Carlos A. Zarate - The Consciousness Library

Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis.

JAMA Psychiatry July 1, 2026 Sung Ryul Shim, Hye Su Jeong, Tanner J. Bommersbach et al. 1 citation

While intravenous ketamine is not approved by the US Food and Drug Administration, it is increasingly used with off-label indications as a novel treatment for suicidal and depressive symptoms. To systematically review and metasynthesize the efficacy and safety data for intravenous ketamine in treating major depressive episodes (MDEs). PubMed, PsycInfo, Cochrane Library, and Embase were...

DOI: 10.1001/jamapsychiatry.2026.0612 Full text

Modulation of early non-rapid eye movement slow wave activity by ketamine in treatment-resistant depression.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 16, 2026 Nadia S. Hejazi, Mina Kheirkhah, Brady A. Riedner et al.

Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample...

DOI: 10.1038/s41386-026-02465-4 Full text

Advancing cancer neuroscience through stress modulation: Interdisciplinary potential of psilocybin and ketamine

General Hospital Psychiatry February 25, 2026 Alan C. Courtes, Blake Myers, Noah Daly et al. 1 citation

Psychological stress not only undermines quality of life for people with cancer but also fuels tumor growth. Emerging evidence from the nascent field of cancer neuroscience suggests that adrenergic signaling from direct tumor-neuron interactions drives cancer progression, resistance to treatment, and worse outcomes. Cancer neuroscientists are increasingly seeking to repurpose psychoactive...

DOI: 10.1016/j.genhosppsych.2026.02.011

Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers.

Research Square February 12, 2026 Jenessa N Johnston, Greg Jones, Shiyong Peng et al.

Rapid-acting antidepressants like ketamine and serotonergic psychedelics show promise for treatment-resistant depression (TRD), but the molecular mechanisms that contribute to their therapeutic effects remain unclear. Induced pluripotent stem cells (iPSCs) offer a platform to model human cortical neurons and investigate drug effects in a human-relevant system. Here, iPSCs from individuals with...

DOI: 10.21203/rs.3.rs-8733841/v1 Full text

A preliminary proof-of-concept trial on the effects of ketamine on fatigue: a randomized crossover trial.

Pharmacological reports : PR January 22, 2026 Taichi Goto, Joy D Kreskow, Alexander L R Ross et al.

Fatigue, a prevalent symptom of chronic illness, impacts quality of life. This proof-of-concept, randomized, double-blind, crossover trial assessed the anti-fatigue effects of ketamine (0.5 mg/kg) versus midazolam (0.045 mg/kg), the active comparator. Ten participants, who were cancer survivors, with fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, or systemic lupus...

DOI: 10.1007/s43440-025-00808-4 Full text Active placebo Chronic illness Glutamate receptor Midazolam +1

Blunted arginine vasopressin secretion in individuals experiencing a major depressive episode with comorbid post-traumatic stress disorder: Results from an exploratory study using copeptin as a surrogate marker.

Journal of Neuroendocrinology 2026 Hiroe Hu, Yoojin Lee, Alaina N Tillman et al. 1 citation

Arginine vasopressin (AVP) modulates stress responsivity and social-affective behaviors, but its role in mood and trauma-related disorders remains poorly defined due to challenges in peripheral measurement. This study used copeptin, a stable, reliable, and well-validated surrogate marker of AVP secretion, to assess vasopressinergic function in a transdiagnostic sample of individuals...

DOI: 10.1111/jne.70133 Full text PTSD Depression Ketamine Copeptin +1

Explainable AI-driven precision clinical trial enrichment: demonstration of the NetraAI platform with a phase II depression trial.

NPJ digital medicine December 8, 2025 Joseph Geraci, Bessi Qorri, Mike Tsay et al.

Clinical trial failures are frequently driven by patient heterogeneity and limited sample sizes that obscure treatment effects by diluting statistical power. We introduce NetraAI, a novel explainable artificial intelligence (AI) platform that integrates dynamical-systems modeling, evolutionary long-range memory feature selection, and large-language model (LLM)-generated insights, to discover...

DOI: 10.1038/s41746-025-02143-7 Full text

Response of iPSC-derived neurons from individuals with treatment-resistant depression to (2 R,6 R)-hydroxynorketamine and reelin: an exploratory study.

Translational Psychiatry November 18, 2025 Jenessa N Johnston, Peixiong Yuan, Bashkim Kadriu et al. 2 citations

Treatment-resistant depression (TRD) is associated with worse clinical outcomes and longer course of illness. However, TRD is more difficult to model in animal phenotypes, suggesting that other experimental and translational models must be considered to properly address and research novel therapeutics. Reelin, an endogenous glycoprotein downregulated in depression, has shown rapid...

DOI: 10.1038/s41398-025-03724-6 Full text Treatment-resistant depression Ipsc model Neuropharmacology Neuronal signaling

Acute ketamine connectivity changes in patients with major depression

Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition September 16, 2025 Jen Evans, Carlos A. Zarate

Motivation: The exact mechanism of action of the rapid acting acting antidepressant ketamine is unknown. Goal(s): Investigation of the functional connectivity changes after acute ketamine in relation to receptor density. Approach: In a double blind placebo controlled clinical trial an infusion of ketamine or placebo was administered during resting state fMRI at 3T and functional connectivity...

DOI: 10.58530/2025/0503

Mindfulness, music, visual occlusion in ketamine therapy for depression: do they change outcomes? A qualitative and quantitative analysis of a randomized controlled trial

Frontiers in Psychiatry September 2, 2025 Mina Kheirkhah, Nastasia McDonald, Julia Aepfelbacher et al. 1 citation

Introduction: This is the first randomized controlled trial to use both qualitative and quantitative methods to evaluate the effects of a combined sensory intervention that included mindfulness, music, and a light-occluding eye mask during antidepressant-dose ketamine treatment for depression. Methods: Forty-three participants with unipolar depressive disorder enrolled in the study; 22...

DOI: 10.3389/fpsyt.2025.1642025 Mindfulness Ketamine Randomized controlled trial Music therapy +3

Effects of Psychedelic Drug Use on Neurocognitive Function and Psychological and Social Quality of Life Domains: An International Online Study

medRxiv August 28, 2025 Franziska Stadler, Johan Saelens, Ioline D. Henter et al. preprint

This international online study (N=759) examined the acute, subacute, and long-term effects of psychedelic drug use on cognitive performance and mental health. Participants completed cognitive tasks assessing working memory, selective attention, and visual/spatial perception, as well as questionnaires assessing mental health outcomes and quality of life. Based on self-reported substance use,...

DOI: 10.1101/2025.08.27.25334164 Full text Neurocognitive Quality philosophy Function biology Drug +8

Assessment of complement cascade components in patients with major depressive disorder.

Brain, behavior, and immunity July 1, 2025 Brandi Quintanilla, Dede Greenstein, Ashutosh Tripathi et al. 7 citations

Recent evidence suggests that the rapid-acting antidepressant ketamine has immune regulatory functions. The complement system is an important component of the innate immune response and plays a key role in synaptic plasticity. An increase in complement component 3 (C3) expression was previously found in the prefrontal cortex of individuals with depression. Given the complement system's role in...

DOI: 10.1016/j.bbi.2025.03.009 Full text Depressive disorder Immune function Antidepressant Depression major depression +6

Can ketamine and other glutamate receptor modulators be considered entactogens?

Psychiatry Research July 1, 2025 Hiroe Hu, Alaina N Tillman, Miyu Fujita et al. 2 citations

Subanesthetic-dose ketamine has recently been reported to improve hedonic pleasures associated with social interactions and altruism in individuals with treatment-resistant depression. However, whether ketamine-among other glutamate receptor modulators-also improves empathy and/or prosocial behavior in humans remains unknown. Under a framework grounded in neurobiology that proposes that...

DOI: 10.1016/j.psychres.2025.116513 Full text Ketamine Entactogen Glutamate receptor modulators Prosocial behavior +7

Ketamine in clinical practice: transitioning from anesthetic agent to psychiatric therapeutic.

CNS Spectrums June 30, 2025 Jose-Manuel Quintero, Rosa-Helena Bustos, Sharon Lechtig-Wassermann et al. 6 citations

Ketamine, originally synthesized in 1962, has gained increasing attention due to its rapid and sustained antidepressant effects in treatment-resistant depression (TRD). Unlike traditional antidepressants, ketamine acts on multiple neurotransmitter systems, including NMDA receptor antagonism and AMPA receptor potentiation, offering a novel mechanism for mood regulation. Beyond psychiatry,...

DOI: 10.1017/S1092852925100333 Full text Ketamine Anesthetic Recreational drug Antidepressant therapy +2

Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens.

Neuron May 7, 2025 Federica Lucantonio, Jacob Roeglin, Shuwen Li et al. 24 citations

Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine's effect in rescuing...

DOI: 10.1016/j.neuron.2025.02.021 Full text Brain plasticity Synaptic plasticity Neuroscience research Reward circuits +10

Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Johan Saelens, Anna Gramser, Victoria Watzal et al. 47 citations

This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at...

DOI: 10.1038/s41386-024-02044-5 Full text Treatment-resistant depression Depression treatment Electroconvulsive therapy Mental health interventions +1

REM density predicts rapid antidepressant response to ketamine in individuals with treatment-resistant depression.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Mina Kheirkhah, Wallace C. Duncan, Qiaoping Yuan et al. 6 citations

Abnormalities during rapid eye movement (REM) sleep contribute to the pathophysiology of major depressive disorder (MDD), but few studies have explored the relationship between REM sleep and treatment-resistant depression (TRD). In MDD, REM sleep abnormalities often manifest as alterations in total night REM Density (RD), RD in the first REM period (RD1), and REM Latency (RL). Among these, RD1...

DOI: 10.1038/s41386-025-02066-7 Full text Depression Ketamine therapy Sleep patterns Rem sleep +1

Ketamine's Influence on Magnetoencephalography Patterns During a Working Memory Task in Treatment-Resistant Depression: An Exploratory Study.

Bipolar Disorders April 2, 2025 Adam Fijtman, Mani Yavi, Abigail Vogeley et al. 2 citations

Treatment-resistant depression (TRD) remains a challenge, necessitating novel interventions that address associated cognitive deficits. The glutamatergic modulator ketamine exerts rapid antidepressant effects, prompting investigators to assess its impact on cognitive function, specifically working memory. This study explored ketamine's influence on working memory and magnetoencephalography...

DOI: 10.1111/bdi.70027 Full text Major depressive disorder Bipolar disorder Cognition Magnetoencephalography +7

Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine.

Journal of Affective Disorders March 15, 2025 Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros et al. 24 citations

Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a...

DOI: 10.1016/j.jad.2024.12.036 Full text Depression Adrenocorticotropic hormone Corticotropin releasing factor Cortisol +4

Ketamine and Hydroxynorketamine as Novel Pharmacotherapies for the Treatment of Opioid Use Disorders.

Biological Psychiatry March 15, 2025 Anna Onisiforou, Andria Michael, Markos Apostolakis et al. 14 citations

Opioid use disorder (OUD) has reached epidemic proportions, with many countries facing high levels of opioid use and related fatalities. Although currently prescribed medications for OUD are considered lifesaving, they inadequately address negative affect and cognitive impairment, resulting in high relapse rates to nonmedical opioid use even years after drug cessation (protracted abstinence)....

DOI: 10.1016/j.biopsych.2024.09.008 Full text Hydroxynorketamine Opioid crisis Opioid use disorders Relapse +4

Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?

The American journal of psychiatry March 1, 2025 Marjorie R Levinstein, Reece C Budinich, Jordi Bonaventura et al. 49 citations

Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders...

DOI: 10.1176/appi.ajp.20240378 Full text Ketamine/esketamine #ketamine esketamine Ketalar Special k +4

Clinical indicators of the suicide crisis and response to ketamine.

Journal of Affective Disorders March 1, 2025 Elizabeth D. Ballard, Lucinda Neely, Laura Waldman et al. 4 citations

This analysis sought to identify potential clinical targets for the suicide crisis. Characteristics of a useful clinical target include elevation at the time of suicide crisis and responsiveness to rapid-acting interventions. Suicidal ideation (SI), depression, and hopelessness were hypothesized to meet these criteria. Participants were 118 adults across the continuum of suicide risk, including...

DOI: 10.1016/j.jad.2024.11.080 Full text Traumatic stress Assessment Hopelessness Psychological pain +5

The effect of intranasal (R,S)-ketamine on symptoms of fatigue in severe major depressive disorder or bipolar depression with and without comorbid alcohol use disorder: Results from a randomized, double-blind, placebo-controlled trial.

Journal of Affective Disorders December 15, 2024 Rodrigo Machado‐Vieira, Gregory H Jones, Alan C. Courtes et al.

Fatigue is a multidimensional condition that may overlap with depression. Initial studies found that fatigue responds in only a limited way to standard monoaminergic antidepressants and mood stabilizers but does respond positively to intravenous (IV) racemic (R,S)-ketamine (ketamine). However, IV ketamine's use is limited by cost and access barriers. To date, no study has evaluated intranasal...

DOI: 10.1016/j.jad.2024.08.183 Full text Alcohol use disorder Bipolar Ketamine therapy Mental health treatments +3

Personalized use of ketamine and esketamine for treatment-resistant depression.

Translational Psychiatry November 29, 2024 Gustavo C Medeiros, Isabella Demo, Fernando S Goes et al. 32 citations

A large and disproportionate portion of the burden associated with major depressive disorder (MDD) is due to treatment-resistant depression (TRD). Intravenous (R,S)-ketamine (ketamine) and intranasal (S)-ketamine (esketamine) are rapid-acting antidepressants that can effectively treat TRD. However, there is variability in response to ketamine/esketamine, and a personalized approach to their use...

DOI: 10.1038/s41398-024-03180-8 Full text Treatment-resistant depression Depression treatment Ketamine therapy Mental health breakthroughs +1

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

Clinical pharmacology and therapeutics November 1, 2024 Shruti M Raja, Jeffrey T Guptill, Michelle Mack et al. 34 citations

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and...

DOI: 10.1002/cpt.3391 Full text Clinical-trials Antidepressants Ketamine-research Psychopharmacology +1

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