OPEN Foundation

D. Martin

Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety

Abstract

BACKGROUND:
Ketamine is swiftly effective in a range of neurotic disorders that are resistant to conventional antidepressant and anxiolytic drugs. The neural basis for its therapeutic action is unknown. Here we report the effects of ketamine on the EEG of patients with treatment-resistant generalized anxiety and social anxiety disorders.
METHODS:
Twelve patients with refractory DSM-IV generalized anxiety disorder and/or social anxiety disorder provided EEG during 10 minutes of relaxation before and 2 hours after receiving double-blind drug administration. Three ascending ketamine dose levels (0.25, 0.5, and 1 mg/kg) and midazolam (0.01 mg/kg) were given at 1-week intervals to each patient, with the midazolam counterbalanced in dosing position across patients. Anxiety was assessed pre- and postdose with the Fear Questionnaire and HAM-A.
RESULTS:
Ketamine dose-dependently improved Fear Questionnaire but not HAM-A scores, decreased EEG power most at low (delta) frequency, and increased it most at high (gamma) frequency. Only the decrease in medium-low (theta) frequency at right frontal sites predicted the effect of ketamine on the Fear Questionnaire. Ketamine produced no improvement in Higuchi’s fractal dimension at any dose or systematic changes in frontal alpha asymmetry.
CONCLUSIONS:
Ketamine may achieve its effects on treatment-resistant generalized anxiety disorder and social anxiety disorder through related mechanisms to the common reduction by conventional anxiolytic drugs in right frontal theta. However, in the current study midazolam did not have such an effect, and it remains to be determined whether, unlike conventional anxiolytics, ketamine changes right frontal theta when it is effective in treatment-resistant depression.
Shadli, S. M., Kawe, T., Martin, D., McNaughton, N., Neehoff, S., & Glue, P. (2018). Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety. International Journal of Neuropsychopharmacology. 10.1093/ijnp/pyy032
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Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial

Abstract

BACKGROUND:
Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments.
METHODS:
This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment.
RESULTS:
Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups.
CONCLUSIONS:
IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.
Gálvez, V., Li, A., Huggins, C., Glue, P., Martin, D., Somogyi, A. A., … & Loo, C. K. (2018). Repeated intranasal ketamine for treatment-resistant depression–the way to go? Results from a pilot randomised controlled trial. Journal of Psychopharmacology32(4), 397-407. 10.1177/0269881118760660
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The Effects of Hallucinogens on Gene Expression

Abstract

The classic serotonergic hallucinogens, or psychedelics, have the ability to profoundly alter perception and behavior. These can include visual distortions, hallucinations, detachment from reality, and mystical experiences. Some psychedelics, like LSD, are able to produce these effects with remarkably low doses of drug. Others, like psilocybin, have recently been demonstrated to have significant clinical efficacy in the treatment of depression, anxiety, and addiction that persist for at least several months after only a single therapeutic session. How does this occur? Much work has recently been published from imaging studies showing that psychedelics alter brain network connectivity. They facilitate a disintegration of the default mode network, producing a hyperconnectivity between brain regions that allow centers that do not normally communicate with each other to do so. The immediate and acute effects on both behaviors and network connectivity are likely mediated by effector pathways downstream of serotonin 5-HT2A receptor activation. These acute molecular processes also influence gene expression changes, which likely influence synaptic plasticity and facilitate more long-term changes in brain neurochemistry ultimately underlying the therapeutic efficacy of a single administration to achieve long-lasting effects. In this review, we summarize what is currently known about the molecular genetic responses to psychedelics within the brain and discuss how gene expression changes may contribute to altered cellular physiology and behaviors.
Martin, D. A., & Nichols, C. D. (2017). The Effects of Hallucinogens on Gene Expression. 10.1007/7854_2017_479
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27 June - Spiritual & Existential Dimensions in Psychedelic Care: Challenges & Insights

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