Antidepressant response and the serotonin transporter gene-linked polymorphic region

Background: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been proposed as a predictor of antidepressant response. Insertion or deletion of a 44bp long region gives rise to short 'S' and long 'L' forms of the promoter region, the 'S' form being associated with reduced serotonin transporter expression. Methods: A systematic review and meta-analysis was performed to clarify the effect of 5-HTTLPR on antidepressant response and remission rates. Data were obtained from 28 studies with 5408 participants. Three genotype comparisons were tested - SS versus (SL or LL), (SS or SL) versus LL, and SS versus LL. Results: There was no statistically significant effect on antidepressant response. Compared to L carriers, there was an apparent effect of the SS genotype on remission rate (RR 0.88; 95% CI 0.79 to 0.98; p=0.02). However, after trim and fill correction for missing data, the effect disappeared (RR 0.92; 95% CI 0.81 to 1.05; p=0.23) indicating that the initial significant effect was likely the result of publication bias. No significant effect on remission rate was seen for SS versus LL and SS/SL versus LL. Substantial unexplained heterogeneity of effect sizes was observed between studies, pointing to additional interacting factors contributing to an association in some cases. Conclusions: The 5-HTTLPR biallelic short/long polymorphism by itself does not appear to usefully predict antidepressant response

Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients

Studies using proton magnetic resonance spectroscopy (1H-MRS) indicate that unmedicated, acutely depressed patients have decreased levels of γ-aminobutyric acid (GABA) in the occipital cortex. The aim of this study was to use 1H-MRS to determine if changes in occipital and frontal cortical GABA levels were present in patients with a history of depression who had recovered and were no longer taking medication. We used 1H-MRS to measure levels of GABA in both occipital cortex and anterior cingulate cortex/prefrontal cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression. Levels of GABA in both occipital and anterior cingulate cortex were significantly lower in recovered depressed subjects than healthy controls. Our data provide preliminary evidence that a history of recurrent depression is associated with decreased GABA levels in anterior cingulate cortex and occipital cortex. These changes could represent part of the neurobiological vulnerability to recurrent depressive episodes

An HPA-1a-positive platelet-depleting agent for prevention of fetal and neonatal alloimmune thrombocytopenia: a randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study

Background: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT. Objectives: To investigate whether a single dose of anti–HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA1a–negative participants as compared with placebo. Methods: This randomized, single-blind, placebo–controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a– and HLA-A2– negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo. Results: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment–emergent adverse events were possibly related to treatment, both in RLYB211–treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks. Conclusion: These data support the hypothesis that anti–HPA-1a could be used as prophylaxis in women at risk of having an FNAIT–affected pregnancy

Serotonin, cortisol and vulnerability to depression

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Antidepressant response and the serotonin transporter gene-linked polymorphic region

Background: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been proposed as a predictor of antidepressant response. Insertion or deletion of a 44bp long region gives rise to short 'S' and long 'L' forms of the promoter region, the 'S' form being associated with reduced serotonin transporter expression. Methods: A systematic review and meta-analysis was performed to clarify the effect of 5-HTTLPR on antidepressant response and remission rates. Data were obtained from 28 studies with 5408 participants. Three genotype comparisons were tested - SS versus (SL or LL), (SS or SL) versus LL, and SS versus LL. Results: There was no statistically significant effect on antidepressant response. Compared to L carriers, there was an apparent effect of the SS genotype on remission rate (RR 0.88; 95% CI 0.79 to 0.98; p=0.02). However, after trim and fill correction for missing data, the effect disappeared (RR 0.92; 95% CI 0.81 to 1.05; p=0.23) indicating that the initial significant effect was likely the result of publication bias. No significant effect on remission rate was seen for SS versus LL and SS/SL versus LL. Substantial unexplained heterogeneity of effect sizes was observed between studies, pointing to additional interacting factors contributing to an association in some cases. Conclusions: The 5-HTTLPR biallelic short/long polymorphism by itself does not appear to usefully predict antidepressant response

Antidepressant response and the serotonin transporter gene-linked polymorphic region

Background: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been proposed as a predictor of antidepressant response. Insertion or deletion of a 44bp long region gives rise to short 'S' and long 'L' forms of the promoter region, the 'S' form being associated with reduced serotonin transporter expression. Methods: A systematic review and meta-analysis was performed to clarify the effect of 5-HTTLPR on antidepressant response and remission rates. Data were obtained from 28 studies with 5408 participants. Three genotype comparisons were tested - SS versus (SL or LL), (SS or SL) versus LL, and SS versus LL. Results: There was no statistically significant effect on antidepressant response. Compared to L carriers, there was an apparent effect of the SS genotype on remission rate (RR 0.88; 95% CI 0.79 to 0.98; p=0.02). However, after trim and fill correction for missing data, the effect disappeared (RR 0.92; 95% CI 0.81 to 1.05; p=0.23) indicating that the initial significant effect was likely the result of publication bias. No significant effect on remission rate was seen for SS versus LL and SS/SL versus LL. Substantial unexplained heterogeneity of effect sizes was observed between studies, pointing to additional interacting factors contributing to an association in some cases. Conclusions: The 5-HTTLPR biallelic short/long polymorphism by itself does not appear to usefully predict antidepressant response