Published Online: 1 May 2009
Authors: Susan H. Fox, MRCP, PhD , Rosalind Chuang, MD, Jonathan M. Brotchie, PhD
Read Article | Listen to Podcast Review
An appreciation of the multiple roles that serotonin (5-HT) may play in Parkinson's disease (PD) has increased in recent years. Early pathological studies in PD demonstrated nonselective reductions of 5-HT in brain tissue but little correlation to comorbidities such as dyskinesia and mood disturbance. This, combined with treatment failures using serotonergic drugs in comparison to levodopa, meant the field was largely neglected until recently. The multitude of subtypes of 5-HT receptors in the brain and an increased understanding of the potential function 5-HT may play in modulating other neurotransmitter systems, including dopamine, GABA, and glutamate, have meant an expansion in efforts to develop potential serotonergic drugs for both motor and nonmotor symptoms in PD. However, several unanswered questions remain, and future studies need to focus on correlating changes in 5-HT neurotransmission in both pathological and in vivo imaging studies with a full clinical phenotype.
© 2009 Movement Disorder Society
Received: 26 November 2008; Revised: 7 January 2009; Accepted: 8 January 2009
Podcast Summary by David Burn, FRCP, MD, Professor of Movement Disorder Neurology at Newcastle University, Honorary Consultant Neurologist for Newcastle upon Tyne Hospitals Foundation Trust, and Director of the Clinical Ageing Research Unit, Campus for Ageing and Vitality
Medical students are traditionally taught that Parkinson's disease (PD) is a motor disorder, related to a profound loss of dopamine in the striatum. This is not to detract from the central importance of this neurotransmitter in PD, but clearly the suboptimal response of motor symptoms to dopamine, complicated by the emergence of levodopa-induced dyskinesias, together with the broad spectrum of non-motor problems at all disease stages, clearly indicates a more widespread involvement of other neurochemical systems.
In a review by Susan Fox, Rosalind Chuang and Jonathan Brotchie, the authors comprehensively appraise the serotonergic system in the context of both motor and non-motor features of PD. To those of us who struggle with serotonergic receptors, the reader will be delighted to learn that there are currently 14 distinct subtypes, with many more isoforms beyond this. This may relate to the evolutionary age of the serotonergic system, which has permitted a considerable degree of diversification to occur. In neuroanatomical terms, it is unsurprising that there is widespread serotonin depletion within the central nervous system in PD, since the dorsal raphe nucleus, which is a site of predilection for Lewy body pathology and cell loss, sends neuronal projections to striatum, frontal cortex, limbic system and diencephalon.
One of the themes emerging from the review is that the potential for manipulating the serotonergic system in PD may not have been realised, primarily due to the use of relatively non-selective agonists and antagonists; in doing so, any beneficial effects that could accrue from binding to one receptor sub-type may have been negated by opposing effects mediated by another sub-type. Furthermore, some agents, like sarizotan, have actions not only on serotonergic receptors (as a 5-HT1A agonist) but also on dopamine receptors (D2/3 antagonist). Thus, the initial promising results of sarizotan as an anti-dyskinetic drug were not realised in randomised controlled trials, where higher doses of the drug were associated with increased OFF time. The drive to develop sub-type specific, high affinity serotonergic drugs is spawning several novel compounds. For example, the sigma-1 antagonist BMY-14802 appears to exert its anti-dyskinetic effects via a 5-HT1A agonist mechanism, similar to buspirone, yet has extremely low affinity for the D2 receptor.
Evidence for a key role of serotonin in mediating depression in PD is inconsistent and the limited trials to date have not established efficacy for selective serotonin reuptake inhibitors in treating mood disorder in PD. An emerging role for serotonergic agents may be the use of receptor sub-type specific drugs to treat psychosis associated with PD. Pimavanserin, an inverse 5-HT2A agonist, has shown encouraging results in phase II trials; the outcome of a phase III study is due within the next few months.
The scope for manipulation of the serotonergic system via receptor sub-types thus seems endless. One cannot help, however, but to sound a note of caution. Despite the relative lack of drug-specificity to date, were there to be significant therapeutic gains to be derived from serotonergic agents, would we not have had more of an indication of this by now? Nevertheless, if the use of a magic bullet, rather than a shot-gun blast, to the serotonergic system can lead to benefits in motor and/or non-motor PD symptoms, then this would be very welcome indeed.
About Prof. David Burn, MD, FRCP
David Burn is Professor of Movement Disorder Neurology at Newcastle University and Honorary Consultant Neurologist for Newcastle upon Tyne Hospitals Foundation Trust. He is also Director of the Clinical Ageing Research Unit, located on the newly established Campus for Ageing and Vitality. He qualified from Oxford University and Newcastle upon Tyne Medical School in 1985.
His MD was in the functional imaging of parkinsonism. He runs the Movement Disorders service in Newcastle upon Tyne and his research programme is conducted through Newcastle University's Institute for Ageing and Health. Research interests include dementia associated with Parkinson's disease and progressive supranuclear palsy. He was the Royal College of Physicians' representative on the NICE National Guidelines writing group for Parkinson's disease (2004-2006) is currently a member of the Medical Advisory Panels for the Progressive Supranuclear Palsy (Europe) Association, Sarah Matheson Trust and Parkinson's Disease Society. He has been the Association of British Neurologists' representative on Parkinson's Disease Subsection of British Geriatric Society since 2003. He was a member of the Special Interest Committee Task Force of the International Movement Disorder Society for Diagnostic Criteria for Parkinsonian Disorders (2002-3) and the Parkinson's Disease Dementia Task Force (2004-6).
He has been Chair of the PD Clinical Study Group of UK DeNDRoN since May 2008 and Clinical Reviews Editor for the Movement Disorder Journal since January 2007. He has published over 150 articles on movement disorders in peer reviewed journals. In his spare time, he runs for Heaton Harriers.