Effects of serotonin 5-HT1A agonist in advanced Parkinson’s disease
Bara-Jimenez W, Bibbiani F, Morris MJ, Dimitrova T, et al.;
Commented by , 23 Oct 2005
Background
Pulsatile stimulation of dopaminergic receptors in the setting of severe dopaminergic terminal loss and subsequent involvement of non-dopaminergic mechanisms have been implicated in the development of motor fluctuations and dyskinesias in patients with advanced PD. Serotonergic pathways may be part of this mechanism.
Objectives
The objective of this study was to assess the acute effects of a selective 5-HT1A receptor agonist, sarizotan, on motor functions and dyskinesias in patients with advanced PD.
Methods
This was a small, double-blind, placebo controlled proof-of-concept study. All together 18 patients at moderate to advanced stages of PD, with motor fluctuations and peak-dose dyskinesias were enrolled.
Fifteen were assigned to receive active treatment, 3 patients received only placebo throughout the study. Patients on active treatment first received a 1-week placebo run-in, followed by 1 week treatment with 2 mg sarizotan b.i.d, and then 1 week at 5 mg b.i.d.
Efficacy evaluations were performed at the end of each one week period. Motor functions were asessed
- when sarizotan was given alone
- when sarizotan was co-administered with steady-state i.v. L-dopa infusion, at both low and optimal doses, together with oral carbidopa 50 mg every 3 hours
- at 30-minute intervals after discontinuation of the optimal L-dopa dose infusion to evaluate the severity of wearing-off
Efficacy evaluations includeded part III (motor subscale) and the modified dyskinesia item of the UPDRS. A within patient analysis was performed using changes in UPDRS scores from the end of week 1 to the end of weeks 2 and 3.
Results
Sarizotan monotherapy failed to improve parkinsonian scores compared to baseline. Likewise sarizotan did not alter the anti-parkinsonian action of optimal-dose or low-dose L-dopa.
In contrast at the higher dose of 5 mg b.i.d., sarizotan reduced L-dopa induced dyskiensias by 40% when compared with L-dopa alone (p<0.05), this effect was not seen at the lower dose.
At each patient’s best dose of sarizotan either 2 or 5 mg b.i.d.), the half-life of L-dopa efficacy incrased by an average of 38% (p=0.05). There were no adverse events thought to be related to sarizotan.
Professor Emre's comments
The role of non-physiological, pulsatile stimulation of striatal dopaminergic receptors and the subsequent involvement of downstream, non-dopaminergic mechanisms in the development of L-dopa induced complications, such as motor fluctuations and dyskinesias, have been increasingly better recognized (ref. 1, ref. 2).
It has also been hypothesized that, as a consequence of severe dopaminergic terminal loss, exogenous L-dopa is largely decarboxylated to dopamine in serotoninergic terminals.
The release of both dopamin and serotonin from these terminals is assumed to be regulated by 5-HT1A autoreceptors; if that were the case inhibition of striatal serotonergic neuron firing by stimulation of their autoreceptors may result in maintaining a more physiological intrasynaptic dopamine concentration, thus improving motor fluctuations and dyskinesias (ref. 3).
Indeed, in rats rendered parkinsonian with 6-OHDA lesions, 5-HT1A receptor stimulation was reported to blunt peak concentrations and prolong the half-life of striatal dopamine (ref. 4).
The above assumptions seem to have gained support from the current study. The results demonstrated that sarizotan, a selective 5HT1A agonist, co-administered with L-dopa, reduced dyskinesias and prolonged the duration of action of L-dopa without reducing its anti-parkinsonian efficacy.
Levodopa still remains to be the most effective medication in the treatment of patients with PD. Its long term complications, however cause hesitation to start a treatment with L-dopa and also makes it diffcult to keep those patients on medication, which already have motor complications.
Accordingly, understanding how these complications occur, and strategies to avoid or to treat them have been in the focus of recent research.
These potential strategies include continous dopaminergic stimulation, modulation of cannoboid, opioid, glutamatergic, noradrenergic, serotonergic and adenozine receptors, some of which are in clinical development.
This small, but carefully conducted proof-of-concept study provides evidence that at least one of these strategis, serotonergic modulation may work.
Obviously a "proof-of-concept" study may prove the concept, but not yet the utility of this strategy, which will await confirmation from large scale randomized controlled trials.
References
1. Chase TN and Oh JD. Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications. Ann Neurol 2000; 47 (4 suppl 1); 122-129
2. Jenner P. Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments. J Neurol 2000; 247 (suppl 2); 1143-1150
3. Brotchie JM. Nondopaminergic mechanisms in levodopa-induced dyskinesia. Mov Disord 2005; 20 (8); 919-931
4. Kannari K, Yamato H, Shen H, et al. Activation of 5-HT(1A) but not 5-HT (1B) receptors attenuates an increase in extracellular dopmaine derived from exogenosuly administered L-dopa in the striatum with nigrostriatal denervation. J Neurochem 2001; 76 (5); 1346-1353