José Antonio Cabranes

Clinical implications of determination of plasma haloperidol levels

ABSTRACT– The aim of this study was to analyze the clinical utility of monitoring plasma levels, since the utility of monitoring is not yet well established. After a washout period, 30 schizophrenic patients were given fixed doses of haloperidol for 3 weeks. A U‐shaped second‐grade polynomic relationship (R = 0.69) was found between steady state of haloperidol and percentage improvement in total score on the Brief Psychiatric Rating Scale. The interval of effective concentrations was between 12 and 59 ng/ml. Fourteen of the 15 patients who had a steady state of haloperidol within that therapeutic interval were responders: only 5 out of the 15 patients below the therapeutic interval were responders. None of the 5 patients who had concentrations below 8 ng/ml was a responder. Furthermore, responder patients showed a steady‐state level of haloperidol significantly higher than that of nonresponders. These data suggest that plasma levels of haloperidol are predictors of therapeutic response in schizophrenic disorders.

The Effect of MAPT H1 and APOE ε4 on Transition from Mild Cognitive Impairment to Dementia

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimers disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition.

P50 sensory gating is a trait marker of the bipolar spectrum

UNLABELLED Sensory gating deficit, assessed by a paired auditory stimulus paradigm (P50), has been reported as a stable marker of schizophrenia. The aim of this study was to explore if this neurophysiological disturbance also fulfilled stability criteria in the bipolar disorder (BD) spectrum bipolar, as state independence is one of the main points to be considered as a potential endophenotype of the illness. The P50 evoked potential was studied in 95 healthy controls and 126 bipolar euthymic patients. Euthymia was established according to Van Gorps criteria. Bipolar I and II subtypes were analyzed separately. The influence of a lifetime history of psychoses was also evaluated in the clinical sample. P50 gating was deficitary in all the subsamples of patients relative to healthy comparison subjects. Bipolar I patients with and without a history of psychosis showed higher P50 ratios than the other subgroups of patients, although these differences were not significant. P50 alterations were mainly due to a deficit in the inhibition of the second wave (test wave or S2) amplitude. CONCLUSIONS The findings suggest that this inhibitory deficit can be considered characteristic of the illness and that the intensity of the gating abnormality varies according to the severity of BD.

Pituitary-Adrenal Disinhibition and Suicide Attempts in Depressed Patients

Recognition of the biological correlates of suicidal behavior is extremely important for identifying high-risk subjects. Of the possible biological correlates, neuroendocrine parameters have received special attention. Various clinical observations suggest that hypothalamus-pituitary-adrenal axis activity is abnormally increased in depressed patients who exhibit suicidal behavior. Bunney et al. (1969) observed an association between suicidal behavior and adrenal hyperactivity, which was reflected in urine levels of 17-hydroxycorticosteroids. The urine concentrations of five patients who later committed suicide were among the 12 highest recorded in a sample of 145 depressed patients. However, these results have not been confirmed by other studies (Levy and Hansen 1969; Krieger 1970). Carroll (1972) found no differences in the serum cortisol levels of eight patients who made serious suicide attempts and those of other subjects in a group of depressed patients (n = 40). More recently, Coryell and Schlesser (1981) published the results of Dexamethasone Suppression Tests (DST) performed on 205 sub-

Sensory gating deficit is associated with catechol-O-methyltransferase polymorphisms in bipolar disorder

Abstract Objectives. Recent studies have evidenced that bipolar patients show a sensory gating deficit (P50). Among the neural systems that could be influencing this electrophysiological phenotype, dopamine seems to play an important role. We hypothesize that catechol-O-methyltransferase (COMT), the main metabolizer of dopamine in prefrontal cortex, is related to this deficit. Methods. We selected three polymorphisms in COMT gene: rs2075507 (Promoter 2 region), Val158Met (rs4680) and rs165599 (3’ region). A case–control study was performed in 784 controls and 238 bipolar patients. Besides, 122 euthymic bipolar subjects and 95 healthy subjects carried out a sensory gating task (P50). Results. Polymorphism rs165599 in the COMT gene was associated with susceptibility to bipolar disorder (BD), mainly in women (AG: OR = 1.46; GG: OR = 1.84; P = 0.03). In the female group, haplotype AAG was associated with an OR = 7.6. Subjects who carried Val158 allele evidenced a deficit in suppression (P = 0.046) and rs165599 allele G carriers (mainly in homozygosis) had a bigger S2 amplitude and a higher S2/S1 ratio (1.6e-5 < P < 0.01). Not a single association was proven in the control group. Conclusions. Our results support the association of the COMT gene with BD and with one of its potential endophenotypes, auditory sensory gating deficit, measured by the P50 paradigm.

Somatomedin-C and growth hormone levels in anorexia nervosa in relation to the puberal or post puberal stages

1. Plasma concentrations of somatomedin-C and GH were determined in 21 patients diagnosed as anorexia nervosa (AN) and in 44 controls. 2. Somatomedin-C concentrations were significantly lower in pubertal AN patients than in controls, but not in post pubertal patients. 3. GH was increased in both pubertal and post pubertal AN patients, although more in pubertal AN patients. 4. Our results suggest that the hormonal alterations that appear in AN constitute a mechanism of defense against starvation. The activation of these defense mechanisms and the degree of modification produced in normal hormonal patterns depend not only on caloric intake but also on metabolic requirements.

Determination of plasma haloperidol concentrations by radioreceptor assay in schizophrenia: clinical utility.

1. Haloperidol concentrations were determined by radioreceptor assay (RRA) and prolactin concentrations were measured in 20 patients diagnosed as schizophrenia (DSM-III). 2. The patients were treated with a fixed dose of haloperidol for 21 days. 3. Our results suggest the existence of a curvilinear relationship, in the form of an inverted U, between stable haloperidol levels and clinical improvement assessed by total BPRS score. 4. We also found a curvilinear relationship between the improvement observed in positive symptoms and state steady levels. 5. No relationship was seen between improvement in negative symptoms and state steady levels. 6. An interval of optimal haloperidol concentration was found: 8.1 ng/ml to 19.6 ng/ml. 7. No relation was found between the dose of haloperidol administered and plasmatic concentration, nor between haloperidol and prolactin levels. 8. Our findings suggest that haloperidol concentrations determined by RRA have clinical utility as predictors of response in schizophrenia.

Cognitive reserve benefits brain efficiency in healthy aging

The concept of cognitive reserve (CR) describes the mind’s resistance to the progressive damage of the brain and probably this can be reflected as the ability to recruit brain networks in an effective way. It is as- sociated with the abilityto copewith the deleterious effects of brain damage,brain degeneration, or age-related changes on cognitive performance.

Mild cognitive impairment subtypes: An MEG study

Previous studies of the dementia continuum have characterized the early disruption of the brain oscillatory activity at the stage of Mild cognitive impairment (MCI). Reduction in power in posterior regions in the alpha band has been one of the landmarks of the Alzheimer Disease accompanied by the anteriorization of the theta band power. However, little is known about the neurophysiological differences between single and multidomain MCI patients.Our goal is to study the differences in oscillatory magnetic activity between amnestic single and multidomain MCI. This will allow us to test whether the effect of the impairment in a single cognitive domain or in a more widespread functional impairment can be reflected in specific neurophysiological profiles.