Novel Pharmacological Targets in Drug Development for the Treatment of Anxiety and Anxiety-Related Disorders
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Pharmacology & Therapeutics 204 (2019) 107402 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders Simone B. Sartori, Nicolas Singewald ⁎ Institute of Pharmacy, Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, Innsbruck, Austria article info abstract Available online 27 August 2019 Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need for improved drug treatments. In this review an overview of drugs being studied in different phases of clin- Keywords: ical trials for their potential in the treatment of fear-, anxiety- and trauma-related disorders is presented. One Anxiolytic strategy followed in drug development is refining and improving compounds interacting with existing anxiolytic Evidence-based drug discovery drug targets, such as serotonergic and prototypical GABAergic benzodiazepines. A more innovative approach in- Hamilton anxiety volves the search for compounds with novel mechanisms of anxiolytic action using the growing knowledge base RDoc concerning the relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anx- SSRI Psychedelics iety. The target systems evaluated in clinical trials include glutamate, endocannabinoid and neuropeptide sys- tems, as well as ion channels and targets derived from phytochemicals. Examples of promising novel candidates currently in clinical development for generalised anxiety disorder, social anxiety disorder, panic dis- order, obsessive compulsive disorder or post-traumatic stress disorder include ketamine, riluzole, xenon with one common pharmacological action of modulation of glutamatergic neurotransmission, as well as the neurosteroid aloradine. Finally, compounds such as D-cycloserine, MDMA, L-DOPA and cannabinoids have shown efficacy in enhancing fear-extinction learning in humans. They are thus investigated in clinical trials as an augmentative strategy for speeding up and enhancing the long-term effectiveness of exposure-based psycho- therapy, which could render chronic anxiolytic drug treatment dispensable for many patients. These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of rel- ative stagnation. © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Contents 1. Introduction................................................ 2 2. Overviewandhistoricalaccountofcurrentmedicationoptionsforanxietyandrelateddisorders......... 2 3. Problemswith,andfailuresin,anxiolyticdrugdevelopment.......................... 4 4. Neurobiologyoffearandanxietyasapotentialsourceofinnovationandprogress................ 6 5. Novel compounds acting on refinedclassicalpharmacologicaltargetsystems.................. 8 6. Novelanxiolyticcompoundsactingonalternativepharmacologicaltargetsystems............... 15 7. Phytochemicals............................................. 19 Abbreviations: 2-AG, 2-arachidonoylglycerol; 5-HT, serotonin, 5-hydroxytryptamine; AEA, anandamide; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; BDZ, benzodiazepine; CB1/CB2, cannabinoid receptor type 1 or 2; CBD, cannabidiol; CBT, cognitive behavioural therapy; CNS, central nervous system; COX-2, cyclooxygenase-2; CRH, corticotropin releasing hormone; D1–5,dopaminereceptorsubtypes1–5; DREADDs, Designer Receptors Exclusively Activated by Designer Drugs; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, version 5; EBT, exposure-based therapy; eCB, endocannabinoid; EMA, European Medicines Agency; ER, extended release; FAAH, fatty acid amide hydrolase; FDA, Food and Drug Administration of the United States; GABA, γ-aminobutyric acid; GAD, generalised anxiety disorder; ICD 10/11, International Statistical Classification of Diseases and Related Health Problems, version 10/11; IL, infralimbic cortex; L-DOPA, L-3,4-dihydroxyphenylalanine; LSD, lysergic acid diethylamide; MAG-L, monoacylglycerol lipase; MAPK, mitogen-activated protein kinase; mGluR, metabotropic glutamate receptor; mPFC, medial prefrontal cortex; mTOR, mammalian target of rapamycin; NCT, National Clinical Trial; NMDA, N-methyl-D-aspartate; NPS, neuropeptide S; NPY, neuropeptide Y; OCD, obsessive compulsive disorder; OXT, oxytocin; PAM, positive allosteric mod- ulator; PD, panic disorder; PFC, prefrontal cortex; PTSD, post-traumatic stress disorder; RDoc, Research Domain Criteria; SAD, social anxiety disorder; SNRI, serotonin and noradrenaline re- uptake inhibitor; SSRI, selective serotonin re-uptake inhibitor; THC, tetrahydrocannabinol; V1A/V1B, vasopressin receptor 1A or 1B. ⁎ Corresponding author at: Institute of Pharmacy, Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. E-mail address: [email protected] (N. Singewald). https://doi.org/10.1016/j.pharmthera.2019.107402 0163-7258/© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 2 S.B. Sartori, N. Singewald / Pharmacology & Therapeutics 204 (2019) 107402 8. Pharmacologicalaugmentationofpsychotherapy.............................. 20 9. Summaryandconclusion......................................... 22 10. Futuredirection............................................. 24 Fundinginformation.............................................. 24 References.................................................. 24 1. Introduction remain substantial issues (Roy-Byrne, 2015; Taylor, Abramowitz, & McKay, 2012). In treatment-resistant patients (Bokma et al., 2019) Anxiety is an emotional response to potential future threat or dan- showing only little or no improvement to pharmaco- and/or psycho- ger, eliciting symptoms of negative affective, somatic, behavioural and therapy, brain stimulation therapies, including electroconvulsive ther- cognitive components along a continuum based on intensity and dura- apy, transcranial magnetic stimulation, vagus nerve stimulation and tion. While ‘normal’ anxiety is adaptive to alert and prepare the organ- deep brain stimulation, can be considered (Kar & Sarkar, 2016; Lebois, ism for the potential threat, anxiety is considered pathologic when it Seligowski, Wolff, Hill, & Ressler, 2019). Taken together, there is still becomes maladaptive, permanent and uncontrollable, negatively affect- an urgent need for the development of novel approaches in the treat- ing daily life. Likewise, fear is an instinctual and/or learned response to ment of anxiety and related disorders (Griebel & Holmes, 2013). immanent threat that is also adaptive and critical for survival when The aim of this review is to discuss the status of new pharmacologi- short-lived, but can lead to anxiety disorders when aberrant and cal approaches in this field. We start with a brief historical account of chronic. Hence, although fear and anxiety are distinct (Perusini & anxiolytic drug development and subsequently discuss new targets Fanselow, 2015; Parsafar & Davis, 2018), there are clear overlaps, as arising from the current neurobiological understanding of anxiety well as co-occurrence, as anxiety often follows a fearful experience mechanisms. We will present four current main avenues for the devel- and in turn modulates the fear responses to a threat. Abnormal, mal- opment of novel anti-anxiety drugs: 1. Refining and improving agents adaptive forms of these emotions are the hallmarks of fear-, anxiety- acting on existing drug targets (Section 5); 2. Investigating drugs with and trauma-related disorders. A vulnerability towards the development novel mechanisms of action (Section 6); 3. Investigating phytochemi- of anxiety disorders (Gottschalk & Domschke, 2018; Otowa et al., 2016) cals (Section 7); and 4. Utilizing the pharmacological augmentation of often starts in childhood or adolescence (Kalin, 2017) and becomes psychotherapy (Section 8). A comprehensive search of the US National chronic, persisting into adulthood (Bandelow & Michaelis, 2015; Institutes of Health's clinicaltrials.gov index for ongoing [active, not Craske et al., 2017). In the Western world, the life time prevalence of yet recruiting, recruiting, enrolling by invitation, and recently these disorders is approximately 20–30% in the general population, suspended (as in September 2018 and updated in April 2019)] trials in- making them the most frequent neuropsychiatric disorders, with volving pharmacotherapy to treat GAD, SAD, specific phobias, PD, PTSD women being significantly more often affected than men (Bandelow & and OCD was complemented with an open search through the internet Michaelis, 2015; DALYs and Collaborators, 2018; Remes, Brayne, van using the terms ‘novel or new’ and ‘anxiolytic or treatment anxiety dis- der Linde, & Lafortune, 2016; Revicki et al., 2012; Wittchen & Jacobi, orders’ to find press releases and announcements. Compounds thereby 2005). The classification of anxiety disorders has a long history (Crocq, identified were then used as search terms in a PubMed search. We will 2015). Based on clinical observation criteria, the current version of the provide