Psychiatric pharmacogenomics

Psychiatric pharmacogenomics is probably the youngest and also one of the most exciting subfields unfolding in the past decade. Its main appeal is the possibility of reaching a truly ‘individualised’ or ‘personalised’ pharmacological treatment, based on the identification of a genotype or genetic profile that, by outlining the metabolic process of individual compounds through specific enzymes, codified by specific genes, would determine the choice of the most specific kind, and most appropriate dose of medications for the diagnosed condition. ^{Reference Mrazek3} Prediction (and, therefore, prevention) of secondary effects is not a small added benefit. And it so happens that the clinical area where psychopharmacogenomics has had its most active and fertile grounds is that of mood disorders, particularly depression and all its clinical variations. ^{Reference Bertilsson, Dahl and Tybring4}

Laboratory studies

1. • Pharmacogenomic testing is not as precise as a mathematical formula. Clinicians using it on a more or less regular basis have observed divergent clinical responses to doses chosen on the basis of similar P450 or serotonin gene findings. The possible explanation is that metabolic processes and their outcomes are not only determined by genetic profiles or enzyme endowments; factors such as age, gender, diet, endocrine status, physical health and level of stress, play a complementary but decisive role. ^{Reference Smith and Lim11}

2. • There are more enzymes (and their corresponding genes) than the number identified so far, besides the large number of polymorphisms (many of them still unidentified). ^{Reference Mandelli, Marino, Pirovano, Calati, Zanardi and Colombo12} On the positive side, the so-called genome-wide associations currently allow the testing of more than 300 single-nucleotide polymorphisms per patient. Greater numbers from larger samples may detect more common susceptibility variants for psychiatric disorders and pharmacological responses. ¹³

3. • Some substrates can also operate as inhibitors of their metabolising enzymes; such competitive inhibition may depend on factors such as affinity, dose, or others similar to those mentioned above. Yet, in cases, the substrates may be‘non-competitive inhibitors’. ^{Reference Ingelman-Sundberg14}

Clinical studies

1. • Follow-up studies are still scarce, samples may not be numerous as yet, even though individual reports abound and are a growing set. Comparisons with placebo users need to be made.

2. • There are already known ethnic differences in genetic profiles: African and African–American populations as a group may have higher proportions of slow CYP2D6 metabolisers than White people; similarly, poor metabolisers predominate among Caribbean Hispanics when compared with Mexican Americans, both being subgroups of the Hispanic or Latino ethnic class. ^{Reference Smith and Lim11}

3. • The diagnostic implications of pharmacogenomic approaches to treatment are still to be examined, for instance, negative links with level of stress, ^{Reference Mandelli, Marino, Pirovano, Calati, Zanardi and Colombo12} and the impact of linkage disequilibrium. ^{Reference Kato, Zanardi, Rossini, De Ronchi, Okugawa and Takekita15} Pharmacogenomics adds a new dimension to the conventional characterisation of clinical entities, particularly those of the mood or bipolar spectra. ^{Reference Alarcón, Mrazek and Silva16}

Financial considerations

1. • The pharmaceutical industry's response to pharmacogenomic testing in psychiatry has been ambiguous at best; some minimise the usefulness of this type of information for fear that the market for their products will be segmented or reduced.

2. • The medical economic benefits of testing are still being debated. Nevertheless, in the USA, insurance companies seem to be willing to cover the testing in cases of repeated failures to traditional pharmacological management, or in the presence of severe side-effects with seemingly low doses of antidepressants.

Other factors

‘Non-biological factors’ such as expectations, adherence, placebo response, and clinician–patient relationship, some or all of them being culturally determined factors, continue to play an important role in shaping the strictly pharmacological response. ^{Reference Kato, Zanardi, Rossini, De Ronchi, Okugawa and Takekita15,Reference Alarcón, Mrazek and Silva16} Ethical considerations, crucial and strong in any genetics-based procedure or intervention, ought to be refined. ^{Reference Novoa and Silva17} Issues such as full disclosure, confidentiality, research use, and the implications of testing vis-à-vis insurance coverage, respect for human dignity, documentation, and overall clinical management in extreme cases (i.e. deleted or inactive polymorphisms) need to be clarified.