Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.

We administered ketamine to schizophrenic individuals in a double-blind, placebo-controlled design using a range of subanesthetic doses (0.1, 0.3, and 0.5 mg/kg) to evaluate the nature, dose characteristics, time course, and neuroleptic modulation of N-methyl-D-aspartate (NMDA) antagonist action on mental status in schizophrenia. Ketamine induced a dose-related, short (< 30 minutes) worsening in mental status in the haloperidol-treated condition, reflected by a significant increase in BPRS total score for the 0.3 mg/kg (p = .005) and 0.5 mg/kg (p = .01) challenges. Positive symptoms (hallucinations, delusions, thought disorder), not negative symptoms accounted for these changes. These ketamine-induced psychotic symptoms were strikingly reminiscent of the subject's symptoms during active episodes of their illness. Results from six patients who were retested in the same design after being neuroleptic-free for 4 weeks failed to indicate that haloperidol blocks ketamine-induced psychosis. Several subjects evidenced delayed or prolonged (8-24 hours) psychotomimetic effects such as worsening of psychosis with visual hallucinations. These data suggest that antagonism of NMDA-sensitive glutamatergic transmission in brain exacerbates symptoms of schizophrenia.

Absence of ketamine effects on memory and other cognitive functions in schizophrenia patients.

Glutamatergic dysfunction may play an important role in both the pathophysiology of schizophrenia, and impaired memory commonly observed in that disorder. NMDA receptor antagonists impair learning/memory in animal models, putatively based on its ability to block long-term potentiation (LTP) in the hippocampus. Although well studied in animal models, research in humans is limited and confounded by administration of NMDA antagonists before the learning experience. Based on presumed glutamatergic dysfunction, it was predicted that the NMDA antagonist ketamine would not effect memory in schizophrenic subjects. Bolus injections of ketamine (0.5 mg/kg) or placebo were given to seven patients with schizophrenia in this double-blind cross-over study. Immediately prior to injection, subjects were administered verbal and figural memory tests. Delayed recalls were obtained 30-45 min postinjection. In order to rule out drug-induced generalized cognitive impairments, other cognitive tasks were administered pre- and postinjection. The results indicate no differences between the drug and placebo conditions for either memory task, and no changes on the other cognitive tasks observed.

The effects of epidural opioids on fetal heart rate variability when coadministered with 0.25% bupivacaine for labor analgesia.

Assessment of fetal heart rate (FHR) variability provides important information regarding fetal well-being. Normal FHR variability is generally associated with fetal normoxia. Opioids are frequently co-administered with local anesthetics to provide epidural analgesia for labor. Epidural opioid effects on FHR variability have not been extensively studied. In a double-blind, randomized study, 109 parturients had their epidural catheter injected with either butorphanol (2 mg), fentanyl (50 microg), sufentanil (15 microg) or saline and bupivacaine (0.25%). FHR tracings of 30 min duration were obtained both before and after epidural analgesia. Each of the 218 tracings was randomly numbered and later graded by the same individual for short- and long-term variability. The two 30-min tracings for each patient were then paired but not ordered as to which tracing was "pre-epidural" or "postepidural" and again compared for change in short- and long-term variability between the paired tracings. The paired tracings were then ordered as "pre-epidural" or "postepidural." A designation was made whether long-term variability was increased, decreased, or stayed the same after induction of epidural analgesia. Short-term variability was initially present in all patients. There were no changes in short-term variability after induction of epidural analgesia. There was no difference in long-term variability in any group receiving opioids as compared to control. There was no difference in the change in long-term variability after induction of epidural analgesia. The addition of butorphanol, fentanyl, or sufentanil to epidural bupivacaine (0.25%) does not-change FHR short- or long-term variability.