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Depressive Disorders

Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes

November 26, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , ,

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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Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

November 22, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

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

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Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects

November 21, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

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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Ketamine: The Glutamatergic Antidepressant and Its Efficacy

November 18, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

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

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Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use

November 15, 2016 / Ayahuasca, Depressive Disorders, Iboga / Ibogaine, Ketamine, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , , , ,

Abstract

Psychedelic drugs have been used as treatments in indigenous cultures for thousands of years. Yet, due to their legal status, there has been limited scientific research into the therapeutic potential of these compounds for psychiatric disorders. In the absence of other effective treatments however, researchers have begun again to systematically investigate such compounds and there is now evidence pointing to the use of psychedelic drugs in the treatment of addiction. In this review we focus on human evidence for the effectiveness of preparations used by indigenous cultures in the Amazon (ayahausca) and Africa (ibogaine) and worldwide (psilocybin), and more recently synthetised drugs such as the serotonergic hallucinogen LSD and the dissociative anaesthetic ketamine. Potential mechanisms explored are anti-depressant effects, changes in neuroplasticity and existential psychological effects of these drugs.

Morgan, C., McAndrew, A., Stevens, T., Nutt, D., & Lawn, W. (2017). Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use. Current Opinion in Behavioral Sciences, 13, 71-76. 10.1016/j.cobeha.2016.10.009
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Cognitive and behavioural effects induced by social stress plus MDMA administration in mice

November 10, 2016 / Depressive Disorders, MDMA, Papers, Psychology, Publications / By / , , , ,

Abstract

Adverse life experiences such as social stress may make an individual more vulnerable to drug addiction and mental disorders associated with drug consumption. The present work aimed to evaluate the effects of stress induced by acute social defeat combined with the administration of 3,4-methylenedioxymethamphetamine (MDMA) on depression-like behaviour, memory function and motor response to drug in late adolescent male mice. Two groups of mice were exposed to social defeat (SD) during four encounters with an aggressive co-specific, which took place on alternate days. Immediately after defeat, animals were treated with saline or MDMA 10mg/kg (SD+SAL and SD+MDMA). In control groups, mice were placed in a neutral cage without an opponent (Control+SAL, Control+MDMA). Corticosterone levels and temperature were measured on the last day of this phase. During the following days, the behaviour of the animals was evaluated in the tail suspension test (an animal model of depression), memory tasks (passive avoidance and object recognition) and, after administration of 5mg/kg of MDMA, in the open-field test. Exposure of adult mice to acute social defeat plus MDMA increased immobility in the tail suspension test (depression-like behaviour), produced cognitive impairment, and reduced the motor response to MDMA. An increase in corticosterone levels and a decrease of temperature were also observed. As hypothesised, a combination of social stress and consumption of MDMA increases the risk of developing mental and cognitive disorders. Our results support the idea that stress is a common contributing factor to the high rate of comorbidity between substance abuse and mental disease.

García-Pardo, M. P., Roger-Sánchez, C., Rodríguez-Arias, M., Miñarro, J., & Aguilar, M. A. (2017). Cognitive and behavioural effects induced by social stress plus MDMA administration in mice. Behavioural Brain Research, 319, 63-72. 10.1016/j.bbr.2016.11.012
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Potential Psychiatric Uses for MDMA

November 9, 2016 / Anxiety Disorders / PTSD, Depressive Disorders, MDMA, Papers, Psychology, Publications / By / ,

Abstract

Phase 2 trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of PTSD, with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as FDA Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches.

Klosinski, B. B., & Mithoefer, M. C. (2016). Potential Psychiatric Uses for MDMA. Clinical Pharmacology & Therapeutics. 10.1002/cpt.565
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Psychedelics as Medicines: An emerging new paradigm

November 4, 2016 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2Areceptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing anti-inflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after acute effects have resolved. Anti-inflammatory effects may hold promise for efficacy in treatment of inflammation-related non-psychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

Nichols, D. E., Johnson, M. W., & Nichols, C. D. (2016). Psychedelics as Medicines: An emerging new paradigm. Clinical Pharmacology & Therapeutics. 10.1002/cpt.557
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Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies

November 3, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Background: An increasing number of studies are reporting that ketamine could be treated as a novel antidepressant for major depressive disorder (MDD). Therefore, we performed this meta-analysis to comprehensively and systematically assess the efficacy of ketamine for treating patients with MDD.

Method: Randomized, double-blind, placebo-controlled studies on ketamine versus placebo for treating MDD were searched up to April 2016 in medical databases (PubMed, CCTR, Web of Science, Embase, CBM-disc, and CNKI). Three treatment time points (24 and 72 h, and day 7) were chosen. Response and remission rates were the main outcomes. The random effects model was used. An intention-to-treat analysis was conducted.

Results: Nine high-quality studies that included 368 patients were selected to compare the efficacy of ketamine to placebo. The therapeutic effects of ketamine at 24 and 72 h, and day 7 were found to be significantly better than placebo. Response and remission rates in the ketamine group at 24 and 72 h, and day 7 were 52.2% and 20.6%; 47.9% and 23.8%; and 39.8% and 26.2%, respectively. No significant heterogeneity existed, and the Egger’s test showed no publication bias.

Conclusion: These results indicated that ketamine could yield a good efficacy in the rapid treatment of MDD. Future large-scale clinical studies are needed to confirm our results and investigate the mid- and long-term efficacy of ketamine in treating MDD.

Han, Y., Chen, J., Zou, D., Zheng, P., Li, Q., Wang, H., … & Xie, P. (2016). Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatric Disease and Treatment, 12, 2859. 10.2147%2FNDT.S117146

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Ketamine: NMDA Receptors and Beyond

November 2, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders / By / , ,

Abstract

Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine’s actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects on N-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its mood enhancing actions. In this viewpoint, we examine the evolving literature on ketamine supporting NMDARs as important triggers for certain psychiatric effects and the possibility that the antidepressant trigger is unrelated to NMDARs. The rapidly evolving story of ketamine offers great hope for untangling and treating the biology of both depressive and psychotic illnesses.
Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016). Ketamine: NMDA receptors and beyond. Journal of Neuroscience, 36(44), 11158-11164. 10.1523/JNEUROSCI.1547-16.2016
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