Investigational Drugs for Treating Major Depressive Disorder

Expert Opinion on Investigational Drugs ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20 Investigational drugs for treating major depressive disorder Ashish Dhir To cite this article: Ashish Dhir (2016): Investigational drugs for treating major depressive disorder, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2017.1267727 To link to this article: http://dx.doi.org/10.1080/13543784.2017.1267727 Published online: 14 Dec 2016. Submit your article to this journal Article views: 11 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieid20 Download by: [University of Regina] Date: 18 December 2016, At: 22:53 EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2016 http://dx.doi.org/10.1080/13543784.2017.1267727 REVIEW Investigational drugs for treating major depressive disorder Ashish Dhir Department of Neurology, School of Medicine, University of California Davis, Sacramento, CA, USA ABSTRACT ARTICLE HISTORY Introduction: Treatment of patients suffering from major depression could be highly challenging for Received 27 September 2016 psychiatrists. Intractability as well as relapse is commonly seen among these patients, leading to Accepted 29 November 2016 functional impairment and poor quality of life. The present review discusses some of the novel KEYWORDS investigational drugs that are under pre-clinical or clinical phases in the treatment of major depression. Major depression; preclinical Areas covered: Molecules belonging to different classes such as triple reuptake inhibitors, opioid and clinical studies; opioid receptors, ionotropic and metabotropic glutamate receptors, and neurotrophin in the treatment of receptors; glutamatergic major depression are covered in this article. receptors; neurotrophins; Expert opinion: Although the historical discovery of earlier antidepressant molecules (iproniazid and triple reuptake inhibitors imipramine) is through serendipitous discovery, the present research focuses on discovering novel molecules based on our current pathophysiological knowledge of the disease condition. The fast-acting antidepressant property of N-methyl-d-aspartate (NMDA) receptor molecules, including ketamine is an exciting area of research. Other drug molecules such as amitifadine (triple reuptake inhibitor), ALKS- 5461 (kappa receptor antagonist and mu opioidergic receptor agonist), rapastinel (NMDA glutamatergic receptor modulator) are under Phase-III clinical trials and could be approved in the near future for the treatment of major depression. 1. Introduction marijuana [15]. There is no clear-cut biomarker for major depression so that early intervention could be initiated [16]. Major depression is a common psychiatric disorder that is Selective serotonin reuptake inhibitors (SSRIs) are the first associated with high rates of mortality and morbidity [1,2]. A choice of drugs for the treatment of major depression; how- genetic make-up plays an important role in its pathophysiol- ever, around half of the depressed patients do not respond to ogy, the difference in maturational white matter microstruc- the monotherapy and often requires a second line of treat- tures in mood regulatory pathways has been noticed in ment in order to achieve full remission [17]. Moreover, con- children who are predisposed to its outcome due to their ventional antidepressants, including SSRIs takes 3–4 weeks in parental history [3]. Major depression is generally comorbid order to show their effectiveness [18]. Antidepressants that with other disorders of the body, including anxiety [4], schizo- could enhance the neuroplasticity and neurogenesis mechan- phrenia [5], diabetes [6], obesity [7], cancer [8], chronic isms, for example agomelatine and novel molecules listed in obstructive pulmonary diseases [9], cardiovascular abnormal- this article, are of particular interest [19]. In present scenarios, ities [10], stroke [11], and many more. As per the findings from researchers have been focusing on some rapidly acting anti- Singapore Mental Health Study, major depression is more depressants such as N-methyl-D-aspartate (NMDA) receptor prevalent in Indian men living in Singapore compared to blockers, including ketamine [18]. This article will discuss other ethnicities such as China [12]. Further, women (7.2%) some of the important investigational drugs that are in pre- are more prone to depression disorder compared to men clinical or clinical stages of drug development. A particular (4.3%), as per the report of Singapore Mental Health emphasis has been given toward opioidergic receptor modu- Study [12]. lators, glutamatergic, triple reuptake inhibitors as well as neu- Stress is an important pathophysiological factor responsible rotrophin class of molecules (Figure 1). The details of these for major depression. Continuous stress could lead to degen- molecules were searched on electronic database (Pubmed, erative changes in different regions of the brain, including Medline, clinicaltrial.gov, molecule originator’s company sites, hippocampus and amygdala, and thus affect synaptic plasti- abstracts in various conferences) from the year of their incep- city and cognitive decline [13]. Besides its effect on the cog- tion until November, 2016. The combination of following text- nitive abilities of the patient, depressed patients could have words were used: major depression, novel molecules, clinical increased suicidal tendencies [14]. The symptoms of depres- trials, neurotrophic factors, opioidergic receptors, triple reup- sion could be commonly seen in patients addicted to various take inhibitors, glutamatergic receptor modulators, preclinical psychotropic and the substance of abuse molecules, including findings. CONTACT Ashish Dhir [email protected] Department of Neurology, University of California Davis, 4635, 2nd Avenue, Suite 1004A, Sacramento, CA 95817, USA © 2016 Informa UK Limited, trading as Taylor & Francis Group 2 A. DHIR correlated to its antagonistic activity at κ-opiodergic receptors Article highlights [28]. The κ-opioidergic receptor antagonists such as buprenorphine by blocking the release of dynorphin could increase ● Major depression is a severe mood disorder that requires immediate clinical investigation. glutamate to its physiological levels in the hippocampus area ● Various conventional antidepressant molecules are available for the of the brain, thus resulting in the antidepressant effect. The κ- – management of major depression; however, 30 40% of these opioidergic knock-out mouse do not respond to the antide- patients do not respond to the monotherapy and therefore requires the addition of 2nd drug in their dosing regimen. pressant effect of buprenorphine [28]. ● There is a continuous effort from researchers exploring the novel Buprenorphine, a κ-receptor antagonist, has been found to drug targets as well as drugs for patients who do not respond to be effective as a rapid antidepressant agent in treatment- drug therapy ● Some of these investigational targets include, opioidergic system, resistant depression when administered as an average dose ionotropic and metabotropic glutamatergic receptors, neurotophins, of 0.4 mg/day among patients of 15–50 years of age [29]. triple reuptake inhibitors and many more. Buprenorphine has shown antidepressant-like effect in certain, ● The investigational molecules discussed in this article include, ALKS 5461, CERC-501, rapastinel, dueteriated dextromethorphan, CERC- but not all strains of rats, when tested in the forced swim test 301, basimglurant, amitifadine, tedatioxetine and ansofaxine. [30]. The molecule did not show an antidepressant-like effect ● Amitifadine, ALKS-5461 and rapastinel are in late clinical trials. These in Wistar or Sprague–Dawley strains of rats [30]. Some of the drugs may soon show up in the clinics for the treatment of major depression. other κ-opioidergic receptor antagonists, such as JDTic and PF-4455242, although active in preclinical animal models of This box summarizes key points contained in the article. depression, have been declined for further clinical development due to their propensity to induce toxic side effects, for example, tachycardia associated with JDTic. In a very recent study, buprenorphine in ultra-low dose (0.1 mg once or twice daily) have been found to prevent suicidal tendencies in 2. Opioid receptor modulators patients without substance abuse [31]. Opioid receptors, well known linked to the pathophysiological Almatroudi and colleagues have discussed the beneficial basis of pain, stress, and drug addiction plays an important effect of combining buprenorphine (a partial μ -receptor ago- role in mood disorders [20]. The opioidergic and/or NMDA nist with κ-receptor antagonistic properties) and naltrexone (a receptor system is partly involved in the antidepressant-like μ-receptor antagonist) in the forced swim test and novelty effect of fluoxetine in animal model of physical stress [21]. induced hypophagia tasks [32]. By combining these two mole- Huang and colleagues have shown that the combination of cules, one can achieve the antidepressant property resulting LY2444296 (a κ-opioidergic receptor antagonist) and ADL5859 from the blockage of κ-opioidergic receptors without activat- (a δ-opioidergic receptor agonist) produces synergistic antide- ing μ receptors. In this manner, the addiction potential that is pressant-like effect when tested in the mouse forced swim associated

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