Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression

A lack of effective treatment for patients with treatment-resistant depression (TRD) has led to the evaluation of ketamine, an N-methyl- D-aspartate receptor antagonist. Despite the demonstrated short-term benefits of using intravenous (IV) ketamine, side effects and the difficulty in administering ketamine outside the health-care setting has raised interest in alternative dosage forms. Research articles evaluating oral or intranasal (IN) ketamine were retrieved from the PubMed database. Patients who received oral or IN ketamine experienced a similar reduction in depressive symptoms within 24 hours of treatment and fewer side effects compared to patients who received IV ketamine. Novel administration forms of ketamine provide an opportunity for patients with TRD to achieve remission with fewer adverse side effects. Future studies should continue to evaluate these administration strategies in the hope of promoting ketamine’s use outside health-care settings and for longer time periods.

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Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

10.1101/581280 ◽

2019 ◽

Cited By ~ 1

Author(s):

Eleanor J. Cole ◽

Katy H. Stimpson ◽

Brandon S. Bentzley ◽

Merve Gulser ◽

Kirsten Cherian ◽

...

Keyword(s):

Side Effects ◽

Rating Scale ◽

Neuropsychological Testing ◽

Anterior Cingulate ◽

High Dose ◽

Delayed Response ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resting Motor Threshold ◽

Resistant Depression

AbstractBackgroundCurrent treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment that is FDA-approved for treatment-resistant depression (TRD). Recent methodological advancements suggest iTBS could be improved through 1) treating with multiple sessions per day at optimally-spaced intervals, 2) applying a higher overall pulse-dose of stimulation and 3) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. We examined the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose, resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for TRD termed ‘Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)’.MethodsTwenty-one participants with TRD received open-label SAINT. FcMRI was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.ResultsNineteen of 21 participants (90.48%) met criteria for remission (≤10 on the Montgomery-Åsberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events.DiscussionOur accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatment-resistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study.Trial registrationClinicalTrials.gov NCT03240692

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Oral ketamine for the treatment of pain and treatment-resistant depression

The British Journal of Psychiatry ◽

10.1192/bjp.bp.115.165498 ◽

2016 ◽

Vol 208 (2) ◽

pp. 108-113 ◽

Cited By ~ 32

Author(s):

Robert A. Schoevers ◽

Tharcila V. Chaves ◽

Sonya M. Balukova ◽

Marije aan Het Rot ◽

Rudie Kortekaas

Keyword(s):

Chronic Pain ◽

Side Effects ◽

Negative Consequences ◽

Treatment Resistant Depression ◽

Dosing Regimen ◽

Treatment Resistant ◽

Oral Ketamine ◽

Study Results ◽

Resistant Depression ◽

Time Periods

BackgroundRecent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.AimsTo review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain.MethodSearches in PubMed with the terms ‘oral ketamine’, ‘depression’, ‘chronic pain’, ‘neuropathic pain’, ‘intravenous ketamine’, ‘intranasal ketamine’ and ‘subcutaneous ketamine’ yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality.ResultsOverall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects.ConclusionsOral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials.

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A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression

10.1101/257238 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ana Cecília de Menezes Galvão ◽

Raíssa Nóbrega de Almeida ◽

Erick Allan dos Santos Silva ◽

Fúlvio Aurélio de Morais Freire ◽

Fernanda Palhano-Fontes ◽

...

Keyword(s):

Single Dose ◽

Salivary Cortisol ◽

Plasma Cortisol ◽

Controlled Trial ◽

Cortisol Response ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Antidepressant Effects ◽

Resistant Depression ◽

New Evidence

ABSTRACTMajor depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized placebo-controlled trial supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients and in healthy volunteers. Subjects received a single dose of ayahuasca or placebo, and both plasma and awakening salivary cortisol response were measured at baseline (before dosing) and 48h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients (DM), both with respect to healthy controls group (C). Salivary cortisol also was measured during dosing session and we observed a large increased for both C and DM that ingested ayahuasca, than placebo groups. After 48h of the dosing session (D2) with ayahuasca, awakening salivary cortisol response (for both sexes) of treated patients became similar to levels detected in controls. This was not observed in patients that ingested placebo. No changes in plasma cortisol were observed after 48 hours of ayahuasca or placebo ingestion for both groups and sexes. Therefore, these findings point to new evidence of modulation of ayahuasca on salivary cortisol levels, as cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes related to etiology of depression, this modulation could be an important part of the antidepressant effects observed with ayahuasca. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.

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Vagus Nerve Stimulation (VNS™) for Treatment-Resistant Depression Efficacy, Side Effects, and Predictors of Outcome

Neuropsychopharmacology ◽

10.1016/s0893-133x(01)00271-8 ◽

2001 ◽

Vol 25 (5) ◽

pp. 713-728 ◽

Cited By ~ 323

Author(s):

H Sackeim

Keyword(s):

Side Effects ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Treatment Resistant Depression ◽

Predictors Of Outcome ◽

Treatment Resistant ◽

Resistant Depression

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Use of ECT in the presence of acute bilateral posterior vitreous detachmanet

Australasian Psychiatry ◽

10.1177/1039856217749023 ◽

2018 ◽

Vol 26 (2) ◽

pp. 193-195

Author(s):

Tesema Taye ◽

Letitia Dobranici ◽

Mark Fisher ◽

Sarah Cullum

Keyword(s):

Side Effects ◽

Elderly People ◽

Electroconvulsive Therapy ◽

Posterior Vitreous Detachment ◽

Clinical Monitoring ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Vitreous Detachment ◽

Risks And Benefits ◽

Resistant Depression

Objectives: We describe a case of acute bilateral posterior vitreous detachment (PVD) in a 71-year-old female, which developed during a course of electroconvulsive therapy (ECT) for treatment-resistant depression. The risks and benefits of continuing ECT were assessed and the patient completed the full course of 16 ECT treatments without further ophthalmic complications. Conclusions: As the incidence of PVD increases with age, and ECT is used more frequently in elderly people with depression, we recommend paying attention to ophthalmic symptoms as part of the routine clinical monitoring of ECT side effects. If ophthalmic symptoms occur, the risks and benefits of ECT need to be weighed up including consultation with an ophthalmologist.

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Fluoxetine Potentiation by Buspirone: Three Case Histories

The Canadian Journal of Psychiatry ◽

10.1177/070674379103601012 ◽

1991 ◽

Vol 36 (10) ◽

pp. 749-750 ◽

Cited By ~ 24

Author(s):

David Bakish

Keyword(s):

Side Effects ◽

Serotonin Reuptake ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Case Histories ◽

Reuptake Inhibition ◽

Resistant Depression

The potentiation of fluoxetine by buspirone is described in three cases of treatment-resistant depression. All three patients improved markedly with very few side-effects from the medication. The possibility of synergy between drugs that affect serotonin reuptake inhibition, 5HT1A receptors and 5HT2 receptors is discussed.

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Ketamine: A tale of two enantiomers

Journal of Psychopharmacology ◽

10.1177/0269881120959644 ◽

2020 ◽

pp. 026988112095964

Author(s):

Luke A Jelen ◽

Allan H Young ◽

James M Stone

Keyword(s):

Side Effects ◽

Receptor Antagonist ◽

The United States ◽

Receptor Activation ◽

Racemic Mixture ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Aspartate Receptor ◽

Antidepressant Effects ◽

Resistant Depression

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

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Occurrence of Side Effects in Treatment-Resistant Depression: Role of Clinical, Socio-Demographic and Environmental Characteristics

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.795666 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anna Levy ◽

Wissam El-Hage ◽

Djamila Bennabi ◽

Etienne Allauze ◽

Alexandra Bouvard ◽

...

Keyword(s):

Side Effects ◽

Emotional Abuse ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Cross Sectional ◽

Pharmacological Management ◽

History Of ◽

Resistant Depression ◽

Main Determinants ◽

Using Data

Introduction: Treatment-resistant depression (TRD) is a disabling psychiatric condition characterized by the failure of two antidepressants (ADs). Since the occurrence of side effects (SEs) appears to be one of the main determinants of early discontinuation of pharmacological treatments contributing to a pseudo-resistance, the purpose of this study was to determine the parameters associated with the occurrence of SEs under ADs in a cohort of patients with TRD.Methods: An observational, cross-sectional, multicentre study was carried out using data from the French network of Expert Centers for TRD. For the 108 patients enrolled in the study, the statistical analyses focused on the overall occurrence and on the profile of the SEs (9 categories, 32 items).Results: SEs were influenced by age and sex and were positively associated with the intensity of anxious, depressive and suicidal symptoms, a history of childhood trauma (sexual abuse, emotional abuse and neglect), and negatively associated with self-esteem, and assessment of overall functioning.Conclusion: Using variables accessible in common practice, these results fall within the dynamic of a more tailored approach to medicine that could allow, through integrated pharmacological management, the continuation of antidepressant treatments, and therefore limit the risk of therapeutic failure.

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The Neurostimulation of the Brain in Depression Trial: Protocol for a Randomized Controlled Trial of Transcranial Direct Current Stimulation in Treatment-Resistant Depression (Preprint)

10.2196/preprints.22805 ◽

2020 ◽

Author(s):

Raheem Suleman ◽

Benjamin V Tucker ◽

Serdar M Dursun ◽

Michael L Demas

Keyword(s):

Side Effects ◽

Adverse Events ◽

Rating Scale ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

University Of Alberta ◽

Randomized Controlled ◽

Resistant Depression ◽

Double Blinded ◽

The Brain

BACKGROUND Major depressive disorder (MDD) is the second highest cause of disability worldwide. Standard treatments for MDD include medicine and talk therapy; however, approximately 1 in 5 Canadians fail to respond to these approaches and must consider alternatives. Transcranial direct current stimulation (tDCS) is a safe, noninvasive method that uses electrical stimulation to change the activation pattern of different brain regions. By targeting those regions known to be affected in MDD, tDCS may be useful in ameliorating treatment-resistant depression. OBJECTIVE The objective of the Neurostimulation of the Brain in Depression trial is to compare the effectiveness of active versus sham tDCS in treating patients with ultraresistant MDD. The primary outcome will be the improvement in depressive symptoms, as measured by the change on the Mongtomery-Asberg Depression Rating Scale. Secondary outcomes will include changes in the Quick Inventory of Depressive Symptomatology Scale (subjective assessment), the World Health Organization Disability Assessment Schedule 2.0 (functional assessment), and the Screen for Cognitive Impairment in Psychiatry (cognitive assessment). Adverse events will be captured using the Young Mania Rating Scale; tDCS Adverse Events Questionnaire; Frequency, Intensity, and Burden of Side Effects Rating Scale; and Patient-Rated Inventory of Side Effects Scale. A parallel component of the study will involve assaying for baseline language function and the effect of treatment on language using an exploratory acoustic and semantic corpus analysis on recorded interviews. Participant accuracy and response latency on an auditory lexical decision task will also be evaluated. METHODS We will recruit inpatients and outpatients in the city of Edmonton, Alberta, and will deliver the study interventions at the Grey Nuns and University of Alberta Hospitals. Written informed consent will be obtained from all participants before enrollment. Eligible participants will be randomly assigned, in a double-blinded fashion, to receive active or sham tDCS, and they will continue receiving their usual pharmacotherapy and psychotherapy throughout the trial. In both groups, participants will receive 30 weekday stimulation sessions, each session being 30 minutes in length, with the anode over the left dorsolateral prefrontal cortex and the cathode over the right. Participants in the active group will be stimulated at 2 mA throughout, whereas the sham group will receive only a brief period of stimulation to mimic skin sensations felt in the active group. Measurements will be conducted at regular points throughout the trial and 30 days after trial completion. RESULTS The trial has been approved by the University of Alberta Research Ethics Board and is scheduled to commence in June 2021. The target sample size is 60 participants. CONCLUSIONS This is a protocol for a multicenter, double-blinded, randomized controlled superiority trial comparing active versus sham tDCS in patients with treatment-resistant MDD. CLINICALTRIAL ClinicalTrials.gov NCT04159012; http://clinicaltrials.gov/ct2/show/NCT04159012. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/22805

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