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Psychopharmacology book


Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the mainstay of treatment for depression, generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder (OCD). By blocking serotonin transporters (SERT), SSRIs keep serotonin in the extracellular space where it can continue to bind serotonin receptors. Although an SSRI blocks SERT immediately, antidepressant effects are generally not seen until 2 to 4 weeks of continuous treatment. Over time, increased extracellular availability of serotonin (5-HT) causes 5HT1A receptors to become desensitized to serotonin. 5HT1A receptors are located on the far end of the presynaptic neuron (not shown, a mile above this page). As desensitization occurs, serotonin stops inhibiting its own release, so serotonin flows more freely from the end of the presynaptic neuron shown below.  5HT1A receptor desensitization takes a few weeks, which correlates with onset of therapeutic effect. Anti-inflammatory effects of SSRIs may also contribute. Refer to Stahl’s Essential Psychopharmacology book for a full visual explanation.

SSRI mechanism by Dr Jason Cafer MD
SSRI mechanism from Psychopharmacology Book by Dr Jason Cafer MD

The main side effect leading to patients quitting their SSRI is sexual dysfunction. Unlike TCAs, SSRIs do not cause hypotension or major anticholinergic effects. Other than citalopram (Celexa), SSRIs do not cause significant cardiac conduction delays. SSRIs are initially associated with modest weight loss, which may be followed by modest weight gain with long-term use. SSRIs can cause hyponatremia (low serum sodium) secondary to inappropriate antidiuretic hormone secretion (SIADH) from the pituitary gland. 

SSRI chart sertraline zoloft lexapro escitalopram citalopram celexa fluoxetine prozac paxil paroxetine fluvoxamine luvox by Dr Jason Cafer MD

Information applicable to all SSRIs:


SSRIs block the serotonin reuptake pump. Onset of therapeutic effect is delayed 2–4 weeks. They start working when serotonin 5HT1A receptors become desensitized. Some patients experience immediate increased energy or unpleasant restlessness, which is more common with bipolar disorder. Side effects occur sooner than therapeutic effects and often improve over time—nausea, sweating, headache, and bruxism (teeth grinding). Sexual dysfunction is often problematic, and less likely than other side effects to improve with time. SSRIs may increase suicidal thoughts in individuals under age 24. 


Following resolution of a single depressive episode, the antidepressant should generally be continued for a year to consolidate recovery. For recurrent episodes, treatment may need to be continued indefinitely. SSRIs are safe and effective for long-term use, but some patients complain of feeling emotionally flat or “blah”, experiencing what has been described as SSRI-Induced Apathy Syndrome. SSRIs may cause a modest weight loss initially, and a modest weight gain with long-term use.


With bipolar individuals, SSRIs may cause “switching” to mania or destabilize mood over time. 


When abruptly discontinued, SSRIs may cause serotonin withdrawal symptoms including lightheadedness, "brain zaps", paresthesias, nausea, fatigue, and irritability. 


SSRIs may decrease serum sodium levels and impair platelet functioning, but risk of significant hyponatremia or bleeding is minimal. 

Uses of SSRIs

  • Depression

  • Anxiety 

  • Panic disorder (start low dose)

  • OCD (titrate to high dose)

  • Menopausal hot flashes

  • Somatoform disorders

  • Premature ejaculation

  • Premenstrual dysphoric disorder (PMS)


SSRI risks

  • GI bleed (inhibition of serotonin uptake by platelets)

  • Hyponatremia (low serum sodium)

  • Serotonin syndrome

  • Suicidality (under age 24)

  • Mania, destabilization of bipolar disorder


SSRI side effects

  • Sexual dysfunction (all, especially paroxetine)

  • Modest weight gain with long term use (especially paroxetine)

  • Insomnia (especially fluoxetine)

  • Nausea (short-lived)

  • Diarrhea (sertraline) or constipation (paroxetine)

  • Restlessness / dizziness (short-lived)

  • Bruxism (teeth grinding) which can improve with addition of buspirone (Buspar) 


FYI—Medications with the -oxetine suffix:

❖ Fluoxetine (Prozac) – SSRI
❖ Paroxetine (Paxil) – SSRI

❖ Duloxetine (Cymbalta) – SNRI

❖ Vortioxetine (Trintellix) – Serotonin modulator & stimulator (SMS)
❖ Atomoxetine (Strattera) – Norepinephrine reuptake inhibitor for ADHD

Copyright 2021 CaferMed Publishing

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