Antidepressants are the most commonly used mental health medications, with prescription rates over 10% in the United States [1]. The potential impact of these medications on cognitive health has been controversial, with some studies finding a protective effect, and other studies suggesting that they increase the risk for cognitive decline [2]. These disparate findings reflect the numerous complexities underlying this relationship, such as the connection between depression and dementia, and the heterogeneity of depression itself.
Depression has been recognized as a potentially modifiable risk factor for dementia by the Lancet Commission on Dementia Prevention, Intervention and Care [3]. The mechanisms by which depression increases dementia risk are not yet clear, but may include chronically elevated levels of stress hormones, such as cortisol, chronic inflammation, and decreased production of brain growth factors [4].
However, diagnoses of late-life depression may not necessarily be the same as depression in early or mid-life [4]. Early in the course of dementia, prior to the onset of cognitive symptoms, called the prodromal phase, brain changes are already taking place. Some of these changes, like the loss of neurons in brain regions involved in emotional regulation [5], may result in depressive symptoms. The activity of these regions is influenced by signaling molecules called neurotransmitters, such as norepinephrine, serotonin and dopamine, and their dysregulation is thought to play a role in depression [6]. The most commonly used antidepressants act on these neurotransmitter systems.
The etiology of depression is unclear, but appears to be heterogenous [6]. Due to differences in the underlying causes, people with depression vary in their responsiveness to different types of interventions, including the various classes of antidepressant medications. A sizable proportion of people with major depressive disorder have treatment-resistant depression, as they are unable to find any medications to properly manage their symptoms [7]. Many others develop tolerance, such that the efficacy of the medication wanes over time, requiring them to frequently switch medications [8]. Adherence to antidepressants can also be influenced by their side effect profile.
These complexities are typically not accounted for in studies assessing the relationship between prescriptions for antidepressants and rates of dementia. They do not provide information about whether the prescribed antidepressants were efficacious. Since depression itself is a risk factor, whether antidepressants have a positive, negative, or neutral effect could be related to the percentage of participants that experienced clinically meaningful improvement. Moreover, it could depend not only on the management of symptoms, but also on the treatment of the underlying causes.
For example, antidepressants would not be expected to treat ongoing neurodegenerative processes in people with prodromal dementia, and could potentially even worsen cognition. Certain classes of antidepressants, namely tricyclics, block the actions of the neurotransmitter acetylcholine, which is important for learning and memory [9]. Some observational studies have found that antidepressant use may accelerate cognitive decline in people with pre-existing dementia [10].
To add to the complexity, other studies suggest that prior treatment with certain classes of antidepressants may reduce the risk or slow the onset of dementia [11]. Long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants for depression was found to be associated with a lower risk of conversion to Alzheimer’s dementia [12]. This may be related to protective changes that only emerge with long-term use, and/or only show benefit prior to the accumulation of brain pathology. SSRIs show protective effects in the brain in animal models [11], but whether these effects occur to a clinically meaningful degree in humans is not yet clear [13].
However, caution is warranted in using observational studies to determine which classes of antidepressants are best or worst for brain health. This is because prescribing practices take into account the health status of the patients. Certain classes of antidepressants may be avoided in patients with other health conditions due to increased risk for certain side effects or interactions with other medications they are taking. As a result, even medications with a strong benefit-to-risk profile may appear to perform poorly if they are preferentially prescribed to the sickest patients.
Many questions remain. We do not yet have a good understanding of the degree to which effective treatment for depression lowers dementia risk, or how cognitive trajectories are influenced by the use of antidepressant medications that don’t adequately treat depression.
What is clear is that major depressive disorder is a serious medical condition that increases the risk for early death. Late-onset depression may also be an early symptom of dementia. Rates of depression have been increasing in recent years, especially among younger people, but around 40% of people do not receive treatment [14]. It is important to seek mental health care, and work with your provider to find the type of treatment that works best for you.
Betsy Mills, PhD, is a member of the ADDF's Aging and Alzheimer's Prevention program. She critically evaluates the scientific evidence regarding prospective therapies to promote brain health and/or prevent Alzheimer's disease, and contributes to CognitiveVitality.org. Dr. Mills came to the ADDF from the University of Michigan, where she served as the grant writing manager for a clinical laboratory specializing in neuroautoimmune diseases. She also completed a Postdoctoral fellowship at the University of Michigan, where she worked to uncover genes that could promote retina regeneration. She earned her doctorate in neuroscience at Johns Hopkins University School of Medicine, where she studied the role of glial cells in the optic nerve, and their contribution to neurodegeneration in glaucoma. She obtained her bachelor's degree in biology from the College of the Holy Cross. Dr. Mills has a strong passion for community outreach, and has served as program presenter with the Michigan Great Lakes Chapter of the Alzheimer's Association to promote dementia awareness.
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