OPEN Foundation

Day: 1 April 2017

Clinical predictors of antidepressant response to ketamine in unipolar treatment-resistant depression



The non-competitive N-methyl-d-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in treatment-resistant depression (TRD). However, only a few studies have investigated which clinical characteristics predict a response to ketamine.


To assess sociodemographic variables and clinical markers that predict response to ketamine in unipolar TRD patients.


Searches of Pubmed, NCBI and Google Scholar were conducted for clinical trials and systematic reviews, through October 2016, using the keywords:
ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, clinical predictors.


Findings support the following clinical predictors:
– sociodemographic variables: positive family history of alcohol abuse disorder in first-degree relative (increased antidepressant response and fewer depressive symptoms for up to 4 weeks post-infusions), higher BMI (improvement in depression severity at 230 minutes and one day post-infusion), negative history of suicide attempt (greater improvement at day 7);
– infusion-associated events: greater dissociation during infusion (better antidepressant response at 230 minutes and one week post-infusion); rapid response to first infusion (sustained response to subsequent infusions in one-third responders for up to 83 days);
– symptomatology: anxious depression (fewer depression symptoms at day one up to 25 associated with longer time to relapse); neurocognitive performance (lower attention) predicts change in severity of depressive symptoms over six infusions.


Findings suggest that specific clinical characteristics are predictors of ketamine response in TRD. Future studies confirming reliable predictors will assist clinicians to implement efficacious and individualized treatment for TRD patients.

Del Sant, L. C., Magalhães, E., Lucchese, A. C., Alves, H. P., Sarin, L. M., Del Porto, J. A., & de Lacerda, A. T. (2017). Clinical predictors of antidepressant response to ketamine in unipolar treatment-resistant depression. European Psychiatry41, S525-S526. 10.1016/j.eurpsy.2017.01.704
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Psychotria viridis: Chemical constituents from leaves and biological properties


The phytochemical study of hexane, chloroform and methanol extracts from leaves of Psychotria viridis resulted in the identification of: the pentacyclic triterpenes, ursolic and oleanolic acid; the steroids, 24-methylene-cycloartanol, stigmasterol and β-sitosterol; the glycosylated steroids 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol; a polyunsaturated triterpene, squalene; the esters of glycerol, 1-palmitoylglycerol and triacylglycerol; a mixture of long chain hydrocarbons; the aldehyde nonacosanal; the long chain fat acids hentriacontanoic, hexadecanoic and heptadenoic acid; the ester methyl heptadecanoate; the 4-methyl-epi-quinate and two indole alkaloids, N,N-dimethyltryptamine (DMT) and N-methyltryptamine. The chemical structures were determined by means of spectroscopic (IR, 1H and 13C NMR, HSQC, HMBC and NOESY) and spectrometric (CG-MS and LCMS-ESI-ITTOF) methods. The study of biologic properties of P. viridis consisted in the evaluation of the acetylcholinesterase inhibition and cytotoxic activities. The hexane, chloroform, ethyl acetate and methanol extracts, the substances 24-methylene-cycloartanol, DMT and a mixture of 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol showed cholinesterase inhibiting activity. This activity induced by chloroform and ethyl acetate extracts was higher than 90%. The methanol and ethyl acetate extracts inhibit the growth and/or induce the death of the tumor cells strains B16F10 and 4T1, without damaging the integrity of the normal cells BHK and CHO. DMT also demonstrated a marked activity against tumor cell strains B16F10 and 4T1.
SOARES, D., DUARTE, L. P., CAVALCANTI, A. D., SILVA, F. C., BRAGA, A. D., LOPES, M. T., … & VIEIRA-FILHO, S. A. (2017). Psychotria viridis: Chemical constituents from leaves and biological properties. Anais da Academia Brasileira de Ciências, 89(2), 927-938. 10.1590/0001-3765201720160411
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S-(+)-ketamine-induced dissociative symptoms as a traumatic experience in patients with treatment-resistant depression


Ketamine, an NMDA receptor antagonist, is a rapid-acting antidepressant and anti-suicidal agent.1 However, most clinical trials assessing its antidepressant action involve RS-(±)-ketamine, which is considered a more dissociative drug than S-(+)-ketamine.2 In this report, we describe severe psychotomimetic side effects after S-(+)-ketamine infusion therapy in two patients with treatment-resistant depression (TRD), contrasting with previous evidence that S-(+)-ketamine is less prone to inducing these side effects.
Correia-Melo, F. S., Silva, S. S., Araújo-de-Freitas, L., & Quarantini, L. C. (2017). S-(+)-ketamine-induced dissociative symptoms as a traumatic experience in patients with treatment-resistant depression. Revista Brasileira de Psiquiatria, 39(2), 188-189. 10.1590/1516-4446-2016-2070
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Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis


Background and Objective We previously discovered that serotonin 5-HT2A receptor activation with psychedelics has potent anti-inflammatory activity in both cell culture and whole animals, which indicated potent anti-inflammatory effects in vascular tissues among others. More recently we found that the psychedelic (R)-DOI potently prevents the development of allergic asthma in a mouse model. The effects of (R)-DOI were found to not result from a generalized anti-inflammatory process, but due to specific inflammatory pathways inhibition in both innate and Th2 cells. In this work, we have examined the therapeutic effects of the psychedelic (R)-DOI in the ApoE −/− high-fat model of atherosclerosis.

Methods Osmotic minipumps were used to deliver very low doses of (R)-DOI to male ApoE −/− mice that were divided into four treatment groups [Saline, normal chow; (R)-DOI, normal chow; Saline, hi-fat diet; (R)-DOI, hi-fat diet]. After 16 weeks, mice were euthanized and tissues collected for analysis

Results Calculated steady state levels of ~0.0013 mg/kg (R)-DOI resulted in a significant reduction of mRNA expression for inflammatory markers like Il6 in vascular tissue, reduced levels of glucose, and a reduction in circulating cholesterol in the high fat fed animals. Additional ongoing studies are examining arterial plaque size and heart pathology.

Summary Extremely low levels of the psychedelic (R)-DOI were sufficient to significantly block the development of vascular inflammation, normalize glucose homeostasis, and prevent the increase in cholesterol associated with a hi-fat ‘western’ high diet. Activation of serotonin 5-HT2A receptor therefore represents a powerful new strategy to treat inflammatory-related vascular disease.

Nichols, C. D., Sebastian, M., & Flanagan, T. (2017). Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis. The FASEB Journal31(1 Supplement), 825-3.
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Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action


Ketamine is an anesthetic drug that is also used for off-label indications such as the mediation of analgesia and sedation in various settings. It is additionally recognized as an agent with antidepressant potential. For depression, it is most commonly administered as a slow intravenous infusion in subanesthetic doses (usually 0.5 mg/kg). As an antidepressant, is strikingly different from conventional antidepressant drugs in that it brings about rapid and marked attenuation of depressive symptoms even in patients with refractory depression. The benefits are observed within hours of administration, peak after about a day, and are lost 3-12 days later. Patients who do not benefit after the initial dose may benefit with serial dosing or at higher doses. Benefits can be maintained for weeks to months by the continuation of ketamine sessions at 2- to 4-day intervals. Adverse effects include dissociative and psychotomimetic changes that are almost always mild and transient, if present; transient elevation of heart rate and blood pressure often occur. These changes are usually well tolerated and are very seldom responsible for treatment discontinuation. Whereas ketamine is an N-methyl-d-aspartate receptor antagonist, and whereas much is known about its different biological effects, its actions that mediate the antidepressant response are presently not known for certain. Although big data on ketamine are presently unavailable, the drug holds promise in the treatment of depression, especially refractory depression.
Andrade, C. (2017). Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. The Journal of clinical psychiatry78(4), e415. 10.4088/JCP.17f11567
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Psychoactive Drugs as a Route to Development of Novel Anti-parasitic Agents


Over a third of the world’s population is infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia) caused by parasitic flatworms of the genus Schistosoma, which afflicts ~200 million people worldwide. Consequently, there is a need to discover and develop next generation anthelmintics, active against a broad spectrum of parasitic helminths.

Flatworm musculature is regulated by bioaminergic signalling: addition of exogenous 5-HT to isolated flatworm muscle fibres causes contraction. This effect is likely mediated by engagement of serotonergic G protein coupled receptors (GPCRs). For example, in free living planarians, knockdown of a serotonergic GPCR (S7.1) impairs worm motility. Here, we demonstrate that the psychoactive agent, lysergic acid diethylamide (LSD) acts as a agonist at the planarian S7.1 receptor (EC50 = 1.3±0.5nM, Emax 99±5% of 5-HT response). LSD evoked contraction inhibited the motility of free living planarian worms (distance moved 16±2% versus control worms) and potently blocked bipolar regeneration evoked by praziquantel (IC50 = 0.5±0.2nM). These data raises the possibility that other psychoactive drugs, including psychotropics with known activity at human 5-HT2 receptors, could serve as efficacious lead compounds to disrupt flatworm mobility.

Therefore, we screened a variety of psychoactive agents on the motility of free living planarian flatworms, as well as the functionality of heterologously expressed S7.1 using a real time cAMP biosensor. Agents were discovered that modulated flatworm movement and regeneration, and efficacy of the screened molecules provided information about structural features necessary for activity at this abundant flatworm serotonergic GPCR. These data also identify features of ligands conveying activity at flatworm 5-HT GPCRs.

Woodhouse, K., Chan, J. D., & Marchant, J. (2017). Psychoactive Drugs as a Route to Development of Novel Anti-parasitic Agents. The FASEB Journal31(1 Supplement), 1002-2.
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Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models


Only recently has the full therapeutic value of serotonin [5-hydroxytryptophan (5-HT)] receptor activation begun to be explored. Currently there are two 5-HT2A receptor agonists in human clinical trials for the treatment of depression and obesity. An exciting new therapeutic avenue in which 5-HT2A agonists might be employed is the modulation of inflammation in allergic airways disease. Our lab has previously used an ovalbumin (OVA)-induced asthma model to demonstrate that administration of (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] prior to allergen challenge prevents many of the symptoms of allergic asthma. Here we have utilized a modified protocol to test the effectiveness of (R)-DOI in treating persistent allergic asthma. We demonstrate that administration of (R)-DOI in a chronic model attenuates the elevated airway hyperresponsiveness (AHR) typically observed in an asthmatic response. We also have probed for the expression of inflammatory markers in the lung and BALF. We concurrently are testing for the impact psilocybin and other tryptamines have on AHR in rodents using our OVA model. Overall our strategy is to develop 5-HT2A receptor agonism as a viable treatment modality against asthma and other inflammatory disorders.
Flanagan, T. W., Sebastian, M. N., & Nichols, C. D. (2017). Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models. The FASEB Journal31(1 Supplement), 820-4.
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A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders


Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., … & Nemeroff, C. B. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. Jama psychiatry74(4), 399-405. 10.1001/jamapsychiatry.2017.0080
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Use of Ketamine in Clinical PracticeA Time for Optimism and Caution


Increasing evidence, primarily from small studies, supports the idea that the dissociative anesthetic ketamine has rapid antidepressant effects in patients with treatment-refractory major depression.1 The beneficial effects of ketamine are observed within hours of administration and can last approximately 1 week. Given that up to one-third of patients with major depression fail current treatments,2 there is a clear need for novel and more effective treatments. Results to date have led to increasing off-label use of ketamine in clinical practices, with little guidance about clinical administration. In this issue of the JAMA Psychiatry, Sanacora and colleagues3 provide a much-needed consensus statement to help guide clinical use of ketamine.
Zorumski, C. F., & Conway, C. R. (2017). Use of ketamine in clinical practice: a time for optimism and caution. Jama psychiatry74(4), 405-406. 10.1001/jamapsychiatry.2017.0078
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