- Serotonin norepinephrine reuptake inhibitors (SNRIs)
- Mechanism of action
- Indications and uses
- Effectiveness and head-to-head clinical trials
- Off-label uses
- Side effects
- Tolerability
- Withdrawal symptoms
- Drug interactions
- Brief comparison chart
Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD
SNRIs - new class of antidepressants
Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used to treat depression and other affective disorders. SNRIs were developed more recently than SSRIs and currently there are four medications in this class approved by the FDA for use: venlafaxine (brand name: Effexor), duloxetine (brand name Cymbalta), milnacipran (Savella, not approved for major depressive disorder), and desvenlafaxine (Pristiq). These new drugs, because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse effects of tricyclic antidepressants and monoamine oxidase inhibitors.
Venlafaxine HCl (Effexor®, Effexor® XR) is the first and most commonly used SNRI. It was introduced by Wyeth in 1994.
Duloxetine HCl (Cymbalta®), manufactured by Eli Lilly, is a newer antidepressant on the market. It was approved by the FDA and released on the market in August 2004.
SNRIs affect two neurotransmitters - serotonin and norepinephrine. Clinical studies have shown that the SNRIs are generally quicker acting and more effective in treating severe major depressive disorder, treatment-resistant depression, and depressive symptom remission than SSRI antidepressants5.
Currently there is not enough information to firmly recommend one antidepressant over another. Selection of antidepressant therapy should be done on an individual basis. Drugs may work differently for different people. What is effective for one patient may not be effective for another. This article provides comparative data based on the analysis of medication prescribing information and scientific studies.
Advertisem*nt
Mechanism of action
When serotonin and noradrenaline are released from nerve cells in the brain they act to lighten mood. When they are reabsorbed into the nerve cells, they no longer have an effect on mood. It is thought that when depression occurs, there may be a decreased amount of serotonin and noradrenaline released from nerve cells in the brain.
SNRI antidepressants work by preventing serotonin and noradrenaline from being reabsorbed back into the nerve cells in the brain. This helps prolong the "mood lightening" effect of any released serotonin and noradrenaline. In this way SNRIs help relieve depression. It may take between two to four weeks to feel the benefits of these medicines.
Venlafaxine (Effexor, Effexor XR) has the flexibility of being an SSRI at lower doses (75 mg/day), affecting the reuptake of serotonin, and an SNRI at higher doses (150-225 mg/day). It also very weakly blocks the reuptake of dopamine at very high doses (above 350 mg/day).
Duloxetine (Cymbalta) is a strong, balanced inhibitor of both norepinephrine and serotonin reuptake.
Duloxetine differs from venlafaxine in that it is comparatively more noradrenergic. Venlafaxine has a 30-fold higher affinity for serotonin than for norepinephrine while duloxetine has a 10-fold selectivity for serotonin6. Approximate potency ratios (5-HT:NE) are 1:10 for duloxetine, and 1:30 for venlafaxine.
Indications and uses
Venlafaxine (Effexor, Effexor XR) is indicated for the treatment of:
- Major Depressive Disorder
- Generalized Anxiety Disorder
- Social Anxiety Disorder
- Panic Disorder
Duloxetine (Cymbalta) is indicated for the treatment of:
- Major Depressive Disorder
- Diabetic Peripheral Neuropathic Pain
- Generalized Anxiety Disorder (GAD)
- Fibromyalgia (FM)
- Chronic musculoskeletal pain
The extended-release formulation of Effexor has been approved for the treatment of panic disorder and social anxiety disorder, these are not labeled indications for Cymbalta.
FDA approved Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy and fibromyalgia. However, these are not labeled indications for Effexor.
Duloxetine is also being evaluated in the treatment of stress urinary incontinence (officially approved in Europe for this problem).
Effectiveness and head-to-head clinical trials
Depression
Both antidepressants have similar effectiveness in the treatment of depression 1, 17.
One randomized, double-blind study compared Cymbalta (duloxetine) 60 mg/day and Effexor XR (extended-release venlafaxine) 150 mg/day in the treatment of major depressive disorder1. Both Cymbalta and Effexor XR demonstrated substantial antidepressant efficacy as measured by the HAMD 17 total score.
Many doctors favour duloxetine over venlafaxine when pain conditions coexist with depression 15.
Anxiety disorder
Duloxetine is just as effective as venlafaxine in the treatment of generalized anxiety disorder (GAD)2.
Off-label & investigational uses
Many doctors are starting to prescribe venlafaxine (Effexor) "off-label" for the treatment of diabetic neuropathy (in a similar manner to Cymbalta) and migraine prophylaxis (in some people, however, venlafaxine can exacerbate or cause migraines). Studies have shown Effexor effectiveness for these conditions. It has also been found to reduce the severity of 'hot-flashes' in menopausal women. Effexor is also prescribed for off-label uses such as chronic fatigue syndrome, and obsessive-compulsive disorder (OCD).
At present, Cymbalta is not approved for treating bipolar depression, but is being prescribed to people with bipolar disorder as an off-label use. Patients who have experienced mania should be monitored carefully when taking this medication.
There are more controlled studies with duloxetine (Cymbalta) showing benefit for all kinds of pain than any other antidepressant. In clinical trials, Cymbalta 60 mg once daily demonstrated efficacy in painful physical symptoms associated with depression. Cymbalta is being studied for the treatment of stress urinary incontinence, which may also respond to treatment with both serotonin and norepinephrine.
Side effects and toxicity
Nausea is the most frequent side effect with SNRIs, and may cause some people to stop treatment. The extended-release formulation of venlafaxine is less likely to cause nausea than the regular tablet. Cymbalta is more likely cause nausea than Effexor XR1.
The most common side effects:
| Venlafaxine (Effexor) | Duloxetine (Cymbalta) |
|
|
Hepatotoxicity
Serious and potentially fatal hepatotoxicity has been reported with duloxetine. Postmarketing reports have described isolated cases of liver failure, including fatalities, which were possibly related to duloxetine. Most cases were in people with past or current risk factors for liver injury, including alcohol abuse.
Duloxetine should not be used in patients with any hepatic function impairment and should not be taken by heavy drinkers.
Unlike duloxetine, venlafaxine is not expected to exert additive hepatotoxic effects in patients susceptible to liver damage.
Increased blood pressure
Both duloxetine (Cymbalta) and venlafaxine (Effexor) can cause increases in blood pressure. The risk of treatment-emergent blood pressure elevations appear to be greater for venlafaxine than with duloxetine1.
Venlafaxine can cause both transient and sustained elevations of diastolic blood pressure and regular monitoring of blood pressure throughout venlafaxine therapy is recommended in the prescribing information. Venlafaxine has a dose-dependent effect on diastolic blood pressure, but clinically significant hypertension is only induced at doses >300 mg/day7.
In studies, duloxetine was shown to slightly increase blood pressure, but this drug does not appear to be associated with sustained hypertension8.
So duloxetine (Cymbalta) may be the preferred for patients with elevated blood pressure.
Mydriasis
Duloxetine (Cymbalta) and venlafaxine (Effexor) can cause mydriasis (excessive dilation of the pupil), and patients with increased intraocular pressure or those at risk of acute narrow-angle glaucoma should use these medications with caution.
The use of Cymbalta is contraindicated in patients with uncontrolled narrow-angle glaucoma.
Sexual side effects
Sexual side effects include decreased libido, anorg*smia and erectile dysfunction. Duloxetine seems less likely to produce sexual dysfunction than venlafaxine9.
Anticholinergic effects
Drugs that antagonize the muscarinic receptor cause anticholinergic side effects, such as dry mouth, constipation, blurred vision and urinary retention. Duloxetine (Cymbalta) has a higher affinity for this type of receptor than venlafaxine (Effexor), which accounts for the somewhat higher rate of dry mouth, constipation, and blurred vision with duloxetine than with venlafaxine.
Insomnia
Both duloxetine and venlafaxine are reported to cause insomnia, probably because of the increase in NE levels. The percentage of patients who experience insomnia increases with higher doses. About 10-16% of patients taking duloxetine and 16-24% of those taking venlafaxine experience insomnia.
Cardiovascular effects
Duloxetine is associated with a small increase in heart rate8. Even low doses of duloxetine can cause tachycardia10.
Venlafaxine can cause cardiovascular side effects11. Fatalities have been reported in patients taking overdoses of venlafaxine, predominantly in combination with alcohol or other drugs. This drug may cause mean increase in heart rate of 4-9 beats/minute.
Overdose toxicity
Venlafaxine is slightly more toxic in overdose compared with duloxetine 16.
Tolerability
Tolerability of SNRI antidepressants varies within the class.
Venlafaxine (Effexor) may be better tolerated than duloxetine (Cymbalta) in the initial period of treatment. In clinical trials, duloxetine 60 mg daily caused more discontinuations due to side effects than venlafaxine 150 mg daily1,2.
The most common events leading to discontinuation of Effexor XR are: nausea, dizziness, somnolence, insomnia, dry mouth.
The most common reasons leading to discontinuation of Cymbalta are: nausea, dizziness, somnolence.
Withdrawal symptoms
As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or "discontinuation syndrome". Withdrawal symptoms may occur on stopping, missing doses or, reducing the dose of the drug.
Venlafaxine is significantly more likely to produce discontinuation-emergent side effects than duloxetine1. This is likely due to venlafaxine's relatively short half-life and therefore rapid clearance upon discontinuation. Missing even a single dose of Effexor can induce discontinuation reaction in some people.
Headache, nausea, fatigue, dizziness, irritability, insomnia and dysphoria are most frequent withdrawal symptoms, and may make cessation of the drug extremely difficult12.
Common withdrawal difficulties following discontinuation of duloxetine are dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmares13.
Drug interactions
Venlafaxine (Effexor) is less likely than duloxetine (Cymbalta) to interact with co-administered medications4.
Unlike venlafaxine, duloxetine is highly protein bound in human plasma. Two highly protein-bound drugs can compete with each other for binding sites and one drug can displace the other from the binding sites. This would lead to higher levels of unbound drug leading to both enhanced pharmacological effect and toxicity. Although there are compensatory mechanisms in the body to buffer against such events, there has been a case report citing such an interaction involving duloxetine and warfarin14. Such interactions are not expected with venlafaxine due to its low protein-binding properties.
Venlafaxine should be used cautiously with drugs that elevate blood pressure because of dose-dependent increases in blood pressure. Duloxetine would be the suitable antidepressant in patients with hypertension.
Duloxetine is extensively metabolized by cytochrome P450 isoenzymes CYP 1A2 and CYP 2D6, creating an important risk of interactions with other drugs. For example, the bioavailability of duloxetine is a third less in smokers compared to nonsmokers because of induction of CYP 1A2 metabolism.
Venlafaxine does not appear to inhibit CYP isoenzymes to any significant degree.
Summary of drug interactions:
| Venlafaxine | Duloxetine |
| Inhibitors of CYP 2D6 and CYP 3A4 → increase in venlafaxine levels | CYP 2D6 and CYP 1A2 substrates → increase in drug levels |
| Inducers of CYP 2D6 and CYP 3A4 → decrease in venlafaxine levels | Inhibitors of CYP 2D6 and CYP 1A2 → increase in duloxetine levels |
| Inducers of CYP 2D6 and CYP 1A2 → decrease in duloxetine level | |
| Highly protein-bound drugs → displacement from protein binding leading to toxicity | |
| MAOIs → serotonin syndrome + HTN crisis | MAOIs → serotonin syndrome + HTN crisis |
| Serotonergic drugs → serotonin syndrome | Serotonergic drugs → serotonin syndrome |
| Drugs that increase BP → Additive increase in BP | Hepatotoxic drugs → additive hepatotoxicity |
| Drugs that alter EKG → additive cardiac conduction changes |
Absorption
Food does not affect the bioavailability of venlafaxine or its active metabolite, ODV (O-desmethylvenlafaxine). Time of administration (AM vs PM) did not affect the pharmaco*kinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule.
Food does not affect the maximal plasma concentrations of duloxetine, but delays the time to reach peak concentration by approximately 4 hours (from 6 to 10 hours) and it marginally decreases the extent of absorption by about 10%. There is a 3-hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
The bioavailability of duloxetine appears to be reduced by about one-third in smokers. However, dosage modifications are not considered necessary. The bioavailability of venlafaxine is not affected by smoking.
Brief comparison table
Venlafaxine (Effexor) | Duloxetine (Cymbalta) | |
|
| |
| Generic name | Venlafaxine hydrochloride | Duloxetine hydrochloride |
| Manufacturer | Wyeth | Eli Lilly |
| FDA approval date | 1993 | 2004 |
| Active Metabolite | O-Desmethylvenlafaxine | 5-hydroxy-duloxetine |
| Half-life | 4 (11 for O-desmethylvenlafaxine) | 12 hours (range 8 to 17 hours) |
| Time to steady-state | 3 days | 3 days |
| Bioavailability, % | 45 | 50 |
| Potential for interactions | Has one of the most favorable drug-interaction profiles4 Weak or negligible inhibitor of CYP isozymes (CYP2D6, CYP1A2, CYP2C19, and CYP3A4) | Moderate inhibitor of CYP2D6, has the potential to interact with other drugs that are also metabolized by this cytochrome P450 system |
| Generic availability | Yes | Yes |
| Pregnancy Category | C | C |
| Most common side effects | nausea headache somnolence dizziness insomnia nervousness dry mouth anorexia sweating abnormal ejacul*tion constipation impotence | nausea somnolence headache dry mouth dizziness insomnia fatigue constipation diarrhea decreased appetite vomiting erectile dysfunction |
| Mode of action | Serotonergic at lower doses, modest noradrenergic effects at higher doses (> 250 mg/day) | Strong, balanced inhibitor of both norepinephrine and serotonin reuptake |
| Tolerability | Venlafaxine is better tolerated than duloxetine 17. | |
Advertisem*nt
Further reading
- Venlafaxine vs Amitriptyline
- Venlafaxine vs Bupropion
- Venlafaxine vs Paroxetine
References
- 1. Perahia DGS, Pritchett YL, Kajdasz DK, et al. A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder. J Psychiatr Res. 2007. 42: 22–34
- 2. Allgulander C, Nutt D, Detke M, et al. A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder. J Psychopharmacol. 2008;22:417–25.
- 3.Thase ME, Tran PV, Wiltse C, et al. Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. J Clin Psychopharmacol. 2005. 25(2): 132–40.
- 4. Spina E, Santoro V, D'Arrigo C. Clinically relevant pharmaco*kinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008 Jul;30(7):1206-27
- 5. Thase ME. Are SNRIs More Effective than SSRIs? Psychopharmacol Bull. 2008;41(2):58-85.
- 6. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT.Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001 Dec;25(6):871-80
- 7. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998 Oct;59(10):502-8
- 8. Wernicke J, Lledó A, Raskin J, Kajdasz DK, Wang F. An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies. Drug Saf. 2007;30(5):437-55.
- 9. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009 Jun;29(3):259-66.
- 10. Stevens DL. Duloxetine-associated tachycardia. The Annals of Pharmacotherapy. 2008 Oct;42(10):1511-3. PubMed
- 11. Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol. 2007 Aug;64(2):192-7.
- 12. Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF. Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. American Journal of Psychiatry. 1997 Dec;154(12):1760-2
- 13. Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. J Affect Disord. 2005 Dec;89(1-3):207-12.
- 14. Glueck CJ, Khalil Q, Winiarska M, Wang P. Interaction of duloxetine and warfarin causing severe elevation of international normalized ratio. JAMA. 2006 Apr 5;295(13):1517-8
- 15. Shi N, Durden E, Torres A, Cao Z, Happich M. Predictors of Treatment with Duloxetine or Venlafaxine XR among Adult Patients Treated for Depression in Primary Care Practices in the United Kingdom. Depress Res Treat. 2012; 2012:815363
- 16. Taylor D, Lenox-Smith A, Bradley A. A review of the suitability of duloxetine and venlafaxine for use in patients with depression in primary care with a focus on cardiovascular safety, suicide and mortality due to antidepressant overdose. Ther Adv Psychopharmacol. 2013 Jun;3(3):151-61. PubMed
- 17. Schueler YB, Koesters M, Wieseler B, Grouven U, Kromp M, Kerekes MF, Kreis J, Kaiser T, Becker T, Weinmann S. A systematic review of duloxetine and venlafaxine in major depression, including unpublished data. Acta Psychiatr Scand. 2011 Apr;123(4):247-65 PubMed
- Cymbalta prescribing information
- Effexor XR prescribing information
Published: August, 2009
Last updated: February 07, 2017
