The use of an antagonist 5-HT2a/c for depression and motor function in Parkinson' disease

Werneck, Antonio Luiz dos Santos; Rosso, Ana Lucia; Vincent, Maurice

doi:10.1590/s0004-282x2009000300007

Cited by 41 publications

(40 citation statements)

References 25 publications

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“…In line with the reported clinical benefit of trazodone in Parkinson disease patients [56], our model suggests that cortical 5-HT 2 A activity is a key modulator of EPS liability and that the fast dissociation rate of JNJ37822681 may only compensate partially for the EPS liability induced by significant D 2 receptor inhibition during burst firing, This is not unlike remoxipride that has a substantial EPS liability despite a low affinity for the D 2 receptor [57]. We believe this translational disconnect is likely due to species difference of the dopaminergic synapse physiology between primates and rodents [10].…”

Section: Discussionsupporting

confidence: 72%

Blinded Prospective Evaluation of Computer-Based Mechanistic Schizophrenia Disease Model for Predicting Drug Response

et al. 2012

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The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published ‘Quantitative Systems Pharmacology’ computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA) and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D2 antagonist and ocaperidone, a very high affinity dopamine D2 antagonist, using only pharmacology and human positron emission tomography (PET) imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS) total score and the higher extra-pyramidal symptom (EPS) liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

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Section: Discussionsupporting

confidence: 72%

Blinded Prospective Evaluation of Computer-Based Mechanistic Schizophrenia Disease Model for Predicting Drug Response

et al. 2012

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“…The UPDRS part III subscale was not worsened by the use of trazodone. The effect of trazodone on dyskinesia was not reported [312]. However, there is one case-report in which trazodone (25–125 mg p.o.…”

Section: Sert Inhibitorsmentioning

confidence: 99%

Monoamine Reuptake Inhibitors in Parkinson’s Disease

Huot

Fox

Brotchie

2015

Parkinson's Disease

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The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia.

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“…5-HT 2A antagonists have also been shown to alleviate L-DOPA-induced dyskinesias in parkinsonian patients [149] and MPTP-treated monkeys [150] and to improve motor impairments in MPTP-treated mice [151]. 5-HT 2C antagonists have been proposed to reduce depression and improve motor function in depressed parkinsonian patients [138,152]. The use of 5-HT 3 antagonists could help reducing excess cortical transmission induced by L-DOPA in psychotic episodes without altering the motor score of patients [143,144].…”

Section: Modifications Of 5-ht Transmission By Acute and Repeated L-dmentioning

confidence: 99%

Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation of the Subthalamic Nucleus or Levodopa in Parkinson’s Disease

Navailles

Deurwaerdère

2012

Mol Neurobiol

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Although they are effective at treating the motor impairments that are the core symptoms of Parkinson's disease, current treatments, namely L: -3,4-dihydroxyphenylalanine (L: -DOPA), the gold standard medication and high-frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It has also been shown that the serotonergic system both plays a major role in the mechanism of action of the current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies targeting the serotonergic system are being developed and could be decisive in limiting L: -DOPA-induced dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies.

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The use of an antagonist 5-HT2a/c for depression and motor function in Parkinson' disease

Cited by 41 publications

References 25 publications

Blinded Prospective Evaluation of Computer-Based Mechanistic Schizophrenia Disease Model for Predicting Drug Response

Blinded Prospective Evaluation of Computer-Based Mechanistic Schizophrenia Disease Model for Predicting Drug Response

Monoamine Reuptake Inhibitors in Parkinson’s Disease

Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation of the Subthalamic Nucleus or Levodopa in Parkinson’s Disease

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