**5. References**

534 Etiology and Pathophysiology of Parkinson's Disease

Drugs acting on the serotonergic system are currently the standard of care for the treatment and management of psychiatric dysfunction, like anxiety, depression and psychosis in PD, despite causal evidence or 5-HT dysfunction in PD-related mood disorders. Most of the SSRIs currently used act by elevating the extracellular 5-HT levels and thus act indirectly on various post-synaptic 5-HT receptors, many of which have been implicated in mood disorders (Dobkin et al., 2011; Dobkin et al., 2010; Fox et al., 2009; Menza et al., 2009; Weintraub et al., 2006). The other potential side effects such as postural hypotension, sedation and 5-HT syndrome, due to 5-HT1 receptor stimulation, continue to limit the use of these antidepressants in PD patients (Veazey et al., 2005). It is important to note that many PD patients suffer from orthostatic hypotension and tremors and these could get exacerbated. Nefazodone, a 5-HT2 receptor antagonist/re-uptake inhibitor has been used as an antidepressant and to reduce

Psychotic complications usually treated with drugs that have an anti-dopaminergic profile are not ideal for the PD patient since it can lead to worsening of motor symptoms. Therefore, atypical antipsychotics, like Clozapine and Quetiapine, have been found to be effective in treating psychosis in PD patients (Kurlan et al., 2007), an effect attributed to their 5-HT2 receptor antagonistic properties. Another non-selective 5-HT2 receptor antagonist Mianserin has been demonstrated to reduce visual hallucinations in a small group of PD patients without affecting the parkinsonian motor symptoms. Preliminary findings from a Phase II study evaluating Pimavanserin, a 5-HT2A receptor inverse agonist, are encouraging and show a

trend in improving psychosis without affecting PD motor scores (Meltzer et al., 2010).

It is of interest to note that l-DOPA therapy has been traditionally assumed to improve affective symptoms, like depression and anxiety; however, emerging evidence suggests that chronic use of l-DOPA may aggravate mood problems (Eskow Jaunarajs et al., 2011). Preclinical investigations have reported that 6-OHDA-lesioned rats chronically treated with l-DOPA exhibit reduced 5-HT and 5-HIAA levels (Carta et al., 2007; Eskow Jaunarajs et al., 2011). Studies employing in vivo microdialysis have confirmed reductions in 5-HT levels, after acute l-DOPA, in the 6-OHDA-lesioned striatum as well as in non-motor affective sites (Navailles et al., 2010). Chronic l-DOPA treatment has been demonstrated to reduce expression of tryptophan hydroxylase within the dorsal raphe nucleus, which may lead to reduced 5-HT synthesis and release in efferent structures (Eskow Jaunarajs et al., 2011). l-DOPA uptake and release of DA by 5-HT terminals into the striatum may compete with native 5-HT function leading to an aggravation of affective disorders like depression and anxiety in PD patients undergoing chronic l-DOPA therapy (Eskow

In sum, drugs acting on the serotonergic system provide some symptomatic relief for PD patients. However, l-DOPA therapy by itself has the potential to exacerbate mood

In conclusion, there exists convincing evidence that both 5-HT and NE systems are severely affected in PD and that they contribute towards PD progression and symptoms. Therapeutics targeting these systems appear beneficial; however, more research is necessary

to develop more efficacious therapeutic targets and strategies.

**3.2.2 Treatment of non-motor symptoms with serotonergic drugs** 

extrapyramidal symptoms in PD patients (Avila et al., 2003).

Jaunarajs et al., 2011) .

disorders.

**4. Conclusion** 


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