Serotonin Modulator Antidepressants
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Serotonin modulators change the activity of various 5-HT receptor subtypes in the brain. Vortioxetine is an agonist of the 5-HT1A receptor, a partial agonist of 5-HT1B, and an antagonist of 5-HT3, 5-HT1D, and 5-HT7. Vilazodone is a partial 5-HT1A agonist. Similar to SSRIs, vortioxetine and vilazodone are also inhibitors of the pre-synaptic serotonin transporter, increasing the synaptic concentration of serotonin. The contribution of the modulating mechanisms of vortioxetine and vilazodone to their antidepressant effects have not been established.
Serotonin Modulators Comparative Efficacy Trials
The primary outcome was a Montgomery-Asberg Depression Rating Scale (MADRS) measurement at baseline and weeks 1, 2, 4, 6, 8, and 10. Safety was measured via recording of adverse events, physical examination, various clinical laboratory and vital sign measures, and the Changes in Sexual Functioning Questionnaire (CSFQ).
vilazodone 20 mg/day, -17.3 (0.6)
vilazodone 40 mg/day, -17.6 (0.7)
citalopram 40 mg/day, -17.5 (0.6)
placebo, -14.8 (0.6)
All active treatment groups were generally well tolerated, with most adverse events being mild or moderate in severity.
The primary outcome was a MADRS measurement at baseline and week 6. Possible treatment-emergent adverse events (TEAEs) were recorded at each visit.
vortioxetine 5 mg/day, -20.4 (1)
vortioxetine 10 mg/day, -20.2 (1)
venlafaxine XR 225 mg/day, -20.9 (1)
placebo, -14.5 (1)
Withdrawal due to adverse events was significantly higher in the venlafaxine group than the placebo group. This was not the case for either dose of vortioxetine.
The primary outcome was a MADRS measurement at baseline and weeks 1, 2, 4, 6, and 8. Adverse events were recorded at every study visit.
vortioxetine 15 mg/day, -1.48 (1.214)
vortioxetine 20 mg/day, -2.75 (1.206)
duloxetine 60 mg/day, -4.07 (1.214)
Rates of reported adverse events between active treatment groups were roughly similar.
Gastrointestinal (GI) side effects are the most common adverse reactions in patients receiving serotonin modulator antidepressant treatment. Nausea is the most common adverse reaction with any serotonin modulator. In patients receiving vortioxetine, nausea was generally reported as mild or moderate in severity and lasted for a median of two weeks. The severity and extent of nausea was not reported for vilazodone. Other less frequently reported GI effects of vortioxetine and vilazodone included diarrhea, dry mouth, constipation, and vomiting.
The most common centrally-mediated adverse reaction of serotonin modulator antidepressants is dizziness. In general, centrally-mediated side effects were reported more commonly with vilazodone than vortioxetine during clinical trials. A wide range of centrally-mediated adverse reactions were reported in patients taking vilazodone, including insomnia, restlessness, somnolence, and paresthesia. Patients who are taking vilazodone should be cautioned about driving or performing other hazardous tasks until they know how vilazodone affects them. One clinical trial found that a 10 mg/day dose of vortioxetine did not impair driving or other psychomotor functions.
Monitor patients taking serotonin modulator antidepressant for signs and symptoms of bleeding. Platelet aggregation may be impaired by serotonin modulator antidepressants due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). In published observational studies, pregnant patients taking SSRIs or SNRIs (other classes of serotonergic antidepressants), particularly in the month prior to obstetric delivery, were at an increased risk of postpartum hemorrhage. Serotonin modulator antidepressants may also cause an increased risk for postpartum hemorrhage. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.
Serotonergic antidepressants may cause hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone secretion. One case of hyponatremia was reported in a pre-marketing clinical study of vortioxetine. No cases of hyponatremia resulting from vilazodone treatment were reported in premarketing clinical studies. Elderly patients, those taking diuretics, or those who are otherwise volume depleted may be at greater risk. Serotonin modulator antidepressants should be discontinued in patients with symptomatic hyponatremia.
Like other serotonergic antidepressants, the serotonin modulators may cause sexual dysfunction in both men and women, leading to 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. Although the reported incidence of sexual dysfunction ranges from less than 1% up to 5% with vortioxetine and less than 1% up to 2% with vilazodone, the actual occurrence is likely higher due to patient underreporting. In one publication, use of the Arizona Sexual Experience Scale (ASEX) in patients receiving vortioxetine yielded rates of sexual dysfunction as high as 34% in females and 29% in males compared to 20% and 14% in females and males taking placebo, respectively. A study conducted using the Changes in Sexual Functioning Questionnaire (CSFQ) in patients receiving vilazodone yielded rates of sexual dysfunction as high as 22.2% in females and 11.6% in males compared to 16.7% and 17.% in females and males taking placebo, respectively. 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.
Serotonin modulators are contraindicated in patients receiving MAO inhibitors (MAOIs) or who have discontinued an MAOI within 2 weeks due to the risk of serotonin syndrome. Medications with MAOI activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with serotonin modulators because of an increased risk of serotonin syndrome.
Any use of a serotonin modulator antidepressant with other serotonergic agents increases the likelihood of serotonergic adverse effects such as serotonin syndrome 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, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin should be administered with caution to any patient taking a serotonin modulator antidepressant, especially in the elderly. Platelet aggregation may be impaired by serotonin modulators 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 a serotonin modulator with an antiplatelet, anticoagulant, or NSAID medication and to promptly report any bleeding events to the practitioner.
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 a serotonin modulator antidepressant.
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.
Changes in efficacy and safety of serotonin modulator antidepressants have not been observed in geriatric patients versus use in younger adults; therefore, dosage adjustments based on age are not recommended. However, geriatric patients may be at an increased risk for hyponatremia, an adverse effect associated with the use of serotonergic antidepressants. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities; therapy should be in accordance with clinical practice guidelines and pertinent literature. Monitor for antidepressant side effects; some of these effects can increase the risk of falls. Per OBRA, review for continued need of the drug at least quarterly and document the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.
Treatment with serotonin modulator antidepressants during pregnancy should be approached with caution. There are limited data regarding the use of serotonin modulator antidepressants in pregnant patients. The American Psychiatric Association guidelines state that treatment of depression during early pregnancy requires careful individualized risk-benefit assessment, in collaboration with the patient and potentially a neonatal specialist. Use of serotonergic antidepressants, including serotonin modulators, during the third trimester may lead to neonatal complications including prolonged hospitalization, respiratory support, and tube feeding. Additionally, data from published observational studies have reported that exposure to SSRIs or SNRIs (other classes of serotonergic antidepressants), particularly in the month before obstetric delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. The serotonin modulator antidepressants may also increase the risk for postpartum hemorrhage. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to antidepressants; information about the registry can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ or by calling 1-866-961-2388.
There are no data regarding the presence of serotonin modulator antidepressants in human breast milk. The benefits of drug treatment to the mother need to be weighed against the potential risk for infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain following exposure to other serotonergic antidepressants through breast milk. Any infant exposed to serotonergic antidepressants through breast-feeding should be monitored for these adverse effects.
The extent of adverse effects resulting from abrupt discontinuation of serotonin modulator antidepressants is not well established; however, serotonergic agents are generally known to cause symptoms upon discontinuation. It is recommended that the dosage of vilazodone be gradually decreased to minimize the risk for developing discontinuation symptoms. Vortioxetine can be discontinued abruptly, however mild symptoms such as headache and muscle tension may occur.
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