Difference Between SNRIs and SSRIs
SNRIs inhibit the reuptake of both serotonin and norepinephrine, while SSRIs selectively inhibit only serotonin reuptake, making SNRIs dual-action antidepressants with potentially broader therapeutic effects but also distinct adverse effect profiles. 1
Mechanism of Action
SSRIs (Selective Serotonin Reuptake Inhibitors)
- Selectively block serotonin (5-HT) transporter to prevent reuptake of serotonin from the synapse into the presynaptic nerve terminal 2
- Single-action mechanism primarily targeting the serotonergic system 3
- Some SSRIs exhibit secondary effects (e.g., paroxetine has norepinephrine reuptake blocking properties, sertraline inhibits dopamine reuptake) 2
SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)
- Inhibit presynaptic reuptake of both norepinephrine and serotonin with varying selectivity ratios 1
- Dual-action mechanism affecting both serotonergic and noradrenergic neurotransmitter systems 3
- Specific SNRI selectivity profiles: 4
- Venlafaxine: 30-fold selectivity for serotonin over norepinephrine
- Duloxetine: 10-fold selectivity for serotonin over norepinephrine
- Milnacipran: 1:1 balanced ratio for both neurotransmitters
- Currently marketed SNRIs in the United States include venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran 1
Clinical Efficacy Differences
Therapeutic Advantages of SNRIs
- Ascending dose-response curve (unlike SSRIs which have flat dose-response curves), allowing for dose titration to optimize response 4
- Potentially greater overall efficacy at higher doses compared to SSRIs 4
- Effective for chronic pain conditions (diabetic neuropathy, fibromyalgia, musculoskeletal pain) where SSRIs are generally ineffective 1, 5, 4
- May have faster onset of action and higher remission rates for physical symptoms of depression compared to SSRIs 3
Comparative Efficacy
- No major differences between SNRIs and SSRIs for anxiety disorders in terms of efficacy 5
- Some pooled analyses suggested therapeutic advantage for SNRIs (venlafaxine, duloxetine) over certain SSRIs, but these findings are limited by dose comparability issues and selective SSRI comparators (primarily fluoxetine and paroxetine at minimum doses) 1
- Both classes improve primary anxiety symptoms in children and adolescents (ages 6-18) with social anxiety, generalized anxiety, separation anxiety, and panic disorder 1
Adverse Effect Profile Differences
SSRI-Related Adverse Effects
- Primarily serotonergic side effects: nausea, sexual dysfunction, withdrawal symptoms 5
- Generally better tolerated than older tricyclic antidepressants 1
- Lower rates of noradrenergic side effects (dry mouth, sweating, constipation) 6
SNRI-Related Adverse Effects
- Combination of serotonergic and noradrenergic adverse effects 1
- Common side effects include: diaphoresis, dry mouth, abdominal discomfort, nausea, vomiting, diarrhea, dizziness, headache, tremor, insomnia, somnolence, decreased appetite, weight loss 1
- Increased fatigue/somnolence compared to placebo (moderate strength of evidence) 1
- Noradrenergic effects more frequent with SNRIs than SSRIs: dry mouth, sweating, constipation 6
Cardiovascular Effects
- SNRIs associated with sustained clinical hypertension, increased blood pressure, and increased pulse 1
- Venlafaxine has dose-dependent blood pressure elevation (most common at doses >225 mg/day), with increased cardiotoxicity in overdose 4, 6
- Duloxetine and milnacipran appear to have less cardiovascular toxicity than venlafaxine 5, 6
- SSRIs generally lack significant cardiovascular effects related to blood pressure 1
Serious Adverse Effects (Both Classes)
- Suicidal thinking and behavior (through age 24 years) 1
- Behavioral activation/agitation, hypomania, mania 1
- Sexual dysfunction 1
- Seizures, abnormal bleeding, serotonin syndrome 1
- Discontinuation syndrome with both classes (agitation, anxiety, dizziness, sensory disturbances including shock-like electrical sensations, nausea) 7
SNRI-Specific Serious Adverse Effects
- Venlafaxine: Greater suicide risk, overdose fatalities, significant discontinuation symptoms 1, 7
- Duloxetine: Hepatic failure (abdominal pain, hepatomegaly, elevated transaminases), cholestatic jaundice, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome) 1, 6
Pharmacokinetic Considerations
Dosing Frequency
- Venlafaxine extended-release, desvenlafaxine, and duloxetine: Single daily dosing due to sufficiently long elimination half-lives 1
- Venlafaxine immediate release: Requires twice- or thrice-daily dosing due to short elimination half-life (~5 hours) 4
- Milnacipran: Twice daily dosing (half-life ~10 hours) 4
Drug Interactions
- Duloxetine: Moderate CYP2D6 inhibitor; may interact with drugs metabolized by CYP1A2 and CYP2D6 1, 4
- Venlafaxine: Least effect on CYP450 system among SNRIs, but subject to CYP2D6 metabolism (significant inter-individual variation) 1, 4
- All SNRIs and SSRIs: Contraindicated with MAOIs due to serotonin syndrome risk 1, 4
Clinical Application Pearls
When to Consider SNRIs Over SSRIs
- Chronic pain conditions (diabetic neuropathy, fibromyalgia) requiring visceral pain management 1, 5
- Depression with prominent physical symptoms requiring dose escalation 4, 3
- Patients requiring noradrenergic modulation for alertness, arousal, and attentiveness 1
Common Pitfalls
- Monitor blood pressure and pulse with all SNRIs, particularly at higher doses of venlafaxine 1
- Gradual dose reduction required for discontinuation to avoid withdrawal syndrome (more problematic with venlafaxine) 7
- Avoid combining SNRIs with opioid analgesics for chronic pain, as opioids delay gastric emptying and risk narcotic bowel syndrome 1
- Duloxetine requires hepatic monitoring; discontinue if jaundice or liver dysfunction develops 1
- Weight loss more common with SNRIs, particularly in pediatric patients; monitor growth parameters 7