Major depressive disorder (MDD), also known as clinical depression, is a chronic medical illness characterized by persistent sadness, loss of interest in normal activities, and in some cases, by physical symptoms.1 MDD is associated with serious emotional and biological manifestations that affect a person’s thoughts, feelings, behavior, mood, and physical health.1
An estimated 25 million people in the United States are affected by MDD annually; however, only 50% of patients with MDD receive treatment.2 Moreover, a national household survey revealed that 6.7% of US adults experienced a major depressive episode within a 12-month period.3
MDD has the potential to disrupt life by causing changes in sleep or appetite, poor concentration, loss of energy, low self-esteem, hopelessness, or guilt.2 Some people experience 1 episode of MDD in the course of a lifetime, whereas many people have recurrent episodes. Without treatment, an episode can last from several months to years.2
Most concerning is the fact that more than 15% of people with MDD take their own lives.4 Untreated MDD increases the risk of suicide—a leading cause of mortality in the United States that is responsible for 30,000 deaths annually.4 In addition, untreated MDD can also lead to a number of emotional, physical, and other health-related complications, including alcohol or substance abuse, anxiety, family conflicts, relationship difficulties, social isolation, and premature death from other medical conditions.1 As many as 30% of drug and alcohol users are estimated to have undetected MDD.4
Individuals who have had a stroke, or those with heart disease, diabetes, cancer, Parkinson’s disease, or HIV/AIDS are at an increased risk for depression.4 In older adults, MDD may go undiagnosed and untreated, because symptoms such as fatigue, loss of appetite, and sleep problems are also caused by other medical conditions.1
According to one study, the average annual cost of MDD in the United States is an estimated $83.1 billion, which includes $26.1 billion in direct medical costs, $5.4 billion in suicide-related mortality costs, and $51.5 billion in workplace costs.5 These totals would be considerably higher if they captured the costs of coexisting psychiatric and medical conditions or the role of related painful conditions.5
A study that assessed the association between treatment-resistant depression (defined as undergoing 4 different antidepressant treatment trials) and medical expenditures showed that treatment-resistant depression was associated with 29.3% higher costs (P <.001) in medical expenditures compared with patients without treatment-resistant depression.6 These higher per-patient medical expenditures were attributed to greater healthcare utilization.6
Treatments for MDD include pharmacologic therapy, psychotherapy, and electroconvulsive therapy (for some severe episodes or severe depression with psychosis).1,2 Other treatments may include transcranial magnetic stimulation, vagus nerve stimulation, aerobic exercise, and complementary and alternative medicines.1,2
The antidepressant medications used to treat patients with MDD include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, atypical antidepressants, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or other medication strategies, including appropriate combination and augmentation approaches.1
The antidepressant drug classes are associated with class-specific side effects.1 Currently, SSRIs and serotonin–norepinephrine reuptake inhibitors are the cornerstones of managing patients with MDD.7 For the majority of adults with MDD, a combination of medication and psychotherapy is the most effective management approach.1 Finding the appropriate medication for a patient with MDD can be challenging, however, often requiring trial and error based on the individual patient’s response.
Genotyping tests, including cytochrome (CY) P450 and other specific genes, can help clinicians predict how well a patient can metabolize a medication and can identify which antidepressant may be a prudent option.1 Early diagnosis and management are crucial to improving the outcomes for patients with this serious and debilitating illness.
A New Serotonin–Norepinephrine Reuptake Inhibitor for the Treatment of MDD
On July 26, 2013, levomilnacipran extended release (Fetzima; Forest Laboratories), a serotonin–norepinephrine reuptake inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of MDD in adults.8 The approval of Fetzima was based on three 8-week, double-blind, placebo-controlled studies.9 Levomilnacipran is an active enantiomer of milnacipran, a drug that was approved by the FDA in 2009 for the treatment of fibromyalgia in adults.7,9 However, levomilnacipran is not approved for the management of fibromyalgia.9
According to Michael R. Liebowitz, MD, Professor of Clinical Psychiatry, Columbia University, New York, “As many people with MDD struggle to find a treatment that works for them, Fetzima provides patients and physicians with an additional option for treating this serious disease.”8
Mechanism of Action
The exact mechanism of the antidepressant action of levomilnacipran is unknown; however, it is believed to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through the inhibition of reuptake at serotonin and norepinephrine transporters. Nonclinical studies have shown that levomilnacipran is a potent and selective serotonin–norepinephrine reuptake inhibitor.9
The recommended dose for levomilnacipran is 40 mg to 120 mg once daily with or without food. The initial dose is 20 mg once daily for 2 days, and then an increase to 40 mg once daily. Based on the efficacy and tolerability, the dose is increased in increments of 40 mg at an interval of 2 or more days. The maximum recommended dose is 120 mg once daily. Capsules should be taken whole without being opened, chewed, or crushed.9
When discontinuing levomilnacipran, the dose should be reduced gradually whenever possible. In patients with moderate renal impairment, the dose should not exceed 80 mg once daily; in patients with severe renal impairment, the dose should not exceed 40 mg once daily.9
Levomilnacipran is available as an extended-release capsule in 20-mg, 40-mg, 80-mg, and 120-mg strengths.9
A dose adjustment is recommended when levomilnacipran is coadministered with strong inhibitors of CYP3A4 (eg, ketoconazole).9
The efficacy of levomilnacipran for the treatment of MDD was evaluated in three 8-week, randomized, double-blind, placebo-controlled studies (at doses of 40-120 mg once daily) in adult outpatients (aged 18-78 years) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for the diagnosis of MDD.
Studies 1 and 2 were fixed-dose trials, and study 3 was a flexible-dose trial.9
The patients in study 1 received 40 mg (N = 178), 80 mg (N = 179), or 120 mg (N = 180) of levomilnacipran once daily or placebo (N = 176).
The patients in study 2 received 40 mg (N = 188) or 80 mg (N = 188) of levomilnacipran once daily or placebo (N = 186).
In study 3 (ie, the flexible-dose trial), the patients received placebo (N = 217) or 40 mg to 120 mg (N = 217) of levomilnacipran once daily, with 21%, 34%, and 44% of patients receiving 40 mg, 80 mg, and 120 mg, respectively, at the end of their treatment.9
Levomilnacipran was shown to be superior to placebo in all 3 studies, based on the improvement of depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale total score (Table 1).
In addition, levomilnacipran demonstrated superiority versus placebo, as measured by improvement on the Sheehan Disability Scale functional impairment total score.9
Post-hoc analyses of the relationships between treatment outcome and age, sex, and race were not suggestive of any differential responsiveness on the basis of these patient characteristics.9
The most common adverse reactions (≥5% incidence and at least twice the rate of placebo) associated with levomilnacipran are nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations. The occurrence rates of these adverse reactions compared with placebo are shown in Table 2.9
Based on pooled data from the short-term, placebo-controlled, fixed-dose studies, there were no dose-related adverse reactions (>2% overall incidence) in patients treated with levomilnacipran across the dose range of 40 mg to 120 mg once daily, with the exception of urinary hesitation and erectile dysfunction (Table 3).9
Levomilnacipran is contraindicated in patients who are hypersensitive to levomilnacipran, milnacipran hydrochloride, or any excipient in the levomilnacipran formulation. MAOIs intended to treat psychiatric disorders should not be used with levomilnacipran or within 7 days of stopping treatment with levomilnacipran. Levomilnacipran should not be used within 14 days of stopping an MAOI that is intended to treat psychiatric disorders. In addition, levomilnacipran should not be initiated in a patient who is being treated with linezolid or intravenous methylene blue. Levomilnacipran is contraindicated in patients with uncontrolled narrow-angle glaucoma.9
Warnings and Precautions
Boxed warning. The prescribing information for levomilnacipran includes a boxed warning about the increased risk of suicidal thinking and behavior in children, adolescents, and young adults who are taking antidepressants; patients should be monitored for worsening and emergence of suicidal thoughts and behaviors. It also states that levomilnacipran is not approved for use in pediatric patients.9
Suicidal thoughts and behaviors in adolescents and young adults. Patients should be monitored for clinical worsening and suicidal thinking or behavior.9
Serotonin syndrome. Serotonin syndrome has been reported with SSRIs and serotonin–norepinephrine reuptake inhibitors, both when taken as monotherapy, but especially when taken in combination with other serotonergic agents (including triptans, tricyclics, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John’s wort). If such symptoms occur, levomilnacipran should be discontinued and supportive treatment should be initiated. If the concomitant use of levomilnacipran with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.9
Elevated heart rate and blood pressure. Heart rate and blood pressure should be measured before the initiation of treatment with levomilnacipran and periodically throughout treatment. Preexisting hypertension should be controlled before initiating therapy with levomilnacipran.9
Abnormal bleeding. Treatment with levomilnacipran can increase the risk of bleeding. Patients should be cautioned about the risk of bleeding associated with the use of nonsteroidal anti-inflammatory drugs, aspirin, or other drugs that affect coagulation.9
Narrow-angle glaucoma. Mydriasis has occurred with levomilnacipran, and therefore it should be used with caution in patients with controlled narrow-angle glaucoma. Patients with or at risk for raised intraocular pressure should be monitored.
Urinary hesitation or retention. Urinary hesitation or retention can occur. If symptoms of these occur, levomilnacipran should be discontinued or other appropriate medical interventions should be considered.
Activation of mania/hypomania. Patients should be screened for bipolar disorder, and should be cautioned about the risk of activation of mania and hypomania.
Seizures. Seizures can occur with levomilnacipran, which should be used with caution in patients with a seizure disorder.
Discontinuation syndrome. When discontinuing levomilnacipran, the dose should be tapered when possible, and patients should be monitored for discontinuation symptoms.
Hyponatremia. Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion.9
The treatment of MDD can often be challenging. Having a novel therapeutic alternative to choose from offers a new and potentially improved option for patients whose symptoms do not improve with current therapies. A new treatment option for adults with MDD became available in July 2013 with the FDA approval of levomilnacipran, an oral, extended-release serotonin–norepinephrine reuptake inhibitor. In three 8-week, randomized, double-blind, placebo-controlled clinical studies, levomilnacipran extended release (at doses of 40-120 mg daily) demonstrated significant superiority over placebo in improving depressive symptoms in adult patients with MDD.
The most common adverse reactions (≥5% incidence and at least twice the rate of placebo) associated with levomilnacipran are nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations.
- Mayo Clinic staff. Depression (major depression). February 10, 2012. www.mayo clinic.com/health/depression/DS00175/METHOD=print. Accessed August 20, 2013.
- National Alliance on Mental Illness. Major depression. Fact sheet. Reviewed April 2013. www.nami.org/factsheets/depression_factsheet.pdf. Accessed August 20, 2013.
- Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-627. Erratum in: Arch Gen Psychiatry. 2005;62:709.
- National Alliance on Mental Illness. The impact and cost of mental illness: the case of depression. www.nami.org/PrinterTemplate.cfm?Section=Policymakers_Tool kit&Template=/ContentManagement/ContentDisplay.cfm&ContentID=19043. Accessed August 15, 2013.
- Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465-1475.
- Olchanski N, McInnis Myers M, Halseth M, et al. The economic burden of treatment- resistant depression. Clin Ther. 2013;35:512-522.
- Thase ME. Levomilnacipran: a brief overview. Medscape. July 26, 2013. www.medscape.com/viewarticle/808378. Accessed August 23, 2013.
- Cassels C. FDA approves new SNRI for major depression. Medscape. July 26, 2013. www.medscape.com/viewarticle/808481. Accessed August 14, 2013.
- Fetzima (levomilnacipran) extended-release capsules [prescribing information]. St Louis, MO: Forest Pharmaceuticals, Inc; July 2013.