Beyond Dopamine

Chapter 24

Beyond Dopamine: The Role of the Serotonergic System and Treatments in Understanding and Treating Visual Hallucinations in Parkinson Disease Dennis Velakoulis Royal Melbourne Hospital, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia

Ramon Mocellin Royal Melbourne Hospital, Melbourne, VIC, Australia; University of Melbourne and Melbourne Health, Melbourne, VIC, Australia

Andrew Evans Royal Melbourne Hospital, Melbourne, VIC, Australia

Mark Walterfang Royal Melbourne Hospital, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia

Visual hallucinations (VH) have long been associated with organic brain disease and are a common presentation in a range of reversible and degenerative brain disorders. One of the more common diseases associated with visual hallucinations is Parkinson disease (PD), and visual hallucinations in PD are often complex and detailed. Because patients are frequently distressed by these experiences, treatment of VH is often required. The pharmacological mainstay of the treatment of VH in PD has been antipsychotic medications such as quetiapine, olanzapine, and clozapine. The evidence base for using these medications is limited and their use is based on an underlying assumption that VH result from dopaminergic overactivity. This chapter reviews the literature regarding the neurobiological basis of VH in PD and uses our current understanding of anatomy and neurotransmitter systems to guide the pharmacological treatment of VH in this disorder. We have previously summarized three mechanisms (deafferentation, disinhibition, and central) for the generation of complex VH (Mocellin, Walterfang, & Velakoulis, 2006); a brief summary of this work is outlined subsequently. This is followed by a more detailed elaboration of the disinhibition mechanism of VH arising from brain stem structures and the contributions of serotonergic ascending systems. This understanding of the neuroanatomical and neurotransmitter underpinnings of VH then forms the foundation for a discussion regarding available and potential pharmacological treatments of complex VH in PD.

SIMPLE VERSUS COMPLEX VISUAL HALLUCINATIONS In 1838, Esquirol provided the earliest and simplest definition of a hallucination as a percept without an object, perceived as real and in the external environment (Esquirol, 1838). Slade refined this definition to refer to a percept-like experience in the absence of an external stimulus that is experienced as a true percept, is spontaneous and unwilled, and cannot readily be controlled (Slade, 1976). The initial understanding of the pathophysiology of VH postulated that their origin lay in irritative foci, such as those causing epileptiform activity after infection or trauma in cortical regions involved in vision (Walsh & Hoyt, 1969). These VH are usually brief, intermittent, and stereotyped, meeting criteria for “simple” VH (Cummings & Miller, 1987), and were informed by the cortical stimulation studies by Penfield and Perot in which occipital stimulation induced simple VH, with temporo-occipital and parieto-occipital stimulation resulting in more complex scenes (Penfield & Perot, 1963).

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Simple VH are perhaps the least common form of VH, and this model did not account for more complex, nonstereotyped, and continuous (or more “complex”) VH. These types of hallucinations were most particularly seen in blind people, which led to the theory first postulated by West (1962) that the loss of afferent input “releases” the visual and nearby cortex. The theory of VH as release phenomena, elaborated by Cogan (1973), provides a model for understanding how VH occur after lesions to more “proximal” structures, particularly in circumstances of visual loss such as Charles Bonnet syndrome (CBS) (Ffytche & Howard, 1999; Manford & Andermann, 1998; Mocellin et al., 2006; Santhouse, Howard, & Ffytche, 2000). This has been supported by functional magnetic resonance imaging (fMRI) studies that show selective tonic activity in visual cortical regions even when an individual is not hallucinating (Ffytche et al., 1998; Howard et al., 1997). Complex visual hallucinations (CVH) are differentiated from more simple, unformed hallucinations such as crudely formed flashes of light and color, or other indistinct forms. Although the form of CVH in organic brain disease can be heterogeneous, common features can be identified. The hallucinations may be vivid and colorful; include small people or children [Lilliputian hallucinations (LHs)]; involve regular patterns or disembodied faces or limbs; or include branching or tessellated patterns, vivid and colorful formed animals (real or bizarre), soldiers or others in uniform, or landscapes and complex scenes. CVH are frequently associated with a variety of visual distortions such as palinopsia, in which repeated images of a perceived image are seen or distortions of a face or head (prosometamorphopsia) (Manford & Andermann, 1998). CVH have been reported in a wide variety of clinical and nonclinical circumstances but are best described and characterized in peduncular hallucinosis, CBS, and the synucleinopathies such as PD and Lewy body dementia (LBD). VH in the presence of frontal dementia or atypical parkinsonian syndromes may indicate testing for genetic syndromes such as PRGN, C9ORF72, FUS, CADASIL, and Niemann Pick type C under the appropriate clinical circumstances. They may also occur as hypnopompic or hypnagogic phenomena in healthy individuals or in those in sensory deprivation states (Merabet et al., 2004) or with narcolepsy-cataplexy syndrome, delirium tremens, intoxication with psychoactive substances, or temporal lobe epilepsy (Manford & Andermann, 1998).

THE VISUAL PATHWAY AND MECHANISMS OF DISRUPTION LEADING TO VISUAL HALLUCINATIONS The anatomy of the primary visual pathway has been well described. Information from the retina passes along the optic nerve, chiasm, and tract to the lateral geniculate nucleus (LGN) in the thalamus, and thence to the optic radiation through the temporal lobe to the primary and secondary visual cortex (Fig. 24.1). The flow of visual information is modulated by ascending input from pedunculopontine and parabrachial nuclei, and raphe nuclei via the superior colliculi (Fig. 24.2), and involves the serotonergic, cholinergic, gamma-aminobutyric acid-ergic (GABAergic), and glutamatergic systems (Fig. 24.2). Interruptions to this system at any point, either in the primary direct pathway or in its ascending modulatory

FIGURE 24.1 Visual pathways. (A) Retinogeniculocalcarine (RGC) tract. Optical information from retina (1) passes along the optic nerve (2) through the optic chiasm (3) and optic tract (4) into the lateral geniculate nucleus of the thalamus (5), where it receives input from the superior colliculus (7) via the pulvinar (6) and then traverses the optic radiation (8 and 9) through temporal lobe (13) into visual cortex (10e12). (B) Intersection of ascending pathways. Optical information in RGC (1e8 and 11, as in Fig. 24.3) is modulated by ascending input from pedunculopontine and parabrachial nuclei (9) and raphe nuclei (10) via the superior colliculus (7). Hash-marked areas show regions where interruptions are known to produce VH: in the RGC tract via deafferentation; in the thalamus through a reduced signal-to-noise ratio, and in the ascending pathways via the removal of inhibitory control.

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FIGURE 24.2 Neurochemistry of vision. Input from the retina (1) reaches the lateral geniculate nucleus of the thalamus (2). This structure and the adjacent pulvinar of the thalamus (3), an accessory visual structure that may act to filter out eye movement “noise,” act as a junction between reticulo-geniculocalcarine and ascending brain stem circuits, receiving inhibitory serotonergic inputs from the raphe nuclei (6) and excitatory cholinergic inputs from the pedunculopontine and parabrachial nuclei (7). The reticular nucleus of the thalamus (8) also provides inhibitory GABAergic innervation to the geniculate, which is itself modulated by the same ascending cholinergic and serotonergic input. The glutamatergic excitatory circuits from the geniculate to the occipital cortex (5) are also modulated by the superior colliculus (4).

projections, may lead to VH. A series by Braun, Dumont, Duval, Hamel-Hebert, and Godbout (2003) suggested that occipital and occipitotemporal regions were the most commonly implicated cortical regions, and midbrain, cerebral peduncles, pons, and thalamus were the typically affected subcortical regions (Braun et al., 2003). The exact mechanisms underlying VH remain unclear but may involve “cortical release” or “deafferentation” phenomena (West, 1962) (Fig. 24.3A) and/or the disinhibition of projections from ascending pathways or intact nearby

FIGURE 24.3 (A) Deafferentation: Lesions responsible for pathway CVH in which deafferentation from ocular input results in “release” activity in the cortex. (B) Disinhibition: Lesions responsible for ascending CVH in which a loss of ascending inhibition to the geniculate results in a hyperexcited geniculate and excess glutamatergic activity in the optic radiation, with resultant poor-quality signal to the cortex. (C) Central: Lesions producing central CVH in which damage to the geniculate may again “deafferent” the striate cortex and lesions to the pulvinar of the thalamus may reduce the signalto-noise ratio of cortical input owing to a loss of the pulvinar’s “visual filter” function.

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visual cortex. Disruption of ascending inputs, for example at the level of the LGN, may lead to aberrant projections forward to the visual cortex (Fig. 24.3B) or a loss of central sensory filtering function and degradation of signal-to-noise (Fig. 24.3C). Lesions anywhere in the visual system, from ocular structures through optic nerve, chiasm, and tract structures, including ascending modulatory midbrain structures, can produce VH, which are usually complex in form (Galasko, Kwo-On-Yuen, & Thal, 1988; Lepore, 1990; Mocellin et al., 2006). To correlate the location of the lesion to the type of VH, Santhouse et al. used factor analysis in patients with CVH to establish anatomicalephenomenological correlates. Their study found that landscapes and groups of figures were associated with pathologically increased activity in the ventral temporal lobe, distorted faces with activity around the superior temporal sulcus, and visual perseveration and palinopsia with activity of the visual parietal lobe (Santhouse et al., 2000). Thus, at an anatomical level, whereas simple VH are most likely related to focal lesions of the ocular apparatus or occipital cortex, CVH occur when the quality or flow of information moving through the visual system is disrupted. Although lesion-based models afford some understanding of the anatomy of normal and abnormal visual processing, they do not shed light on functional or neurochemical changes such as are seen in substance intoxication or withdrawal, medication-related VH, or VH seen in global neurometabolic or neurodegenerative disorders such as delirium and dementia. Medications with anticholinergic (particularly antimuscarinic) properties are the most visually hallucinogenic (Perry & Perry, 1995), particularly in elderly people who generally have lower cholinergic tone than younger adults (Perry et al., 1992). Altered dopaminergic transmission in stimulant misuse and dopaminergic treatment of PD and other synucleinopathies suggest a role for dopamine transmission in VH (Angrist, Sathananthan, Wilk, & Gershon, 1974; Goetz, Vogel, Tanner, & Stebbins, 1998). Alterations in the GABAergic system that occur in benzodiazepine and alcohol withdrawal, which are often associated with CVH, implicate a loss of GABAergic cortical inhibition in withdrawal-associated VH (Nevo & Hamon, 1995), although this is likely to be mediated through other monoaminergic systems (Manford & Andermann, 1998). Finally, but less often considered, VH may also occur with perturbations to serotonergic transmission, an area which forms the focus of subsequent discussion. These otherwise disparate anatomical and neurochemical models of VH have been united in the perception and attentional-deficit model of Collerton et al., which focuses on deficits in object-based attention resulting from dysfunction in lateral frontal cortical systems combined with object-based perceptual deficits due to dysfunction in the ventral (“what”) as opposed to dorsal (“where”) visual stream (Collerton, Perry, & Mckeith, 2005). This can also be understood as a failure to integrate current sensory input with prior expectations and is consistent with intrusion of previously generated proto-objects into a currently perceived scene. Generation of multiple copies of previously perceived objects in this manner can explain repetitive VH or palinopsias. Unlike other models, this can account for VH whose origin is either predominantly lesion based or neurochemically driven, in addition to VH that occur in states of sensory deprivation or in hypnagogic or hypnopompic states.

COMPLEX VISUAL HALLUCINATIONS: THE ROLE OF LESION LOCATION The anatomy of the retinogeniculocalcarine tract is well understood, including how lesions of the tract at different levels produce classically described visual field defects (Fig. 24.3). The thalamic structures, the dorsal lateral geniculate nucleus, and the lateral pulvinar, lie at the center of this system and receive a number of inputs, predominately cholinergic and serotonergic, from the brain stem (Manford & Andermann, 1998). Although these inputs are not completely characterized in mammals, it appears that cholinergic input is predominately excitatory, originating from the parabrachial and parabigeminal nuclei, and serotonergic inputs are inhibitory. These mainly arise from the serotonergic nuclei of the dorsal raphe nuclei and also inhibit retinal input (Fig. 24.3B). Brain stem lesions may disrupt these serotonergic inhibitory raphe nucleus inputs, resulting in excitation of the dorsal LGN and dysregulation of retinal inputs resulting in CVH (Fig. 24.3B). Many hallucinogenic compounds, such as lysergic acid, are serotonergic agonists and may produce CVH (Siegel & Jarvik, 1975). The dorsal raphe nuclei have also been implicated in both the sleepewake cycle (Abrams, Johnson, Hollis, & Lowry, 2004) and regulation of REM and non-REM sleep (Wu et al., 2004) in mammals. Sleep-associated CVH may be seen in normal sleep (hypnopompic and hypnagogic hallucinations), sleep disorders (narcolepsy-cataplexy syndromes), delirium, and LBD. CVH in CBS are often accentuated in states of reduced consciousness or fading light. These clinical findings further suggest an important role of the dorsal raphe system in generating CVH. Thalamic lesions may directly affect critical structures such as the pulvinar or the associated brain stem inputs described previously. The primate pulvinar has an important role in simple visual processing but also visual salience (generating signals related to the salience of visual objects) and linking eye movement to this function (Grieve, Acuna, & Cudeiro,

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2000). Lesions in this area may generate CVH by disrupting these functions (Fig. 24.3C). Damage to retinal inputs in this area may also operate in the same fashion as a more proximal differentiating lesion. Whereas differing pathologies may lead to CVH, the form these hallucinations take may relate to particular cortical locations. Using factor analysis of clinical information collected from patients with CBS linked with predominately primate fMRI and neurophysiological information, Santhouse et al. (2000) postulated that CVH in CBS can be linked to hierarchical visual pathway streams. These workers suggested that hallucinations of extended scenes and people and objects (including LHs) are associated with the ventral occipitotemporal cortex, hallucinations of faces and facial distortions (prosopometamorphosia) with the superior temporal sulcus, and visual perseveration and delayed palinopsia (reappearance of a percept with shift in gaze after time delay) with visual parietal regions. These findings await further study and clarification.

SYNUCLEINOPATHY AND VISUAL HALLUCINATIONS Synucleinopathies are a diverse group of related neurodegenerative diseases characterized by abnormal a-synuclein metabolism, which in some instances result in the formation of intracellular inclusions known as Lewy bodies. PD-related dementia (PDD) and LBD are associated with cortical Lewy bodies and marked cholinergic deficit in areas involved in visual perception (Bohnen et al., 2003; Harding, Broe, & Halliday, 2002), loss of serotonergic and cholinergic neurons in brain stem nuclei that modulate transmission of visual information (Halliday, Blumbergs, Cotton, Blessing, & Geffen, 1990; Jellinger, 1990), and impaired contrast vision resulting from disrupted retinal dopaminergic function (Bodis-Wollner & Tagliati, 1993), each of which is a factor in the development of VH. Lewy bodies in mesial temporal structures (parahippocampal gyrus and amygdala) are particularly associated with an increased incidence of VH (Harding et al., 2002). VH may also relate to synuclein deposition in visual areas and altered ascending input from loss of serotonergic and cholinergic brain stem nuclei, whereas the use of dopaminergic medications in PD may worsen or bring forward the development of hallucinations.

The Origins of Visual Hallucinations in Parkinson Disease In a seminal study of VH in PD, Fenelon et al. found that VH are present in up to 40% of patients with PD and may consist of passage hallucinations, presence hallucinations, and formed or CVH (Fenelon, Mahieux, Huon, & Ziegler, 2000). These authors noted that dopaminergic treatments are not enough to explain the VH of PD and that the main predictors of CVH were cognitive impairment, daytime somnolence, and longer duration of PD (Fenelon et al., 2000). Based on their findings and the literature, they argued that the role of dopamine in VH in PD is complex. 1. 2. 3. 4. 5. 6.

Hallucinations were described in PD before the introduction of L-dopa. Early studies varied in terms of inclusion criteria, doses of dopa, and the description of psychiatric symptoms. There is no clear relationship between dose and hallucinations in PD. Anticholinergics can produce hallucinations in PD. Patients with non-LBD disorders treated with L-dopa rarely develop VH. VH occur early in the course of LBD (Fenelon et al., 2000).

In patients with unclassifiable parkinsonism, the presence of VH has been regarded as a “red flag” for underlying Lewy body pathology (Williams & Lees, 2005; Williams, Warren, & Lees, 2008). The same group identified that VH correlate highly with Lewy body pathology but not other parkinsonian syndromes such as progressive supranuclear palsy or multisystem atrophy (Williams & Lees, 2005). This latter study examined 788 cases of parkinsonism (445 patients with PD, 44 with LBD, and 255 with noneLewy body parkinsonism. The latter group included 127 with progressive supranuclear palsy, 91 with multisystem atrophy, 27 with vascular parkinsonism, nine with Alzheimer disease, nine with cortical-basal ganglionic degeneration, and eight with postencephalitic parkinsonism) (Williams & Lees, 2005). VH were identified in 50%, 73%, and 7% of patients with PD, LBD, and noneLewy body syndromes, respectively, and were best associated with cognitive dysfunction, autonomic dysfunction, early axial rigidity, and age at onset. VH were not correlated with the use of L-dopa or anticholinergics. The authors hypothesized that VH are not directly related to dopaminergic medication but could arise from an interaction between dopaminergic treatment and progressive Lewy body involvement of the visuoperceptual systems. In a postmortem study of patients with PD and VH, a strong relationship was identified between the presence of Lewy bodies in the amygdala and parahippocampal regions and CVH (Harding et al., 2002). A patient with severe, recurrent complex VH was scanned using fMRI and found to have increased activation in anterior regions (cingulate, insula, and frontal lobe), thalamus, and brain stem and decreased activation in visual processing

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posterior cortical regions (lingual, fusiform gyri, inferior occipital gyrus, and superior temporal lobes). The authors proposed that there is a desynchronization between posterior and anterior cortical areas during VH (Goetz, Vaughan, Goldman, & Stebbins, 2014). VH in the synucleinopathies are associated with cognitive impairment and disease severity but generally not medication (Barnes & David, 2001). In a study matching patients with DLB, PD, and Alzheimer disease on degree of cognitive impairment and visual acuity, individuals who had PDD and DLB had significantly impaired visual processing compared with those who had Alzheimer disease, and commensurately higher rates of VH (PDD, 75%; DLB, 90%; and AD, 8%) (Mosimann et al., 2004).

THE SEROTONERGIC SYSTEM AND VISUAL HALLUCINATIONS Anatomy of the Serotonergic System Serotonin (5-hydroxy tryptamine [5-HT]) was first linked to psychiatric symptoms, particularly depression and anxiety, in the 1950s. 5-HT cell bodies are found in the dorsal and basal raphe nuclei of the brain stem and provide serotonergic innervation to entire brain. To date, seven 5-HT receptors have been identified, most of which are postsynaptic receptors (Alex & Pehek, 2007). 5-HT neurons of the raphe nucleus innervate dopaminergic cell bodies and terminal regions within the midbrain and basal ganglia (Alex & Pehek, 2007). Of the seven receptor subtypes, the 5-HT2a and the 5-HT2c receptors are most relevant to models of VH in PD and are the best characterized with regard to medications used in the treatment of VH. 5-HT2a receptors are normally greatest in the middle layers of prefrontal and cingulate cortex, with lower levels identified in the striatum (Hall, Farde, Halldin, Lundkvist, & Sedvall, 2000). 5-HT2a receptor activation stimulates dopamine release from all three major dopaminergic pathways (nigrostriatal, mesocortical, and mesolimbic) (Alex & Pehek, 2007). In patients with PD, reduced levels of 5-HT2a receptor are found in temporal cortex, although increased levels of 5-HT2a receptors have been identified in the temporal cortex (Huot et al., 2010) and the ventral visual pathway (Ballanger et al., 2010) of patients with PD and VH. These latter findings have potential treatment implications for patients with PD and VH. 5-HT2c receptors are found in the ventral tegmentum, substantia nigra, striatum, and nucleus accumbens and the anterior cingulate cortex. These receptors are anatomically placed to modulate dopaminergic function, and in contrast to 5-HT2a receptors, they predominantly act to inhibit dopamine release (Alex & Pehek, 2007). It has been proposed that actions of antipsychotic drugs in schizophrenia may rely on a combination of dopaminergic blockade and 5-HTedriven dopaminergic modulation in prefrontal cortex, whereby the effect of differential antagonism of 5-HT receptors is to produce an elevation of tonic dopamine release and block phasic dopaminergic within the prefrontal cortex. Antagonism of 5-HT2c receptors may also be the reason why atypical antipsychotic drugs have fewer extrapyramidal side effects compared with typical antipsychotic drugs (Alex & Pehek, 2007; Meltzer & Massey, 2011).

Psilocybin and the Serotonergic System The best characterized substance relevant to the relationship between the serotonergic system and VH is psilocybin, a psychoactive alkaloid, which together with its active metabolite, psilocin, is a main ingredient of hallucinogenic mushrooms (Tyls, Palenicek, & Horacek, 2014). Psilocybin is structurally similar to serotonin and its hallucinogenic effects are associated with 5-HT2a agonism (Nichols, 2004), with subsequent increased striatal dopamine release (Vollenweider, Vollenweider-Scherpenhuyzen, Babler, Vogel, & Hell, 1998). Psilocybin was widely investigated in the 1960s as a research drug and is considered the archetypal drug for a serotonergic model of psychosis. Psilocybin induces a plethora of psychotomimetic effects including VH (but not auditory hallucinations), changes in body image, thought disorder, and religious and mystical experiences (Geyer & Vollenweider, 2008; Hasler, Grimberg, Benz, Huber, & Vollenweider, 2004). The nature of VH induced by psilocybin (tessellated and branching patterns, palinopsias, and color distortions) is similar to those experienced in a number of organic brain disorders including PD. Although psilocybin psychosis has been used as a model for schizophrenia, its clinical effects are equally relevant, if not more so, to an understanding of the neurobiology of VH in PD. Psilocybin-induced psychotic experiences are reversed by risperidone (5-HT2c and D2 antagonist) and ketanserin (5-HT2a antagonist) but not by haloperidol (D2 antagonist) (Kometer, Schmidt, Jancke, & Vollenweider, 2013; Vollenweider et al., 1998). The failure of D2 antagonists to treat psilocybin-induced VH has implications for the treatment of VH in PD, especially because D2 antagonists are undesirable in PD owing to their motor effects.

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Parkinson Disease and the Serotonergic System The nigrostriatal dopaminergic pathway begins with cell bodies in the substantia nigra projecting to the caudate and putamen. 5-HT neurons of the raphe nucleus innervate dopaminergic cell bodies and terminal regions within the midbrain and basal ganglia (Alex & Pehek, 2007). 5-HT neurones are able to metabolize exogenous L-dopa into dopamine and may release dopamine into the striatum. This is thought to be a possible mechanism for the induction of dyskinesias in patients with PD who are treated with L-dopa (Huot, Fox, & Brotchie, 2011). Postmortem studies of patients with PD have identified neuronal loss and Lewy bodies within raphe 5-HT neurons (Halliday et al., 1990), up to 50% reduction in 5-HT transporter levels within cortical areas to which the neurones project (Damato et al., 1987), and reduced 5-HT levels in basal ganglia, hypothalamus, and thalamus (Huot et al., 2011). However, clinicopathological studies have failed to identify a significant relationship between the raphe pathology and clinical features of PD. A study using a 5-HT2a positron emission tomography ligand in patients who had PD with and without VH found that the patients with VH had increased 5-HT2a binding in the ventral visual pathway and frontal cortex (Ballanger et al., 2010). These findings add weight to evidence for the potential use of selective 5-HT2a antagonists in the treatment of VH.

PHARMACOLOGICAL INTERVENTIONS FOR VISUAL HALLUCINATIONS IN PARKINSON DISEASE D2 Antagonism Traditionally, dopamine D2 receptor blocking antipsychotic agents have been used to treat psychotic symptoms in PD, with a preference for atypical agents that have less extrapyramidal symptoms such as clozapine and quetiapine (Chou, Borek, & Friedman, 2007; Weintraub & Stern, 2005). Clozapine remains the only antipsychotic considered to be effective and tolerable in PD with psychosis, but its side-effect profile (agranulocytosis) and frequent local restrictions on prescribing prevents its widespread use for this indication. It is effective in PD with psychosis at doses much lower than those used in schizophrenia (25e50 mg compared with 300e800 mg). At these low doses, clozapine has a far greater 5-HT2a antagonist effect than dopamine D2 effect (Meltzer, Kennedy, Dai, Parsa, & Riley, 1995). Quetiapine is a widely used alternative to clozapine in PD with a receptor profile similar to that of clozapine, with high 5-HT2a receptor antagonism and lower D2 antagonism (Gefvert et al., 2001). Despite this favorable profile, several placebo-controlled trials have not shown quetiapine to be better than placebo in the treatment of psychosis in PD (Ondo, Tintner, Voung, Lai, & Ringholz, 2005; Rabey, Prokhorov, Miniovitz, Dobronevsky, & Klein, 2007; Shotbolt, Samuel, & David, 2006). In their study, Rabey et al. attributed this finding to a high incidence of patients with delusions and hallucinations compared with an earlier study which found quetiapine to be better than placebo (Juncos et al., 2004) and which included a high proportion of patients with VH. An alternative explanation, however, may relate to the dose of Ldopa drugs used in each study. The average L-dopa dose used in the study by Rabey et al. was about 600 mg daily, compared with 300 mg in the study by Juncos et al. It could be that the psychotic symptoms of the patients receiving higher doses of L-dopa (Rabey et al., 2007) were related to L-dopa rather than to the neurobiological effect of PD, and that quetiapine is effective in those patients with PD whose VH were induced by the PD itself.

Serotonin Antagonism Because of the problematic clinical problem of treating VH in PD with drugs which block dopaminergic receptors, attention has been drawn to medications which act at 5-HT receptors but not dopaminergic receptors (Meltzer et al., 2010; Meltzer & Roth, 2013). Pimavanserin, a 5-HT2a inverse agonist, has 40 times lower affinity for the 5-HT2c receptor and no activity at dopaminergic, muscarinic, adrenergic, or histaminergic receptors (Vanover et al., 2006). A number of studies have investigated its role in the treatment of psychosis in PD. In a placebo-controlled, double-blind trial of 30 patients with PD and psychosis, pimavanserin was shown to have minimal impact on motor symptoms in PD and to improve hallucinations (visual and auditory) in patients with PD and psychosis (Meltzer et al., 2010; Meltzer & Roth, 2013). Pimavanserin was significantly better than placebo in treating delusions and thought disorder. In contrast to antipsychotic medications, the side-effect profile of pimavanserin was similar to that of placebo. The authors of that study did not report L-dopa doses of the patients, which preclude any comment on whether the patient group may have been vulnerable to the psychotogenetic effects of higher-dose L-dopa induced.

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In a larger, more recent phase III study, 199 patients with PD and psychosis were randomly allocated to placebo or pimavanserin. The treated group had significantly reduced psychotic symptoms with a 37% improvement at 6 weeks compared with a 14% improvement in the placebo group. Pimavanserin treatment was associated with less carer burden, better sleep, and no motor dysfunction compared with the placebo treatment group. The authors did not comment on any differential effect of pimavanserin on hallucination subtypes. Because of its potential antipsychotic effect, pimavanserin has also been investigated in the treatment of schizophrenia. In a double-blind, randomized control study of 423 patients with schizophrenia, the addition of pimavanserin to 2 mg risperidone produced better outcomes (efficacy and safety) than 6 mg risperidone or haloperidol (Meltzer et al., 2012). The authors advocated for its use as an adjunctive treatment in schizophrenia to reduce extrapyramidal motor side effects of traditional antipsychotic medications.

SUMMARY The treatment of VH in PD poses a significant clinical issue for neurologists, psychiatrists, and geriatricians. To date, antipsychotic medications have been the mainstay of treatment based on the assumption that dopaminergic blockade is required for the treatment of psychotic symptoms. However, these drugs are associated with motor and other side effects which limit their dosing and compliance. Current knowledge about the visual pathways and the role of the serotonergic system suggests that serotonergic systems are affected by the PD process and may have a significant role in the genesis of hallucinations. Treatments aimed at 5-HT antagonism may offer more effective, safer, and better tolerated pharmacologic treatment for patients than may dopaminergic-blocking drugs.

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