The high prevalence of depression in people with cognitive impairment could be due to some similarities of pathological processes between depression and dementia. These similarities include changes in neurotransmitters, especially serotonin, brain vascular changes and beta amyloid deposits as will be explained in the following paragraphs.

Alzheimer’s disease causes serotoninergic and noradrenergic denervation ^{5, 6} and loss of serotonin receptors ⁷. Serotonin is involved in sexual behavior, appetite and aggression and together with norepinephrine in mood state, irritability and thought processes. High prevalence of depression in individuals with Alzheimer’s disease can be expected because of these monoaminergic deficits. The importance of serotonin for depression is supported by the most effective medications which are selective serotonin reuptake inhibitors (SSRIs). Treatment with antidepressants that potentiate the effect of serotonin may be similar to treatment with cholinesterase inhibitors that potentiate the effect of acetylcholine.

Vascular etiology of depression was proposed already 20 years ago ⁸. Recent studies found that white matter hyperintensities increase the risk of depression development 8.1 times during 3-year follow up study ⁹ and it is proposed that the damage of brain structure reflected by these hyperintensities, indicating reduced white matter microstructural integrity, is a pathophysiological mechanism of late-life major depressive disorder ¹⁰. Presence of white matter hyperintensities also predicted development of functional disability in depressed individuals ¹¹. Vascular etiology of depression is supported by association of depression with hypertension in a large epidemiological study ¹². White matter hyperintensities are also hallmarks of one type of vascular dementia – Binswanger disease ^{13, 14}.

Availability of detection of beta amyloid levels in the brain in vivo, opened another avenue for investigation of relationship between Alzheimer’s disease and depression. A recent review reported that out of 19 studies investigating beta amyloid levels in people with depression, 15 found significant differences between depressed and non-depressed older adults ¹⁵. Another more recent study also found correlation between depressive symptoms and mean cortical beta amyloid burden in older cognitively normal persons ¹⁶. A longitudinal study found that elevated beta amyloid levels are associated with a 4.5-fold increase likelihood of developing significant depressive symptoms during the 54-months follow-up ¹⁷. Therefore, it was proposed that late-life depression could be considered as predementia state and the persons with this condition could be candidates for participation in anti-amyloid drug trials ¹⁸. However, beta amyloid may not be always involved because one study found that people with subjective and mild cognitive impairments and depressive symptoms did not have pathological and biochemical biomarkers of Alzheimer’s disease ¹⁹.

Unrecognized and/or untreated depression has serious effects on people with dementia that include increased dementia progression, decreased quality of life and increased risk of developing behavioral symptoms of dementia. Depression in patients also increases burden of their caregivers. Unfortunately, depression in people with dementia is often unrecognized and even when it is recognized and treated the treatment is not always effective. Using Minimum Data Set (MDS) information, clinical and MDS-based diagnoses of depression were compared in 1851 residents of 8 Dutch nursing homes 3. A clinical diagnosis of depression was present only in 14.4% of residents while 42.5% had an MDS diagnosis. This difference was mainly due to decreased prevalence of clinical diagnosis of depression in persons with more advanced dementia. Antidepressants were used only in 33.9% of residents with an MDS diagnosis of severe depression and symptoms of depression were present even in residents treated with antidepressants. Antidepressants were also used less often in older residents with a clinical diagnosis of depression. There is some evidence that the use of antidepressants in persons with dementia is increasing ²⁰ but it is not clear if the treatment is completely effective.

There is an evidence that treatment of depression in people with dementia delays progression of dementia, while untreated depression increases the rate of dementia progression. A study comparing 13 hospitalized older adults with dementia syndrome of depression (DSD) with 14 adults with Alzheimer's dementia with a concurrent major depression on a battery of neuropsychological tests found that successful treatment of depression delayed progression of dementia for up to 3 years ²¹. Another study, however, found that successful treatment of depression improved only processing speed and attention and that development of depression exacerbated cognitive decline in dementia-free persons 60 years old and older ²². A three year follow-up study found that 43% of patients with depression and cognitive impairment, whose cognitive impairment improved by antidepressant treatment, and therefore could be considered having reversible dementia, eventually developed irreversible dementia ²³. Thirteen-year follow-up study found that the effect on dementia progression differ according to the type of depression. Surprisingly, persons who had initially nondysphoric depression were more cognitively impaired, and impaired in basic and instrumental activity of daily living at the follow-up than persons who had initially major depression ²⁴. This may be partially explained by 8-10% of persons with subthreshold depression who develop major depression per year, and by a low remission rate ²⁵. Depressive symptoms also increase risk of progression of mild cognitive impairment into dementia ²⁶.

Presence of depression decreases significantly quality of life of elderly persons even when the depression is minor ²⁷. Depression is also associated with disability ²⁸, decreased active life expectancy ²⁹, worsened outcomes of comorbid chronic medical diseases ³⁰, and may even cause nocturia ³¹. Geriatric depression amplifies physical/somatic complaints and pain, increases outpatient visits, prescription medications, risk of hip fracture due to falls, and admission to nursing homes. Depressive symptoms also increase mortality in both the whole community based sample of older persons, and in persons with incident Alzheimer’s disease ³².

The most common behavioral symptoms are agitation and rejection of care, that may result in reactive aggression. Agitation may be defined as a motor restlessness, heightened responsivity to stimuli, irritability, inappropriate and/or purposeless verbal or motor activity, decreased sleep, with fluctuation of symptoms over time ³³ (p.6). It is often caused by boredom and is ameliorated by meaningful activities ³⁴. In people with dementia who were depressed there was a significant correlation between depression and agitation scores. Depression scores increased in residents whose agitation worsened and decreased in residents whose agitation improved ³⁵. These results indicate that depression is an important factor associated with agitation in nursing home residents with dementia.

Rejection of care is a very common and the most disturbing behavioral symptom of dementia ³⁶. It is caused mostly by the lack of understanding by persons with dementia of intentions of a care provider. The persons with dementia defend themselves against unwanted attention and this defense may escalate into combativeness and reactive aggression (called behaviors directed towards others in MDS 3.0). Depression is the second most important factor for development of rejection of care which may result in behaviors directed towards others ³⁷. Depression was also found to be the most important factor increasing risk for development of physical and verbal aggression in 3 national samples of nursing home residents (>500,000 total) in >9,000 facilities ³⁸. Another study found that physically aggressive behavior is associated with depression, male gender, impairment in ADLs after adjustment for delusions, hallucinations, sleep disturbances and severity of dementia. After adjustment for depression, gender and impairment in ADLs there was no association with either delusions or hallucinations indicating that depression was the most important factor ³⁹. Antidepressant treatment decreases behavioral symptoms of dementia, but only if it is successful in treatment of depression ⁴⁰.

Antidepressant treatment may need to be long-term because the underlying conditions are not improving with progression of dementia. Treatment of depression in elderly individuals may not be effective because of several reasons: underrecognition of depression, inadequate doses of antidepressants, inadequate duration of treatment, failure to recognize and treat relapse, failure to recognize and treat comorbid conditions, and patient noncompliance ⁴¹. A single antidepressant may not be always effective in resolving depressive symptoms because single antidepressant treatment is effective only in one third of even cognitively intact patients ⁴² and may require augmentation by an atypical antipsychotic ⁴³.

Behavioral symptoms in dementia patients are associated with increased caregiver´s burden ^{44, 45} carer depression and increased rates of institutionalization of patients ^{46, 47}. One study explicitly confirmed that clinician-rated patient depression scores are independently and significantly associated with caregiver psychological morbidity ⁴⁸. In conclusion, treatment of depression in dementia patients provides benefits not only for patients but it is very important also for their caregivers.