Ketamine-induced psychosis

Individual Differences in Psychotic Effects of Ketamine Are Predicted by Brain Function Measured under Placebo
The Journal of Neuroscience, 18 June 2008,  28(25): 6295-6303
Garry D. Honey, et al.
http://www.jneurosci.org/content/28/25/6295.full

The symptoms of major psychotic illness are diverse and vary widely across individuals.
Furthermore, the prepsychotic phase is indistinct, providing little indication of the precise pattern of symptoms that may subsequently emerge.
Likewise, although in some individuals who have affected family members the occurrence of disease may be predicted, the specific symptom profile may not.
An important question, therefore, is whether predictive physiological markers of symptom expression can be identified.
We conducted a placebo-controlled, within-subjects study in healthy individuals to investigate whether individual variability in baseline physiology, as assessed using functional magnetic resonance imaging, predicted psychosis elicited by the psychotomimetic drug ketamine and whether physiological change under drug reproduced those reported in patients.
Here we show that brain responses to cognitive task demands under placebo predict the expression of psychotic phenomena after drug administration.
Frontothalamic responses to a working memory task were associated with the tendency of subjects to experience negative symptoms under ketamine.
Bilateral frontal responses to an attention task were also predictive of negative symptoms.
Frontotemporal activations during language processing tasks were predictive of thought disorder and auditory illusory experiences.
A subpsychotic dose of ketamine administered during a second scanning session resulted in increased basal ganglia and thalamic activation during the working memory task, paralleling previous reports in patients with schizophrenia.
These results demonstrate precise and predictive brain markers for individual profiles of vulnerability to drug-induced psychosis.

We used a drug model of psychosis to relate presymptomatic physiology to symptom outcome.
Ketamine induces transient psychotic symptoms in healthy volunteers (Krystal et al., 1994) …

=================================

Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Science 7 December 2007: Vol. 318  no. 5856  pp. 1645-1647
M. Margarita Behrens
https://www.sciencemag.org/content/318/5856/1645.abstract

Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia.
In animals, repetitive exposure to this N-methyl-d-aspartate–receptor antagonist induces the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin and the γ-aminobutyric acid–producing enzyme GAD67.
We show here that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.
Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. These results suggest that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.

=========================

Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics
Neuropsychopharmacology (1997) 17 141–150.
Anil K Malhotra MD, et al.
http://www.nature.com/npp/journal/v17/n3/full/1395017a.html

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia.
We administered subanesthetic doses of the NMDA receptor antagonist ketamine in a double-blind, placebo–controlled design to 13 neuroleptic-free schizophrenic patients to investigate if schizophrenics will experience an exacerbation of psychotic symptoms and cognitive impairments with ketamine.
We also examined whether schizophrenics experienced quantitative or qualitative differences in ketamine response in comparison to normal controls.
Schizophrenics experienced a brief ketamine-induced exacerbation of positive and negative symptoms with further decrements in recall and recognition memory. They also displayed greater ketamine-induced impairments in free recall than normals. Qualitative differences included auditory hallucinations and paranoia in patients but not in normals.
These data indicate that ketamine is associated with exacerbation of core psychotic and cognitive symptoms in schizophrenia.
Moreover, ketamine may differentially affect cognition in schizophrenics in comparison to normal controls.

Keywords: Ketamine; NMDA; Schizophrenia; Cognition; Psychosis

Depression: ketamine gains traction

Club Drug Ketamine Gains Traction As A Treatment For Depression
September 28, 2015
http://www.npr.org/sections/health-shots/2015/09/28/443203592/club-drug-ketamine-gains-traction-as-a-treatment-for-depression

in 2006, a team from the National Institute of Mental Health published a landmark study showing that a single intra venous dose of ketamine produced “robust and rapid antidepressant effects” within a couple of hours.
http://www.ncbi.nlm.nih.gov/pubmed/16894061

Since then, thousands of depressed patients have received “off-label” treatment with ketamine.

A major study on antidepressant medication published in 2008 seemed to confirm his suspicions. It found that current antidepressants really aren’t much better than a placebo.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253608

Many psychiatrists criticized that study. But not Feifel. “I was kind of like, I’m not surprised,” he says. “These really don’t seem like powerful tools.”
He knew the drug had risks. It could be abused. It could produce hallucinations.

“There are a lot of pundits who remain skeptical or feel we need to research this ad infinitum before it’s ready, which doesn’t make sense to me,” Feifel says. It’s hard to take the wait-and-see approach when you’re treating patients who are desperate for help, he adds.

For the past year, Paul has been getting ketamine every four to six weeks. He feels an altered sense of reality for an hour or two after getting the drug. The effect on depression and anxiety, though, lasts more than a month.

One is that its ability to keep depression at bay can fade pretty quickly. Feifel recalls one patient whose depression would disappear like magic after a dose of ketamine. But “we could never get it to sustain beyond maybe a day,” he says.

Also, ketamine treatment is expensive because patients need to be monitored so closely. Feifel charges about $500 for each injection and $1,000 for an intra venous infusion, which takes effect more quickly. Insurers don’t cover the cost because the treatment is still considered experimental.

Even so, ketamine clinics are popping up around the country and they have already treated thousands of patients willing and able to pay out of pocket. Some of the clinics are run by psychiatrists. Others have been started by entrepreneurial anesthesiologists and emergency room doctors, who are familiar with ketamine but may not know much about depression.

Director’s Blog: Ketamine
By Thomas Insel on October 1, 2014
http://www.nimh.nih.gov/about/director/2014/ketamine.shtml

https://www.npr.org/sections/health-shots/2017/03/20/520169959/ketamine-for-severe-depression-how-do-you-not-offer-this-drug-to-people

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders
Gerard Sanacora, et al. for the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments
JAMA Psychiatry. 2017;74(4):399-405.
https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2605202

Ketamine for Depression

KETAMINE FOR DEPRESSION: AN OLD DRUG WITH A NEW INDICATION
Clinical Neuropsychiatry (2014) 11, 2, 55-60
Chiara Schepisi, Diletta Sabatini, Paolo Nencini

ketamine exhibits antidepressant properties in different validated models of depression. These effects are mediated by activation of different pathways that results in neurogenesis and synaptic consolidation.

A Trip Out of Depression
SCIENTIFIC AMERICAN MIND May/June 2013
KETAMINE, AN ANESTHETIC AND ILLICIT PARTY DRUG, IS EMERGING AS A FAST-ACTING ANTIDEPRESSANT
http://www.scientificamerican.com/article/is-ketamine-next-big-depression-drug
BY SIMONE GRIMM AND MILAN SCHEIDEGGER
Ketamine, appears to ease the most severe symptoms of depression within minutes or hours, even in patients who have a dismal track record with other treatments. The effects of a single dose can last at least a week in some patients.

Rapid Antidepressant Effects of Ketamine in Major Depression
https://www.clinicaltrials.gov/ct2/show/NCT00088699
Estimated Study Completion Date: April 2017

How An Unlikely Drug Helps Some Children Consumed By Fear

How An Unlikely Drug Helps Some Children Consumed By Fear
March 25, 2013
http://www.npr.org/blogs/health/2013/03/25/174928768/how-an-unlikely-drug-helps-some-children-consumed-by-fear
Ketamine is approved as an anesthetic.
It’s also a club drug that can cause out-of-body experiences. And research in the past few years shows that ketamine can lift severe depression, often in a matter of minutes.

related:
http://www.npr.org/blogs/health/2012/01/31/146096540/i-wanted-to-live-new-depression-drugs-offer-hope-for-toughest-cases

China’s ketamine craze – BBC News
2015