Aging and Mental Health: A Focus on Depression and Dementia

Aging and Mental Health: A Focus on Depression and Dementia

Tags: , ,

 

Author: Tarek Rajji, MD, FRCPC

Affiliations: Chief, Geriatric Psychiatry Division, Centre for Addiction and Mental Health; Associate Professor, Department of Psychiatry, University of Toronto; IMS Associate Member

About 5 million Canadians were aged 65 or older in 2011 and this number will increase rapidly over the next 15 to 20 years such as by 2036, about 1 in 4 Canadians will be a senior. While we are getting older as Canadians and our life expectancy is above 81 years on average, our functional abilities decline at an accelerated speed after the age of 65.

Brain health and disease states are critical factors in determining functional decline in late life. About 10% of people aged 65 or older and up to 50% of those aged 85 or older have Alzheimer’s or another form of dementia. About 6% will experience depression and others will experience other forms of mental illness including anxiety, bipolar disorder, and schizophrenia. Some older people will experience these disorders for the first time in late life, others would have had them since earlier age and have grown older with them.

Understanding the relation between aging, mental illness, and cognitive disorders in late life is critical for the development of interventions that will maintain brain health and prevent the onset of cognitive decline and dementia. Most mental illnesses in late life are associated with cognitive deficits. Moreover, some mental illnesses, in particular depression, are not only associated with cognitive deficits, but also increase the risk of developing Alzheimer’s dementia (AD).

Late-life depression (LLD), defined has having depression for the first time in late life or having a major depressive disorder that started earlier in life but is recurrent into late life, is a serious public health problem. LLD is the second most promising modifiable risk factor for AD after physical inactivity.1 In two meta-analyses, a life-time history of depression doubles the risk of AD; a depressive episode within 10 years increases the risk of dementia 4-6 fold. Among patients with LLD and cognitive impairment, conversion rates to dementia are 30-45% over follow-up of up to three years and > 50% over longer periods.2 Cognitive deficits in non-demented patients with LLD are highly prevalent and they lead to dementia in a large proportion of patients. These deficits are observed in attention, executive functions, information processing speed, and both verbal and visuospatial memory.3 Deficits in executive function and memory both increase the risk of depression relapse during antidepressant maintenance and predict conversion to dementia.

The association between depression and dementia follows more than one pathway. Cerebrovascular disease could be a common pathway that leads to both depression and dementia especially through its impact on the frontostriatal network. Depressed patients also experience increased activity in the hypothalamic-pituitary-adrenal axis resulting in high levels of glucocorticoids and related hippocampal atrophy. This atrophy increases the risk of AD through the increase in susceptibility to Alzheimer’s disease processes. Depression and dementia are also associated with inflammatory changes in the brain and the peripheral systems. Neuroinflammation can also be a common mechanism and a pathway linking depression to dementia.

Current treatments of depression do not prevent the development of dementia among patients with LLD. Over the past 20 years, several studies assessed the impact of antidepressants on cognition. Tricyclic antidepressants are typically associated with deleterious effects on cognition, especially on memory. These negative effects are attributed to the anticholinergic properties of the tricyclic antidepressants. This is particularly true in patients with LLD. Monoamine oxidase inhibitors have neither positive nor a negative impact on cognition.

In general, selective serotonin reuptake inhibitors (SSRIs) have not been associated with a negative impact on cognition. Paroxetine has been shown to cause deleterious effect on verbal memory, and this effect has also been attributed to its higher anticholinergic activity than that of other SSRIs. In contrast, some studies found that some SSRIs, particularly sertraline, noradrenergic reuptake inhibitor (reboxetine), and serotonin-norepinephrine reuptake inhibitor (duloxetine) have pro-cognitive effects in patients with depression, especially on attention, processing speed, and verbal memory. However, notwithstanding these positive results, it is not likely that these cognitive benefits are beyond the improvement in mood symptoms. Further, more recent studies using detailed neuropsychological tests and controlling for practice effects show that while cognition improves, it does not normalize even after LLD responds to antidepressants. Finally, long-term antidepressant maintenance alone does not prevent decline in cognition, despite maintenance of recovery from LLD.

Other than antidepressants, one relatively recent randomized controlled trial assessed the combination of donepezil with standard antidepressant maintenance in preventing cognitive decline and the incidence of dementia in patients with LLD.4 Although the addition of donepezil was effective in preventing cognitive decline and the incidence of dementia over a period of two years, it caused severe mood symptoms in many of these patients supporting the need for a different intervention.

The frontal lobes are promising targets for such an intervention. Several lines of evidence demonstrate that the prefrontal cortex provides a neural substrate for cognitive compensatory mechanisms that are recruited in old age.5,6 The prefrontal cortex is hyperactive in healthy individuals who are carriers of ApoE4 during learning and recall. It is also hyperactive in patients with mild cognitive impairment during a semantic task. Further, amyloid plaques and thinning of micro-columns in the prefrontal cortex of patients with mild AD are associated with decreased cognitive compensatory capacity rather than with cognitive deficits thought to be more specific to AD. Finally, the prefrontal cortex has the capacity to experience neuroplasticity in response to injury to compensate for the cognitive effects of plaques and tangles in other regions of the brain.

Taken together, one approach our research team is adapting to prevent cognitive decline among patients with LLD is to target the prefrontal cortex with neuroplasticity-inducing interventions to enhance its compensatory capacity and therefore, prevent cognitive decline and dementia. We have been using the combination of neurostimulation with cognitive remediation, two types of interventions that we think are synergistic in promoting neuroplasticity, and therefore enhancing prefrontal cortex function.7,8 A large 5-year and multi-site trial is underway to test whether the combination of these two interventions can prevent cognitive decline and AD among patients with LLD.

Discovering an intervention that can prevent or even delay Alzheimer’s dementia will have a tremendous impact on our society and worldwide given the severe burden that this illness imposes on the individuals, their caregivers, and the public at large.

References:

  1. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurology. 2011 Sep;10(9):819-28.
  2. Alexopoulos GS, Meyers BS, Young RC, Mattis S, Kakuma T. The course of geriatric depression with reversible dementia – A controlled-study. American Journal of Psychiatry. [Article]. 1993 Nov;150(11):1693-9.
  3. Butters MA, Whyte EM, Nebes RD, Begley AE, Dew MA, Mulsant BH, et al. The nature and determinants of neuropsychological functioning in late-life depression. Archives of General Psychiatry. 2004 Jun;61(6):587-95.
  4. Reynolds CF, Butters MA, Lopez O, Pollock BG, Dew MA, Mulsant BH, et al. Maintenance Treatment of Depression in Old Age A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined With Antidepressant Pharmacotherapy. Archives of General Psychiatry. [Article]. 2011 Jan;68(1):51-60.
  5. Grady C. BRAIN AGEING The cognitive neuroscience of ageing. Nat Rev Neurosci. [Review]. 2012 Jul;13(7):491-505.
  6. Fuster JM. Cortex and Memory: Emergence of a New Paradigm. Journal of Cognitive Neuroscience. [Review]. 2009 Nov;21(11):2047-72.
  7. Wolkenstein L, Plewnia C. Amelioration of Cognitive Control in Depression by Transcranial Direct Current Stimulation. Biological Psychiatry. [Article]. 2013 Apr;73(7):646-51.
  8. Bowie CRP, Gupta MM, Holshausen KM. Cognitive Remediation Therapy for Mood Disorders: Rationale, Early Evidence, and Future Directions. Canadian Journal of Psychiatry. 2013;58(6):319-25.