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.
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
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.
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