What are the commonly used serotonergic agents, including Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), in psychopharmacology?

Serotonergic Agents in Psychopharmacology

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the most extensively studied and widely used serotonergic agents in psychopharmacology, with proven efficacy across depression, anxiety disorders, and OCD. 1

Individual SSRI Agents

• Fluoxetine (Prozac) - FDA-approved SSRI with 30-fold selectivity for serotonin over norepinephrine reuptake inhibition 2
• Sertraline (Zoloft) - FDA-approved SSRI available in doses of 25-200 mg daily or situationally at 50 mg 1, 3
• Paroxetine (Paxil) - FDA-approved SSRI associated with higher discontinuation syndrome risk and increased suicidal thinking compared to other SSRIs; should generally be avoided in older adults 1
• Fluvoxamine - FDA-approved SSRI with greater potential for drug-drug interactions via multiple CYP450 pathways (CYP1A2, CYP2C19, CYP2C9, CYP3A4, CYP2D6) 1
• Citalopram (Celexa) - FDA-approved SSRI with least CYP450 interactions but contraindicated at doses exceeding 40 mg/day due to QT prolongation risk 1
• Escitalopram (Lexapro) - FDA-approved SSRI with minimal CYP450 interactions, preferred in older adults 1

Clinical Considerations for SSRIs

• SSRIs require 8-12 weeks at optimal dose to determine full efficacy, with statistically significant improvement by week 2 but clinically meaningful improvement not apparent until week 6 4
• All SSRIs carry risk of serotonin syndrome when combined with other serotonergic agents including MAOIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, dextromethorphan, and St. John's Wort 1, 3
• Common adverse effects include nausea, sexual dysfunction, behavioral activation/agitation, and discontinuation syndrome (particularly with paroxetine, fluvoxamine, and sertraline) 1

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs are slightly more effective than SSRIs for depression symptom improvement but have higher rates of adverse effects, particularly nausea and vomiting. 1, 5

Individual SNRI Agents

• Venlafaxine - SNRI with 30-fold selectivity for serotonin over norepinephrine; associated with dose-dependent hypertension and appears least well-tolerated within the SNRI class 6, 2
• Duloxetine (Cymbalta) - SNRI with 10-fold selectivity for serotonin over norepinephrine; effective for chronic pain and better tolerated than venlafaxine but has 40% higher discontinuation risk than SSRIs 1, 7, 2
• Milnacipran - SNRI with equal affinity for serotonin and norepinephrine reuptake; better tolerated than venlafaxine and devoid of cardiovascular toxicity 2

Clinical Considerations for SNRIs

• SNRIs require 2-4 weeks for efficacy onset, with optimal duration of 8-12 weeks to determine full therapeutic response 4
• All SNRIs carry risk of serotonin syndrome with concomitant serotonergic agents, orthostatic hypotension, falls, and syncope (particularly in geriatric patients) 6, 7
• SNRIs have demonstrated efficacy in chronic pain conditions independent of depression, unlike SSRIs 2

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are contraindicated with any other serotonergic drug due to severe serotonin syndrome risk and should be avoided in combination therapy. 1

MAOI Agents

• Phenelzine - Traditional MAOI with high serotonin syndrome risk 1
• Isocarboxazid - Traditional MAOI with high serotonin syndrome risk 1
• Moclobemide - Reversible inhibitor of monoamine oxidase A (RIMA) 1
• Linezolid - Antibiotic with MAOI properties; contraindicated with SSRIs and SNRIs 3, 6, 7
• Intravenous methylene blue - MAOI used in medical procedures (1-8 mg/kg IV); contraindicated with SSRIs and SNRIs 3, 6, 7

Tricyclic Antidepressants (TCAs) with Serotonergic Properties

• Clomipramine - Tricyclic antidepressant with serotonin reuptake inhibition effects; effective at 25-50 mg daily or situationally for premature ejaculation; requires 1-3 weeks for efficacy 1, 4

Other Serotonergic Agents

Atypical Antidepressants

• Combination olanzapine-fluoxetine - FDA-approved for bipolar depression in adults 1
• Vortioxetine - Classified as "other antidepressant" with serotonergic properties; one RCT demonstrated efficacy in social anxiety disorder 1

5-HT Receptor Agonists

• 5-HT1A partial agonists - Used extensively for depression and generalized anxiety disorder but equivocal efficacy in other anxiety disorders 8
• Buspirone - 5-HT1A partial agonist; can contribute to serotonin syndrome when combined with SSRIs or SNRIs 1, 3, 6, 7

Serotonin Antagonists

• 5-HT antagonists - Least well-studied class; may have activity in depression and potential use as adjuvants in treatment-refractory OCD 8
• Serotonin 2 antagonist and reuptake inhibitors (SARIs) - Limited evidence in social anxiety disorder 1

Critical Safety Warnings

All serotonergic antidepressants require monitoring for suicidality, especially during initial months of treatment and after dose changes, with particular vigilance in pediatric and young adult populations. 3, 6, 7

• Serotonin syndrome symptoms include mental status changes (confusion, agitation, hallucinations, coma), autonomic instability (tachycardia, hypertension, hyperthermia, diaphoresis), neuromuscular hyperactivity (tremor, clonus, hyperreflexia, rigidity), and can progress to seizures and death 1, 3, 6, 7
• Treatment requires immediate discontinuation of all serotonergic agents, hospital-based supportive care, and continuous cardiac monitoring 1
• A 14-day washout period is required when switching between MAOIs and SSRIs/SNRIs 3, 6, 7