life Review Drug Repurposing for the Management of Depression: Where Do We Stand Currently? Hosna Mohammad Sadeghi 1,†, Ida Adeli 1,† , Taraneh Mousavi 1,2, Marzieh Daniali 1,2, Shekoufeh Nikfar 3,4,5 and Mohammad Abdollahi 1,2,* 1 Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Iran; [email protected] (H.M.S.); [email protected] (I.A.); [email protected] (T.M.); [email protected] (M.D.) 2 Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran 3 Personalized Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran 1417614411, Iran; [email protected] 4 Pharmaceutical Sciences Research Center (PSRC) and the Pharmaceutical Management and Economics Research Center (PMERC), Evidence-Based Evaluation of Cost-Effectiveness and Clinical Outcomes Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Iran 5 Department of Pharmacoeconomics and Pharmaceutical Administration, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran * Correspondence: [email protected] † Equally contributed as first authors. Citation: Mohammad Sadeghi, H.; Abstract: A slow rate of new drug discovery and higher costs of new drug development attracted Adeli, I.; Mousavi, T.; Daniali, M.; the attention of scientists and physicians for the repurposing and repositioning of old medications. Nikfar, S.; Abdollahi, M. Drug Experimental studies and off-label use of drugs have helped drive data for further studies of ap- Repurposing for the Management of proving these medications. A deeper understanding of the pathogenesis of depression encourages Depression: Where Do We Stand novel discoveries through drug repurposing and drug repositioning to treat depression. In addition Currently? Life 2021, 11, 774. to reducing neurotransmitters like epinephrine and serotonin, other mechanisms such as inflam- https://doi.org/10.3390/ mation, insufficient blood supply, and neurotoxicants are now considered as the possible involved life11080774 mechanisms. Considering the mentioned mechanisms has resulted in repurposed medications to treat treatment-resistant depression (TRD) as alternative approaches. This review aims to discuss the Academic Editors: Anna Serefko, Ewa Poleszak and Aleksandra Szopa available treatments and their progress way during repositioning. Neurotransmitters’ antagonists, atypical antipsychotics, and CNS stimulants have been studied for the repurposing aims. However, Received: 29 June 2021 they need proper studies in terms of formulation, matching with regulatory standards, and efficacy. Accepted: 26 July 2021 Published: 30 July 2021 Keywords: clinical trials; depression; major depressive disorder; new drugs; repurposing; reposition- ing; strategies Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Despite the high rate of technological progress and improvements in knowledge of different diseases, the discovery of new medications demonstrated a lower speed [1]. As the regulatory requirements for bringing a new medication to the market is becom- Copyright: © 2021 by the authors. ing more challenging to meet, medication cost increases globally [2]. Licensee MDPI, Basel, Switzerland. Drug repositioning, also called drug repurposing or re-tasking, is a promising strategy This article is an open access article to introduce new indications for other therapeutic goals for an available drug in the distributed under the terms and market [3]. Since the safety profile of these medications was studied thoroughly before, conditions of the Creative Commons the development of their formulation has been analyzed, and the medicines successfully Attribution (CC BY) license (https:// passed the preclinical and clinical steps, the risk of failure decreases significantly [4]. To creativecommons.org/licenses/by/ apply a drug repositioning strategy, three main steps are needed to be concluded; first, a 4.0/). Life 2021, 11, 774. https://doi.org/10.3390/life11080774 https://www.mdpi.com/journal/life Life 2021, 11, 774 2 of 35 molecule/substance should be suggested for the mentioned indication; second, preclinical models, including animal and computational models, should be assessed and last the efficacy of medication should be analyzed [5]. As a significant mental disorder, major depressive disorder (MDD) affects approxi- mately 264 million globally [6]. Due to the insufficient therapeutic response of patients to the available medications, the need for new medicines has attracted scientists world- wide [7]. Various mechanisms have been associated with the prevalence of MDD, and these mechanisms directly influence medication selection. Changes in inflammatory biomarkers, neurotransmitters, age-related, and genetic factors are among the mechanisms constituting the indications of medications [8]. Moreover, new antidepressant medications usually act on multiple intra- and extra-cellular markers, indicating their poly-pharmacology indi- cations [9]. This review aims to provide a complete insight into the drug repositioning strategy, especially the candidates that could be beneficial in managing MDD. 2. Drug Repurposing 2.1. History Drug repurposing is the procedure of finding new indications for approved or in- vestigational medications [10,11]. Investigational medicines may have had a desirable safety profile in phase I/II clinical trials [12] but never reached the market [11,12] due to reasons unrelated to safety [12], such as lack of efficacy [11]. Drug repurposing can emerge in different forms like repositioning, reformulation, and combination [13,14]. Drug repurposing was serendipitous and accidental in the past; whenever a medication had shown an off-target or a new on-target effect, it was investigated for commercial exploita- tion. [10]. So far, the most successful repurposed drugs have been found accidentally, and no systematic approach has been involved in the process [10,15]. Sildenafil citrate was an antihypertensive medication that got repurposed as retrospective clinical data analysis showed its positive effect on erectile dysfunction [10,16]. The year sildenafil got marketed by Pfizer for erectile dysfunction under the name Viagra® [17], it held a 47% share of this problem’s market, and the total sales were USD 2.05 billion worldwide [10]. Thalidomide is another well-known instance causing many severe skeletal birth defections in children whose mothers had taken this medication during the first trimester of pregnancy [1,10]. In consequence, thalidomide was withdrawn for four years [10]. In 1964, thalidomide was fortuitously recognized to be effective in erythema nodosum leprosum (ENL) [18]. Decades later, in 1999, thalidomide was discovered to be effective in multiple myeloma [19]. The positive outcome in multiple myeloma led to further derivative developments like lenalidomide [10]. Bupropion, an antidepressant medication got approved by the United States Food and Drug Administration (US-FDA) for smoking cessation [13], botulinum toxin A, the compound used for eye muscle disorders with cosmetic impacts [18] and mi- noxidil, the antihypertensive medication, became established for pattern hair loss in male and female [17,20] are some instances of well-known repurposed drugs [12]. Iproniazid, an antitubercular compound, was the first medication got reported for its antidepressant effect. This compound showed euphoria, psychostimulation, increased appetite, and im- proved sleep as the side effects [21]. The story of finding D-lysergic acid diethylamide (LSD) psychedelic effects is another exciting example of serendipitous discovery in the field of psychiatry. LSD was first synthesized in 1938, but it did not show considerable physiological effects in animal testing. LSD’s strong and extraordinary influences on the mind were accidentally discovered for the first time in 1943 [22]. Thirteen medications have been repurposed for depression or bipolar depression treatment by 2017 [13]. 2.2. Different Types of Drug Repurposing Drug reformulation, repositioning, and combination are counted as different drug repurposing/repositioning [13,14]. Life 2021, 11, 774 3 of 35 2.2.1. Drug Repositioning It finds new indications for a medication that already has other therapeutic indica- tions [13,14]. For instance, mifepristone, an anti-progesterone drug with an initial indication for abortion, was experimentally effective in psychotic depression [3,23]. 2.2.2. Drug Reformulation It is about using a medication in a new dosage form [13,14]. The new formulation can both be taken via the same old route or a different route of administration. An example of drug reformulation is formulating ketamine for intranasal and sublingual routes to treat MDD [13]. 2.2.3. Drug Combination It refers to using two or more medications together [13,14] to improve efficacy and safety [13]. For example, using quetiapine and antidepressants in combination leads to the increased effect of antidepressant medications in the elderly suffering from MDD and cerebrovascular deterioration. In addition, taking anti-inflammatory medicines with antidepressants enhances responses to first-line antidepressants [13]. 2.3. Common Approaches Before the development stage