Psychiatry & Neurology

Psychiatry & Neurology

The impact of CYP allelic variation on antidepressant metabolism: a review.

Black III, JL et al., 2007.  Expert Opinion on Drug Metabolism & Toxicology 3(1):21-31.

Abstract

Psychiatric diseases that are treated with antidepressants are the leading causes of morbidity and mortality in humankind. Although antidepressants are generally well tolerated and widely available, they are not equally effective in all patients and only 35 – 45% of patients treated for depression with these drugs recover to premorbid levels of functioning. There is a need for an effective, individualized approach to antidepressant selection. One promising lead in the development of personalized medicine is the emerging field of pharmacogenomics, whereby pharmacologic agents are selected on the basis of the genotype of patients, with particular attention to drug targets and phase I- and phase II-metabolizing enzymes. This review article focuses on phase I antidepressant-metabolizing enzymes (e.g., relevant CYP enzymes). The authors first briefly review CYP nomenclature, the relevant members of the CYP superfamily and their alleles, the metabolic categories and CYP antidepressant substrates, inhibitors and inducers. The literature on the impact of CYP polymorphisms on antidepressant metabolism are also reviewed.

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Comment

Genomewide linkage scan for opioid dependence and related traits.

Gelernter, J et al., 2006. Am J Hum Genet 78(5):759-69.

Abstract:

Risk of opioid dependence is genetically influenced. We recruited a sample of 393 small nuclear families (including 250 full-sib and 46 half-sib pairs), each with at least one individual with opioid dependence. Subjects underwent a detailed evaluation of substance dependence-related traits. As planned a priori to reduce heterogeneity, we used cluster analytic methods to identify opioid dependence-related symptom clusters, which were shown to be heritable. We then completed a genomewide linkage scan (with 409 markers) for the opioid-dependence diagnosis and for the two cluster-defined phenotypes represented by >250 families: the heavy-opioid-use cluster and the non-opioid-use cluster. Further exploratory analyses were completed for the other cluster-defined phenotypes. The statistically strongest results were seen with the cluster-defined traits. For the heavy-opioid-use cluster, we observed a LOD score of 3.06 on chromosome 17 (empirical pointwise P = .0002) for European American (EA) and African American (AA) subjects combined, and, for the non-opioid-use cluster, we observed a LOD score of 3.46 elsewhere on chromosome 17 (empirical pointwise P = .00002, uncorrected for multiple traits studied) for EA subjects only. We also identified a possible linkage (LOD score 2.43) of opioid dependence with chromosome 2 markers for the AA subjects. These results are an initial step in identifying genes for opioid dependence on the basis of a genomewide investigation (i.e., a study not conditioned on prior physiological candidate-gene hypotheses).

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Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.

Kachergus, J et al., 2005. Am J Hum Genet 76(4):672-80.

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.

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