Clinical Utility and Implementation of Pharmacogenomics for the Personalisation of Antipsychotic Treatments.

Decades of pharmacogenetic research have revealed genetic biomarkers of clinical response to antipsychotics. Genetic variants in antipsychotic targets, dopamine and serotonin receptors in particular, and in metabolic enzymes have been associated with the efficacy and toxicity of antipsychotic treatments. However, genetic prediction of antipsychotic response based on these biomarkers is far from accurate. Despite the clinical validity of these findings, the clinical utility remains unclear. Nevertheless, genetic information on CYP metabolic enzymes responsible for the biotransformation of most commercially available antipsychotics has proven to be effective for the personalisation of clinical dosing, resulting in a reduction of induced side effects and in an increase in efficacy. However, pharmacogenetic information is rarely used in psychiatric settings as a prescription aid. Lack of studies on cost-effectiveness, absence of clinical guidelines based on pharmacogenetic biomarkers for several commonly used antipsychotics, the cost of genetic testing and the delay in results delivery hamper the implementation of pharmacogenetic interventions in clinical settings. This narrative review will comment on the existing pharmacogenetic information, the clinical utility of pharmacogenetic findings, and their current and future implementations.

Review of pharmacogenomics of psychiatric comorbidities in autism spectrum disorder.

Approximately 70% of individuals diagnosed with autism spectrum disorder (ASD) receive at least one psychotropic medication to treat comorbidities. However, the response to treatment with these drugs is far from satisfactory, with 30-50% of treated patients not responding adequately or developing severe and long-lasting side effects. There is strong evidence of the clinical utility of pharmacogenetics for the personalization of antipsychotic and antidepressant treatments in adult populations. However, the use of pharmacogenetic interventions for the personalization of treatment in ASD populations is minimal. The aim of this review is to summarize the findings of pharmacogenetic studies conducted in subjects with ASD and illustrate their utility in the personalization of treatment with psychoactive drugs in this population group.

CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders.

Purpose: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety. Patients and Methods: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype. Results: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05). Conclusion: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

Pharmacogenetic Interventions Improve the Clinical Outcome of Treatment-Resistant Autistic Spectrum Disorder Sufferers.

BACKGROUND: Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in social communication and repetitive and restricted behaviours. About a third of patients receive pharmacological treatment for comorbid symptoms. However, 30-50% do not respond adequately and/or present severe and long-lasting side effects. METHODS: Genetic variants in CYP1A2, CYP2C19, CYP2D6 and SLC6A4 were investigated in N = 42 ASD sufferers resistant to pharmacological treatment. Clinical recommendations based on their pharmacogenetic profiles were provided within 24-48 h of receiving a biological sample. RESULTS: A total of 39 participants (93%) improved after the pharmacogenetic intervention according to their CGI scores (difference in basal-final scores: 2.26, SD 1.55) and 37 participants (88%) according to their CGAS scores (average improvement of 20.29, SD 11.85). Twenty-three of them (55%) achieved symptom stability (CGI ≤ 3 and CGAS improvement ≥ 20 points), requiring less frequent visits to their clinicians and hospital stays. Furthermore, the clinical improvement was higher than that observed in a control group (N = 62) with no pharmacogenetic interventions, in which 66% responded to treatment (difference in CGI scores: -0.87, SD 9.4, p = 1 × 10-5; difference in CGAS scores: 6.59, SD 7.76, p = 5 × 10-8). CONCLUSIONS: The implementation of pharmacogenetic interventions has the potential to significantly improve the clinical outcomes in severe comorbid ASD populations with drug treatment resistance and poor prognosis.