Normalisation of immune cell imbalance after pharmacological treatments of patients suffering from obsessive-compulsive disorder.

Recent data have shown the presence of immunological alterations in adult patients suffering from obsessive-compulsive disorder (OCD). The objective of this study was to examine the possible effects of 12 months of treatment with different serotonergic drugs, such as clomipramine and selective serotonin reuptake inhibitors (SSRIs) on peripheral immunological cells of 18 OCD patients. Both the absolute number and percent of CD4+, CD8+, CD3+, CD19+ and CD56+ cells were measured in peripheral blood before and after treatment by means of a Facstar Flow Sorter apparatus. At baseline, all patients showed a significant increase of CD8+ and decrease of CD4+ lymphocytes when compared with a similar group of healthy control subjects; after the treatment, CD8+ and CD4+ cells, respectively, decreased and increased significantly, and the CD4+/CD8+ ratio increased, when compared with baseline values, in parallel with the clinical improvement. These data suggest that the alterations of immune cells reported in patients with OCD at baseline may be reverted by treatment with SRIs and should be considered a state-dependent marker, perhaps related to a condition of stress.

Gender moderates the relationship between mania spectrum and serotonin transporter polymorphisms in depression.

The short (s) variant of the serotonin transporter gene linked functional polymorphic region (5-HTTLPR) is associated with depression. Stressful life events, gender, and race have been shown to moderate this association. Because features of mania/hypomania seem to constitute an indicator of higher severity of depression, we examined the relationship between 5-HTTLPR genotype and symptoms of mania-hypomania spectrum occurring over the lifetime in patients with major depression. The possible moderating role of gender in this relationship was taken into account. Two hundred twenty-two patients with unipolar major depression were genotyped for 5-HTTLPR and nine other representative polymorphisms, and were administered the Mood Spectrum Questionnaire, Lifetime Version (MOODS-SR). The manic-hypomanic (MH) component score was used for analysis. Using a linear model of the MH score as a function of genotypes and gender, controlling for age, severity of depression, and site, we found significant effects of gender (F = 8.003, df = 1, P = 0.005), of the interaction gender x genotype (F = 4.505, df = 2, P = 0.012), and of the baseline Hamilton score (F = 5.404, df = 1, P = 0.021), non-significant effects of genotype (F = 1.298, df = 2, P = 0.275), age (F = 0.310, df = 1, P = 0.578) site (F = 0.504, df = 1, P = 0.479). Significant associations were also detected at three other SNPs. The association between the manic/hypomanic component of the MOODS-SR and the polymorphisms of the 5-HTTLPR is moderated by gender. This finding is intriguing from a clinical point of view because women with unipolar disorder and the "ss" genotype seem to constitute a sub-group with higher severity of depression. These results should be considered tentative pending replication in other samples.

Regulation of the platelet serotonin transporter by protein kinase C in the young and elderly.

BACKGROUND: Some data show that different factors may influence the serotonin (5-HT) uptake rate. Our study aimed at evaluating the possible role of a protein kinase C (PKC) activator, i.e., 4-beta-12-tetradecanoylphorbol-13-acetate (beta-TPA) on the platelet 5-HT uptake of young and elderly subjects, through the measurement of the 5-HT uptake itself and 3H-paroxetine ([3H]PAR) binding sites, which correspond to the transporter protein. METHODS: Human platelets and 5-HT uptake were evaluated according to the method of Arora and Meltzer, while [3H]PAR binding was performed following the Marazziti et al method. RESULTS: The results showed that beta-TPA reduced significantly the maximal velocity (Vmax) of 5-HT uptake, with no change in the Michaelis constant or in [3H]PAR binding parameters, in platelets of both young and elderly subjects. Although this last group of subjects had a significantly lower Vmax than the other, the degree of inhibition was almost the same (75%) in both. CONCLUSIONS: These findings indicate that PKC decreases the 5-HT uptake rate by modifying the phosphorylation state of the transporter and with no change in the number of [3H]PAR binding sites. The responsiveness of this pathway is identical in both young and elderly subjects.

Decreased platelet [3H]paroxetine binding sites in suicide attempters.

Research to date would suggest the possible involvement of the serotonin (5-HT) system in the pathophysiology of suicide. With this study, we aimed to investigate the platelet 5-HT transporter, by means of the specific binding of tritiated paroxetine ([3H]Par), in a sample of 20 suicide attempters recruited at a first-aid service, as compared with healthy control subjects and psychiatric patients with no current or previous history of suicide attempt. The results, showing a decreased number of [3H]Par binding sites in suicide attempters, would suggest the involvement of the presynaptic 5-HT transporter in self-aggressive behavior.

Platelet [3H]paroxetine binding in patients with OCD-related disorders.

The recently introduced notion of clinical conditions being related one to another, the spectrum concept, permits the testing of the involvement of serotonergic systems in a broad range of disorders tentatively linked to obsessive-compulsive disorder (OCD) for which no pathophysiological hypotheses yet exist. We therefore compared the binding of [3H]paroxetine ([3H]Par), a ligand that specifically labels the serotonin (5-HT) transporter, in platelets of drug-free outpatients suffering from various OCD-related disorders with binding in platelets of OCD patients and healthy subjects. Diagnoses were made according to DSM-IV criteria. The most frequent diagnosis was that of body dysmorphic disorder, followed by impulse control disorder, kleptomania, Tourette's syndrome and trichotillomania. Platelet membranes and [3H]Par binding were studied according to standardized protocols. The results, showing a similarly decreased density of [3H]Par binding sites in both patient groups as compared with healthy subjects, suggest the presence of a shared abnormality at the level of the presynaptic 5-HT transporter, probably linked to a common dimension yet to be identified.

Adenylate-cyclase activity in platelets of patients with obsessive-compulsive disorder.

Although the main biological hypothesis on the pathophysiology of obsessive-compulsive disorder (OCD) is centered on the serotonin system, indications are available that other neurotransmitters, and even second messengers, particularly the cyclic adenosine monophosphate (cAMP) signaling, may be involved, though effective data are few. Therefore, the aim of the present study was to evaluate and compare the basal and isoprenaline (ISO)-stimulated velocity of adenylate-cyclase (AC) in human platelet membranes of patients with OCD and healthy control subjects. The results showed that the basal and ISO-stimulated AC activity, as well as the dose-response curves of ISO by using agonist concentrations ranging between 0.1 nM and 10 muM, were not different in the two groups. However, OCD patients showed lower EC(50) and higher E(max) values than healthy subjects. These findings suggest the presence of supersensitive beta-adrenergic receptors in platelets of OCD patients.

Distribution of [3H]GR65630 binding in human brain postmortem.

We investigated the distribution of serotonin (5-HT) receptors of type 3 (5-HT3) in human brain areas, by means of the the specific binding of [3H]GR65630. The brains were obtained during autoptic sessions from 6 subjects. Human brain membranes and the binding of [3H]GR65630 were carried out according to standardized methods. The highest density (Bmax +/- SD, fmol/mg protein) of [3H]GR65630 binding sites was found in area postrema (13.1+/-9.7), followed at a statistically lower level, by nucleus tractus solitarius (6.7+/-3.4), nervus vagus (5.5+/-2.1), striatum (4.8+/-2.4) with a progressive decrease in amygdala, olivar nuclei, hippocampus, olfactory bulbus and prefrontal cortex, and then by the other cortical areas and the cerebellum, where no binding was detected. These observations extend previous findings on the distribution of 5-HT3 receptors and confirm interspecies variations that might explain the heterogeneous properties of 5-HT3 receptors in different animals.

Pharmacological characterization of the serotonin transporter in young and elderly subjects.

The potency of some tricyclics (imipramine and clomipramine) and selective 5-HT reuptake inhibitors (fluoxetine, paroxetine, and citalopram) in displacing the [(3)H]paroxetine binding to platelet membranes was measured in young and elderly subjects of both sexes. The results showed that the most potent compound in all subjects was paroxetine, followed by clomipramine, citalopram, fluoxetine, and imipramine, with no differences between male and female subjects. All drugs, except paroxetine and clomipramine, showed significantly lower pKi values in the elderly subjects of both sexes. These findings would suggest that although the pharmacological profile of the 5-HT transporter is not modified qualitatively by age, quantitative changes in its affinity do perhaps occur which would justify more careful studies on this topic in order to get optimal dosages of drugs acting at this level.

Correlation between platelet alpha(2)-adrenoreceptors and symptom severity in major depression.

BACKGROUND: Abnormalities in different parameters of the norepinephrine system have been widely described in major depression. The presence of alpha(2)-adrenoreceptors in blood platelets, similar to those in the brain, prompted us to evaluate them in depressed patients, as compared with healthy controls. METHODS: Fifteen outpatients affected by major depression, according to DSM IV criteria, and 15 comparable healthy control subjects, were included in the study. The alpha(2)-adrenoreceptors were measured by means of the specific binding of [(3)H]rauwolscine, a highly selective antagonist for this receptor subtype. The severity of depression was assessed by means of the Hamilton Rating Scale for Depression (HRSD). RESULTS: The results did not show any difference in [(3)H]rauwolscine binding parameters (B(max) and K(d)) between patients and controls. However, in the patients, a significant and positive correlation between B(max), which measures the density of the receptors, and HRSD total score was detected. CONCLUSIONS: Therefore, although no change in alpha(2)-adrenoreceptors seems to occur in major depression, the density of these receptors would seem to be related to the severity of depressive symptoms.

Increased density of the platelet serotonin transporter in autism.

BACKGROUND: Various data have shown the involvement of serotonin (5-HT) in autism. The presence of the 5-HT transporter in platelets, similar to the same structure located in presynaptic serotonergic neurons, has produced a series of studies aimed at assessing its functionality in this disorder, but the ensuing findings are quite controversial. For this reason, we investigated the 5-HT transporter by means of the specific binding of [3H]-Paroxetine ([3H]-Par), which is currently considered the first-choice ligand for labeling it, in platelets of 20 autistic children and adolescents, as compared with healthy control subjects. METHODS: Twenty children and adolescents of both sexes suffering from autism according to DSM IV criteria were included in the study and compared with a similar group of healthy control subjects. Platelet membranes and the binding of [3H]-Par were carried out according to standardized protocols. RESULTS: The results showed a significantly higher density of [3H]-Par binding sites in autistic children than in healthy control subjects. CONCLUSIONS: These findings support the presence of a serotonergic dysfunction in autism and would suggest that the 5-HT transporter may have a specific role in this disorder, also in the light of its recently proposed role in brain development.

Increased inhibitory activity of protein kinase C on the serotonin transporter in OCD.

Different observations show a reduced functionality of the serotonin (5-HT) transporter in obsessive-compulsive disorder (OCD) that might be due to a disturbance of its regulation at intracellular level. Protein kinase C (PKC) has been reported to provoke a decrease in the number of the 5-HT transporter proteins. Therefore, we investigated whether OCD patients differed from control subjects in the effect of PKC upon the 5-HT transporter, after stimulation of this enzyme with 4beta-12-tetradecanoylphorbol 13-acetate (beta-TPA). Fifteen patients affected by OCD, according to DSM-IV criteria, were compared with a similar group of healthy subjects. The determination of 5-HT uptake was carried out according to the method of Arora and Meltzer with slight modifications. At baseline, OCD patients showed a significant decrease in the maximal velocity (V(max)) of 5-HT uptake, as compared with control subjects, with no change in the Michaelis-Menten constant (K(m)). The activation of PKC with beta-TPA provoked a significant decrease in V(max) values in both groups, but the effect was significantly more robust in OCD patients who, in turn, also showed also an increase in K(m) values. These findings could indicate the presence of hyperactivity of PKC in OCD that could be the result of increased activity of the phosphatidylinositol pathway. In addition, this suggests new potential therapeutic targets in OCD.