VORTIOXETINE (Trintellix) Side Effects Guide

Table of Contents

Intro

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Trintellix

The Worst Side Effects

The Most Common Side Effects

Nausea and upset stomach

Increased or new anxiety

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 Trintellix

The Worst Side Effects

The Most Common Side Effects

Nausea and upset stomach

Increased or new anxiety

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

Trintellix (vortioxetine) can cause nausea, GI upset, and sexual side effects—most common in the first weeks. Real-world experiences show mild, transient nausea and rare persistent issues. Explore alternatives and monitoring tips.

Medication: Trintellix (VORTIOXETINE) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Intro

Day 1: That familiar gut churn. Day 5: Nausea peaking, maybe a hint of unease. Week 3: Stomach settles (if you're lucky), but maybe your sex drive doesn't quite come back. And through it all, you're wondering: Is this just what antidepressants are, or is this Trintellix (vortioxetine) being "special"?

Roughly 1 in 3 patients in trials reported nausea, and nearly as many flagged sexual side effects (though you'd barely guess it from FDA voluntary reporting stats). Most people will feel at least some startup effects, and for a rare unlucky few, the problems just don't fade away. Why do doctors keep prescribing it? Because the clinical remission numbers nudge just a bit higher than with some older meds, and it's engineered to dodge some of the worst SSRI baggage—but it's far from side-effect free. We'll dig into what real patients actually experience and what the numbers don't always tell you.

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
Nausea and upset stomach	21–32%	🔴 very_frequent (13 posts)	🟢 Mild	First 2–7 weeks, often resolves	"The worst of it was nausea for the first 2 weeks, but it was mostly in the first few hours after taking it."
Digestive upset and bloating	N/A	🟠 frequent (7 posts)	🟢 Mild	Ongoing or improves after weeks	"I felt really great on it for about 6 months, but it messed up my digestion badly."
Changes in sexual desire or delayed orgasm	16–34% (ASEX); 1–5% (voluntary)	🟠 frequent (7 posts)	🟢 Mild	Ongoing, may improve or persist	"...no weight gain, no libido problems just takes a little more time to cum which was manageable."
Increased or new anxiety	N/A	🟠 frequent (6 posts)	🟡 Moderate	First 1–3 weeks, sometimes longer	"I was on just 5mg and it sent my anxiety through the roof and gave me terrible insomnia."
Vomiting after starting medication	3–6%	🟡 occasional (5 posts)	🟢 Mild	First 1–2 weeks, often resolves	"Trintellix potentially causes both nausea and vomiting via two different mechanisms. The vomiting pathway resolves itself shortly after treatment initiation."
Constipation	3–6%	🟡 occasional (5 posts)	🟢 Mild	Ongoing, often manageable	"Easily manageable constipation."
Frequent headaches	Up to 15% (other sources), not in core FDA stats	🟢 rare (3 posts)	🟢 Mild	Ongoing	"Constant headaches - Late & very painful periods ..."
Loss of appetite	N/A	🟢 rare (3 posts)	🟢 Mild	First weeks, sometimes ongoing	"I was losing my appetite..."
Dizziness or feeling light-headed	6–9%	🟢 rare (3 posts)	🟢 Mild	First 1–2 weeks, sometimes longer	"bad light-headedness and head buzzing..."
Agitation and irritability	N/A	🟢 rare (3 posts)	🟢 Mild	First weeks, sometimes ongoing	"I have seen increases in irritability/agitation, as well as akathisia."
Fatigue and weakness	N/A	🟢 rare (2 posts)	🟡 Moderate	Ongoing	"...constantly felt weak and thirsty, and sick to my stomach so often."
Dry mouth and sinuses	6–8%	🟢 rare (2 posts)	🟢 Mild	Ongoing	"mouth and sinuses feeling dry ..."
Painful periods	N/A	🟢 rare (1 post)	🟡 Moderate	Ongoing	"...Late & very painful periods ..."
Forgetfulness	N/A	🟢 rare (1 post)	🟢 Mild	Ongoing	"Forgetfulness - No motivation ..."
Lack of motivation	N/A	🟢 rare (1 post)	🟡 Moderate	Ongoing	"No motivation - Constant headaches ..."

→ View all 82 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

If you're weighing options, here's how Trintellix (vortioxetine) stacks up against alternatives:

Metric	Trintellix (Antidepressant)	Bupropion (NDRI)	CYB003 (Psilocybin analog, Phase 2)	Osavampator (AMPA-PAM, Phase 3)
MECHANISM
Drug class	Serotonin modulator & stimulator (SMS)	Norepinephrine-dopamine reuptake inhibitor	Deuterated psilocybin analog (5-HT2A agonist)	AMPA receptor positive allosteric modulator
How it works	Modulates multiple serotonin receptors; also weakly inhibits reuptake of serotonin (keeps more serotonin at synapses, tweaks receptor activity in various ways)	Blocks reuptake of norepinephrine and dopamine (boosts these neurotransmitters)	Stimulates 5-HT2A receptor, causing altered neural network activity	Enhances glutamate signaling by amplifying AMPA receptor activity
EFFICACY
Response rate	~48% (short-term trials) FDA	~50–60% (meta-analysis, depends on population) source	53% (3 wks, 16mg dose, Phase 2) source	Phase 2: Statistically significant improvement; response rates not reported
Remission rate	~32% (short-term trials) FDA	~35–40% (meta-analysis)	75% (4 months, OLE)	Not reported
Time to effect	2–6 weeks	2–4 weeks	1–3 weeks	~2 weeks (class effect)
KEY SIDE EFFECTS
Nausea and upset stomach	21–32%	<5%	8% (transient dosing day)	N/A
Sexual dysfunction	16–34% (ASEX)	<5%	0%	N/A
Weight gain	0%	<5%	0%	0%
Sedation/fatigue	~2–5%	~2%	0%	0%

→ 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, digestive upset, headache	Startup effects	Severe anxiety, suicidal thoughts
Week 2–3	GI issues fade, some sexual side effects show	Still adjusting	Worsening depression
Week 4–6	Side effects usually taper, may start to feel benefits	Gradual improvement	No improvement at all
Week 6–8	Full effect for most	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 Trintellix

Trintellix (vortioxetine) works as a serotonin modulator and stimulator, which—translated from the marketing gobbledygook—means it not only prevents reuptake of serotonin (stopping your brain from vacuuming up this mood-related chemical quite so fast) but also tweaks a few different serotonin receptors (proteins on cells that sense these chemicals). This approach was supposed to finesse the blunt-force side effects of old-school SSRIs—fewer flat moods, less sexual funkiness.

But any drug monkeying with serotonin will hit your gut and other "serotonin-rich" zones (about 90% of serotonin in your body is in your intestines). That's why the first effects are so often things like nausea, weird dreams, and a sense of everything being just a little bit off. It's not all bad: The multiple receptor actions might reduce cognitive fog compared to other antidepressants, and, for some, fewer sexual side effects. So why do prescribers reach for it? Decades of safety data, predictability (at least, within a range), and for many, just enough of a difference that it's worth a shot—especially if you've had SSRI side effect nightmares.

The Worst Side Effects

1. Increased or new anxiety

"I was on just 5mg and it sent my anxiety through the roof and gave me terrible insomnia." source

Reported as moderate-to-severe by 3/6 users.
Management tip: Some patients take Trintellix in the morning to reduce sleep problems; adding a short course of low-dose benzodiazepine (under doctor supervision) for the first 1–2 weeks is sometimes used. If it doesn't improve by week 3, dose adjustment or alternative meds are considered.

2. Fatigue and weakness

"...constantly felt weak and thirsty, and sick to my stomach so often." source

Moderate/severe in 1/2 users.
Management tip: Stay hydrated and try taking the dose at night if possible; check for low sodium if persistent, and discuss switching with your doctor if this doesn't lift.

3. Painful periods (dysmenorrhea)

"Cons (which are just too much): ...very painful periods..." source

Only reported in 1 user, but rated moderate severity; unresolved during use.
Management tip: NSAIDs and heating pads can help; switching antidepressants might be needed if this persists.

How Clinical Trials Compare

Most serious side effects in trials (nausea, sexual dysfunction, vomiting) are generally mild to moderate; rare serious events include serotonin syndrome, acute pancreatitis, seizure, and hyponatremia FDA label.
No fatal outcomes attributed to Trintellix in trials.
Novel trial drugs like CYB003 and AMPA modulators report lower sexual side effect and sedation rates (e.g., 0% sexual dysfunction on CYB003 vs ~30% on Trintellix, source).

→ Find trials with lower rates of these side effects

The Most Common Side Effects

1. Nausea and upset stomach

FDA: 21–32% (dose-related), Reddit: 13 posts, mostly mild
What helps: Take after a meal, divide dose if needed, ginger chews
Timeline: Peaks first 1–2 weeks, resolves by week 7 for most

"The worst of it was nausea for the first 2 weeks, but it was mostly in the first few hours after taking it." source

2. Digestive upset and bloating

FDA: Not specified; Reddit: 7 posts, mild
What helps: Try with food, increase fiber, probiotics sometimes help
Timeline: First days to weeks, resolves for most

"I felt really great on it for about 6 months, but it messed up my digestion badly..." source

3. Changes in sexual desire or delayed orgasm

FDA: 16–34% (ASEX scale); Reddit: 7 posts, mostly mild
What helps: Dose reduction, drug holidays (ask your doctor!), switching meds
Timeline: Can be persistent; sometimes improves

"...no weight gain, no libido problems just takes a little more time to cum which was manageable." source

4. Vomiting

FDA: 3–6%; Reddit: 5 posts, mild
What helps: Take with food; divide dose; antiemetic only short-term
Timeline: First days to 1–2 weeks, then usually fades

"...vomiting pathway resolves itself shortly after treatment initiation." source

5. Constipation

FDA: 3–6%; Reddit: 5 posts, mild
What helps: Hydration, fiber, stool softener short-term
Timeline: Ongoing, but many find it manageable

"Easily manageable constipation." source

Nausea and upset stomach

"It took 7 weeks for me to get over the constant nausea. But worth it compared to other antidepressants." source

Nausea is Trintellix's calling card, hitting up to 1 in 3 patients in the first week or two (21–32% in trials, vs. 9% for placebo). Reddit users almost universally put it in the "annoying but manageable" box, but that doesn't mean it's a non-issue: one user described nausea peaking "in the first few hours after taking it," while another took nearly two months for their stomach to chill out.

Why does this happen? The drug cranks up serotonin not just in your brain, but in the gut too. Serotonin is infamous for making stomach nerves twitchy. Even with slow titration (gradually adjusting the dose), some people lose their appetite or feel queasy just looking at breakfast.

Management tips:

Take after a substantial meal (not just coffee and a bagel)
Consider splitting the dose, if your prescriber okays it
Ginger chews, peppermint tea—small studies suggest both help
Most cases resolve by week 2–7; hang in there if you can

FDA vs. Reddit Reality: Clinical trials catch about 1 in 3, but in Reddit threads, it's almost a rite of passage. The difference? Mild cases get ignored in "official" reporting, and persistence is rarely documented beyond the first month. If you're still queasy at week 8, it's time for a medication review.

"I've heard a lot of positive experiences with Vortioxetine, but also about significant nausea and vomiting, leading to treatment non-adherence." source

Increased or new anxiety

Antidepressants are supposed to quiet the mental storm, but sometimes the first few weeks are like turning up the volume on everything you're trying to tune out. "I started 10 mg two weeks ago and the first few days, I was fine but the anxiety has been pretty bad since," one user shared source. Another posted, "I've now been on it again another week and my anxiety has certainly reduced and intrusive thoughts still there just a little quieter" source.

What's going on here? Boosting serotonin can temporarily "activate" brain circuits, amping up alertness (and, for some, agitation or anxiety). This is usually a startup phenomenon. In FDA trials, new or worsening anxiety isn't specifically tracked—it's often lumped into broader "psychiatric" categories. But 6 Redditors cited it as moderate and hard to ignore.

Management tips:

Dose timing: Try dosing in the morning
Mindfulness/breathing apps may help offset acute anxiety
Short-term anti-anxiety meds (prescription, not over-the-counter) are sometimes used, but always under close supervision
If it doesn't improve after 2–3 weeks, consider switching

"I was on just 5mg and it sent my anxiety through the roof..." source

Discontinuation & Withdrawal

Percentage who experience withdrawal symptoms is not well-established, but abrupt discontinuation at higher doses (15–20mg) triggers headaches, muscle tension, mood swings, anger outbursts, dizziness, and runny nose—usually within the first week after stopping FDA label.

Why? The half-life (how long the drug stays active in your body) of Trintellix is about 66 hours, which softens (but doesn't eliminate) withdrawal. Still, the FDA recommends a slow taper (gradually reducing the dose) to avoid "discontinuation syndrome"—with reductions every 1–2 weeks depending on starting dose and individual tolerance.

Typical timeline: symptoms emerge days 1–7 after dose cut, and resolve within 1–2 weeks for most. Don't go cold turkey, and always do a taper under medical supervision.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Major depressive disorder	10 mg once daily	10–20 mg once daily	20 mg once daily

Dose increases (titration) can heighten the risk of nausea and GI side effects. Start low if sensitive, especially in those prone to GI upset.
Lower doses (5mg) may be used in patients with sensitivity or hepatic impairment.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

If you're ready to ghost the side effects but not the hope for feeling better, a few FDA-approved options might fit your personality (and your GI tract) better:

Bupropion: The "activating one," famous for minimal sexual side effects and no weight gain—but it can increase anxiety for some.
SNRIs (e.g., venlafaxine, duloxetine): Tend to cause more sweating and hypertension but less GI upset than SSRIs for some.
MAOIs (rarely used): Strict dietary rules; side effect heavy but can work where others fail.
Spravato (esketamine nasal spray): For treatment-resistant depression; administered in clinic; dissociative but rapid-acting.
TMS (transcranial magnetic stimulation): Non-drug; can cause scalp discomfort, rare seizures, but no GI or sexual side effects.

If sexual side effects are your personal dealbreaker, bupropion and novel trial drugs (see below) are worth a look.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analog, Cybin Inc.)

Phase 2: 53% response at 3 weeks; 75% remission at 4 months; 0% chronic sexual dysfunction; headaches/anxiety only around dosing source.

Osavampator (NBI-1065845/TAK-653, Neurocrine Biosciences)

AMPA modulator; Phase 3 ongoing; early data: no increase in weight, sexual dysfunction, or sedation source.

D-cycloserine

NMDA receptor partial agonist; adjunct trials in TRD; no significant sedation, weight, or sexual dysfunction source.

Psilocybin (COMP360, Usona, others)

Single/few doses can produce sustained remission with few lingering side effects; no withdrawal source.

Trial participation can mean free treatment, close monitoring, and a shot at a novel mechanism—just remember, Phase 2 or 3 means data is still emerging, and you might get a placebo arm.

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 nausea and upset stomach is the dealbreaker → Bupropion (minimal GI side effects) OR CYB003, Osavampator, or D-cycloserine trials

If sexual dysfunction is intolerable → Bupropion, or Psilocybin/CYB003 trials (0% sexual side effects in trials)

If increased anxiety is the issue → Mirtazapine or TCA (can have sedation), OR consider AMPA/NMDA modulator trials

If fatigue or cognitive fog is dominant → Bupropion, TMS, or trials with novel mechanisms

Always discuss with your clinician before making a switch, and check for emerging trials matching your side effect profile.

Trintellix (Vortioxetine) - antidepressant medication Image: Plushcare.com

Monitoring & What to Track

Depression: PHQ-9 or Hamilton (HAM-D) scores regularly
Anxiety (if present): GAD-7 or HAM-A scores
Weight: Periodically, though Trintellix rarely causes gain
Suicidality: Especially in the first 1–2 months or under age 25
Electrolytes and liver function: If at higher risk or with certain meds

What You Should Track

Mood/anxiety diary (1–10 scale daily)
Side effects: Which, when, severity, and whether they fade or persist
Sleep quality (hours, refreshment, disturbances)
Energy, concentration

If your doctor isn't tracking these, ask them to (and bring your logs to the next appointment).

Pregnancy & Breastfeeding

FDA pregnancy category: Not assigned under new labeling; animal studies show no major birth defects at normal doses, but human data is limited
Risks: Untreated depression has its own dangers (preterm birth, low birth weight); TRINTELLIX has not been linked to major birth defects but all antidepressants may carry risk of pulmonary hypertension and neonatal withdrawal if used in the third trimester
Breastfeeding: Small amounts found in milk; unknown long-term effects, but low relative infant dose; monitor baby for feeding, irritability

This is a risk-benefit balancing act—never a cut-and-dried yes/no. Do NOT stop suddenly if you find out you're pregnant; discuss a taper or switch with your doctor if needed.

Emergency Warning Signs

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

Suicidal thoughts or plans
Signs of serotonin syndrome (confusion, fever, sweating, muscle twitching, rapid heartbeat)
Severe allergic reaction (rash, swelling of face/lips/tongue, difficulty breathing)

📞 Call your doctor urgently if:

Unusual bleeding or bruising
Severe anxiety, agitation, or hostility
Worsening depression or new/worsening suicidal ideation
Seizures
Acute pancreatitis symptoms (severe abdominal pain, vomiting)

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

Summary & Next Steps

Key takeaways:

Nausea (21–32%), GI discomfort, and sexual dysfunction (16–34%) are the most frequent side effects on Trintellix, but most are mild and fade within weeks.
Real-world patients mostly rate side effects as tolerable, but 6/15 side effects are frequent, and anxiety/agitation can be severe for some.
Trials of novel antidepressants (e.g., CYB003) show 0% sexual side effects and rapid remission for some.

If Trintellix is working for you: Keep tracking your mood and side effects, take after food, and watch for any new or worsening symptoms, especially in the first 1–2 months.

If side effects are intolerable: Ask your doctor about dose changes or switching to options with a different mechanism (like bupropion, or a trial drug). Nausea, sexual dysfunction, and anxiety are legitimate reasons to consider alternatives.

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
treatment-emergent sexual dysfunction (female, ASEX scale)	34%	20%	very common	Reproductive/Sexual
treatment-emergent sexual dysfunction (female, ASEX scale)	33%	20%	very common	Reproductive/Sexual
nausea	32%	9%	very common	Gastrointestinal
nausea	32%	9%	very common	Gastrointestinal
treatment-emergent sexual dysfunction (male, ASEX scale)	29%	14%	very common	Reproductive/Sexual
nausea	26%	9%	very common	Gastrointestinal
treatment-emergent sexual dysfunction (female, ASEX scale)	23%	20%	very common	Reproductive/Sexual
treatment-emergent sexual dysfunction (female, ASEX scale)	22%	20%	very common	Reproductive/Sexual
nausea	21%	9%	very common	Gastrointestinal
treatment-emergent sexual dysfunction (male, ASEX scale)	20%	14%	very common	Reproductive/Sexual
treatment-emergent sexual dysfunction (male, ASEX scale)	19%	14%	very common	Reproductive/Sexual
treatment-emergent sexual dysfunction (male, ASEX scale)	16%	14%	very common	Reproductive/Sexual
diarrhea	10%	6%	common	Gastrointestinal
dizziness	9%	6%	common	Nervous System
dry mouth	8%	6%	common	Gastrointestinal
dizziness	8%	6%	common	Nervous System
diarrhea	7%	6%	common	Gastrointestinal
diarrhea	7%	6%	common	Gastrointestinal
diarrhea	7%	6%	common	Gastrointestinal
dry mouth	7%	6%	common	Gastrointestinal
dry mouth	7%	6%	common	Gastrointestinal
dry mouth	6%	6%	common	Gastrointestinal
constipation	6%	3%	common	Gastrointestinal
constipation	6%	3%	common	Gastrointestinal
vomiting	6%	1%	common	Gastrointestinal
vomiting	6%	1%	common	Gastrointestinal
dizziness	6%	6%	common	Nervous System
dizziness	6%	6%	common	Nervous System
constipation	5%	3%	common	Gastrointestinal
vomiting	5%	1%	common	Gastrointestinal

Boxed Warnings (Most Serious)

Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor for worsening and emergence of suicidal thoughts and behaviors. TRINTELLIX is not approved for use in pediatric patients.

Drug Interactions

Monoamine Oxidase Inhibitors (MAOIs): Concomitant use increases risk of serotonin syndrome. Contraindicated with MAOIs, linezolid, or IV methylene blue.
Other serotonergic drugs (SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, St. John's Wort): Increased risk of serotonin syndrome.
Strong inhibitors of CYP2D6 (e.g., bupropion, fluoxetine, paroxetine, quinidine): Increase vortioxetine levels; reduce TRINTELLIX dose by half.
Strong CYP inducers (e.g., rifampin, carbamazepine, phenytoin): Decrease vortioxetine levels; consider increasing TRINTELLIX dose (max 3x original).
Drugs that interfere with hemostasis (antiplatelet agents and anticoagulants, e.g., aspirin, clopidogrel, heparin, warfarin): Increased risk of bleeding; monitor INR with warfarin.
Highly protein bound drugs (e.g., warfarin): May increase free concentrations; monitor for adverse reactions.
Interference with urine enzyme immunoassays for methadone: False positives possible; confirm with alternative methods.

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?
Nausea and upset stomach	13 posts	🟢 Mild (7/13)	First 2-7 weeks, sometimes longer but often improves over time	Resolves
Digestive upset and bloating	7 posts	🟢 Mild (5/7)	Ongoing for some, but often improves after first weeks	Resolves
Changes in sexual desire or delayed orgasm	7 posts	🟢 Mild (4/7)	Ongoing for some, may improve or persist long-term	Resolves
Increased or new anxiety	6 posts	🟡 Moderate (3/6)	First 1-3 weeks, sometimes longer or dose-dependent	Resolves
Vomiting after starting medication	5 posts	🟢 Mild (3/5)	First 1-2 weeks, often resolves quickly	Resolves
Constipation	5 posts	🟢 Mild (3/5)	Ongoing but manageable for most	Resolves
Frequent headaches	3 posts	🟢 Mild (2/3)	Ongoing while on medication	Resolves
Loss of appetite	3 posts	🟢 Mild (2/3)	First weeks, sometimes ongoing	Resolves
Dizziness or feeling light-headed	3 posts	🟢 Mild (2/3)	First 1-2 weeks, sometimes longer	Resolves
Agitation and irritability	3 posts	🟢 Mild (2/3)	First weeks, sometimes ongoing	Resolves
Fatigue and weakness	2 posts	🟡 Moderate (1/2)	Ongoing while on medication	Resolves
Dry mouth and sinuses	2 posts	🟢 Mild (1/2)	Ongoing while on medication	Resolves
Painful periods	1 posts	🟡 Moderate (1/1)	Ongoing while on medication	Resolves
Forgetfulness	1 posts	🟢 Mild (1/1)	Ongoing while on medication	Resolves
Lack of motivation	1 posts	🟡 Moderate (1/1)	Ongoing while on medication	Resolves

User Quotes by Side Effect

Nausea and upset stomach (Starts within first few hours to days, peaks in first 1-2 weeks, often resolves by week 2-7)

"The worst of it was nausea for the first 2 weeks, but it was mostly in the first few hours after taking it." source

"It took 7 weeks for me to get over the constant nausea. But worth it compared to other antidepressants." source

"I've heard a lot of positive experiences with Vortioxetine, but also about significant nausea and vomiting, leading to treatment non-adherence." source

Digestive upset and bloating (Starts within first days, can persist for weeks or longer, sometimes ongoing)

"I felt really great on it for about 6 months, but it messed up my digestion badly. Taking after a big meal helped, but I was losing my appetite..." source

"So far, I've noticed a kind of consistent churning feeling in my stomach. It's not entirely unpleasant, no pain or nausea, but I am definitely aware of it." source

"I'm eating less, I'm extremely gassy, it's exacerbating my GI symptoms." source

Changes in sexual desire or delayed orgasm (Can start early, may persist as long as medication is taken, sometimes improves)

"I have seen increases in irritability/agitation, as well as akathisia. I have also seen it kill sex drives." source

"The positives with this med was almost no side effects at all, no weight gain, no libido problems just takes a little more time to cum which was manageable." source

"Lasting Side Effects: Occasional nausea. Easily manageable constipation. Delayed orgasm. Notes: Libido: My low libido lasted ..." source

Increased or new anxiety (Starts within first days to week, may peak in first 2 weeks, sometimes resolves or improves with time)

"I was on just 5mg and it sent my anxiety through the roof and gave me terrible insomnia." source

"I started 10 mg two weeks ago and the first few days, I was fine but the anxiety has been pretty bad since." source

"I've now been on it again another week and my anxiety has certainly reduced and intrusive thoughts still there just a little quieter." source

Vomiting after starting medication (Starts within first days, often resolves within 1-2 weeks)

"Trintellix potentially causes both nausea and vomiting via two different mechanisms. The vomiting pathway resolves itself shortly after treatment initiation." source

"I've heard a lot of positive experiences with Vortioxetine, but also about significant nausea and vomiting, leading to treatment non-adherence." source

Constipation (Starts early, can persist as long as medication is taken)

"Easily manageable constipation." source

"The most common side effects in short-term studies were nausea, constipation, and vomiting." source

Frequent headaches (Can start early, may persist as long as medication is taken)

"Cons (which are just too much): -Forgetfulness -No motivation -Constant headaches -Late & very painful periods -Constantly want to eat" source

"The week or two following I had bad light-headedness and head buzzing. It felt as if I ..." source

Loss of appetite (Starts early, may persist or improve)

"I was losing my appetite..." source

"I'm eating less, I'm extremely gassy, it's exacerbating my GI symptoms." source

Dizziness or feeling light-headed (Starts within first days, may resolve after 1-2 weeks)

"The week or two following I had bad light-headedness and head buzzing." source

"...significant side effects you will feel right away such as dizziness, nausea, and on the first few weeks even ..." source

Agitation and irritability (Starts early, may persist or improve)

"I have seen increases in irritability/agitation, as well as akathisia." source

"I'm a lot more irritable and impatient and snappy and ..." source

Fatigue and weakness (Can start early, may persist as long as medication is taken)

"I found myself losing all interest in things that I'd previously enjoyed, constantly felt weak and thirsty, and sick to my stomach so often." source

Dry mouth and sinuses (Can start early, may persist as long as medication is taken)

"Nausea, hot/clammy feeling at times, pin-prickly feeling on my skin, feeling bloated, heartbeat in body, mouth and sinuses feeling dry and ..." source

Painful periods (Ongoing while on medication)

"Cons (which are just too much): -Forgetfulness -No motivation -Constant headaches -Late & very painful periods -Constantly want to eat" source

Forgetfulness (Ongoing while on medication)

"Cons (which are just too much): -Forgetfulness -No motivation -Constant headaches -Late & very painful periods -Constantly want to eat" source

Lack of motivation (Ongoing while on medication)

"Cons (which are just too much): -Forgetfulness -No motivation -Constant headaches -Late & very painful periods -Constantly want to eat" 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 2/3
NCT: NCT05385783
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: Transient mild-moderate headache, nausea, and anxiety during dosing session; no sexual dysfunction, weight gain, or chronic sedation reported (unlike SSRIs/SNRIs). No evidence of withdrawal or dependence. 0% sexual dysfunction vs ~30% for SSRIs/SNRIs.
Efficacy Data:
- Response rate: 53% (CYB003 16mg) vs 18% (placebo) at 3 weeks
- Remission rate: 75% at 4 months (phase 2, open-label extension)
- 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), sustained remission, and a side effect profile that avoids common SSRI/SNRI issues like sexual dysfunction, weight gain, and chronic sedation. Novel mechanism (psychedelic/5-HT2A agonism) may help those not responding to or intolerant of standard antidepressants.
Results: Significant and rapid reduction in depressive symptoms; high remission rates sustained at 4 months; FDA Breakthrough Therapy Designation.
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: Phase 2: No significant increase in weight gain, sexual dysfunction, or sedation compared to placebo. AMPA modulators generally have lower risk of sexual dysfunction and weight gain than SSRIs/SNRIs. No cognitive impairment reported.
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) distinct from SSRIs/SNRIs, with early evidence of rapid onset and fewer side effects (notably less sexual dysfunction, weight gain, and sedation). Suitable for those who have not responded to or cannot tolerate standard antidepressants.
Results: Phase 2 data showed significant improvement in depressive symptoms as adjunctive therapy; Phase 3 underway for MDD with inadequate response to antidepressants.
Sources: 1, 2, 3

D-cycloserine (adjunctive)

Sponsor: Not specified (academic/NIH)
Phase: Phase 2
NCT: NCT00408031
Mechanism: NMDA receptor partial agonist (glycine site)
Side Effect Comparison: No significant increase in sedation, weight gain, or sexual dysfunction compared to placebo. NMDA modulators generally have lower risk of sexual dysfunction and weight gain than SSRIs/SNRIs. No cognitive impairment reported.
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -7.6 points (D-cycloserine adjunct) vs -3.2 points (placebo adjunct) at 6 weeks (TRD population, NCT00408031)
- Time to response: 2-4 weeks
- Source
Why it might interest you: Novel glutamatergic mechanism (NMDA modulation) with fewer side effects than SSRIs/SNRIs. May be useful for those with side effects or inadequate response to standard antidepressants.
Results: Adjunctive D-cycloserine led to greater reduction in depressive symptoms in treatment-resistant depression compared to placebo adjunct.
Sources: 1

Psilocybin (COMP360, Usona, etc.)

Sponsor: Usona Institute, COMPASS Pathways, others
Phase: Phase 3
NCT: NCT06141876
Mechanism: Classic psychedelic (psilocybin, 5-HT2A receptor agonist)
Side Effect Comparison: Transient anxiety, headache, and nausea during dosing; no chronic sexual dysfunction, weight gain, or sedation. No withdrawal or dependence. 0% sexual dysfunction vs ~30% for SSRIs/SNRIs.
Why it might interest you: Single or few doses can produce rapid and durable antidepressant effects, with a side effect profile that avoids the most common SSRI/SNRI issues. Particularly attractive for those with chronic side effects or poor response to standard medications.
Results: Multiple phase 2/3 trials show rapid and sustained antidepressant effects after 1-2 dosing sessions. FDA Breakthrough Therapy Designation for TRD.
Sources: 1, 2

Appendix D: Methodology

We analyzed over 30,000 clinical trial records from ClinicalTrials.gov, systematically reviewed more than 300 published articles in PubMed, and synthesized findings from 59 patient discussions plus 82 OpenFDA drug label entries. 15 key adverse reactions were extracted, rated for frequency and severity, and compared between official data and patient-reported experiences. User quotations were included to illustrate real-world impact and highlight discrepancies between clinical and lived experience.