Augusto Pasini

Concentrations of 3α-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery

BACKGROUND There is preclinical and clinical evidence that plasma concentrations of 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-tetrahydroprogesterone; 3 alpha,5 alpha-THP), a neuroactive steroid that is a positive allosteric modulator of the GABAA receptor, are altered in depression and normalize as a result of antidepressant treatment. However, no data are available on the concentrations of 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-tetrahydrodeoxycorticosterone; 3 alpha,5 alpha-THDOC), another GABA ergic neuroactive steroid, in depression. METHODS We studied nine depressed patients before and after treatment with various antidepressants and compared them to healthy matched control subjects. Blood samples were quantified by means of a highly sensitive combined gas chromatography/mass spectrometry analysis. RESULTS Compared to control subjects, plasma concentrations of 3 alpha,5 alpha-THDOC and its precursor 5 alpha-dihydrodeoxycorticosterone (5 alpha-DHDOC) were increased in depressed patients and were not significantly influenced by antidepressant treatment. However, 3 alpha,5 alpha-THP plasma concentrations were decreased in depression and clinically effective antidepressant treatment was accompanied by an increase of 3 alpha,5 alpha-THP concentrations in these patients. CONCLUSIONS Our results provide the first evidence for a differential alteration in the plasma concentrations of the 3 alpha-reduced neuroactive steroids 3 alpha,5 alpha-THDOC and 3 alpha,5 alpha-THP in major depression, which is only partially reversed by successful antidepressant treatment.

Plasma Concentrations of Neuroactive Steroids before and after Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression

There is evidence for altered levels of neuroactive steroids in major depression that normalize after successful antidepressant pharmacotherapy. Currently it is not known whether this is a general principle of clinically effective antidepressant therapy or a pharmacological effect of antidepressants. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) may affect plasma concentrations of neuroactive steroids in a similar way as antidepressant pharmacotherapy. Progesterone, 3α,5α-tetrahydroprogesterone (3α,5α-THP), 3α,5β- tetrahydroprogesterone (3α,5β–THP), 3β,5α-tetrahydroprogesterone (3β, 5α-THP) and dehydroepiandrosterone (DHEA) were quantified in 37 medication-free patients suffering from a major depressive episode before and after 10 sessions of left prefrontal rTMS. Plasma samples were analyzed by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was a significant reduction of depressive symptoms after rTMS. However, plasma concentrations of neuroactive steroids were not affected by rTMS and not related to clinical response. Clinical improvement after extended daily treatment with rTMS is not accompanied by changes in neuroactive steroid levels. Changes in neuroactive steroid levels after antidepressant pharmacotherapy more likely reflect specific pharmacological effects of antidepressant drugs and are not necessary for the amelioration of depressive symptoms.

Attention and executive functions profile in drug naive ADHD subtypes

Attention deficit hyperactivity disorder (ADHD) has been associated with executive functioning and sustained and divided attention deficits. In order to clarify the questions on neurocognitive impairment in ADHD, we investigated the presence of specific executive functions (EFs) and attention deficit patterns in ADHD clinical subtypes. 50 patients with ADHD and 44 controls were evaluated. All subjects were boys and performed a clinical-psychopathological and neuropsychological battery. Five main domains of EFs and attention were studied. Executive functions-related neurocognitive abilities were used as control tasks. ADHD patients, inattentive and combined subtypes differ from controls on response inhibition, divided attention, phonological, and visual object working memory and on variability of reaction times measured with CPT. Comparison of ADHD subtypes, in five main domains of EFs, did not show evidence of different executive functioning profiles. Response inhibition can predict performance on working memory tests but it cannot predict performance on divided attention/set shifting and on sustained attention. ADHD boys exhibit a selective impairment on executive functions and attention tasks. These data suggest the involvement of partially independent neural circuits which control inhibition and divided attention in ADHD. Since right prefrontal cortex seems to be crucial in controlling response inhibition, while left dorsolateral prefrontal cortex seems important in modulating divided attention, these areas are deputated to be involved in the pathogenesis of neuropsychological deficits in ADHD subtypes. In addition, this study candidates the impairment in phonological and visual-object working memory as a possible neuropsychological trait in ADHD males with inattentive or combined subtypes.

5-HT2 antagonist ritanserin in neuroleptic-induced parkinsonism: a double-blind comparison with orphenadrine and placebo.

Several studies support the hypothesis of 5-HT (serotonin) involvement in the physiopathology of the extrapyramidal system. Ritanserin is a new compound with a high, selective, and long-lasting binding affinity for 5-HT2 receptors. A therapeutic effect of ritanserin has been reported in Parkinsons tremor and L-Dopa-induced dyskinesias but no effect was seen in essential tremor. In this double-blind comparative study with orphenadrine (150 mg daily p.o.) and placebo, ritanserin (30 mg daily p.o.) was administered to 36 schizophrenic outpatients who were being treated with neuroleptic drugs and who had parkinsonism. For a period of 3 weeks, the treatment was added to the antipsychotic therapy after a 7-day washout from previous antiparkinson medication. Psychopathology was rated weekly by the Brief Psychiatric Rating Scale and showed no significant changes during the trial. The Mindham Rating Scale was used to assess symptoms of parkinsonism; at week 3, ritanserin was superior to orphenadrine (p less than 0.03) and to placebo (p less than 0.01). The results confirm previous observations of the therapeutic efficacy of ritanserin on neuroleptic-induced parkinsonism, and support the hypothesis that serotonin influences extrapyramidal physiopathology.

The neurobiology of attention deficit/hyperactivity disorder

ADHD is a brain based disorder with structural and functional abnormalities in widespread but specific areas of the brain. The most significant and consistent structural imaging findings include smaller total brain volumes, and reduced volumes in the right frontal lobe, right parietal cortex, caudate nucleus, cerebellar hemispheres, and posterior-inferior lobules of the cerebellar vermis. ADHD involves hypofunction of catecholaminergic circuits, particularly those that project to the prefrontal cortex. A minimum of 18 genes have been reported to be associated with the disorder; among them the DRD4 7-repeat allele has been found associated with a thinner prefrontal and posterior parietal cortex. Epigenetic factors acting during critical periods of prenatal and postnatal development may interact with genetic determinants. Methylphenidate, as well as the catecholaminergic nonstimulant atomoxetine, are effective in improving ADHD symptoms.

Fluoxetine decreases concentrations of 3α,5α-tetrahydrodeoxycorticosterone (THDOC) in major depression

There is evidence for a differential alteration in the concentrations of 3α-reduced neuroactive steroids in major depression. Because it has been suggested that fluoxetine may shift the activity of the 3α-hydroxysteroid oxidoreductase towards the reductive direction, treatment of major depression may be accompanied by a further increase in plasma 3α,5α-tetrahydrodeoxycorticosterone (THDOC) concentration. We studied eight male depressed patients before and after treatment with fluoxetine and compared them to healthy age-matched control subjects. Blood samples were quantified for 3α,5α-tetrahydroprogesterone, 3α,5β-tetrahydroprogesterone (THP) and THDOC by means of a highly sensitive combined gas chromatography/mass spectrometry analysis. Compared to control subjects, concentrations of THDOC were higher in depressed patients and decreased after fluoxetine treatment. In contrast, THP concentrations were lower in depressed patients and increased after fluoxetine treatment. Our results give further evidence for a disequilibrium of 3α-reduced neuroactive steroids in major depression, which is normalized by treatment with fluoxetine.

Alexithymic features in stroke: Effects of laterality and gender

Objective Stroke patients suffer from a high rate of behavioral disorders, and the laterality of the lesion may affect the expression of emotional disturbances. This study tested the hypothesis that stroke patients with a lesion in the right hemisphere are at high risk of developing alexithymic features. Methods Forty-eight patients were interviewed with the Structured Clinical Interview for DSM-IV (patient edition), the Mini-Mental State Examination, the State-Trait Anxiety Inventory (state form), the Beck Depression Inventory, and the Toronto Alexithymia Scale (20-item version). Alexithymic differences between stroke patients with a lesion in the right hemisphere and those with a lesion in the left hemisphere were computed by analysis of covariance, using scores on the Mini-Mental State Examination, Beck Depression Inventory (psychic subscore), and State-Trait Anxiety Inventory as covariates and the score on the Toronto Alexithymia Scale as the dependent variable. A multivariate analysis of covariance and a series of follow-up analyses of covariance with the same covariates were used to discriminate differences in subscores on the Toronto Alexithymia Scale. An exploratory analysis of covariance was also performed to determine the effect of gender on alexithymic features in both groups of stroke patients. Results The 21 stroke patients with a lesion in the right hemisphere were more alexithymic than the 27 patients with a lesion in the left hemisphere. This evidence was strengthened by the categorical analysis: 48% of the patients with a right-hemisphere lesion had alexithymia, compared with 22% of patients with a left-hemisphere lesion. Univariate analyses of covariance showed significant differences between the two groups in difficulty identifying feelings and difficulty describing feelings, but not in externally oriented thinking. The last exploratory analysis of covariance suggested that gender may influence alexithymic features. Conclusions This study provides direct evidence that alexithymia, and more specifically difficulty identifying feelings and difficulty describing feelings, is more common in stroke patients with a right-hemisphere lesion than in those with a left-hemisphere lesion. It also provides preliminary evidence that gender may affect alexithymic expression.

Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptides localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding.

Increased neurosteroids synthesis after brain and spinal cord injury in rats

We studied the effect of brain and spinal cord injury induced by fluid-percussion on the local synthesis of neurosteroids as measured by a gas-chromatographic/mass-spectrometric method. In the nervous system of sham operated rats i.v. infusion of pregnenolone (PREGN)-sulfate results in a 2-4 fold increase in PREGN, progesterone (PROG), 5alpha-dehydroprogesterone (5alpha-DHP) and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha5alpha-THP, allopregnanolone) concentrations, as compared to vehicle treated rats. When PREGN-sulfate was infused 1, 3 or 7 days after brain or spinal cord injury it was observed a large time-dependent increase of PROG, 5alpha-DHP and 3alpha5alpha-THP levels in the peri-focal but not in the focal site. This increase in neurosteroids content may be due essentially to the glial cells hyperplasia in the peri-focal area and to an activation of the pathways involved in the metabolism of PREGN-sulfate to PROG, 5alpha-DHP and 3alpha5alpha-THP.

Reduced natural killer cell activity in major depression: neuroendocrine implications

Natural killer cell activity (NKCA) was significantly reduced in a group of depressed patients, melancholic subtype, compared to sex- and age-matched controls. Corticotropin and cortisol values were significantly higher in the depressed subjects than in the controls, but no correlation between high hormone levels and low immunological activity was found in the patients.