: Cybin Inc.
Phase: Phase 2 (Breakthrough Therapy Designation)
NCT: NCT06141876
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: CYB003 showed a favorable side effect profile: transient mild-moderate headache and nausea were most common. No serious adverse events, no sexual dysfunction, weight gain, or cognitive blunting as seen with SSRIs/SNRIs. No evidence of dependence or withdrawal.
Efficacy Data:
- Response rate: 53.3% (CYB003 16mg) vs 20% (placebo) at 3 weeks
- 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: CYB003 offers a rapid onset of antidepressant effect (within 1-3 weeks), with high remission rates and a side effect profile that avoids common SSRI/SNRI issues like sexual dysfunction, weight gain, and cognitive dulling. It is a single or few-dose therapy, reducing daily medication burden and risk of chronic side effects.
Results: Significant and rapid reduction in depressive symptoms, high remission rates sustained at 4 months, rapid onset of action.
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 the sexual dysfunction, weight gain, or sedation typical of SSRIs/SNRIs. Early data suggest a favorable tolerability profile, with headache and mild GI symptoms most common. No cognitive impairment reported.
Efficacy Data:
- Response rate: Not yet published (Phase 3 ongoing)
- Remission rate: Not yet published (Phase 3 ongoing)
- MADRS change: Not yet published (Phase 3 ongoing); Phase 2 showed significant improvement over placebo
- Time to response: Early studies suggest faster onset (within 1-2 weeks)
- Source
Why it might interest you: Osavampator works via a completely different mechanism (AMPA modulation) than standard antidepressants, with early evidence of faster onset and fewer side effects such as sexual dysfunction, weight gain, or sedation. It may be especially appealing for those who have not tolerated or responded to SSRIs/SNRIs.
Results: Phase 2 data showed significant improvement in depressive symptoms as adjunctive therapy. Phase 3 is ongoing to confirm efficacy and safety.
Sources: 1, 2, 3

D-cycloserine (adjunctive)

Sponsor: Not specified (academic/NIH)
Phase: Phase 2 (completed)
NCT: NCT00408031
Mechanism: NMDA receptor partial agonist (glycine site)
Side Effect Comparison: D-cycloserine is generally well-tolerated; most common side effects are mild (headache, dizziness). No sexual dysfunction, weight gain, or sedation as seen with SSRIs/SNRIs. No evidence of dependence or withdrawal.
Efficacy Data:
- Response rate: Not specified
- Remission rate: Not specified
- MADRS change: Not specified for D-cycloserine in MDD; in TRD, significant improvement over placebo in phase 2 trial (NCT00408031)
- Time to response: Within 2 weeks (reported in adjunctive use)
- Source
Why it might interest you: D-cycloserine targets glutamatergic neurotransmission (NMDA receptor), offering a novel mechanism with rapid onset and minimal side effects compared to standard antidepressants. It avoids common SSRI/SNRI side effects and may be useful for those with inadequate response or intolerable side effects from standard drugs.
Results: Adjunctive D-cycloserine improved depressive symptoms in treatment-resistant depression and bipolar depression.
Sources: 1

Psilocybin (various sponsors)

Sponsor: Multiple (Compass Pathways, Usona, academic centers)
Phase: Phase 2/3 (Breakthrough Therapy Designation)
NCT: NCT06141876
Mechanism: Classic psychedelic (5-HT2A receptor agonist)
Side Effect Comparison: Psilocybin is associated with transient anxiety, headache, and nausea, but lacks the chronic side effects of SSRIs/SNRIs (sexual dysfunction, weight gain, emotional blunting). No evidence of dependence or withdrawal. Effects are typically limited to the dosing session and shortly after.
Efficacy Data:
- Response rate: 37% (psilocybin) vs 18% (placebo) at 3 weeks (TRD)
- Remission rate: 29% (psilocybin) vs 8% (placebo) at 3 weeks (TRD)
- MADRS change: Psilocybin: -17.6 points vs -5.4 points (placebo) at 3 weeks (in TRD, not MDD)
- Time to response: 1-3 weeks
- Source
Why it might interest you: Psilocybin offers a rapid, robust antidepressant effect with a single or few doses, and avoids the chronic side effects of standard antidepressants. It is especially promising for those who have not responded to or cannot tolerate SSRIs/SNRIs.
Results: Rapid and robust antidepressant effects in TRD, with significant improvements in depressive symptoms and sustained remission in a subset of patients.
Sources: 1, 2

Appendix D: Methodology

We examined over 30,000 clinical trial entries from ClinicalTrials.gov, referenced 300+ peer-reviewed journal articles from PubMed, and incorporated insights from 35 online patient discussions, as well as 60 FDA drug label records. A total of 15 distinct adverse effects were identified and prioritized by frequency in both clinical trials and patient forums. Expert reviewers assessed severity, duration, and curated direct patient quotations with proper source citations.