September/October 2023

The Link Between Dementia and Depression
By Mark Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 16 No. 5 P. 16

Depression may increase the risk of dementia and worsen symptoms in those already experiencing cognitive decline.

Dementia describes a gradual and progressive decline in memory, thinking, and reasoning abilities. It can have many causes; however, Alzheimer’s disease (AD) is the most common, accounting for 60% to 80% of cases.1 An estimated 6.7 million Americans 65 and older are living with Alzheimer’s dementia today, with the number of persons with dementia projected to grow to 13.8 million by 2060.1

Depression in persons with AD is also a tremendous problem, with up to 40% suffering to a significant degree. It’s important to consider the consequences of depression in persons with AD, the link between depression and AD, how symptoms and risk factors are different in persons with AD, identification of depression in persons with dementia, and treatment options.

Consequences of Depression in AD
Depression is a complex mood condition that can cause persistent sadness, hopelessness, and loss of interest in activities and can impair a person’s ability to function. It can result from many causes and factors, including a chemical imbalance in the brain, stressful life events, and genetic predisposition, and also may occur as the consequence of another medical condition such as AD.

Depression is common in persons with AD and can worsen the cognitive decline and functional impairments seen in patients with the disease. It’s also associated with increased disability, poorer quality of life, shorter life expectancy, increased risk for nursing home placement, and increased caregiver burden.

Pathology
As people age, it’s normal for the brain to shrink over time but without a significant loss of neurons. However, in AD, neurons in the brain responsible for memory, language, and thinking become damaged. Over time, the accumulation of protein beta-amyloid outside neurons and neurofibrillary tangles of protein tau inside neurons leads to the death of neurons and damage to brain tissue. Additionally, inflammation and atrophy of brain tissue occur.2 Further, persons with AD and depression appear to have more severe tau, amyloid, and vascular burden than do those without depression and show more severe loss of serotonin receptors and serotonin transporter binding.3 These changes may also contribute to the difficulty in treating depression in persons with AD.3,4 It’s also possible that pathological changes in dementia are associated with the development of depression.5

Depression May Increase Risk of Dementia
Although depression and dementia are two distinct conditions with different symptoms and treatments, they are closely linked. Research suggests that depression not only is a potential symptom of dementia but also may increase the risk of dementia. In a 2020 study, researchers in Sweden compared dementia risk in people with and without depression and found that the risk of dementia is increased for decades after a diagnosis of depression; those diagnosed with especially severe depression are at increased risk.6 For the study, researchers formed two cohorts, both with all patients aged 50 years or older. One cohort consisted of 119,386 individuals with depression matched 1:1 with controls without depression. The second cohort consisted of 50,644 full sibling pairs discordant for depression. Both cohorts were evaluated for dementia during follow-up. In both cohorts, the risk of dementia increased 10 to 20 times in the first year after a diagnosis of depression. And while the risk of dementia decreased rapidly after the first year, an increased risk was still evident more than 20 years after the diagnosis of depression. The risk of dementia was also higher for those with severe depression compared with those with mild depression, and a stronger association was seen with vascular dementia.

Neuropsychiatric Symptoms of AD
The hallmark features of AD and other dementias include cognitive and functional impairment; however, behavioral and psychological symptoms in dementia or “neuropsychiatric symptoms” are very common and difficult to manage; they’re associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, medication misuse, and increased health care costs.4 Depression is second to apathy as the most common neuropsychiatric symptoms in patients with AD.4 Other neuropsychiatric symptoms include agitation, aggression, delusions, hallucinations, paranoia, aberrant motor behaviors (eg, fidgeting, repetitive behaviors, wandering), disinhibition, and sleep disturbances.

Symptoms of Depression in Older Adults
Symptoms of depression in older adults look different than those in younger adults. Depression in older individuals has been referred to as “depression without sadness,” as sad or depressed mood often is not present in older adults with depression.7 This is important as the focus on depressed mood may result in an underestimation of depression in older adults. Instead of depressed mood, older adults with depression tend to experience a decreased interest and pleasure in activities that they once enjoyed.

Other characteristics of depression in older adults often include anxiety and irritability, physical and psychological concerns, complaints of poverty and hypochondrial delusions, and sleep disturbances. Older adults suffering from depression are also at higher risk of suicide and recurrence of depressive episodes.

Symptoms of Depression in AD
The ways persons with AD present with depression may not look the same as they do with other older adults suffering from depression, making identification of depression in AD especially challenging.8 Furthermore, some symptoms common to depression and dementia may overlap, such as apathy, loss of interest in activities and hobbies, social withdrawal, isolation, trouble concentrating, and impaired thinking. Additionally, the symptoms of depression are frequently masked by the cognitive impairments of dementia, and persons with dementia are often unable to express their sadness, hopelessness (strongly associated with suicidal ideation), loss of self-esteem, and other feelings associated with depression. As such, depression in these individuals may not look the same as it does in people without Alzheimer’s. Their symptoms of depression may be less severe, may not last as long, and may come and go, and these patients may be less likely to talk about or attempt suicide. More prominent symptoms of depression in AD include anhedonia (loss of interest in previous pleasurable stimuli), anxiety, expression of somatic concerns, a subjective unpleasant experience of fear manifested as apprehension, tension, panic, or worry associated with autonomic activation and observable physical and motor manifestations of tension.9

Risk Factors for Depression in AD
A recent study published in the Journal of Alzheimer’s Disease Reports found that risk factors for depression in persons with AD may differ from those without AD.10 For the study, researchers from Bristol’s Dementia Research Group wanted to investigate whether risk factors known to increase the risk of depression in adults without dementia also increased the risk of depression in those with AD. Using data from three major dementia-focused cohorts, the team analyzed depression ratings on 2,112 individuals with AD and compared them with data from 1,380 participants with normal cognition.

They noted that previous studies have identified risk factors of depression as including female sex, years of education, smoking, alcohol consumption, stroke, previous psychiatric illness, family history or past history of depression, cardiovascular disease, diabetes, drug use, and neurological illnesses such as Parkinson’s disease. However, the researchers found that with the exception of family or past history of depression—which was the strongest individual risk factor, suggesting a possible genetic predisposition—these traditional risk factors did not increase the risk of depression in AD. The researchers noted that these findings suggest that risk factors for depression in AD differ from those for depression in general, supporting suggestions of a different pathological process leading to depression in AD. They also suggested that depression in those with AD may have a different underlying cause than depression in those without dementia, which may explain why antidepressants may not be effective in treating it. They also found that patients with AD and depression were more likely than those with the disease who are not depressed to develop apathy and anxiety, and other nonmemory symptoms of AD.

Diagnosing Depression in AD
No one test or set of questions is available to diagnose depression in dementia patients. Diagnosis is complex and requires a thorough evaluation by a medical professional consisting of a review of the person’s medical history, a physical and mental examination, and interviews with family members or caregivers who know the person well. The Alzheimer’s Association recommends that due to the complexities involved, it may be helpful to consult a geriatric psychiatrist who specializes in recognizing and treating depression in older adults.11

Ruling Out Medications as a Cause
Medications that can increase the likelihood of depression should also be ruled out. These include anti-inflammatories (corticosteroids), stimulants, anticonvulsants, some blood pressure drugs (beta-blockers), hormone altering drugs, and medications for anxiety (benzodiazepines), Parkinson’s disease, lowering cholesterol (statins), and anticholinergic medications.

Testing for Depression in Patients With AD
Screening tests such as the National Institute of Mental Health (NIMH) guideline and the Cornell Scale for Depression in Dementia (CSDD) may be used to help identify dementia patients who may have depression.

NIMH Guideline
The NIMH established a guideline for diagnosing depression in people with AD that’s similar to general diagnostic standards for major depression. However, the guidelines for depression in dementia patients reduce the emphasis on verbal expression and increase the focus on irritability and social isolation.

According to the NIMH guideline, for patients with AD to be diagnosed with depression, they must have either a depressed mood (sad, hopeless, discouraged, or tearful) or decreased pleasure in usual activities, along with two or more of the following symptoms for two weeks or longer:

• social isolation or withdrawal;
• disruption in appetite that’s not related to another medical condition;
• disruption in sleep;
• agitation or slowed behavior;
• irritability;
• fatigue or loss of energy;
• feelings of worthlessness, hopelessness, or inappropriate or excessive guilt; and
• recurrent thoughts of death, suicide plans, or a suicide attempt.

CSDD
The CSDD is a very effective screening tool designed to assess signs and symptoms of major depression in people with dementia. The CSDD has a sensitivity of 93% and a specificity of 97%.12 Because persons with underlying cognitive deficits may provide unreliable answers, the CSDD is designed to be completed by family members or caregivers who have regular contact with the patient and understand the patient’s symptoms of depression over the previous week.

The CSDD takes approximately 20 minutes to administer and consists of 19 items scored on a scale of 0 to 2 based on observation and interviews with the person and caregiver. Items scored 0 indicate an absence of symptoms, 1 for mild or intermittent symptoms, and 2 for severe symptoms. Both the patient and caregiver are asked the same questions related to mood-related signs of anxiety, sadness, lack of reactivity to pleasant events, and irritability; behavioral disturbance including psychomotor agitation and retardation, physical complaints, acute loss of interest; physical signs such as appetite loss, weight loss, and lack of energy; cyclic functions including diurnal variations and sleep difficulties; and ideation disturbance including suicide, self-deprecation, pessimism, and mood-congruent delusions. The total score range is 0 to 38. A total score of 10 indicates probable depression, and a score greater than 18 indicates definite major depression.

Treatment of Depression in Patients With AD
Both nonpharmacologic and pharmacologic interventions have been used to treat depression in people with AD.

For patients with dementia, nonpharmacological interventions are preferred to pharmacological interventions in those with mild to moderate depression. A recent systematic review reported that nonpharmacological interventions are more effective than pharmacological interventions in reducing symptoms of depression in dementia patients without a major depressive disorder. Potential nonpharmacological interventions include animal-assisted activities, listening to preferred music, tai chi exercise, painting intervention, reminiscence group therapy, mindfulness and psychoeducation-based interventions, and creative expression therapy.

Antidepressants are widely used in persons with depression and AD; however, the evidence for antidepressants in the treatment of depression in patients with dementia is inconclusive. That isn’t to say that antidepressants are ineffective for some patients, but rather that a more cautious approach to utilizing antidepressants may be appropriate, as these agents can have side effects such as worsening apathy13 and increasing fall risk. In case of severe depression, or mild to moderate depression where nonpharmacologic interventions were not successful, the use of antidepressants may be appropriate.

Opportunity for Health Care Professionals
Depression in persons with AD is challenging for both the individuals and their caregivers. Depression in this population is often misunderstood, and the consequences can greatly reduce quality of life and lead to increased institutionalization and overall negative outcomes. Health care professionals have an opportunity to increase awareness of depression in both older adults and those with dementia and to assist with earlier identification of depression by routinely screening for depression and, when appropriate, referring these patients for closer evaluation by a geriatric specialist who focuses on depression in dementia.

— Mark Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
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2. What happens to the brain in Alzheimer’s disease? National Institute on Aging website. https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease. Updated May 16, 2017.

3. Holmes C, Arranz M, Collier D, Powell J, Lovestone S. Depression in Alzheimer’s disease: the effect of serotonin receptor gene variation. Am J Med Genet B Neuropsychiatr Genet. 2003;119B(1):40-43.

4. Burke AD, Goldfarb D, Bollam P, Khokher S. Diagnosing and treating depression in patients with Alzheimer's disease. Neurol Ther. 2019;8(2):325-350.

5. Tetsuka S. Depression and dementia in older adults: a neuropsychological review. Aging Dis. 2021;12(8):1920-1934.

6. Holmquist S, Nordström A, Nordström P. The association of depression with subsequent dementia diagnosis: a Swedish nationwide cohort study from 1964 to 2016. PLOS Medicine. 2020;17(1):e1003016.

7. Gallo JJ, Rabins P V, Lyketsos CG, Tien AY, Anthony JC. Depression without sadness: functional outcomes of nondysphoric depression in later life. J Am Geriatr Soc. 1997;45(5):570-578.

8. Prado-Jean A, Couratier P, Druet-Cabanac M, et al. Specific psychologicaland behavioral symptoms of depression in patients with dementia. Int J Geriatr Psychiatry. 2010;25(10):1065-1072.

9. Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73.

10. Sinclair LI, Lawton MA, Palmer JC; Alzheimer’s Disease Neuroimaging Initiative; Ballard CG. Characterization of depressive symptoms in dementia and examination of possible risk factors. J Alzheimers Dis Rep. 2023;7(1):213-225.

11. Depression. Alzheimer’s Association website. https://www.alz.org/help-support/caregiving/stages-behaviors/depression

12. Kørner A, Lauritzen L, Abelskov K, et al. The Geriatric Depression Scale and the Cornell Scale for Depression in Dementia. A validity study. Nord J Psychiatry. 2006;60(5):360-364.

13. Masdrakis VG, Markianos M, Baldwin DS. Apathy associated with antidepressant drugs: a systematic review. Acta Neuropsychiatr. 2023;35(4):189-204.