Antidepressant Initiation Tied to Hip Fracture Risk in Older Patients

Damian McNamara

January 02, 2019

In addition to previous studies showing a higher number of hip fractures following initiation of antidepressant medications, new research suggests that the period immediately before treatment is also associated with an elevated risk for these injuries.

A study of more than 408,000 older adults showed that those who started antidepressants experienced more than twice as many hip fractures compared with their peers who did not take such medications, both in the year before (5642 vs 2189, respectively) and after (7137 vs 2625) initiation of treatment.

However, these findings should not necessarily dissuade clinicians from prescribing antidepressants in this population, principal investigator Jon Brännström, MD, PhD candidate in the Department of Community Medicine and Rehabilitation, Geriatric Medicine, Umea University in Sweden, told Medscape Medical News.  

The decision of whether to prescribe antidepressants to older patients should be based on the potential therapeutic benefit and not on the risk of falling, he said.

"However, since the evidence for positive effects of antidepressant drugs is limited in elderly patients, the treatment should always be closely monitored," he added.

The study was published online today in JAMA Psychiatry.

Expanding on Existing Evidence

An increased risk for falls is one of the adverse events associated with the use of most antidepressants in the elderly, as shown in past research.

However, the current investigators note that the observational design of previous studies raises questions about causality, confounding, and bias in the results.

One exception, a randomized clinical trial, was "underpowered and unable to establish any association between selective serotonin reuptake inhibitor (SSRI) use and falls," the current researchers write.

To learn more, they assessed individuals 65 years or older who were prescribed an antidepressant between July 2006 and December 2011. They matched each one of these 204,072 people in the Prescribed Drugs Register of Sweden's National Board of Health and Welfare with another individual in a group of 204,072 not receiving an antidepressant during that time.

The mean age of participants in this matched cohort study was 80 years and 63% were women. Almost two thirds (63%) were prescribed an SSRI, the most commonly prescribed class of agents.

Peak Risk Periods

The strongest association for risk of a hip fracture emerged in the weeks just prior to initiation of antidepressant therapy in the study.

The link between any antidepressant drug use and hip fracture peaked 16 to 30 days before patients started taking an antidepressant (odds ratio [OR], 5.76; 95% confidence interval [CI], 4.73 - 7.01).

The second greatest peak occurred 31 to 91 days before therapy initiation (OR, 4.14; 95% CI, 3.71 - 4.61).

Similarly, when the investigators analyzed the three most commonly used antidepressants in a separate analysis, they found a peak in the pretreatment period. The risk of hip fracture was greatest 16 to 30 days before the initiation of citalopram (OR, 5.47; 95% CI, 4.20 - 7.13), mirtazapine (OR, 8.54; 95% CI, 5.70 - 12.80), and amitriptyline (OR, 3.95; 95% CI, 1.77 - 8.80).

The researchers also assessed any effect of sex or low- vs high-dose medication on the risk of hip fracture. They found, for example, men experienced a stronger association in the 16 to 30 days prior to initial antidepressant use (OR, 9.38; 95% CI, 6.11 - 14.40) compared with women (OR, 4.82; 95% CI, 3.85 - 6.02).

When they compared low-dose and high-dose antidepressant prescriptions, mixed findings emerged. "No clear dose-response relationship was seen," the investigators write.

High Prevalence of Depression

The risk of hip fracture, as well as other injuries caused by falling, is elevated among older adults with considerable comorbidity, Brännström said.

"Also, the prevalence of depression is high in this group. Both are conditions with high morbidity and mortality and should be addressed thoroughly through prevention, screening, and treatment," he said.

Despite the high prevalence of both, "knowledge on how to prevent fractures is definitely greater than that on how to treat and prevent depression in old age," he added.

The increased risk for hip fracture just prior to antidepressant initiation in the study population does not necessarily mean that the two are dependent on each other, the researchers note. The elevated risks could be parallel and "may reflect general susceptibility during times of other hardship."

Bone metabolism can be altered by both antidepressant use and depression, which could contribute to the higher incidence of hip fracture they observed. In addition, hospitalization due to hip fracture could in turn increase the likelihood of depression and a subsequent initiation of antidepressant medication, the investigators note.

The researchers recommend careful initiation of treatment and close monitoring of any positive and adverse effects in the elderly population.

The American Geriatrics Society also provides some guidance on the issue. They state in their Beers Criteria that antidepressants should be avoided in older people with histories of falling unless safer alternatives are not available.

Future Research

A study strength was its evaluation of a large nationwide cohort of patients over time. A limitation was the lack of information on comorbidities such as dementia, diabetes, or mild-to-moderate depression because the registry did not include primary care encounters.

The authors call for further research into the association between risk of hip fractures both before and after initiation of antidepressant medication to "shed further light on the possible residual risk associated with treatment."

The current study is part of a series of reports from the same research team.

"We are still deciding the topic of the fourth and last manuscript, which might either be a register study of discontinuation of antidepressants and its effects on injurious falls, or a study of the association between antidepressants and suicide in old age," they write.

In addition, Brännström is working on a thesis addressing adverse reactions to psychotropic drugs among elderly people.

"My dream, if someone would be so kind to fund that, is to design and conduct a multicenter randomized clinical trial on the treatment of depression among people aged 80 years and older," he said.

He added this is a group "where depressive symptoms are very common, who use large amounts of psychotropic drugs and where there is basically no scientific evidence on how to best conduct treatment."

Consider the Big Picture

"Patients are routinely prescribed antidepressants following a fracture. Depressive symptoms and disorders are common after hip fracture, even in individuals without a history of depression, and can persist for as long as one year after the hip fracture event," Andrea Iaboni, MD, DPhil, Department of Psychiatry, University of Toronto, Canada, and Donovan T. Maust, MD, Department of Psychiatry, University of Michigan, Ann Arbor, write in an accompanying editorial.

"In fact, in the first few months post-fracture, new antidepressants are administered at 10 times the typical rate for older adults," add Iaboni and Maust.

They note that the current investigators favor an elevated risk of fall or fracture before antidepressant exposure as the explanation behind the association, which is known as residual confounding.

"However…it is also important to recognize that during the post-fracture period, rightly or wrongly, antidepressants are prescribed at a high rate," they write.

Iaboni and Maust note that comorbidities could also play a role.

"Many of the characteristics that might predispose an older adult to becoming depressed and receiving an antidepressant, such as cerebrovascular disease burden, cognitive impairment, frailty, and impaired functional status, are the same traits that predispose the patient to a fall or fracture independent of the antidepressant exposure," the editorialists write.

The study was funded by the Swedish Research Council. Dr Brännström and Dr Maust have disclosed no relevant financial relationships. Dr Iaboni is a scientific advisor for Winterlight Labs.

JAMA Psychiatry. Published online January 2, 2019. Abstract, Editoral

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