Drug insight: new drugs in development for Parkinson's disease

For many years, levodopa has given most patients with Parkinson's disease excellent symptomatic benefit. This agent does not slow down the progression of the disease, however, and it can induce motor fluctuations and dyskinesias in the long term. The other available antiparkinsonian agents also have drawbacks, and as a consequence research into antiparkinsonian drugs is expected to take new and different directions in the coming years. The most promising approaches include the development of 'neuroprotective' drugs that are capable of blocking or at least slowing down the degenerative process that is responsible for cellular death; 'restorative' strategies intended to restore normal brain function; more-effective agents for replacing dopamine loss; and symptomatic and antidyskinetic drugs that act on neurotransmitters other than dopamine or target brain areas other than the striatum. In this Review, we discuss the numerous drugs in development that target the primary motor disorder in Parkinson's disease

Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT2A) receptor blockade. We postulated that pimavanserin (ACP-103), a highly selective 5-HT2A inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of pimavanserin was compared with placebo in 60 patients with -DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosis-relevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to pimavanserin, the SAPS total domain score, only showed a trend. However, the pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT2A receptor antagonism