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Psychiatry

Altered Insula Connectivity Under MDMA

February 14, 2017 / MDMA, Neuroscience, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Recent work with noninvasive human brain imaging has started to investigate the effects of 3, 4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations-both of which are known to be associated with insular functioning.

Walpola, I. C., Nest, T., Roseman, L., Erritzoe, D., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L. (2017). Altered Insula Connectivity Under MDMA. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 10.1038/npp.2017.35
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Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects

February 14, 2017 / LSD, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , , , , ,

Abstract

Background and Objective: Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure–response relationship of oral LSD.

Methods: We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.

Results: Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2–1.9) and 3.1 (2.6–4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2–3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups.

Conclusions: The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance.

Dolder, P. C., Schmid, Y., Steuer, A. E., Kraemer, T., Rentsch, K. M., Hammann, F., & Liechti, M. E. (2017). Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects. Clinical Pharmacokinetics, 1-12. 10.1007/s40262-017-0513-9

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Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

February 8, 2017 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

BACKGROUND AND PURPOSE: Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes’ morphology in a genetic animal model of depression.

EXPERIMENTAL APPROACH: S-Ketamine (15 mg·kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test.

KEY RESULTS: FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment.

CONCLUSIONS AND IMPLICATIONS: Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour.

Ardalan, M., Rafati, A. H., Nyengaard, J. R., & Wegener, G. (2017). Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. British Journal of Pharmacology, 174(6), 483-492. 10.1111/bph.13714
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Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

February 3, 2017 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

Clinical studies on the role of the glutamatergic system in the pathogenesis of depression found that ketamine induces an antidepressant response, but the molecular mechanisms remain unclear. The present study investigated the effects of sub-anesthetic doses of ketamine on the glutamate reuptake function in the rat hippocampus. Chronic unpredictable mild stress (CUMS) was applied to construct animal models of depression. Sixty adult male Sprague-Dawley rats were randomly assigned to 5 groups and received a different regimen of CUMS and ketamine (10, 25, and 50 mg/kg) treatment. The sucrose preference test and open-field test were used to assess behavioral changes. The expression levels of excitatory amino acid transporters (EAATs) were measured by western blot. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect hippocampal glutamate concentrations. We found that the expression of EAAT2 and EAAT3 were obviously downregulated, and extracellular concentrations of glutamate were significantly increased in the hippocampi of depressive-like rats. Ketamine (10, 25, and 50 mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the hippocampal concentration of extracellular glutamate, and alleviated the rats’ depressive-like behavior. The antidepressant effect of ketamine may be linked to the regulation of EAAT expression and the enhancement of glutamate uptake in the hippocampus of depressive-like rats.

Zhu, X., Ye, G., Wang, Z., Luo, J., & Hao, X. (2017). Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats. Neuroscience Letters, 639, 132-137. 10.1016/j.neulet.2016.12.070
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Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report

February 1, 2017 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / ,

Abstract

Objective: Depression is a common condition among patients with multiple sclerosis and often becomes resistant to oral antidepressants. We report a patient with multiple sclerosis who developed severe treatment-resistant depression and who was successfully treated with intravenous ketamine over the period of two years.
Methods: Ketamine treatment protocol included an initial series of six treatments administered every other day, followed by a maintenance schedule. Ketamine was administered intravenously at 0.5mg/kg of ideal body weight over 40 minutes. Depression symptoms were measured using Beck Depression Index.
Results: The patient’s Beck Depression Index score prior to initiating ketamine treatment was 38, corresponding to severe depression. Response to treatment, defined as 50-percent reduction in Beck Depression Index score, was observed after five treatments. For this patient, the maintenance schedule ranged from a weekly treatment to one treatment every three weeks. During the two-year observation period, this patient was able to maintain a stable non-depressed mood and had no worsening of her MS symptoms.
Conclusion: Ketamine may be an alternative treatment for resistant depression and may have a special use in patients with multiple sclerosis.
Messer, M. M., & Haller, I. V. (2017). Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report. Innovations in clinical neuroscience, 14(1-2), 56.
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Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task

February 1, 2017 / Depression, Ketamine, Papers, Psychiatry, Psychology, Publications / By / , ,

Abstract

RATIONALE: Depression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants.

OBJECTIVES: In the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties-ketamine (KET)-on the sensitivity of rats to positive and negative feedback in the PRL paradigm.

METHODS: We trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration.

RESULTS: We report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose-shift responses made by rats after receiving negative feedback.

CONCLUSION: Present results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action.

Rychlik, M., Bollen, E., & Rygula, R. (2016). Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task. Psychopharmacology, 1-8. 10.1007/s00213-016-4497-1
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Prophylactic Ketamine Attenuates Learned Fear

January 27, 2017 / Anxiety disorders / PTSD, Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Ketamine has been reported to be an efficacious antidepressant for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown if ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience in order to determine when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg kg−1) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 week, but not 1 month or 1 h before CFC, exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. However, ketamine administered before reinstatement increased the number of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic fashion 1 week before a stressor in order to protect against heightened fear responses to aversive stimuli.

McGowan, J. C., LaGamma, C. T., Lim, S. C., Tsitsiklis, M., Neria, Y., Brachman, R. A., & Denny, C. A. (2017). Prophylactic Ketamine Attenuates Learned Fear. Neuropsychopharmacology. 10.1038/npp.2017.19
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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

January 27, 2017 / Ayahuasca, Depression, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / , , , , , ,

Abstract

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-Asberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0.019; Cohen’s d=0.98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0.04; at D7, p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d=0.84; D2: Cohen’s d=0.84; D7: Cohen’s d=1.49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4.95; p = 0.04; NNT = 2.66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M., Pessoa, J., … & Tofoli, L. (2017). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial. bioRxiv, 103531. 10.1101/103531
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The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation

January 26, 2017 / LSD, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Psychotherapy, Publications / By / , , , , , ,

Abstract

A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2 and 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution.

Preller, K. H., Herdener, M., Pokorny, T., Planzer, A., Kraehenmann, R., Stämpfli, P., … & Vollenweider, F. X. (2017). The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Current Biology, 27(3), 451-457. 10.1016/j.cub.2016.12.030
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The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Bouso et al., 2016

January 25, 2017 / Mushrooms / Psilocybin, Mystical experiences, Papers, Psychiatry, Psychology, Publications, Spirituality / By / ,

Barrett, F. S., & Griffiths, R. R. (2017). The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Bouso et al., 2016. Human Psychopharmacology: Clinical and Experimental, 32(1). 10.1002/hup.2564
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