Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3ß phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.

Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

This corrects the article DOI: 10.1038/mp.2016.204.

High frequency of CYP2D6 ultrarapid metabolizer genotypes in an Ashkenazi Jewish population from Argentina.

A twofold higher frequency of CYP2D6 ultrarapid metabolizers (estimated from genotype: gUMs) was reported among Ashkenazi Jews (AJ) living in New York (USA) than in other North American Caucasians, which might be important to guide the prescription for CYP2D6 substrates in AJ communities around the world. This study was aimed to determine whether the high frequency of CYP2D6 gUMs described in AJ from USA was replicated in AJ from Argentina when compared with other multiethnic admixture Argentines (GA). The frequency of the most common allelic variants and of CYP2D6 gUMs (>2 active genes) and poor metabolizers (0 active genes, gPMs) was also compared among the studied Argentine populations. CYP2D6 genotyping was performed in 173 AJ and 246 GA DNA samples of unrelated donors from the metropolitan area of Buenos Aires. CYP2D6 alleles (*2, *3, *4, *5, *6, *10, *17, *35, *41 and multiple copies), genotypes and functional phenotype frequencies were determined. The frequencies of gUMs and gPMs in AJ from Argentina were 11.5% and 5.2%, respectively, whereas in GA, the frequencies of gUM and gPMs were 6.5% and 4.9%, respectively. Comparisons between AJ and GA showed that gUMs frequencies were twofold higher (P<0.05) in AJ than GA. CYP2D6*35 allele was more frequent in GA than AJ, whereas CYP2D6*41 and *1xN were more frequent in AJ than in GA (P<0.05). This study supports the previously reported high frequency of gUMs on another Ashkenazi population in New York. The present findings also support the interethnic variability of CYP2D6 genetic polymorphism in the overall Argentine population.

High frequency of CYP2D6 ultrarapid metabolizers in Spain: controversy about their misclassification in worldwide population studies.

A high frequency (7-10%) of CYP2D6 ultrarapid metabolizers estimated from the genotype (gUMs) has been claimed to exist among Spaniards and Southern Europeans. However, methodological aspects such as the inclusion of individuals carrying non-active multiplied alleles as gUMs may have led to an overestimation. Thus, this study aimed to analyze the gUM frequency (considering only those carrying more than two active genes) in 805 Spanish healthy volunteers studied for CYP2D6*2, *3, *4, *5, *6, *10, *17, *35, *41, and multiplications. Second, all worldwide studies reporting gUM frequencies were reviewed in order to evaluate potential misclassifications. The gUM frequency in this Spanish population was 5.34%, but increased to 8.3% if all individuals with CYP2D6 multiplications were classified as gUMs without considering the activity of the multiplied alleles. Moreover, among all reviewed worldwide studies only 55.6% precisely determined whether the multiplied alleles were active. Present results suggest that the evaluation of CYP2D6 ultrarapid metabolism should be standarized, and that the frequency of gUMs should be reconsidered in Spaniards and globally.

Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms.

Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg(-1)), intravenous diazepam (0.3 mg kg(-1)), and intravenous phenytoin with an initial-loading dose of 15 mg kg(-1). However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l(-1); normal range: 10-20 mg l(-1)), and the patient was homozygous for the CYP2C9*2 allele, heterozygous for the CYP2C19*4 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient.

CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans.

CYP2D6 genotype and debrisoquine metabolic ratio (MR) were analyzed in 133 Nicaraguan Mestizos (NMs) and 260 Cubans divided into Cuban Mestizos (CMs) and White Cubans (WCs). The frequencies of poor metabolizers (MR12.6) were 6% in NMs, 3.9% in CMs and 5.3% in WCs. The frequencies of ultrarapid metabolizers (MR0.1) were 0% in NMs, 2.3% in CMs and 5.3% in WCs. Mean (±s.d.) MR among extensive metabolizers (MR<12.6) was higher in NMs (1.5±1.6; n=118) than in CMs (1.0±1.3; n=124; P<0.001) and WCs (0.7±1.0; n=124; P<0.001). MR correlated with the 'activity score' of CYP2D6 genotypes (P<0.05; r=-0.55). Mean MR was higher among NMs than WCs and CMs for groups classified as 1 (P<0.05) or 2 (P<0.01) 'activity score'. In addition, mean (±s.d.) MR was higher among subjects carrying CYP2D6*17 than in CYP2D6 wt/wt (P<0.001). The CYP2D6*10 allele was higher in NMs (3.1%) than in CMs (0.8%; P<0.05) and WCs (0.4%; P<0.05). CYP2D6*17 allele was higher in CMs (10.2%) than WC (2.7%; P<0.005) and NMs (0%). Thus, the variability in CYP2D6 phenotypes found may be related to differences in allele frequency among groups (that is, CYP2D6*10 and *17 highest in NMs and CMs, respectively). However, the influence of environmental factors or alleles different than those studied here cannot be ruled out.

CYP2D6 polymorphism in patients with eating disorders.

CYP2D6 polymorphism is associated with variability in drug response, endogenous metabolism (that is, serotonin), personality, neurocognition and psychopathology. The relationship between CYP2D6 genetic polymorphism and the risk of eating disorders (ED) was analyzed in 267 patients with ED and in 285 controls. A difference in the CYP2D6 active allele distribution was found between these groups. Women carrying more than two active genes (ultrarapid metabolizers) (7.5 vs 4.6%) or two (67 vs 58.9%) active genes were more frequent among patients with ED, whereas those with one (20.6 vs 30.2%) or zero active genes (4.9 vs 6.3%) were more frequent among controls (P<0.05). Although further research is needed, present findings suggest an association between CYP2D6 and ED. CYP2D6 allele distribution in patients with ED seems related to increased enzyme activity.

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards.

Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP subjects, respectively. In agreement with our hypothesis, CYP2C9*2 was significantly lower in the Mexican populations than in the SP (P<0.05), and among Mexicans in the MT than in the MM and MA groups (P<0.05), which presented similar frequencies. Moreover, the frequency of CYP2C9*3 was found to be lower (P<0.05) in MM (0.015) and MT (0.015) than in MA (0.06) and SP (0.08). Finally, the CYP2C9*6 allele was present just in one MM subject, and CYP2C9*4 and *5 were not found in the studied populations. Therefore, these findings add further evidence about CYP2C9 genetic diversity within Hispanic populations with regard to their ancestry. Considering that CYP2C9*2 and CYP2C9*3 alleles have altered catalytic activities relative to CYP2C9*1, the present data suggest the need for pharmacogenetic studies to optimize drug dosages in different populations.

Increased risk for major depression associated with the short allele of the serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele.

In the present study, we aimed to analyze the potential relevance of the polymorphism in the promoter region of the serotonin transporter (SERT or 5-HTT) gene (5-HTTLPR) and the risk of suffering major depression (MDD) in a population of patients previously genotyped for CYP2C9. Seventy white European psychiatric outpatients suffering from MDD and a group of 142 healthy volunteers (HVs) were studied. The frequency of subjects carrying the 5-HTTLPR-S allele was higher (P < 0.05) among MDD than in HV. The odds ratio associated with 5-HTTLPR-S allele was 2.03 for the MDD patients in comparison with the HV group. Previously, we found in this population that the CYP2C9*3 allele frequency was higher among this population of MDD patients than in HV. The frequency of subjects with the combination 5-HTTLPR-S and CYP2C9*3 alleles was higher (P < 0.01, odds ratio 3.47) in MDD than in HV. The present findings provide preliminary evidence about the greater risk of suffering MDD for individuals carrying both 5-HTTLPR-S and CYP2C9*3 alleles.

Anterior cingulate activity in bulimia nervosa: a fMRI case study.

INTRODUCTION: Eating disordered patients (EDp) who binge-eat appear to present impulse control deficits that influence treatment outcome. The present bulimia nervosa (BN) study tests the function of brain areas involved in top-down control of behavior, associated with the anterior cingulate cortex (ACC), at the individual level. METHODS: ACC activity was analyzed in two women with BN and one matched control with a reliable and simple cue imperative target paradigm for response anticipation and response conflict processing using an event-related functional magnetic resonance imaging (fMRI) design. RESULTS: Patients showed meaningful ACC patterns of activation, less recruitment for response anticipation, and abnormal for response conflict, when they had to suppress an inappropriate response. DISCUSSION: Preliminary evidence suggests a BN neurocognitive model of impaired executive control-related brain activity. Reliable fMRI paradigms may be clinically useful to determine ACC dysfunction in EDp, to inform treatment and track changes.

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients.

CYP2D6 has been suggested to be functionally similar to the dopamine transporter. The present study was aimed at analysing the frequency of CYP2D6 alleles and genotype among schizophrenic patients compared to healthy volunteers. CYP2D6 *3, *4, *5, *6, *10 and duplicated alleles were analysed in 128 unselected schizophrenia inpatients (SP) and 142 unrelated white European Spanish healthy volunteers (HV). SP and HV with >2, 2, 1 or 0 CYP2D6 active genes were 4.7, 64.8, 28.1 and 2.3%, and 6.3, 52.1, 33.1 and 8.5%, respectively. The frequency of homozygous for CYP2D6 inactive alleles or poor metabolizers (PMs) was lower (P<0.05) in SP than in HV. Furthermore, the frequency of CYP2D6 inactive alleles was also lower in SP than in HV (16.8 vs 25.7; P<0.05), specifically the CYP2D6*6 allele was not found among patients. The present study shows a lower frequency of PMs in schizophrenic patients than in healthy volunteers supporting the hypothesis of a potential role of CYP2D6 in the vulnerability to schizophrenia.

Clinical implications of CYP2D6 genetic polymorphism during treatment with antipsychotic drugs.

CYP2D6 is described as the most relevant enzyme in the metabolism of many antipsychotic drugs. Its contribution to the interindividual differences in drug response is reviewed here highlighting its role in the kinetics of antipsychotic drugs and the occurrence of drug interactions. The activity of CYP2D6 is inherited as a monogenetic trait and the CYP2D6 gene appears highly polymorphic in humans. The polymorphic alleles may lead to altered activity of the CYP enzymes causing absent, decreased (poor), or increased (ultrarapid) metabolism that in turn influence the disposition of the antipsychotic drugs. Antipsychotic drug biotransformation is mainly determined by genetic factors mediating CYP2D6 gene polymorphism, however the importance of environmental factors (dietary, smoking, diseases, etc.) is also recognized. Additionally, the potential interaction between CYP2D6 and the endogenous metabolism must be taken into consideration. The present review summarizes the relevance of physiological and environmental factors in CYP2D6 hydroxylation capacity, the inhibition of CYP2D6 activity during treatment, the use of drug/metabolite ratio as a tool to evaluate CYP2D6 hydroxylation capacity in a patient, and the relevance of CYP2D6 for drug plasma concentration and for QTc interval lengthening during treatment with antipsychotic drugs.

[Prevalence of polydipsia and water intoxication in psychiatric inpatients]. / Prevalencia de polidipsia e intoxicación por agua en pacientes psiquiátricos hospitalizados.

INTRODUCTION: The prevalence of polydipsia and water intoxication among psychiatric inpatients has been described in different countries, however few studies have been conducted in Europe. The present study was aimed at evaluating the prevalence of polydipsia and water intoxication in an European Psychiatric Hospital. METHODS: SPGU (Specific Gravity of Urine) and Normalised Diurnal Weight Gain (NDWG) were evaluated among 201 inpatients. RESULTS: Risk of polydipsia and water intoxication were found among 51% of all patients. Risk of primary polydipsia was present in 25% of patients, and primary polydipsia and risk of water intoxication among 25% of all patients. CONCLUSIONS: This is one of the unique studies of polydipsia and water intoxication in psychiatric inpatients in Europe, and the first one conducted in Spain. The development of specific preventative and clinical programmes in psychiatric patients is suggested due to the clinical relevance and high prevalence of this pathology.

CYP2C9 gene and susceptibility to major depressive disorder.

Alteration of monoaminergic neurotransmission has been implicated in the pathophysiology of mood disorders, and CYP2C9 enzyme activity has been shown to be modulated by serotonin in vitro. The present study was aimed at analysing the frequency of CYP2C9 alleles (*1, *2, *3) among patients suffering from major depressive disorder. In all, 70 such suffering psychiatric outpatients were studied. The CYP2C9 genotypes were determined by allele-specific PCR. The CYP2C9*3 allele frequency was higher (P<0.01) among the patients suffering from major depression than in a population of 89 schizophrenic patients (odds ratio=3.3) and 138 healthy volunteers (odds ratio=2.8). The results suggest that CYP2C9 genetic polymorphism may be related to a major depressive disorder due to an alteration in endogenous metabolism, although a linkage between CYP2C9 and some other gene related to depression cannot be ruled out.

[Differential study of the complete and subclinical presentations of bulimia nervosa]. / Estudio diferencial de las formas completas y subclínicas de bulimia nerviosa.

INTRODUCTION: We examined the subtyping criteria for bulimia nervosa by comparing atypical and full-blown syndrome patients. METHODS: Sixty-one bulimic patients were compared on a number of demographic, clinical, and psychopathological variables. Thirty-nine patients met definite DSM-IV diagnostic criteria for bulimia nervosa and twenty-two had a subclinical form of this disorder. RESULTS: Although patients with less severe eating disorder experienced substantial distress and impairment, the study revealed some interesting clinical differences between the two groups. DISCUSSION: Subclinical bulimia nervosa may be more common in young women than now believed, and seems to be associated with persistent body image dissatisfaction, higher weight, non-purgative methods for controlling weight gain, and lower associated psychopathology.

[Psychopathology of bulimia nervosa: a multidimensional model]. / Psicopatología de la bulimia nerviosa: un modelo multidimensional1

INTRODUCTION: In recent years, a number of studies have been carried out with the intention of isolating clinical dimensions in the psychopathology of bulimia nervosa. Although borderline personality has been considered a core element of the bulimic psychopathology by most of the authors, it has not been incorporated into any of these models. In this context, the present study was aimed at testing the consistence of the more complex model proposed until now, including in the analysis borderline personality as a clinical variable. SAMPLE AND METHODS: A group of 66 female patients fulfilling DSM-IV criteria for bulimia nervosa were assessed using a set of clinical instruments. The isolated items were processed using factor analysis techniques. RESULTS: Five basic dimensions of bulimia nervosa were obtained: 1. body disatisfaction; 2. restrictive eating behaviors; 3. purging behaviors; 4. emotional instability; and 5. disocial behavior. CONCLUSIONS: Our results support the idea that bulimia nervosa is a multidimensional condition. In our model, the dimension emotional instability incorporated borderline features, which tended to be strongly associated to self-defeating behaviors and depressive symptoms.