Anticholinergic Antidepressants Research Articles

Centrally-acting anticholinergic drugs– associations with mortality, hospitalisation and cognitive decline following dementia diagnosis in people receiving antidepressant and antipsychotic drugs

Objectives Long-term use of anticholinergic medication in older people is associated with increased risk of cognitive decline and mortality, but this relationship could be confounded by the underlying illness the drugs are treating. To investigate associations between central anticholinergic antidepressants or antipsychotics and mortality, hospitalisation and cognitive decline in people with dementia. Method In cohorts of patients with a dementia diagnosis receiving antidepressant and/or antipsychotic medication (N = 4,380 and N = 2,335 respectively), assembled from a large healthcare database, central anticholinergic burden scores were estimated using the Anticholinergic Effect on Cognition (AEC) scale. Data were linked to national mortality and hospitalisation data sources, and Mini-Mental State Examination (MMSE) scores were used to investigate cognitive decline. Results There was a reduced mortality risk in people receiving agents with high central anticholinergic burden compared to those with no or low burden which was statistically significant in the antidepressant cohort (Hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.79-0.98; p = 0.023) but not the antipsychotic one (HR: 0.91; 95% CI: 0.82-1.02; p = 0.105). Patients on antidepressants with no central anticholinergic burden had accelerated cognitive decline compared with other groups, whereas no differences were found in the antipsychotic cohort. No significant associations were detected between antidepressant or antipsychotic-related central anticholinergic burden and hospitalisation. Conclusion These counter-intuitive findings may reflect factors underlying the choice of psychotropics rather than the agents themselves, although do not support a strong role for central anticholinergic drug actions on dementia outcomes. Further studies, including randomized switching of agents are needed to clarify this relationship.

The effects of anticholinergic medications on cognition in children: a systematic review and meta-analysis

Cognitive side effects of anticholinergic medications in older adults are well documented. Whether these poor cognitive outcomes are observed in children has not been systematically investigated. We aimed to conduct a systematic review and meta-analysis on the associations between anticholinergic medication use and cognitive performance in children. Systematic review was conducted using Medline, PsychInfo, and Embase, identifying studies testing cognitive performance relative to the presence versus absence of anticholinergic medication(s) in children. We assessed effects overall, as well as relative to drug class, potency (low and high), cognitive domain, and duration of administration. The systematic search identified 46 articles suitable for meta-analysis. For the most part, random effects meta-analyses did not identify statistically significant associations between anticholinergic exposure and cognitive performance in children; the one exception was a small effect of anticholinergic anti-depressants being associated with better cognitive function (Hedges’ g = 0.24, 95% CI 0.06–0.42, p = 0.01). Anticholinergic medications do not appear to be associated with poor cognitive outcomes in children, as they do in older adults. The discrepancy in findings with older adults may be due to shorter durations of exposure in children, differences in study design (predominantly experimental studies in children rather than predominantly epidemiological in older adults), biological ageing (e.g. blood brain barrier integrity), along with less residual confounding due to minimal polypharmacy and comorbidity in children.

Features of anticholinergic prescriptions and predictors of high use in the elderly: Population-based study.

Older people are especially vulnerable to negative anticholinergic effects. Although anticholinergic drugs are commonly used among older people, drugs with potent antimuscarinic properties are considered as potentially inappropriate medications for older people. Here, we examined features of anticholinergic use and investigated predictors for the high use of strong anticholinergic agents (ACs) in the elderly. A total of 388,629 Korean elderly aged ≥70 years were recruited from the 2012 National Health Insurance Service Elderly cohort database. The use of ACs in 2012 was quantitatively assessed by calculating standardized prescribed doses. Multivariate logistic regression was conducted to identify predictors of the high use of strong ACs (≥90 doses). Almost half of the subjects (47.2%) used more than 15 doses of strong ACs during 2012. 17.0% of the subjects had an annual cumulative use of strong ACs over 90 doses. Morbidities such as depression (odds ratio [OR], 95% confidence interval [CI] = 2.56, 2.48-2.63), Parkinson's disease (2.41, 2.26-2.56), genitourinary diseases (2.12, 2.07-2.16), polypharmacy (3.28, 3.21-3.36), and low income (1.29, 1.25-1.33) were strong predictors of their high use. Antihistamines (chlorpheniramine) and antidepressants (amitriptyline) greatly contributed to the total prescription of strong ACs. Despite the vulnerability of older people to the adverse reactions of strong ACs, their use seems to be at a high level in terms of cumulative usage among some elderly. More attention should be paid to older people with predictive factors of high use of strong ACs. Key points Despite the susceptibility of older people to negative anticholinergic effects, high use of strong anticholinergic agents was is quite frequent; 17.0% of the elderly had an annual cumulative use of these drugs ≥90 doses. Parkinson's disease, depression, genitourinary diseases, low income, and polypharmacy strongly predicted the high use of strong anticholinergic agents. A few strong anticholinergic agents, including antihistamines (chlorpheniramine) and antidepressants (amitriptyline), accounted for the majority of medications prescribed. Understanding the predictors of their high use by medical practitioners may result as more appropriate anticholinergic medications.

Anticholinergics Linked to Increased Risk of Dementia

Anticholinergics Linked to Increased Risk of Dementia

Anticholinergic Drug Exposure and the Risk of Dementia

Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia. To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older. This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018. The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date). Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables. Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%. Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

Psychoactive Medications and Adverse Outcomes among Older Adults Receiving Hemodialysis.

Guidelines recommend avoidance of several psychoactive medications such as hypnotics in older adults due to their adverse effects. Older patients on hemodialysis may be particularly vulnerable to complications related to use of these agents, but only limited data are available about the risks in this population. To evaluate the association between the use of psychoactive medications and time to first emergency department visit or hospitalization for altered mental status, fall, and fracture among older patients receiving hemodialysis. Observational cohort study. National registry of patients receiving hemodialysis (US Renal Data System). A total of 60 007 adults 65 years or older receiving hemodialysis with Medicare Part D coverage in 2011. The predictors were use of sedative-hypnotics and anticholinergic antidepressants (modeled as separate time-varying exposures). The outcomes were time to first emergency department visit or hospitalization for altered mental status, fall, and fracture (modeled separately). Overall, 17% and 6% used sedative-hypnotics and anticholinergic antidepressants, respectively, in 2011. In multivariable-adjusted Cox regression, anticholinergic antidepressant use was associated with a 25%, 27%, and 39% higher hazard of altered mental status, fall, and fracture, respectively, compared with no use. Use of sedative-hypnotics was not associated with adverse outcomes. Anticholinergic antidepressants were associated with adverse outcomes in older hemodialysis patients, and alternative treatments should be considered. Sedative-hypnotics were not associated with the risks evaluated in this study, but further investigation of the harms of this class of agents is warranted before their recommendation as a treatment option for insomnia in this population. J Am Geriatr Soc 67:449-454, 2019.

Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study.

To determine whether antidepressant use is associated with dementia risk. Prospective cohort study. Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system. Community-dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059). Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10-year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models. During a mean follow-up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0-90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18-2.42; 91-365 TSDDs: HR=1.40, 95% CI=0.88-2.23; 366-1095 TSDDs: HR=2.13, 95% CI=1.32-3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82-2.46). Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations.

Factors That Influence the Prescription of Antipsychotics for Patients with Schizophrenia in China

ObjectiveTo investigate the patterns of antipsychotic use in China and to analyze the factors that influence antipsychotic prescriptions.MethodsA standardized survey was conducted from May 20 to 24 2002 in five different regions of China with varying economic levels. The patterns of antipsychotic medication use were analyzed in a sample of 4,779 patients with schizophrenia. The survey gathered information on demographic characteristics, clinical profiles, and antipsychotic medications prescribed. Multiple logistic regression was used to analyze factors related to patterns of antipsychotic medication use.ResultsA plurality of patients with schizophrenia was treated with clozapine (39%); this was followed by risperidone, sulpride, chlorpromazine, perphenazine, and haloperidol. More than 56.3% of patients were treated with only one atypical antipsychotic. The mean daily dose of chlorpromazine was 365±253 mg (mean±standard deviation), and 6.5% of patients were treated with depot injections of typical antipsychotic medications. A total of 73.7% (n=3,523) of patients with schizophrenia received monotherapy, 24.8% (n=1,183) received two antipsychotics, 1.1% (n=52) received three antipsychotics, and one received four different antipsychotics. Patients often simultaneously received other classes of medications including anticholinergic agents, benzodiazepines, β-blockers, antidepressants, and mood stabilizers. Economic status and clinical symptoms were the main factors that contributed to the patterns of antipsychotic prescription.ConclusionThe present study suggests that atypical antipsychotic medications, especially clozapine, are the primary psychiatric treatments of choice in the management of schizophrenia in China. Moreover, the economic status and clinical profile of the patient are the major factors affecting the prescription of antipsychotic medication.

Acute Angle Closure Glaucoma Presented with Nausea and Epigastric Pain

A 78-year-old woman was admitted to our department with nausea, vomiting, epigastric pain, and intense headache of the left side of 1 day duration. She had suffered from diabetes mellitus for the last 7 years and was being treated with a combination of metoformin (850 mg twice daily) and glimepiride (1 mg/day). In addition, for the last 5 years she was being treated for atrial fibrillation with acenocoumarol 1 mg/day. The patient also suffered from lumbar pain due to osteoarthritis and was being treated with a combination of paracetamol plus orphenadrine citrate (Norgesic) (450 + 35 mg per day) for the last 10 days. On admission, the patient was afebrile and the clinical examination revealed obesity, high arterial blood pressure (170/95 mmHg), and epigastric pain without clinical signs of peritonitis. Her left eye was red, and the pupil was more dilated and less reactive to light compared to the right eye. Laboratory findings included a hematocrit measurement of 44.5%, WBC at 8,900/mm, C-reactive protein of 4 mg/l, and total bilirubin at 1.3 mg/dl (direct 0.5 mg/dl). An ultrasound of the upper abdomen was without abnormal findings. A CT scan of the head was normal. Antiemetics and proton pump inhibitors were initiated, and with the diagnosis of possible conjunctivitis, a tobramycin eye ointment was given. The next day, the patient’s nausea had improved, but her headache had worsened and she reported a blurred vision from her left eye and photophobia. After reevaluation of her history and clinical findings, a digital tonometer was used which revealed an opening pressure of 62 mmHg on the left and 32 mmHg on the right eye. The diagnosis of acute angle closure glaucoma (AACG) was made, treatment was immediately started (eye drops of pilocarpine 2% and timolol 0.5%, acetazolamide 250 mg per os, and mannitol 1.0 mg/kg IV), and the patient was transferred to the ophthalmology department for further evaluation and management. AACG is an acute increased pressure in the front chamber (anterior chamber) of the eye due to sudden blockage of the normal circulation of fluid within the eye [1]. The high intraocular pressure can damage the optic nerve and lead to blindness. It is more common in elderly people and women, and is considered an emergency because vision loss can occur within hours of the onset of the symptoms [2]. Prompt diagnosis needs high index of suspicion, and it is based on topical symptoms (ocular pain, redness, blurred vision with coloured halos) and clinical examination (dilated and fixed pupil) [1]. These findings must be differentiated from other ocular diseases such as keratitis and conjunctivitis. In our case, unfortunately, the initial findings were attributed to conjunctivitis. In addition, as was seen in our patient, there are systemic symptoms as well (intense headache, nausea, vomiting, abdominal pain), which may be so severe that patients are misdiagnosed as having a neurologic or gastrointestinal disease [2–4]. Another important issue is the patient’s recent medications because several classes of drugs, including anticholinergic agents, tricyclic antidepressants, and SSRIs can precipitate AACG [5]. Our patient had no known previous history of glaucoma, but we believe that orphenadrine citrate was the provocative agent. Orphenadrine is a muscle relaxant, which is extensively used in painful muscular conditions [6]. It is a well tolerated drug, There are no conflicts of interest. All the authors have read and approved the submitted manuscript. The study complies with current ethical considerations.

Is inappropriate medication use a major cause of adverse drug reactions in the elderly?

To study the occurrence of adverse drug reactions (ADRs) linked to inappropriate medication (IM) use in elderly people admitted to an acute medical geriatric unit. All the elderly people aged > or = 70 years admitted to the acute medical geriatric unit of Limoges University hospital (France) over a 49-month period were included, whatever their medical condition. For all the patients, clinical pharmacologists listed the medications given before admission and identified the possible ADRs. The appropriateness of these medications and the causal relationship between drugs (either appropriate or not) and ADRs were evaluated. Two thousand and eighteen patients were included. The number of drugs taken was 7.3 +/- 3.0 in the patients with ADRs and 6.0 +/- 3.0 in those without ADRs (P < 0.0001). Sixty-six percent of the patients were given at least one IM prior to admission. ADR prevalence was 20.4% among the 1331 patients using IMs and 16.4% among those using only appropriate drugs (P < 0.03). In only 79 of the 1331 IM users (5.9%) were ADRs directly attributable to IMs. The IMs most often involved in patients with ADRs were: anticholinergic antidepressants, cerebral vasodilators, long-acting benzodiazepines and concomitant use of two or more psychotropic drugs from the same therapeutic class. Using multivariate analysis, after adjusting for confounding factors, IM use was not associated with a significant increased risk of ADRs (odds ratio 1.0, 95% confidence interval 0.8, 1.3). Besides a reduction in the number of drugs given to the elderly, a good prescription should involve a reduction in the proportion of IMs and should take into consideration the frailty of these patients.

Evaluation of patient outcomes in an area where prescribing of anticholinergic antidepressants was influenced by academic detailing.

To evaluate, on a patient level, the effect of a "physician-level intervention" that successfully reduced the incidence of anticholinergic antidepressant prescribing. Cross-sectional surveys with questionnaires sent before and after intervention. Additional study in an RCT to reduce the prescribing of highly anticholinergic antidepressants in the elderly in the South Holland Islands. Elderly patients (age 60-95 years) who used antidepressants in 1995 and 1996 in our research area according to a health insurance prescription database. Prevalence of adverse events related to antidepressant use, severity of depression and quality of life were compared in users living in the intervention and control areas. Prior to our intervention we sent 2,359 questionnaires of which we could use 827 (35%) for analysis. At baseline, there were no statistically significant differences between the intervention and control areas. After the intervention 3,375 questionnaires were sent, of which 939 (28%) could be used. The occurrence of "dry mouth" and "coughing" and the "amount of pain" were lower in the intervention area compared to the control area (p < 0.05). We found no indications that adverse events, severity of depression or quality of life were changed in an unfavourable direction, when comparing patients inside and outside the intervention area.

Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing

Objective: To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people.Design: Randomised controlled trial with three...

Use of prevalence and incidence measures to describe age-related prescribing of antidepressants with and without anticholinergic effects

To evaluate whether physicians avoid prescribing highly anticholinergic antidepressants (AAD) in the elderly, a population-based retrospectively data analysis was performed using databases from a Dutch health insurance company. Data collected on approximately 240,000 persons covered the period from 1 July 1993 to 1 January 1996. The prevalence and the incidence (number of new starters) of antidepressant use was measured over 1994 and 1995. Use of AAD was proportionally higher in the elderly in terms of both prevalence and incidence rates; the ratio of starters of AAD versus starters of non-AAD in 1994 increased steadily with age (from 0.54 in the age group 20–29 to 1.15 in the age group 60–69). In 1995 these incidence ratios decreased (0.41 to 0.99, respectively); however, the decrease was higher in the younger age groups. The data indicate that in the population studied, physicians do not refrain from prescribing highly anticholinergic agents to older patients despite their potential adverse drug reactions in this age group. This study also indicates that prevalence and incidence rates can be extracted from reimbursement data and give insight into actual prescribing practices.

The impact of OBRA-87 on psychotropic drug prescribing in skilled nursing facilities.

This study examined the impact of regulations established by the Omnibus Budget Reconciliation Act of 1987 (OBRA-87) on prescriptions for psychotropic drugs, and on research on their use in nursing homes. Data were collected on drugs prescribed for residents of 39 skilled nursing facilities over the four-year period from 1989 to 1992, bracketing the implementation of OBRA-87 in the fall of 1990. Changes in prescribing patterns were analyzed by drug class, specific target medications and doses, number of drugs prescribed, and multidrug combinations. To determine the effect of OBRA-87 on research, peer-reviewed journals were searched for the number and content of publications on psychotropic drug use in skilled nursing facilities between 1980 and 1996. The number of prescriptions for antipsychotics, sedative antihistamines, and sedative-hypnotics decreased significantly, while prescribing of anxiolytics increased. Qualitative, but not quantitative, shifts occurred in prescriptions for antidepressant drugs, the most frequently used psychotropic medications in all years. Rates of psychotropic polypharmacy remained stable. The number of data-based publications on psychotropic drug use in nursing homes increased after implementation of OBRA-87, but few were related to the effectiveness of drug treatment. Implementation of OBRA-87's nursing home regulations was associated with reductions in use of drugs specifically targeted by this legislation and was a potent stimulus to research, an unanticipated benefit of legislative action. Increased use of anxiolytics, persistent prescribing of anticholinergic antidepressants, enthusiastic adoption of new agents despite a limited research database involving frail patients, and the paucity of new studies reporting data on clinical effectiveness suggest a need for targeted research on treatment outcomes to improve the care of this population.

Anticholinergic Drug Use and Bowel Function in Nursing Home Patients

We sought to measure the relationship between the use of anticholinergic drugs and bowel dysfunction in nursing home patients. The study population consisted of 800 residents (average age, 84.7 years; range, 65 to 105 years) from 12 intermediate-care facilities in Massachusetts. Patient characteristics and actual medication use were documented during a 1-month observation period. Neuropsychological and functional testing was performed on all residents receiving psychoactive medications. Constipation was assessed by measuring the frequency of laxative use. Laxatives were used daily by 74% of residents; 45% received more than one laxative a day. After adjusting for potential confounding by logistic regression modeling, we found that daily laxative use was significantly more common in residents taking highly anticholinergic antidepressants such as amitriptyline (odds ratio, 3.12), diphenhydramine (odds ratio, 2.18), highly anticholinergic neuroleptics such as thioridazine (odds ratio, 2.01), and in the very old (odds ratio, > or = 85 years = 2.23). Gender, decreased functional status, impaired cognitive function, and the use of benzodiazepines or antiparkinsonian agents were not associated with increased use of laxatives. A strong association exists in institutionalized elderly between the use of specific anticholinergic medications and constipation, as reflected in the increased use of laxatives. This effect was not seen with nonanticholinergic sedatives, nor was it explained by the patients' cognitive or functional status. These drugs may be responsible for substantial iatrogenic effects on bowel function in elderly patients.

Epidemiology of toxic delirium due to psychotropic drugs in psychiatric hospitals

Toxic delirium (TxD) was studied within a West German multicenter drug surveillance system monitoring 11,308 drug-treated, acutely ill psychiatric inpatients. The risk for TxD increased steadily with age and was about sixfold higher in the patient group older than 60 years of age than in that below. For the group of antidepressants with known anticholinergic effects (i.e., dibenzepine, imipramine, amitriptyline, maprotiline, clomipramine, doxepin), exposure-related incidence rates for TxD ranged near 1.2%; observed differences between particular drugs could be due to the heterogeneity of patients and treatment conditions. For other antidepressants (i.e., tranylcypromine, mianserin, nomifensine), incidence rates were significantly lower (0.6%; P < .05). For low-potent neuroleptics (i.e., perazine, thioridazine, levomepromazine except clozapine), the risk ranged near 0.8%, which was increased by combination with biperidene to 1.2% (assessed in patient groups younger than 43 years) and with (anticholinergic) antidepressants to 1.5% (in patients older than 45 years of age).

Physostigmine Reversal Of Sedative Drugs

To the Editor.— Physostigmine is an effective antidote to the central effects of scopolamine and a variety of other drugs that may have anticholinergic activity, eg, tricyclic antidepressants and antihistamines. 1 Animal studies have suggested that physostigmine will reverse sedation from the butyrophenone haloperidol. 2 In man, there are indications of its usefulness in antagonizing phenothiazine- and diazepam-induced coma. 3 The following case history describes the use of physostigmine in the reversal of sedation from the butyrophenone droperidol and diazepam without effecting narcotic analgesia. Report of a Case.— A healthy, but extremely anxious, 37-year-old man was scheduled to undergo right inguinal hernia repair. He was premedicated with morphine sulfate, 12 mg, diazepam, 10 mg, and atropine, 0.4 mg, one hour prior to surgery. In the operating room he was alert and cooperative but quite apprehensive. Anesthesia was induced with diazepam, 20 mg, and 5 ml of a mixture of droperidol