Limits...
Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations.

Ivanova SA, Loonen AJ, Bakker PR, Freidin MB, Ter Woerds NJ, Al Hadithy AF, Semke AV, Fedorenko OY, Brouwers JR, Bokhan NA, van Os J, van Harten PN, Wilffert B - SAGE Open Med (2016)

Bottom Line: These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations.This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population.

View Article: PubMed Central - PubMed

Affiliation: Mental Health Research Institute, Tomsk, Russian Federation; National Research Tomsk Polytechnic University, Tomsk, Russian Federation.

ABSTRACT

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.

Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.

Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

No MeSH data available.


Related in: MedlinePlus

The indirect and direct extrapyramidal pathways.ENK: enkephalin; GPe: globus pallidus, external segment; GPi: globus pallidus, internal segment; SNc: substantia nigra, pars compacta; SNr: substantia nigra, pars reticulata; SP/DYN = substance P/dynorphin; STh: subthalamic nucleus; D1, D2: medium sized spiny neurons with D1 or D2 receptors.Red: excitatory and blue: inhibitory (colour figure in DOI: 10.1177/2050312116643673)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2 - License 3
getmorefigures.php?uid=PMC4834466&req=5

fig1-2050312116643673: The indirect and direct extrapyramidal pathways.ENK: enkephalin; GPe: globus pallidus, external segment; GPi: globus pallidus, internal segment; SNc: substantia nigra, pars compacta; SNr: substantia nigra, pars reticulata; SP/DYN = substance P/dynorphin; STh: subthalamic nucleus; D1, D2: medium sized spiny neurons with D1 or D2 receptors.Red: excitatory and blue: inhibitory (colour figure in DOI: 10.1177/2050312116643673)

Mentions: It can be concluded that DA is unlikely to compete with antipsychotics for the DA type 2 receptor, even when it has far greater affinity than normal to a genetic variant of DRD2, DRD3, or DRD4. Moreover, most antipsychotics are full antagonists and dysfunctional variants of DRD2, DRD3, or DRD4 do not modify the influence of these drugs. This probably explains why genetic variants of DRD2, DRD3, or DRD4 have very little influence on the prevalence of TD in patients treated with antipsychotic drugs. Any possible influence of the genetically determined receptor inactivity on the vulnerability of TD should have taken place before treatment with DA antagonists was started. Moreover, atypical antipsychotics would be expected to increase dyskinesia instead of having protective activity, as atypical antipsychotics are known to facilitate DA release.12 Any extra DA would likely augment dyskinesia by activating excitatory DRD1, expressed by medium spiny neurons (MSNs) of the direct extrapyramidal pathway (Figure 1), which is far less potently antagonized by antipsychotic drugs. Moreover, release of extra DA would increase oxidative stress within indirect pathway MSNs, augmenting neurotoxicity.


Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations.

Ivanova SA, Loonen AJ, Bakker PR, Freidin MB, Ter Woerds NJ, Al Hadithy AF, Semke AV, Fedorenko OY, Brouwers JR, Bokhan NA, van Os J, van Harten PN, Wilffert B - SAGE Open Med (2016)

The indirect and direct extrapyramidal pathways.ENK: enkephalin; GPe: globus pallidus, external segment; GPi: globus pallidus, internal segment; SNc: substantia nigra, pars compacta; SNr: substantia nigra, pars reticulata; SP/DYN = substance P/dynorphin; STh: subthalamic nucleus; D1, D2: medium sized spiny neurons with D1 or D2 receptors.Red: excitatory and blue: inhibitory (colour figure in DOI: 10.1177/2050312116643673)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4834466&req=5

fig1-2050312116643673: The indirect and direct extrapyramidal pathways.ENK: enkephalin; GPe: globus pallidus, external segment; GPi: globus pallidus, internal segment; SNc: substantia nigra, pars compacta; SNr: substantia nigra, pars reticulata; SP/DYN = substance P/dynorphin; STh: subthalamic nucleus; D1, D2: medium sized spiny neurons with D1 or D2 receptors.Red: excitatory and blue: inhibitory (colour figure in DOI: 10.1177/2050312116643673)
Mentions: It can be concluded that DA is unlikely to compete with antipsychotics for the DA type 2 receptor, even when it has far greater affinity than normal to a genetic variant of DRD2, DRD3, or DRD4. Moreover, most antipsychotics are full antagonists and dysfunctional variants of DRD2, DRD3, or DRD4 do not modify the influence of these drugs. This probably explains why genetic variants of DRD2, DRD3, or DRD4 have very little influence on the prevalence of TD in patients treated with antipsychotic drugs. Any possible influence of the genetically determined receptor inactivity on the vulnerability of TD should have taken place before treatment with DA antagonists was started. Moreover, atypical antipsychotics would be expected to increase dyskinesia instead of having protective activity, as atypical antipsychotics are known to facilitate DA release.12 Any extra DA would likely augment dyskinesia by activating excitatory DRD1, expressed by medium spiny neurons (MSNs) of the direct extrapyramidal pathway (Figure 1), which is far less potently antagonized by antipsychotic drugs. Moreover, release of extra DA would increase oxidative stress within indirect pathway MSNs, augmenting neurotoxicity.

Bottom Line: These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations.This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population.

View Article: PubMed Central - PubMed

Affiliation: Mental Health Research Institute, Tomsk, Russian Federation; National Research Tomsk Polytechnic University, Tomsk, Russian Federation.

ABSTRACT

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.

Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.

Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

No MeSH data available.


Related in: MedlinePlus