Neurobiological Mechanisms Involved in Antidepressant Therapies

Briley, Mike; Moret, Chantal

doi:10.1097/00002826-199310000-00002

Cited by 182 publications

(99 citation statements)

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“…47 Because increased 5-HT 2C R editing can hamper the responsivity of this receptor subtype to serotonin, our findings suggest that antidepressant therapies, especially those that involve serotonin reuptake inhibition, may be less effective in blunting suicidal tendencies in a subpopulation of patients with an inherently high level of the VSV isoform. Moreover, the proportion of the VSV isoform could be additionally enhanced in these individuals during the initial stages of SSRI therapy as an adaptation to the augmented levels of serotonin in the synapse 22,42 contributing to suicidality in this vulnerable subgroup of patients.…”

Section: Discussionmentioning

confidence: 86%

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

et al. 2007

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Suicide is a major public health problem with B1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT 2C R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT 2C R mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior.

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Section: Discussionmentioning

confidence: 86%

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

et al. 2007

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“…Furthermore, SSRIs are believed to exert their effect on raphe nuclei serotonin neurons, as well as at their targets. 30 Therefore a priori one would predict that GCHFR variants However, a larger study sample will be required to confirm these observations. We also investigated the consequences of GCHFR promoter haplotypes on transcriptional activity, using luciferase reporter gene assays.…”

Section: Discussionmentioning

confidence: 99%

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

et al. 2010

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Tetrahydrobiopterin (BH 4 ) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH 4 is tightly regulated by GTP-cyclohydrolase I feedback regulator (GFRP). Given the pivotal role of the serotonergic system in mood disorders and selective serotonin reuptake inhibitors (SSRIs) antidepressant function, we tested the hypothesis that GFRP gene (GCHFR) variants would modify response to antidepressants in subjects with major depression. Two single nucleotide polymorphisms (rs7164342 and rs7163862) in the GCHFR promoter were identified and occurred as two haplotypes (GA or TT). A multiple regression analysis revealed that homozygous individuals for the TT haplotype were less likely to respond to the SSRI fluoxetine than to the tricyclic antidepressant nortriptyline (P ¼ 0.037). Moreover, the TT haplotype showed a reduced transcription rate in luciferase reporter gene assays, which may impact on BH 4 -mediated neurotransmitter production, thus suggesting a biological process through which GCHFR promoter variants might influence antidepressant response.

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“…CIT inhibits the reuptake of serotonin, consequently increasing its synaptic availability and enhancing its inhibitory effect on aggressive behavior. On the other hand, the repeated administration of selective serotonin reuptake inhibitors can produce downregulation both of the post-and presynaptic 5-HT 1B receptors, in this case improving the serotonin release (19). According to Saudou et al (20), the 5-HT 1B receptors seem to be very important in the control of aggressive behavior, since mutant mice lacking these receptors presented exacerbated aggressiveness.…”

Section: Experimental Groupsmentioning

confidence: 99%

Reduction of intraspecific aggression in adult rats by neonatal treatment with a selective serotonin reuptake inhibitor

Castro

Medeiros

Silva

et al. 2001

Braz J Med Biol Res

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Most studies suggest that serotonin exerts an inhibitory control on the aggression process. According to experimental evidence, this amine also influences growth and development of the nervous tissue including serotoninergic neurons. Thus, the possibility exists that increased serotonin availability in young animals facilitates a long-lasting effect on aggressive responses. The present study aimed to investigate the aggressive behavior of adult rats (90-120 days) treated from the 1st to the 19th postnatal day with citalopram (CIT), a selective serotonin reuptake inhibitor (20 mg/kg, sc, every 3 days). Aggressive behavior was induced by placing a pair of rats (matched by weight) in a box (20 x 20 x 20 cm), and submitting them to a 20-min session of electric footshocks (five 1.6-mA -2-s current pulses, separated by a 4-min intershock interval). When compared to the control group (rats treated for the same period with equivalent volumes of saline solution), the CIT group presented a 41.4% reduction in the duration of aggressive response. The results indicate that the repeated administration of CIT early in life reduces the aggressive behavior in adulthood and suggest that the increased brain serotoninergic activity could play a role in this effect.

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Neurobiological Mechanisms Involved in Antidepressant Therapies

Cited by 182 publications

References 0 publications

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

Reduction of intraspecific aggression in adult rats by neonatal treatment with a selective serotonin reuptake inhibitor

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