Serotonergic basis of antipsychotic drug effects in schizophrenia

Lieberman, Jeffrey A.; Mailman, Richard B.; Duncan, Gary E.; Sikich, Lin; Chakos, Miranda; Nichols, David E.; Kraus, John E.

doi:10.1016/s0006-3223(98)00187-5

Cited by 196 publications

(92 citation statements)

References 169 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, other studies report that 5-HT2A agonists increase but 5-HT2A antagonists decrease prefrontal dopamine efflux (Bortolozzi et al, 2005;Pehek et al, 2006). In general, a complex link between 5-HT2A and dopamine tone appears to modulate brain activity (Di Pietro and Seamans, 2007;Lieberman et al, 1998). Consistently, 5-HT2A and D2 receptors are both located on prefrontal pyramidal and nonpyramidal neurons (Fink and Gothert, 2007;Goldman-Rakic, 1998, 2000;Seamans and Yang, 2004), and their signaling is also transmitted through the common intraneuronal pathways (Beaulieu, 2012;de Bartolomeis et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n ¼ 63 and n ¼ 54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.

show abstract

Section: Introductionmentioning

confidence: 97%

“…The 5-HT2A receptor interacts with dopamine systems (Di Giovanni et al, 2010;Fink and Gothert, 2007;Lieberman et al, 1998). In particular, some studies indicate that antagonism on 5-HT2A receptors indirectly increases DA release in the prefrontal cortex (Fink and Gothert, 2007).…”

Section: Introductionmentioning

confidence: 99%

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4] Disturbances in serotonergic systems in brain have been implicated in mental illness, including schizophrenia, 5,6 anxiety disorders, 7 obsessivecompulsive disorders, 8 addiction, 9-12 depression [13][14][15][16] and suicide. 15,17 After release from axonal terminals of serotonergic neurons, synaptic effects of serotonin are terminated by reuptake into the nerve endings.…”

Section: Introductionmentioning

confidence: 99%

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

Papp

Pinsonneault

et al. 2006

Mol Psychiatry

View full text Add to dashboard Cite

An insertion/deletion polymorphism in the SERT linked promoter region (SERTLPR), previously reported to regulate mRNA expression in vitro, has been associated with mental disorders and response to psychotropic drugs. Contradictory evidence, however, has raised questions about the role of SERTLPR in regulating mRNA expression in vivo. We have used analysis of allelic expression imbalance (AEI) of SERT mRNA to assess quantitatively the contribution of SERTLPR to mRNA expression in human post-mortem pons tissue sections containing serotonergic neurons of the dorsal and median raphe nuclei. Any difference in the expression of one allele over the other indicates the presence of cis-acting elements that differentially affect transcription and/or mRNA processing and turnover. Using a marker SNP in the 3 0 untranslated region of SERT mRNA, statistically significant differences in allelic mRNA levels were detected in nine out of 29 samples heterozygous for the marker SNP. While the allelic expression differences were relatively small (15-25%), they could nevertheless be physiologically relevant. Although previous results had suggested that the long form of SERTLPR yields higher mRNA levels than the short form, we did not observe a correlation between SERTLPR and allelic expression ratios. Also in contrast to previous results, we found no correlation between SERTLPR and allelic expression ratios or SERT mRNA levels in Blymphocytes. This study demonstrates that regulation of SERT mRNA is independent of SERTLPR, but could be associated with polymorphisms in partial linkage disequilibrium with SERTLPR.

show abstract

“…The efficacy of 5-HT uptake inhibitors in the treatment of depression has suggested that major depression is due mainly to a disorder of central 5-HT transmission (Charney 1998). Furthermore, the therapeutic success of clozapine and, more recently, risperidone has focused attention on the 5-HT system and its interaction with the dopaminergic system as an avenue for improved treatment of psychotic illnesses (Lieberman et al 1998). It is suggested, moreover, that an abnormality in the 5-HT system is second only to the dopamine hypothesis as a potential neurochemical factor involved in schizophrenia (Lieberman et al 1998).…”

mentioning

confidence: 99%

“…Furthermore, the therapeutic success of clozapine and, more recently, risperidone has focused attention on the 5-HT system and its interaction with the dopaminergic system as an avenue for improved treatment of psychotic illnesses (Lieberman et al 1998). It is suggested, moreover, that an abnormality in the 5-HT system is second only to the dopamine hypothesis as a potential neurochemical factor involved in schizophrenia (Lieberman et al 1998). On the other hand, animal studies have clearly documented an action of estradiol on neurotransmitters such as dopamine (Di Paolo 1994) and 5-HT (Bethea et al 1998), and similar effects are likely to occur in humans.…”

mentioning

confidence: 99%

Modulation by Estrogen-Receptor Directed Drugs of 5-Hydroxytryptamine-2A Receptors in Rat Brain

Cyr

Landry

Paolo

2000

Neuropsychopharmacology

View full text Add to dashboard Cite

show abstract

Serotonergic basis of antipsychotic drug effects in schizophrenia

Cited by 196 publications

References 169 publications

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

Modulation by Estrogen-Receptor Directed Drugs of 5-Hydroxytryptamine-2A Receptors in Rat Brain

Contact Info

Product

Resources

About