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Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant

June 16, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Rapid reduction of suicidal thoughts is critical for treating suicidal patients. Clinical trials evaluating these treatments require appropriate measurement. Key methodological issues include: 1) the use of single or multi-item assessments, and 2) evaluating whether suicidal ideation measures can track rapid change over time. The current study presents data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment-resistant depression (n = 60). Participants were assessed for suicidal thoughts using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Scale for Suicidal Ideation (SSI) at eight time points over three days. Assessments were compared using correlational analyses and effect sizes at 230 min and three days after ketamine infusion. Linear mixed models evaluated change in ideation across all time points. The HAM-D and MADRS suicide items demonstrated correlations of r > .80 with the first five items of the SSI (SSI5). On linear mixed models, an effect for ketamine was found for the HAM-D, MADRS, BDI items, and SSI5 (p < .001), but not for the full SSI (p = .88), which suggests a limited ability to assess change over time in patients with low levels of suicidal thoughts. Taken together, the results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo. The MADRS suicide item, BDI suicide item, and SSI5 may be particularly sensitive to rapid changes in suicidal thoughts.

Ballard, E. D., Luckenbaugh, D. A., Richards, E. M., Walls, T. L., Brutsché, N. E., Ameli, R., … & Zarate, C. A. (2015). Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant. Journal of psychiatric research, 68, 68-73. dx.doi.org/10.1016/j.jpsychires.2015.06.003
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Ketamine and Phencyclidine: the good, the bad and the unexpected

June 15, 2015 / Humanities & Art, Ketamine, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics, through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The finding of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms.

Lodge, D., & Mercier, M. S. (2015). Ketamine and Phencyclidine: the good, the bad and the unexpected. British journal of pharmacology.  https://dx.doi.org/10.1111/bph.13222
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Restructuring consciousness -the psychedelic state in light of integrated information theory

June 12, 2015 / LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Publications / By /

Abstract

The psychological state elicited by the classic psychedelics drugs, such as LSD and psilocybin, is one of the most fascinating and yet least understood states of consciousness. However, with the advent of modern functional neuroimaging techniques, the effect of these drugs on neural activity is now being revealed, although many of the varied phenomenological features of the psychedelic state remain challenging to explain. Integrated information theory (IIT) is one of the foremost contemporary theories of consciousness, providing a mathematical formalization of both the quantity and quality of conscious experience. This theory can be applied to all known states of consciousness, including the psychedelic state. Using the results of functional neuroimaging data on the psychedelic state, the effects of psychedelic drugs on both the level and structure of consciousness can be explained in terms of the conceptual framework of IIT. This new IIT-based model of the psychedelic state provides an explanation for many of its phenomenological features, including unconstrained cognition, alterations in the structure and meaning of concepts and a sense of expanded awareness. This model also suggests that whilst cognitive flexibility, creativity, and imagination are enhanced during the psychedelic state, this occurs at the expense of cause-effect information, as well as degrading the brain’s ability to organize, categorize, and differentiate the constituents of conscious experience. Furthermore, the model generates specific predictions that can be tested using a combination of functional imaging techniques, as has been applied to the study of levels of consciousness during anesthesia and following brain injury.

Gallimore, A. R. (2015). Restructuring Consciousness–the Psychedelic State in Light of Integrated Information Theory. Name: Frontiers in Human Neuroscience, 9, 346. https://dx.doi.org/10.3389/fnhum.2015.00346
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A Thread in The Vine: The Deep Ecology of Contemporaray Ayahuasca Discourse

June 11, 2015 / Anthropology & Sociology, Ayahuasca, Biology & Ethnobotany, Papers, Philosophy & Religious Studies, Publications / By / ,

Abstract

This thesis uses the philosophy of deep ecology as a theoretical framework to explore ecospiritual themes as a key feature of increasing discourse around the ayahuasca phenomenon. The broad objective of the research is to use contemporary ayahuasca discourse to reveal the way cross-cultural seekers engage with and discuss shamanic practices that inform a postmodern ecosophical ontology and deep ecological praxis. Three convergent discourses inform this research; the transcultural ayahuasca phenomenon, nature-based spiritualities of the New Age and the philosophy of deep ecology. Threading through these discourses are ecological and spiritual themes that capture a web of meanings for contextualising the transcultural emergence of ayahuasca
spirituality. A key paradigmatic shift suggested by contemporary ayahuasca discourse is a shift in human consciousness toward a non-dualistic ontology regarding humanity’s place in nature. An ecocultural studies approach provides theoretical support for interpreting how the elements of this paradigmatic shift are discussed, understood and practiced. As the internet functions as a superlative site for discursive formations of ayahuasca, a thematic content analysis of selected discussion forums within the Ayahuasca.com website was conducted using a multiparadigmatic, deductive and inductive approach. Naess and Sessions’ (1984) eight platform principles of deep ecology were used as a framework to deductively locate textual articulations of the philosophy. Further inductive analysis revealed not only embedded deep ecological themes but also articulations of an ecocentric praxis arising from experiences of unitary consciousness and plant sentience. The deep ecology articulated in contemporary ayahuasca discourse further raised an explicit challenge to hegemonic anthropocentricism through expressions of an expanded sense of self that accentuates the countercultural bearings of entheogenic informed ecospirituality.

Baker, J., & Coco, D. A. A Thread in the Vine: The Deep Ecology of Contemporary Ayahuasca Discourse. https://dx.doi.org/10.13140/RG.2.1.3040.2729

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Chronic MDMA induces neurochemical changes in the hippocampus of adolescent and young adult rats: Down-regulation of apoptotic markers

June 9, 2015 / MDMA, Neuroscience, Papers, Publications / By / ,

Abstract

While hippocampus is a brain region particularly susceptible to the effects of MDMA, the cellular and molecular changes induced by MDMA are still to be fully elucidated, being the dosage regimen, the species and the developmental stage under study great variables. This study compared the effects of one and four days of MDMA administration following a binge paradigm (3×5 mg/kg, i.p., every 2 h) on inducing hippocampal neurochemical changes in adolescent (PND 37) and young adult (PND 58) rats. The results showed that chronic MDMA caused hippocampal protein deficits in adolescent and young adult rats at different levels: (1) impaired serotonergic (5-HT2A and 5-HT2C post-synaptic receptors) and GABAergic (GAD2 enzyme) signaling, and (2) decreased structural cytoskeletal neurofilament proteins (NF-H, NF-M and NF-L). Interestingly, these effects were not accompanied by an increase in apoptotic markers. In fact, chronic MDMA inhibited proteins of the apoptotic pathway (i.e., pro-apoptotic FADD, Bax and cytochrome c) leading to an inhibition of cell death markers (i.e., p-JNK1/2, cleavage of PARP-1) and suggesting regulatory mechanisms in response to the neurochemical changes caused by the drug. The data, together with the observed lack of GFAP activation, support the view that chronic MDMA effects, regardless of the rat developmental age, extends beyond neurotransmitter systems to impair other hippocampal structural cell markers. Interestingly, inhibitory changes in proteins from the apoptotic pathway might be taking place to overcome the protein deficits caused by MDMA.

García-Cabrerizo, R., & García-Fuster, M. J. (2015). Chronic MDMA induces neurochemical changes in the hippocampus of adolescent and young adult rats: Down-regulation of apoptotic markers. Neurotoxicology, 49, 104-113. http://dx.doi.org/10.1016/j.neuro.2015.06.001

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Antidepressant drug action – From rapid changes on network function to network rewiring

June 9, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

There has been significant recent progress in understanding the neurobiological mechanisms of antidepressant treatments. The delayed-onset of action of monoamine-based antidepressant drugs have been linked to their ability to slowly increase synaptic plasticity and neuronal excitability via altering neurotrophic signaling (synthesis of BDNF and activation of its receptor TrkB), dematuration of GABAergic interneurons and inhibition of “breaks of plasticity”. On the other hand, antidepressants rapidly regulate emotional processing that – with the help of heightened plasticity and appropriate rehabilitation – gradually lead to significant changes on functional neuronal connectivity and clinical recovery. Moreover, the discovery of rapid-acting antidepressants, most notably ketamine, has inspired renewed interest for novel antidepressant developments with better efficacy and faster onset of action. Therapeutic effects of rapid-acting antidepressants have been linked with their ability to rapidly regulate neuronal excitability and thereby increase synaptic translation and release of BDNF, activation of the TrkB-mTOR-p70S6k signaling pathway and increased synaptogenesis within the prefrontal cortex. Thus, alterations in TrkB signaling, synaptic plasticity and neuronal excitability are shared neurobiological phenomena implicated in antidepressant responses produced by both gradually and rapid acting antidepressants. However, regardless of antidepressant, their therapeutic effects are not permanent which suggests that their effects on neuronal connectivity and network function remain unstable and vulnerable for psychosocial challenges.

Rantamäki, T., & Yalcin, I. (2015). Antidepressant drug action–from rapid changes on network function to network rewiring. Progress in Neuro-Psychopharmacology and Biological Psychiatry. https://dx.doi.org/10.1016/j.pnpbp.2015.06.001
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In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept

June 6, 2015 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy (H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

Rodriguez, C. I., Kegeles, L. S., Levinson, A., Ogden, R. T., Mao, X., Milak, M. S., … & Simpson, H. B. (2015). In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept. Psychiatry Research: Neuroimaging. http://dx.doi.org/10.1016/j.pscychresns.2015.06.001
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Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

June 5, 2015 / Neuroscience, Papers, Psychology, Publications, Salvia / Salvinorin A / By / , , , , , ,

Abstract

Background: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profile of subjective effects of increasing doses of salvinorin-A in healthy volunteers with special emphasis on interoception.

Methods: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1 mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included among others: the Hallucinogen Rating Scale (HRS), the Altered States of Consciousness (APZ), and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness (MAIA).

Results: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the high dose led to a sense of a complete loss of contact with the body.

Conclusions: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception and the sense of body ownership in humans.

Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Riba, J. (2015). Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. International Journal of Neuropsychopharmacology, pyv065. http://dx.doi.org/10.1093/ijnp/pyv065
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