On the Optimal Diagnosis and the Evolving Role of Pimavanserin in Parkinson's Disease Psychosis.

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.

A case report of a patient with Turner syndrome who develops catatonia secondary to psychotic symptoms.

RATIONALE: Turner syndrome (TS) is a genetic disorder associated with partial or complete monosomy X abnormalities; some patients may have a higher risk of psychiatric symptoms. Catatonia is associated with a wide range of life-threatening complications with complex pathogenesis; However, It very rare for patients with TS to develop psychotic symptoms and eventually progress to catatonia. This case report describes the diagnostic and therapeutic course of catatonia-associated TS. PATIENT CONCERNS: In this study, we report the case of a patient with TS who initially developed sudden hallucinations, delusions, and emotional instability, followed by catatonia. DIAGNOSES: The patient was diagnosed with: unspecified catatonia; TS. INTERVENTIONS: Treatment included administering a combination of esazolam injections and olanzapine tablets, placing a gastric tube and urinary catheter, and providing nutritional support. OUTCOMES: After treatment, the patient's hallucinations, delusions, and catatonia disappeared, with no residual sequelae, and social functioning returned to normal. LESSONS: For patients with TS who present with psychotic symptoms and catatonia, a comprehensive evaluation is necessary, and treatment with antipsychotics and benzodiazepines is effective.

Psychotic Disorder after Left Posterior Cerebral Artery Stroke-An Atypical Event.

INTRODUCTION: Stroke survivors usually present physical and neuropsychiatric complications. Post-stroke psychosis (PSPsy) is a particularly neglected sequel despite its disruptive nature. OBJECTIVES: To present a case of early emerging neuropsychiatric symptoms following a left posterior cerebral artery (PCA) stroke. To review and discuss PSPsy clinical manifestations, pathophysiology, and clinical outcomes. CLINICAL CASE: A previously autonomous 68-year-old woman with vascular risk factors and depressive disorder presented to the emergency department with a 5-day history of disorientation, motor aphasia, and right hypoesthesia. Computer tomography revealed a left PCA stroke. She was started on acetylsalicylic acid and rosuvastatin and discharged the next day. Afterward, the patient developed a depressive mood, emotional lability, periods of confusion, delusions of persecution, guilt and unworthiness, auditory hallucinations, and suicide ideation. She was admitted to a psychiatric hospital and started on risperidone with a good response, being discharged after 15 days with the resolution of psychiatric symptoms. CONCLUSIONS: PSPsy is more common after right hemisphere lesions and usually develops after some months. Nevertheless, our patient presented PSPsy following an ischemic event of the left PCA, with neuropsychiatric symptomatology dominating the clinic since the beginning. The involvement of the retrosplenial cortex or its connections was likely important for this atypical presentation. Due to the lack of guidelines on approaching PSPsy, most patients are treated with the same strategies used for non-stroke patients. A better comprehension of the anatomical basis underlining the symptomatology in these patients could deepen the understanding of psychosis and psychotic disorders.

Urbanization and psychosis: an update of recent evidence.

PURPOSE OF REVIEW: Urbanization, a complex global phenomenon, has a significant bearing on schizophrenia/psychosis burden through various socioeconomic and environmental factors. This review focuses on recent evidence (2019-2023) linking urbanization, schizophrenia, and the role of green space. RECENT FINDINGS: This review analyzed 43 articles that examined the correlation between urban birth or upbringing, urban living (urbanicity), and various schizophrenia/psychosis-related outcomes such as incidence, psychotic experiences, etc. The studies showed differing results across geographical locations. Socioeconomic factors like area deprivation, migrant status (ethnic density) and social fragmentation were independently associated with the risk of schizophrenia/psychosis irrespective of urbanicity. More recently, environmental factors such as green space reduction and air pollution have been explored in urban living conditions and were positively associated with an increased risk of schizophrenia/psychosis. SUMMARY: There is a need for further investigation in low and middle-income countries. The impact of urbanization-related factors and green space on the risk of schizophrenia/psychosis calls for appropriate governmental commitments toward structured and healthy urban planning.

Predictors for early-onset psychotic symptoms in patients newly diagnosed with Parkinson's disease without psychosis at baseline: A 5-year cohort study.

AIMS: To investigate the risk factors for early-onset psychosis in Parkinson's disease (PD) in a cohort of patients from the Parkinson's Progression Markers Initiative. METHODS: Longitudinal data on motor and non-motor features, dopamine transporter (DAT) imaging, and cerebrospinal fluid (CSF) measurements were collected. The survival probability of psychotic symptoms, potential risk factors for psychosis development over a 5-year follow-up period, and the performance of the prediction model were evaluated. RESULTS: Among the 338 newly diagnosed patients with PD, 83 developed psychotic symptoms. Gastrointestinal autonomic dysfunction, presence of probable rapid-eye-movement sleep behavior disorder, and the ratio Aß42: total-tau could independently predict onset of psychosis in PD (hazard ratio (HR) = 1.157, 95% confidence interval (CI) 1.022-1.309, p = 0.021, HR = 2.596, 95% CI 1.287-5.237, p = 0.008, and HR = 0.842, 95% CI 0.723-0.980, p = 0.027, respectively). The combined model integrating baseline clinical predictors, DAT imaging, and CSF measurements achieved better sensitivity than the clinical predictors alone (area under the curve = 0.770 [95% CI 0.672-0.868] vs. 0.714 [95% CI 0.625-0.802], p = 0.098). CONCLUSION: We identified clinical and CSF predictors of early-onset psychosis in patients with PD. Our study provides evidence and implications for prognostic stratification and therapeutic approaches for PD psychosis.

Bane or boon regarding urbanicity and psychotic spectrum disorders: a scoping review of current evidence.

PURPOSE OF REVIEW: This review aims to provide an update on the association between urbanization and psychotic spectrum disorders, focusing on specific aspects of the urban environment that could be a bane or boon for the risk of psychosis. RECENT FINDINGS: Majority of the included studies support previous evidence suggesting that urbanization is linked to a higher risk of psychotic experiences and psychotic spectrum disorders. A small minority, however, have also found specific factors in the urban environment that could give rise to positive outcomes, such as better social functioning and lower mortality rates in psychotic spectrum disorders, or mitigate the risks associated with urbanization. The perception of the urban environment was also an important factor that increased or mitigated stress levels in patients with psychosis, which in turn affected their susceptibility to psychotic symptoms. SUMMARY: Specific aspects of the urban environment such as the availability and density of greenspaces are crucial for mitigating the effect of urbanization on risk of psychotic spectrum disorders, and should be incorporated into urban planning. At the same time, there is a need to further explore how modifiable risk factors of the urban environment such as air and noise pollution can be minimized to allow for more liveable cities in the context of psychotic spectrum conditions.

Medical cannabis authorization and risk of emergency department visits and hospitalization due to psychotic disorders: A propensity score-matched cohort study.

Despite evidence showing that recreational cannabis use is associated with a higher risk of psychotic disorders, this risk has not been well characterized for patients using medical cannabis. Therefore, this study assessed the risk of emergency department (ED) visits and hospitalization for psychotic disorders (the study outcome) among adult patients authorized to use medical cannabis. We performed a retrospective cohort study on patients authorized to use medical cannabis in a group of Ontario cannabis clinics between 2014 and 2019. Using clinical and health administrative data, each patient was matched by propensity scores to up to 3 population-based controls. Conditional Cox proportional hazards regressions were used to assess the risk. Among 54,006 cannabis patients matched to 161,265 controls, 39 % were aged ≤50 years, and 54 % were female. Incidence rates for psychotic disorders were 3.00/1000 person-years (95%CI: 2.72-3.32) in the cannabis group and 1.88/1000 person-years (1.75-2.03) in the control group. A significant association was observed, with an adjusted hazard ratio of 1.38 (95%CI: 1.19-1.60) in the total sample and 1.63 (1.40-1.91) in patients without previous psychotic disorders. The results suggest that cannabis authorization should include a benefit-risk assessment of psychotic disorders to minimize the risk of events requiring emergency attention.

Parkinson's disease psychosis management: an evidence based, experience informed, pragmatic approach.

INTRODUCTION: Psychotic symptoms in people with Parkinson's disease (PD) have attracted increasing. Recommendations on treating psychosis often fail to take into account what psychotic symptoms require treatment, which has been complicated by the increasing number of reports documenting the frequency of 'minor' hallucinations. AREAS COVERED: This article focuses both on the phenomenology of psychotic symptoms and their management. EXPERT OPINION: Understanding the nature and implications of the types of psychotic symptoms in PD is the key to proper treatment. Evidence and experience-based data on the effect of anti-psychotic medications will be reviewed and how the various clinical settings should determine the treatment approach. The evidence base consists of all reported blinded trials recorded in PubMed and the experience-based studies are those chosen by the author from PubMed as illustrative. Specific recommendations for the treatment of psychosis will be listed for specific situations. Pimavanserin is the first-line choice for mild symptoms; quetiapine for symptoms that require improvement in a short period and clozapine for urgent problems or those which fail the other approaches.

Psychotic symptoms are common in PD, affecting the majority of patients by the time of death. 'Minor hallucinations' rarely require treatment but formed hallucinations and delusions often do. The vast majority of patients requiring treatment are on medications for PD motor problems. Some patients can be treated with reduction of psychoactive medications that are unrelated to PD, and some may tolerate reductions in PD medications without intolerable worsening of motor function. The remainder require treatment with medications that reduce psychotic symptoms, which include cholinesterase inhibitors, clozapine, pimavanserin, and possibly quetiapine and electroconvulsive therapy. Only clozapine and pimavanserin have unequivocal evidence for efficacy and motor tolerance. Data will be reviewed in support of each of these medications will be reviewed and pragmatic suggestions based on a large experience on when each might be used, and in what order they may be tried if initial approaches fail.

Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis.

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.

A general clinical overview of the non-motor symptoms in Parkinson's disease: Neuropsychiatric symptoms.

The heterogeneity of non-motor features observed in people with Parkinson's disease (PD) is often dominated by one or more symptoms belonging to the neuropsychiatric spectrum, such as cognitive impairment, psychosis, depression, anxiety, and apathy. Due to their high prevalence in people with PD (PwP) and their occurrence in every stage of the disease, from the prodromal to the advanced stage, it is not surprising that PD can be conceptualised as a complex neuropsychiatric disorder. Despite progress in understanding the pathophysiological mechanisms underlying the neuropsychiatric signs and symptoms in PD, and better identification and diagnosis of these symptoms, effective treatments are still a major unmet need. The impact of these symptoms on the quality of life of PwP and caregivers, as well as their contribution to the overall non-motor symptom burden can be greater than that of motor symptoms and require a personalised, holistic approach. In this chapter, we provide a general clinical overview of the major neuropsychiatric symptoms of PD.

Second-generation antipsychotics for Parkinson's disease psychosis: A systematic review and network meta-analysis.

OBJECTIVE: This network meta-analysis assessed the efficacy, tolerability, and acceptability of second-generation antipsychotics (SGAs) for Parkinson's disease psychosis (PDP). METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials investigating SGAs for PDP up to October 26, 2023. RESULTS: We included 16 trials (N = 1252) investigating clozapine, melperone, olanzapine, pimavanserin, quetiapine, ulotaront, and placebo. In comparisons between SGAs and placebo, the findings were: i) Standardized mean differences, 95% confidence intervals (SMDs, 95%CIs), for psychotic-symptom reduction revealed the first rank of clozapine (-1.31, -1.73 to -0.89), the second rank of pimavanserin, with significant inferiority of quetiapine (SMD = 0.47, 0.02 to 0.92); ii) Mean differences (MDs, 95%CIs) for abnormal movement, as assessed by the Unified Parkinson's Disease Rating Scale - Part III, indicated that clozapine had the least motor side effects (-0.92, -2.75 to 0.91); iii) Risk ratios (RRs, 95% CIs) for adverse-effect dropout rates were lowest for melperone (1.02, 0.20 to 5.24); and iv) RRs (95% CIs) for all-cause dropout rates were lowest for clozapine (0.73, 0.42 to 1.25). CONCLUSIONS: For patients with PDP, clozapine may substantially reduce psychotic symptoms with minimal abnormal movement, high acceptability, and moderate overall tolerability. Pimavanserin, not quetiapine, could be an alternative.

Childhood adversities and psychotic symptoms among high school students in China: The role of dissociation.

Adverse childhood experiences (ACEs) are well-established risk factors for psychotic symptoms. This study replicated the relationship between ACEs and positive symptoms of psychosis in the Asian context and explored the moderating effect of dissociation. We analyzed data from 1439 high school students in China who completed validated measures of ACEs, positive symptoms of psychosis, and dissociative symptoms. The positive relationship between ACEs and psychotic symptoms was confirmed in our sample (r =0.244, p <0.001). Among different ACEs, childhood emotional neglect (ß =0.139, p <0.001) and emotional abuse (ß =0.125, p <0.001) had the strongest relationship with psychotic symptoms. Dissociative symptoms were also found to be a statistically significant moderator. We provide cross-cultural evidence for the relationship between ACEs and psychotic symptoms. Dissociative symptoms may exacerbate such effects. These results highlight the importance of child protection to prevent psychotic symptoms. Individuals with higher levels of dissociation may be at higher risk of developing psychotic symptoms when exposed to adversities. A trauma-informed approach to addressing psychotic symptoms in the community is recommended.

Unveiling Assessment Gaps in Parkinson's Disease Psychosis: A Scoping Review.

BACKGROUND: Parkinson's disease psychosis (PDP) is a multidimensional construct that is challenging to measure. Accurate assessment of PDP requires comprehensive and reliable clinical outcome assessment (COA) measures. OBJECTIVE: To identify PDP measurement gaps in available COAs currently used in clinical and research settings. METHODS: We conducted a scoping review using Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines. We implemented a three-step search strategy in international databases with keywords related to Parkinson's disease (PD), psychosis, and COA. We analyzed studies using COA to assess PDP, classifying their items according to domains and subdomains. RESULTS: From 5673 identified studies, we included 628 containing 432 PDP core items from 32 COAs. Among the 32 COAs, 19 were PD-specific, containing 266 items, constructed as clinician-reported outcomes (ClinRO) (148 items), patient-reported outcomes (PRO) (112 items), and observer-reported outcomes (ObsRO) (six items). Across all PD-specific COAs, regardless of structure, 89.4% of the items from 27 COAs focused primarily on assessing PDP symptoms' severity, and only 9.7% of items probed the impact of PDP on a person's daily functioning. CONCLUSIONS: Symptom-based domains are currently prioritized for measuring the severity of PDP, with limited coverage of the functional impact of PDP on patients' lives. Whereas the International Parkinson and Movement Disorder Society has traditionally developed a "Unified" COA that culls items from prior COAs to form a new one, a new COA will largely need newly developed items if the functional impact of PDP is prioritized. © 2024 International Parkinson and Movement Disorder Society.

Parkinson disease psychosis: from phenomenology to neurobiological mechanisms.

Parkinson disease (PD) psychosis (PDP) is a spectrum of illusions, hallucinations and delusions that are associated with PD throughout its disease course. Psychotic phenomena can manifest from the earliest stages of PD and might follow a continuum from minor hallucinations to structured hallucinations and delusions. Initially, PDP was considered to be a complication associated with dopaminergic drug use. However, subsequent research has provided evidence that PDP arises from the progression of brain alterations caused by PD itself, coupled with the use of dopaminergic drugs. The combined dysfunction of attentional control systems, sensory processing, limbic structures, the default mode network and thalamocortical connections provides a conceptual framework to explain how new incoming stimuli are incorrectly categorized, and how aberrant hierarchical predictive processing can produce false percepts that intrude into the stream of consciousness. The past decade has seen the publication of new data on the phenomenology and neurobiological basis of PDP from the initial stages of the disease, as well as the neurotransmitter systems involved in PDP initiation and progression. In this Review, we discuss the latest clinical, neuroimaging and neurochemical evidence that could aid early identification of psychotic phenomena in PD and inform the discovery of new therapeutic targets and strategies.

Childhood Adversity and Emerging Psychotic Experiences: A Network Perspective.

BACKGROUND AND HYPOTHESIS: Childhood adversity is associated with a myriad of psychiatric symptoms, including psychotic experiences (PEs), and with multiple psychological processes that may all mediate these associations. STUDY DESIGN: Using a network approach, the present study examined the complex interactions between childhood adversity, PEs, other psychiatric symptoms, and multiple psychological mediators (ie, activity-related and social stress, negative affect, loneliness, threat anticipation, maladaptive cognitive emotion regulation, attachment insecurity) in a general population, adolescent sample (n = 865, age 12-20, 67% female). STUDY RESULTS: Centrality analyses revealed a pivotal role of depression, anxiety, negative affect, and loneliness within the network and a bridging role of threat anticipation between childhood adversity and maladaptive cognitive emotion regulation. By constructing shortest path networks, we found multiple existing paths between different categories of childhood adversity and PEs, with symptoms of general psychopathology (ie, anxiety, hostility, and somatization) as the main connective component. Sensitivity analyses confirmed the robustness and stability of the networks. Longitudinal analysis in a subsample with Wave 2 data (n = 161) further found that variables with higher centrality (ie, depression, negative affect, and loneliness) better predicted follow-up PEs. CONCLUSIONS: Pathways linking childhood adversity to PEs are complex, with multifaceted psychological and symptom-symptom interactions. They underscore the transdiagnostic, heterotypic nature of mental ill-health in young people experiencing PEs, in agreement with current clinical recommendations.