Ketamine for Treatment-Resistant Depression
Mathew, S. J., & Zarate Jr, C. A. Ketamine for Treatment-Resistant Depression. 10.1007/978-3-319-42925-0
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Therapeutic Application
Capturing the different health conditions that PAP may adress
The Therapeutic Potential of Ayahuasca
Abstract
Ayahuasca is a plant-based psychoactive decoction traditionally utilized by cultural groups throughout parts of Brazil, Peru, Colombia, Bolivia, Venezuela, and Ecuador during rites of passage, divination, warfare, magico-religious practices, and for healing in ethnomedical contexts. Over the last 150 years, ayahuasca has entered the global sphere and become a focus of scientific inquiry due to its reported use as an effective medicine to diagnose and treat illness. As a result, the use of ayahuasca within a healing context has become widespread and prompted researchers to investigate its putative therapeutic potential. In this chapter, the authors discuss current therapeutic applications of ayahuasca to treat addiction, depression, and anxiety. In this context, we highlight several studies to help facilitate a greater understanding of the therapeutic potential of ayahuasca.
Coe, M. A., & McKenna, D. J. (2017). The Therapeutic Potential of Ayahuasca. In Evidence-Based Herbal and Nutritional Treatments for Anxiety in Psychiatric Disorders (pp. 123-137). Springer International Publishing. 10.1007/978-3-319-42307-4_7
Ketamine’s Mechanisms of Rapid Antidepressant Activity: Evidence from Preclinical Studies
Abstract
Enthusiasm over the growing series of reports describing ketamine’s rapid onset of robust antidepressant activity in clinical trials has ignited a large number of back-translational efforts attempting to employ rodent models to better characterize the antidepressant properties of the drug and to improve our understanding of its underlying mechanisms of antidepressant action. On balance, these preclinical studies have yielded fairly consistent findings demonstrating that ketamine has a broad range of behavioral effects consistent with antidepressant activity in a variety of rodent models. Many of these studies further suggest that ketamine’s effects are unique from other classic antidepressant drugs in producing more durable effects in some models and more rapidly reversing the behavioral effects of chronic stressor exposure in other models. The preclinical studies are also beginning to elucidate the drug’s mechanisms of antidepressant activity, with the majority of recent studies suggesting that increased levels of regional alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor activation and brain-derived neurotrophic factor (BDNF) expression, as well as enhanced synaptic plasticity, are critical components of the response. However, there remain several points of disagreement and inconsistency in the preclinical literature that require additional investigation, including the effectiveness of other NMDA receptor-targeting drugs and the specific targets of ketamine’s proximal effects. This chapter provides an overview and critical review of this preclinical literature. It is anticipated that a more complete understanding of ketamine’s mechanisms of antidepressant action will allow for a safer and more efficient use of ketamine in the clinical setting and afford us new opportunities for novel drug development.
Hermes, G., & Sanacora, G. (2016). Ketamine’s Mechanisms of Rapid Antidepressant Activity: Evidence from Preclinical Studies. In Ketamine for Treatment-Resistant Depression (pp. 73-98). Springer International Publishing. 10.1007/978-3-319-42925-0_6
Psycho-existential distress in cancer patients: A return to “entheogens”
Blinderman, C. D. (2016). Psycho-existential distress in cancer patients: A return to “entheogens”. Journal of Psychopharmacology, 30(12), 1205-1206. 10.1177/0269881116675761
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Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes
Abstract
In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest — particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N-methyl-d-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies.
Saland, S. K., Duclot, F., & Kabbaj, M. (2017). Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes. Current Opinion in Behavioral Sciences, 14, 19-26. 10.1016/j.cobeha.2016.11.002
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d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology
Abstract
d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2Areceptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors.
De Gregorio, D., Comai, S., Posa, L., & Gobbi, G. (2016). d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology. International Journal of Molecular Sciences, 17(11), 1953. 10.3390/ijms17111953
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Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant
Abstract
Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Conventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hindered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N-methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast-acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concern. In this review, we focus on the limitations of ketamine, including neurotoxicity, cognitive dysfunction, adverse events associated with mental status, psychotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine (esketamine) and R-ketamine, are also discussed. R-ketamine has greater antidepressant actions than S-ketamine, without ketamine-related side-effects. Future treatment strategies should consider using R-ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term ketamine use.
Zhu, W., Ding, Z., Zhang, Y., Shi, J., Hashimoto, K., & Lu, L. (2016). Risks associated with misuse of ketamine as a rapid-acting antidepressant. Neuroscience Bulletin, 32(6), 557-564. 10.1007/s12264-016-0081-2
Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects
Abstract
Ketamine’s antidepressant effects have variously been attributed to its wide-acting N-methyl-D-aspartate (NMDA) antagonism, its high-affinity for the NMDA receptor (Sanacora et al., 2008), and its trapping mechanism of blockade (Autry et al., 2011; Duman et al., 2016; Zarate et al., 2013). Several novel agents are being developed and tested that attempt to maintain ketamine’s antidepressant efficacy while minimizing its side effects, particularly its psychotomimetic properties and abuse potential.
Lepow, L., Luckenbaugh, D. A., Park, L., Henter, I. D., & Zarate, C. A. (2017). Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects. Journal of psychiatric research, 86, 55-57. 10.1016/j.jpsychires.2016.10.023
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Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase
Abstract
Salvia divinorum commonly known as diviner’s sage, is an ethnomedicinal plant of the mint family (Lamiaceae). S. divinorum is rich in clerodane-type diterpenoids, which accumulate predominantly in leaf glandular trichomes. The main bioactive metabolite, salvinorin A, is the first non-nitrogenous natural compound known to function as an opioid-receptor agonist, and is undergoing clinical trials for potential use in treating neuropsychiatric diseases and drug addictions. We report here the discovery and functional characterization of two S. divinorumditerpene synthases (diTPSs), the ent-copalyl diphosphate (ent-CPP) synthase SdCPS1, and the clerodienyl diphosphate (CLPP) synthase SdCPS2. Mining of leaf- and trichome-specific transcriptomes revealed five diTPSs, two of which are class II diTPSs (SdCPS1-2) and three are class I enzymes (SdKSL1-3). Of the class II diTPSs, transient expression in Nicotiana benthamianaidentified SdCPS1 as an ent-CPP synthase, which is prevalent in roots and, together with SdKSL1, exhibits a possible dual role in general and specialized metabolism. In vivo co-expression and in vitro assays combined with NMR analysis identified SdCPS2 as a CLPP synthase. A role of SdCPS2 in catalyzing the committed step in salvinorin A biosynthesis is supported by its biochemical function, trichome-specific expression and absence of additional class II diTPSs in S. divinorum. Structure-guided mutagenesis revealed four catalytic residues that enabled the re-programming of SdCPS2 activity to afford four distinct products, thus advancing our understanding of how neo-functionalization events have shaped the array of different class II diTPS functions in plants, and may promote synthetic biology platforms for a broader spectrum of diterpenoid bioproducts.
Pelot, K. A., Mitchell, R., Kwon, M., Hagelthorn, D. M., Wardman, J. F., Chiang, A., … & Zerbe, P. (2016). Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase. The Plant Journal. 10.1111/tpj.13427
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Ketamine: The Glutamatergic Antidepressant and Its Efficacy
Abstract
Ketamine, an uncompetitive glutamatergic NMDA antagonist, was first synthesised as an anaesthetic agent, though its unwanted induction of post-operative ‘dissociative’ states led to its gradual withdrawal from mainstream use. It has remained a common drug of abuse ever since, in the same class as the more powerful phencyclidine (‘PCP’ or ‘angel-dust’). However, as well as subjectively pleasurable perceptual changes and alterations to consciousness, data began to emerge of a positive effect upon depressed mood states. Of particular interest, such effects, where they occurred, were seen to develop far more rapidly than with ‘traditional’ antidepressants. Scientific trials of effectiveness have included work exploring ketamine as the sole medication, co-prescribing studies, and work looking at augmentation of ECT. Overall these early data are showing some interesting and exciting results, with general support for efficacy in all settings tested. However, significant challenges remain. Firstly, benefits derived tend to be temporary, with rapid relapse after several weeks, and there is a need to find a mechanism to sustain the drug effects. Secondly, most studies utilised intravenous administration, which carries an obvious clinical burden. Finally, the risks of dependency and ketamine-induced psychosis remain as yet uncertain. Nevertheless the societal burden of depression mandates further work on this compound, not least to better understand the mechanism of action of any therapeutic changes.
Tracy, D. K., Caddy, C., & Shergill, S. S. (2016). Ketamine: The Glutamatergic Antidepressant and Its Efficacy. In Melatonin, Neuroprotective Agents and Antidepressant Therapy (pp. 687-706). Springer India. 10.1007/978-81-322-2803-5_41
