Neuropsychiatric symptoms in parkinsonian syndromes: A narrative review

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ACHAIKI IATRIKI | 2024; 43(3):118–131

Review

Antonios Alexandros Demertzis1, Aikaterini Andrianopoulou1, Maria Karampa1, Dorothea Maria Kechagia1, Asimina Pachi1,2, Marina Charalampopoulou3, Panagiotis Felemegkas3, Eliza Eleni-Zacharoula Georgiou3, Eleni Konidari3, Maria Skondra3,4, Panagiotis Alexopoulos3,5,6,7

1Department of Medicine, School of Health Sciences, University of Patras, Patras, Greece
2Skopelos Primary Healthcare Centre, Skopelos, Greece
3Mental Health Services, Patras University General Hospital, Department of Medicine, School of Health Sciences, University of Patras, Patras, Greece
4Department of Nursing, School of Health Rehabilitation Sciences, University of Patras, Patras, Greece
5Global Brain Health Institute, Medical School, Trinity College Dublin, The University of Dublin, Dublin, Republic of Ireland
6Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich, Munich, Germany
7Patras Dementia Day care centre, Patras, Greece

Received: 02 Jan 2024; Accepted: 24 May 2024

Corresponding author: Dr. Panagiotis Alexopoulos, Mental Health Services, Patras University General Hospital, Department of Medicine, School of Health Sciences, University of Patras, Tel.: +30 2613 603728, Fax: +30 2610 996664, E-mail: panos.alexopoulos@upatras.gr

Key words: Parkinson’s disease, dementia with lewy bodies, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, behavioral and psychological symptoms in dementia

 

Abstract

Parkinsonian syndromes, the most common of which are Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and Multiple System Atrophy (MSA), manifest with motor symptoms, cognitive deficits and neuropsychiatric symptoms. This narrative review offers valuable insights into the neuropsychiatric phenotypes of diseases causing parkinsonian syndromes. Depressive symptoms, apathy and anxiety are common across these disorders. Conversely, hallucinations and delusions are significantly more characteristic of PD and DLB pathology. The involvement of diverse symptomatology renders treatment challenging, especially since interventions targeting specific symptoms can potentially exacerbate others. In particular, the pharmacological management of psychosis in PD and DLB presents a dilemma as treatment with antipsychotic agents that are included in the World Health Organisation (WHO) model list of essential medicines can in many cases aggravate motor symptoms, while cholinesterase inhibitors are commonly not reimbursed or entirely unavailable in low- and middle-income countries (LMIC). In addition, data on the efficacy of non-pharmacological interventions in managing neuropsychiatric symptoms in parkinsonian syndromes are succinctly presented. Our review highlights the need for a comprehensive delineation of neuropsychiatric symptoms as a core, albeit commonly neglected, aspect of the phenotypes of parkinsonian syndromes and as a therapeutic challenge.

BACKGROUND

Parkinsonian syndromes are characterized by complex phenotypes which comprise but are not restricted to extrapyramidal symptoms, including bradykinesia, ataxia, resting tremor and rigidity [1,2]. These syndromes can encompass cognitive deficits, occurring in early or more advanced stages of the syndrome course, dysautonomia, gaze palsy, myoclonus, pyramidal tract signs and the alien limb phenomenon, as well as neuropsychiatric symptoms. The latter refer to symptoms like apathy, depressive mood, aggression, anxiety, irritability, appetite disturbances, delusions, disinhibition, hallucinations, euphoria [3,4]. Of note, neuropsychiatric symptoms are very common in the course of neurodegenerative diseases and pose a heavy burden to both patients and their care partners [5,6].

Parkinsonian syndromes are commonly caused by Parkinson’s disease (PD) or by Parkinson-plus diseases [2], which are pathophysiologically classified either as alpha-synucleinopathies or tauopathies [1,7]. The most common Parkinson plus conditions are dementia with Lewy bodies (DLB), multiple system atrophy (MSA), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) [7]. PD, DLB and MSA are characterized by inclusions formed by alpha-synuclein, i.e. Lewy bodies, while in CBD and PSP cytoskeleton proteins become abnormally phosphorylated, leading to the development of tau inclusions in neurons and glial cells [8,9].

Here, a succinct overview of neuropsychiatric symptoms in parkinsonian syndromes is provided. The terms neuropsychiatric symptoms, behavioural and psychological symptoms and non-cognitive symptoms of dementia are commonly interchangeably used. The objective of this narrative literature review is to synthesize the emerging literature detailing neuropsychiatric symptoms in parkinsonian syndromes. The review sheds light on neuropsychiatric symptoms that shape the clinical phenotypes of these syndromes. Additionally, it reports on strategies that have been developed for their management with special focus on low- and middle-income settings and on the World Health Organisation (WHO) recommendations for essential medicines for mental disorders [10].

Search strategy and eligibility criteria

A non-systematic approach was employed, searching the PubMed, PubMed Central, and Google Scholar databases from December 2022 to January 2023 for relevant articles. Search terms included: “neuropsychiatric symptoms”, “behavioral and psychological symptoms”, “non-cognitive symptoms”, “depression”, “anxiety”, “aggression”, “irritability”, “appetite disturbances”, “delusions”, “disinhibition”, “hallucinations”, “euphoria” and PD, DLB, MSA, CBD or PSP. Eligible studies were studies published in English and which referred to people diagnosed with PD, DLB, MSA, CBD or PSP.

Parkinson’s disease

PD is the second most common neurodegenerative disease, following Alzheimer’s disease [11]. Its prevalence is expected to increase significantly over the following 20 years, propelled by the aging population and the advancements in clinical care and therapeutic strategies. In addition to motor symptoms, the clinical presentation of PD encompasses cognitive changes, behavioral/neuropsychiatric changes, and symptoms related to autonomic nervous system failures [12].

Depression is among the most common non-motor symptoms of PD. Approximately 40-50% of people with PD experience mild to severe depressive symptoms [13]. The point prevalence for major depression is reported to be 17% [14]. Clinical signs of depression in patients with PD include psychomotor retardation, decreased energy, fatigue, sleep- and appetite changes as well as mood alterations. Diagnosing depression in individuals with PD can be challenging due to the overlapping clinical presentations of the two conditions [15].

Depression has detrimental effects on quality of life, symptoms and the burden on care partners [15,16]. Besides the emotional toll associated with the confrontation with a progressive neurodegenerative disease leading to multifaceted disability, the development of depressive symptoms appears to be linked to neurobiological factors [13]. Of note, the onset of depressive symptoms can even precede motor symptoms. Thus, the neurodegenerative process may contribute to prodromal mood disturbances. Interestingly, in PD related brain pathological changes can extend beyond the midbrain and can include discrete loss of noradrenergic and serotonergic neurons, pertaining to mood regulation [13].

Treatment involves different strategies, depending on the severity of depressive symptoms. Pharmacotherapy of depressive symptoms in PD includes selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) (Table 1) [15,17]. SSRIs, especially citalopram and sertraline, are well tolerated and relatively safe for people with PD [16], while TCAs have more adverse effects and should be carefully used despite their high antidepressive efficiency. Of note both SSRIs and TCA amitriptyline are included in the 2023 WHO list of essential medicines and are expected to be available in all countries across the globe [10]. Serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and dopamine agonists have also been used in the treatment of depressive symptoms in PD [17]. Non-pharmacological interventions such as electroconvulsive therapy, transcranial brain stimulation and cognitive-behavioral therapy (CBT) were shown to be effective in managing depressive symptoms in PD [17]. In particular, CBT is very promising regarding working both with people with PD and their care partners, so that their distress is diminished [17,18].

Psychotic symptoms and Impulsive-compulsive Behaviors (ICBs) are further neuropsychiatric symptoms of PD. Psychosis in PD has been associated with older age and longer disease duration. In particular, the prevalence of psychosis increases from 3% around the time of PD diagnosis to 10% two years after the initial diagnosis [19]. In another study, in 82.7% of individuals with PD, psychosis spectrum symptoms were observed over a period of 36 months [20]. The point prevalence of psychotic symptoms in PD is 25–40%, while the cumulative incidence during the disease is 50–60% [14]. Even though visual hallucinations are the most common psychotic symptoms in PD, minor hallucinatory phenomena (sense presence, passage hallucinations, illusions), delusions and non-visual hallucinations may also exist [21]. In addition, ICBs have been reported in 3.5 to 43% of people with PD using dopamine replacement therapy, while people manifesting ICBs are more likely to use dopamine agonists than individuals with PD but without ICB [22]. Point prevalence of ICBs is estimated to be 14% and 5-year cumulative incidence 46% [14]. ICBs include among others hypersexuality, pathological gambling, excessive eating and buying, hoarding and the Dopamine Dysregulation Syndrome which is characterized by addictive behavior and excessive use of dopamine replacement therapy [23,24,25]. Both psychotic symptoms and ICBs in PD are pathogenetically linked to the treatment with dopamine agonists (DA) [16,26].

Regarding the management of psychotic symptoms in PD, it is important to differentiate the treatment strategy of an acute and potentially life-threatening PD psychosis, the onset of which is sudden, from a chronic setting. Acute psychotic symptoms are primarily managed with the treatment of the underlying cause, including general measures, treatment of specific triggers, adaptation of medication, and/or addition of cholinesterase inhibitors in cognitively impaired individuals with PD (rivastigmine, donepezil, or galantamine) and antipsychotics such as clozapine or quetiapine when not manageable with the previously mentioned steps [27]. Of note, quetiapine is considered a therapeutic alternative to risperidone in the 2023 WHO model list of Essential Medicines [10]. The treatment of chronic psychotic symptoms in Parkinson’s Disease (PD) focuses on adjusting dopaminergic medication without worsening motor function or causing withdrawal symptoms from dopamine agonists. These withdrawal symptoms can include anxiety, dysphoria, fatigue, dysautonomia, sleep disturbances, generalized pain, and medication cravings. This severe and stereotyped withdrawal syndrome is specific to dopamine agonists and cannot be alleviated by levodopa or other PD medications [28,29]. The recommended order for reducing medication is as follows: anticholinergic agents, selegiline, amantadine, dopamine receptor agonists, COMT-inhibitors, and lastly levodopa [27]. If reduction of medication does not improve psychosis, the use of cholinesterase inhibitors or antipsychotic medication, similar to the treatment of acute psychotic symptoms, should be considered [27]. Pimavanserin, which acts as both an inverse agonist and antagonist at the 5-HT2A serotonin receptors, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of PD psychosis and does not affect the motor symptoms of the disease [30].

In the lack of effective medications, managing ICBs in PD embodies a therapeutic challenge. Once again, a cautious reduction or discontinuation of dopaminergic agonists is recommended to minimize the risk of motor symptom deterioration or withdrawal symptoms. This careful balance aims to control both motor symptoms and aberrant behaviors [23]. Findings related to the efficacy of selective serotonin reuptake inhibitors, bupropion, antipsychotics, mood stabilizers, and zonisamide in managing ICBs in PD are conflicting, while a beneficial impact of amantadine on treating pathological gambling has been reported, even though amantadine has been associated with the presence of ICBs [31,32,33]. Non-pharmacological interventions which are increasingly receiving empirical support in the management of neuropsychiatric symptoms in dementia [34], may be encouraged in people with ICBs in PD, too.

Anxiety symptoms have a point prevalence of 30% in individuals with PD. They can present with many forms, including generalized anxiety disorder, acute stress disorder, panic attacks, phobias and post-traumatic stress disorder [16,35]. The treatment of anxiety symptoms relies on antidepressants such as SSRIs [36]. Fluoxetine or a therapeutic alternative to it (e.g. citalopram, escitalopram, sertraline) are included in the WHO list of Essential Medicines and are supposed to be available even in LMIC [10]. The use of benzodiazepines might be helpful, but their excessive use in people with PD should be avoided, due to the high risk of balance loss and falls [36]. CBT for the treatment of PD anxiety is also being reported [37].

The prevalence of apathy in PD is estimated up to 35-70% and might be present at the prodromal stage [14]. It includes lack of motivation and initiative and indifference. Although depression often occurs alongside apathy in Parkinson’s disease, it is important to distinguish between these two symptom categories [38]. Numerous drugs are studied for their role in the management of apathy in PD but there is still no approved treatment [39]. Apathy might improve with dopaminergic medication, especially if it is associated with off periods or occurs during dopaminergic medication decrease [14].

Sleep can also be affected in PD, with a wide phenotypic spectrum, such as insomnia, daytime sleepiness, circadian disturbances and parasomnias [40,41]. Rapid Eye Movement (REM)-sleep Behavior Disorder (RBD) is a parasomnia highly associated with synucleinopathies and is characterized by loss of REM sleep muscle atonia, resulting in undesirable, recurrent complex motor or vocal dream enactment behavior [42]. Since RBD often occurs years before the onset of the motor symptoms and the diagnosis of PD, it could potentially be useful in early diagnosis and treatment of the disease [42]. Of note, medications (e.g. antidepressants including venlafaxine, mirtazapine, and selective serotonin reuptake inhibitors) used for managing neuropsychiatric symptoms can worsen RBD [42]. Treatment of RBD includes melatonin and clonazepam [43], which are not included in the WHO list of Essential Medicines resulting in care inequity. Pramipexole has been assessed in observational studies as a potentially effective treatment for RBD in individuals with Parkinson’s disease, but it increases the risk of psychosis [44,45].

Dementia with Lewy Bodies

DLB is probably the second most common cause of dementia, even though it largely remains under-detected or misdiagnosed [46,47,48]. Clinically, DLB manifests as progressive cognitive decline, along with recurrent complex visual hallucinations, REM sleep behavior disorder and one or more spontaneous cardinal features of parkinsonism namely bradykinesia, rigidity or rest tremor which occur after or simultaneously with the onset of dementia [49]. The cognitive deficits in DLB and in the oligosymptomatic, pre-dementia clinical entity of Mild Cognitive Impairment with Lewy Bodies (LB) mainly pertain to fluctuating attention/executive dysfunction and visual processing rather than memory and object naming [50].

Psychotic symptoms are prominent among individuals with DLB. Recurrent, complex, well-formed visual hallucinations, featuring people or animals are present in approximately 80% of people with DLB and are characteristic of LB pathology [49]. They can be accompanied by typically verbal and often incomprehensible auditory hallucinations and can sometimes co-occur with other disturbances of visual perception, such as passage hallucinations, sense of presence and visual illusions [49,50,51]. Of note, unimodal auditory hallucinations are uncommon. Auditory hallucinations in DLB are described as a “background soundtrack” accompanying visual hallucinations and their content as non-paranoid, non-imperative and mood-incongruent [51,52]. Interestingly, among people with DLB, female sex, visual hallucinations, hearing impairment, depression and delusions are risk factors for the development of auditory hallucinations [51]. Furthermore, the most common types of delusions in DLB are delusional misidentification (e.g. phantom boarder, delusional misidentifications of people, objects and reduplication of people) and paranoid delusions, particularly delusions of theft and persecution [52-53]. In addition, Capgras syndrome, characterized by the delusional belief that a person has been replaced by an identical imposter, is common in DLB and usually occurs in the presence of anxiety and visual hallucinations [54]. Delusions in individuals with DLB have been linked to poorer cognitive function and more severe neuropsychiatric symptoms [53].

The management of hallucinations and other psychotic symptoms in DLB may prove to be tantalizing for clinicians. Use of antipsychotics should be approached with considerable caution, due to the neuroleptic sensitivity of approximately 50% of people with LBD which represents a potentially fatal complication (Table 1) [49,55,56]. In addition, exposure to dopaminergic therapy and anticholinergic medication within the frames of treatment of extrapyramidal symptoms may induce or exacerbate psychotic symptoms [49,55]. Interestingly, the cholinesterase inhibitors donepezil and rivastigmine are efficacious in improving cognition, reducing hallucinations and delusions and improving daily activities [55,56], with rivastigmine having been more extensively studied than donepezil. Moreover, pimavanserin is more effective and tolerable than quetiapine in managing psychotic symptoms [57]. Even though quetiapine and olanzapine are efficient in reducing hallucinations and delusions, individuals with DLB often do not tolerate them [57,58]. Treatment with the atypical antipsychotic risperidone appears to be inefficacious and even less tolerable [58]. Of note, a study across 40 nursing homes in Sweden revealed that more fluctuating cognitive deficits, visual hallucinations, and parkinsonian symptoms in DLB pertained to higher antipsychotic usage and were inversely related to anti-dementia medication [59]. These observations could imply a trend of the most vulnerable residents of the nursing homes to be treated with antipsychotics, which is in fact inappropriate given that they are at higher risk for adverse events such as parkinsonism, hypersomnia, sedation, extrapyramidal symptoms, delirium and increased mortality. In addition, it could indicate insufficient use of anti-dementia medication in older patients [59]. Despite the fact that expert opinion from Delphi consensus group and national guideline bodies have endorsed the use of rivastigmine and donepezil for neuropsychiatric symptoms in patients with DLB and the lack of evidence supporting the use of any antipsychotic drug in such patients [60], cholinesterase inhibitors are not included in the WHO model list of essential medicines, while in many LMIC no access to them is granted [61]. Thus, care inequities arise for people with psychotic symptoms in DLB across the globe.

Apathy, anxiety and depressive symptoms are common symptoms in people with DLB and embody supportive clinical features for DLB diagnosis [49]. For instance, depression is present in about a third of DLB patients [60]. Apathy, which is linked to faster cognitive decline [62,63], anxiety and appetite disturbances are useful predictors of conversion from MCI-LB to DLB [51,64]. Interestingly, anxiety may develop even four to five years before diagnosis and can manifest as panic attacks [65], while long-lasting, pervasive anhedonia [66] has been reported to be a characteristic depressive symptom of DLB, compared to other types of dementia [67,68,69]. Of note, individuals with DLB are at higher risk of suicidal ideation compared to those with other types of dementia. Data on the use of antidepressants among individuals with DLB are limited to citalopram, which does not appear to be beneficial nor well tolerated [58]. In addition, there are concerns that antidepressants might affect sleep and worsen RBD [58].

Sleep disturbances are part of the LBD phenotype. RBD can occur even years before the onset of full-blown LBD [70]. People with DLB and/or their bed partners might experience serious injuries from limb movements or falls from bed during episodes of RBD, and commonly report vivid or violent dreams [71]. Interestingly, RBD in men develops at a younger median age than cognitive symptoms, whereas in women RBD and cognitive symptoms tend to emerge concurrently [72]. Moreover, hypersomnia is considered a supportive clinical feature for the diagnosis of DLB and is significantly more frequent and more severe in DLB and MCI-LB than in other neurocognitive disorders [71,73]. DLB and MCI-LB patients also exhibit a higher prevalence and severity of other sleep disorders, including insomnia, restless leg syndrome (RLS), periodic limb movements, sleep-related leg cramps, sleepwalking, and sleep-disordered breathing [71]. Retrospective case series in patients with RBD point to the usefulness of clonazepam, even though it should be prescribed with caution, since people with LBD are prone to gait disturbance, further cognitive decline, and are at high risk of falls [74]. Memantine, an NMDA receptor partial antagonist, is indicated for the treatment of moderate to severe dementia due to Alzheimer’s disease. A 24-week randomized controlled study showed that memantine decreased physical activity during sleep in 20 patients with DLB, whereas the 22 patients in the placebo group worsened over the same period [75]. Limited data imply that armodafinil, which promotes wakefulness, may be a potential treatment for hypersomnia, while gabapentin may alleviate symptoms of restless leg syndrome [58].

Despite the weak evidence for people with DLB, non-pharmacological interventions (e.g. musical therapy and environmental modifications) are usually recommended as a first-line treatment for neuropsychiatric symptoms in DLB [60]. Non-pharmacological strategies which have been shown to be effective in individuals with Alzheimer’s disease may be helpful in the management of neuropsychiatric symptoms in DLB. Nevertheless, no specific consensus exists, since these recommendations are mainly based on case reports and case series data [76].

Progressive supranuclear palsy

The key clinical features of progressive supranuclear palsy (PSP) are supranuclear gaze palsy, bradykinesia, rigidity, gait imbalance with frequent falls and subcortical and frontolimbic cognitive dysfunction [77]. The disease usually begins in the presenile period, with a mean age of onset at 63 years of age. Its prevalence is approximately 5/100.000 cases and it increases with age. Mean duration of illness is estimated at 5.9 years [77]. There are various clinical variants of the disease, the most important of which are: The classic phenotype, named Richardson syndrome (RS), PSP Parkinsonism (PSP-P), PSP-pure akinesia, PSP-corticobasal syndrome, PSP with frontal lobe cognitive or behavioral presentation, which includes the behavioral variant frontotemporal dementia (bvFTD) [77,78,79]. Depending on the distribution of tau pathological proteins, certain PSP phenotypes may resemble other disorders: PSP-P is similar to Parkinson’s disease, PSP-PNFA resembles frontotemporal dementia, and CBS is akin to corticobasal degeneration. They differ from each other in terms of the severity and frequency of certain clinical and pathological features [77,79,80,81,82]. Patterns of neurocognitive deficits are executive dysfunction, apathy, bradyphrenia and disinhibition, decreased phonemic verbal fluency and impaired episodic memory to an extent similar to Parkinson’s disease and frontotemporal dementia and less severe than in Alzheimer’s disease [79,83,84,85,86,87]. Despite lack of consensus, the severity of executive dysfunction has been related to behavioral abnormalities (apathy in particular). Imaging reveals the characteristic “hummingbird sign” or “penguin sign”. Atrophy of the midbrain results in a brainstem image (in the sagittal plane) in which the preserved pons form the “body of the bird” and the atrophic midbrain the “head” [88].

Neuropsychiatric symptoms may be the first signs of PSP, potentially leading to a misdiagnosis of the disease as a purely mental disorder rather than a neurodegenerative condition. Negative behavioral elements (apathy and depression) are more frequent than positive ones (irritability, impulsivity, and inappropriate social behavior) [77,83,84,87,89]. Of note, neuropsychiatric symptoms manifest in pathologically confirmed PSP at disease onset in 8% of individuals with the condition and in 60% of them 3 years after disease onset [77,90]. People with PSP are described as irritable, suspicious, arrogant, opinionated, and demanding, while a decrease in self-care and personal hygiene and a general feeling of anhedonia are also observed [77,84].

Apathy is the most common neuropsychiatric symptom in people with PSP [83,84,89,91]. A difficulty is observed in the processing of emotions, while individuals show a reduced ability to recognize emotions and look at faces, compared to healthy controls and individuals with PD patients [92,93]. Apathy is pathophysiologically related to dysfunction of the ventral prefrontal cortex (PFC) network which is particularly involved in reward and threat processing, as well as of subcortical regions of the thalamus and basal ganglia [77,87]. Since no disease-modifying treatments are available, the management of apathy may be based on non-pharmacological interventions, which include recreational activities and psychoeducation with the care partner’s aid (Table 1) [94]. SNRIs, as for instance venlafaxine, as well as bupropion and amantadine could be prescribed [95]. In one case report, the use of zolpidem – a GABA agonist – greatly improved apathy [96].

Depression is also a prominent neuropsychiatric finding in PSP [77,83,84]. It usually manifests itself within one year from the time of diagnosis, but cases have been recorded where its appearance precedes the motor symptoms of the disease [97,98]. Its severity is not related to the severity of symptoms or cognitive impairment. Therefore, it remains unclear whether the genesis of depressive symptoms in PSP pertains to brain dysfunction or is the consequence of the effects of the disease itself (motor problems, loss of autonomy, difficulty in social life). The prevalence of depressive symptoms in PSP is approximately three times higher than in healthy controls [99]. Complicating the diagnosis of depression is the pseudobulbar affect (PBA), which in many ways mimics depressive symptoms and is present in approximately 50% of individuals with PSP, even though PBA can occur in other parkinsonian syndromes, too [100]. PBA is characterized by emotional lability and highlighted by a discrepancy between the emotional expressions of the individuals and their emotional experiences. Involuntary, sudden, and recurrent episodes of laughing and/or crying occur that tend to be inappropriate or disproportionate to the social context or stimuli [100]. Even though tricyclic antidepressants, like amitriptyline, have been used in the treatment of depression in PSP and they may even improve motor symptoms [101], they are not currently used because of their anticholinergic effects [101,102,103]. SSRIs (fluoxetine, paroxetine, sertraline, citalopram) and SNRIs (venlafaxine) are both effective at treating depressive symptoms in PSP and agents of the former category are included in the WHO model list of Essential Medicines [95] but their use could paradoxically worsen symptoms of apathy [101]. Interestingly, transcranial magnetic stimulation was proven effective in one case of treatment-resistant depression [94]. Moreover, SSRIs, dextromethorphan and quinidine have been used to control PBA and abrupt laughing or crying episodes [101].

Sleep disorders are also common in PSP. Decreased sleep duration and quality have been observed, as well as RBD. Risk of obstructive sleep apnea and restless legs syndrome were also detected [104]. Lifestyle changes, such as stopping diuretics, avoiding amantadine administration late at night and increasing exercise during the day could improve the quantity and quality of sleep [94]. Agents like mirtazapine, melatonin, clonazepam, zolpidem and trazodone are currently used for treating sleep disturbances in PSP [95,101,103]. Mirtazapine is particularly potent in treating difficulties with sleep initiation.

Approximately one-third of individuals with PSP experience significant anxiety-, agitation-, irritability- and disinhibition symptoms [77,84,87]. Adjustment disorder with anxiety as well as generalized anxiety disorder have also been reported in a smaller proportion of people with PSP [77]. SSRIs are prescribed for alleviating depressive and anxiety symptoms. Clozapine is used to treat agitation symptoms in PSP despite uncertainties related to its beneficial effects [101].

Psychotic symptoms, such as hallucinations and delusions are rarely observed in PSP [95,101,105]. This is the reason why psychosis is the only group of neuropsychiatric symptoms that separates PSP from other parkinsonian syndromes, as it occurs with a much lower frequency in the former. For instance, the presence or absence of visual hallucinations can contribute to the differential diagnosis of the disease that causes the Parkinsonian syndrome [77]. In cases with psychotic symptoms, quetiapine or clozapine can be used [102].

A significant percentage of patients suffering from PSP seem to present with obsessive-compulsive personality disorder (OCPD) symptoms [106]. Such symptoms include preoccupation and insistence on details, rules, lists, order and organization, perfectionism, excessive conscientiousness, rigidity and stubbornness. A study comparing individuals with PSP and MSA found that more than one-third of patients suffered from OCPD, a rate significantly higher than that of individuals with MSA [106]. The presence of OCPD symptoms in these patients is probably attributable to a malfunction of the basal ganglia system, which includes the orbitofrontal circuits [106].

Non-pharmacological measures may prove useful in managing neuropsychiatric symptoms in PSP. Reduction of anticholinergic drugs, identification of potential distress causes and occupational therapy have been proposed as strategies contributing to the management of behavioral and psychological symptoms in PSP [95]. Person-centered, multidisciplinary approaches have been proposed so that neuropsychiatric symptoms of individuals with PSP are treated in a holistic and individualized way [101].

Corticobasal Degeneration

The most common CBD clinical phenotype is Corticobasal Syndrome (CBS) an akinetic-rigid parkinsonian syndrome with poor response to levodopa and a combination of asymmetric motor and non-motor symptoms which may be associated with cognitive-behavioral disorders such as apathy, depression, difficulty in performing commands, aphasia, apraxia and the alien limb phenomenon [95]. Neuropsychiatric disorders are common in CBD, clinically heterogeneous and may occur at the onset of the disease before motor symptoms. Thus, they are not of secondary importance in relation to motor impairment. They can be detrimental to the quality of life of both people with CBD and their care partners [107,108,109,110].

Depressive symptoms are the most common neuropsychiatric symptoms in individuals with CBD [90,107,108,109,110] and were shown to be more severe in CBD than in PSP or in Alzheimer’s disease [89,111,112]. The prevalence of depressive symptoms in CBD seems to exceed 70%. Interestingly, a depressive profile dominated by high hopelessness predicted early-stage CBD with an accuracy of 70% [113]. People with CBS have higher prevalence of suicidal and death ideation than those with PD [114]. Anxiety symptoms are less prevalent than depressive symptoms in CBD, but they also appear to reduce quality of life. SSRIs are administered in the case of depression, while SNRIs are preferred for managing apathy [115].

Signs of frontal lobe dysfunction such as voracious appetite, inappropriate behavior, executive dysfunction, and impaired spontaneity have been reported in a few systematic studies and several case reports [109]. Of note, some of these manifestations were related to certain clinical phenotypes of pathologically confirmed CBD. In particular, phenotypes dominated by aphasia and frontal symptoms included compulsive behaviors, socially inappropriate and disinhibited behavior, and a voracious appetite; Individuals with CBD exhibiting a predominantly frontotemporal dementia phenotype manifested irritability, aggression, and impaired judgment, while those with a CBS phenotype were more prone to depression [107].

Certain neuropsychiatric symptoms are less prevalent in CBD compared to other parkinsonian syndromes. For instance, the prevalence of RBD is remarkably lower in CBD than in other diseases causing parkinsonism. Nonetheless, there have been case reports in which insomnia and restless leg syndrome have been described in CBD [116,117,118]. In addition, the presence of hallucinations excludes CBD from the differential diagnosis [119]. Furthermore, photophobia is less common in CBD patients compared to those with PSP [116].

Treatment of neuropsychiatric symptoms of CBD is currently limited to symptomatic relief (Table 1) [95]. The management of neuropsychiatric symptoms includes reducing drugs that may exacerbate them, such as benzodiazepines and tricyclic antidepressants. Recently, a multidisciplinary approach to patients has been proposed to alleviate neuropsychiatric symptoms and improve the quality of life of both people with CBD and their care partners [120].

Multiple System Atrophy

Multiple System Atrophy (MSA) is a rare, sporadic, rapidly progressive neurodegenerative disorder [121]. Its clinical features are a combination of parkinsonian symptoms (bradykinesia, rigidity, postural instability, resting tremor), cerebral symptoms (ataxic gait with early falls, ocular movement abnormalities, pyramidal signs) and autonomic failure (orthostatic hypotension, urogenital/gastrointestinal dysfunction), which is an early manifestation of the disease and a sine qua non for its diagnosis [86,122,123,124,125,126]. There are two clinical subtypes of MSA: MSA-P with predominant parkinsonism and MSA-C with predominant cerebral symptoms. Both subtypes include dysfunction of the autonomic nervous system [86,125]. In MSA, impairment in visuospatial, constructional, and verbal functions is observed [87,125,127].

Even though neuropsychiatric symptoms have not been the focus of MSA research for many years, it has recently been found that these symptoms are not only very common in MSA, but also have a strong negative impact on the quality of life of individuals with MSA and their care partners [86,123]. The most common neuropsychiatric symptoms in MSA are depression, apathy, anxiety disorders and RBD [126,127,128].

Depression is the most common neuropsychiatric symptom in MSA. It is estimated to affect as many as 80% of individuals with MSA [87]. It also varies in severity, spanning from mild to severe depression with suicidal ideation [86,87,128]. According to most studies, depression seems to be independent of the severity of the motor and autonomic dysfunction of MSA, suggesting that it is part of the spectrum of the clinical manifestations of the disease, rather than a consequence of other symptom groups [121,123,127]. Interestingly, people with MSA appear to be more severely affected by depression than individuals with PD or PSP [129]. Antidepressants, mainly SSRIs, are commonly used to treat depression, but are not effective for apathy, while tricyclic antidepressants are usually avoided in MSA as they worsen autonomic failure symptoms [86].

Apathy, anxiety and RBD can be present in MSA. Apathy is the second most common neuropsychiatric symptom in MSA [127,128]. Of note, the occurrence of apathy in the absence of depressive symptoms is reported to be lower in MSA compared to PSP [129]. Moreover, individuals with MSA exhibit more symptoms of anxiety compared to healthy controls. Nonetheless, anxiety symptoms are less common and less severe in MSA in comparison to PSP and PD patients [87]. RBD is the most common sleep disorder in MSA, while in some rare cases restless leg syndrome, sleep apnea and extremely vivid dreams have been reported [86,87,121]. Clonazepam may be used for RBD [87].
The management of neuropsychiatric symptoms of MSA is symptomatic (Table 1). Non-pharmacological interventions such as psychotherapy, physiotherapy and occupational therapy can be used to alleviate the symptoms of MSA and improve the quality of life of both people with the disease and their care partners [86,87,127].

CONCLUSIONS

To conclude, neuropsychiatric symptoms are present in all parkinsonian syndromes. They may contribute to the differential diagnosis of their cause, while they pose in many cases a heavy burden to people with such syndromes and their care partners and families. The impact of these symptoms on performance in activities of daily living is a research question warranting investigation. The management of neuropsychiatric symptoms in parkinsonian syndromes embodies a daunting task, since it is purely symptomatic while people with these syndromes are very sensitive to the side effects of medications commonly used in treating neuropsychiatric symptoms and the access to modern antipsychotics and/or antidepressants is not always granted in LMIC. Finally, there is an urgent need for studies aiming at standardizing pragmatic and non-pharmacological interventions that are applicable even in primary healthcare settings to manage neuropsychiatric symptoms in parkinsonian syndromes. These interventions are crucial as they are commonly well tolerated, help manage symptoms, and improve quality of life.

Conflict of interest disclosure

P. Alexopoulos is an editorial board member of Achaiki Iatriki. The remaining authors declare no conflicts of interest.

Declaration of funding sources

None to declare.

Author contributions

Antonios Alexandros Demertzis: Writing – original draft, Writing – review & editing, final approval of the article. Asimina Pachi: Writing – original draft, final approval of the article. Dorothea Maria Kechagia: Writing – original draft, final approval of the article. Eleni Konidari: Critical revision of the article for important intellectual content, final approval of the article. Eleni-Zacharoula Georgiou: Critical revision of the article for important intellectual content, final approval of the article. Panagiotis Felemegkas: Critical revision of the article for important intellectual content, final approval of the article. Aikaterini Andrianopoulou: Critical revision of the article for important intellectual content, final approval of the article. Maria Karampa: Critical revision of the article for important intellectual content, final approval of the article. Marina Charalampopoulou: Critical revision of the article for important intellectual content, final approval of the article. Maria Skondra: Critical revision of the article for important intellectual content, final approval of the article. Panagiotis Alexopoulos: Conception and design, writing – original draft, final approval of the article

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