Do Antidepressants Speed Cognitive Decline in Dementia?

Antidepressants, particularly selective serotonin reuptake (SSR) inhibitors, were associated with significantly faster cognitive decline in individuals with dementia, results of a real-world national cohort study showed.

However, the investigators caution that the clinical significance of the observed changes are uncertain and the possibility that they are because of depression, rather than antidepressant use, can’t be ruled out.

Based on this study, it would be “premature” to make any changes to existing recommendations with regard to antidepressant use in patients with dementia, corresponding author Sara Garcia-Ptacek, MD, PhD, neurologist and researcher with Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

“We need more data to compare antidepressants and also personalize treatment (eg, with information on genetics),” Garcia-Ptacek added.

The study was published online on February 24 in BMC Medicine.

Knowledge Gaps

Research has shown that psychiatric symptoms increase with the onset of dementia and can be the first signs of the disease. Typically, SSR inhibitors are the first-line treatment for depression in this patient population. However, there is a gap in understanding how different antidepressant classes, specific drugs, and doses affect progression of cognitive decline.

To investigate, researchers used the Swedish Registry for Cognitive/Dementia Disorders, SveDem, to identify 18,740 patients (mean age, 78; 55% women) newly diagnosed with dementia. They used linear mixed models to examine the association between antidepressant use and cognitive trajectories assessed by the Mini-Mental State Examination (MMSE) scores.

During average follow-up of 4.3 years, 23% of patients received a new prescription for an antidepressant — most commonly an SSR inhibitor (65%).

Overall, antidepressant use (vs no use) was associated with faster cognitive decline, with an overall MMSE score decline of 0.30 points per year.

Among SSR inhibitors, the annual decline in MMSE scores were 0.25 points with sertraline, 0.41 points with citalopram, and 0.76 points with escitalopram. The decline with mirtazapine, a tetracyclic antidepressant, was 0.19 points per year.

The authors noted that the magnitude of the effect antidepressant use on cognitive functioning appeared to be lower than the minimum clinically significant change in MMSE score of 1-3 points.

Serotonin-norepinephrine reuptake inhibitors were not associated with cognitive decline, but the study may have been underpowered for this analysis.

The researchers also found that higher daily doses of SSR inhibitors were associated with more cognitive decline during follow-up, and higher risk for severe dementia, fractures, and all-cause mortality.

“When patients have severe symptoms of anxiety or depression, antidepressants are sometimes very useful and necessary. I think our findings can guide choice of antidepressant, although this was a cohort study, and it is hard to infer causation,” said Garcia-Ptacek.

“We need more studies to determine if certain patients react particularly well or poorly to certain medications, including antidepressants, to personalize treatment. The negative effects on cognition (if they can be confirmed), were not large with sertraline or mirtazapine, so those remain good choices,” she added.

Interpret with Caution 

Commenting on this study for Medscape Medical News, Ipsit Vahia, MD, McLean Hospital, Belmont, Massachusetts, and Harvard Medical School, Boston, said it’s “critical to recognize that every individual with dementia is different” and because this study relies on an existing database, it’s not set up to answer questions that reflect “our evolving understanding of the relationship between mood symptoms and dementia.”

“For instance, we are only beginning to understand differences between depression and mild behavioral impairment with mood symptoms. The latter is often difficult to distinguish from the former and does not respond reliably to antidepressants. A study like this risks conflating very distinct clinical scenarios and must be interpreted with caution. These findings, while striking, cannot replace the need for individualized assessment and intervention,” Vahia said.

Several UK-based experts also urged caution in interpreting the results, in statement from the UK Science Media Centre.

Emma Anderson, PhD, with University College London, London, England, said, “there is substantial risk with this study design for confounding by indication, which could explain the results either in part, or entirely. More robust study designs, which overcome this very important limitation, are needed before such bold conclusions can be made.”

Prasad Nishtala, PhD, with University of Bath, Bath, England, felt the study was “well-conducted” but “one major issue is that the severity of depression in dementia patients wasn’t fully accounted for, which has the potential to bias the results.”

Additionally, there may be a “channeling bias,” Nishtala said, “meaning that certain antidepressants like citalopram and sertraline might have been more commonly prescribed to patients with severe dementia, which could also bias the results.”

Echoing the investigators, Nishtala also noted that the small change in MMSE scores “may not be meaningful in everyday clinical practice.”

The study also doesn’t explain how or why at a biological level SSR inhibitors might speed up cognitive decline. “Because of these limitations, the study’s findings should be interpreted with caution and ideally replicated using other real-world data sources,” Nishtala said. 

Tara Spires-Jones, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, noted that this type of data “cannot prove that it was antidepressant use that caused the faster decline.”

“People who needed antidepressants may have had more aggressive disease or the depression itself could have been affecting disease progression. It is also worth noting that the effect was not the same for all types of dementia; people with frontotemporal dementia (FTD) did not have accelerated cognitive decline when taking antidepressants,” Spires-Jones said.

This study had no commercial funding. The authors had declared no conflicts of interest. Vahia had served as a consultant to Otsuka Pharmaceutical Co. Anderson and Spires-Jones had no relevant disclosures. Nishtala is on the editorial board for BMC Medicine.

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