Philip Tibbo

Drug metabolism and atypical antipsychotics.

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.

Elevated 3T proton MRS glutamate levels associated with poor Continuous Performance Test (CPT-0X) scores and genetic risk for schizophrenia.

Glutamate was quantified by proton magnetic resonance spectroscopy ((1)H-MRS) in the medial frontal lobes of 15 adult siblings of individuals with schizophrenia (HR) and 14 healthy volunteers (HV), all of whom also completed a Continuous Performance Test (CPT). Subjects were free of psychopathology but the HR group showed greater variability in glutamate levels. After median stratification, the high glutamate group contained a larger proportion of HR than HV subjects and scored lower on the CPT. Elevated glutamate may relate to poor sustained attention and elevated risk of schizophrenia, suggesting a potential role for glutamate in an endophenotype for schizophrenia.

Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder.

BACKGROUND Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). METHODS Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. RESULTS A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. CONCLUSIONS The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

Investigation of Turner syndrome in schizophrenia.

Both Turner syndrome and schizophrenia are relatively infrequent conditions. Consequently, individuals having both illnesses are rare. Previous reviews of sex chromosome abnormalities in schizophrenia have focused primarily on the presence of supernumerary X-chromosomes. After identifying two female patients with schizophrenia and Turner syndrome, we reevaluated the available literature that survey female schizophrenics for the presence of chromosomal abnormalities. Eleven patients with Turner syndrome were identified among 6,483 females with schizophrenia in non-case-report studies. These survey results indicate that Turner syndrome occurs approximately three-fold more frequently in schizophrenic females than in the general female population (P < 0.02). Including 6 other case reports and our 2 cases, a total of 19 females with both schizophrenia and Turner syndrome were reported. Interestingly, whereas most Turner syndrome patients have the 45,X karyotype, the majority (18/19) of women with both illnesses have a mosaic karyotype (P < 0.0002). Given the potential role of genes on the X-chromosome in the pathogenesis of schizophrenia, the study of unique populations with abnormalities in this chromosome, such as women with Turner syndrome, may offer clues into this illness.

Association of NPAS3 exonic variation with schizophrenia.

BACKGROUND We previously identified the neuronal PAS3 (NPAS3) gene as a candidate gene for schizophrenia. A mother and daughter, both with schizophrenia, were carriers of a translocation, t(9;14)(q34;q13), that disrupts the NPAS3 gene. The gene is located at 14q13, a region implicated in schizophrenia and bipolar disorder in various linkage studies. NPAS3 belongs to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor family, involved in diverse processes including the regulation of cell differentiation and circadian rhythms, and the development and function of the nervous system. METHODS The 12 exons encoding NPAS3 were sequenced in DNA from individuals with schizophrenia. NPAS3 variants were identified in exons 6 and 12, initially in 12 patients only. These two exons were then sequenced in 83 patients and 83 controls. RESULTS AND CONCLUSION Three common variants of NPAS3, also found in controls, showed a positive association with schizophrenia (NM_001164749: rs12434716, c.1654G>C, p=0.009; rs10141940, c.2208C>T, p=0.01; rs10142034, c.2262C>G, p=0.01). The c.1654G>C variant, results in an p.Ala552Pro change and may affect NPAS3 protein function directly. Alternatively, the three SNPs may affect the splicing of NPAS3 transcripts, as they are each located within putative exonic splicing enhancer (ESE) motifs (ESEFinder). A c.726C>T variant, identified in three patients, is located in an ESE element and is predicted to reduce the function of the motif. Other variants, identified in controls, included c.2089G>A (p.Gly697Ser) and c.2097T>C. Our identification of potentially defective NPAS3 variants supports recent studies that implicate perturbations in NPAS3 pathways in impaired neurogenesis and psychosis.

Measurement of glycine in human brain by triple refocusing 1H-MRS in vivo at 3.0T

A new 1H‐MRS filtering strategy for selective measurement of glycine (Gly) in human brain in vivo at 3.0T is proposed. Investigation of multiple refocusing following a 90° excitation pulse indicated that triple refocusing is most effective for suppression of the strongly coupled resonances of myo‐inositol (mI) at the Gly 3.55‐ppm resonance. The echo times of the triple refocusing were optimized, with numerical analysis of the filtering performance, as {TE1, TE2, TE3} = {67, 62, 69} ms. Compared with the 90°‐acquired mI signal the mI suppression ratios of the filter were 170 and 1000, in terms of peak amplitude and area, respectively, between 3.51 and 3.59 ppm. From LCModel analyses, using density‐matrix calculated spectra as basis functions, the concentration of Gly in parieto‐occipital cortex of healthy adults was estimated to be 0.5 ± 0.1 mM (mean ± SD, n = 6), with reference to creatine at 8 mM. Magn Reson Med, 2007.

Burden in adolescent children of parents with schizophrenia. The Edmonton High Risk Project.

Abstract.Objective:Adolescent children of parents with schizophrenia are generally overlooked in studies of family burden. Few published data exist about this younger cohort compared to adult family members such as parents, spouses, and siblings. This pilot study aims to examine the types of burden described by adolescent children of parents with a diagnosis of schizophrenia.Methods:Thirteen adolescents (9F: 4M) between the ages of 13 and 18 who had at least one parent diagnosed with schizophrenia were administered a semi-structured interview as part of a pilot project to examine burden in this group. Questions asked during the interview were directed at the subject’s knowledge of the disorder, relationship with the parent, impact of the disorder on personal life, coping strategies used, and future concerns.Results:Responses showed that the adolescents were uninformed about their parent’s illness, had difficulties dealing with symptoms (positive and negative), were required to assume additional household responsibilities, and were concerned about their parent’s future welfare.Conclusion:This pilot study illustrates that children of individuals with schizophrenia feel their lives are impacted by their parent’s illness. More research is needed in this area to quantify and describe the types of burden experienced by this vulnerable group to ensure availability of adequate support.

White matter changes in early phase schizophrenia and cannabis use: An update and systematic review of diffusion tensor imaging studies

OBJECTIVES The impact of cannabis use on the brain tissue is still unclear, both in the healthy developing brain and in people with schizophrenia. The focus of this review is on white matter, the primary connective infrastructure of the brain. METHODS We systematically reviewed diffusion tensor imaging (DTI) studies of early phase schizophrenia (illness effect), of cannabis use in otherwise healthy brains (drug effect), and of early phase schizophrenia with cannabis use (combined effects). Studies had to include a healthy, non-cannabis using, control group as well as report on fractional anisotropy as it is the most commonly used DTI index. We excluded cohorts with heavy alcohol or illicit drug use and studies with a sample size of less than 20 in the clinical group. RESULTS We retained 17 studies of early phase schizophrenia, which together indicate deficits in white matter integrity observed in all fiber tract families, but most frequently in association, callosal and projection fibers. In otherwise healthy cannabis users (2 studies), deficits in white matter tracts were reported mainly in callosal fibers, but also in projection and limbic fibers. In cannabis users with early phase schizophrenia (1 study), deficits in white matter integrity were also observed in all fiber tract families, except for limbic fibers. CONCLUSIONS The current literature points to several families of white matter tracts being differentially affected in early phase schizophrenia. Further work is required to reveal the impact of cannabis use in otherwise healthy people as well as those with schizophrenia. LIMITATIONS Paucity of available studies as well as restricting analysis to FA values represent the main limitations of this review.

3-T proton magnetic spectroscopy in unmedicated first episode psychosis: a focus on creatine.

Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy (1H‐MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr240), mainly Cr was detectable. The target region was an 18 cm3 prefrontal volume. A negative association was found between age of patients and tCr240 levels referenced to internal water, with 20% of the variance in tCr240 accounted for by Age. A secondary finding revealed 16% reduction of tCr240 levels in patients, solely when comparing participants older than the median age of patients. No association existed between tCr240 levels and clinical variables. These findings support previous data reporting abnormalities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implications of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr240 signal, and of potential group differences in T2 times. Magn Reson Med, 2013.

Neuroactive Steroids in Schizophrenia

Schizophrenia is a psychiatric disorder with a complicated pathophysiology, involving many biochemical abnormalities in the brain. Because neuroactive steroids (NASs) modulate neurotransmitter systems that are implicated in the pathology of schizophrenia, recent research has focused on examining the role that NASs play in the illness. Although research in this area is relatively new, it appears that NASs may potentially be implicated in the pathophysiology of the illness. This paper reviews the current understanding of NASs, the research literature on NASs in schizophrenia and in animal models of the illness (including the effects of antipsychotic medication on NASs) and on the potential antipsychotic role of NASs themselves and, finally, discusses future directions for this area of schizophrenia research.