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Impact of Trazodone on Dementia Risk: New Data

Trazodone (multiple brands) is not associated with reduced dementia risk compared to other antidepressants, new research suggests.

Investigators searched primary care electronic health records for people aged 50 years or older who took antidepressants during a 7-year period. They compared dementia risk in close to 5000 users of trazodone to the risk in more than 400,000 users of other antidepressants.

They found that the incidence of dementia in trazodone users was higher than in matched users of other antidepressants. The median time to dementia diagnosis in trazodone users was 1.8 years.

“Our findings suggest that trazodone is unlikely to protect against dementia,” study coauthor Wallis C. Y. Lau, PhD, research associate in pharmacoepidemiology and medication safety, University College London (UCL) School of Pharmacy, United Kingdom, told Medscape Medical News.

“Prevention of dementia should therefore not be considered as a major factor for prescribing trazodone,” he said.

The study was published online February 5 in PLOS Medicine.

Potential Repurposing?

“Dysregulation of the pancreatic endoplasmic reticulum kinase branch of the UPR [unfolded protein response] and its downstream target, eukaryotic initiation factor 2 (eIF2α), have been identified as potential targets in the treatment of AD [Alzheimer dementia], but no safe and effective drugs acting on this pathway exist,” the authors write.

It has been suggested that trazodone 2 hydrochloride, an agent with anti-eIF2α therapeutic activity currently used as an antidepressant, might be repurposed for use in AD.

In mouse studies, trazodone was found to be associated with markedly reduced neuronal loss, the authors state.

“Recent in vitro and animal studies have suggested that trazodone might be neuroprotective against dementia, but no studies were conducted to assess the effects of trazodone on dementia in humans in clinical settings,” Lau said.

To investigate the question, the researchers drew on data from the Health Improvement Network, an archive of deidentified medical and prescribing records from primary practices in the United Kingdom. They identified patients who were at least 50 years old and who received ≥2 consecutive prescriptions for an antidepressant between January 2000 and January 2017.

Patients were considered to have been exposed to trazodone if they had received two trazodone prescriptions but had not received any other antidepressant prior to using trazodone.

Using a Cox regression model with a 1:5 propensity score matching, the researchers compared the risk for dementia among patients who were prescribed trazodone to the risk among patients with similar baseline characteristics who used as antidepressant monotherapy a drug other than trazodone.

The primary outcome was the first recording of a diagnosis of dementia after the index date. The secondary outcome was median time to a diagnosis of dementia.

Dementia” was defined either as AD, vascular dementia, or a nonspecific code. Patients with other identifiable causes of dementia (eg, Parkinson disease) were excluded.

A total of 465,628 patients received ≥2 consecutive prescriptions for an antidepressant during the study period. Of these, 4716 trazodone users met the inclusion criteria and were matched to 22,980 users of other antidepressants.

The median follow-up time was 3.9 years for patients prescribed trazodone (interquartile range [IQR] = 1.2–8.8) and 5.1 years for those prescribed other antidepressants (IQR = 2.1–9.2).

Unlikely to Offer Protection

The crude incidence rate of dementia per 100 person-years was more than twice as high in the trazodone group than in the group who had taken other antidepressants (1.8 vs 0.7 per 100 person-years).

Moreover, crude results revealed that trazodone users were more likely to have received a diagnosis of dementia earlier (median, 1.7 years; IQR = 0.4–4.7 years) than users of other antidepressants (median, 4.3 years; IQR = 1.7–7.8 years).

After propensity score matching, the absolute number of dementia cases was found to be 1997 (434 in the trazodone group and 1563 in the users of other antidepressants).

The incidence of dementia was higher in the trazodone cohort than in the matched cohort (1.8 vs 1.1 per 100 person-years). The hazard ratio (HR) demonstrated an association between the use of trazodone and the onset of dementia (HR = 1.80; 95% confidence interval [CI], 1.56–2.09; P < .001).

The median time to a diagnosis of dementia was shorter among individuals using trazodone than among those taking other antidepressants (1.8 years [IQR = 0.5–5.0 years] vs 4.1 years [IQR = 1.7–7.7 years]).

The researchers reanalyzed the data by changing the primary outcome variable from a generic dementia diagnosis to AD and found no evidence of an association (HR = 0.80; 95% CI, 0.50–1.29; P = .36).

However, when they censored follow-up at the end of trazodone therapy, their analysis showed an even stronger association between the use of trazodone and the risk for dementia, compared with the results of the main analysis (HR = 2.57; 95% CI, 2.11–3.11; P < .001).

The association with dementia was greater with current use of trazodone than with past use, and short exposure to trazodone (<2 years) was found to be more strongly associated with dementia risk.

“Our findings suggest that trazodone is unlikely to protect against dementia,” Lau commented.

“In this context, we feel our study would suggest that prevention for dementia should not override other considerations when assessing the benefits and harms of prescribing trazodone to an individual,” he added.

Confounding Variables?

Commenting on the study for Medscape Medical News, Tiffany Schwasinger-Schmidt, MD, PhD, assistant professor of medicine, Department of Internal Medicine, University of Kansas School of Medicine, and neurology clerkship director, Wesley Medical Center, Wichita, who was not involved with the study, called it “unfortunately a little underpowered to assess the effects of this medication on the development of dementia.”

She noted that the average age of patients taking trazodone was 70 years and that many patients could have had underlying undiagnosed dementia.

“A lot of people in primary care are not necessarily screened for dementia, and the subject often comes up only when the patient or a family member indicates memory issues, so there is a great deal of underdiagnosis,” she said.

Additionally, retrospective data include many confounding variables, so it is hard to ascertain the particular effects of the medications when conducting a review of records, she said.

She added that in the United States, trazodone is rarely used for depression or as monotherapy. Rather, it is frequently used as augmentation and is also more commonly used for insomnia.

Sleep disturbances are often associated with the development of dementia, she pointed out.

Whether trazodone is used for sleep disturbances or depression will have a bearing on dosing, and dosing in turn can affect the potential impact on the development of dementia, she observed.

“The take-home message is that we really need better prospective studies looking at trazodone and its associations before we can make a true jump to say it is or isn’t associated with the development of dementia,” she said.

The authors acknowledge, “Although the patients were well-matched on many baseline characteristics using propensity scores, it is possible that the observed comorbidities were insufficient to identify and account for patients experiencing early symptoms of dementia.”

They also acknowledge that “nondifferential misclassification of undiagnosed or wrongfully diagnosed patients” may have affected their results.

Nevertheless, they conclude that these results “refute the suggestions from animal studies that trazodone might stop or delay the onset of dementia in patients at the prodromal stage of dementia.”

The collaboration between the Department of Pharmacology and Pharmacy of the University of Hong Kong and the UCL School of Pharmacy is funded by the University of Hong Kong–University College London. The coauthors’ disclosures of relevant financial relationships are listed on the original article. Lau and Schwasinger-Schmidt have disclosed no such financial relationships.

PLoS Med. Published online February 5, 2019. Full text

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