title: Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders.
abstract: Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: nicolas.singewald@uibk.ac.at.
authors.forename: N
authors.initials: N
authors.lastname: Singewald
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Schmuckermair
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Whittle
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Ressler
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000628:therapy; D003131:Combined Modality Therapy; D005108:Extinction, Psychological / Q000187:drug effects*; D006801:Humans; D007171:Implosive Therapy; D008959:Models, Neurological; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010698:Phobic Disorders / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D018697:Nootropic Agents
keywords: Augmented relearning; Cognitive enhancer; Drug development; Exposure therapy; Fear extinction; Reconsolidation