Exposing fetal drug exposure

Pregnancy neither protects women from susceptibility to illness nor generally decreases drug dosage requirements of preexisting pharmacotherapy. Thus, a major concern of drug use during pregnancy is maintenance of maternal health while minimizing fetal drug exposure. Important assumptions in reproductive medicine are that fetal exposure to any medication can present risks in pregnancy--because not all risks are known, as little exposure as possible is desirable.     

Stereoselective and regiospecific hydroxylation of ketamine and norketamine

The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.     

Hoofbeats and zebras: neurodegenerative disorder presenting as a “first episode” of psychosis

Neurodegenerative disorders can include diverse neuropsychiatric symptoms. Here we present a case referred to a “first-episode” psychosis clinic with socio-occupational decline, auditory hallucinations and paranoid ideation who subsequently exhibited a rapid, severe cognitive and behavioral decline. The brain magnetic resonance imaging findings of the patient have shown a progressive cortical atrophy prominent in the frontal lobes due to a neurodegenerative disorder.     

Mediators and moderators in early intervention research

Aim: The goal of this paper is to provide clarification with regard to the nature of mediator and moderator variables and the statistical methods used to test for the existence of these variables. Particular attention will be devoted to discussing the ways in which the identification of mediator and moderator variables may help to advance the field of early intervention in psychiatry. Methods: We completed a literature review of the methodological strategies used to test for mediator and moderator variables. Results: Although several tests for mediator variables are currently available, recent evaluations suggest that tests which directly evaluate the indirect effect are superior. With regard to moderator variables, two approaches (‘pick-a-point’ and regions of significance) are available, and we provide guidelines with regard to how researchers can determine which approach may be most appropriate to use for their specific study. Finally, we discuss how to evaluate the clinical importance of mediator and moderator relationships as well as the methodology to calculate statistical power for tests of mediation and moderation. Conclusion: Further exploration of mediator and moderator variables may provide valuable information with regard to interventions provided early in the course of a psychiatric illness.     

Disability after encephalitis: development and validation of a new outcome score

Objective

To develop a simple tool for assessing the severity of disability resulting from Japanese encephalitis and whether, as a result, a child is likely to be dependent.

Methods

A new outcome score based on a 15-item questionnaire was developed after a literature review, examination of current assessment tools, discussion with experts and a pilot study. The score was used to evaluate 100 children in Malaysia (56 Japanese encephalitis patients, 2 patients with encephalitis of unknown etiology and 42 controls) and 95 in India (36 Japanese encephalitis patients, 41 patients with encephalitis of unknown etiology and 18 controls). Inter- and intra-observer variability in the outcome score was determined and the score was compared with full clinical assessment.

Findings

There was good inter-observer agreement on using the new score to identify likely dependency (Κ = 0.942 for Malaysian children; Κ = 0.786 for Indian children) and good intra-observer agreement (Κ = 1.000 and 0.902, respectively). In addition, agreement between the new score and clinical assessment was also good (Κ = 0.906 and 0.762, respectively). The sensitivity and specificity of the new score for identifying children likely to be dependent were 100% and 98.4% in Malaysia and 100% and 93.8% in India. Positive and negative predictive values were 84.2% and 100% in Malaysia and 65.6% and 100% in India.

Conclusion

The new tool for assessing disability in children after Japanese encephalitis was simple to use and scores correlated well with clinical assessment.