Efficacy of the mixed 5-HT2 antagonist/SSRI, nefadozone in Parkinson’s disease

The aging population, combined with new and improved treatments for neurodegenerative disorders such as Alzheimer's and Parkinson's disease will lead to an expansion of the already $30 billion neurodegenerative market. The market for Alzheimer's disease therapeutics is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Between 2005 and 2010, drugs for treating Alzheimer's disease could achieve sales of well over $2 billion. Parkinson's disease affects some four million people worldwide. It is a progressive disorder of movement characterized by a progressive loss of dopamine neurons in the pars compacta of the substantia nigra and various extrapyramidal features including resting tremor, rigidity, bradykinesia, postural instability, and freezing. The current worldwide market for the treatment of Parkinson's disease is estimated to be approximately $1.5 billion with an estimated annual growth of 10% (click here for a full analysis of this field see our recent feature “Neurodegenerative Disorders: World Markets 2002-2007”).

Depression is thought to affect 40-50% of Parkinson’s disease sufferers, a symptom that has been treated with the usual antidepressants from the tricyclic and more recently the selective serotonin uptake inhibitor (SSRI) classes of drug. Treatment has however been reported to speed the development of Parkinson’s disease in some patients.

In a recent study Avila et al have investigated the therapeutic activity of BMS’s nefadozone, a serotonin 5-HT2 receptor antagonist with additional SSRI activity. In their single-blinded study of 16 patients treated for 90 days with either nefadozone or the SSRI, fluoxetine, Avila et al found that nefadozone reduced overall Parkinson’s disease activity, including a reduction in the aspects of disease related to motor dysfunction. Fluoxetine was without affect. Depression was reduced equally by both treatments suggesting that antidepressants with a mixed 5-HT2 receptor antagonist/SSRI profile may be of especial benefit to Parkinson’s disease patients with depression. This effect is likely related to the inhibitory role that 5-HT2A receptor have in the nigrostriatal dopamine pathway. Thus, while SSRIs increase synaptic 5-HT facilitating 5-HT2A receptor activation, which in turn initiates a dopamine break, SSRIs with additional 5-HT2 receptor antagonist activity would be expected to limit serotonergic inhibition of dopamine release. Further clinical trials are awaited.

Entry date Wednesday, November 12, 2003

Adapted from Avila et al, J Clin Psychopharmacol. 2003 Oct;23(5):509-13.