New Insights in the Pharmacotherapy of Psychosis: The Example of Parkinson's Disease Psychosis

IntroductionWith 10 million of patients across the world, Parkinson's disease is the second most common form of neurodegeneration, after Alzheimer's. Among half of patients develop psychotic symptoms, such as visual hallucinations and delusions, which are correlated with higher rate of placement in nursing home, are difficult to treat and severely affect quality of life, making Parkinson's disease psychosis (PDP) a major public health issue.ObjectivesThe aim of this study is to identify treatment options that could be used to treat PDP and clarify underlying pathophysiology.MethodWe conducted a literature review on Pubmed, Goggle scholar and Cochrane library, using a combination of the following: “Parkinson's disease Psychosis” “visual hallucinations” “Pimavanserin” “Clozapine” “atypical anti-psychotics” 120 articles were screened.ResultsConsidering that hallucinations arise from overactivation of dopaminergic receptors, treatment options include reducing the dopaminergic drugs used to control motor symptoms; using atypical anti-psychotics such as Risperidone, Olanzapine, Quetiapine, which often results in the worsening of extra-pyramidal symptoms. Another option is the use of low doses of Clozapine, which has been proven efficient with no worsening of non-motor symptoms, suggesting the implication of other pathways, such as serotonin. Finally, Pimavanserin, a 5-HT2A receptor inverse agonist, without any dopaminergic activity, has been demonstrated to be effective in the treatment of PDP, well tolerated and easy to use.ConclusionSerotonin inverse agonists represent a major breakthrough in the pharmacotherapy of PDP, and may lead the way to changes in the treatment of schizophrenia and other psychotic disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Confusion between symptom and disease. Parkinson vs meningioma

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.605 ◽

2017 ◽

Vol 41 (S1) ◽

pp. s493-s493

Author(s):

M.J. Gordillo Montaño ◽

S. Ramos Perdigues ◽

C. Merino del Villar ◽

C. Caballero Roy ◽

S. Latorre ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Differential Diagnosis ◽

Dopaminergic Neurons ◽

Poor Response ◽

Auditory Hallucinations ◽

Psychotic Symptoms ◽

Visual Hallucinations ◽

Dopaminergic Drugs ◽

Competing Interest

IntroductionParkinson's disease is caused by decreased dopaminergic neurons of the substantia nigra. Psychosis occurs between 20 and 40% of patients with Parkinson's disease. Dopaminergic drugs act as aggravating or precipitating factor. Before the introduction of levodopa patients had described visual hallucinations but the frequency was below 5%.ObjectiveIllustrated importance of treatment, reassessment after its introduction and refractoriness to answer; as well as the importance of a differential diagnosis at the onset of psychotic symptoms later in life.MethodClinical case: female patient 75 years tracking Neurology by parkinsonism in relation to possible early Parkinson disease. She was prescribed rasagiline treatment. Begins to present visual and auditory hallucinations, delusional self-referential and injury. She had no previous psychiatric history. She went on several occasions to the emergency room, where the anti-Parkinson treatment is decreased to the withdrawal point and scheduled antipsychotics did not answer. Doses of antipsychotics are increased despite which symptoms persist and even increase psychotic symptoms. In this situation it is agreed to extend the study. Subsequently an NMR of the skull where the image is suggestive of a right occipital meningioma appears.Results/conclusionsWith the emergence of psychotic symptoms later in life it will be important to ask a broad differential diagnosis, since in a large number of cases will be secondary to somatic or to drug therapies.Parkinsonism can be a symptom of occipital meningioma, presenting in the psychotic clinic. Refractoriness, on one hand to the suspension of treatment for Parkinson's disease, such as poor response to antipsychotics, did extend the study, which ultimately gave us the diagnosis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Dual-task training on gait, motor symptoms, and balance in patients with Parkinson’s disease: a systematic review and meta-analysis

Clinical Rehabilitation ◽

10.1177/0269215520941142 ◽

2020 ◽

Vol 34 (11) ◽

pp. 1355-1367

Author(s):

Zhenlan Li ◽

Tian Wang ◽

Haoyang Liu ◽

Yan Jiang ◽

Zhen Wang ◽

...

Keyword(s):

Systematic Review ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dual Task ◽

Meta Analysis ◽

Cochrane Library ◽

Motor Symptoms ◽

Gait Parameters ◽

Task Training ◽

Dual Task Training

Objective: The aim of the present study was to systematically evaluate and quantify the effectiveness of dual-task training on gait parameters, motor symptoms and balance in individuals diagnosed with Parkinson’s disease. Data resources: A systematic review of published literature was conducted until May 2020, using PubMed, EMBASE, Cochrane Library, Web of Science, EBSCO and CNKI databases. Methods: We included randomized controlled trials (RCTs) and non-RCTs to evaluate the effects of dual-task training compared with those of non-intervention or other forms of training. The measurements included gait parameters, motor symptoms and balance parameters. Methodological quality was assessed using the PEDro scale. Outcomes were pooled by calculating between-group mean differences using fixed- or random-effects models based on study heterogeneity. Results: A total of 11 RCTs comprising 322 subjects were included in the present meta-analysis. Results showed that dual-task training significantly improved gait speed (standardized mean difference [SMD], −0.23; 95% confidence interval [CI], −0.38 to −0.08; P = 0.002), cadence (SMD, −0.25; 95% CI, −0.48 to −0.02; P = 0.03), motor symptoms (SMD, 0.56; 95% CI, 0.18 to 0.94; P = 0.004) and balance (SMD, −0.44; 95% CI, −0.84 to −0.05; P = 0.03). However, no significant changes were detected in step length or stride length. Conclusion: Dual-task training was effective in improving gait performance, motor symptoms and balance in patients with Parkinson’s disease relative to other forms of training or non-intervention.

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A New Perspective in the Treatment of Parkinson’s Disease Psychosis

US Neurology ◽

10.17925/usn.2016.12.02.93 ◽

2016 ◽

Vol 12 (02) ◽

pp. 93

Author(s):

Rajesh Pahwa ◽

Kelly E Lyons ◽

◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuropsychiatric Symptoms ◽

Unmet Need ◽

Controlled Study ◽

Psychotic Symptoms ◽

Dopamine Antagonists ◽

Motor Symptoms ◽

Double Blind ◽

Good Tolerability

Neuropsychiatric symptoms, such as psychosis, are well described in Parkinson’s disease (PD); most appear to be due to disease pathology with exacerbation caused by dopaminergic treatment. More than 50% of patients with PD develop psychosis at some point throughout their disease course. Clinicians need to routinely assess patients with PD for psychotic symptoms, particularly hallucinations. Treatment of psychotic symptoms in PD is an unmet need as there are currently no US Food and Drug Administration (FDA) approved medications specifically for PD psychosis (PDP). Current treatments for PDP have been adapted from dopamine antagonists used to treat psychosis in other conditions, such as schizophrenia. Typical antipsychotics, as well as some atypical antipsychotics, worsen PD motor symptoms due to blockade of dopamine D2 receptors. Quetiapine and clozapine have been studied in PDP and are the most commonly used treatments for PDP. Clozapine has been shown to be effective; however, regular bloodwork is required, while data for quetiapine are inconsistent. Pimavanserin, a highly selective serotonin (5HT2A subtype) receptor inverse agonist, is not associated with motor worsening in PDP patients due to the absence of dopamine blockade. In a double-blind, placebo-controlled study, pimavanserin showed significant improvement in moderate to severe psychosis compared to placebo, with good tolerability and without worsening of PD motor symptoms. These data suggest that pimavanserin is a safe and efficacious treatment for PDP psychosis and could be a potential new treatment option for PDP.

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Management of visual hallucinations in dementia and Parkinson’s disease

International Psychogeriatrics ◽

10.1017/s1041610218001400 ◽

2018 ◽

Vol 31 (06) ◽

pp. 815-836 ◽

Cited By ~ 5

Author(s):

Peter Swann ◽

John T. O’Brien

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rating Scales ◽

Neuropsychiatric Symptoms ◽

Functional Decline ◽

Evidence Base ◽

Psychotic Symptoms ◽

Common Symptom ◽

Visual Hallucinations

ABSTRACTObjectives:Visual hallucinations are a common symptom in dementia and Parkinson’s disease and have been associated with greater cognitive and functional decline, but optimal management strategies are unclear. We review the frequency and pathogenesis of visual hallucinations in dementia and Parkinson’s disease and examine the evidence base for their management.Design:We undertook a systematic review of the visual hallucinations in dementia, searching studies published between January 1980 and July 2017 using PubMed with the search terms visual hallucinations AND review AND (dementia OR parkinson*).Results:We found 645 articles and screened them for relevance, finally including 89 papers (11 meta-analyses, 34 randomized controlled trials, six other trials and a number of relevant review articles). Only six of the trials reported visual hallucination outcomes separately from other neuropsychiatric symptoms.Conclusions:Atypical antipsychotics were frequently studied, but with the exception of clozapine in Parkinson’s disease dementia, results were equivocal. There was some evidence that acetylcholinesterase inhibitors may help visual hallucinations. Overall, effect sizes for most treatments were small and there were few studies with long term follow up. Treatments need to be carefully weighed up with the risks and reviewed often, and many patients improved without treatment. There is a lack of data regarding visual hallucinations due to the grouping of psychotic symptoms together in commonly used rating scales. The lack of a specific rating scales, or analyzable items within other scales, for visual hallucinations, limited efficacy of current and small evidence base with short follow up are important areas for future studies to address.

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Orthostatic Hypotension in Patients with Parkinson’s Disease and Atypical Parkinsonism

Parkinson s Disease ◽

10.1155/2014/475854 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Seyed-Mohammad Fereshtehnejad ◽

Johan Lökk

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Orthostatic Hypotension ◽

Treatment Options ◽

Motor Symptoms ◽

Atypical Parkinsonism ◽

Medical Databases ◽

Risk Of Falls ◽

Review Current

Orthostatic hypotension (OH) is one of the commonly occurring nonmotor symptoms in patients with idiopathic Parkinson’s disease (IPD) and atypical parkinsonism (AP). We aimed to review current evidences on epidemiology, diagnosis, treatment, and prognosis of OH in patients with IPD and AP. Major electronic medical databases were assessed including PubMed/MEDLINE and Embase up to February 2013. English-written original or review articles with keywords such as “Parkinson’s disease,” “atypical parkinsonism,” and “orthostatic hypotension” were searched for relevant evidences. We addressed different issues such as OH definition, epidemiologic characteristics, pathophysiology, testing and diagnosis, risk factors for symptomatic OH, OH as an early sign of IPD, prognosis, and treatment options of OH in parkinsonian syndromes. Symptomatic OH is present in up to 30% of IPD, 80% of multiple system atrophy (MSA), and 27% of other AP patients. OH may herald the onset of PD before cardinal motor symptoms and our review emphasises the importance of its timely diagnosis (even as one preclinical marker) and multifactorial treatment, starting with patient education and lifestyle approach. Advancing age, male sex, disease severity, and duration and subtype of motor symptoms are predisposing factors. OH increases the risk of falls, which affects the quality of life in PD patients.

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Increased substantia nigra echogenicity correlated with visual hallucinations in Parkinson’s disease: a Chinese population-based study

Neurological Sciences ◽

10.1007/s10072-019-04110-z ◽

2019 ◽

Vol 41 (3) ◽

pp. 661-667 ◽

Cited By ~ 1

Author(s):

Ting Li ◽

Jing Shi ◽

Bin Qin ◽

Dongsheng Fan ◽

Na Liu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Odds Ratio ◽

Rating Scales ◽

Binary Logistic Regression Analysis ◽

Motor Symptoms ◽

Visual Hallucinations ◽

Roc Curve Analysis ◽

Non Motor Symptoms

AbstractAs a noninvasive technique, transcranial sonography (TCS) of substantia nigra (SN) has gradually showed its effectiveness not only in diagnosis but also in understanding clinical features of Parkinson’s Disease (PD). This study aimed to further evaluate TCS for clinical diagnosis of PD, and to explore the association between sonographic manifestations and visual hallucinations (VH). A total of 226 subjects including 141 PD patients and 85 controls were recruited. All participants received TCS. A series of rating scales to evaluate motor and non-motor symptoms were performed in PD patients. Results showed that 172 subjects were successfully assessed by TCS. The area of SN was greater in PD patients than that in controls (P < 0.001). As receiver-operating characteristic (ROC) curve analysis showed, the best cutoff value for the larger SN echogenicity size was 23.5 mm2 (sensitivity 70.3%, specificity 77.0%). Patients with VH had larger SN area (P = 0.019), as well as higher Non-Motor Symptoms Scale (NMSS) scores (P = 0.018). Moreover, binary logistic regression analysis indicated that SN hyperechogenicity (odds ratio = 4.227, P = 0.012) and NMSS scores (odds ratio = 0.027, P = 0.042) could be the independent predictors for VH. In conclusion, TCS can be used as an auxiliary diagnostic tool for Parkinson’s disease. Increased SN echogenicity is correlated with VH in Parkinson’s disease, possibly because the brain stem is involved in the mechanism in the onset of VH. Further studies are needed to confirm these findings.

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Polymorphisms in the dopamine transporter gene are associated with visual hallucinations and levodopa equivalent dose in Brazilians with Parkinson's disease

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145712001666 ◽

2013 ◽

Vol 16 (6) ◽

pp. 1251-1258 ◽

Cited By ~ 13

Author(s):

Artur F Schumacher-Schuh ◽

Carolina Francisconi ◽

Vivian Altmann ◽

Thais L Monte ◽

Sidia M Callegari-Jacques ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Adverse Effects ◽

Dopamine Transporter ◽

Prevalence Ratio ◽

Synaptic Cleft ◽

Equivalent Dose ◽

Visual Hallucinations ◽

Dopaminergic Drugs ◽

Dat1 Gene

Abstract The requirement for dopaminergic drugs in Parkinson's disease (PD) is highly variable. Visual hallucinations are a frequent and serious complication of chronic levodopa therapy. Polymorphisms in the DAT1 gene might affect the reuptake of dopamine in the synaptic cleft, but the influence of this variability on adverse effects or levodopa equivalent dose on PD patients is still poorly investigated. Therefore, the aim of the present study was to investigate DAT1 gene polymorphisms on levodopa equivalent dose and visual hallucination occurrence in PD patients. Altogether, 196 PD patients in treatment with at least 200 mg levodopa equivalent dose for at least 1 yr were included. These patients were genotyped for the −839 C > T and 3′ VNTR DAT1 polymorphisms by PCR-based methodologies. Visual hallucinations occurred in 25.5% of the sample. After controlling for confounders, the dopamine transporter (DAT) −839 C allele was associated with visual hallucinations (prevalence ratio 2.5, 95% confidence intervals 1.13–5.5, p = 0.02). Levodopa equivalent dose was lower in carriers of the nine repeat allele of the DAT 3′UTR VNTR (741.2 ± 355.0 vs. 843.4 ± 445.7), explaining 21% of dose variability (p = 0.01). Our results support an effect of DAT1 polymorphisms in adverse effects of anti-Parkinsonian drugs and in levodopa equivalent dose usage.

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Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2016/2531812 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Antonio Daniele ◽

Francesco Panza ◽

Antonio Greco ◽

Giancarlo Logroscino ◽

Davide Seripa

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Clinical Trials ◽

Allosteric Modulation ◽

Motor Symptoms ◽

Dopaminergic Drugs ◽

Internal Globus Pallidus ◽

Gabaergic Neurotransmission ◽

Increased Activity

At present, patients with advanced Parkinson’s disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only forGABAAreceptors containing theα-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation ofGABAAreceptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce throughGABAAreceptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD.

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Antipsychotics for the management of psychosis in Parkinson's disease: systematic review and meta-analysis

BJPsych Open ◽

10.1192/bjpo.bp.115.000927 ◽

2015 ◽

Vol 1 (1) ◽

pp. 27-33 ◽

Cited By ~ 14

Author(s):

Ketan Dipak Jethwa ◽

Oluwademilade A. Onalaja

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Meta Analysis ◽

Drop Out ◽

Psychotic Symptoms ◽

Motor Symptoms ◽

Promising Treatment ◽

Randomised Controlled ◽

Meta Analyses ◽

Final Selection

BackgroundAntipsychotics can exacerbate motor symptoms in Parkinson's disease psychosis.AimsTo systematically review the literature on the efficacy and acceptability of antipsychotics for Parkinson's disease psychosis.MethodRandomised controlled trials comparing an antipsychotic with placebo were systematically reviewed.ResultsThe final selection list included nine studies using quetiapine (3), clozapine (2), olanzapine (3) and pimavanserin (1). A narrative synthesis and meta-analyses (where appropriate) were presented for each antipsychotic. Clozapine demonstrated superiority over placebo in reducing psychotic symptoms. Quetiapine and olanzapine did not significantly improve psychotic symptoms. All three antipsychotics may exacerbate motor symptoms. Quetiapine studies were associated with high drop-out rates due to adverse events. Pimavanserin is a novel treatment that warrants further investigation.ConclusionsFurther research is needed. Clozapine and pimavanserin appear to be a promising treatment for Parkinson's disease psychosis.

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Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease?

International Journal of Molecular Sciences ◽

10.3390/ijms22063038 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3038

Author(s):

Javier Navarro-Zaragoza ◽

Lorena Cuenca-Bermejo ◽

Pilar Almela ◽

María-Luisa Laorden ◽

María-Trinidad Herrero

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Heat Shock ◽

Stress Proteins ◽

Small Heat Shock Protein ◽

Substantia Nigra Pars Compacta ◽

Motor Symptoms ◽

Dopaminergic Drugs ◽

Non Motor Symptoms

Small heat shock proteins (HSPs), such as HSP27, are ubiquitously expressed molecular chaperones and are essential for cellular homeostasis. The major functions of HSP27 include chaperoning misfolded or unfolded polypeptides and protecting cells from toxic stress. Dysregulation of stress proteins is associated with many human diseases including neurodegenerative diseases, such as Parkinson’s disease (PD). PD is characterized by the presence of aggregates of α-synuclein in the central and peripheral nervous system, which induces the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in the autonomic nervous system. Autonomic dysfunction is an important non-motor phenotype of PD, which includes cardiovascular dysregulation, among others. Nowadays, the therapies for PD focus on dopamine (DA) replacement. However, certain non-motor symptoms with a great impact on quality of life do not respond to dopaminergic drugs; therefore, the development and testing of new treatments for non-motor symptoms of PD remain a priority. Since small HSP27 was shown to prevent α-synuclein aggregation and cytotoxicity, this protein might constitute a suitable target to prevent or delay the motor and non-motor symptoms of PD. In the first part of our review, we focus on the cardiovascular dysregulation observed in PD patients. In the second part, we present data on the possible role of HSP27 in preventing the accumulation of amyloid fibrils and aggregated forms of α-synuclein. We also include our own studies, highlighting the possible protective cardiac effects induced by L-DOPA treatment through the enhancement of HSP27 levels and activity.

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