**3.2.1 5-HT loss and non-motor symptoms**

As previously mentioned depression and anxiety are some of the most common nonmotor symptoms in PD and are even associated with an elevated risk towards the development of PD (Leentjens et al., 2003; Schuurman et al., 2002; Shiba et al., 2000). The underlying pathophysiological mechanisms remain to be completely understood; however, it is well established that 5-HT dysfunction plays an important role in several mood-disorders in non-PD patients (Michelsen et al., 2008). Depression not only reduces the quality of life for PD patients but has a negative effect on caregivers as well (Schrag et al., 2000; 2004).

During the progression of PD it has been observed that brain regions, like rostral raphe, thalamus and cortex, that mediate mood disturbances in PD are severely affected by the presence of Lewy bodies (Braak and Del Tredici, 2008). Currently, most evidence linking abnormal serotonergic neurotransmission to mood disturbances in PD is corroborative but points to a role for 5-HT pathology. For example, depressed PD patients display reduced brainstem raphe echogenicity, in comparison to non-depressed PD patients (Walter et al., 2007a). Post-mortem comparisons of neuronal density in the dorsal raphe nucleus between depressed and non-depressed PD patients found lower neuronal density in depressed PD patients (Paulus and Jellinger, 1991). In vivo studies measuring cerebrospinal fluid levels found lower levels of 5-HIAA in depressed PD patients indicating reduced 5-HT metabolism (Mayeux et al., 1986). Imaging studies have been less conclusive and have found either no change in SERT uptake (Kim et al., 2003) or reported elevated 5-HT receptor binding in depressed PD patients when compared to non-depressed PD patients (Boileau et al., 2008). Interestingly, acute tryptophan depletion in a small group of PD patients did not produce depression or anxiety in these patients (Leentjens et al., 2006). Another major nonmotor symptom affecting PD patients is the development of psychosis that may lead to development of paranoid delusions in some PD patients (Ravina et al., 2007). The underlying cause remains to be elucidated and some investigators have postulated that there may be a serotonergic involvement. 5-HT2 receptors, responsible for hallucinations and psychosis, are relatively intact or may even be upregulated in the cortex of PD patients suffering from psychosis compared to PD patients free from any psychotic disorder (Cheng et al., 1991; Huot et al., 2010a).

Pathophysiology of Non-Dopaminergic Monoamine

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

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

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 Jaunarajs et al., 2011) .

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 disorders.
