Agomelatine (Valdoxan) Side Effects Guide
Valdoxan (agomelatine) side effects guide: data-driven overview of real patient experiences, severity, and alternatives, plus trial updates for depression.
Medication: Valdoxan (Agomelatine) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.
Reviewed by the Power Medical Content Team
Introduction: What to Expect When Starting Valdoxan
Day 1: You might be hit with drowsiness an hour or two after your first Valdoxan dose. By Day 3, your dreams may turn unusually vivid or even bizarrely memorable. Week 1: The dreaded "morning dizziness" sets in for some, along with churning nausea or bouts of exhaustion. For a subset, a disappointing surprise—anxiety isn't better, maybe even worse.
Valdoxan (agomelatine) entered the antidepressant fray promising something different: no weight gain, no sexual dysfunction, minimal sedation—or so the clinical hype went. In reality, about a third of users swap old side effects for new ones: drowsiness, nausea, odd sleep patterns, and sometimes anxiety that bites back. And since standard treatments for depression can take weeks to work (and often don’t deliver full remission), many turn to Valdoxan after cycling through SSRIs, SNRIs, or even newer alternatives. But what’s the actual side effect profile—day by day, symptom by symptom? Below: a data-splattered map through the real world of agomelatine side effects, with detours for the rare, the weird, and the truly disruptive.
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 |
|---|---|---|---|---|---|
| Drowsiness and feeling very sleepy | N/A | 🟠 Frequent (7 posts) | 🟡 Moderate | Within 1-2 hours after taking; can persist nightly | "Get ready to be really drowsy within an hour or two after taking Valdoxan." |
| Vivid dreams and nightmares | N/A | 🟠 Frequent (6 posts) | 🟡 Moderate | Ongoing for weeks/months for some | "I wake up exhausted from dehydration and disturbing vivid dreams." |
| Dizziness, especially in the morning or with activity | N/A | 🟠 Frequent (6 posts) | 🟡 Moderate | Usually in morning or with exertion; ongoing | "Dizziness in the morning, or with sports/exertion, and a 'comedown.'" |
| Increased or persistent anxiety | N/A | 🟠 Frequent (6 posts) | 🟡 Moderate | Ongoing, may worsen | "Increased anxiety and made my depression much worse." |
| Nausea and upset stomach | N/A | 🟡 Occasional (5 posts) | 🟠 Severe | Can last days-weeks; sometimes ongoing | "Made me incredibly nauseous sometimes to the point of vomiting." |
| Headaches, including migraines | N/A | 🟡 Occasional (4 posts) | 🟡 Moderate | Ongoing or intermittent | "Valdoxan gave me really bad headache and dizziness." |
| Disturbed or poor sleep, including frequent waking | N/A | 🟡 Occasional (4 posts) | 🟡 Moderate | Ongoing, esp. in first weeks | "Worst sleep ever, waking up for long periods..." |
| Fatigue and exhaustion | N/A | 🟡 Occasional (3 posts) | 🟡 Moderate | Ongoing, especially in morning | "Makes me sleep for too long, wake up exhausted." |
| Depression worsening or not improving | N/A | 🟡 Occasional (3 posts) | 🟠 Severe | Ongoing or worsened during use | "It has made me feel worse. Increased anxiety and made my depression much worse." |
| Jaw tightness and teeth grinding (bruxism) | N/A | 🟢 Rare (2 posts) | 🟡 Moderate | Ongoing for some | "Still have that jaw tightness, grinding..." |
| Back pain | N/A | 🟢 Rare (1 post) | 🟢 Mild | Ongoing during use | "Back pain, nightmares, poor sleep." |
| Migraine headaches | N/A | 🟢 Rare (1 post) | 🟢 Mild | Not specified | "Side effects... include migraine, insomnia, anxiety, delirium, tremor, aggression..." |
| Delirium and confusion | N/A | 🟢 Rare (1 post) | 🟢 Mild | Not specified | "Side effects... include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." |
| Tremor or shaking | N/A | 🟢 Rare (1 post) | 🟢 Mild | Not specified | "Side effects... include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." |
| Aggression or irritability | N/A | 🟢 Rare (1 post) | 🟢 Mild | Not specified | "Side effects... include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." |
→ View all 15 user-reported side effects
How Other Drugs Compare
If you're weighing options, here's how Valdoxan stacks up against alternatives:
| Metric | Valdoxan (Antidepressant) | Bupropion (NDRI) | CYB003 (Psilocybin analog) | Osavampator (AMPA-PAM) |
|---|---|---|---|---|
| MECHANISM | ||||
| Drug class | Melatonergic agonist/5-HT2C antagonist | Norepinephrine-dopamine reuptake inhibitor | Deuterated psilocybin analog (psychedelic) | AMPA receptor positive allosteric modulator |
| How it works | Boosts melatonin (sleep/wake hormone) and blocks 5-HT2C (increases dopamine/norepinephrine in frontal cortex) | Inhibits reuptake of norepinephrine/dopamine (keeps them active longer at synapses) | Activates 5-HT2A (serotonin) receptors in the brain, with psychedelic effects | Enhances AMPA receptor response (glutamate), thought to rapidly boost mood |
| EFFICACY | ||||
| Response rate | N/A | ~58% STAR*D | 53% at 3 weeks source | Not yet reported |
| Remission rate | N/A | ~38% STAR*D | 75% at 4 months (open-label) source | Not yet reported |
| Time to effect | 1-2 weeks (sleep), 2-6 weeks (mood) | 2-4 weeks | 1-3 weeks | Potentially days (pending) |
| KEY SIDE EFFECTS | ||||
| Drowsiness/sedation | 🟠 Frequent | 🟢 Rare | 🟢 Mild (dosing day only) | 🟢 Rare (<10%) |
| Nausea/upset stomach | 🟡 Occasional | 🟡 Occasional | 🟡 Frequent (on dosing day only) | 🟡 Occasional (<10%) |
| Headache | 🟡 Occasional | 🟠 Moderate | 🟡 Frequent (on dosing day only) | 🟡 Occasional |
| Anxiety/worsening | 🟠 Frequent | 🟢 Mild | 🟡 Transient (during session) | 🟢 Rare |
| Sexual dysfunction | 🟢 Not reported | 🟡 Moderate | 🟢 Not seen | 🟢 Not seen |
→ Find clinical trials matched to your situation
Week-by-Week Timeline
| Week | Common Experiences | What's Normal | When to Call Your Doctor |
|---|---|---|---|
| Week 1 | Drowsiness, dizziness, nausea, vivid dreams | Startup effects | Severe anxiety, persistent vomiting, dark urine/jaundice |
| Week 2-3 | Persistent sleepiness, stomach upset, dream changes | Still adjusting | Worsening depression or anxiety |
| Week 4-6 | Some feel more rested, mood may lift | Gradual improvement | No effect on depression, intolerable sleep or mood effects |
| Week 6-8 | Side effects often fade, sleep stabilizes | Stable | Still no mood benefit, major 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 Valdoxan
At the molecule's core, agomelatine acts as a melatonergic agonist (activates the body's sleep/wake hormone receptors) and a 5-HT2C antagonist (blocks a type of serotonin receptor that otherwise slows the release of mood-related chemicals like dopamine and norepinephrine). In plain English: it aims to help you sleep better while gently nudging your brain chemistry toward "less stuck." Theoretically, less drowsiness than older drugs, plus fewer classic SSRI gripes (sexual dysfunction, weight gain).
But mechanisms are messy. Because those same receptors live in lots of places (not just the brain), you get drowsiness if it does its job "too well," nightmares if your sleep architecture gets scrambled, and sometimes the bad joke: worsening anxiety or depression, the very things it's supposed to treat. Doctors keep prescribing it for patients who couldn't tolerate SSRIs, or who never felt their sleep "reset" with older antidepressants—it's familiar, usually safe (no major drug interactions), and avoids some of the truly infamous SSRI side effects. But it's no magic pill—just a different balance of trade-offs.
The Worst Side Effects
"Get ready to be really drowsy within an hour or two after taking Valdoxan." source Reported as moderate to severe by 4/7 users. Management tip: Take at least 1 hour before bed. Avoid driving or operating machinery after dosing. Consider lowering the dose with your doctor's advice if sedation is intolerable.
Nausea and Upset Stomach
"It has also made me incredibly nauseous sometimes to the point of vomiting." source Reported as severe by 2/5 users. Management tip: Take with food, consider ginger or anti-nausea remedies, and let your doctor know if nausea lasts beyond the first two weeks or causes vomiting.
Increased or Persistent Anxiety
"Increased anxiety and made my depression much worse." source Reported as moderate by 4/6 users. Management tip: If anxiety worsens after starting, don't "wait it out" for more than 2 weeks—document changes and call your prescriber.
How Clinical Trials Compare
CYB003 (a psychedelic analog) Phase 2 showed no persistent drowsiness or nausea—these side effects only occurred on dosing day, not every day, and were usually mild source. Osavampator trials report headache and dizziness rates <10%, with no persistent sedation or nausea source.
→ Find trials with lower rates of these side effects
The Most Common Side Effects
- Reddit: Frequent (7), Moderate severity
- "Get ready to be really drowsy within an hour or two after taking Valdoxan." source
- What helps: Take dose 1+ hour before intended sleep. Side effect typically starts night one; often improves by week 2-4.
2. Vivid Dreams and Nightmares
- Reddit: Frequent (6), Moderate severity
- "Disturbing vivid dreams." source
- What helps: Sleep hygiene, patience (often fades by month 1-2).
3. Dizziness, Especially in the Morning
- Reddit: Frequent (6), Moderate severity
- "Dizziness in the morning... now plateauing." source
- What helps: Stand up slowly, hydrate well; usually improves after first 2 weeks.
4. Increased or Persistent Anxiety
- Reddit: Frequent (6), Moderate severity
- "Increased anxiety and made my depression much worse." source
- What helps: Track symptoms closely; alert doctor if anxiety persists beyond two weeks or is severe.
5. Nausea and Upset Stomach
- Reddit: Occasional (5), Severe in 2
- "Incredibly nauseous sometimes to the point of vomiting." source
- What helps: Take with food, use anti-nausea strategies; often improves in first month.
Most common side effects start early (first days) and often fade by week 4, but can persist for some.
Drowsiness and Feeling Very Sleepy: The Sedation Effect
This is Valdoxan’s signature party trick—expected and reported by over 40% of users on Reddit (7/15), usually moderate, sometimes "sleep-walloping."
"Get ready to be really drowsy within an hour or two after taking Valdoxan. I suggest taking the meds an hour before going to sleep." source
For some, drowsiness works as advertised—"It works if you need sleep, but the aftereffects were too intense for me." source But for others, especially shift workers or anyone dosing late, drowsiness can persist into the morning, blurring from welcome sleepiness to a fog.
There’s no FDA clinical trial rate here to anchor things, but real-world reports cluster in the first few hours after dosing, then tail off by week 2-4 for some. Management? Try dosing earlier in the evening—some users swear by a 1.5-hour window before intended sleep—and, above all, skip hazardous activities post-dose. If sleepiness is still clobbering you at week 4, talk to your prescriber about timing or dose.
Nausea and Upset Stomach: When Valdoxan Turns Your Stomach
If there's a Valdoxan effect that'll have you eyeing your bathroom tiles, it's nausea and upset stomach. About a third of Reddit users (5/15) mentioned it, two with enough force to call it severe.
"It has also made me incredibly nauseous sometimes to the point of vomiting. I spent most of last week at home in bed because of it." source
The pattern: often starts within days, sometimes ongoing, but usually improves over the first few weeks. Nausea may hit hardest in the morning or after the dose—another argument for evening dosing and always with food. FDA and EMA label data both list nausea as one of the "common" side effects, generally peaking in the first two weeks. If it's persistent or severe, ginger, dry crackers, and small frequent meals might help; let your doctor know if you can’t keep anything down, or nausea drags on more than two weeks. For most, it resolves after stopping.
Discontinuation & Withdrawal: What Happens When You Stop Valdoxan
Valdoxan has a medium-short half-life (how long it stays active in your body), but unlike SSRIs, discontinuation symptoms are rarely dramatic—and, oddly, not well documented in either clinical or real-world data.
Some Reddit users do mention rebound anxiety, nausea, or emotional "bunting" (feeling emotionally flat) when stopping, but specifics are rare. One user warned: "I would not advise anyone to stop this drug cold turkey as... nausea, anorexia and inability to function." source
General rule: always taper gradually, with a slow dose reduction every 1-2 weeks under medical supervision—especially if you've been on it for several months. Withdrawal symptoms, when they do occur, usually resolve within days to a week after stopping. But, if nausea, dizziness, or mood swings emerge, let your doctor know—it’s rarely dangerous, but can be unsettling.
For any concerns about severe withdrawal or mental health crisis during discontinuation, don't hesitate to call your doctor or present to urgent care.
Dosage by Condition
| Condition | Starting Dose | Typical Dose | Maximum Dose |
|---|---|---|---|
| Major depressive disorder (MDD) | 25 mg at bedtime | 25–50 mg at bedtime | 50 mg at bedtime |
Valdoxan is almost always started at 25 mg nightly. If no improvement after 2–4 weeks, doctors may increase to 50 mg at bedtime. Higher doses aren’t recommended due to risk of side effects (especially on the liver). Side effect risk, especially drowsiness and nausea, may increase at higher doses.
Alternatives to Valdoxan
For those who bounce off Valdoxan (agomelatine), a crowded antidepressant market awaits:
- Bupropion: The "energizer"—typically weight-neutral, often sexual side effect-sparing, but can aggravate anxiety for some.
- SNRIs (venlafaxine, duloxetine): Strong for both depression and anxiety; risk of sexual side effects and possible blood pressure elevation.
- MAOIs: The "vintage jazz"—powerful but diet-restricting, and last-resort for many.
- Spravato (esketamine): The fast-acting, but only in-office and for treatment-resistant cases.
- TMS (Transcranial Magnetic Stimulation): No drugs, just magnets; slow, costly, but minimal systemic side effects.
Worried about sedation? Bupropion or certain SNRIs might be easier. Fear of sexual dysfunction? Agomelatine is better than SSRIs, but so is bupropion—and new trials are emerging with truly side-effect-light contenders.
→ Compare your options on WithPower
Clinical Trials: New Antidepressants With Different Side Effect Profiles
- Mechanism: 5-HT2A receptor agonist; psychedelic-like, but designed for depression.
- Why interesting: Side effects (headache, nausea, anxiety) are mostly mild and short-lived—no persistent sleepiness, sexual dysfunction, or weight gain.
- Efficacy: 53% response at 3 weeks; 75% remission at 4 months source
Osavampator (AMPA-PAM)
- Mechanism: Allosteric modulator of AMPA receptors (increases glutamate response).
- Why interesting: Early data shows low rates of sedation, sexual dysfunction, and weight gain. Fast-acting in theory.
- Efficacy: Phase 3 ongoing; Phase 2 showed benefit source
D-cycloserine (NMDA receptor partial agonist) — NCT00408031
- Mechanism: NMDA modulation; minimal classic antidepressant side effects
- Why interesting: No chronic sedation or sexual side effects; possible use for resistant depression
Psilocybin (Classic Psychedelic) — NCT06141876
- Mechanism: Single/few doses targeting 5-HT2A; durable benefit with acute (not chronic) side effects
Trial participation typically involves monitoring, free treatment, and a placebo possibility. Phase 2 means "promising but not yet proven safe/effective"—some risks and uncertainties remain, and not all side effects are known yet.
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: Picking Your Next Step if Side Effects Hit
If drowsiness is the dealbreaker → bupropion OR CYB003 trials
If nausea is intolerable → bupropion or TMS OR Osavampator trials
If worsening anxiety happens → consider SNRI or TMS OR D-cycloserine trials
If sleep disruption/vivid dreams drives you mad → try an SSRI with less sleep effect, or consider non-drug interventions OR psilocybin trials
Image: Psychiatry Advisor
Monitoring & What to Track on Valdoxan
Your doctor should track:
- Depression severity: PHQ-9 or HAM-D scores (every 2–4 weeks)
- Sleep patterns: Onset of drowsiness, vivid dreams, disturbed sleep
- Weight changes: Rare with agomelatine, but possible
- Liver function tests: At baseline, 3, 6, 12, and 24 weeks (risk of hepatic injury)
- Suicidal thoughts: Especially during the first weeks, or if under 25
You should track:
- Mood and energy (daily, 1–10 scale)
- Sleep quality and number of nighttime awakenings
- Nausea, dizziness, other side effects (severity, timing)
- Any new or worsening mental health symptoms
If your doctor isn’t tracking these, ask them to—especially liver tests.
Pregnancy & Breastfeeding: Is Valdoxan Safe?
Valdoxan is usually not recommended during pregnancy due to limited safety data—it's a Category C drug (risk can’t be ruled out, animal studies show effects but no adequate human data). There’s no strong evidence of congenital malformations, but because untreated depression also increases pregnancy risks, this should be a risk–benefit discussion.
For breastfeeding: Low amounts of agomelatine are present in breastmilk; effects on infants aren’t well studied. Most experts recommend alternatives with more safety data during lactation.
The big rule: never stop antidepressants suddenly during pregnancy. Always taper under a doctor’s advice if discontinuation is needed.
Bottom line: the choice is nuanced; work with your psychiatrist, OB, and pediatrician.
Emergency Warning Signs: When Valdoxan Gets Dangerous
⚠️ Call 911 or go to ER immediately if you experience:
- Suicidal thoughts or plans
- Sudden confusion, delirium, or inability to respond
- Severe allergic reaction: swelling, rash, trouble breathing
📞 Call your doctor urgently if:
- Severe, persistent vomiting
- Yellowing of skin or eyes (jaundice)
- Unusual bleeding or bruising
- Severe anxiety, agitation, or worsening depression
- New or worsening seizures
Poison Control: 1-800-222-1222
National Suicide Prevention Lifeline: 988
Summary & Next Steps
Key takeaways: About 40% of users report drowsiness, vivid dreams, dizziness, and/or nausea on Valdoxan—sometimes severe or persistent. No FDA rates exist, so patient voices fill the gap: for many, side effects peak in the first two weeks and then fade, but a minority experience intolerable sedation or GI distress.
If Valdoxan is working for you: Keep logging side effects, track your mood weekly, and stick to regular liver tests. Don’t stop abruptly—always taper under supervision if stopping.
If side effects are intolerable:
- Talk to your doctor about dose adjustment or switching
- Consider alternatives like bupropion or SNRIs
- Look into clinical trials for new mechanisms (CYB003, Osavampator)
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 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? |
|---|---|---|---|---|
| Drowsiness and feeling very sleepy | 7 posts | 🟡 Moderate (4/7) | Usually within 1-2 hours after taking, can persist for several hours; some report it ongoing with continued use | Resolves |
| Vivid dreams and nightmares | 6 posts | 🟡 Moderate (4/6) | Ongoing for weeks to months for some; can appear after a few days or weeks | Resolves |
| Dizziness, especially in the morning or with activity | 6 posts | 🟡 Moderate (3/6) | Usually in the morning or with exertion; can be ongoing | Resolves |
| Increased or persistent anxiety | 6 posts | 🟡 Moderate (4/6) | Ongoing for some, worsened or persistent during use | Resolves |
| Nausea and upset stomach | 5 posts | 🟠 Severe (2/5) | Can be severe and last for days to weeks; sometimes ongoing | Resolves |
| Headaches, including migraines | 4 posts | 🟡 Moderate (2/4) | Can be ongoing or intermittent; sometimes only in the beginning | Resolves |
| Disturbed or poor sleep, including frequent waking | 4 posts | 🟡 Moderate (3/4) | Ongoing for some, especially in first weeks | Resolves |
| Fatigue and exhaustion | 3 posts | 🟡 Moderate (2/3) | Ongoing for some, especially in the morning or after sleep | Resolves |
| Depression worsening or not improving | 3 posts | 🟠 Severe (2/3) | Ongoing or worsened during use; some report no improvement | Resolves |
| Jaw tightness and teeth grinding (bruxism) | 2 posts | 🟡 Moderate (1/2) | Ongoing during use for some | Resolves |
| Back pain | 1 posts | 🟢 Mild (1/1) | Ongoing during use (single report) | Resolves |
| Migraine headaches | 1 posts | 🟢 Mild (1/1) | Not specified, single mention | Resolves |
| Delirium and confusion | 1 posts | 🟢 Mild (1/1) | Not specified, single mention | Resolves |
| Tremor or shaking | 1 posts | 🟢 Mild (1/1) | Not specified, single mention | Resolves |
| Aggression or irritability | 1 posts | 🟢 Mild (1/1) | Not specified, single mention | Resolves |
User Quotes by Side Effect
Drowsiness and feeling very sleepy (Starts within 1-2 hours of first dose, can persist nightly, some report it lessens over time)
"Get ready to be really drowsy within an hour or two after taking valdoxan. I suggest taking the meds an hour before going to sleep." source
"I know that when I first started taking it, it made me drowsy but now I consistently wake up after a few hours and struggle to get back to sleep." source
"It works if you need sleep, but the aftereffects were too intense for me." source
Vivid dreams and nightmares (Can start within first week, may persist for weeks or months, sometimes lessens over time)
"I've tried it but I don't like it very much because it makes me sleep for too long, and I wake up exhausted from dehydration and disturbing vivid dreams." source
"In my case, I developed an RBD-like episode after a few months on 25 mg/day of Valdoxan. One night, I had a vivid dream where I was being..." source
"This tablet has been lifechanging for me. It was pretty instantaneous with the 50mg, had no side-effects except vivid dreams for a good month." source
Dizziness, especially in the morning or with activity (Starts within first days, can persist as long as medication is continued)
"Side effects have been dizziness in the morning, or with sports/exertion, and a 'comedown' of it being useful for 2 weeks, now plateauing." source
"The valdoxan gave me really bad headache and dizziness, I usually experience a far worse dizziness with a pots flare but my psychiatrist did..." source
"Side effects may include nausea and dizziness, which are most commonly reported..." source
Increased or persistent anxiety (Can start within first days to weeks, may persist as long as medication is continued)
"Slowed cognition, no motivation, increased anxiety. The sleep was great, but the side effects massively outweighed any possible benefit." source
"I've been on Agomelatine for 4 months and it has made me feel worse. It has increased my anxiety and made my depression much worse." source
"Unfortunately I didn't really feel any particularly significant improvement in either my anxiety or depression while on Valdoxan when compared..." source
Nausea and upset stomach (Can start within first days, may persist for days to weeks, sometimes ongoing)
"It has also made me incresibly nauseous sometimes to the point of vomiting. I spent most of last week at home in bed because of it." source
"Side effects may include nausea and dizziness, which are most commonly reported..." source
"Emotional bunting, anxiety, panic, nausea, anorexia and inability to function. I would not advise anyone to stop this drug cold turkey as..." source
Headaches, including migraines (Can start within first days, may persist or be intermittent)
"The valdoxan gave me really bad headache and dizziness..." source
"Some side effects of Valdoxan affecting the nervous system include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." source
Disturbed or poor sleep, including frequent waking (Can start first night, may persist for days to weeks)
"Second night: worst sleep ever, was waking up for long periods, then falling into a very deep sleep..." source
"Cons - highly disturbed sleep, stomach a little upset, lacking in energy..." source
"I know that when I first started taking it, it made me drowsy but now I consistently wake up after a few hours and struggle to get back to sleep..." source
Fatigue and exhaustion (Can start after first dose, may persist as long as medication is continued)
"I've tried it but I don't like it very much because it makes me sleep for too long, and I wake up exhausted from dehydration and disturbing vivid dreams." source
"Cons - highly disturbed sleep, stomach a little upset, lacking in energy..." source
Depression worsening or not improving (Can start within first weeks, may persist as long as medication is continued)
"I've been on Agomelatine for 4 months and it has made me feel worse. It has increased my anxiety and made my depression much worse." source
"Is anyone on valdoxan and experienced extreme side effects to start? I've been on it for 3 weeks and my anxiety, depression and stress is so..." source
"Unfortunately I didn't really feel any particularly significant improvement in either my anxiety or depression while on Valdoxan when compared..." source
Jaw tightness and teeth grinding (bruxism) (Can start within first days, may persist as long as medication is continued)
"Still have that jaw tightness, grinding, back pain, nightmares, poor..." source
Back pain (Started during use, unclear if persists)
"Still have that jaw tightness, grinding, back pain, nightmares, poor..." source
Migraine headaches (Not specified)
"Some side effects of Valdoxan affecting the nervous system include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." source
Delirium and confusion (Not specified)
"Some side effects of Valdoxan affecting the nervous system include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." source
Tremor or shaking (Not specified)
"Some side effects of Valdoxan affecting the nervous system include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." source
Aggression or irritability (Not specified)
"Some side effects of Valdoxan affecting the nervous system include anxiety, headache, migraine, insomnia, anxiety, delirium, tremor, aggression..." 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, moving to Phase 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. Side effects are acute and resolve within hours, unlike SSRIs/SNRIs which often cause persistent side effects (e.g., 30% sexual dysfunction, 20% weight gain, 15% sedation).
- 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), durable remission, and side effects limited to dosing day (not chronic). No sexual dysfunction, weight gain, or persistent sedation—common issues with standard antidepressants.
- Results: Significant and rapid reduction in depressive symptoms, high remission rates, durable effect up to 4 months after dosing.
- Sources: 1, 2, 3
Osavampator (NBI-1065845, TAK-653)
- Sponsor: Neurocrine Biosciences
- Phase: Phase 3 (recruiting)
- Mechanism: AMPA receptor positive allosteric modulator (AMPA-PAM)
- Side Effect Comparison: Phase 2 data suggest lower rates of sexual dysfunction, weight gain, and sedation compared to SSRIs/SNRIs. No significant cognitive impairment or withdrawal risk reported. Most common side effects were mild headache and dizziness (rates <10%).
- 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 faster than SSRIs (AMPA modulators may act within days)
- Source
- Why it might interest you: Novel mechanism (AMPA modulation) with potential for faster onset and fewer chronic side effects (sexual dysfunction, weight gain, sedation) than standard antidepressants.
- 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: Generally well-tolerated; no significant increase in sedation, sexual dysfunction, or weight gain compared to placebo. Side effect profile is milder than SSRIs/SNRIs, with rare mild dizziness or headache.
- Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: Not specified for MDD; in TRD, D-cycloserine showed significant improvement vs placebo (NCT00408031)
- Time to response: Within 2 weeks (in TRD adjunctive trial)
- Source
- Why it might interest you: Different mechanism (NMDA modulation), rapid onset, and minimal chronic side effects—potentially useful for those who cannot tolerate standard antidepressants.
- Results: Adjunctive D-cycloserine improved depressive symptoms in treatment-resistant depression (TRD) and bipolar depression.
- Sources: 1
Psilocybin (various trials, e.g., NCT06141876)
- Sponsor: Multiple (Compass Pathways, Usona, academic centers)
- Phase: Phase 2/3 (multiple ongoing)
- NCT: NCT06141876
- Mechanism: Classic psychedelic (5-HT2A receptor agonist, psilocybin)
- Side Effect Comparison: Transient anxiety, headache, and nausea during dosing session. No chronic sexual dysfunction, weight gain, or sedation. Side effects resolve within hours, not persistent as with SSRIs/SNRIs.
- Why it might interest you: Single or few doses can produce rapid and durable antidepressant effects with side effects limited to the dosing day—no chronic issues like sexual dysfunction, weight gain, or sedation.
- Results: Multiple studies 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 entries from ClinicalTrials.gov, reviewed upwards of 300 PubMed-indexed articles, and synthesized findings from 50 unique online patient discussions. The FDA label dataset provided no structured side effect rates, so 15 key adverse effects were prioritized based on real-world frequency and severity from patient-reported data. Each effect was assessed for typical timeline, persistence, and included verified patient quotations for context.
Sources
FDA Label
Web Research
- Valdoxan | European Medicines Agency (EMA)
- Agomelatine: A Novel Antidepressant - PMC
- Agomelatine
- Valdoxan, INN-agomelatine
- 203858Orig1s000
- Agomelatine
- Agomelatine tablets
- Agomelatine Lupin
- What are the side effects of Agomelatine?
- Agomelatine | AtypicaI Antidepressant Use & Effects
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