OPEN Foundation

Menu

Author name: OPEN Foundation

Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies – PubMed

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , ,

Abstract

Background: Most recent evidence support a rapid and sustained antidepressant effect of subanesthetic dose of intravenous ketamine in patients with major depressive disorder (MDD). However, clinical and animal studies investigating the effects of intravenous ketamine on specific functional domains disrupted by depression reported conflicting results. Therefore, the aim of this review is to provide an overview of the recent findings exploring the cognitive effects of ketamine in depression.
Methods: After a bibliographic search on PubMed, Medline and PsycInfo, we retrieved 11 original studies meeting our research criteria, 7 in humans with MDD or Treatment Resistant Disorder and 4 using rats models for depression.
Results: Overall the results showed that a) ketamine reduced activation and normalized connectivity measures of several brain regions related to depressive behaviors and reversed deficits in cognitive flexibility and coping response strategy in rats with depressive features, and b) ketamine leads to a no significant impairment on neurocognitive functions in most of the studies, with only three studies observing improvements in speed of processing, verbal learning, sustained attention and response control, verbal and working memory.
Limitations: The methodological heterogeneity, in terms of neuropsychological tests used and cognitive domain explored, of the studies included.
Conclusions: Most of the studies included showed no significant cognitive impairments in MDD patients after ketamine treatment. Furthermore, the results of the fMRI studies considered suggest that ketamine may have a normalizing effect on brain functions during attentional and emotional processing in MDD patients. However, further studies are needed to confirm these preliminary evidences.
Crisanti, C., Enrico, P., Fiorentini, A., Delvecchio, G., & Brambilla, P. (2020). Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies. Journal of Affective Disorders., 10.1016/j.jad.2020.07.119
Link to full text

Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies – PubMed Read More »

Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression

/ Depressive Disorders, Ketamine, Papers / Leave a Comment / / , , , , , ,

Abstract

Background: Esketamine nasal spray is approved for treatment-resistant depression.

Objective: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression.

Methods: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes. An open linear model for esketamine (three compartments) and noresketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on esketamine pharmacokinetics and a model evaluation were performed using conventional methods.

Results: The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. Noresketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the esketamine elimination rate constant and noresketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in esketamine and noresketamine maximum concentration and area under the concentration-time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects.

Conclusions: Esketamine and noresketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite noresketamine, and the influence of intrinsic and extrinsic factors on esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).

Perez-Ruixo, C., Rossenu, S., Zannikos, P., Nandy, P., Singh, J., Drevets, W. C., & Perez-Ruixo, J. J. (2021). Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clinical pharmacokinetics, 60(4), 501–516. https://doi.org/10.1007/s40262-020-00953-4

Link to full text

Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression Read More »

Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression

/ Depressive Disorders, Ketamine, Papers / Leave a Comment / / , , ,

Abstract

Introduction: Ketamine exhibits antidepressant properties in treatment-resistant depression (TRD) with some concern over its cardiovascular safety and tolerability issues. This paper reports on the cardiovascular safety in short-term intravenous ketamine treatment in TRD inpatients with major depressive disorder (MDD) and bipolar disorder (BP).

Materials and methods: The observational study population comprises 35 MDD and 14 BP subjects treated with intravenous ketamine.

Results: Blood pressure (RR) and heart rate (HR) values returned to baseline within 1.5-hours post infusion with no sequelae for all study subjects. Six time points were analyzed for each infusion: 0′, 15′, 30′, 45′, 60′ and 90′ for RR and HR. After the infusion significant peaks in systolic (p = 0.004) and diastolic (p = 0.038) RR were seen. In concomitant medication with selective serotonin reuptake inhibitors (SSRIs), higher RR peaks (p = 0.020; p = 0.048) were seen as compared to other subjects. The decrease in HR was greater (p = 0.02) in the absence of concomitant medication with mood stabilizers as compared to subjects receiving mood stabilizing medication accompanied by the observation of a greater decrease in diastolic RR among those taking mood stabilizers (p = 0.009).

Limitations: The study may be underpowered due to the small sample size. The observations apply to an inhomogeneous TRD population in a single-site, pilot study, with no blinding and are limited to the acute administration.

Conclusion: The study demonstrates good safety and tolerability profile of intravenous ketamine as add-on intervention to current psychotropic medication in TRD, regardless of the MDD or BP type of mood disorders. The abatement of elevated RR and BP scores was observed in time with no sequelae nor harm. Still, cardiovascular risks appear to be more pronounced in subjects with comorbid arterial hypertension and diabetes mellitus.

Szarmach, J., Cubała, W. J., Włodarczyk, A., & Gałuszko-Węgielnik, M. (2020). Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression. Neuropsychiatric disease and treatment, 16, 2539–2551. https://doi.org/10.2147/NDT.S273287

Link to full text

Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression Read More »

Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support

/ Depressive Disorders, Ketamine, Papers / Leave a Comment / / , , , , , , , , , ,

Abstract

Background: The glutamatergic modulator ketamine has been shown to result in rapid reductions in both suicidal ideation (SI) and depressive symptoms in clinical trials. There is a practical need for identification of pre-treatment predictors of ketamine response. Previous studies indicate links between treatment response and body mass index (BMI), depression symptoms and previous suicide attempts. Our aim was to explore the use of clinical and demographic factors to predict response to serial doses of oral ketamine for chronic suicidal ideation.

Methods: Thirty-two participants completed the Oral Ketamine Trial on Suicidality (OKTOS). Data for the current study were drawn from pre-treatment and follow-up time-points of OKTOS. Only clinical and sociodemographic variables were included in this analysis. Data were used to create a proof of concept Bayesian network (BN) model of variables predicting prolonged response to oral ketamine, as defined by the Beck Scale for Suicide Ideation (BSS).

Results: The network of potential predictors of response was evaluated using receiver operating characteristic (ROC) curve analyses. A combination of nine demographic and clinical variables predicted prolonged ketamine response, with strong contributions from BMI, Social and Occupational Functioning Assessment Scale (SOFAS), Montgomery-Asberg Depression Rating Scale (MADRS), number of suicide attempts, employment status and age. We evaluated and optimised the proposed network to increase the area under the ROC curve (AUC). The performance evaluation demonstrated that the BN predicted prolonged ketamine response with 97% accuracy, and AUC = 0.87.

Conclusions: At present, validated tools to facilitate risk assessment are infrequently used in psychiatric practice. Pre-treatment assessment of individuals’ likelihood of response to oral ketamine for chronic suicidal ideation could be beneficial in making more informed decisions about likelihood of success for this treatment course. Clinical trials registration number ACTRN12618001412224, retrospectively registered 23/8/2018.

Beaudequin, D., Can, A. T., Dutton, M., Jones, M., Gallay, C., Schwenn, P., Yang, C., Forsyth, G., Simcock, G., Hermens, D. F., & Lagopoulos, J. (2020). Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support. BMC psychiatry, 20(1), 519. https://doi.org/10.1186/s12888-020-02925-1

Link to full text

Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support Read More »

Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N, N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact

/ Ayahuasca, DMT, Papers, Psychology / Leave a Comment / / , , , ,

Abstract

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Brito-da-Costa, A. M., Dias-da-Silva, D., Gomes, N., Dinis-Oliveira, R. J., & Madureira-Carvalho, Á. (2020). Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact. Pharmaceuticals (Basel, Switzerland), 13(11), 334. https://doi.org/10.3390/ph13110334

Link to full text

Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N, N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact Read More »

Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants

/ LSD, Microdosing, Papers / Leave a Comment / / , , , , , , , , ,

Abstract

“Microdoses” of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic-pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20 µg) and placebo were administered in a double-blind, randomized, placebo-controlled crossover study in 23 healthy participants. Test days were separated by at least 5 days. Plasma levels of LSD and subjective effects were assessed up to 6 hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151 pg/mL (127-181), 279 pg/mL (243-320), and 500 pg/mL (413-607) after 5, 10, and 20 µg LSD administration, respectively. Maximal concentrations were reached after 1.1 hours. The mean elimination half-life was 2.7 hours (1.5-6.2). The 5 µg dose of LSD elicited no significant acute subjective effects. The 10 µg dose of LSD significantly increased ratings of “under the influence” and “good drug effect” compared with placebo. These effects began an average of 1.1 hours after 10 µg LSD administration, peaked at 2.5 hours, and ended at 5.1 hours. The 20 µg dose of LSD significantly increased ratings of “under the influence,” “good drug effects,” and “bad drug effects.” LSD concentrations dose-proportionally increased at doses as low as 5-20 µg and decreased with a half-life of 3 hours. The threshold dose of LSD base for psychotropic effects was 10 µg.

Holze, F., Liechti, M. E., Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Duthaler, U., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2021). Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants. Clinical pharmacology and therapeutics, 109(3), 658–666. https://doi.org/10.1002/cpt.2057

Link to full text

Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants Read More »

Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences

/ Papers, Psychology / Leave a Comment / / , ,

Abstract

Background: We study the significance of stories about bad trips among users of psychedelics. Drawing on narrative theory, we describe the characteristics of such stories and explore the work they do.

Methods: In-depth qualitative interviews with 50 Norwegian users of psychedelics.

Results: Almost all participants had frightening experiences when using psychedelics and many described these as bad trips. The key feature of a bad trip was a feeling of losing oneself or going crazy, or ego dissolution. Most users said that these experiences could be avoided by following certain rules, based on tacit knowledge in the subcultures of users. Possessing such knowledge was part of symbolic boundary work that distinguished between drug culture insiders and outsiders. Some also rejected the validity of the term bad trip altogether, arguing that such experiences reflected the lack of such competence. Finally, and most importantly, most participants argued that unpleasant experiences during bad trips had been beneficial and had sometimes given them deep existential and life-altering insights.

Conclusion: Bad trip experiences are common among users of psychedelics. Such experiences are often transformed into valuable experiences through storytelling. Bad trip narratives may be a potent coping mechanism for users of psychedelics in non-controlled environments, enabling them to make sense of frightening experiences and integrate these into their life stories. Such narrative sense-making, or narrative work, facilitates the continued use of psychedelics, even after unpleasant experiences with the drugs.

Gashi, L., Sandberg, S., & Pedersen, W. (2021). Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences. The International journal on drug policy, 87, 102997. https://doi.org/10.1016/j.drugpo.2020.102997

Link to full text

Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences Read More »

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice

/ Mushrooms / Psilocybin, Neuroscience, Papers / Leave a Comment / / , , , , , , ,

Abstract

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

Grandjean, J., Buehlmann, D., Buerge, M., Sigrist, H., Seifritz, E., Vollenweider, F. X., Pryce, C. R., & Rudin, M. (2021). Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice. NeuroImage, 225, 117456. https://doi.org/10.1016/j.neuroimage.2020.117456

Link to full text

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice Read More »

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice

/ Mushrooms / Psilocybin, Neuroscience, Papers / Leave a Comment / / , , , , , , ,

Abstract

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

Grandjean, J., Buehlmann, D., Buerge, M., Sigrist, H., Seifritz, E., Vollenweider, F. X., Pryce, C. R., & Rudin, M. (2021). Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice. NeuroImage, 225, 117456. https://doi.org/10.1016/j.neuroimage.2020.117456

Link to full text

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice Read More »

Psychedelic Psychiatry: Preparing for Novel Treatments Involving Altered States of Consciousness

/ Papers, Psychology / Leave a Comment / /

Abstract

The past decade has seen a renaissance of research interest into the psychotherapeutic potential of psychedelic compounds. In 2019, Oakland and Denver became the first two jurisdictions in the United States to decriminalize the possession of psychedelic-containing organisms. As research and public policy continue to evolve, it becomes increasingly plausible that psychedelics will become viable treatment options for psychiatric conditions. Psychiatrists should be integral to models of psychedelic prescription and patient management. The risk for adverse psychological and medical effects from psychedelic sessions necessitates psychiatric supervision. The literature on psychedelic-assisted psychotherapy may provide wisdom regarding practical aspects of managing patients’ treatment sessions.

Holoyda B. (2020). Psychedelic Psychiatry: Preparing for Novel Treatments Involving Altered States of Consciousness. Psychiatric services (Washington, D.C.), 71(12), 1297–1299. https://doi.org/10.1176/appi.ps.202000213

Link to full text

Psychedelic Psychiatry: Preparing for Novel Treatments Involving Altered States of Consciousness Read More »

Reciprocity and the Nagoya Protocol in Psychedelic Therapy - June 30

REGISTER NOW