Two studies have investigated the potential benefits of targeting serotonergic neurotransmission in patients with Parkinson’s disease.
The first study investigated the role of serotonin terminal function in levodopa-induced dyskinesias (LID) in PD subjects using radiolabelled PET imaging (Politis et al. J Clin Invest 2014;124:1340-1349; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3934188/pdf/JCI71640.pdf). PD patients with LIDs demonstrate higher synaptic levels of dopamine compared to non-dyskinetic patients due to abnormal release and clearance of striatal dopamine, and it was hypothesized that this may be due in part to dopamine storage and release by non-dopaminergic terminals. Serotonergic terminals were a candidate for having a role in mishandling exogenous levodopa and the development of LIDs because of the relative preservation of serotonergic terminals throughout the course of PD.
The investigators found that when buspirone, a serotonin 1A receptor agonist, was administered prior to levodopa, there were decreases in striatal synaptic dopamine and a reduction in LIDs. This finding suggests that serotonergic terminals may be processing levodopa and releasing dopamine in the striatum of PD patients with LIDs. Modulation of dopamine levels by buspirone was more pronounced in patients with mild rather than more severe LIDs. The study also concluded that serotonin 1A receptor agonists may be useful as dyskinetic agents in PD.
A separate study investigated the effective of a serotonin 2A receptor inverse agonist, pimavanserin, on PD psychosis (Cummings et al. Lancet 2014;383:533-540). A total of 199 PD patients with psychosis were randomized to pimavanserin 40 mg/day or placebo for six weeks. Concomitant antipsychotic use was not permitted. The primary outcome was change from baseline in the PD-adapted Scale for Assessment of Positive Symptoms (SAPS-PD).
Pimavanserin was associated with a greater decrease in SAPS-PD scores compared to placebo (-5.79 vs. -2.73). Pimavanserin was generally well tolerated. Sleep was also improved with the drug. Ten of 95 patients (10.5%) discontinued active treatment due to adverse effects, including four cases of psychotic disorder or hallucinations in the first 10 days of therapy (vs. 2 in the placebo group).
Dr. Susan Fox: Serotonergic agents have been investigated in PD for a number of motor and non-motor symptoms. The study by Politis et al is important in confirming the findings from preclinical studies of aberrant 5HT neurotransmission underlying LID in patients with PD. The concept of 5HT1A agonists reducing dopamine release from remaining serotonergic terminals as a means of reducing LID was the rationale behind the prior RCT using the 5HT1A agonist, sarizotan. However this study did not show significant benefit on reducing LID compared to placebo and some patients developed worsening of PD motor symptoms, possibly due to excessive reduction in dopamine release. Buspirone appears to have some benefit on LID, without side effects. Further studies may be warranted.
Serotonin has also been implicated in PD psychosis, particularly via the 5HT2A receptor. Targeting non-dopaminergic receptors is important to prevent worsening of PD motor symptoms. The RCT using pimavanserin shows benefit on psychosis, and other symptoms such as sleep, with no worsening of PD motor symptoms. Longer studies are needed to show this benefit is maintained, but this agent appears to show promise for patients with bothersome symptoms.