A synthesis of the current knowledge regarding dopaminergic alterations in schizophrenia as a core element of the disease is proposed. Schizophrenia is a disabling pathology with a lifetime prevalence of approximately 1% worldwide. The discovery of antipsychotics drugs that block the dopamine D2 receptor led to both improved disease management and to the dopamine hypothesis of schizophrenia, perhaps one of the most enduring in psychiatry. However, a clear understanding of the etiopathological mechanism(s) remain elusive. New therapies are also needed for the cognitive and negative symptoms of the disease which appear central to functional outcomes and yet which remain poorly served by current therapies
Large multicentre GWAS studies have identified multiple risk alleles, including genes for the dopamine D2 receptor, GABAergic neurons, and ion channels, and genes involved in glutamatergic neurotransmission and synaptic plasticity. Interestingly, these large schizophrenia–genetic association studies also suggest an immune control of synaptic maturation. Immune dysregulation has long been suspected in the etiology of schizophrenia, most notably in relation to synaptic remodeling. These new data are of great interest for understanding brain development processes in schizophrenia, and synaptic dysfunction within the glutamatergic system. A direct involvement of NMDA receptor function in psychotic events is well accepted, but receptor dynamic studies and the translatability of preclinical models are showing the limits of our current understanding on this matter.
How does the dopaminergic system fit within these new findings? Changes in dopamine function are well documented in schizophrenia and generally confirm reduced mesocortical tone associated with hypersensitive/hyperactive sub-cortical dopamine function which appear to be a hallmark of the disease. Dopaminergic cells may have a self-modeling potential through combined BDNF/TrkB and dopamine D1 and D3 intraneuronal crosstalk and this may be relevant to more general plastic mechanisms. In addition, dopamine may be the key endpoint of interactions with other transmitter systems such as endocannabinoids or acetylcholine which may be dysfunctional in disease. Thus, even though the causal processes leading to schizophrenia may be multifactorial, [converging toward synaptic dysfunction], targeting the dopaminergic system remains of therapeutic interest.
The hypothesis that selectively targeting dopamine sub-systems will provide improved therapies for this devastating disorder, including for currently unmet need will be addressed. The network of therapeutic effects triggered by a standard of care medications and other agents will be dissected using imaging technologies, integrated with target engagement measurements and functional outcomes. In this context sleep and circadian rhythms alterations are a relatively unexplored but potentially important subject for future research. Moreover, the impact of new clinical data on biomarkers will be discussed and put in perspective for the next round of interventional and non-interventional studies.
The contributions proposed for this Research Topic should provide new paths for clinical and preclinical research focusing on new elements in the neuroanatomy and genetics of the dopaminergic circuits targeted by schizophrenia. This may help define a new baseline for discovery and novel therapies to come.
Topics Editors Silvia Gatti-McArthur and Jean-Claude Martel are employed by company Pierre Fabre and Andrew Grottick is employed by company Beacon Discovery. All other Topic Editors declare no competing interests with regards to the Research Topic subject.?
A synthesis of the current knowledge regarding dopaminergic alterations in schizophrenia as a core element of the disease is proposed. Schizophrenia is a disabling pathology with a lifetime prevalence of approximately 1% worldwide. The discovery of antipsychotics drugs that block the dopamine D2 receptor led to both improved disease management and to the dopamine hypothesis of schizophrenia, perhaps one of the most enduring in psychiatry. However, a clear understanding of the etiopathological mechanism(s) remain elusive. New therapies are also needed for the cognitive and negative symptoms of the disease which appear central to functional outcomes and yet which remain poorly served by current therapies
Large multicentre GWAS studies have identified multiple risk alleles, including genes for the dopamine D2 receptor, GABAergic neurons, and ion channels, and genes involved in glutamatergic neurotransmission and synaptic plasticity. Interestingly, these large schizophrenia–genetic association studies also suggest an immune control of synaptic maturation. Immune dysregulation has long been suspected in the etiology of schizophrenia, most notably in relation to synaptic remodeling. These new data are of great interest for understanding brain development processes in schizophrenia, and synaptic dysfunction within the glutamatergic system. A direct involvement of NMDA receptor function in psychotic events is well accepted, but receptor dynamic studies and the translatability of preclinical models are showing the limits of our current understanding on this matter.
How does the dopaminergic system fit within these new findings? Changes in dopamine function are well documented in schizophrenia and generally confirm reduced mesocortical tone associated with hypersensitive/hyperactive sub-cortical dopamine function which appear to be a hallmark of the disease. Dopaminergic cells may have a self-modeling potential through combined BDNF/TrkB and dopamine D1 and D3 intraneuronal crosstalk and this may be relevant to more general plastic mechanisms. In addition, dopamine may be the key endpoint of interactions with other transmitter systems such as endocannabinoids or acetylcholine which may be dysfunctional in disease. Thus, even though the causal processes leading to schizophrenia may be multifactorial, [converging toward synaptic dysfunction], targeting the dopaminergic system remains of therapeutic interest.
The hypothesis that selectively targeting dopamine sub-systems will provide improved therapies for this devastating disorder, including for currently unmet need will be addressed. The network of therapeutic effects triggered by a standard of care medications and other agents will be dissected using imaging technologies, integrated with target engagement measurements and functional outcomes. In this context sleep and circadian rhythms alterations are a relatively unexplored but potentially important subject for future research. Moreover, the impact of new clinical data on biomarkers will be discussed and put in perspective for the next round of interventional and non-interventional studies.
The contributions proposed for this Research Topic should provide new paths for clinical and preclinical research focusing on new elements in the neuroanatomy and genetics of the dopaminergic circuits targeted by schizophrenia. This may help define a new baseline for discovery and novel therapies to come.
Topics Editors Silvia Gatti-McArthur and Jean-Claude Martel are employed by company Pierre Fabre and Andrew Grottick is employed by company Beacon Discovery. All other Topic Editors declare no competing interests with regards to the Research Topic subject.?
