SSRI: Straight to the Synapse

Question 1

Fill in the blank: SSRIs prevent reuptake of serotonin in the ______.

  • A. Liver
  • B. Presynaptic neuron
  • C. Kidney
  • D. Postsynaptic neuron

Serotonin is implicated in neurological functions that regulate memory processing, sleep, cognition, and mood. 

This reuptake inhibition occurs immediately after SSRI initiation, but the true therapeutic benefit of SSRIs occurs on the scale of weeks, suggesting other mechanisms by which it treats depression including serotonin receptor modulation and in certain neuroprotective proteins, but research is ongoing. 

Who Benefits from Antidepressants?

Some reports suggest that the efficacy of antidepressant medications versus placebo may be overstated, possibly as a result of publication bias and less efficacy for mildly depressed patients; however, a 2012 research synthesis using complete longitudinal person-level data found that fluoxetine and venlafaxine were efficacious for major depression, in all age groups although more so in youth and adults compared with geriatric patients, and baseline severity was not significantly related to degree of treatment advantage over placebo.

Source: Gibbons et al. Arch Gen Psychiatry. 2012

Drug Names & Pharmacokinetics

6 FDA-approved SSRIs:

  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac)
  • Fluvoxamine (Luvox)
  • Paroxetine (Paxil)
  • Sertraline (Zoloft)


  • Absorbed in the GI tract; food does not affect absorption
  • Peak plasma levels in 1-8 hours
  • Half-life is approximately 20-30 hours
    • Exceptions: fluoxetine and fluvoxamine are closer to 2-3 days
  • Metabolized in the liver
  • Significant cytochrome inhibitors
    • Citalopram and escitalopram have less strong inhibition and are thus good choices when concerned for possible drug-drug interactions
    • Pro tip: Check out UpToDate or Lexacomp for potential drug-drug interactions!

Question 2

Which of these SSRI side-effects is most common?

  • A. Sexual dysfunction
  • B. Diarrhea
  • C. Stomach upset
  • D. Weight loss
Source: UpToDate

A 2004 phone survey of 401 Northern California Kaiser Permanente patients taking SSRIs for depression found that 86% reported at least one side effect and 55% reported at least one bothersome side effect. The most common bothersome side effects were sexual dysfunction and drowsiness, as below.

Source: Hu et al. J Clin Psychiatry. 2004

Adverse effects of SSRI

Suicidal Ideation

A few large trials (see below) led to the FDA’s black box warning on this topic: There is an increased risk of suicidal thinking/behavior in pts <25yo with depression and other psychiatric disorders who are on antidepressants [includes 32 drugs (!) from SEVERAL different categories: SSRIs, SNRIs, serotonin modulators (e.g. trazodone), TCAs, and MAOIs]

  • 2006 JAMA meta-analysis of 24 placebo-controlled trials in 4500 children/adolescents on 9 medications (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, bupropion, venlafaxine, nefazodone, mirtazapine) showed 2% increase in suicidal thoughts/behavior (4% vs 2% overall) but no actual suicides
  • 2007 JAMA meta-analysis of 27 placebo-controlled trials in 5300 children/adolescents on the same 9 medications as above showed 0.7% increase in suicidal thoughts/behavior; NNH = 143
  • 2012 Cochrane Review of 17 placebo-controlled trials in 3200 children/adolescents on same 9 medications as above showed 1.5% increase in suicidal thoughts/behavior [vs 6.8% rate of remission (i.e. rate of remission was 4.5x higher)]

Sexual Dysfunction

Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with SSRIs, although the mechanism remains unknown. 

A 2009 nested case-control study of over 1,400 Caucasian patients taking citalopram found that sexual dysfunction was quite common: 

  • Decreased libido: 54%
  • Difficulty achieving orgasm: 36%
  • Erectile dysfunction: 37%

However, there is no compelling evidence that sexual dysfunction persists after discontinuation of SSRI therapy. 

Management strategies: 

  • For patients with depression taking an SSRI who develop sexual dysfunction, consider trialing a 2-8 week period to see if spontaneous remission of dysfunction occurs.
  • Try reducing the SSRI dose. If depressive symptoms worsen or if sexual dysfunction persists and the patient is at the lowest therapeutic dose, then consider switching to an alternative antidepressant. 
  • If the patient has achieved at least moderate relief of depressive symptoms and sexual dysfunction is mild/moderate (i.e., impairment occurs less than half the time during sexual activity), then consider augmenting therapy with PDE-5 inhibitor or high-dose bupropion. 

Weight Gain

Short-term treatment for two to three months with SSRIs usually causes little or no weight change; however, short-term therapy is not clinically appropriate for most patients.

Although treatment with SSRIs for longer periods of time may result in weight gain, in some cases it is not clear if this is a true medication side effect or the result of recovery from depression and the reversal of undesired weight loss. 

  • Fluoxetine appears to be the most weight neutral (-0.2% to +0.9% gain in baseline body weight), followed by sertraline
  • Citalopram, escitalopram, fluvoxamine, and especially paroxetine all appear to be associated with weight gain

Prolonged QTc

SSRIs can prolong the QTc, but the clinical effect is often small. In a 2014 meta-analysis of 10 trials (n = 2599 patients) comparing SSRIs with placebo, SSRIs were associated with an increase in QTc of 6 milliseconds, and prolongation was dose-dependent.

Source: Beach et al. J Clin Psychiatry. 2014

Citalopram and escitalopram appear to be the worst offenders:

Source: Beach et al. J Clin Psychiatry. 2014
  • In 2011-12, the FDA limited citalopram to dosages of 40 mg daily or less (and 20 mg daily or less in those older than 60yo years and/or with hepatic impairment) because of the increased risk of QTc prolongation at higher doses. 

Teratogenic effects?

There is no clear data that SSRIs are harmful in pregnancy. Most studies indicate that SSRIs as a group are not major teratogens and are not associated with birth defects. 

Serotonin Syndrome

Serotonin syndrome is most often caused by interactions among multiple serotonergic agents, but can occur after initiating or increasing a single serotonergic drug, including SSRIs (but no clear difference in risk between SSRIs.)

Remember that there are MANY drugs that can precipitate serotonin syndrome: 

  • Increases release of serotonin:
    • Amphetamines (including dextroamphetamine, methamphetamine)
    • MDMA (ecstasy)
    • Amphetamine derivatives (including fenfluramine, dexfenfluramine, phentermine)
    • Cocaine
    • Mirtazapine
  • Impairs serotonin reuptake from the synaptic cleft into the presynaptic neuron:
    • Cocaine
    • MDMA (ecstasy)
    • Meperidine
    • Tramadol
    • Pentazocine
    • Dextromethorphan
    • SNRIs (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine)
    • Sibutramine
    • Bupropion
    • Serotonin modulators (nefazodone, trazodone, vilazodone, and vortioxetine)
    • Cyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine)
    • St. John’s wort (Hypericum perforatum)
    • 5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)
    • Cyclobenzaprine
    • Methylphenidate
    • Dexmethylphenidate
  • Inhibits serotonin metabolism by inhibition of MAO:
    • MAO inhibitors, nonselective (isocarboxazid, linezolid, phenelzine, Syrian rue [Peganum harmala, harmine], and tranylcypromine)
    • MAO-A inhibitors (methylene blue, moclobemide)
    • MAO-B inhibitors (rasagiline, safinamide, and selegiline)
  • Direct serotonin receptor agonists:
    • Buspirone
    • Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)
    • Ergot derivatives (including dihydroergotamine, ergotamine, methylergonovine)
    • Fentanyl
    • Lysergic acid diethylamide (LSD)
    • Lasmiditan
    • Lorcaserin
    • Metaxalone
  • Increases sensitivity of postsynaptic serotonin receptor:
    • Lithium

Question 3

What is the earliest amount of time that SSRIs start to show a therapeutic benefit when compared to placebo?

  • A. 1 day
  • B. 1 week
  • C. 1 month
  • D. 1 year

Considerations for SSRI treatment initiation: 

  • Review possible drug-drug interactions (e.g., other serotonergic meds?)
  • Review PMHx (e.g., known arrhythmia or conduction disease?)
  • Discuss possible side effects
  • Review family history (some predictive value if 1st degree relative had success with a particular SSRI)
  • Start at the lowest therapeutic dose

Question 4

In patients greater than 60yo, what baseline study should you consider obtaining before starting or up-titrating a patient on citalopram?

  • A. IGRA
  • B. SARS-CoV-2 PCR
  • C. ECG
  • D. UA

General principles of titration: 

  • Give ~4-6 weeks at initial dose to assess response and side effects, then slowly up-titrate from there
  • Subsequent dose increases can occur every 1-4 weeks up to max dose

Cross-tapering (usually over 1-2 weeks): 

  • SSRI to SSRI: switch to equivalent dose without taper
  • SSRI to SNRI: consider equivalent switch without taper if low-dose SSRI, but generally cross-taper if high-dose SSRI
  • SSRI to TCA: cross-taper
  • SSRI to other antidepressants (e.g., MAOIs or newer drugs): cross-taper


  • Rapid tapering or stopping cold-turkey should be avoided if possible
  • Discontinuation symptoms are typically withdrawal (i.e., agitation, anxiety, chills, diaphoresis, dysphoria, insomnia, irritability, myalgias, rhinorrhea, tremor, etc.)
    • Highest risk with paroxetine
    • Lowest risk with fluoxetine
  • Generally taper over 2-4 wks

Follow-Up Questions!

5. What organ is predominantly responsible for SSRI metabolism?

  • A. Kidneys
  • B. Liver
  • C. Depends on the SSRI
  • D. Spleen

6. Which of these SSRIs has the longest half-life?

  • A. Sertraline
  • B. Citalopram
  • C. Paroxetine
  • D. Fluoxetine

7. 1 week into starting an SSRI, your otherwise healthy patient starts to notice some therapeutic effect but also some decreased libido. The patient is asking for your advice. What should you advise?

  • A. Reassure and reassess side effects in a few weeks
  • B. Stop the SSRI now
  • C. Switch to another antidepressant class
  • D. Recommend a natural aphrodisiac such as pistachio nuts

8. An otherwise healthy patient is interested in starting SSRI therapy but wants to minimize the chances of gaining weight. Which medication do you recommend?

  • A. Paroxetine
  • B. Citalopram
  • C. Fluoxetine
  • D. Fluvoxamine

9. Which SSRI is associated with the highest degree of QTc prolongation?

  • A. Paroxetine
  • B. Citalopram
  • C. Fluoxetine
  • D. Fluvoxamine

10. Which medication change does not normally require a taper?

  • A. SSRI discontinuation
  • B. High-dose SSRI to SNRI
  • C. SSRI to SSRI
  • D. SSRI to MAOI

Blog post based on Med-Peds Forum talk by Fritz Siegert, PGY4

Answers: 1) Presynaptic neuron. 2) Sexual dysfunction. 3) 1 week. 4) ECG. 5) Liver. 6) Fluoxetine. 7) Reassure and reassess side effects in a few weeks. 8) Fluoxetine. 9) Citalopram. 10) SSRI to SSRI.

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