Summary Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the ...disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.
Prolonged treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of uncontrolled movements (L-DOPA-induced dyskinesias (LID)) in Parkinson's disease (PD). There is currently ...only a single approved drug for the treatment of LID, a long-acting preparation of the NMDA antagonist, amantadine, that has variable benefits and side-effects. Therefore, new treatments for LID remain an unmet in PD.
We review the current strategies for the management of LID; the pathogenic mechanisms underlying the development of LID, which provides the rationale for clinical trials of novel targets for LID and provide a review of phase II/III trials for emerging drugs for LID, with either positive results, or ongoing studies, reported between January 2014 and December 2019.
There are several ongoing studies for agents that showed possible benefit at phase Ib/IIa for reducing LID. However, there are no new positive phase III double-blind randomized controlled clinical trials (DBRCT) for emerging treatments for LID. Generating better preclinical models, more precise recruitment tools and better outcome measures remain a priority. The pharmacology of drugs investigated for LID may be too selective; therefore, evaluating combinations of drugs is worthy of consideration as is the repurposing of existing drugs with multiple pharmacological targets.
5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are widely expressed in the brain and have been implicated in mood and behavior. Based on the use of atypical antipsychotics in schizophrenia, antagonism ...of 5-HT2A-Rs initially emerged as a potential intervention capable of reducing the incidence of extrapyramidal symptoms, while exerting an effective antipsychotic action. More recently, highly selective 5-HT2A-R antagonists have been evaluated in the treatment of a wide range of other psychiatric disorders.
The aim of the current review is to present important clinical studies investigating the potential therapeutic effects of 5-HT2A-R antagonists in both primary psychiatric disorders, such as schizophrenia and mood disorders, as well as in psychiatric manifestations of neurodegenerative disorders. We present an overview of 5-HT2A-Rs in normal brain function and the rationale for use in (neuro) psychiatric disease based on significant findings from genetic association studies, neuroimaging data and postmortem studies. The majority of the studies relate to schizophrenia, depression, anxiety, obsessive compulsive disorder and psychosis in Parkinson's disease and Alzheimer's disease. To date, there is sparse literature on 5-HT2A-Rs in Gilles de la Tourette syndrome, attention deficit hyperactivity disorder, eating disorders and autism spectrum disorders. The authors conclude by reviewing recent clinical trials investigating highly selective 5-HT2A-R antagonists in schizophrenia, psychosis in Parkinson's disease, insomnia and generalized anxiety.
Despite the potential, to date, 5-HT2A-R antagonists have not made an impact in the management of psychiatric disorders and psychiatric symptoms of neurodegenerative conditions.
L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A ...(5-HT(1A)) receptor agonists and serotonergic type 2A (5-HT(2A)) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair l-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT(1A) and 5-HT(2A) receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT(1A)- and 5-HT(2A)-modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT(1A) and 5-HT(2A) receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.
Parkinson’s disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now ...overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of other neurotransmitters are affected by the disease process. One such neurotransmitter is serotonin (5-HT). 5-HT has been shown to play a role in several motor and nonmotor manifestations of PD, including tremor, cognition, depression and psychosis. 5-HT also seems to play a critical role in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. A breadth of preclinical studies and clinical trials have been conducted that aimed at modulating the 5-HT system in order to alleviate depression, cognitive deficits, psychosis, and dyskinesia. In this Review, we summarize recent advances in the 5-HT field in PD, but with a translational emphasis. We start by presenting a novel nonhuman primate model of PD that presents with dual dopamine and 5-HT lesions. We then present preclinical and clinical data that introduce new concepts, such as the use of biased and partial agonists, as well as molecules recently introduced to the field of PD, such as eltoprazine, pimavanserin, nelotanserin, and SYN-120, to enhance therapeutic benefit while minimizing adverse events, notably on parkinsonian disability.
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