The effect of anticholinergic drugs on cognition of patients with Parkinson's disease: a cohort study from the Egyptian population.

BACKGROUND: Cognitive dysfunction is a non-motor manifestation of Parkinson's disease (PD). We aimed to determine the frequency and patterns of cognitive dysfunction in treated patients with PD and their predictors. RESEARCH DESIGN AND METHODS: This study included 80 patients (male = 48; female = 32) and 30 healthy individuals. They underwent neuropsychiatric evaluations. Measurements included Beck's depression inventory - II (BDI-II), mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). RESULTS: Patients had mean age of 55.56 ± 9.06 yrs, duration of PD of 4.86 ± 2.71 yrs and Hoehn and Yahr Scoring of 2.19 ± 0.89. They were on levodopa/carbidopa therapy and adjuvant therapy with benztropine mesylate, an anticholinergic drug, (n = 51) or amantadine sulfate, a dopaminergic drug, (n = 29). Sixteen (20%) had moderate depressive symptoms. Mild and moderate cognitive impairments were reported in 38.8% and 28.8% (by MMSE) and 46.3% and 31.3% (by MoCA). Patients had lower global cognitive scoring (p = 0.0001) and scorings of different cognitive functions (naming, attention, language, abstraction, memory and orientation) than controls. Patients treated with benztropine had lower cognition than with amantadine. Correlation analyses showed that lower cognition was only associated with chronic PD and its treatment (p = 0.0001). CONCLUSIONS: Cognitive dysfunction is common with PD (77.5%) particularly with anticholinergic drugs. De-prescription of anticholinergics is recommended for patients with PD.

Withdrawal-Emergent Dyskinesia Related to Benztropine: A Case Report.

INTRODUCTION: Benztropine is an anticholinergic drug used as a therapy for Parkinson's disease and treatment for extrapyramidal side effects. While tardive dyskinesia is an involuntary movement disorder that often occurs gradually after long-term use of medications, it does not commonly present acutely. CASE PRESENTATION: A 31-year-old White woman experiencing psychosis presented with spontaneous, acute-onset dyskinesia induced with the withdrawal of benztropine. She had been followed in our academic outpatient clinic for medication management and intermittent psychotherapy. DISCUSSION: The pathophysiology of tardive dyskinesia is not fully understood, but several hypotheses exist, including the involvement of changes in basal ganglia neuronal systems. To our knowledge, this is the first case report to document acute-onset dyskinesia associated with the withdrawal of benztropine. CONCLUSION: his case report, which describes an atypical response to discontinuing benztropine, might offer the scientific community potential clues to better understand the pathophysiology of tardive dyskinesia.

Actualización en enfermedad con cuerpos de Lewy / Update in Lewy body disease

La enfermedad con cuerpos de Lewy incluye 2 entidades que podrían ser consideradas variantes clínicas de una misma patología: la demencia con cuerpos de Lewy y la demencia en enfermedad de Parkinson. Con la finalidad de describir correctamente lo que sucede en la evolución de la enfermedad se divide el cuadro en etapa prodrómica y de demencia propiamente dicha. La primera está clínicamente representada por aquel período en el cual, si bien el paciente exhibe algunos signos y síntomas propios de la enfermedad, no reúne criterios de demencia. A pesar de ser difícil de definir y por carecerse todavía de contundentes datos clínicos y biomarcadores, se caracteriza principalmente por deterioro leve selectivo en función atencional ­ visuoespacial, trastorno del sueño REM y disautonomía‒. La segunda etapa está claramente caracterizada en los criterios de consenso del año 2005. Recientemente hemos publicado la validación de un instrumento llamado ALBA Screening Instrument, que permite diagnosticar con alta sensibilidad y especificidad la enfermedad aun en etapas tempranas y diferenciarla de otras patologías semejantes. La tomografía por emisión de positrones (PET) para transportador de dopamina es el procedimiento de referencia (gold standard) del diagnóstico. El tratamiento sintomático con anticolinesterásicos y neurolépticos atípicos favorece una buena evolución de la enfermedad y es fundamental tener en cuenta evitar medicamentos que pueden dañar gravemente a los pacientes como los anticolinérgicos y antipsicóticos típicos. Los avances en el diagnóstico y la difusión del impacto de esta enfermedad en la población contribuirán a generar mayores esfuerzos de investigación para hallar un tratamiento eficaz, preventivo o curativo o de ambas características. (AU)

Lewy body disease includes 2 entities that could be considered clinical variants of the same pathology: Dementia with Lewy bodies and Parkinson's disease Dementia. Two stages of the disease are described in this review, a prodromal stage and one of explicit dementia. The first one is clinically represented by that period in which, the patient exhibits some typical features of the disease, but not dementia criteria. Despite being difficult to define the prodromal stage and that strong clinical data and biomarkers are still lacking, there is evidence to characterize it mainly by mild selective impairment in attention and visuo-spatial function, REM sleep disorder and dysautonomia. The second stage is clearly characterized in the known consensus criteria of 2005. We have recently published the validation of an instrument called ALBA Screening Instrument which showed a high sensitivity and specificity for diagnosis of the disease even in the early stages. It´s useful to differentiate the disease from other similar pathologies. Positron Emission Tomography for dopamine transporter is the gold standard of diagnosis in life. Symptomatic treatment with anticholinesterases and atypical neuroleptics help patients in their evolution of the disease. Anticholinergics and typical antipsychotics are agents to avoid in the treatmen of the disease because can severely damage patients. Future advances in the diagnosis and dissemination of the knowledge of the disease will contribute to generate greater research efforts to find an effective preventive and / or curative treatment. (AU)

Prolonged Antimuscarinic Delirium in a Child Due to Benztropine Exposure Treated With Multiple Doses of Physostigmine.

An 11-year-old boy presented with an antimuscarinic toxidrome due to benztropine and risperidone ingestion. His delirium was prolonged and difficult to treat with benzodiazepines. Multiple doses of physostigmine successfully treated it. Benztropine is a potent antimuscarinic agent, whereas risperidone has not been reported to cause antimuscarinic toxicity. The use of physostigmine to treat benztropine intoxication in a pediatric patient has not previously been described. In this case, multiple doses were used and were well tolerated.

A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder.

Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Full circle-old drugs prove more beneficial than newer agents for schizophrenia: a case report.

A 55-year-old female with a diagnosis of schizophrenia currently resides in an assisted living facility in a large metropolitan suburb. For approximately 25 years, the patient was relegated to a life of poor symptom control and social adjustment, largely due to nonadherence, relapse, and rehospitalization. The patient experienced a trial-and-error approach to drug therapy, which resulted in reliance on the older or first generation agents for symptom improvement. This case supports the assertion that the second-generation or atypical antipsychotics used to treat schizophrenia are no better than older drugs in terms of efficacy or tolerability.

Olanzapine and benztropine as a cause of ischemic colitis in a 27-year-old man.

Ischemic colitis is a rare adverse effect of antipsychotic medications and is most commonly associated with the phenothiazine class of antipsychotics and atypical antipsychotics such as clozapine and olanzapine. The risk is further increased when antipsychotics are taken in conjunction with anticholinergics. A 27-year-old man with a history of bipolar disorder and depression presented to the emergency department with 6 days of constipation, abdominal pain, nausea, and nonbloody vomiting. He later developed multiple episodes of hematochezia and fever. Within the preceding 2 weeks, his medication regimen of divalproex sodium, aripiprazole, and trihexyphenidyl, had been changed to olanzapine, benztropine, and bupropion. The patient's physical examination showed diffuse abdominal tenderness, guarding, and distension and laboratory tests revealed a leukocytosis. A computed tomographic scan of the abdomen/pelvis showed colitis extending from the splenic flexure to the sigmoid colon, without evidence of perforation. A colonoscopy revealed severe ischemic colitis involving the descending and sigmoid colon, which was confirmed on biopsy. Given the temporal association between the new medications and onset of symptoms, the patient's ischemic colitis was likely caused by olanzapine or the combination of olanzapine and benztropine, likely secondary to their anticholinergic properties. Thus, providers should take a thorough history and counsel patients regarding the risks of constipation when starting antipsychotic medications, particularly those with anticholinergic activity. Despite the fact that ischemic colitis is such a rare adverse effect of antipsychotic medications, it is important to consider because of its potentially fatal outcomes.

Paralytic ileus requiring hospitalization secondary to high-dose antipsychotic polypharmacy and benztropine.

Ileus can result from the combined activity of antipsychotic and anticholinergic medications. Despite frequent use, case reports in the literature are sparse. We present a patient who developed a paralytic ileus requiring extended hospitalization. Providers should minimize antipsychotic and concurrent anticholinergic medications, consider prophylactic bowel regimens and monitor for constipation.

Fatal exertional heat stroke in a patient receiving zuclopenthixol, quetiapine and benztropine.

OBJECTIVE: To report a case of fatal exertional heat stroke associated with the use of zuclopenthixol, quetiapine and benztropine. CASE SUMMARY: A 36-year-old male with a history of schizophrenia and bipolar disease was working as a roofer during the third day of a heat wave. His medications included zuclopenthixol, quetiapine, benztropine, carbamazepine and levothyroxine. He developed loss of consciousness late in the day and presented to hospital with a Glasgow Coma Scale 3 and a rectal temperature of 42.2 degrees C. He progressed to severe multiple organ dysfunction and asystole, and expired the following morning. Neuroleptic and anticholinergic agents have long been associated with heat alteration, but there are few reports involving the newer antipsychotic agents. Physicians and pharmacists should ensure that appropriate counseling is given to patients receiving these medications regarding early recognition of signs and symptoms and prompt treatment of heat related illness and heat stroke.

Benztropine pretreatment does not affect responses to acute cocaine administration in human volunteers.

Benztropine (Cogentin ) was evaluated for its ability to block cocaine's physiological and subjective effects in humans. In healthy, recreational users of cocaine, placebo, or benztropine (1, 2, and 4 mg orally) was given 2 hr before subjects self-administered 0.9 mg/kg of cocaine intranasally. Measurements were made for 2 hr following cocaine administration, and plasma cocaine and cocaine metabolites were assayed. Cocaine produced typical increases in heart rate and alterations in self-reports measured by visual analog scales (VAS). Benztropine alone did not produce changes on any of these measures. Responses to cocaine with and without benztropine pretreatment were similar: benztropine did not change cocaine's effects. This study of one of the tropane-ring analogs that is approved for human use suggests this compound does not alter cocaine-induced effects, but just as importantly, does not produce any adverse behavioral or physiological effects. The exact therapeutic application of benztropine as a possible adjunct treatment for cocaine abuse in humans require further exploration.

Incidence of delirium in older adults newly prescribed lithium or valproate: a population-based cohort study.

BACKGROUND: The use of lithium carbonate for the treatment of mood disorders in old age has decreased at a dramatic rate in favor of valproate. Because of lithium's narrow therapeutic range, neurotoxicity can be an important complication in lithium therapy and potentially influence prescription patterns. Therefore, we compared the incidence of delirium in older adults with mood disorders who were newly dispensed either lithium or valproate. METHOD: Using 4 population-based administrative databases from the province of Ontario, Canada (the Ontario Drug Benefit program, the Canadian Institute for Health Information, the Ontario Health Insurance Plan, and the Registered Persons Data Base), we were able to identify a cohort of mood disorder patients 66 years and older who were newly dispensed lithium or valproate over an 8-year period (1993-2001). Measures were taken to ensure that the sample was composed of mood disorder patients. As a comparator, we included a known deliriogenic drug, benztropine. The main outcome measure was a new diagnosis of delirium on a hospitalization record during 1 year of follow-up. RESULTS: Our study cohort consisted of 2422 new users of lithium and 2918 new users of valproate over an 8-year period. There was no statistically significant difference in the incidence of delirium between lithium (2.8 per 100 person-years) and valproate (4.1 per 100 person-years). Compared with patients who received lithium, patients who received benztropine had a significantly higher risk of delirium (p < .001). CONCLUSION: The incidence of hospitalizations with delirium was similar in patients treated with lithium and valproate. These findings add to the evidence suggesting that the shift away from the use of lithium carbonate to manage mood disorders in older adults is not justified on the basis of concerns of neurotoxicity.

Analogue functional analysis of movements associated with tardive dyskinesia.

We studied whether movements associated with tardive dyskinesia (TD) served operant functions in 2 men with developmental disabilities. We found that TD-related movements occurred more frequently in the alone and attention conditions and less frequently in control and demand conditions. Our findings suggest that TD-related movements may not be maintained by social reinforcers and that decreases in TD movements are possibly a result of engagement in activities that are incompatible with TD movements.