Laura Genn

Patients 55 or older who take anticholinergic drugs daily face increased risk of dementia, according to a new study.

The nested case-control study drew from England’s QResearch primary care database to compare odds ratios (ORS) of dementia between 58769 patients diagnosed with dementia and 225574 controls. All included patients were 55 years or older (mean age 82.2), and 179365 (63.1%) were female. Each patient with dementia was matched to 5 controls by age (within a year,) sex, general practice, and calendar time via incidence density sampling.

All subjects of analysis took one of 56 anticholinergics daily and, if in the dementia group, had begun taking the drugs 1-11 years prior to diagnosis. Primary exposure was tracked in total standardized daily doses (TSDDs). Adjustments were made to the data to account for population-attributable fractions, protopathic bias, and additional variables such as patients with high BMI or alcohol consumption.

Julia Hippisley-Cox, MD, professor of clinical epidemiology and general practice at University of Oxford, England, led the team of investigators. Analysis of compiled data continued from May 2016 through June 2018.

The lowest anticholinergic exposure category, total exposure of 1-90 TSDDs, saw an increase in the adjusted OR for dementia from 1.06 (95% CI, 1.03-1.09). The highest category, >1095 TSDDs, increased to an OR of 1.49 (95% CI, 1.44-1.54). Both categories’ associations with dementia increased even further in patients who were diagnosed before age 80.

On the other hand, relevant antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinic drugs, and antiepileptic drugs all didn’t demonstrate any significant increases in dementia risk.

An editorial accompanying the study noted that despite the proven mechanistic link between anticholinergic drugs and dementia diagnosis, further research was vital to prove causation altogether. The editorial also recommended conducting deprescribing trials to consider the harms of ceasing anticholinergic treatments for fear of an increased dementia risk. Furthermore, what is the time window when ceasing anticholinergic medications could still benefit the patient?

These and other questions, the editorial emphasizes, necessitate further studies.

“We propose deprescribing research as a high priority in the effort to reduce the burden of ADRD (Alzheimer disease and related dementias), while also learning about efficient and safe approaches to optimize medication use in older adults,” the editorial said.

Previous studies throughout the past several years have stoked similar fears about anticholinergic drugs and their use in older patients. In a 

 of older patients (mean age 73.3 years) using anticholinergic medications, brain scans and cognitive tests indicated both physical and physiological manifestations of reduced brain function.

 demonstrated an increased risk of dementia and Alzheimer’s disease in patients 65 or older who took anticholinergic medications regularly (usually antidepressants, first-generation antihistamines, or bladder control antimuscarinics).

As evidence of the association between anticholinergics and dementia mounts, medical practitioners may be forced to reconsider the benefits of prescribing such drugs to middle-aged or older adults in light of the risks. Further research ought to further illuminate whether association does in fact indicate causation.

The study, “Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study,” was published by 

Articles

Taking daily anticholinergic drugs when 55 or older increases the risk of dementia, according to this nested case-control study.

Anticholinergics Increase Dementia Risk in Middle-Aged, Older Adults

 who experienced pediatric-onset (POMS) before the age of 18 face greater cognitive decline than patients who experienced onset as adults (AOMS), according to a new study.

Jan Hillert, MD, PhD, of the Department of Clinical Neuroscience at Karolinska Institute, Sweden, led the team of investigators. They drew data from the Swedish MS Registry (SMSreg)—a national database established in 2001 that contains critical information from all 64 of Sweden’s neurology clinics&mdash;and analyzed said data April-August 2018.

All participants in the study had been diagnosed with clinically definite MS, having experienced onset (onset being the first recorded clinical manifestation) before April 15, 2018. Participants were also between the ages 18-55, and each had an individual disease duration of less than or equal to 30 years. The pool of participants began at 8247, but after inclusion criteria were applied, that number dropped to 5704 (300 with POMS and 5407 with AOMS; 1689 male [29.6%] and 4015 female [70.4%]). The median age for the POMS group was 25.6 versus 38.3 in the AOMS group.

The Pearson χ2 test or the Fisher exact test compared baseline clinical and demographic characteristics of the POMS group versus the AOMS group; the unpaired, 2-tailed 

 test or the Wilcoxon rank sum test analyzed continuous variables.

The key focus, however, was the comparative levels of cognition decline in the two patient groups. This was measured via the Symbol Digit Modalities Test (SDMT) score of 0-120, which investigators administered at baseline, at 6 months, and annually thereafter to those participating in the study. Linear mixed-effects models compared SDMT scores between POMS and AOMS participants.

According to the study’s accompanying editorial, many younger patients with MS appear mostly stable, only to decline sharply within 5 years of follow-up or fail to acquire age-appropriate gains relative to their peers.

“Those with a younger age at onset could be expected to be at increased risk for cognitive problems, but older pediatric patients have been found to have higher rates of impairment in some reports,” the editorial read.

In a multivariable analysis model that accounted for age, disease duration, etc., SDMT scores for the POMS group were drastically lower than those of the AOMS group (β coefficient, −3.59 [95% CI, −5.56 to −1.54]).

Logistic regression analyses similarly showed high odds of cognitive impairment in the POMS group versus the AOMS group (odds ratio, 1.44; 95% CI, 1.06-1.98). At the median follow-up time of 3 years, only 59.8% of patients with AOMS met the definition for cognitive impairment as compared to 70.7% of patients with POMS.

In addition, the POMS sample qualified as “employed but work challenged” (according to the SDMT anchor score of 55) at approximately 34 years of age, while the AOMS sample avoided this until an average of 50 years of age—a marked 16-year difference.

The investigation has the potential to increase common knowledge of pediatric-onset MS and, as a result, increase resources available to that patient population.

“The increased awareness that children and adolescents can develop MS and that these individuals can experience cognitive and mood-related difficulties should help lead to more rapid interventions,” the editorial read.

Long-term Cognitive Outcomes in Patients With Pediatric Onset vs Adult-Onset Multiple Sclerosis

When onset occurs before the age of 18, multiple sclerosis causes more severe cognitive impairment than in equivalent adult-onset cases.

Pediatric-Onset MS Exhibits Worse Cognitive Symptoms than Adult-Onset

The US Food and Drug Administration (FDA) has expanded 

its previous approval for ages 12 and older

 to include patients aged 6 years and older who have the same particular genetic mutations.

“Based on their individual genetic makeup, individuals may respond differently to certain drugs, so it is important to provide a variety of options,” said Banu Karimi-Shah, MD, acting deputy director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA's Center for Drug Evaluation and Research, in a statement.

Symdeko tablets, a combination of tezacaftor and ivacaftor, are used treat cystic fibrosis, a disease that was once known to shorten life expectancy to 10 years but can now be treated, although not cured.

“Today's approval of Symdeko for children as young as 6 years old provides an important treatment option for younger patients, and also provides more context on the safety and dosing specific to this population,” said Karimi-Shah.

Data from a 24-week, open-label treatment trial period, during which 70 cystic fibrosis patients aged 6-12 years old received Symdeko tablets, supported the FDA’s decision to approve expansion to patients 6 years or older. The FDA also granted priority review to Vertex Pharmaceuticals Incorporated’s application for Symdeko.

Presently, no one has conducted research on the safety and/or efficacy of Symdeko in patients with cystic fibrosis who are younger than 6 years old.

The FDA had previously only certified Symdeko tablets for treatment of children aged 12 years and older.

FDA Approves Symdeko Tablets for Ages 6 and Older

A new meta-analysis comparing psychotherapeutic and pharmacological treatments for posttraumatic stress disorder (PTSD) exposed the profound lack of studies from which to draw data.

Despite the prevalence, high risk of chronicity, comorbidity, and functional impairment associated with PTSD, research on which form of treatment ought to be preferred is stretched tenuously thin. Patients are more frequently directed to psychotherapeutic avenues of treatment, but the amount of data to support that decision, beyond clinicians’ anecdotal preferences, is minimal.

Comparative Efficacy and Acceptability of Pharmacological, Psychotherapeutic, and Combination Treatments in Adults With Posttraumatic Stress Disorder: A Meta-analysis

 Heike Gerger, PhD, of the University of Basel (UNIBAS), led the team of investigators.

 about the meta-analysis’ significance, the dearth of available studies, and how research regarding the most effective treatments for PTSD ought to progress in the future.

: What was the most important finding in this study?

 The ridiculously small number of available studies. 

Where should future studies of how to best treat PTSD concentrate their efforts?

Large-scaled comparative trials preferably including all three approaches (i.e., psychotherapeutic and pharmacological treatments and the combination of the 2) reporting long-term outcomes are urgently needed.

Given that many patients ask for medication, and in the face of the increasing amount of research demonstrating considerable benefits of placebo pills, for future research it would also be interesting to compare the effects of combining psychotherapeutic treatments and placebo pills with the effects seen in either psychotherapeutic or pharmacological or combined treatments. 

Why is there such a lack of research regarding treatment despite the estimated 8% of people who have PTSD?

There is not a lack of research on PTSD treatment in general. Meta-analyses on psychotherapeutic treatments identified many RCTs (e.g. Gerger et al., 

, 2014 included 66 RCTs), just as did meta-analyses on pharmacological treatments (e.g. Cipriani et al., Psychological Medicine, 2017 included 51 RCTs). Just, RCTs comparing different kinds of treatment—i.e. psychotherapeutic and pharmacological treatments or their combination&mdash;are scarce.

One reason for this observation may be that researchers (and clinicians) tend to have a rather strong preference for one or the other kind of treatment. In their studies they then use the treatment they expect to be most efficacious in order to prove its efficacy.

Therefore, in many cases, only one kind of treatment is compared with control treatments. This is particularly problematic if we want to determine which treatment is best suited for which patients.

What was the most surprising finding in this study?

 Researchers conducting meta-analyses have read the included studies several times before conducting the final analyses. Therefore, especially when the number of studies is as small as in this meta-analysis, the results are not very surprising in the end.

The lead investigator of a new meta-analysis shared the critical need for further studies on psychotherapeutic versus pharmacological treatments for PTSD.