Hrdina PD, Bakish D, Chudzik J, Ravindran A, Lapierre YD. Serotonergic markers in platelets of patients with major depression. Upregulations of 5-HT2 receptors. J Psychiatry Neurosci 20: 11-19

Department of Psychiatry, University of Ottawa, Ontario, Canada.
Journal of psychiatry & neuroscience: JPN (Impact Factor: 5.86). 02/1995; 20(1):11-9.
Source: PubMed


The uptake of [3H]5-HT and the density (Bmax) as well as affinity (Kd) of 5-HT uptake sites labelled with [3H]paroxetine and of 5-HT2 receptors labelled by [3H]LSD were determined in platelets from 25 medication-free patients with major depression and 20 normal controls. The density (Bmax) of 5-HT2 receptors was found to be significantly increased (by 52%) in platelets from depressed patients, particularly females. No changes were found in the affinity (Kd) of 5-HT2 receptors and in 5-HT uptake or [3H]paroxetine binding parameters. Density of 5-HT2 receptors positively correlated with that of [3H]paroxetine sites in control but not in depressed subjects. No correlation was found between the HAMD scores and Bmax of [3H]LSD binding. The results suggest that upregulation of platelet 5-HT2 receptors is a useful biological marker in major depression, particularly in females.

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    • "Mean V max after the treatment was not different from baseline. This result is in agreement with the study of Hrdina et al. (1995, 1997). However, the great range of relative change of V max from pre-to post-treatment indicates a large interindividual variability. "
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    ABSTRACT: We investigated the kinetic parameters of serotonin (5-HT) uptake into platelets in a group of 26 drug-naïve patients suffering from major depression before and after 3-7 weeks of treatment with citalopram. The degree of depression was rated using the Hamilton Depression Rating Scale (HDRS). The 5-HT uptake characteristics in untreated depressive patients were not significantly different from those of normal subjects. The apparent Michaelis constant (K(M)) was significantly increased, the apparent maximal velocity (V(max)) was not different from baseline, and the uptake efficiency (V(max)/K(M)) was significantly decreased after citalopram treatment. A significantly positive correlation between K(M) and V(max) was found in all groups. There was a significantly lower V(max) and V(max)/K(M) in the female compared with the male depressed patients before citalopram treatment; a hypothesis was supported that lowered 5-HT uptake may reflect a gender-linked vulnerability to a serotonin-related depression. A significant negative correlation between 5-HT uptake efficiency and the initial HDRS score suggests that platelet 5-HT uptake can be used as a marker of effective depressive disorder pharmacotherapy. The initial severity of depression was significantly negatively correlated with V(max), which supported a hypothesis that the initial severity of depressive disorder could be related to the lower V(max).
    Psychiatry Research 10/2008; 161(2):185-94. DOI:10.1016/j.psychres.2007.06.022 · 2.47 Impact Factor
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    • "Postmortem studies of 5-HT 2A receptor binding have found an increase in 5-HT 2A receptor density in depressed individuals and in suicide victims (Arango et al 1990; Arora and Meltzer 1989b; Hrdina et al 1993; Mann et al 1986; Pandey et al 2002; Stanley and Mann 1983; Turecki et al 1999; Yates et al 1990), although others reported a decrease or no change (Cheetham et al 1988; Gross-Isseroff et al 1990; Rosel et al 1998, 2000). Similarly, several studies in human platelets have documented increased 5-HT 2A receptor density (Arora and Meltzer 1989a; Hrdina et al 1995, 1997; Pandey et al 1990; Sheline et al 1995), whereas others have found no change (Khait et al 2005; Mann et al 1992; McBride et al 1994; Rosel et al 1999). Genetic variation in the regulatory region of the 5-HT 2A receptor gene (HTR2A) may contribute to these discrepancies in 5-HT 2A receptor expression. "
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    ABSTRACT: Genomic variation in the regulatory region of the serotonin (5-HT) 2A receptor gene (HTR2A) may contribute to altered levels of 5-HT2A receptor and to psychiatric disease. Frequency and linkage disequilibrium (LD) were determined for promoter single nucleotide polymorphisms (SNPs) -1438A/G, -1420C/T, and -783A/G in 156 subjects. Functional relevance of -1438A/G and -783A/G was assayed in vitro using a luciferase reporter assay and ex vivo using quantitative real time polymerase chain reaction in a set of human fibroblast cell lines. Significant LD was observed between SNPs -1438A/G and -783A/G. In vitro assays showed no significant differences in promoter activity between the A- and G-allele of -1438 locus when expressed with the major alleles at -1420C/T and -783A/G; however, when the minor allele G at -783 was expressed with G-allele at -1438, promoter activity was significantly decreased. 5-HT2A receptor mRNA expression in human fibroblast cell lines confirmed that -783A/G polymorphism significantly modified the effects of -1438A/G SNP. Our results demonstrate that SNP -783A/G modifies the effects of the major SNP -1438A/G. Future studies examining the association of -1438A/G polymorphism with diseases and 5-HT2A receptor expression analyses should account for this epistasis.
    Biological Psychiatry 02/2007; 61(2):167-73. DOI:10.1016/j.biopsych.2005.12.018 · 10.26 Impact Factor
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    • "In these types of studies it is important to assess the functional phenotype as well as the genotype, although this is not frequently done. The human platelet has been used extensively as a model in psychiatry [Bylund et al., 1984; Shekim et al., 1984, 1990; Kanof et al., 1988; Hrdina et al., 1995; Sheline et al., 1995; Gurguis et al., 1999b,c] because changes in receptor characteristics of platelets can be used as an indirect marker of neurotransmitter receptor alterations in psychiatric disorders [Wirz-Justice, 1988]. In a study with 23 boys with ADHD and 11 age-matched controls, the ADHD boys tended to have a lower alpha-2 adrenergic receptor density suggesting that the characteristics of platelet alpha-2 adrenergic receptors may be different in ADHD patients as compared to controls [Shekim et al., 1994]. "
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    ABSTRACT: Neuropharmacological and genetic association studies have implicated norepinephrine and adrenergic receptors in the pathogenesis of ADHD. The purpose of this study was to compare genetic association studies of three polymorphisms of the alpha-2A adrenergic receptor gene (ADRA2A) with radioligand binding studies of the alpha-2A adrenergic receptor protein in platelets from a sample of children without or with ADHD. The pediatric subjects ranged from 6 to 18 years of age. A thorough clinical assessment of each child resulted in one of the following DSM-IV ADHD diagnoses: inattentive, hyperactive/impulsive, combined, or no ADHD. No significant linkage was found between the ADRA2A polymorphisms (MspI, HhaI, and DraI) and any of the phenotypes tested. Association analysis, however, did detect significant linkage disequilibrium for the DraI polymorphism. Association was also evaluated considering the three ADRA2A single nucleotide polymorphisms as haplotypes. The HhaI-DraI and the MspI-HhaI-DraI haplotypes were significantly associated with ADHD. The platelet alpha-2 adrenergic receptor density did not differ between children without or with ADHD. The affinity of the receptor for the radioligand however, differed significantly between those without and with ADHD. In addition, there were some significant correlations between binding parameters and severity of ADHD in this well-characterized clinical population, and significant association was found between these measures of receptor function and MspI and DraI polymorphisms. Thus, both the genetic and the binding studies indicate that the alpha-2 adrenergic receptor may play a role in ADHD.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2006; 141B(8):877-84. DOI:10.1002/ajmg.b.30371 · 3.42 Impact Factor
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