Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
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SNRIs inhibit the reuptake of both serotonin and norepinephrine. Although this reuptake blockade is thought to contribute to the therapeutic effects of SNRIs in depression and anxiety, the exact mechanism is not known. The members of the class differ in their relative potency at serotonin and norepinephrine auto-receptors; duloxetine and desvenlafaxine demonstrate a 10-fold higher selectivity for serotonin reuptake inhibition than norepinephrine reuptake inhibition and venlafaxine has a 30-fold higher affinity for the reuptake inhibition of serotonin compared to norepinephrine. Conversely, levomilnacipran and milnacipran demonstrate a 2-fold and 3-fold greater potency for norepinephrine reuptake inhibition than serotonin reuptake inhibition, respectively. Norepinephrine receptor blockade is considered important in the treatment of pain, as SSRIs have not been proven efficacious for pain disorders. Thus, some SNRIs, including milnacipran and duloxetine, have FDA-approved indications in the treatment of some pain disorders. All SNRIs inhibit serotonin uptake in human platelets, which has been associated with an increased risk of bleeding adverse events. SNRIs do not have a significant affinity for histaminergic, muscarinic, alpha1-adrenergic, postsynaptic serotonin or dopamine, GABA, or glutamate receptors in vitro, nor do they inhibit monoamine oxidase (MAO). Duloxetine and venlafaxine at high doses weakly inhibit the reuptake of dopamine, which may contribute to effects on blood pressure.
Meta-Analysis of SNRIs vs. SSRIs for Depression
SSRI, all-cause withdrawal (n)/total randomizedd (N) (%)
aResponse = a reduction of at least 50% from the baseline score on the Hamilton Depression Rating Scale (HAM-D) or Montgomery-Asberg depression rating scale (MADRS), or a score of "much improved" or "very much improved" on the Clinical Global Impression scale (CGI) at 8 weeks (intention to treat; last observation carried forward [ITT-LOCF]); bITT population; cstatistically significant (lower limit of 95% confidence interval [CI] 1 or greater); dsafety population
SNRIs Comparative Efficacy Trials
Data pooled from 2 similarly designed, double-blind, parallel group studies; patients with major depressive disorder were randomized to duloxetine (n=330) or venlafaxine XR (n=337) x 12-weeks
The primary outcome measure was Global Benefit-Risk (GBR). In the GBR analysis, benefit was defined as remission at end point (17-item HAM-D score of 7 or less). Risk was defined by 4 categories: i) patients having no adverse events (AEs); ii) AEs with no severity rating greater than moderate; iii) AEs with at least 1 severity rating of severe; and iv) having discontinued with a reason of self-reported AE. GBR scores ranged from +5 (remission and no AEs) to -5 (no remission and discontinued due to AE)
GBR at 12 weeks (LOCF, linear score, mean [SE]): duloxetine vs venlafaxine, -0.35 (0.21) vs -0.12 (0.20), p=0.44
Completion rates: 74.5% for venlafaxine XR vs 64.8% for duloxetine, p < 0.01
Remission rates at 12 weeks: duloxetine, 48.1% vs venlafaxine, 50.3%
Common AEs: nausea (43.6% vs 35.0%, p=0.02) and dizziness (16.1% vs 10.4%, p=0.03) were more frequent in duloxetine group
Discontinuation due to AEs: occurred more frequently in the duloxetine group at 12 weeks (14.5% vs 9.2%; p=0.03)
Double-blind, placebo-controlled comparison of the efficacy and safety of venlafaxine XR and venlafaxine immediate-release (IR) x 12 weeks.
Primary efficacy variables were the 21-item HAM-D Rating Scale total score and depressed mood item, the MADRS total scores, and the CGI severity scale. Safety/tolerability were assessed by AEs, physical exam, sentinel events, vital signs, electrocardiogram, and lab tests
Efficacy at week 12: HAM-D: XR, 9.4; IR, 12.3; placebo, 15.8 (p < 0.05 favoring XR vs IR) MADRS: XR, 10.6; IR, 13.3; placebo, 18.3 (p < 0.05 favoring XR vs IR) CGI: XR, 2.08; IR, 2.67; placebo, 3.18 (p < 0.05 favoring XR vs IR) Both XR and IR were superior to placebo at weeks 6 and 12
Completion rates: XR group had a higher rate (71%) than IR (60%) or placebo (59%) (p=NS)
AEs: Nausea most common in XR and IR (45% each); sexual dysfunction in men highest in XR (27%) vs IR (6%) and placebo (0%)
Double-blind, duloxetine-referenced, placebo-controlled, parallel-group, 8-week study comparing desvenlafaxine (50 or 100 mg/day) to duloxetine (60 mg/day) in 615 adults with major depressive disorder (HAMD-17 score of 20 or more).
Primary outcome measure was HAMD-17 total score at final evaluation. Additional measures included the CGI-I, MADRS, and CGI-S. Tolerability assessments included discontinuation rates, AEs, vital signs, and lab tests. Post hoc pooled analysis was performed using data from the current study and 2 previous similar studies that compared the efficacy and tolerability of desvenlafaxine with placebo for major depressive disorder
HAMD-17: desvenlafaxine 100 mg/day (-10.5, p=0.03) and duloxetine 60 mg/day (-10.3, p < 0.05) groups compared with placebo (-8.7). Desvenlafaxine 50 mg did not differ from placebo.
CGI-I, MADRS, and CGI-S: desvenlafaxine 100 mg/day and duloxetine 60 mg/day had significantly better scores compared with placebo; desvenlafaxine 50 mg was not superior to placebo.
Discontinuation rates due to AEs: 5%, 7%, 13%, and 6% for the desvenlafaxine 50 mg/day, desvenlafaxine 100 mg/day, duloxetine 60 mg/day, and placebo groups, respectively.
Post hoc pooled HAM-D(17) (N=1388): desvenlafaxine 50 mg/day (-11.5, p < 0.001), desvenlafaxine 100 mg/day (-11.8, p < 0.001) were superior to placebo (-9.6)
HAMD17, MADRS, and CGI: No significant differences were noted on any outcome measure between groups
Safety/tolerability: No major safety issues were noted; tolerability was similar
Gastrointestinal (GI) side effects are the most common adverse reactions in patients receiving SNRI treatment. Nausea is the most common adverse reaction with any SNRI. It is most often transient and of mild to moderate intensity. Other less frequently reported GI effects include dry mouth (xerostomia), constipation, and vomiting. One review noted that venlafaxine, one of the SNRIs, was associated with a higher risk for nausea when compared to agents in the SSRI class.
Headache, dizziness, drowsiness, and insomnia are the most common centrally-mediated adverse reactions, but are rarely severe and usually do not lead to treatment discontinuation.
Monitor patients taking an SNRI for signs and symptoms of bleeding. Impaired platelet aggregation may occur during treatment with SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. In published observational studies, pregnant patients taking SSRIs, particularly in the month prior to obstetric delivery, were at an increased risk of postpartum hemorrhage; this effect is also possible with the SNRIs. A postmarketing study showed a higher incidence of postpartum hemorrhage in mothers taking the SNRI duloxetine. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of these bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.
All SNRIs have been associated with sustained elevation of blood pressure, most notably venlafaxine. Blood pressure should be monitored closely when initiating therapy or increasing SNRI dosages, and routinely thereafter. Orthostatic hypotension has also been reported, particularly in the elderly.
SNRIs may cause hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone secretion; serum sodium levels less than 110 mmol/L have been reported. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume-depleted (e.g., hypovolemia) appear to be at greatest risk. The syndrome is reversible upon discontinuation of the causative SNRI.
Hyperhidrosis (increased sweating) is the most common adverse dermatologic effect associated with SNRIs. Severe reactions, including anaphylactoid reactions, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been reported rarely with the various SNRIs. The SNRI should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other cause can be identified.
Sexual dysfunction is commonly reported with the use of serotonergic agents such as SNRIs and may result in treatment discontinuation in some patients. In men, these symptoms may include ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Women may experience decreased libido and delayed or absent orgasm. Clinicians should discuss sexual function with patients prior to initiating treatment and throughout treatment to identify any changes in sexual function and determine if they are medication-related or attributed to the underlying psychiatric disorder. Patients should also be provided with management strategies and treatment options for symptoms of sexual dysfunction.
Closed-angle glaucoma has occurred in patients with untreated anatomically narrow angles during treatment with antidepressants. Duloxetine is contraindicated in patients with uncontrolled angle-closure glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.
Elevated liver function tests (LFTs) have been reported with all SNRIs and appear to be dose-related. Hepatitis and hepatic failure have occurred during administration of some SNRIs; fatalities have been reported. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative to consider in patients with hepatic disease.
Symptoms consistent with a neonatal discontinuation syndrome (e.g., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting) have been reported in infants exposed to SNRIs in utero, particularly during the third trimester. SNRIs should be used in pregnancy only where the benefit to the mother clearly outweighs any potential risk to the fetus. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. If clinically feasible, and taking the drug half-life into consideration, tapering of the antidepressant prior to delivery may be considered.
SNRIs are contraindicated in patients receiving MAO inhibitors (MAOIs) or within 2 weeks of their discontinuation due to the risk of serotonin syndrome. Medications with MAOI activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with SNRIs because of an increased risk of serotonin syndrome.
Any use of an SNRI with other serotonergic agents increases the likelihood of serotonergic adverse effects and should be monitored closely. Drugs that have serotonergic properties include opiates, triptans, most antidepressants, amphetamines, St. John's wort, tramadol, lithium, buspirone, and others.
Anticoagulants, antiplatelet drugs (e.g., aspirin), and nonsteroidal anti-inflammatory drugs (NSAIDs) should be administered with caution to any patient taking an SNRI. Platelet aggregation may be impaired by SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
Levomilnacipran and milnacipran are not metabolized to any significant extent by CYP450 isoenzymes and are not inducers or inhibitors of any of these isoenzymes. Venlafaxine is metabolized by CYP2D6, and CYP2D6 inhibitors may increase venlafaxine concentrations. A dose-related CYP2D6 inhibitory effect has been observed with desvenlafaxine; therefore, the dose of primary CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day. Duloxetine is metabolized by CYP1A2 and CYP2D6; inhibitors of CYP1A2 and CYP2D6 may increase duloxetine concentrations.
Allergic reactions may occur with the use of any SNRI. Because some SNRIs are available as both a racemic compound (e.g., milnacipran) and a single enantiomer of the racemic compound (e.g., levomilnacipran), cross-sensitivity should be expected. Similarly, cross-sensitivity is possible between desvenlafaxine and venlafaxine, since venlafaxine is the parent compound of desvenlafaxine. Levomilnacipran and milnacipran are contraindicated in patients exhibiting hypersensitivity to the related drug; desvenlafaxine and venlafaxine are contraindicated in patients who have demonstrated a hypersensitivity to the related drug.
The approved labeling for all antidepressants carries a boxed warning of an increased risk of suicidal thoughts and behavior in children and young adults, particularly during the first few months of therapy. Experts state that the apparent increase in suicidality reflected by a greater number of spontaneously reported events is mitigated by the lack of any completed suicides, the decline in overall suicidality on rating scales, and the greater number of patients who benefit from antidepressants than who experience these serious adverse effects. Careful assessment and monitoring of suicidality are warranted in all patients initiating treatment with an SNRI.
The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, the antidepressant should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
SNRI use has been associated with elevated hepatic enzymes. Duloxetine is not recommended in patients with any degree of hepatic impairment. Avoidance of duloxetine is recommended in patients with substantial alcohol use, alcoholism, hepatic necrosis, and/or chronic liver disease. Dosage adjustments of venlafaxine and desvenlafaxine are recommended in patients with hepatic impairment. Milnacipran can be used cautiously in patients with hepatic impairment. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative option in patients with hepatic disease.
The American Psychiatric Association guidelines state that treatment of depression during early pregnancy requires careful risk-benefit assessment, in collaboration with the patient and potentially a neonatal specialist. Use of serotonergic antidepressants, including SNRIs, during the third trimester has been associated with neonatal complications, including prolonged hospitalization, respiratory support, and tube feeding. In addition, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia; this potential has been reported for venlafaxine. Data indicate exposure to SNRIs, particularly in the month before obstetric delivery, may be associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Treatment with any SNRI during pregnancy should be individualized.
Small concentrations of SNRIs have been measured in breast milk, with uncertain consequences for the infant. The benefits of drug treatment to the mother need to be weighed against the potential risk of infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain following exposure to serotonergic antidepressants through breast milk. Any infant exposed to an SNRI through breast-feeding should be monitored for these adverse effects.
Similar to other antidepressants, a discontinuation syndrome can occur when SNRIs are abruptly halted. This syndrome is characterized by dizziness, weakness, nausea, headache, lethargy, insomnia, anxiety, poor concentration, paresthesias (tactile sensations), and increased gastrointestinal motility. Symptoms occur most frequently and severely with shorter-acting agents (e.g., immediate-release venlafaxine). A slow, individualized taper is advisable, particularly after chronic use, to minimize discontinuation symptoms.
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