The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

<p>Abstract</p> <p>Background</p> <p>Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (<it>SLC6A4</it>) and the response of ADHD relevant behaviors with methylphenidate treatment.</p> <p>Methods</p> <p>Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the <it>SLC6A4 </it>gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.</p> <p>Results</p> <p>Mixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (<it>s+l_G= s'</it>) responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (<it>l_A</it>). No genotype main effects on either CGI-Parents or CGI-teachers were observed.</p> <p>Conclusions</p> <p>A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the <it>SLC6A4 </it>gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00483106</p

Negative feedback of secretion of follicle stimulating hormone by the pituitary gland of developing male rats

Rabbit antiserum to human seminal plasma inhibin (hSPI) was administered subcutaneously to developing male rats of 5, 10, 14, 17 and 24 days of age and the size of the endogenous FSH rise in serum was measured. The FSH levels were threefold higher on day 9 and 1.5-fold higher on days 14 and 18 when compared with levels in control rats treated with normal rabbit serum. Furthermore, the in-vitro binding capacity of pituitary plasma membrane to 125I-labelled hSPI declined with increase in age of the rats. Thus, the results of the present study suggest that the sensitivity of the testicular inhibin-FSH feedback relationship is related to age-dependent changes in pituitary binding of inhibin

Metabolic clearance rate of inhibin in mature and immature male rats

The half-life and metabolic clearance rate of human seminal plasma inhibin after injection into male rats was studied. Labeled inhibin was injected i.v. into 27-day-old rats (10 ng, 3.5 × 105 cpm) and 75-day-old rats (15 ng, 5.5 × 105 cpm). In both age groups, rats were killed at intervals between 1-5 and 480 min later, and samples of blood and tissues were taken for radioimmunoassay. [125I]-hSPI disappeared from blood plasma in a multiexponential fashion. The first exponential curve, which represents the actual half-life of hSPI, was 2.34 min in adult rats and 90 min in 27-day-old rats. The slower component of each curve had values of 231 and 365 min, respectively. The initial distribution volume was 13.6 ml and 4.13 ml for the adult and immature animals. The metabolic clearance rate of inhibin in adult rats was 0.12 ml/min and 0.019 ml/min in immature rats. In both groups, only the pituitary and the pineal gland showed specific uptake of inhibin. The pituitary and the pineal uptake (tissue/plasma) was maximal at 120 min (3.9 and 3.4) in immature rats, while in adults pituitary uptake was maximal (1.55) at 10 min and the pineal gland showed uptake (2.4) only at 8 min. In vitro binding of labeled inhibin to the pituitary plasma membrane supported the above observations. We conclude that the metabolic clearance rate of inhibin was fasten in adult rats, whereas specific uptake of [125I]-hSPI was greater in the pituitary and pineal glands of immature rats

Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2) in ADHD: relation to maternal smoking during pregnancy.

Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.Children (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003).By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106

Symptom Persistence and Memory Performance in Posttraumatic Stress Disorder: A Gene X Environment Pilot Study

The FKBP5 gene, a glucocorticoid receptor (GR)-regulating co-chaperone of stress proteins, is of special interest because of its role in hypothalamic-pituitary-adrenal (HPA)-axis regulation. However, studies finding a genetic relationship between posttraumatic stress disorder (PTSD) and the FKBP5 gene have failed to distinguish between the development and persistence of PTSD, thereby limiting the prognostic usefulness of such a finding. The present study sought to longitudinally explore this question by examining the association between four single-nucleotide polymorphisms (SNPs) in the FKBP5 gene (rs3800373, rs9470080, rs1360780, and rs9296158), the persistence of PTSD (severity and diagnostic status), and memory performance among twenty-two treatment-seekers diagnosed with acute PTSD. Results showed that the four SNPs significantly interacted with improvement in PTSD symptoms as well as PTSD diagnostic status. Individuals homozygous for the dominant allele and having experienced higher levels of peritraumatic responses subsequently showed more memory dysfunction. The results of this study suggest that SNPs in the FKBP5 gene are associated with symptom persistence and memory dysfunction in acute PTSD

Association between <i>SLC6A2</i> SNPs and ADHD cognitive dimensions in the total sample.

<p>WISC = Wechsler Intelligence Scale, SOPT = Self-Ordered Pointing Task, FW = Finger Windows, CPT = Continuous Performance Test, SE = standard error, RT = reaction time, ISI = inter-stimulus interval, WCST = Wisconsin Card Sorting Test, TOL = Tower of London.</p><p>Standard scores were used for all WCST and TOL measures, and T-scores were used for CPT measures (excl. overall index).</p><p>Three major haplotype blocks in <i>SLC6A2</i> are depicted above: Block 1 (rs1362621, rs2397771, rs168924, rs2242446, rs3785143, rs192303, rs41154); Block 2 (rs36017, rs10521329, rs3785155, rs5564, rs11568324, rs2279805, rs8047672, rs5569, rs998424, rs36009); and Block 3 (rs1800887, rs2242447, rs15534).</p><p>Significance (p) value ranges are depicted as follows: For OVER-TRANSMISSION of alleles = <b>+4</b> (≤0.00001), <b>+3</b> (0.0001–0.0009), <b>+2</b> (0.001–0.009), and <b>+1</b> (0.01–0.049).</p><p>For UNDER-TRANSMISSION of alleles = −<b>4</b> (≤0.00001), −<b>3</b> (0.0001–0.0009), −<b>2</b> (0.001–0.009) and −<b>1</b> (0.01–0.049).</p

Linkage disequilibrium between <i>SLC6A2</i> markers.

<p>Five SNPs towards the 5′end of <i>SLC6A2</i> (rs41154, rs187714, rs4783899, rs2397771, rs192303) are in strong linkage disequilibrium (LD) with rs36021. LD = linkage disequilibrium</p

Association between <i>SLC6A2</i> SNPs and ADHD cognitive dimensions in the sample where mothers did not smoke during pregnancy.

<p>WISC = Wechsler Intelligence Scale, SOPT = Self-Ordered Pointing Task, FW = Finger Windows, CPT = Continuous Performance Test, SE = standard error, RT = reaction time, ISI = inter-stimulus interval, WCST = Wisconsin Card Sorting Test, TOL = Tower of London.</p><p>Standard scores were used for all WCST and TOL measures, and T-scores were used for CPT measures (excl. overall index).</p><p>Three major haplotype blocks in <i>SLC6A2</i> are depicted above: Block 1 (rs1362621, rs2397771, rs168924, rs2242446, rs3785143, rs192303, rs41154); Block 2 (rs36017, rs10521329, rs3785155, rs5564, rs11568324, rs2279805, rs8047672, rs5569, rs998424, rs36009); and Block 3 (rs1800887, rs2242447, rs15534).</p><p>Significance (p) value ranges are depicted as follows: For OVER-TRANSMISSION of alleles = <b>+4</b> (≤0.00001), <b>+3</b> (0.0001–0.0009), <b>+2</b> (0.001–0.009), and <b>+1</b> (0.01–0.049).</p><p>For UNDER-TRANSMISSION of alleles = −<b>4</b> (≤0.00001), −<b>3</b> (0.0001–0.0009), −<b>2</b> (0.001–0.009) and −<b>1</b> (0.01–0.049).</p

Association between <i>SLC6A2</i> SNPs and ADHD behavioural dimensions in the group where mothers smoked during pregnancy (MSDP).

<p>ADHD = Attention-Deficit/Hyperactivity Disorder, DISC = Diagnostic Interview Schedule for Children, ODD = Oppositional Defiant Disorder, CD = Conduct Disorder, CBCL = Child Behaviour Checklist, Conners’ P = Conners’ Parents, Conners’ T = Conners’ Teachers, RI = Restless-Impulsive, EL = Emotional Lability.</p><p>Three major haplotype blocks in <i>SLC6A2</i> are depicted above: Block 1 (rs1362621, rs2397771, rs168924, rs2242446, rs3785143, rs192303, rs41154); Block 2 (rs36017, rs10521329, rs3785155, rs5564, rs11568324, rs2279805, rs8047672, rs5569, rs998424, rs36009); and Block 3 (rs1800887, rs2242447, rs15534).</p><p>Significance (p) value ranges are depicted as follows: For OVER-TRANSMISSION of alleles = <b>+4</b> (≤0.00001), <b>+3</b> (0.0001–0.0009), <b>+2</b> (0.001–0.009), and <b>+1</b> (0.01–0.049).</p><p>For UNDER-TRANSMISSION of alleles = −<b>4</b> (≤0.00001), −<b>3</b> (0.0001–0.0009), −<b>2</b> (0.001–0.009) and −<b>1</b> (0.01–0.049).</p