Ketamine may cause psychosis-like symptoms among healthy individuals

Ketamine appeared associated with psychosis-like symptoms among healthy individuals, according to results of a systematic review and meta-analysis published in JAMA Network Open.

Researchers noted that the bolus administration of ketamine should not be used in therapeutic contexts.

“The development of ketamine and its derivatives as antidepressants means that determining the extent to which ketamine induces schizophrenia-like or psychotomimetic symptoms and what factors are associated with this outcome is particularly timely in order to understand and minimize the risks [for] adverse events associated with the therapeutic use of ketamine,” Katherine Beck, MRCPsych, of the department of psychosis studies at King’s College London in the U.K., and colleagues wrote.

Although prior research has shown that ketamine may cause transient schizophrenia-like symptoms, the magnitude and consistency of its effect on positive and negative symptoms is unclear. Further, data are lacking regarding how infusion method, blinding status, ketamine preparation, and time between ketamine and placebo conditions are linked to symptom generation.

Beck and colleagues conducted a meta-analysis of the psychopathological outcomes associated with ketamine among healthy participants and patients with schizophrenia to determine the experimental factors associated with these outcomes. They searched three databases for within-participant, placebo-controlled studies that reported symptoms using the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS) in response to an acute ketamine challenge among patients with schizophrenia or healthy participants. They included 36 studies involving healthy participants that:

• reported symptoms occurring in response to acute IV administration of subanesthetic ketamine doses;

• contained a placebo condition with a within-subject, crossover design;

• measured total positive or negative symptoms using PANSS or BPRS; and

• provided data allowing the estimation of the mean difference and deviation between the placebo condition and ketamine.

Independent investigators included study-level data in a random-effects meta-analysis and extracted total, positive and negative BPRS and PANSS scores. The investigators conducted subgroup analyses examining the effects of infusion method, ketamine preparation, blinding status and time between ketamine and placebo conditions.

Among 735 healthy volunteers exposed to the ketamine and placebo conditions, racemic ketamine and S-ketamine were associated with a statistically significant increase in transient psychopathology for total (standardized mean difference [SMD] = 1.5; 95% CI, 1.23-1.77) , positive (SMD = 1.55; 95% CI, 1.29-1.81) and negative (SMD = 1.16; 95% CI, 0.96-1.35) symptom ratings compared with the placebo condition. The association’s effect was significantly greater for positive vs. negative psychosis symptoms, with an estimate of 0.36 (95% CI, 0.12-0.61).

Beck and colleagues noted significant outcome inconsistency between studies, with an I² range of 77% to 83%. Further, they found that bolus followed by constant infusion increased the association between ketamine and positive symptoms compared with infusion alone (effect size = 1.63; 95% CI, 1.36-1.9 vs. 0.84; 95% CI, 0.35-1.33). Although age and sex did not moderate outcomes, single-day study design increased ketamine’s ability to generate total symptoms (effect size = 2.29; 95% CI, 1.69-2.89 vs. 1.39; 95% CI, 1.12-1.66). The researchers were unable to conduct meta-analysis of studies in schizophrenia because insufficient studies were available. Among available studies, two showed a statistically significant increase in symptoms with ketamine administration in total and positive symptoms, and one showed an increase in negative symptom severity with ketamine.

“These findings support the use of ketamine as a pharmacological model of schizophrenia and, given that using a bolus plus continuous infusion method leads to greater positive psychotic symptoms, indicate that the bolus plus infusion is the best approach for this model,” the researchers wrote. “Ketamine is used to treat pain and for major depression. Our findings indicate a potential risk [for] ketamine inducing schizophreniform symptoms when it is used for these indications and that a slow infusion without bolus is preferable to minimize these risks. Further research is needed to determine the risk [for] these effects when ketamine is used therapeutically.” – by Joe Gramigna

Disclosures: Beck reports grants from the Royal College of Psychiatrists and Rosetrees Trust during the conduct of the study. Please see the study for all other authors’ relevant financial disclosures.