Serotonin transporter gene promoter region polymorphism associated with poststroke major depression

The authors examined variations of serotonin transporter-linked promoter region (5-HTTLPR) functional polymorphism in 26 stroke patients with major depression and in 25 unrelated nondepressed stroke subjects of Caucasian descent. Findings indicate a significant association between 5-HTTLPR short variant genotype and poststroke major depression.     

Reduced whole blood serotonin in major depression

Whole blood serotonin (WBS) was measured in 17 patients with DSM-III-R major depression and compared to a healthy control group of 57. Values were significantly lower in the depressed group, but there was no correlation with the degree of depression. Four patients with a history of suicide attempts had even lower levels, but this was not statistically significant. Across all subjects, there was an effect of season of sampling, with values in spring significantly higher than those in autumn. Since blood serotonin is primarily produced peripherally, these results suggest that some aspect of peripheral serotonin metabolism is abnormal in major depression. Depression and Anxiety 5:108–111, 1997. © 1997 Wiley-Liss, Inc.     

Cytokines and serotonin transporter in patients with major depression

Altered cytokine secretion as a mechanism in the etiology of depression is still obscure. The serotonin transporter (5-HTT) may play an important role in the termination of serotonergic neurotransmission by serotonin (5-HT) uptaking into presynaptic neurons and representing as an initial action site for selective 5-HTT reuptake inhibitors (SSRI). In our study, we evaluated whether cytokines and 5-HTT acted as biological markers for depression. Blood samples were collected from 42 participants. The differences in cytokine and 5-HTT mRNA expressions of leukocytes were assessed between the patients with major depression (n=20) and the healthy controls (n=22), along with the measurements prior and after treatment with a SSRI, fluoxetine, for 3 months in the follow-up patient group (n=8). The results revealed that the mRNA expressions of IL-1beta, IL-6, IFNgamma, TNFalpha, and 5-HTT were higher in the depressed patients than those of the healthy controls. The higher level of mRNA expressions of IFNgamma and 5-HTT diminished after fluoxetine treatment. Furthermore, we found a positive correlation between 5-HTT and cytokines mRNA expressions in total participants, which suggested that pro-inflammatory cytokines and 5-HTT might play critical roles in the pathogenesis of major depression and that their levels were affected by chronic treatment with 5-HTT inhibitors.     

Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression

CONTEXT: Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity, which is believed to be altered in patients with major depression. OBJECTIVE: To examine the effect of the BDNF Val66Met polymorphism on hippocampal and amygdala volumes in patients with major depression and in healthy control subjects. DESIGN: Cross-sectional comparison between patients and controls. SETTING: Inpatients with major depression from the Department of Psychiatry and Psychotherapy and healthy controls from the community were recruited. PARTICIPANTS: The study population of 120 subjects included 60 patients with major depression and 60 healthy controls. MAIN OUTCOME MEASURES: Using a combined strategy, hippocampal and amygdala volumes were estimated on high-resolution magnetic resonance images, and genotyping was performed for the BDNF Val66Met polymorphism. RESULTS: Patients had significantly smaller hippocampal volumes compared with controls (P = .02). Significantly smaller hippocampal volumes were observed for patients and for controls carrying the Met-BDNF allele compared with subjects homozygous for the Val-BDNF allele (P = .006). With respect to amygdala volumes, no significant differences between patients and controls and no significant main effects for the BDNF Val66Met polymorphism were observed. CONCLUSIONS: These genotype-related alterations suggest that Met-BDNF allele carriers might be at risk to develop smaller hippocampal volumes and may be susceptible to major depression. This study supports findings from animal studies that the hippocampus is involved in brain development and plasticity.     

Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression.

The monoamine neurotransmitters serotonin, norepinephrine and dopamine have been implicated in the pathogenesis of depression, schizophrenia and mood disorders. The mechanism of action of certain antidepressant drugs, particularly the tricyclics and the newly available norepinephrine and serotonin reuptake inhibitors (NSRIs) drugs, venlafaxine and nefazodone, suggest that the norepinephrine transporter, which is a target for these antidepressant drugs, and its malfunction may be involved in major depression. In this association study, we tested the hypothesis that variants of the human norepinephrine transporter (NET) gene confer susceptibility to major depression. One hundred and five patients with major depression and 74 unrelated matched controls were analyzed for a silent 1287G/A polymorphism (NET-8) in exon 9 of the NET gene. No significant differences in genotype or allele frequencies were found between controls and patients, nor between subgroups of depressed patients classified by suicidal ideation. In addition, 60 controls and 60 patients were genotyped for a missense substitution Thr99Ile in exon 2 of the NET gene (NET-1), but only one control was heterozygous for this variant. These results suggest that the NET gene is unlikely to be involved in the susceptibility to major depression.     

Reduced hippocampal volume correlates with executive dysfunctioning in major depression

OBJECTIVE: Dysfunction of neuronal plasticity or remodelling seems to contribute to the pathopysiology of major depression and may cause the well-documented hippocampal changes in depression. We aimed to investigate whether reduced hippocampal volumes correlate with executive dysfunctioning or memory dysfunctioning or with depression severity. METHODS: We recruited 34 inpatients with a previous or current episode of major depression from the department of psychiatry at the Ludwig-Maximilians University of Munich, Germany. We examined the 34 patients and 34 healthy control subjects with structural high resolution MRI. We assessed cognitive functions with the Wisconsin Card Sorting Test (WCST) and the Rey Auditory Verbal Learning Test (RAVLT) and severity of depression with the Hamilton Depression Rating Scale. RESULTS: Hippocampal volumes and frontal lobe volumes were significantly smaller in patients, compared with healthy control subjects. Furthermore, lower hippocampal volumes were correlated with poorer performance in the WCST. No significant correlations were found between hippocampal volumes and RAVLT performance or severity of depression. CONCLUSIONS: The present findings emphasize that patients with reduced hippocampal volumes show more executive dysfunctions than their counterparts. Thus, the mechanisms resulting in reduced hippocampal volumes seem to be related to the development of major depression.     

5-羟色胺基因多态性与抑郁症的相关性研究

目的：探讨5-羟色胺转运体(5-HTT)基因启动子区多态性(5-HTTLPR)与抑郁症的相关性及其对抗抑郁药疗效的影响。方法：运用聚合酶链反应技术(PCR)检测51例抑郁症患者(患者组)和60名健康对照者(对照组)5-HTTLPR的分布频率；并予文拉法辛治疗，用汉密尔顿抑郁量表(HAMD)观察疗效。结果：患者组5-HTTLPR的短重复序列／短重复序列(short／short，S／S)基因型和短重复序列(short，S)等位基因频率分别为71％和81％，对照组为45％和69％差异显著。治疗4周后，长重复序列／长重复序列(long／long，L／L)基因型患者的减分率显著高于其他两型。结论：5-HTTLPR的S／S基因型可能是抑郁症的易感基因之一，L／L基因型可能和更好的选择性5-羟色胺受体阻滞剂类(SSRIs)疗效有关。     

The serotonin transporter in the midbrain of suicide victims with major depression.

BACKGROUND: The involvement of serotonin in depression and suicide has been proposed, because major depression is successfully treated by medications that specifically block the serotonin transporter, and there is evidence for a decrease in serotonin transporters in major depression and suicide. The midbrain dorsal raphe nucleus (DR) has been implicated as a site for diminished serotonergic activity in that suicide victims with major depression have a significant increase in serotonin-1A autoreceptors in the DR. METHODS: [(3)H]Paroxetine was used to label the serotonin transporter in the subnuclei of the DR at several rostral-to-caudal levels of the midbrain in ten pairs of suicide victims with major depression and age-matched psychiatrically normal control subjects. RESULTS: There was a significant increase in serotonin transporters in the entire DR progressing from rostral-to-caudal levels in both normal control subjects and suicide victims with major depression. At comparable rostral-to-caudal levels, there were no significant differences in [(3)H]paroxetine binding between depressed suicide victims and normal control subjects in either the entire DR or its constituent subnuclei. CONCLUSIONS: The pathophysiology of serotonin mechanisms in suicide victims with major depression does not appear to involve alterations in the binding of [(3)H]paroxetine to the serotonin transporter in the midbrain DR.     

Subregion‐specific decreases in hippocampal serotonin transporter protein expression and function associated with endophenotypes of depression

Stress influences the development of depression, and depression is associated with structural and functional changes in the hippocampus. The current study sought to determine whether chronic corticosteroid (CORT) treatment influences serotonin transporter (5‐HTT) protein expression and function in the CA1, CA3, and dentate gyrus (DG) subregions of the hippocampus. Male CD‐1 mice were subcutaneously injected with CORT at a dose of 20 mg/kg once daily for 3 weeks. Behavioral state was assessed using sucrose preference, physical state of the coat, forced swimming test, and tail suspension test. We then determine 5‐HTT protein expression and synaptosomal 5‐HT uptake in the CA1, CA3 and DG subregions. CORT treatment induced anhedonia and behavioral despair, two core endophenotypes of clinical depression; 5‐HTT protein expression levels and synaptosomal 5‐HT uptake were both decreased in a subregion‐specific manner, with the greatest decrease observed in the DG, a moderate decrease in the CA3, and the CA1 showed no apparent change. In addition, a reduction in tissue mass was detected in the DG following the CORT treatment. These data indicate that subregion‐specific decreases in hippocampal 5‐HTT protein expression and function are associated with endophenotypes of depression. © 2014 Wiley Periodicals, Inc.     

Alterations in platelet serotonin transporter binding in women with postpartum onset major depression

There is considerable debate as to whether postpartum depression (PPD) is biologically distinct from other depressive syndromes. Although abnormalities in serotonergic neural systems have repeatedly been reported in depression, few such studies have been conducted in PPD. In the present study, platelet serotonin transporter (SERT) binding was assessed using [(3)H]paroxetine in 14 depressed pregnant women, 31 normal healthy pregnant women, 39 depressed postpartum women, and 27 normal healthy postpartum women; all of the subjects were drug-free. Significant differences were detected among the 4 groups with respect to the dissociation constant (Kd) of platelet binding sites for [(3)H]paroxetine with the highest Kd values among those with PPD. The density (Bmax) of platelet binding sites for [(3)H]paroxetine did not differ between the study groups. These data suggest that PPD may be associated with unique alterations in serotonergic function that are specific to the puerperium.     

No Influence of a functional polymorphism within the serotonin transporter gene on partial sleep deprivation in major depression.

Sleep deprivation exerts transient antidepressant efficacy. As a potential mechanism of action an enhancement of serotonergic and dopaminergic neurotransmission within the CNS is discussed. Because genetic variations influencing neurotransmission could have an impact on therapeutic outcome and stability of improvement, we investigated the functional polymorphism of the serotonin transporter (5-HTT) gene, the 5-HTT-linked polymorphic region (5-HTTLPR), to examine the serotonergic pathway. We included 56 patients with major depression (DSM-IV). Psychiatric ratings including the HAM-D21 and HAM-D6 scale were assessed on the day prior to partial sleep deprivation (PSD) and on day 1 and 2 after PSD and related to the different genotypes. The 5-HTTLPR variants were determined following PCR amplification using genomic DNA. 58.1% of the patients were responders to PSD. A significant overall reduction in depression scores could be observed on day 1. Subdivision according 5-HTTLPR gene variants showed no differences in clinical outcome on day 1. As expected the therapeutical effect of PSD was only transient and most patients experienced an exacerbation of depressive symptoms on day 2. 5-HTTLPR variants had no influence on reduction of depressive symptoms on day 2 or relapse on day 3. Thus, the previously reported influence of the serotonin transporter gene on PSD outcome in bipolar depression could not be confirmed in unipolar depressed patients.     

Sex differences in diencephalon serotonin transporter availability in major depression.

BACKGROUND: Major depression is more prevalent in women than men. The present study evaluated if previous findings that demonstrated decreased 5-hydroxytryptamine (5-HT) transporter availability in depressed patients would be confirmed in a larger sample and also evaluated sex differences. METHODS: Depressed (n = 32) and healthy subjects (n = 32), including 16 pairs of women and men, participated in an iodine-123-2 beta-carbomethoxy-3beta-(4-iodophenyltropane) ([(123)I]beta-CIT) single photon emission computed tomography (SPECT) and a magnetic resonance imaging (MRI) scan. Participants were administered [(123)I]beta-CIT (225.7 +/- 3.7 MBq) and imaged 23.0 +/- 1.6 hours later. Statistical analyses included analysis of variance and a regression analysis of the main and interactive effects of age, sex, and depression. RESULTS: Overall, depressed patients demonstrated 12% lower diencephalon and no change in striatal or brainstem [(123)I]beta-CIT uptake. Significant age by sex, sex by depression, and age by sex by depression interactions were noted due to 22% lower diencephalon [(123)I]beta-CIT uptake in depressed women compared with less than a 1% decrease in depressed men. CONCLUSIONS: As observed previously, diencephalon 5-HT transporter availability is decreased in depressed patients. However, the decrease appears to be sex-specific and age-dependent. These findings suggest that serotonergic mechanisms mediating depressed mood differ between men and women in an age-dependent manner and may explain why young women respond better to treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants.     

A functional serotonin transporter gene polymorphism is associated with migraine with aura

An association study was performed in 197 migraineurs with regard to a functional serotonin (5-HT) transporter (5-HTT) gene promoter polymorphism that leads to low or high 5-HT uptake activity. The frequency of the less active short allele was increased in migraineurs with aura but not in migraineurs without aura in comparison with the control population (p < 0.001). This indicates that the 5-HTT may be involved in the polygenic etiology of migraine with aura.     

Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression

BACKGROUND: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.