SSRIs and Serotonin Modulators
Selective serotonin reuptake inhibitors are the most prescribed antidepressants worldwide. Newer serotonin modulators expand options for treatment-resistant depression and anxiety disorders.
## Mechanism of Action
SSRIs selectively inhibit the serotonin transporter (SERT) at presynaptic nerve terminals, increasing serotonin (5-HT) concentration in the synaptic cleft. Despite rapid transporter blockade, clinical improvement takes 2-6 weeks -- a delay attributed to autoreceptor desensitization, downstream receptor changes, and neuroplasticity mechanisms involving BDNF upregulation.
## Available SSRIs
- **Fluoxetine** -- Longest half-life (1-3 days; active metabolite norfluoxetine: 4-16 days). Self-tapering on discontinuation. Potent CYP2D6 inhibitor.
- **Sertraline** -- Most serotonin-selective. Common first choice due to favorable drug interaction profile. Also a weak dopamine transporter inhibitor.
- **Escitalopram** -- S-enantiomer of citalopram with higher SERT affinity. Generally well-tolerated with minimal CYP inhibition.
- **Paroxetine** -- Most potent SERT inhibitor but also anticholinergic. Associated with more weight gain and withdrawal symptoms. Avoid in pregnancy (cardiac malformations).
- **Citalopram** -- QTc prolongation at doses >40 mg limits use in elderly patients (max 20 mg if age >60).
- **Fluvoxamine** -- Primarily used for OCD. Strong CYP1A2 and CYP2C19 inhibitor (interacts with caffeine, theophylline, warfarin).
## Clinical Uses
SSRIs are first-line for major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, OCD, PTSD, and premenstrual dysphoric disorder. Sertraline and escitalopram are the most commonly recommended first-line agents due to their efficacy-to-side-effect ratio.
## Adverse Effects
**Common:** Nausea (transient, 1-2 weeks), headache, insomnia or somnolence, sexual dysfunction (delayed ejaculation, anorgasmia in 30-50% of patients -- often the reason for discontinuation).
**Serotonin syndrome** -- A potentially fatal condition from excessive serotonergic activity. Risk increases with concurrent MAOIs, tramadol, linezolid, or triptans. Presents with hyperthermia, clonus, agitation, and autonomic instability.
**Discontinuation syndrome** -- Dizziness, paresthesias ("brain zaps"), irritability, and flu-like symptoms upon abrupt cessation. Most common with paroxetine and venlafaxine due to short half-lives. Fluoxetine rarely causes this.
**Hyponatremia** -- SIADH-mediated, particularly in elderly patients on diuretics. Monitor sodium in at-risk populations.
## Serotonin Modulators Beyond SSRIs
- **SNRIs** (venlafaxine, duloxetine) -- Block both serotonin and norepinephrine reuptake. Useful for depression with comorbid pain or when SSRIs are inadequate.
- **Vilazodone** -- SSRI plus 5-HT1A partial agonist. May cause less sexual dysfunction.
- **Vortioxetine** -- Multimodal: SERT inhibitor, 5-HT3 antagonist, 5-HT1A agonist, 5-HT7 antagonist. Shown to improve cognitive function in depression.
- **Trazodone** -- 5-HT2A antagonist and weak SERT inhibitor. More commonly used at low doses as a sleep aid than as an antidepressant.
## Key Takeaways
- SSRIs take 2-6 weeks for full clinical effect -- counsel patients on this delay.
- Sexual dysfunction is the leading cause of non-adherence; switching agents or adding bupropion can help.
- Always taper SSRIs gradually, except fluoxetine (self-tapering due to long half-life).
- Serotonin syndrome is a medical emergency -- avoid combining SSRIs with MAOIs or serotonergic drugs.