Drugs in Perspective: Takeda's and Lundbeck’s Brintellix

Introduction

Major depressive disorder (MDD) is a medical illness that is characterized by depressed mood, hopelessness, and loss of interest.¹ According to the National Institute of Mental Health (NIMH), approximately 6.7% of US adult population experienced MDD, with 30.4% of these cases (2.0% of US adult population) classified as severe.²

The novel antidepressant agent vortioxetine (Brintellix) is comarketed by Takeda Pharmaceuticals and Lundbeck and was FDA approved for the treatment of MDD in adult patients earlier September.³ The exact mechanism of vortioxetine is not fully understood; however, it is thought that this agent enhances the serotonergic activity in the central nervous system (CNS) by inhibiting the reuptake of serotonin (5-HT). In addition, vortioxetine has other activities such as 5-HT₃ receptor antagonism and 5-HT_1A agonism.³ Thus, vortioxetine is the only compound that exhibits multimodal actions within the selective serotonin reuptake inhibitor drug class. This agent does carry a black-boxed warning cautioning physicians and patients that selective serotonin reuptake inhibitors (SSRIs) can increase the risk of suicidal ideations and behavior in children, adolescents and young adults between aged 18 and 24 years.³

Relevance

Despite several antidepressants available in the market, there is a necessity for new treatment options, as treatment response to depression is heterogeneous. Vortioxetine provides benefits to patients who have failed first-line therapy, as it is the first and only compound within its drug class to have multiple pharmacodynamic activities.⁴

The safety and efficacy of vortioxetine was evaluated in six 6- to 8-week randomized, double-blind, placebo-controlled, fixed-dose clinical studies in adults (aged 18 to 75 years), including 1 study in the elderly population (aged 64 to 88 years) and 1 maintenance study in inpatient and outpatient adults who met the criteria for MDD in accordance with the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV-TR).^5-7 These clinical trials also demonstrated that in patients taking vortioxetine, the likelihood of becoming clinically depressed after successful treatment for a previous episode was decreased. ^5-7

The recommended initial dose is 10 mg administered orally daily with or without food; if tolerated, increase dose to 20 mg per day. The safety and efficacy of doses greater than 20 mg/day have not been studied in controlled clinical trials. In patients who do not tolerate higher doses, it is recommended that the dose be reduced to 5 mg/day.³

Impact on patient subpopulation

Patients with MDD have limited normal functioning capabilities due to the emotional, cognitive and physical symptoms associated with the complex illness. According to the World Health Organization (WHO), approximately 350 million people of all ages are affected by depression.⁸ Fewer than half of those affected by depression receive treatment; however, discontinuation of antidepressants are common.⁸

There are no robust findings to establish a clinically significant difference between mechanisms of action of antidepressants, as there are currently no head-to-head clinical trials comparing vortioxetine to other SSRIs. In majority of patients, the efficacy is generally comparable between classes or within classes of antidepressants.⁹ Therefore, initial selection of antidepressants is primarily based on safety, tolerability and cost of the medication, patient preference, and history of prior medication therapy.⁹

Vortioxetine may have positive impact on this patient population since it provides another treatment option for patients with MDD. This is increasingly important since MDD is a heterogeneous disorder that does not consistently respond to treatment. Due to the medication’s recent introduction into the market, vortioxetine is not available generically; however, the other SSRIs are. Consequently, the costs associated with this agent compared to the older SSRIs are substantial. A cost analysis of SSRIs is as follows:

Vortioxetine (#30)

Fluoxetine

(#100)

Citalopram

(#100)

Escitalopram

(#100)

Paroxetine

(#30)

Sertraline

(#30)

Impact on selective serotonin reuptake inhibitors

Unlike most SSRIs, vortioxetine has multiple mechanisms of action that works through receptor activity modulations and reuptake inhibition. Serotonin is a monoamine neurotransmitter that is believed to be a contributor of mood, appetite, memory and learning, and sleep regulation.⁴ An imbalance of this neurotransmitter may influence mood that can result in depression. Modulation of this neurotransmitter at synapses is believed to decrease symptoms of depression.⁴ Preclinical data on animal studies evaluated the pharmacological profile of vortioxetine and its potential effects on cognitive functions, including memory, attention and executive function via the modulating action of GABAergic activity through 5-HT₃ receptor antagonism.⁴ The preclinical data demonstrated positive results in memory, attention and executive functioning improvement.⁴ Although these studies were conducted in animal models, the findings provide supportive evidence for the drug’s potential to improve cognitive functions, which is key in the treatment of depression.

Impact on patient outcomes and safety

Five 6- to 8-week trials were conducted in adult patients with MDD, including a 12-week open-label maintenance study. These studies were randomized, double-blind, parallel-group, multicenter trials that assessed improvement in overall symptoms of depression at week 8 with vortioxetine compared with placebo. One 8-week trial was conducted in elderly patients with recurrent MDD. A summary of three of the six studies, all published in peer-reviewed journals, is as follows:

·       In Henigsberg et al, investigators evaluated the efficacy and tolerability of 1mg, 5mg, or 10mg of vortioxetine versus placebo for 8 weeks.⁵  There was a significant reduction in the 24-item Hamilton Depression Rating Scale (HDRS-24) total score with the 10-mg dose compared with placebo after 8 weeks of treatment. Additionally, vortioxetine was well tolerated.

·       In the 52-week, open-label extension maintenance trial, Baldwin et al evaluated the safety and tolerability of vortioxetine in long-term treatment.⁶ Based on the findings in this trial, vortioxetine (2.5, 5, 10 mg/day) demonstrated favorable safety and tolerability and maintained effectiveness over 12 months of therapy.

·       The efficacy and tolerability of vortioxetine 5 mg compared to duloxetine 60 mg (reference group) or placebo were assessed in elderly patients with recurrent MDD.⁷ At week 8, vortioxetine compared with placebo showed significantly greater improvement on the primary efficacy outcome (P=.0011). Duloxetine likewise showed superiority compared to placebo at week 8, thus confirming the study. Nausea was the only adverse event with the highest incidence with vortioxetine (21.8%) compared with placebo (8.3%); however, incidence of nausea, dry mouth, constipation, hyperhidrosis, and somnolence was higher with duloxetine. Vortioxetine was efficacious and well tolerated in elderly patients with MDD. 

Common adverse reactions include nausea (21% to 32%), constipation (3% to 6%), and vomiting (3% to 6%). Serious adverse reactions include hyponatremia, hypomania (<0.1%), mania (<1%), suicidal thoughts, serotonin syndrome, and increased risk of bleeding.³ Avoid concomitant use of linezolid, monoamine oxidase inhibitors (MAO-Is), methylene blue, pimozole, lobenguane I 123, and tryptophan with vortioxetine.³ Other agents, such as anticoagulants, antiplatelet therapy, benzodiazepines, nonselective non-steroidal anti-inflammatory drugs (NSAIDs), and lithium, may interact with vortioxetine; thus, caution when used.³

Dr Pham is a PGY1 pharmacy resident at Harris Health System in Houston, and Dr Alvidrez is a clinical pharmacist specialist – formulary management/pharmacoeconomics in the department of pharmacy at Harris Health System.

Disclosure information: The authors report no financial disclosures as related to products discussed in this article.

References

1.      Lyness JM, et al. Clinical manifestations and diagnosis of depressionhttp://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of depression?detectedLanguage=en&source=search_result&search=major+depressive+disorder&selectedTitle=1%7E150&provider=noProvider. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013.

2.      Major Depressive Disorder among Adults. The National Institute of Mental Health website. Available at: http://www.nimh.nih.gov/statistics/1MDD_ADULT.shtml. Accessed October 19, 2013.

3.      Brintellix prescribing information. Deerfiled, IL: Takeda Pharmaceuticals America and Lundbeck; September 2013.

4.      Lundbeck website. Vortioxetine, a new multimodal agent in development for the treatment of major depression, shows effects on cognitive function in several preclinical animal models. Available at: http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=766412. Accessed November 2, 2013.

5.      Henigsberg N, Mahableshwarkar AR, Jacobsen P, et al. A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of Lu AA21004 in adults with major depressive disorder. J Clin Psychiatry. 2012; 73(7): 953-9.

6.      Baldwin DS, Hansen T, and Florea I. Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder. Curr Med Res Opin. 2012; 28(10): 1717-24.

7.      Katona C, Hansen T, and Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012; 27(4): 215-23.

8.      World Health Organization website. Depression. Available at: http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed November 2, 2013.

9.      American Psychiatric Association: Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatr.  2010. DOI: 10.1176/appi.books.9780890423387.654001

10.   Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; December 5, 2013.