Clearing the Fog: A Review of Antipsychotics for Parkinson's-Related Hallucinations: A Focus on Pimavanserin, Quetiapine and Clozapine.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care.

Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

Hoigné's syndrome, an uncommon mimicker of anaphylaxis: Systematic literature review.

The term Hoigné's syndrome denotes a mimicker of anaphylaxis, which occurs immediately after the parenteral administration of a drug and is likely caused by non-thrombotic pulmonary and systemic drug micro-embolization. It has so far been documented uniquely in case reports and small case series. Because this condition has never been systematically evaluated, we performed a structured literature review (pre-registered as CRD42023392962). The search was carried out in Excerpta Medica, National Library of Medicine, and Google Scholar. Cases with features consistent with anaphylaxis, urticaria, angioedema, asthma, syncope, anxiety, or panic attack triggered by needle phobia, and local anesthetic systemic toxicity were excluded. For the final analysis, we retained reports published between 1951 and 2021, which presented 247 patients with Hoigné's syndrome: 37 children and 211 adults with a male: female ratio of 2.1 : 1.0. The patients presented within 1 min after parenteral administration of a drug (intramuscular penicillin in 90 % of the cases) with chest discomfort, shortness of breath, fear of death, psychomotor agitation, and auditory or visual hallucinations and impairment. Recovery occurred within 30 min. The diagnosis of Hoigné's syndrome was also established in five patients 66-91 years of age with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the aforementioned symptoms. It was therefore speculated that pulmonary drug micro-embolization induced a lethal cardiovascular compromise in these individuals. Histologic investigations supporting this hypothesis were performed in only one case. The diagnosis of Hoigné's pulmonary drug micro-embolization was established also in five patients with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the afore mentioned symptoms. Histologic investigations supporting this hypothesis were performed in only one case. In conclusion, Hoigné's syndrome is an uncommon non-immune-mediated reaction. This report seeks to promote broader awareness and knowledge regarding this alarming mimicker of anaphylaxis. Diagnosis relies solely on clinical evaluation.

[Severe neuropsychiatric disorder developing during busulfan-containing regimen for stem cell transplantation].

Here we describe two patients that required interruption of a busulfan (BU) containing conditioning regimen due to severe mental disorder before stem cell transplantation. The first patient was a 66-year-old man scheduled for unrelated peripheral blood stem cell transplantation with fludarabine/BU conditioning for myelodysplastic syndrome. He received 9.6 mg/kg BU and developed hallucinations that worsened the next day. BU was stopped on the final day, but the patient became comatose (grade 4). He recovered the next day. The second patient was a 69-year-old man scheduled for autologous peripheral blood stem cell transplantation with thiotepa (TT)/BU conditioning for cerebral nervous system relapse of mantle cell lymphoma. He received 12.8 mg/kg BU and developed hallucinations. His mental symptoms worsened on the next day, and thus administration was stopped on the second day of TT. His symptoms improved the next day. Both patients were over 65 years old, and their psychiatric symptoms worsened 1-2 days after the final dose of BU. Our findings suggest that BU may cause psychiatric disorders in elderly patients. When performing BU conditioning, it may be necessary to avoid azole antifungal medication and acetaminophen and to reduce the dose or perform therapeutic dose monitoring for elderly patients.

Hallucinating hallucinogens.

Fighting the designer drug epidemic with generative AI.

Amantadine for Refractory Tremor in Parkinson Disease and Other Indications: A Chart Review With Long-Term Follow-up.

OBJECTIVES: The aim of this study was to determine how amantadine was used in a movement disorders clinic and how effective it was. METHODS: A chart review over a 2-month period in 2022 of all patients in a movement disorders clinic who had ever taken amantadine was undertaken. RESULTS: One hundred six charts were included. Amantadine was initiated primarily for tremor and secondly for l -dopa-induced dyskinesias (LIDs). Sixty-two percent of tremor patients improved and tolerated amantadine; 74% of those with LID improved and tolerated the drug. Hallucinations occurred in 23%. Initiating amantadine as a syrup allowed a more conservative titration than other formulations, which is attractive given the high percentage of hallucinations that may occur. Patients who tolerated drug initiation were generally kept on the drug for many years. CONCLUSIONS: Amantadine should be considered as adjunctive therapy in Parkinson disease patients with refractory tremor as well as for LIDs.

The Risk of Neuropsychiatric Adverse Events With Use of Leukotriene Receptor Antagonists in Patients With Asthma: Analysis of Korea's National Health Insurance Sharing Service Database.

BACKGROUND: Montelukast, a selective leukotriene receptor antagonist, is a commonly prescribed allergy medication but its potential association with neuropsychiatric adverse events is concerning. OBJECTIVE: To analyze Korea's National Health Insurance System claims records to identify the risk of neuropsychiatric adverse events in patients with asthma treated with montelukast. METHODS: This retrospective population-based study analyzed the National Health Insurance claims records of the entire Korean population between 2008 and 2015. We compared the risk of neuropsychiatric adverse events among patients with asthma using inhaled corticosteroids and/or long-acting ß2-agonists with montelukast or pranlukast and those not using leukotriene receptor antagonists (control group). RESULTS: There was no increased risk of the composite outcome of all measured neuropsychiatric adverse events in patients with asthma who were prescribed montelukast or pranlukast compared with those who were not. However, montelukast use was associated with an increased risk of hallucinations (inverse probability treatment weighting hazard ratio, 1.45; 95% CI, 1.07-1.96) and attention problems (inverse probability treatment weighting hazard ratio, 1.24; 95% CI, 1.01-1.52). Significant negative hazards for disorientation, anxiety, stress reactions, and somatic symptoms were observed in the montelukast group. When grouped by sex, the risk of hallucinations and attention problems was higher in men prescribed montelukast compared with the controls. CONCLUSIONS: We did not observe an increase in all neuropsychiatric adverse events in the leukotriene receptor antagonist-treated group; however, an increased risk of hallucinations and attention problems was observed in those taking montelukast, regardless of the medication administration period.

Association of cannabis, cannabidiol and synthetic cannabinoid use with mental health in UK adolescents.

BACKGROUND: Cannabis has been associated with poorer mental health, but little is known of the effect of synthetic cannabinoids or cannabidiol (often referred to as CBD). AIMS: To investigate associations of cannabis, synthetic cannabinoids and cannabidiol with mental health in adolescence. METHOD: We conducted a cross-sectional analysis with 13- to 14-year-old adolescents across England and Wales in 2019-2020. Multilevel logistic regression was used to examine the association of lifetime use of cannabis, synthetic cannabinoids and cannabidiol with self-reported symptoms of probable depression, anxiety, conduct disorder and auditory hallucinations. RESULTS: Of the 6672 adolescents who participated, 5.2% reported using of cannabis, 1.9% reported using cannabidiol and 0.6% reported using synthetic cannabinoids. After correction for multiple testing, adolescents who had used these substances were significantly more likely to report a probable depressive, anxiety or conduct disorder, as well as auditory hallucinations, than those who had not. Adjustment for socioeconomic disadvantage had little effect on associations, but weekly tobacco use resulted in marked attenuation of associations. The association of cannabis use with probable anxiety and depressive disorders was weaker in those who reported using cannabidiol than those who did not. There was little evidence of an interaction between synthetic cannabinoids and cannabidiol. CONCLUSIONS: To our knowledge, this study provides the first general population evidence that synthetic cannabinoids and cannabidiol are associated with probable mental health disorders in adolescence. These associations require replication, ideally with prospective cohorts and stronger study designs.

Amantadine toxicity causing visual hallucinations.

Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat fatigue in multiple sclerosis. It is primarily renally excreted and so impaired kidney function prolongs its half-life and may lead to toxicity. We describe a woman with multiple sclerosis taking amantadine who developed acute renal impairment, which triggered florid visual hallucinations that resolved on stopping the medication.

Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin.

Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-hydroxytryptamine2A (5-HT2A ) receptor. The safety and efficacy of pimavanserin 34 mg once daily were studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model-based simulations of pimavanserin steady-state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34 mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (ie, actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (aged 13-17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (ie, simulated) group of pediatric patients (aged 5-17 years). Steady-state measures of the area under the plasma concentration-time curve (AUC) and maximum drug concentration (Cmax ) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (aged 18-49 years). The simulated mean AUC ranged from 47.41 to 54.73 ng d/mL and the mean Cmax ranged from 41.13 to 50.07 ng/mL in adults receiving pimavanserin 34 mg. The simulated mean (SD) Cmax of 56.54 (24.58) ng/mL with pimavanserin 34 mg in patients aged 10-17 years was similar to that in adults. Pimavanserin 20 mg yielded a mean (SD) Cmax of 45.30 (21.31) ng/mL in patients aged 5-9 years and 49.18 (22.91) ng/mL in the pediatric patient weight group of 14-25 kg, which are values close to the Cmax in adults treated with 34 mg. Pimavanserin 20 and 34 mg in pediatric patients aged 5-9 and 10-17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18-49 years.

[Contribution of serotonin 5-HT2A receptor to antidepressant effect of serotonergic psychedelics].

Major depressive disorder presents a substantial global health burden, and at least 30-40% of patients exhibit treatment resistance to antidepressants. Ketamine, an NMDA receptor antagonist, is used as an anesthetic agent. In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine (the S-enantiomer of ketamine) as a therapeutic agent for treatment-resistant depression; however, this drug has reportedly been associated with serious side effects such as dissociative symptoms, thus limiting its clinical use as an antidepressant. Recently, various clinical studies have reported that psilocybin, the psychoactive substance found in magic mushrooms, has a fast-acting and long-lasting antidepressant effect in patients with major depressive disorder, including those resistant to conventional treatment. Furthermore, psilocybin is a psychoactive drug that is relatively harmless compared to ketamine and other similar substances. Accordingly, the FDA has designated psilocybin as a "breakthrough therapy approach" for the treatment of major depressive disorder. Additionally, serotonergic psychedelics such as psilocybin and lysergic acid diethylamide show some potential in the treatment of depression, anxiety, and addiction. The increased attention the use of psychedelics has attracted as a psychiatric disorder treatment approach is referred to as the "psychedelic renaissance". Pharmacologically, psychedelics cause hallucinations by stimulating cortical serotonin 5-HT2A receptors (5-HT2A), although whether 5-HT2A is responsible for the manifestation of their therapeutic effects remains unclear. Furthermore, it is unclear whether the hallucinations and "mystical experience" that the patients go through because of 5-HT2A activation by psychedelics is essential for the therapeutic effect of these substances. Future research should elucidate the molecular and neural mechanisms underlying the therapeutic effects of psychedelics. This review summarizes the therapeutic effects of psychedelics on psychiatric disorders such as major depressive disorder in clinical and pre-clinical studies, and discusses the possibility of 5-HT2A as a novel therapeutic target.

Alucinaciones como efecto adverso del topiramato / Hallucinations as an adverse effect of topiramate

El topiramato es un fármaco antiepiléptico que bloquea los canales de sodio voltaje-dependientes y potencia la actividad gabaérgica. Entre sus posibles efectos adversos se han descrito algunos muy infrecuentes como las alucinaciones visuales o auditivas. Presentamos un caso de una niña de 7 años con antecedentes de migraña sin aura sin otros antecedentes personales ni familiares de interés que, tras 15 días de tratamiento preventivo con topiramato, desarrolló alucinaciones, cambios de humor bruscos, negativismo e ideas de muerte. Dada la clínica no explicable por otra circunstancia o fármaco se retiró el topiramato con desaparición completa de los síntomas a los 20 días, sin reaparición de estos. Las alucinaciones son un efecto adverso muy inusual del topiramato. El mecanismo fisiopatológico podría estar relacionado con su efecto sobre la actividad GABA. Existen muy pocos casos de este efecto adverso descritos. En pacientes pediátricos solo se han descrito dos casos, siendo este el primer caso descrito en el contexto de tratamiento profiláctico de la migraña (AU)

Topiramate is an antiepileptic drug which blocks voltage-gated sodium channels and enhances GABAergic activity. We report the case of a 7-year-old girl with a medical history of migraine without aura who, after fifteen days of preventive treatment with topiramate developed visual and tactile hallucinations. She also presented sudden mood swings, negativism and even death ideation. She had no other personal or family medical or psychiatric history. Due to the symptomatology, Topiramate was stopped, with a complete disappearance of symptoms twenty days after its suspension, and without the recurrence of them.Hallucinations are a very unusual side effect of Topiramate. There are very few cases of this adverse effect described in the literature. In pediatric patients, there were only two cases, this being the first case described in the context of prophylactic treatment of migraine. (AU)

Varenicline induced auditory hallucinations in a young female with bipolar disorder: a case report.

BACKGROUND: Creating appropriate and sustainable treatment plans for patients with concurrent disorders presents a challenge to psychiatrists and addiction medicine specialists alike. Although varenicline has been found to be the most effective medication for smoking cessation and abstinence when compared to results from placebo medications, nicotine patches and bupropion, caution is needed when starting patients on this medication. With the high prevalence of concurrent mental health and substance use disorders in vulnerably-housed populations in Canada, it becomes increasingly important to advocate for increased guidance and research into treating concurrent disorders. CASE PRESENTATION: In this case, a young female patient provisionally diagnosed with bipolar I disorder was hospitalized for a manic episode in the context of substance use and medication noncompliance. She also endorsed a long history of tobacco, alcohol, cocaine, cannabis and ketamine use. Perceptual abnormalities, including auditory hallucinations, were not recorded at admission. In addition to being stabilized for bipolar diagnosis, the patient was started on nicotine replacement therapy on Day 7 of admission followed by initiation of varenicline for smoking cessation on Day 14 of admission. Soon after the varenicline treatment was started, the patient developed auditory hallucinations, paranoia and referential beliefs. However, her insight was intact, and she had minimal thought form disorganization. In this case, these symptoms were thought to be secondary to varenicline after the consideration of potential alternative contributors. CONCLUSION: The occurrence of side effects as a result of varenicline use in patients with diagnosed mental health conditions is rare and underlying psychiatric illness is not labeled as an absolute contraindication in the prescription of varenicline. However, it is important to advocate for increased guidance and research on the treatment of substance use disorders in patients with bipolar I disorder. Patients may also benefit from increased collaboration between psychiatric and addiction services as that may allow for earlier recognition and intervention of symptoms to minimize distress.

Delirium secondary to anticholinergics.

We present a case of a young man who developed sudden deterioration in his physical and mental state whilst being treated as an inpatient for substance-induced psychosis. This deterioration was manifested by sudden disorientation, change in behaviour and visual hallucinations. It was only after excluding other potential causes that this presentation was attributed to the regular administration of procyclidine that was being used to counteract the extrapyramidal side effects from antipsychotics. The patient showed a dramatic improvement on stopping procyclidine. This case highlights the importance of awareness of rare adverse drug reactions and the resultant distressing effect for the patient himself.

Adverse Events and Measurement of Dissociation After the First Dose of Esketamine in Patients With TRD.

BACKGROUND: "Dissociation" comprises distinct phenomena, some of which are associated with esketamine treatment and some may overlap with positive symptoms of psychosis. Relationships between dissociation and psychotic symptoms assessed by -clinician report vs conventional rating scales were investigated in a post hoc analysis of data from the initial treatment session in an -open-label, -long-term safety, phase 3 study of esketamine plus a newly initiated oral antidepressant in patients with treatment-resistant depression. METHODS: Adverse events of dissociation or psychosis were examined via investigator report and the Clinician Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale-Plus, respectively, 40 minutes post first esketamine dose. The range of CADSS total scores associated with investigator-reported severity of dissociation was determined by equipercentile linking. Logistic regression models and receiver operating curve analysis explored the CADSS cutoff point for determining presence/absence of dissociation. Frequency of response to specific CADSS items was examined to investigate qualitative differences in the pattern of symptoms reported across investigator-reported levels of adverse event severity. RESULTS: Dissociation was reported as an adverse event in 14.3% (109/764) of patients. Severity of most CADSS items increased with the severity of investigator-reported dissociation. No CADSS cutoff point discriminated well between the presence and absence of dissociation events. Hallucinations were reported as adverse events in 5 patients; none reported delusions. CONCLUSIONS: CADSS scores and severity of dissociation adverse events move generally in the same direction; however, there is substantial variability in this relationship. No signature profile of dissociative experiences was revealed, and psychotic symptoms were uncommon. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02497287.

Psychosis in Parkinson's Disease: Looking Beyond Dopaminergic Treatments.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. The symptoms of PD are characterized not only by motor alterations but also by a spectrum of nonmotor symptoms. Some of these are psychiatric manifestations such as sleep disorders; depression; cognitive difficulties that can evolve into dementia; and symptoms of psychosis, which include hallucinations, illusions, and delusions. Parkinson's disease psychosis (PDP) occurs in 18-50% of patients with PD. Treating PDP is challenging because antipsychotic drugs tend to be inefficient or may even worsen the disease's motor symptoms. OBJECTIVE: This review aims to summarize the current understanding of the molecular mechanisms involved in PDP and recent innovative alternatives for its treatment. METHODS: This is a narrative review in which an extensive literature search was performed on the Scopus, EMBASE, PubMed, ISI Web of Science, and Google Scholar databases from inception to August 2021. The terms "Parkinson's disease psychosis", "Parkinson psychosis," "neurodegenerative psychosis", and "dopamine psychosis" were among the keywords used in the search. RESULTS: Recently, views on the etiology of hallucinations and illusions have evolved remarkably. PDP has been cemented as a multifactorial entity dependent on extrinsic and novel intrinsic mechanisms, including genetic factors, neurostructural alterations, functional disruptions, visual processing disturbances, and sleep disorders. Consequently, innovative pharmacological and biological treatments have been proposed. Pimavanserin, a selective 5-HT2A inverse agonist, stands out after its approval to treat PDP-associated hallucinations and illusions. CONCLUSION: Future results from upcoming clinical trials should further characterize the role of this drug in the management of PDP as well as other treatment options with novel mechanisms of action, such as saracatinib, SEP-363856, cannabidiol, electroconvulsive therapy, and transcranial magnetic stimulation.