Research & Resources

Video: The Doctors: Woman Shares Her Experience Undergoing Ketamine Injections for Depression

Julie, who says she has suffered with clinical depression almost her entire life, underwent two ketamine injection treatments to treat her condition. She joins The Doctors to share her experience and a Los Angeles clinic doctor describes how IV ketamine helps patients.

Resources

Overview

Ketamine for Depression: A Q&A with Psychiatrist Alexander Papp, MD

Alexander Papp, MD, psychiatrist at UC San Diego Health, discusses the potential of ketamine as a remedy for depression when other treatments fail.

https://health.ucsd.edu/news/features/Pages/2018-01-03-q-and-a-ketamine-for-depression.aspx

How ketamine works

Ketamine works its magic on depression by ‘stabilizing the brain in a well state’ (CBC)

When stressed, which includes periods of severe mood disorders, such as major depression, the hormone cortisol is released. Cortisol can damage neural connections and ketamine acts to restore some of the connections that have been lost.

https://www.cbc.ca/radio/quirks/april-13-2019-black-hole-imaged-a-new-tiny-human-rebuilding-coral-reefs-and-more-1.5093713/ketamine-works-its-magic-on-depression-by-stabilizing-the-brain-in-a-well-state-1.5093729

Listen: From Chaos To Calm: A Life Changed By Ketamine

Patient James talks about how ketamine helped him, and experts talk about how it works on depression and other conditions, like PTSD.

https://www.npr.org/sections/health-shots/2018/06/04/615671405/from-chaos-to-calm-a-life-changed-by-ketamine

About ketamine treatments

Ketamine for major depression: New tool, new questions

https://www.health.harvard.edu/blog/ketamine-for-major-depression-new-tool-new-questions-2019052216673

Video: Rapid relief of treatment-resistant depression through ketamine treatment (first-person)

https://www.youtube.com/watch?v=7A26miRlYBc

Ketamine for Depression
Rapid relief

‘Club Drug’ Ketamine Lifts Depression in Hours

http://healthland.time.com/2013/05/22/club-drug-ketamine-lifts-depression-in-hours/

Video: It’s hard to get mental-health treatment fast

Dr. Paul Garfinkel, psychiatrist and former CEO at the Centre for Addiction and Mental Health, and Professor Emeritus of Psychiatry at the University of Toronto, discusses why a fast-acting treatment such as IV ketamine is critical when access to mental-health services can take a long time to access. Dr. Garfinkel is an advisor to the Toronto Ketamine Clinic: https://torontoketamineclinic.com. Shot by Craig Henry. 

Lasting relief

New study shows ketamine provides lasting relief of severe depression (The Royal Institute of Mental Health Research)

https://www.theroyal.ca/research/news/new-study-shows-ketamine-provides-lasting-relief-severe-depression

Video: Ketamine Infusion – Day 1 Report (first-person)

https://www.youtube.com/watch?v=qAEb2LB1vQM

Ketamine’s effect on people feeling suicidal
The off-label use of ketamine to treat mood disorders

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders (Jama Psychiatry)

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.

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2605202

Other links

https://www.frontiersin.org/articles/10.3389/fnhum.2016.00612/full

Why administering ketamine by IV is considered most efficient

Ketamine: 50 Years of Modulating the Mind (Frontiers in Human Neuroscience)

IV administration is 100% bioavailable and considered the ideal route of administration.

https://www.frontiersin.org/articles/10.3389/fnhum.2016.00612/full

The Use of Ketamine in the Acute Management of Depression

The bioavailability of ketamine has been reported to be 100% following IV and intraosseous administration, 93% IM, 16% to 20% oral, 30% sublingual, 45% to 50% intranasal, and 25% to 30% rectal. https://www.uspharmacist.com/article/the-use-of-ketamine-in-the-acute-management-of-depression

Rapid action

Highlight: Ketamine: A New (and Faster) Path to Treating Depression

In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom: loss of interest in pleasurable activities

https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treating-depression.shtml

How ketamine works as an antidepressant

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

https://science.sciencemag.org/content/329/5994/959.abstract

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

https://royalsocietypublishing.org/doi/full/10.1098/rstb.2011.0357

Treatment-resistant depression

Ketamine for treatment-resistant depression: recent developments and clinical applications (Evidence-Based Mental Health, a BMJ publication)

Approximately one-third of patients with major depressive disorder (MDD) do not respond to existing antidepressants, and those who do generally take weeks to months to achieve a significant effect. This article reviews developments in the study of ketamine, which has shown significant promise as a rapidly acting antidepressant in treatment-resistant patients with unipolar MDD, focusing on clinically important aspects such as dose, route of administration and duration of effect. 

https://ebmh.bmj.com/content/19/2/35.long

Other links

https://science.sciencemag.org/content/364/6436/eaat8078

PTSD

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder (JAMA Psychiatry)

A randomized clinical trial of 41 patients with chronic PTSD to test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms. Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity.

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/1860851

Video: Could a drug prevent depression and PTSD? (TED talk by neuroscientist Rebecca Brachman)

Accidental, or off-label, discoveries in medicine include the breakthrough discovery of ketamine as a treatment for disorders like depression and PTSD.

https://www.youtube.com/watch?v=j-SqQDPGW2k

Other links

https://www.sciencedirect.com/science/article/pii/S0969996116303163?via%3Dihub

https://link.springer.com/article/10.1007%2Fs00213-017-4793-4

https://pediatrics.aappublications.org/content/136/3/e694.long

Anxiety

Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders (Journal of Psychopharmacology)

An uncontrolled, open-label maintenance treatment study, evaluating the effect on anxiety ratings, safety and tolerability of 3 months of weekly ketamine in 20 patients with treatment-refractory DSM IV generalised anxiety disorder (GAD) and/or social anxiety disorder (SAD), and subsequent assessment of remission post-treatment. Conclusions: Weekly ketamine dosing was safe and well tolerated, and post-dose dissociative symptoms tended to reduce after repeated dosing. Patients reported marked improvements in functionality and in their personal lives.

https://www.ncbi.nlm.nih.gov/pubmed/?term=SAD+GAD+ketamine

Other links

https://academic.oup.com/ijnp/article/21/8/717/4989167

Suicidal ideation

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial (Psychological Medicine)

A randomized, controlled trial of ketamine in 24 patients with mood and anxiety spectrum disorders who presented with clinically significant suicidal ideation. Findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. 

https://www.cambridge.org/core/journals/psychological-medicine/article/ketamine-for-rapid-reduction-of-suicidal-ideation-a-randomized-controlled-trial/330D776E6A800D3EAA0DBFED09665FB4

Other links

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2017.17040472?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=ajp

Bipolar Disorder

A single infusion of ketamine improves depression scores in patients with anxious bipolar depression (Bipolar Disorders)

Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non‐anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. A study of 36 patients with anxious (n = 21) and non‐anxious (n = 15) treatment‐resistant bipolar depression. Conclusions: results suggested that both anxious and non‐anxious groups had an antidepressant response to ketamine.

https://onlinelibrary.wiley.com/doi/abs/10.1111/bdi.12277

Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis

The large and statistically significant effect of ketamine on depressive symptoms supports a promising, new and effective pharmacotherapy with rapid onset, high efficacy and good tolerability.

https://www.sciencedirect.com/science/article/abs/pii/S0163834315000043

Highlight: Ketamine: A New (and Faster) Path to Treating Depression

In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities.

https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treating-depression.shtml

Obsessive-Compulsive Disorder (OCD)

Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept (Neuropsychopharmacology)

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2–3 months lag time before clinically meaningful improvement. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, a randomized, double-blind, placebo-controlled, crossover design, study of 15 drug-free OCD adults tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. Conclusions: ketamine’s effects showed significant carryover effects (ie, lasting longer than 1 week). 

https://www.nature.com/articles/npp2013150

K for OCD: The pros and cons of ketamine

Stanford psychiatrist Carolyn Rodriguez, MD, PhD, researches the use of ketamine to treat obsessive-compulsive disorder and seeks to understand why, in studies, the drug has provided relief from symptoms.

https://stanmed.stanford.edu/2017summer/carolyn-rodriguez-ketamine-OCD.html

Research

The off-label use of ketamine to treat mood disorders

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders (Jama Psychiatry)

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.

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2605202

Other links

https://www.frontiersin.org/articles/10.3389/fnhum.2016.00612/full

Why administering ketamine by IV is considered most efficient

Ketamine: 50 Years of Modulating the Mind (Frontiers in Human Neuroscience)

IV administration is 100% bioavailable and considered the ideal route of administration.

https://www.frontiersin.org/articles/10.3389/fnhum.2016.00612/full

The Use of Ketamine in the Acute Management of Depression

The bioavailability of ketamine has been reported to be 100% following IV and intraosseous administration, 93% IM, 16% to 20% oral, 30% sublingual, 45% to 50% intranasal, and 25% to 30% rectal. https://www.uspharmacist.com/article/the-use-of-ketamine-in-the-acute-management-of-depression

Rapid action

Highlight: Ketamine: A New (and Faster) Path to Treating Depression

In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom: loss of interest in pleasurable activities

https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treating-depression.shtml

How ketamine works as an antidepressant

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

https://science.sciencemag.org/content/329/5994/959.abstract

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

https://royalsocietypublishing.org/doi/full/10.1098/rstb.2011.0357

Treatment-resistant depression

Ketamine for treatment-resistant depression: recent developments and clinical applications (Evidence-Based Mental Health, a BMJ publication)

Approximately one-third of patients with major depressive disorder (MDD) do not respond to existing antidepressants, and those who do generally take weeks to months to achieve a significant effect. This article reviews developments in the study of ketamine, which has shown significant promise as a rapidly acting antidepressant in treatment-resistant patients with unipolar MDD, focusing on clinically important aspects such as dose, route of administration and duration of effect. 

https://ebmh.bmj.com/content/19/2/35.long

Other links

https://science.sciencemag.org/content/364/6436/eaat8078

PTSD

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder (JAMA Psychiatry)

A randomized clinical trial of 41 patients with chronic PTSD to test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms. Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity.

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/1860851

Video: Could a drug prevent depression and PTSD? (TED talk by neuroscientist Rebecca Brachman)

Accidental, or off-label, discoveries in medicine include the breakthrough discovery of ketamine as a treatment for disorders like depression and PTSD.

https://www.youtube.com/watch?v=j-SqQDPGW2k

Other links

https://www.sciencedirect.com/science/article/pii/S0969996116303163?via%3Dihub

https://link.springer.com/article/10.1007%2Fs00213-017-4793-4

https://pediatrics.aappublications.org/content/136/3/e694.long

Anxiety

Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders (Journal of Psychopharmacology)

An uncontrolled, open-label maintenance treatment study, evaluating the effect on anxiety ratings, safety and tolerability of 3 months of weekly ketamine in 20 patients with treatment-refractory DSM IV generalised anxiety disorder (GAD) and/or social anxiety disorder (SAD), and subsequent assessment of remission post-treatment. Conclusions: Weekly ketamine dosing was safe and well tolerated, and post-dose dissociative symptoms tended to reduce after repeated dosing. Patients reported marked improvements in functionality and in their personal lives.

https://www.ncbi.nlm.nih.gov/pubmed/?term=SAD+GAD+ketamine

Other links

https://academic.oup.com/ijnp/article/21/8/717/4989167

Suicidal ideation

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial (Psychological Medicine)

A randomized, controlled trial of ketamine in 24 patients with mood and anxiety spectrum disorders who presented with clinically significant suicidal ideation. Findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. 

https://www.cambridge.org/core/journals/psychological-medicine/article/ketamine-for-rapid-reduction-of-suicidal-ideation-a-randomized-controlled-trial/330D776E6A800D3EAA0DBFED09665FB4

Other links

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2017.17040472?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=ajp

Bipolar Disorder

A single infusion of ketamine improves depression scores in patients with anxious bipolar depression (Bipolar Disorders)

Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non‐anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. A study of 36 patients with anxious (n = 21) and non‐anxious (n = 15) treatment‐resistant bipolar depression. Conclusions: results suggested that both anxious and non‐anxious groups had an antidepressant response to ketamine.

https://onlinelibrary.wiley.com/doi/abs/10.1111/bdi.12277

Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis

The large and statistically significant effect of ketamine on depressive symptoms supports a promising, new and effective pharmacotherapy with rapid onset, high efficacy and good tolerability.

https://www.sciencedirect.com/science/article/abs/pii/S0163834315000043

Highlight: Ketamine: A New (and Faster) Path to Treating Depression

In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities.

https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treating-depression.shtml

Obsessive-Compulsive Disorder (OCD)

Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept (Neuropsychopharmacology)

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2–3 months lag time before clinically meaningful improvement. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, a randomized, double-blind, placebo-controlled, crossover design, study of 15 drug-free OCD adults tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. Conclusions: ketamine’s effects showed significant carryover effects (ie, lasting longer than 1 week). 

https://www.nature.com/articles/npp2013150

K for OCD: The pros and cons of ketamine

Stanford psychiatrist Carolyn Rodriguez, MD, PhD, researches the use of ketamine to treat obsessive-compulsive disorder and seeks to understand why, in studies, the drug has provided relief from symptoms.

https://stanmed.stanford.edu/2017summer/carolyn-rodriguez-ketamine-OCD.html