Statement of Need

Major depressive disorder (MDD) affects 7.1% of individuals each year and 14.4% of individuals over the course of a lifetime (Kessler, Petukhova et al. 2012) and is associated with substantial morbidity, mortality and healthcare costs (Kessler, Berglund et al. 2003; Stewart, Ricci et al. 2003; Kessler, Chiu et al. 2005; Wang, Lane et al. 2005; Shim, Baltrus et al. 2011).

Despite numerous treatment options for depression, this disorder continues to be inadequately treated, and lack of treatment response and relapse is common. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study examined responses of a large cohort of MDD patients who underwent up to four successive treatment steps. This study demonstrated that only about 30-40% of patients with MDD attain full remission with first- or second-line treatment (Rush, Trivedi et al. 2006; Trivedi, Rush et al. 2006; Sinyor, Schaffer et al. 2010; Perlis 2013). Even after instituting third- and fourth-line treatments, which included a multitude of switching and augmentation strategies, only 67% achieved remission. The results of this study underscored the limitations of current options to treat to meaningful clinical improvement as well as the fact that responses to current antidepressant options are suboptimal.

Current strategies for managing treatment non-response and resistance in MDD include dose optimization, switching antidepressant medications or medication classes, and augmenting therapy by adding another treatment, such as a different medication or psychotherapy (Thase 2011). Focusing on neurotransmitters other than serotonin may advance treatment for resistant MDD; this can be achieved by utilizing combination therapy with lithium, atypical antipsychotics and other pharmacological agents (Mathews, Henter et al. 2012; Schlaepfer, Agren et al. 2012; Murrough, Iosifescu et al. 2013; Pehrson and Sanchez 2013). Other options include transcranial magnetic stimulation (TMS), which has been shown to have a modest effect in patients with treatment-resistant depression, and electroconvulsive therapy, which is usually reserved for severe treatment-resistant MDD or MDD with psychotic or catatonic features (APA 2010; Lee, Hermens et al. 2012). Deep brain stimulation (DBS) is another option, generally reserved as a last resort (Schlaepfer, Agren et al. 2012).

MDD management often falls short of achieving meaningful clinical response because not all symptoms of depression are uniformly well-recognized (Ravnkilde, Bruun et al. 2007; Rizzo 2008). Clinical diagnosis of MDD remains challenging for caregivers, as both patients and physicians have difficulty accurately evaluating the symptoms (Mitchell, Vaze et al. 2009; Tyrer 2009). Clinicians and patients may also fail to recognize that multiple MDD symptoms can contribute to poor response (Mitchell, Vaze et al. 2009; Tyrer 2009).

Due to the frequency of inadequate response to MDD treatment, additional therapeutic options are greatly needed. New MDD drug development efforts have focused on therapeutics with reduced side effects in order to improve patient adherence to treatment plans (Sheehan, Croft et al. 2009; Baldwin, Hansen et al. 2012). A larger variety of neurotransmitter targets are also being explored beyond the serotonergic and noradrenergic systems that may result in improved response rates and assist in addressing some of the symptoms of MDD that are overlooked by currently available therapies.

APA. Practice Guideline for Treatment of Patients With Major Depressive Disorder. Washington, D.C., American Psychiatric Association Press. 2010.

Baldwin DS, Hansen T, et al. Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder. Curr Med Res Opin. 2012;28(10):1717-1724.

Kessler RC, Berglund P, et al. (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.

Kessler RC, Chiu WT, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627.

Kessler RC, Petukhova M, et al. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169-184.

Lee RS, Hermens DF, et al. A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J Affect Disord. 2012;140(2):113-124.

Mathews DC, Henter ID, et al. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Mitchell AJ, Vaze A, et al. Clinical diagnosis of depression in primary care: a meta-analysis. Lancet. 2009; 374(9690):609-619.

Murrough JW, Iosifescu DV, et al. Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. Am J Psychiatry. 2013 Oct 1;170(10):1134-1142. doi: 10.1176/appi.ajp.2013.13030392.

Pehrson AL, Sanchez C. Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction. CNS Spectr. 2013;1-13.

Perlis RH. A clinical risk stratification tool for predicting treatment resistance in major depressive disorder. Biol Psychiatry. 2013;74(1):7-14.

Ravnkilde B, Bruun LM, et al. Cognitive symptoms of depression--importance for treatment and prognosis. Ugeskr Laeger. 2007;169(16):1459-1462.

Rizzo ALR. Major depression and explicit memory. latreia. 2008;21(2):177-185.

Rush AJ, Trivedi MH, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

Schlaepfer TE, Agren H, et al. The hidden third: improving outcome in treatment-resistant depression. J Psychopharmacol. 2012;26(5):587-602.

Sheehan DV, Croft HA, et al. Extended-release Trazodone in Major Depressive Disorder: A Randomized, Double-blind, Placebo-controlled Study. Psychiatry (Edgmont). 2009;6(5):20-33.

Shim RS, Baltrus P, et al. Prevalence, treatment, and control of depressive symptoms in the United States: results from the National Health and Nutrition Examination Survey (NHANES), 2005-2008. J Am Board Fam Med. 2011;24(1):33-38.

Sinyor M, Schaffer A, et al. The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Can J Psychiatry. 2010;55(3):126-135.

Stewart WF, Ricci JA, et al. Cost of lost productive work time among US workers with depression. JAMA. 2003;289(23):3135-3144.

Thase ME, Trivedi MH, et al. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995;12(3):185-219.

Trivedi MH, Rush AJ, et al. Factors associated with health-related quality of life among outpatients with major depressive disorder: a STAR*D report. J Clin Psychiatry. 2006;67(2):185-195.

Tyrer P. Are general practitioners really unable to diagnose depression? Lancet. 2009;374(9690):589-590.

Wang PS, Lane M, et al. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):629-640.