The relationship between Alzheimer’s disease and depression in the elderly has always been relevant and controversial. The concept of pseudodementia is intimately related to the modern history of Alzheimer’s disease Citation[1]. For many years, researchers believed that patients with depression could present with a full dementia syndrome and, when treated, the observed dementia syndrome would be totally reversed. It has been assumed that a cognitive disorder that impairs function will always have a deteriorating prognosis. Any type of cognitive impairment with irreversible deterioration was considered to be a ‘real’ dementia. Then the concept of pseudodementia, considered to be a reversible form of cognitive impairment due to depression, emerged. This concept of reversible dementia due to depression was challenged. Kral and colleagues suggested that patients suffering from depression, and as a consequence of this depression, presented with severe cognitive impairment, were at a much higher risk of developing ‘real dementia’ than those who managed to go through depression without the high level of cognitive impairment Citation[1]. The concept was that depression may be a kind of ‘stress test’ that will expose inherited weaknesses in brain function, resulting in a negative outcome for those patients.
More recently, neuroimaging studies have supported the concept of a relationship between depression and cognitive impairment by showing the reduction in volume of brain structures; for example, the hippocampus, which is believed to be intimately related to cognitive functions in patients suffering from chronic depression Citation[2,3]. These findings, although interesting, did not help the field to understand whether depression is a risk factor for cognitive impairment and eventually dementia, or whether depression is an independent event that aggravates cognitive impairment owing to its impact on an emotionally related cognitive function, such as attention and motivation. Moreover, what about those patients who only present depression after they develop a dementing syndrome such as Alzheimer’s disease? In this case, is depression another behavioral manifestation of Alzheimer’s disease, or is it a comorbid disorder that further contributes to brain stress and declining cognitive function? Finally, regardless of the relationship, would the treatment of depression result in a measurable improvement in cognition? Is this improvement in cognition related to a response to treatment in terms of mood improvement, or would those be independent responses to treatment? It is clear that in order to try to find some of these answers the field had to develop definitions of terms and a conceptual framework that would allow for the development of a research agenda that will address these issues and increase our knowledge.
In putting this framework together, clinicians raised the issue of the existence of depression as a biological disorder resulting from a consequence of brain damage or a psychological response to the loss of cognitive function that results in dementia. The clarification of these issues appears to be critical and was considered to have major consequences for patients’ care. For example, if depression in dementia was a ‘logical outcome’ of the terrible situation these patients confronted, then the treatment was to improve the situation. So if a patient in a nursing home was suffering from depression and this was considered to be the result of the often precarious conditions of nursing home facilities, then the treatment was to develop better nursing homes. On the other hand, if depression was a biological syndrome resulting from anatomical damage to the brain or brain dysfunction, then the logical treatment would be a biological treatment that aids the brain in fulfilling the lost function Citation[4].
Work from the group led by Olin and collaborators clearly show the biological basis of depression in this population Citation[5]. They managed to demonstrate clear improvement in patients’ mood and function when depression was appropriately treated. But was this depression the consequence or a contributory factor to the basic biological process that resulted in Alzheimer’s disease and other types of dementia? Is there a difference in the depression related to early onset or after diagnosis of dementia? The field evaluated the available literature and concluded that, clinically, both syndromes were different Citation[5].
In recent years, researchers and clinicians adopted a definition of depression of Alzheimer’s disease Citation[6]. There was hope that now that at least one syndrome was appropriately defined we would be able to validate the syndrome through an assessment of the efficacy of well-established treatments for depression. Furthermore, biological studies have suggested a decrease of neurotransmitters known to be involved in the regulation of mood, such as serotonin, in patients with Alzheimer’s disease and other types of dementia. It was then expected that the treatment of patients with dementia with these compounds will result in an improvement in mood. The field was looking forward to learning whether this improvement in mood would result in clinically significant enhancement in cognitive function in those that responded to treatment.
In early studies, Constantine Lyketsos and his collaborators suggested that patients suffering from Alzheimer’s disease and depression appear to respond to treatments that improve activity of these very same neurotransmitters that seem to be decreased in Alzheimer’s disease Citation[7,8]. A second study conducted with a larger sample of patients found that in those indivduals who met all criteria for depression of Alzheimer’s disease, this very same treatment (sertraline) was not more effective than placebo. Unfortunately, an increase in adverse events in populations receiving sertaline treatment was noted. No differences in cognitive function were noted between participants receiving drug or placebo. Furthermore, there was no difference in response from those subjects who met the criteria of major depression in addition to depression of Alzheimer’s disease Citation[9–11]. These disappointing results unfortunately generate more questions than answers. Were these results a reflection of the lack of activity of this drug in this very specific population? Was the inefficiency of the drug a result of the lack of validity of the clinical construct that was used? Or were other factors playing important roles that were not noticed or considered in the design of the study?
It is believed that every big controversy is based on shared ignorance. The existence of a clinical association between changes in mood (depression) and cognitive impairment is clearly established. The nature of this relationship, the prognostic value of the simultaneous presence of depression and dementia, and the impact of treatments in either one of the syndromes in the cognitively impaired patient remain unknown. What is the value of this commentary? There is a difference between what we know and what we believe. What we know is based on data. Our conclusion is based on years of clinical experience, research we have conducted and the current available literature. Because clinicians are influenced by knowledge but also by their clinical experience, both concepts can easily be confused. It is the role of this article to make all of us aware of how much we do not know about the relationship of depression and dementia. Only acknowledging our ignorance will allow us to refine the questions we ask. Better questions will put us on the right track to find better answers in the future. Our patients deserve no less.
Financial & competing interests disclosure
Jacobo Mintzer is supported by NIH grant U01MH066136. Jacobo Mintzer is a part-time staff physician at the Ralph H Johnson VA Medical Center, and he is supported to conduct clinical and research activities in this facility. The contents of this article do not represent the views of the Department of Veterans Affairs or the US Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Kral VA, Emery OB. Long-term follow-up of depressive pseudodementia of the aged. Can. J. Psychiatry34, 445–446 (1989).
- Sheline YI. Depression and the hippocampus: cause or effect? Biol. Psychiatry70, 308–309 (2011).
- Steffens DC, Payne ME, Greenberg DL et al. Hippocampal volume and incident dementia in geriatric depression. Am. J. Geriatr. Psychiatry10, 62–71 (2002).
- Parmelee PA, Katz IR, Lawton MP. Incidence of depression in long-term care settings. J. Gerontol.47, M189–M196 (1992).
- Olin JT, Schneider LS, Katz IS et al. National Institute of Mental Health – provisional diagnostic criteria for depression of Alzheimer disease. Am. J. Ger. Psychiatry10, 125–128 (2002).
- Olin JT, Schneider LS, Katz IR et al. Provisional diagnostic criteria for depression of Alzheimer disease. Am. J. Geriatr. Psychiatry10, 125–128 (2002).
- Lyketsos CG, Baker L, Warren A et al. Major and minor depression in Alzheimer’s disease: prevalence and impact. J. Neuropsychiatry Clin. Neurosciences9, 556–561 (1997).
- Lyketsos CG, Sheppard JME, Steele CS et al. A randomized, placebo-controlled, double-blind, clinical trial of sertraline in the treatment of depression complicating Alzheimer disease: initial results from the Depression in Alzheimer Disease Study (DIADS). Am. J. Psychiatry157, 1686–1689 (2000).
- Drye LT, Martin BK, Frangakis CE et al. Do treatment effects vary among differing baseline depression criteria in depression in Alzheimer’s disease study ± 2 (DIADS-2)? Int. J. Geriatr. Psychiatry26, 573–583 (2011).
- Weintraub D, Rosenberg PB, Drye LT et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am. J. Geriatr. Psychiatry18, 332–340 (2010).
- Rosenberg PB, Drye LT, Martin BK et al. Sertraline for the treatment of depression in Alzheimer disease. Am. J. Geriatr. Psychiatry18, 136–145 (2010).