Serotonin-norepinephrine reuptake inhibitors

Definition and Pharmacological Classification
Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of psychotropic medications that inhibit the reuptake of serotonin (5-HT) and norepinephrine (NE) in the central nervous system (CNS) by blocking their respective transporters (SERT and NET). This dual-action increases the synaptic concentration of these neurotransmitters, enhancing their mood-regulating, analgesic, and anxiolytic effects.

SNRIs are primarily used in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Unlike SSRIs, which are selective for serotonin, SNRIs affect both monoamine pathways, offering broader therapeutic benefits but with a distinct adverse effect profile.

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Mechanism of Action

SNRIs act by selectively inhibiting the presynaptic reuptake of:

• Serotonin (5-HT) via serotonin transporter (SERT)

• Norepinephrine (NE) via norepinephrine transporter (NET)

This leads to increased synaptic levels of these neurotransmitters, which:

• Improve mood and anxiety symptoms (via 5-HT and NE in limbic system)

• Modulate pain transmission (via descending noradrenergic and serotonergic pathways in spinal cord)

• Support cognitive function and alertness (via NE activity in prefrontal cortex)

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Common SNRIs and Brand Names

Generic Name	Brand Name(s)	Key Indications
Venlafaxine	Effexor XR	Depression, GAD, panic disorder, SAD
Desvenlafaxine	Pristiq	MDD
Duloxetine	Cymbalta	MDD, GAD, fibromyalgia, diabetic neuropathy
Milnacipran	Savella (US)	Fibromyalgia
Levomilnacipran	Fetzima	MDD

Clinical Indications

Indication	Preferred SNRI(s)
Major depressive disorder (MDD)	All SNRIs
Generalized anxiety disorder (GAD)	Venlafaxine, Duloxetine
Panic disorder	Venlafaxine
Social anxiety disorder (SAD)	Venlafaxine
Fibromyalgia	Duloxetine, Milnacipran
Neuropathic pain	Duloxetine (diabetic neuropathy, chronic pain)
Chronic musculoskeletal pain	Duloxetine (osteoarthritis, low back pain)
Menopausal hot flashes (off-label)	Venlafaxine

Pharmacokinetics

Drug	Half-life	Metabolism	Elimination
Venlafaxine	~5 h (parent), 11 h (O-desmethyl metabolite)	Hepatic (CYP2D6 to active form)	Renal
Desvenlafaxine	~11 h	Minimal CYP involvement	Renal
Duloxetine	~12 h	CYP1A2 and CYP2D6	Hepatic, renal
Milnacipran	~8 h	Minimal CYP metabolism	Renal
Levomilnacipran	~12 h	CYP3A4 (minor)	Renal

Dosing and Administration

Drug	Initial Dose	Titration	Max Daily Dose
Venlafaxine XR	37.5–75 mg/day	↑ by 75 mg every 4 days	225–375 mg/day (MDD)
Desvenlafaxine	50 mg/day	No titration needed	100 mg/day
Duloxetine	30–60 mg/day	May increase to 120 mg/day	120 mg/day
Milnacipran	12.5 mg BID → 50 mg BID	Over 1 week titration	100 mg/day
Levomilnacipran	20 mg/day	↑ every 2 days	120 mg/day

Adverse Effects

Systemic Area	Common Effects	Serious Effects
Gastrointestinal	Nausea, dry mouth, constipation	GI bleeding (esp. with NSAIDs)
Cardiovascular	Hypertension (dose-dependent, esp. venlafaxine)	Orthostatic hypotension (milnacipran)
Neurological	Insomnia, dizziness, headache	Serotonin syndrome
Psychiatric	Anxiety, agitation, sexual dysfunction	Suicidal ideation (black box warning)
Genitourinary	Urinary retention (duloxetine, milnacipran)	SIADH/hyponatremia
Others	Sweating, tremor	Hepatotoxicity (duloxetine)

Contraindications

Condition	Explanation
MAOI use (within 14 days)	Risk of serotonin syndrome
Uncontrolled narrow-angle glaucoma	SNRIs may increase intraocular pressure
Severe hepatic impairment	Avoid duloxetine
Severe renal impairment (CrCl <30 mL/min)	Avoid desvenlafaxine, milnacipran

Drug Interactions

Interacting Agent	Mechanism / Risk	Affected SNRI(s)
MAOIs	Serotonin syndrome risk	All
SSRIs, Triptans	Serotonin syndrome	All
NSAIDs, Aspirin	↑ Bleeding risk	All
CYP1A2 inhibitors	↑ Duloxetine levels	Duloxetine
CYP2D6 inhibitors	↑ Venlafaxine and duloxetine levels	Venlafaxine, Duloxetine
CYP3A4 inhibitors	↑ Levomilnacipran levels	Levomilnacipran
Alcohol	CNS depression, liver toxicity	All, especially Duloxetine
Beta-blockers	Enhanced bradycardia (caution)	Venlafaxine

Discontinuation and Withdrawal

SNRIs should be tapered gradually to minimize discontinuation syndrome, which can include:

• Dizziness

• Irritability

• Insomnia

• Flu-like symptoms

• Electric shock sensations (“brain zaps”)

Venlafaxine has the highest risk of discontinuation symptoms due to its short half-life.

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Special Populations

Population	Consideration
Elderly	Start at low dose; monitor for hyponatremia
Pediatrics	Use in adolescents with caution (black box warning)
Pregnancy	Category C (some); weigh risk vs benefit
Hepatic/Renal Impairment	Dose adjustment required; avoid in severe cases

Comparison with SSRIs and Other Antidepressants

Feature	SSRIs	SNRIs	TCAs/MAOIs
Primary Action	↑ 5-HT	↑ 5-HT + ↑ NE	↑ 5-HT, ↑ NE, ↑ DA
Sedation	Variable	Less sedating	Often sedating
Weight Gain	Moderate	Less than SSRIs	Higher risk
Cardiovascular	Minimal (except QT)	Hypertension risk	Arrhythmias
Pain Indications	Rare	Approved (e.g., duloxetine)	Limited
Discontinuation Risk	Moderate	Higher (esp. venlafaxine)	High

Monitoring Parameters

• Blood pressure (baseline and periodic)

• Liver function tests (especially duloxetine)

• Suicidality assessment (especially during initiation)

• Renal function (for desvenlafaxine and milnacipran)

• Hyponatremia risk in elderly

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Emerging and Investigational Uses

• Chronic fatigue syndrome (experimental)

• Stress urinary incontinence (duloxetine in some regions)

• Menopausal symptoms

• Post-traumatic stress disorder (PTSD) – under exploration