Psychiatric depression is thought to be underdiagnosed and undertreated in the elderly. The suicide rate in the over-65 age group (twice the national average) supports this view. Unfor tunately, the apathy, flat affect, and social withdrawal of major depression may be mistaken for senile dementia. Clinical evidence suggests that the elderly are as responsive to antidepressants (of all types) as younger patients but are more likely to experience adverse effects. This factor along with the reduced clearance of some of these drugs underlines the importance of careful dos ing and strict attention to the monitoring of toxic effects. Some to tricyclic antidepressants because the SSRIs have fewer auto nomic adverse effects. If a tricyclic is to be used, a drug with reduced antimuscarinic effects should be selected, eg, nortriptyline or desipramine (see Table 30–2).
Alzheimer’s disease (AD) is characterized by progressive memory impairment, dementia, and cognitive dysfunction, and may lead to a completely vegetative state, resulting in early death. Prevalence increases with age and may be as high as 20% in individuals over 85, although long-term epidemiologic studies suggest that the overall prevalence of dementia has decreased in the USA and Europe over the last 15–30 years (see Langa 2017). The annual cost of dementia in the United States is estimated at $150–$215 billion annually. Both familial and sporadic forms have been identified. Early onset of Alzheimer’s disease is associated with several gene defects, including trisomy 21 (chromosome 21), a mutation of the gene for presenilin-1 on chromosome 14, and an abnormal allele, ε4, for the lipid-associated protein, ApoE, on chromosome 19. Unlike the common forms (ApoE ε2 and ε3), the ε4 form strongly correlates with the formation of amyloid β deposits (see below).
Pathologic changes include increased deposits of amyloid beta (Aa) peptide in the cerebral cortex, which eventually forms extracellular plaques and cerebral vascular lesions, and intraand interneuronal fibrillary tangles consisting of the tau protein (Figure 60–2). There is a progressive loss of neurons, especially cholinergic neurons, and thinning of the cortex. An inflammatory process involving the NLRP3 inflammasome appears to contribute to this pathology, and anti-inflammatory nonsteroidal anti-inflammatory drugs (NSAIDs), eg, mefenamic acid, reverse some of the markers of Alzheimer’s disease in animal models. The loss of cholinergic neurons results in a marked decrease in choline acetyltransferase and other markers of cholinergic activity. Patients with Alzheimer’s disease are often exquisitely sensitive to the central nervous system toxicities of drugs with antimuscarinic effects. Some evidence implicates excess excitation by glutamate as a contributor to neuronal death. In addition, abnormalities of mitochondrial function may contribute to neuronal death.
Many methods of treatment of Alzheimer’s disease have been explored (Table 60–3). Much attention has been focused on the cholinomimetic drugs because of the evidence of loss of cholinergic neurons noted earlier. Monoamine oxidase (MAO) type B inhibition with selegiline (l-deprenyl) has been suggested to have some beneficial effects. One drug that inhibits N-methyld-aspartate (NMDA) glutamate receptors is available (see below), and “ampakines,” substances that facilitate synaptic activity at glutamate AMPA receptors, are under intense study. Some evidence suggests that lipid-lowering statins are beneficial. So-called cerebral vasodilators are ineffective.