Serotonin transporter binding sites and mRNA levels in depressed persons committing suicide

doi:10.1016/S0006-3223(96)00301-0

Biological Psychiatry

Volume 41, Issue 12, 15 June 1997, Pages 1156-1164

https://doi.org/10.1016/S0006-3223(96)00301-0 Get rights and content

The serotonin transporter (5-HTT) has been found altered in postmortem brain samples from persons committing suicide, but the results of radioligand binding studies have been inconsistent. In the present series of experiments, autoradiographic radioligand binding and in situ hybridization techniques were utilized to examine 5-HTT function in the brains of 8 depressed subjects who had committed suicide, and matched controls. It was hypothesized that depressed subjects would demonstrate decreased numbers of 5-HTT binding sites and mRNA; however, [¹²⁵I]RTI-55 binding to the 5-HTT was not different in the midbrain, hippocampus, or frontal cortex of depressed subjects. Also, 5-HTT mRNA levels in dorsal and median raphe nuclei were not different between controls and depressed subjects. The current results, although limited in scope because of the small number of subjects included, offer no evidence that alterations in the 5-HTT occur in pertinent brain regions of depressed individuals.

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It is widely accepted that an overall downregulation of the 5-HT1A system is characteristic for depression (Yohn et al., 2017), without an influence of suicide (López et al., 1998). Where the concentrations of 5-HT and its turnover and transporter were not altered by suicidality (Anisman et al., 2008; Cheetham et al., 1989; Little et al., 1997), its main metabolite, i.e. 5-hydroxyindoleacetic acid, was increased in the HC of depressed patients who died by suicide (Cheetham et al., 1989; Owen et al., 1986). Also, 5-HT2AR is abundant in the HC of patients who completed suicide.
Suicide is a major global hazard. There is a need for increasing suicide awareness and effective and evidence-based interventions, targeting both suicidal ideation and conduct. However, anti-suicide pharmacological effects are unsatisfactory. The human hippocampus is vulnerable to neuropsychiatric damages and subsequently releases psychobiological signals. Human hippocampal studies of suicide completers have shown mechanistic changes in neurobiology, which, however, could not reflect the neuropathological ‘fingerprints’ of fatal suicide ideations and suicide attempts. In this review, we provide several leading theories of suicide, including the serotoninergic system, Wnt pathway and brain-derived neurotrophic factor/tropomyosin receptor kinase B signalling, and discuss the evidence for their roles in suicide and treatment. Moreover, the cognitive dysfunctions associated with suicide risk are discussed, as well as the novel evidence on cognitive therapies that decrease suicidal ideation. We highlight the need to apply multi-omics techniques (including single-nucleus RNA sequencing and mass spectrometry histochemistry) on hippocampal samples from donors who died by suicide or legal euthanasia, to clarify the aetiology of suicide and propose novel therapeutic strategies.
Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode
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Post mortem studies revealed a decreased concentration of the 5-HTT protein in the prefrontal cortex, the hypothalamus and the brainstem of depressed patients died by suicide compared to matched controls (Purselle and Nemeroff, 2003; Stanley et al., 1982). In this context, some authors have also compared the expression levels of SLC6A4 mRNA in post mortem brains between suicide completer and healthy-matched control samples, without showing any difference (Arango et al., 2001; Little et al., 1997; Perroud et al., 2010). By quantifying regional brain 5-HTT binding in vivo using PET, Miller et al. (2013) reported that depressed suicide attempters had lower 5-HTT binding in midbrain compared with depressed non-attempters and healthy controls.
The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η²=0.008; ICC=0.91, 95% CI [0.87–0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340–0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2^nd week (β=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2^nd and 8^th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438–83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice.
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Over the past 20 years, psychotropics affecting the serotonergic system have been used extensively in the treatment of psychiatric disorders. Molecular imaging, in particular PET, has allowed for elucidation of the essential contribution of the serotonin transporter to the pathophysiology of various psychiatric disorders and their treatment. We review studies that use PET to measure cerebral serotonin transporter activity in psychiatric disorders, focusing on major depressive disorder and antidepressant treatment. We also discuss opportunities and limitations in the application of this neuroimaging method in clinical practice. Although results from individual studies diverge, meta-analysis indicates a trend towards reduced serotonin transporter availability in patients with major depressive disorder. Inconsistencies in results might suggest symptom heterogeneity in major depressive disorder and might therefore be relevant for stratification of patients into clinical subsets. PET has enabled the elucidation of mechanisms of response to selective serotonin reuptake inhibitors (SSRIs) and hence provides a basis for rational pharmacological treatment of major depressive disorder. Such imaging studies have also suggested that the pattern of serotonin transporter binding before treatment might predict response to antidepressant treatment, which could potentially be clinically useful in the future. Additionally, this Review discusses PET studies investigating the serotonin transporter in anxiety, obsessive–compulsive disorder, and eating disorders. Few studies have shown changes in serotonin transporter activity in schizophrenia and attention deficit hyperactivity disorder. By showing the scarcity of data in these psychiatric disorders, we highlight the potential for further investigation in this field.
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Further, there is a relatively common, functional A > G single-nucleotide polymorphism (SNP) within the L allele,86 the LG allele being equivalent to the S allele in transcriptional efficiency.86 Further supporting the functional effect of HTTLPR, this locus has been shown to regulate serotonin transporter expression in postmortem brain87 and in vivo using single-photon emission computed tomography (SPECT) imaging88 although not in all studies.89 Low-transcribing HTTLPR genotypes have been inconsistently associated with anxiety, depression, and alcoholism.
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2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry
The serotonin transporter gene promoter region polymorphism (5-HTTLPR) has been linked to psychiatric disorders, mostly anxiety and affective disorders. In elderly populations 5-HTTLPR polymorphism has also been reported to be associated with serum lipid levels. We have examined the interaction of the 5-HTTLPR polymorphism and the markers of lipid metabolism at young age in a longitudinal, population-representative cohort study. The sample of the Estonian Children Personality Behaviour and Health Study (initially cohorts of 9 and 15 year old children, complete lipid and genotype data for n = 1176) was examined throughout 10 years. Subjects were genotyped and the levels of low-density lipoproteins, high-density lipoproteins, triglycerides, and total cholesterol were measured. Children and adolescents carrying the s allele of the 5-HTTLPR polymorphism had lower levels of low-density lipoprotein and total cholesterol. At the age of 25, the s allele carriers had higher levels of high-density lipoproteins. These associations were independent of gender. Thus the 5-HTTLPR can be associated with the serum lipid levels and in particular low-density lipoproteins already in a young age.

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: This work was partially supported by NIH award DA09491.

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Original articleSerotonin transporter binding sites and mRNA levels in depressed persons committing suicide

Brain Res

Biol Psychiatry

Psychiatry Res

Neuropharmacoloby

Brain Res

Biol Psychiatry

Biochem Pharmacol

Brain Res

Biol Psychiatry

Mol Brain Res

Life Sci

Brain Res

Biol Psychiatry

Pharmacol Biochem Behav

Neurochem Int

Brain Res

Eur J Pharmacol

Biochem Pharmacol

Neurotransmitter transporters: Recent progress

Ann Rev Neurosci

Unaltered number of brain serotonin uptake sites in suicide victims

J Psychopharmacol

Expression of serotonin transporter messenger RNA in the human brain

J Neurochem

High affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain

Synapse

p1B15: a cDNA clone of the rat mRNA encoding cyclophilin

DNA

Selective labeling of serotonin uptake sites in rat brain by [3H]citalopram contrasted to labeling of multiple sites by [3H]imipramine

J Pharmacol Exp Ther

The Human Hippocampus

Platelets 3H 5-HT uptake in descendants from alcoholic patients: a potential risk factor for alcohol dependence

Life Sci

Original article
Serotonin transporter binding sites and mRNA levels in depressed persons committing suicide

High affinity binding of [¹²⁵I]RTI-55 to dopamine and serotonin transporters in rat brain

Selective labeling of serotonin uptake sites in rat brain by [³H]citalopram contrasted to labeling of multiple sites by [³H]imipramine