Current level of evidence for improvement of antidepressant efficacy and tolerability by pharmacogenomic-guided treatment: A Systematic review and meta-analysis of randomized controlled clinical trials.

The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.

The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia.

AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

Pharmacogenomics in treatment of depression and psychosis: an update.

Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.

Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids.

The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.

CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability.

The inter-individual variability in CYP2C19-mediated metabolism may affect the antidepressant treatment. The aim of this study is to evaluate differences in antidepressant efficacy and tolerability between different CYP2C19 metabolizer categories in inpatients suffering from major depressive disorder. The cohort was divided into experimental groups based on CYP2C19 genotype and it contained 24 slow (SMs), 41 normal (NMs), and 37 fast metabolizers (FMs). Efficacy and tolerability were assessed at baseline, and after two and four weeks as a follow-up. The primary efficacy measurement was the change from baseline in Hamilton's Depression Rating Scale (HAMD), while the primary tolerability measurement was the Toronto Side-Effects Scale (TSES) intensity scores at the last visit. The reduction in HAMD score was 36% less pronounced and response rate was exceedingly less prevalent (75% lower) in SMs, compared with NMs. The TSES intensity score was increased in SMs, compared with NMs, by 43% for central nervous system and by 22% for gastrointestinal adverse drug reactions. No significant differences in measured parameters were observed between NMs and FMs. Compared with NM and RM, lower antidepressant efficacy and tolerability was observed in SMs; this association is likely connected with the lower SM capacity to metabolize antidepressant drugs.

Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis.

Importance: Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. Objective: To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions. Study Selection: Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies. Main Outcomes and Measures: Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category. Results: Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies. Conclusions and Relevance: In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.

Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats.

Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.