OPEN Foundation

Menu
Search
Close this search box.

Psychiatry

On the transmethylation hypothesis: stress, N,N-dimethyltryptamine, and positive symptoms of psychosis

November 2, 2014 / DMT, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / ,

Abstract

Past research suggests a relationship between stress and positive symptoms of psychosis. However, the biological substrate of this relationship remains unknown. According to the transmethylation hypothesis, schizophrenia could result from a biochemical disruption in the stress mechanism. This biochemical disruption would lead to the production of a substance that would account for the symptoms of psychosis. Moreover, some studies have tested endogenous N,N-dimethyltryptamine (DMT) in the context of the transmethylation hypothesis. Stress has been found to elevate DMT levels in rodents. Also, elevated DMT levels have been associated with positive features of psychosis in psychiatric patients. Additionally, healthy participants treated with exogenous DMT experience predominantly positive symptoms of psychosis. The present paper examines endogenous DMT as a possible biological mediator of the relationship between stress and positive symptoms of psychosis.

Grammenos, D., & Barker, S. A. (2014). On the transmethylation hypothesis: stress, N, N-dimethyltryptamine, and positive symptoms of psychosis. Journal of Neural Transmission, 1-7. https://dx.doi.org/10.1007/s00702-014-1329-5
Link to full text

Single Ketamine Infusion and Neurocognitive Performance in Bipolar Depression

October 27, 2014 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

We estimated neurocognitive performance using the trail making test (TMT) and the Stroop color-word interference test before, and on the 3rd day after a single infusion of ketamine, in 18 bipolar depressed patients receiving mood-stabilizing drugs. The performance on all tests significantly improved on the 3rd day after ketamine infusion which correlated positively with baseline intensity of neuropsychological impairment and was not associated either with baseline intensity of depression or reduction of depressive symptoms after 3 or 7 days. The results suggest that in such population of patients, single ketamine infusion may improve neuropsychological performance independently of antidepressant effect.

Permoda-Osip, A., Kisielewski, J., Bartkowska-Sniatkowska, A., & Rybakowski, J. K. (2014). Single Ketamine Infusion and Neurocognitive Performance in Bipolar Depression. Pharmacopsychiatry. https://dx.doi.org/10.1055/s-0034-1394399

Link to full text

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

October 22, 2014 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

Large ‘real world’ studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss paths to move the field forward.

Sanacora, G., & Schatzberg, A. F. (2015). Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders&quest. Neuropsychopharmacology, 40(2), 259-267. https://dx.doi.org/10.1038/npp.2014.261

Link to full text

Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics

October 17, 2014 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Safety / By / , , ,

Abstract

Ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent antidepressant effects of ketamine in treatment-resistant depression. Moreover, preclinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. This article discusses the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants.

Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2015). Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics. Medicine, 66. https://dx.doi.org/10.1146/annurev-med-053013-062946

Link to full text

Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression

October 14, 2014 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

Anhedonia—which is defined as diminished pleasure from, or interest in, previously rewarding activities—is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine’s anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia.

Lally, N., Nugent, A. C., Luckenbaugh, D. A., Ameli, R., Roiser, J. P., & Zarate, C. A. (2014). Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Translational psychiatry, 4(10). https://dx.doi.org/10.1038/tp.2014.105

Link to full text

Treating drug dependence with the aid of ibogaine: A retrospective study

September 29, 2014 / Iboga / Ibogaine, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety, Substance Use Disorder, Toxicology / By / , , ,

Abstract

Ibogaine is an alkaloid purported to be an effective drug dependence treatment. However, its efficacy has been hard to evaluate, partly because it is illegal in some countries. In such places, treatments are conducted in underground settings where fatalities have occurred. In Brazil ibogaine is unregulated and a combined approach of psychotherapy and ibogaine is being practiced to treat addiction. To evaluate the safety and efficacy of ibogaine, we conducted a retrospective analysis of data from 75 previous alcohol, cannabis, cocaine and crack users (72% poly-drug users). We observed no serious adverse reactions or fatalities, and found 61% of participants abstinent. Participants treated with ibogaine only once reported abstinence for a median of 5.5 months and those treated multiple times for a median of 8.4 months. This increase was statistically significant (p < 0.001), and both single or multiple treatments led to longer abstinence periods than before the first ibogaine session (p < 0.001). These results suggest that the use of ibogaine supervised by a physician and accompanied by psychotherapy can facilitate prolonged periods of abstinence, without the occurrence of fatalities or complications. These results suggest that ibogaine can be a safe and effective treatment for dependence on stimulant and other non-opiate drugs.

Schenberg, E.E., de Castro Comis, M.A., Rasmussen Chaves, B. & da Silveira, D. X. (2014). Treating drug dependence with the aid of ibogaine: A retrospective study. Journal of Psychopharmacology, 28(11), 993-1000. http://dx.doi.org/10.1177/0269881114552713
Link to full text

Back to the future: A return to psychedelic treatment models for addiction

September 24, 2014 / LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Substance Use Disorder / By /

Abstract

The discovery of the 5HT2aR agonist hallucinogen (i.e. classic psychedelic) lysergic acid diethylamide (LSD) by Albert Hofmann in 1943 was a global watershed event. Not only did it spark wide interest in the nature of consciousness and the role of neurotransmission in brain function, it opened new avenues of potential treatment for a range of mental health conditions (Hofmann, 2013). The scientific community of the 1950s through the early 1970s responded to Hofmann’s discovery by producing more than 1000 manuscripts describing the treatment of 40,000 patients (Nutt et al., 2013). Despite promising if not remarkable indications of efficacy (Krebs and Johansen, 2012; Savage and McCabe, 1973),sensationalized reports of recreational LSD use prompted legal restrictions that ultimately rendered research with LSD and …

Hendricks, P. S. (2014). Back to the future: A return to psychedelic treatment models for addiction. Journal of Psychopharmacology, 28(11), 981-982. http://dx.doi.org/10.1177/0269881114550935
Link to full text

The role of ketamine in treatment-resistant depression: a systematic review

September 12, 2014 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

BACKGROUND:

At least 10-20% of the patients suffering from depression meet criteria for treatment-resistant depression (TRD). In the last decades, an important role of glutamate in mood modulation has been hypothesized and ketamine, a non noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, has been demonstrated to be effective in both MDD and TRD. However, concerns emerged about the optimal dosage, and frequency of administration of this treatment.

METHODS:

aiming to systematically review the current literature focusing on the main pharmacological properties and impact of ketamine in TRD, a detailed literature search in PubMed/Medline and ScienceDirect databases was conducted. Twenty-four manuscripts including a total of 416 patients fulfilled inclusion criteria.

RESULTS:

Most studies demonstrated that the NMDA antagonist ketamine has rapid antidepressant effects in TRD patients, confirming the active role of glutamate in the pathophysiology of this complex condition. Ketamine has been demonstrated to be rapidly effective and was associated with a significant clinical improvement in depressive symptoms within hours after administration. Also, ketamine was also found to be effective in reducing suicidality in TRD samples.

LIMITATIONS:

The long-term efficacy of ketamine has not been investigated by most studies. The psychotomimetic properties may complicate the application of this pharmacological agent.

CONCLUSIONS:

Ketamine may be considered a valid and intriguing antidepressant option for the treatment of TRD. Further studies are needed to evaluate its long-term antidepressant efficacy in patients with TRD.

Serafini, G., H Howland, R., Rovedi, F., Girardi, P., & Amore, M. (2014). The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review. Current neuropharmacology, 12(5), 444-461. https://dx.doi.org/10.2174/1570159X12666140619204251
Link to full text

Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction

September 11, 2014 / Mushrooms / Psilocybin, Mystical experiences, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety, Substance Use Disorder / By / , , ,

Abstract

Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.

Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P., & Griffiths, R. R. (2014). Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. Journal of Psychopharmacology, 28(11), 983-992. http://dx.doi.org/10.1177/0269881114548296
Link to full article

Blood d-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine

September 5, 2014 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Excerpt from the content

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is the most effective antidepressant drug for patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) (Krystal et al. 2013). A single subanesthetic dose (0.5 mg/kg) of ketamine produces rapid antidepressant effects in up to two-thirds of patients with MDD and BD, and this effect can last for 7 days or more (Krystal et al. 2013; Zarate et al. 2012). However, the biochemical pathways defining the differences between patients who respond to ketamine and those who do not are currently unknown.

We read with great interest the article entitled “d-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression,” by Moaddel et al. (2014). d-Serine acts as an endogenous, obligatory co-agonist at the NMDA receptor, and in their study, the authors reported that plasma levels of d-serine in the ketamine responder group (3.02 ± …

Hashimoto, K. (2014). Blood d-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine. Psychopharmacology, 231(20), 4081-4082. https://dx.doi.org/10.1007/s00213-014-3735-7

Link to full text