Multilocus Genetic Profile Reflecting Low Dopaminergic Signaling Is Directly Associated with Obesity and Cardiometabolic Disorders Due to Antipsychotic Treatment.

Treatment with second-generation antipsychotics (SGAs) can cause obesity and other cardiometabolic disorders linked to D2 receptor (DRD2) and to genotypes affecting dopaminergic (DA) activity, within reward circuits. We explored the relationship of cardiometabolic alterations with single genetic polymorphisms DRD2 rs1799732 (NG_008841.1:g.4750dup -> C), DRD2 rs6277 (NG_008841.1:g.67543C>T), COMT rs4680 (NG_011526.1:g.27009G>A), and VNTR in both DRD4 NC_000011.10 (637269-640706) and DAT1 NC_000005.10 (1392794-1445440), as well as with a multilocus genetic profile score (MLGP). A total of 285 psychiatric patients treated with SGAs for at least three months were selected. Cardiometabolic parameters were classified according to ATP-III and WHO criteria. Blood samples were taken for routinely biochemical assays and PCR genotyping. Obesity (BMI, waist (W)), high diastolic blood pressure (DBP), and hypertriglyceridemia (HTG) were present in those genetic variants related to low dopaminergic activity: InsIns genotype in rs1799732 (BMI: OR: 2.91 [1.42-5.94]), DRD4-VNTR-L allele (W: OR: 1.73 [1.04-2.87]) and 9R9R variant in DAT1-VNTR (W: OR: 2.73 [1.16-6.40]; high DBP: OR: 3.33 [1.54-7.31]; HTG: OR: 4.38 [1.85-10.36]). A low MLGP score indicated a higher risk of suffering cardiometabolic disorders (BMI: OR: 1.23 [1.05-1.45]; W: OR: 1.18 [1.03-1.34]; high DBP: OR: 1.22 [1.06-1.41]; HTG: OR: 1.20 [1.04-1.39]). The MLGP score was more sensitive for detecting the risk of suffering these alterations. Low dopaminergic system function would contribute to increased obesity, BDP, and HTG following long-term SGA treatment.

Genetic variables of the glutamatergic system associated with treatment-resistant depression: A review of the literature.

Depression is a common, recurrent mental disorder and one of the leading causes of disability and global burden of disease worldwide. Up to 15%-40% of cases do not respond to diverse pharmacological treatments and, thus, can be defined as treatment-resistant depression (TRD). The development of biomarkers predictive of drug response could guide us towards personalized and earlier treatment. Growing evidence points to the involvement of the glutamatergic system in the pathogenesis of TRD. Specifically, the N-methyl-D-aspartic acid receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), which are targeted by ketamine and esketamine, are proposed as promising pathways. A literature search was performed to identify studies on the genetics of the glutamatergic system in depression, focused on variables related to NMDARs and AMPARs. Our review highlights GRIN2B, which encodes the NR2B subunit of NMDAR, as a candidate gene in the pathogenesis of TRD. In addition, several studies have associated genes encoding AMPAR subunits with symptomatic severity and suicidal ideation. These genes encoding glutamatergic receptors could, therefore, be candidate genes for understanding the etiopathogenesis of TRD, as well as for understanding the pharmacodynamic mechanisms and response to ketamine and esketamine treatment.

Attachment anxiety as mediator of the relationship between childhood trauma and personality dysfunction in borderline personality disorder.

Insecure attachment has been described as mediating the relationship between childhood trauma and dysfunctional personality traits in different mental disorders. Despite the role insecure attachment and childhood trauma have independently demonstrated to play as determinants of borderline personality disorder, less is known about the mediating mechanisms explaining these associations. For the first time, we assessed adult attachment, childhood trauma and dimensional personality pathology in a sample of outpatients with borderline personality disorder and tested whether the association between childhood trauma and personality dysfunction was at least partially attributable to insecure attachment. The results showed that attachment anxiety fully mediated the relationship between specific types of trauma (emotional abuse and physical neglect) and emotional dysregulation. Further, emotional abuse was both directly associated with dissocial behaviour and indirectly via attachment anxiety (partial mediation). Emotional abuse has been described as an essential environmental factor for the development of borderline personality disorder and emotional dysregulation, on its part, as the core feature of the condition. Our results indicate that attachment anxiety explains the link between these central aspects of borderline personality disorder. Our findings are consistent with previous research and current etiological understanding of the condition and provide support for recommending a careful assessment of childhood traumatic experiences and adult attachment style to gain a more comprehensive insight into the symptoms and its heterogeneity. As a secondary aim, we assessed the effect parental mental illness may have in these mediation models, but no significant influence on childhood trauma, attachment or personality was found.

Genetics of adult attachment: An updated review of the literature.

Attachment style, which has been theorized to be rooted in childhood bonding experiences, influences adult cognitive, emotional and interpersonal functioning. Despite its relationship with early experiences, research indicates that the continuity of attachment style across childhood and adulthood is only partial, being a malleable tendency that is shaped throughout development, with an increasing influence of genetics, as it occurs in other cognitive and behavioral phenotypes. Genetic research indicates that up to 45% of the variability in anxious and 39% in avoidant adult attachment style could be explained by genetic causes, but the precise mechanisms remain unclear. A narrative review is conducted analyzing the existing literature regarding the implication of candidate genes related to oxytocin, dopaminergic pathways, serotonergic pathways and brain-derived neurotrophic factor in adult attachment, with both vulnerability and differential susceptibility approaches, yielding mixed results. We highlight the lack of genome-wide studies and the scarcity of epigenetic investigation. Based on the existing data, we conclude that the genetics of adult attachment is an area that requires further research to clarify its etiological role and that it should be preferably approached as an interaction between nature and nurture.

Lithium: An old treatment for a new indication.

Subacute necrotising encephalopathy or Leigh syndrome is a congenital neuro-metabolic disease that is part of a group of diseases called mitochondrial encephalopathies. The form inherited is variable and it has a multisystemic effect, although with a predominance of lesions in the central nervous system. Prognosis is poor and there is no specific treatment for it. In 2007, we published the case of a 23-year- old patient, with severe psychomotor agitation crises, who responded favourably to lithium1 after the failure of several previous treatments. Here, we describe the follow-up of this patient during the 5 years after discharge from hospital, until her death at 29 years of age. Her improvement was maintained, she was not hospitalised again and the patient’s level of autonomy increased. The possible relationship of this improvement to new data on the neuroprotective and neurotropic effects of lithium are discussed.

NOTA CLÍNICA: Litio: Un tratamiento antiguo para una nueva indicación / CLINICAL NOTE: Lithium: An Old Treatment for a New Indication a new indication

La encefalopatía necrotizante subaguda o síndrome deLeigh es una enfermedad neuro-metabólica congénita queforma parte de un grupo de enfermedades llamadas encefalopatías mitocondriales. Presenta una forma de herenciavariable y se produce una afectación multisistémica, aunquecon predominio de lesiones en el sistema nervioso central. Elpronóstico es malo y no existe un tratamiento específico. Enel año 2007, publicamos el caso de una paciente de 23 añosde edad con graves crisis de agitación psicomotriz, que tras elfracaso de varios tratamientos previos respondió favorablemente al litio1. Ahora describimos el seguimiento de esta paciente durante los 5 años posteriores tras el alta hospitalaria,hasta su fallecimiento a los 29 años. La mejoría se mantuvo,no volvió a ser hospitalizada y el nivel de autonomía de lapaciente aumentó. Se discuten las posibles relaciones de estamejoría con los nuevos datos sobre el efecto neuroprotectory neuroregenerador del litio. (AU)

Subacute necrotizing encephalopathy or Leigh’s syndrome is a congenital neuro-metabolic disease that is part ofa group of diseases called mitochondrial encephalopathies. Itpresents a variable form of inheritance and a multisystemicaffectation is produced, although with predominance of lesions in the central nervous system. The prognosis is poor andthere is no specific treatment. In 2007 we published the caseof a 23-year-old patient with severe psychomotor agitationcrises, who after the failure of several previous treatments,responded favorably to lithium1. We now describe the follow-up of this patient during the 5 years following her discharge from hospital, until her death at the age of 29. Theimprovement was maintained, she was not re-hospitalizedand the patient’s level of autonomy increased. The possiblerelationships of this improvement with the new data on theneuroprotective and neurotropic effects of lithium are discussed. (AU)

Episodios repetidos de psicosis de inicio tardío asociados a efavirenz / No disponible

No disponible

Genetic modulation of facial emotion recognition in borderline personality disorder.

Facial emotion recognition (FER) has been described to be impaired in borderline personality disorder (BPD), especially for neutral faces. Genetic modulation of FER has been studied in healthy individuals and some psychiatric conditions, but no genetic association studies have been conducted in BPD hitherto. The main objective of our study was to explore the influence of the serotonin-transporter-linked promoter region (5HTTLPR) and catechol-o-methyltransferase (COMT) Val158Met on facial emotion processing among BPD patients. To that end, seventy-six BPD outpatients were asked to complete a computer-based facial affect recognition task, representing four emotions (neutral, happy, fearful or angry). Accuracy of FER and perceptual biases were calculated. The 5HTTLPR and COMT Val158Met polymorphisms were genotyped using saliva samples. Individuals with the high-activity serotonin-transporter genotype and those with the low-activity COMT genotype had significantly more difficulties identifying neutral faces; the former showed stronger bias to perceive neutral faces as happy, and the latter, neutral faces as fearful. Interestingly, the perceptual biases observed in our patients are similar to previous reports in healthy individuals. The authors propose that the ability to accurately recognize neutral faces might be a possible endophenotype of BPD. Sex-genotype interactions were also observed in relation to angry faces and 5HTTLPR, and neutral faces and COMT Val158Met polymorphisms, in line with sex-related differences previously described for both polymorphisms in relation to FER and other cognitive and behavioral outcomes. The impact of inaccurate FER on psychosocial functioning and potential interventions are also discussed.

Manía y cáncer de páncreas / No disponible

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COMT haplotypes, catecholamine metabolites in plasma and clinical response in schizophrenic and bipolar patients.

AIM: We examined the association of COMT haplotypes and plasma metabolites of catecholamines in relation to the clinical response to antipsychotics in schizophrenic and bipolar patients. PATIENTS & METHODS: We studied 165 patients before and after four weeks of treatment, and 163 healthy controls. We assessed four COMT haplotypes and the plasma concentrations of HVA, DOPAC and MHPG. RESULTS: Bipolar patients: haplotypes are associated with age at onset and clinical evolution. In schizophrenic patients, an haplotype previously associated with increased risk, is related to better response of negative symptoms. CONCLUSION: Haplotypes would be good indicators of the clinical status and the treatment response in bipolar and schizophrenic patients. Larger studies are required to elucidate the clinical usefulness of these findings.

The influence of the Val158Met catechol-O-methyltransferase polymorphism on the personality traits of bipolar patients.

INTRODUCTION: Certain personality traits and genetic polymorphisms are contributing factors to bipolar disorder and its symptomatology, and in turn, this syndrome influences personality. The aim of the present study is to compare the personality traits of euthymic bipolar patients with healthy controls and to investigate the effect of the catechol-O-methyltransferase (COMT) Val158Met genotype on those traits. We recruited thirty seven bipolar I patients in euthymic state following a manic episode and thirty healthy controls and evaluated their personality by means of the Cloninger's Temperament and Character Inventory (version TCI-R-140). We assessed the influence of the polymorphism Val158Met in the COMT gene on the personality of these patients. The patients scored higher than controls in harm avoidance (61.3±12.5 vs. 55.3±8.1) and self-transcendence (45.3±12.8 vs. 32.7±8.2) and scored lower than controls in self-directedness (68.8±13.3 vs. 79.3±8.1), cooperativeness (77.1±9.1 vs. 83.9±6.5) and persistence (60.4±15.1 vs. 67.1±8.9). The novelty seeking dimension associates with the Val158Met COMT genotype; patients with the low catabolic activity genotype, Met/Met, show a higher score than those with the high catabolic activity genotype, Val/Val. CONCLUSIONS: Suffering from bipolar disorder could have an impact on personality. A greater value in harm avoidance may be a genetic marker for a vulnerability to the development of a psychiatric disorder, but not bipolar disorder particularly, while a low value in persistence may characterize affective disorders or a subgroup of bipolar patients. The association between novelty seeking scores and COMT genotype may be linked with the role dopamine plays in the brain's reward circuits.

Role of GIRK channels on the noradrenergic transmission in vivo: an electrophysiological and neurochemical study on GIRK2 mutant mice.

Dysfunctional noradrenergic transmission is related to several neuropsychiatric conditions, such as depression. Nowadays, the role of G protein-coupled inwardly rectifying potassium (GIRK)2 subunit containing GIRK channels controlling neuronal intrinsic excitability in vitro is well known. The aim of this study was to investigate the impact of GIRK2 subunit mutation on the central noradrenergic transmission in vivo. For that purpose, single-unit extracellular activity of locus coeruleus (LC) noradrenergic neurons and brain monoamine levels using the HPLC technique were measured in wild-type and GIRK2 mutant mice. Girk2 gene mutation induced significant differences among genotypes regarding burst activity of LC neurons. In fact, the proportion of neurons displaying burst firing was increased in GIRK2 heterozygous mice as compared to that recorded from wild-type mice. Furthermore, this augmentation was even greater in the homozygous genotype. However, neither the basal firing rate nor the coefficient of variation of LC neurons was different among genotypes. Noradrenaline and serotonin basal levels were altered in the dorsal raphe nucleus from GIRK2 heterozygous and homozygous mice, respectively. Furthermore, noradrenaline levels were increased in LC projecting areas such as the hippocampus and amygdale from homozygous mice, although not in the prefrontal cortex. Finally, potency of clonidine and morphine inhibiting LC activity was reduced in GIRK2 mutant mice, although the efficacy remained unchanged. Altogether, the present study supports the role of GIRK2 subunit-containing GIRK channels on the maintenance of tonic noradrenergic activity in vivo. Electric and neurochemical consequences derived from an altered GIRK2-dependent signalling could facilitate the understanding of the neurobiological basis of pathologies related to a dysfunctional monoaminergic transmission.

Aripiprazole reverses paliperidone-induced hyperprolactinemia.

Hyperprolactinemia is a common side effect of antipsychotic treatments. Existing alternatives to resolve this problem include decreasing the antipsychotic dose or switching to a different antipsychotic agent. Nevertheless, said modifications can sometimes lead to decompensation of the patient. We report a clinical case of a female patient in whom the combined treatment of 5 mg/day of aripiprazole (5 mg/day) reversed paliperidoneinduced hyperprolactinemia within four weeks.

Aripiprazol como corrector de la hiperprolactinemia causada por paliperidona / Aripiprazole reverses Paliperidone-induced Hyperprolactinemia

La hiperprolactinemia es un efecto secundario frecuente provocado por los fármacos antipsicóticos. Una opción para resolver este problema es disminuir las dosis o cambiar de antipsicótico, pero en ocasiones se produce la descompensación del paciente. Comentamos el caso de una paciente en la que la combinación con 5 mg/día de aripiprazol resolvió en 4 semanas la hiperprolactinemia producida por la paliperidona (AU)

Hyperprolactinemia is a common side effect of antipsychotic treatments. Existing alternatives to resolve this problem include decreasing the antipsychotic dose or switching to a different antipsychotic agent. Nevertheless, said modifications can lead to other adverse consequences, such as the worsening of psychotic symptoms. We report a clinical case in which an adjunctive treatment with aripiprazole (5 mg/day) reversed paliperidoneinduced hyperprolactinemia within four weeks (AU)

Variability of plasma homovanillic acid over 13 months in patients with schizophrenia; relationship with the clinical response and the Wisconsin card sort test.

In the present study we have measured, on a monthly basis, the concentration of plasma homovanillic acid (pHVA) in schizophrenic patients during 13 months of their pharmacological treatment. The average pHVA values of each patient were within the range of 7.30-17.70 ng/ml and the coefficients of variation for each patient (CV %) were within the range of 13-33%. Half of the patients that showed higher pHVA CV% values also showed higher scores on the Brief Psychiatric Rating Scale at the beginning of the study, and improved more after 6 months, when compared to the remaining 50% with lower CV% values. There was no significant relationship between the scores of the Wisconsin Card Sort Test and the concentration or the CV% of the pHVA of each patient. A greater variability in the pHVA may be associated with a greater plasticity of the dopaminergic system and a better clinical response.

Catechol O-methyltransferase and monoamine oxidase A genotypes, and plasma catecholamine metabolites in bipolar and schizophrenic patients.

Metabolites of dopamine and norepinephrine measured in the plasma have long been associated with symptomatic severity and response to treatment in schizophrenic, bipolar and other psychiatric patients. Plasma concentrations of catecholamine metabolites are genetically regulated. The genes encoding enzymes that are involved in the synthesis and degradation of these monoamines are candidate targets for this genetic regulation. We have studied the relationship between the Val158Met polymorphism in catechol O-methyltransferase gene, variable tandem repeat polymorphisms in the monoamine oxidase A gene promoter, and plasma concentrations of 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid in healthy control subjects as well as in untreated schizophrenic and bipolar patients. We found that the Val158Met substitution in catechol O-methyltransferase gene influences the plasma concentrations of homovanillic and 3,4-dihydroxyphenylacetic acids. Although higher concentrations of plasma homovanillic acid were found in the high-activity ValVal genotype, this mutation did not affect the plasma concentration of 3-methoxy-4-hydroxyphenylglycol. 3,4-dihydroxyphenylacetic acid concentrations were higher in the low-activity MetMet genotype. Interestingly, plasma values 3-methoxy-4-hydroxyphenylglycol were greater in schizophrenic patients and in bipolar patients than in healthy controls. Our results are compatible with the previously reported effect of the Val158Met polymorphism on catechol O-methyltransferase enzymatic activity. Thus, our results suggest that this polymorphism, alone or associated with other polymorphisms, could have an important role in the genetic control of monoamine concentration and its metabolites.