Venlafaxine (V) is a serotonin-norepinephrine inhibitor, mainly metabolized by the highly polymorphic CytochromeP450 isoenzyme 2D6 (CYP2D6) to its major active metabolite O-desmethylvenlafaxine (ODV) and to a lesser extent by CYP3A4 to the inactive metabolite N-desmethylvenlafaxine (NDV). Depending on CYP2D6 activity, patients may be grouped into four classes of phenotypes, namely Poor (PMs, representing 7-10% of the general population), Intermediate (IMs, 35% of the population), Extensive (EMs, 48% of the population) or Ultrarapid Metabolizers (UMs, 5-7% of the population). Literature suggests PMs show poor tolerance, while UMs need a greater dose of V. As part of the pilot study “Venlafaxine and CYP2D6 in clinical practice”, which is being conducted at the Institute of Psychiatry at AOU Maggiore della Carità in Novara, in collaboration with the Molecular Diagnostics Laboratory, we describe the case of RP, diagnosed with Major Depressive Disorder (according to the DSM-IV-TR criteria) under treatment with V. The study design was approved by the local Ethics Committee (study n. CE 78/10, reference number 451/CE), in accordance with the declaration of Helsinki (2008). The aim of this observational study is to evaluate the impact of CYP2D6 phenotype on V efficacy/tolerability.
Together with all patients recruited for our study, after providing his written informed consent, RP underwent venous blood sampling, which was performed in an anonymous 3cc EDTA test-tube, which only could be identified through a numerical code and sampling date. CYP2D6 genotyping was performed using a new technology based on DNA microarray (BioFilmChip® CYP4502D6 INFINITI® – AutoGenomics – Medical systems s.p.a.), allowing to identify 16 allele variants. We also assessed sociodemographical features, duration of treatment and clinical outcome, through the Hamilton Rating Scale for Depression (HAM-D) and Montgomery- Asberg Depression Rating Scale (MADRS). A clinical evaluation was performed at T0, T1 (1 week) and T2 (4 weeks). Adverse events were evaluated by means of the self-rated SIDE scale of the Psychiatric Department of Vanderbilt University.
Being heterozygous for the CYP2D6*XN allele, encoding an enzyme with increased activity, RP was identified as a UM. RP responded to an average dose of V (300 mg/die) during acute phase of illness, with no need of a dosage augmentation.
Our results are in contrast with current literature suggesting the importance of genetic risk stratification in order to administer the subject a correct dosage, yet it does not dismiss its possible role in predicting adverse events.