A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder within hours. In this randomized clinical trial of 38 adults, higher ketamine doses and blood levels correlated with greater improvement on the Hamilton Depression Rating Scale 24 hours later. However, the brain's glutamate+glutamine (Glx) response to ketamine mediated this relationship: lower Glx responses predicted better antidepressant effects. GABA levels did not correlate with antidepressant benefit. Adverse effects were linked to blood levels only in men. The findings suggest that ketamine's antidepressant mechanism involves reducing Glx levels in the ventromedial prefrontal cortex.
In a randomized, midazolam-controlled trial of 40 suicidal, depressed participants given intravenous ketamine, acute dissociative and psychotomimetic effects were not associated with changes in suicidal ideation or depressive symptoms from before to after infusion. Norketamine showed a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection, suggesting dissociation may be more an effect of the parent drug. Dehydronorketamine correlated with dissociative symptoms at multiple time points. No evidence was found that ketamine's acute, transient dissociative or psychotomimetic effects contribute to its antidepressant or anti-suicidal actions.
A midazolam-controlled trial of intravenous ketamine for suicidal depressed patients found that ketamine rapidly reduced suicidal ideation within 24 hours. An exploratory analysis measured saliva cortisol awakening response at baseline and 24 hours after infusion. Waking cortisol significantly increased 24 hours after ketamine treatment. The increase in waking cortisol from baseline to post-infusion showed a small to medium, nonsignificant correlation with decreased suicidal ideation. These preliminary results, pending replication, align with evidence that moderate cortisol increases may enhance stress-resilience.
Cannabis acutely worsened cognitive control and produced more aversive intoxication in cannabis users at clinical high-risk for psychosis, but not in psychiatrically-healthy cannabis users. Six high-risk and six healthy users smoked either active (5.5% THC) or placebo cannabis under double-blind conditions. High-risk participants showed decreased response inhibition and aversive intoxication after active cannabis, along with changes in psychomotor speed and cannabis-related attentional bias. No such effects appeared in healthy users. The findings provide preliminary evidence of a deleterious cognitive and reward-related response to cannabis in individuals with preexisting psychosis risk.