2.1. Treatments for Non-Motor Symptoms in the Early Stage

2.1.1. Olfactory Dysfunction
Olfactory dysfunction is a typical symptom complained about in the early stage of the disease. It seems to affect more than 80% of patients, but only about 40% of them are aware of an impaired sense of smell [21]. A recent study has reported that olfactory dysfunction is associated with decreased dopamine transporter binding in more than 40% of patients [22]. In a small cohort of patients with idiopathic RBD (iRBD), the presence of smell impairment has been detected as a predictive value for conversion to PD and to Parkinson disease with dementia (PDD) over 5 years [23].
According to previous studies, hyposmia seems to be related to neuronal loss in cortico-medial amygdala or to decreased dopaminergic neurons in the olfactory bulb. This disturbance, which generally affects both nostrils, tends to correlate directly with disease duration and severity [24,25]. Furthermore, smell loss has been related to an increased risk of cognitive decline and it is consequently a prodromal symptom of PDD onset. Currently, hyposmia cannot be treated by any anti-PD drugs [26,27].

2.1.2. REM Sleep Behavior Disorder (RBD)
RBD is a parasomnia characterized by loss of REM sleep atonia, which results in vigorous, violent motor jerks, and nocturnal vocalizations in association with vivid dreams [28]. The prevalence of iRBD is not well known, although about 5%–8% of the Caucasian population aged over 60 years seems to be affected by this sleep disturbance [29]. RBD occurs in up to 50% of PD patients and it can precede by several years the onset of synucleinopathies, such as PD, Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA) [30]. Some evidence suggests that RBD, which is a potential predictor of disease severity, can be associated with an akinetic-rigid subtype of PD, characterized by a more pronounced autonomic dysfunction and an increased risk of cognitive impairment or dementia [31]. Diagnosis is based on polysomnography (PSG), because other pathological conditions, such as non-REM parasomnias and obstructive sleep apnea, can mimic RBD [17].
Clonazepam and melatonin are first-line treatments for RBD. Clonazepam is a long-lasting benzodiazepine, which does not suppress motor tone during REM sleep but prevents dream enactment behavior onset, through uncertain mechanisms [25]. The treatment dose is 0.5 to 2.0 mg before bedtime and it is rarely associated with dosage tolerance and side effects (<10% of cases), such as daytime sedation, worsening of obstructive and central sleep apnea, alopecia, depression, memory impairment, and gastroesophageal reflux. Thus, Clonazepam is completely or partially successful in up to 90% of patients with RBD [32,33]. Although it is the most common used drug for RBD, current evidence about its effectiveness have only been based on observational studies (retrospective cohorts and case-series). In addition, clinical studies have been conducted with small cohorts of patients and without using PSG to value treatment response [34].
Melatonin can be prescribed as a first-line therapy for patients with poor tolerance or contraindications to Clonazepam, such as dementia, obstructive sleep apnea, and an increased risk of falls [35]. It is a hormone released by the pineal gland in a circadian pattern, whose levels rise shortly after nightfall reaching a peak in the middle of the night [36]. Thus, its role is to regulate the sleep-wake-cycle. Treatment should be administered at high doses (2 to 10 g) at bedtime. Melatonin can be used in monotherapy or as add-on therapy in PD patients with RBD [37,38], as suggested in previous studies in which doses of this substance have successfully treated RBD with few side effects [39,40].
A limited number of studies have examined the efficacy of melatoninergic agonists in RBD, such as Agomelatine, Ralmeteon, and Tasimelton. One case series [41] has reported a positive effect of agomelatine in three patients with iRBD without adverse effects. Recently, two studies [39,42] have reported the clinical effectiveness of Ralmeteon, a new melatoninergic agonist, already released in some countries to treat insomnia. To date, no studies on Tasimelton efficacy for RBD treatment have been published.
Dopaminergic drugs have demonstrated contrasting profiles of efficacy in RBD. A prospective case series has reported RBD onset after 1 year of Levodopa (l-dopa) treatment in five out of 15 PD patients [43]. Another study has reported that PD patients with RBD generally used higher doses of l-dopa [44] in comparison with those without RBD at the same stage of disease. Pramipexole, in doses up to 2–4 mg at bedtime, has been shown to be effective in 62%–89% of patients with iRBD, RBD associated with mild cognitive impairment, or RBD with mild PD [45,46]. In contrast, another study has not reported severity or frequency decrease of RBD when pramipexole has been added to a stable l-dopa dose [47].
Acetylcholinesterase inhibitors (AChEI), such as Donepezil, in doses of 10–20 mg, and Rivastigmine, in doses up to 6 mg at bedtime, seem to be effective in RBD treatment. The role of AChEI in RBD is supported by experimental studies which have documented that cholinergic neurons, situated in upper pontine tegmentum and mesencephalon, become active during REM phase and may regulate REM sleep and atonia [48,49]. These neurons are involved via direct or indirect inhibitory descending pathway through the reticular magnocellular tract and glycinergic neurons on the spinal motor neurons [50]. Thus, neurodegenerative processes in PD may induce a dysfunction of this nucleus and its afferent or efferent pathways, resulting in loss of the normal inhibition of motor neurons [51].
Effects of Memantine on sleep disturbances have been evaluated in a multicenter study, in which [45] patients with RBD were included. Memantine, a glutamatergic antagonist, might reduce these disorders, but its validity has been limited by the absence of PSG to support RBD diagnosis [52]. Sodium oxybate, an agent used to treat narcolepsy, has been documented to be effective as monotherapy or as add-on therapy in RBD in some cases [53,54]. The role of Cannabidiol (CBD) in PD with RBD has also been evaluated in a pilot study. CBD, used in doses ranging from 75 to 300 mg for six consecutive weeks, has shown up to 80% frequency decrease of sleep disturbances [55].

2.1.3. Constipation
Constipation, the most common gastrointestinal disturbance in PD, may occur in up to 29% of patients [56] and it can be present 20 years before the onset of motor symptoms [57]. Therefore, disease-related pathophysiological mechanisms and drug side effects have been identified to cause this gastrointestinal disturbance, although physical weakness and lifestyle risks, such as reduced fluid intake, may promote its onset [58]. According to recent evidence, prebiotic fibers and probiotics have been considered efficacious and clinically useful to treat constipation [59]. Macrogol, an osmotic laxative, is an alternative drug with a good efficacy and safety profile. Lubiprostone, an intestinal chloride secretagogue, is an oral bicyclic fatty acid derived from prostaglandin E1 that selectively activates type 2 chloride channels (ClC-2) in the apical membrane of the gastrointestinal epithelium. It therefore softens stools and increases motility [60]. Currently, its use is not accepted in all countries. Use of antiparkinsonian drugs for constipation remains a subject of controversial debate. Whereas some authors have related constipation to dopaminergic treatments [60,61], others have contrarily suggested that l-dopa might improve gastrointestinal symptoms [62]. Moreover, anticholinergics drugs are contraindicated in PD patients suffering from constipation [63].

2.1.4. Depression and Anxiety
Depression may precede motor symptoms in 30% of PD patients [64]. It may be explained through a decreased activity in orbitofrontal and limbic cortices. Moreover, previous studies have documented a correlation between disease severity and depression [65]. The prevalence of anxiety in PD patients is 25%–40%, which is generally characterized by panic attacks, phobias, and generalized anxiety disorder [66]. Approximately 92% of patients tends to manifest anxiety disturbances in association with depression. It is suggested that it can be related to several neurotransmitter deficits, involving serotonergic, adrenergic, and dopaminergic systems.
According to a recent update [60], Tricyclic Antidepressants (TCAs) can be considered “possibly useful” to treat depression. Evidence seems to be insufficient for the use of Amitriptyline, although a recent review has shown that it seems to be more effective than other antidepressants [67]. Treatment of PD patients with TCAs may result in psychosis, sedation, and daytime sleepiness as well as in cognitive dysfunction or delirium when used in patients with PDD. Regarding the use of Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Venlafaxine seems to present the best effective profile, although other antidepressants such as Citalopram, Sertraline, Paroxetine, and Fluoxetine are considered possibly useful in clinical practice. As a result of conflicting efficacy data, there are still “insufficient evidence” for all SSRIs reviewed. SSRIs have been found to present an improved safety profile in comparison with TCAs in studies conducted in psychiatric populations. SSRIs may worsen PD tremors in up to 5% of patients and occasionally worsen other features of parkinsonism [68]. In addition, Citalopram, used in a daily dose of more than 20 mg, may cause a QT interval (QTc) prolongation in patients over 60 years [60]. Moreover, Serotonin syndrome may occur when SSRIs or SNRIs are used in association with Monoamine oxidase B inhibitors (MAO-BIs), such as Selegiline and Rasagiline [69]. PD-related depression may also be treated with second generation non-ergot Dopamine agonists (DA) such as Pramipexole [70]. A new study has evaluated Rotigotine with negative outcomes. Currently, insufficient evidence is present for the use of MAO-BIs [60].
Anxiety disturbances in PD patients may contribute to relevant impairments in cognitive functions, in motor performances, and in quality of life. Pharmacological agents, including benzodiazepines, Buspirone, and SSRIs, may reduce anxiety. For example, although benzodiazepines (such as Bromazepam) seem to be effective, their long-term use is associated with confusion, gait disturbance, and increased risk of falls. However, because of the current lack of evidence in efficacy and safety profile, pharmacological therapies should be used under careful evaluation [70].

2.1.5. Impulse Control Disorder
Impulse Control Disorder (ICD) (i.e., hypersexuality, gambling, binge-eating, compulsive shopping or hobbying, punding, and homeostatic hedonism disorders) are more frequent in young, male patients [71]. ICD main risk factors include dopaminergic replacement therapy, in particular with DAs (14%–17% of cases), and disease duration [72,73]. In these patients, DA therapy should be discontinued (or at least reduced until ICD cessation) with proportional l-dopa dose adjustment. However, some patients could experience DAWS, with mood, autonomic, and sleep disorders, requiring careful symptomatic management [72].
Other NMS, which can appear in the early stage but are prominent during the progression of disease, will be later discussed.