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Antidepressant mechanism of ketamine: perspective from preclinical studies

/ Depressive Disorders, Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Publications / / , , ,

Abstract

A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine’s rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine’s antidepressant mechanism of action. Recent preclinical studies indicate that ketamine’s antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine’s efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.

Scheuing, L., Chiu, C. T., Liao, H. M., & Chuang, D. M. (2015). Antidepressant mechanism of ketamine: perspective from preclinical studies. Frontiers in Neuroscience, 9. http://dx.doi.org/10.3389/fnins.2015.00249
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Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats.

/ Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / / , , , , , ,

Abstract

RATIONALE:

Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders.

OBJECTIVES:

We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe.

METHODS:

Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity.

RESULTS:

In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia.

CONCLUSIONS:

This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.

Grimm, O., Gass, N., Weber-Fahr, W., Sartorius, A., Schenker, E., Spedding, M., … & Meyer-Lindenberg, A. (2015). Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats. Psychopharmacology, 1-11.
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Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

/ Mushrooms / Psilocybin, Neuroscience, Papers, Publications / / , , , , ,

Abstract

The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N = 6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data.

Spain, A., Howarth, C., Khrapitchev, A., Sharp, T., Sibson, N. R., & Martin, C. (2015). Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain. Neuropharmacology. https://dx.doi.org/10.1016/j.neuropharm.2015.07.018
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Ketamine induces anxiolytic effects in adult zebrafish: A multivariate statistics approach.

/ Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / / , ,

Abstract

Ketamine inappropriate use has been associated with serious consequences for human health. Anesthetic properties of ketamine are well-known but its side effects are poorly described, including the effects on anxiety. In this context, animal models are a safe way to conduct this neurobehavioral research and zebrafish (Danio rerio) is an interesting model which has several advantages. The validation and interpretation of results of behavioral assays requires a suitable statistical approach and the use of multivariate statistical methods has been little explored, especially in zebrafish behavioral models. Here, we investigated the anxiolytic-induced effects of ketamine in adult zebrafish, using Light-Dark Test and Multivariate Statistics methods (PCA, HCA and SIMCA). In addition, we compared the processing of data to the one carried out by analysis of variance (ANOVA) Ketamine produced significant concentration of exposure-dependent anxiolytic effects, increasing time in white area and number of crossings and decreasing latency to first access to white area. Average entry duration behavior resulted in a slight decrease from control to treatment groups, with an observed concentration-dependent increase among the exposed groups. PCA results indicated that two principal components represent 88.74% of all the system information. HCA and PCA results showed a higher similarity among control and treatment groups exposed to lower concentrations of ketamine and among treatment groups exposed to concentrations of 40 and 60 mg.L-1. In SIMCA results, interclasses distances were concentration of exposure-dependent increased and misclassifications and interclasses residues results also support these findings. These findings confirm the anxiolytic potential of ketamine and zebrafish sensibility to this drug. In summary, our study confirms that zebrafish and multivariate statistics data validation is an appropriate and viable behavioral model for the study of psychoactive substances, providing a detailed and reliable analysis.

De Campos, E. G., Bruni, A. T., & De Martinis, B. S. (2015). Ketamine induces anxiolytic effects in adult zebrafish: A multivariate statistics approach. Behavioural Brain Research.  https://dx.doi.org/10.1016/j.bbr.2015.07.017
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‘Whatever you want to believe’ kaleidoscopic individualism and ayahuasca healing in Australia

/ Anthropology & Sociology, Ayahuasca, Biology & Ethnobotany, Papers, Psychology, Publications / /

Abstract

Over the last fifteen years the use of the indigenous Amazonian psychoactive beverage ayahuasca has been reimagined in alternative healing circles of Western countries. This paper explores the practice of ayahuasca neoshamanism in Australia and examines ways in which acts of vomiting and ecstatic trance-visions involve heightened affective states and moral projects of healing. Aspects of everyday life are purged, rearticulated, and reconstituted in rituals where codes of conduct and discursive exchange encourage practices of personal evaluation and reflexivity that appear to index ideologies of individualism. Through exploring social and discursive prohibitions and forms of sensory organisation, the practice of drinking ayahuasca in Australia is shown to be constituted by ritual conventions that define the individual as autonomous and responsible in relation to ecstatic trance and articulations of wellbeing.

Gearin, A. K. (2015). ‘Whatever you want to believe’kaleidoscopic individualism and ayahuasca healing in Australia. The Australian Journal of Anthropology. https://dx.doi.org/10.1111/taja.12143
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Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

/ DMT, LSD, MDMA, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Publications / /

Abstract

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Szabo, A. Psychedelics and immunomodulation: Novel approaches and therapeutic opportunities. Frontiers in Immunology, 0. https://dx.doi.org/10.3389/fimmu.2015.00358
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A Model of Enlightened/Mystical/Awakened Experience.

/ Papers, Psychology, Publications / /

Abstract

Awakening experiences are powerful and transcendent experiences that profoundly affect the individual. There appears to be an essential core experience of oneness. It is experienced as a completely subjective phenomenon where awareness contains reality and the notions of an external reality and a separate self are perceived as delusions. A model is presented of awakening experiences that postulates 3 layers of processing, sensory, perceptual, and cognitive, that separate external energy from awareness. The model hypothesizes that awakening experiences results from the progressive removal of the cognitive, perceptual, and sensory layers of information processing. This to some extent returns awareness to a primal state that was present before the development of neural information processing. The model simplifies, summarizes, and explains awakening experiences and is consistent with neural system activity observed during contemplative practice, transcendent states, and hallucinatory drug use and with the effects of changes in the neural systems on experiences.

de Castro, J. M. (2015). A Model of Enlightened/Mystical/Awakened Experience. http://dx.doi.org/10.1037/rel0000037
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Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

/ Depressive Disorders, Neuroscience, Papers, Psychology, Publications / / ,

Abstract

Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments—especially for treatment-resistant depression (TRD)—are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.

Papakostas, G. I., & Ionescu, D. F. (2015). Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder. Molecular psychiatry. https://dx.doi.org/10.1038/mp.2015.92
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Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe

/ Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / / , , , , ,

Abstract

Ketamine produces effects in healthy humans that resemble the positive, negative and cognitive symptoms of schizophrenia. We investigated the effect of ketamine administration on brain activity as indexed by blood-oxygen-level-dependent (BOLD) signal change response, and its relationship to ketamine-induced subjective changes, including perceptual distortion. Thirteen healthy participants volunteered for the study. All underwent a 15-min functional MRI acquisition with a ketamine infusion commencing after 5 min (approx 0.26 mg/kg over 20s followed by an infusion of approx. 0.42 mg/kg/h). Following the scan, participants self-rated ketamine-induced effects using the Psychotomimetic States Inventory. Ketamine led to widespread cortical and subcortical increases in BOLD response (FWE-corrected p < 0.01). Self-rated perceptual distortions and delusional thoughts correlated with increased BOLD response in the paracentral lobule (FWE-corrected p < 0.01). The findings suggest that BOLD increases in parietal cortices reflect ketamine effects on circuits that contribute to its capacity to produce perceptual alterations and delusional interpretations.

Stone, J., Kotoula, V., Dietrich, C., De Simoni, S., Krystal, J. H., & Mehta, M. A. (2015). Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. Journal of Psychopharmacology, 0269881115592337. https://dx.doi.org/10.1177/0269881115592337
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Therapy with Substance: Psycholytic psychotherapy in the twenty first century

/ Publications /

Therapy with substance“A unique account and the definitive guide for a future generation of psychedelic psychotherapists. Therapy with Substance is a comprehensive guide for the medical use of psychedelic substances in the therapy of emotional and psychosomatic disorders based on years of work that she had conducted with her clients without official permission. It describes in clear and articulate language everything that is necessary to know for effective and safe use of this treatment modality and for work with non-ordinary states of consciousness in general.”

Stanislav Grof (from the foreword)

In this groundbreaking book, Doctor Friederike Meckel Fischer explores how the skillful use of psychedelic substances in psycholytic psychotherapy can cause dramatic breakthroughs for people who have not responded to traditional methods of psychotherapy. Her extraordinary conclusion is that psycholytic psychotherapy is the only method that reaches the depth of the psyche required to resolve and heal our deepest wounds. Psychedelic drugs were routinely used in clinical research and psychotherapy until the 1960s. Since then they have been illegal except for a short period in the 1990s in Switzerland. During this window of opportunity, Dr Fischer developed her unique method using these substances to assist the progress of those of her patients who were “stuck”.  This book is a description of her use of psychedelic-assisted psychotherapy; the group work, the family constellation work, the body work, the spiritual experiences, how to work with the substances themselves, together with moving accounts of her patients and their stories. This is a unique account and the definitive guide for the new generation of psychedelic psychotherapists.

Dr Meckel is a medical doctor who has trained in individual, group and family psychotherapy and, with Stanislav Grof, in transpersonal psychotherapy.

Therapy with Substance: Psycholytic psychotherapy in the twenty first century, by Friederike Meckel Fischer, Muswell Hill Press, 244 pages.
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