Nieves Basterreche

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.

GABA and Homovanillic Acid in the Plasma of Schizophrenic and Bipolar I Patients

We have determined the plasma (p) concentration of gamma-aminobutyric acid (GABA) and the dopamine metabolite homovanillic acid (HVA), and the pHVA/pGABA ratio in schizophrenic and bipolar patients. The research was undertaken in a geographic area with an ethnically homogeneous population. The HVA plasma concentrations were significantly elevated in the schizophrenic patients compared to the bipolar patients. The levels of pGABA was significantly lower in the two groups of patients compared to the control group, while the pHVA/pGABA ratio was significantly greater in the both groups of patients compared to the controls. As the levels of pHVA and pGABA are partially under genetic control it is better to compare their concentrations within an homogeneous population. The values of the ratio pHVA/pGABA are compatible with the idea of an abnormal dopamine-GABA interaction in schizophrenic and bipolar patients. The pHVA/pGABA ratio may be a good peripheral marker in psychiatric research.

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.

Biological Correlates of the Congruence and Incongruence of Psychotic Symptoms in Patients with Type 1 Bipolar Disorder

We examined the catechol-O-methyl transferase (COMT) Val108/158Met genotype in 160 type 1 bipolar patients. We also analyzed the plasma concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylenglycol (MHPG) and 3,4-dihydroxyphenylacetic acid in 60 of those patients who had been without mood stabilizers or neuroleptic treatment for at least 8 days. Results: Patients with congruent psychotic symptoms presented a higher plasma concentration of HVA than mood incongruent psychotic patients. The Val/Val genotype was associated with higher plasma concentrations of HVA and MHPG. We detected a larger proportion of patients with psychotic symptoms in the Val/Val genotype group, although this did not reach statistical significance. It was found that the distribution of the COMT genotype was not influenced by the congruent/incongruent nature of the psychotic symptoms. Limitations: The proportion of patients without psychotic symptoms in our sample was low. This fact limits the value of some comparisons. Conclusions: Congruent and incongruent psychotic patients can be distinguished in terms of the concentration of plasma HVA. Based on the presence or absence of mood incongruent symptoms, the Val108/158Met polymorphism of the COMT gene alone does not appear to be a crucial determinant in the division of psychotic bipolar patients. Nevertheless, COMT polymorphisms may influence some of the characteristics of the patients by their effect on monoamine metabolism.

Plasma homovanillic acid levels in schizophrenic patients: Correlation with negative symptoms

The relation between changes in the levels of plasma homovanillic acid (pHVA) and clinical evolution during neuroleptic treatment of schizophrenic patients has not been satisfactorily characterized, as a number of conflicting findings have been reported. Significant correlations have generally been found using the assessment of positive symptoms as an index of clinical outcome. Nevertheless, attempts to correlate pHVA concentrations with negative symptoms have yielded contradictory results. With a view to evaluating if different responses in negative symptoms are associated with distinct pHVA profiles, we examined the levels of pHVA in 46 neuroleptic-free schizophrenic patients and in these patients after neuroleptic treatment. Negative and positive symptoms were also addressed before and after treatment. Our results reveal that at least two classes of negative symptoms exist; the clinical evolution of the first class of negative symptoms parallels that of positive symptoms, and clinical improvement correlates with reduced dopaminergic activity. In contrast, in the second class, reduced dopaminergic activity is associated with a further deterioration of negative symptoms. These findings corroborate the heterogeneity of negative symptoms and may contribute to a better definition of endophenotypes in the schizophrenic syndrome.

Plasma homovanillic acid and family history of psychotic disorders in bipolar I patients

It has been suggested that the family history of psychotic disorders is useful in defining homogeneous groups of bipolar patients. The plasma homovanillic acid (pHVA) concentrations have been related to the effect of antipsychotic treatment in psychotic patients. We have studied the influence of a positive family history of psychotic disorders both on the variation of pHVA levels and on the relation between pHVA concentrations and the clinical response to treatment. Clinical status and pHVA levels were assessed in 58 medication free patients before and after 4 weeks of treatment with olanzapine and lithium. Clinical improvement correlated positively with pHVA levels on the 28th day of treatment only in the patients having first degree relatives with psychotic disorders. The pHVA levels did not decrease after 28 days of treatment. Our results reinforce the idea that a positive family history of psychosis in psychotic bipolar disorders may constitute a good basis for sub-grouping these patients.

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.

Por qué no hablamos de síntomas psicóticos negativos en el trastorno afectivo bipolar

The classifications of the psychiatric disorders that we manage1 contemplate the possibility of positive psychotic symptoms being present in bipolar disorder. They describe how these symptoms can appear in both the depressive and the manic and the mixed phases, how they can be congruent or incongruent with patient mood and, lastly, how they can adopt the form of delirium and/or hallucinations. These classifications also add that these symptoms cannot persist more than 2 weeks once the affective episode has been resolved, because we would have to change the diagnosis if they did last longer. We often notice that symptomatic recovery is not accompanied by functional recovery in the bipolar patient.2 Among other factors, this deficiency is attributed to the proven cognitive deterioration3 and to what are called interepisode subsyndromal depressive symptoms4 that these patients suffer. In this sense, it would be interesting to try to discriminate (which is sometimes quite complicated) whether these subsyndromal depressive symptoms are really negative psychotic symptoms in some cases. Perhaps we should consider a differential diagnosis of these symptoms that is the «inverse» of what we do with the schizophrenic patient and their negative symptoms.5 We feel that, in schizophrenic patients, it is useful to carry out a differential diagnosis of the negative psychotic symptoms with possible depressive symptoms and we also consider this fact to be important in treatment. Bipolar patients sometimes show a type of symptoms that, in a schizophrenic patient, would be called negative psychotic symptoms.6 In fact, the clinical presentation is identical and we do not know the aetiopathogenesis. Our reticence to speak about negative psychotic symptoms in bipolar disorder could be related to our fear of creating even more confusion than what already exists. If these symptoms are found even when the patient is euthymic and the symptoms persist over time, it is possible

Disminución de la actividad noradrenérgica durante el tratamiento en pacientes bipolares: independencia de los polimorfismos de la COMT

Introduccion Los estudios mas recientes apoyan la idea de que la fisiopatologia del sindrome bipolar se sustenta en diversas interacciones de varios sistemas de neurotransmision. Datos clinicos y preclinicos sugieren tambien que la actividad noradrenergica esta elevada en estos pacientes antes del tratamiento. Metodo En nuestro estudio se ha medido la concentracion plasmatica del 3-metoxi-4-hidroxifenilglicol (MHPG), principal metabolito de la noradrenalina (NA), en 50 pacientes bipolares tipo I, 29 varones y 21 mujeres, diagnosticados segun el Diagnostic and Statistical Manual of Disorders (DSM-IV). Tambien se determinaron los polimorfismos Val108/158Met de la catecol-O-metiltransferasa (COMT). Los pacientes se trataron con olanzapina, a la que posteriormente se anadio litio. Resultados y Conclusiones El tratamiento demostro ser eficaz, tanto en pacientes psicoticos como en no psicoticos; y no se encontro una relacion significativa entre los polimorfismos estudiados de la COMT y la respuesta clinica medida por la escala de Young para la mania. Si se puso de manifiesto una correlacion significativa y positiva entre los valores plasmaticos de MHPG antes del tratamiento y despues de 3 dias de tratamiento con la respuesta a este.

Efecto paradójico del tratamiento con aripiprazol en un paciente bipolar: de la psicofarmacología a la psicopatología

El trastorno bipolar es una enfermedad cronica, caracterizada por remisiones y exacerbaciones, cuya evolucion puede modificarse favorablemente con un tratamiento apropiado. Aunque el tratamiento de los episodios agudos es importante, la prevencion de recaidas mediante un tratamiento de mantenimiento es el objetivo terapeutico principal. Se ha estimado que aproximadamente el 60% de la poblacion diagnosticada de trastorno bipolar I experimenta de forma cronica dificultades en la actividad sociolaboral. Los sintomas subclinicos entre los episodios agudos son, en un gran numero de pacientes, la causa de esas dificultades. Presentamos el caso de una paciente con subsintomas interepisodicos, a la que instauramos un tratamiento con aripiprazol. Este neuroleptico, de singular mecanismo de accion, ha producido en nuestra paciente sorprendentes consecuencias clinicas de interesante discussion.