Platelet Serotonin Level Predicts Survival in Amyotrophic Lateral Sclerosis

International audienceBACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown. METHODOLOGY: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects. PRINCIPAL FINDINGS: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. CONCLUSIONS/SIGNIFICANCE: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

BACKGROUND:Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain. METHODOLOGY/PRINCIPAL FINDINGS:Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition. CONCLUSIONS/SIGNIFICANCE:Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies

The lack of effect of ziprasidone on platelet serotonin concentration in schizophrenic patients

Rationale Ziprasidone is an atypical antipsychotic, with the unique multireceptor-binding profile. If affects multiple serotonergic (5-HT) receptors, inhibits 5-HT transporter (5-HTT) and inhibits synaptic 5-HT reuptake. These effects might be responsible for the antidepressant effect of ziprasidone. Objectives Since there is a lack of in vivo data on the effects of ziprasidone on 5-HT concentration in humans, the aim of the study was to investigate the effect of ziprasidone treatment on platelet 5-HT concentration in patients with schizophrenia or schizoaffective disorders. Methods In and open-label study, the effect of ziprasidone (average dose of 109 mg/day) on platelet 5-HT concentration (determined fluorimetrically) was evaluated at baseline and after 7 and 28 days of treatment in 21 male and female patients with schizophrenia or schizoaffective disorders. Results Ziprasidone treatment for 7 or 28 days did not significantly change baseline platelet 5-HT concentration in male and female schizophrenic patients. Platelet 5-HT concentration was not correlated with gender, age and smoking status of patients. Conclusions There was a lack of effect of ziprasidone treatment on platelet 5-HT concentration in male and female schizophrenic patients. Although the clinical effects of ziprasidone were evident after 28 days of treatment, and ziprasidone has the highest potency among atypical antipsychotics to block 5-HTT, our data did not confirm the hypothesis that ziprasidone treatment decreases platelet 5-HT concentration, at least not in the doses used in our study

Alzheimer's disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-?) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-? gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-? gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-? gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D