Over the past few years, there has been an explosion in new scientific evidence showing that antidepressants such as Prozac can reverse the clinical symptoms of Alzheimer's disease. Some preclinical and preclinical studies have shown that AD patients who have a history of depression and were given antidepressants improved their cognitive skills and clinical symptoms compared to patients that did not have depression and were not taking antidepressants or compared to AD patients who were taking placebo only. Moreover, there is a high prevalence of depression among AD patients (40-60%) showing a causal association of AD and depression. A few clinical studies suggest a beneficial role of combinatorial therapies that employ both FDA approved anticholinergic drugs and tricyclic antidepressants or serotonin reuptake receptor inhibitor such as Prozac (SSRI). However, the mechanism by which antidepressants reverse AD pathology is not known. This article will highlight two interesting research articles showing that antidepressants have a great therapeutic potential for reversing AD symptoms and even growing new neurons (also known as neurogenesis).

Alzheimer's disease is characterized by the presence of very toxic protein aggregates that accumulate in neurons throughout the progression of the disease which leads to the ultimate demise of memory neurons, memory lost and a decrease in higher cognitive skills in humans. One interesting research article published approximately 5 weeks ago in the Journal of PLOS One showed that antidepressants such as imitriptyline can completely reverse the symptoms of AD in a very well characterized mouse model of AD (3X Tg AD). In this study, the authors showed that mice given the antidepressant for 4 months showed a partial reduction in the concentration of toxic beta amyloid aggregates in neurons of the hippocampus (memory brain center) and the cortex (judgement and higher cognitive center) while the number of non-toxic beta amyloid aggregates increased. Not only did treating AD mice with imitryptiline significantly reversed AD pathology but it actually improved that cognitive skills and behavioral tests in AD mice (ie., Morris water maze). Surprisingly, imitryptiline treatment had the exciting effect of forming new neurons that replaced dead neurons in the hippocampus and cortical regions as shown by a variety biochemical assays.

Interestingly, stress and anxiety can also lead to a decrease in brain connectivity and decreased neurogenesis. More importantly, normal mice treated with antidepressants do show enhanced brain function and neurogenesis suggesting that antidepressants enhance normal brain function and may delay age-related decline in cognitive skills/ memory. Other studies had demonstrated that depression and anxiety can cause loss of neurons .The second study published about a week ago in the journal of Molecular Psychiatry showed that treating human progenitor hippocampal cells with imitriptyline lead to an increase in the number of new neurons and a significant increase in the number of differentiated (maturation) of these neurons. The authors elegantly showed that trycyclic antidepressants such as imitryptiline mediate neurogenesis through the glucocorticoid receptor, a receptor that initiates stress and anxiety related responses in cells. In further support of the notion that antidepressants are neuroprotective, other studies have shown antidepressants increase the survival of neurons in models of stroke. Indeed, the authors of the Molecular Psychiatry paper showed that mice treated with imitryptiline showed a higher concentration of neurotrophic factors such as brain derived growth factor (BDNF) and the activation of prosurvival signaling pahways mediated by protein kinase A and CREB.

In summary, SSRI antidepressants such as fluoxetine, sertaline, citalopram and third generation TCAs which have fewer unwanted side effects (venalafaxine) can be used in combination therapies to reverse the pathology of AD and improve the quality of life in AD patients. If the current phase I and phase II clinical trials this year show that antidepressants can significantly improve AD symptoms, there will be no doubt that the use of currently available antidepressants will be prescribed for treating brain degenerative diseases such as AD and other brain disorders.

What is Alzheimer's Disease?

Alzheimer’s disease(AD) is an age-related, chronic, and relentless, devastating neurodegenerative disease which leads to the most common form of dementia. Brain pathology shows an abnormal accumulation of protein aggregates known as tangles and plaques, protein aggregates consisting of tau and beta-amyloid protein respectively, in post-mortem AD brains. Generally, the age of onset of this disease is around 60-65 years of age, although there are familial manifestations of the disease which can lead to a much earlier age of onset. This disease affects an estimated 26.6 million people worldwide.To this date, there is no cure for the disease and only supportive treatment is available which includes administering patients with a cocktail of antioxidants, NMDA and glutamate receptor inhibitors to slow down degeneration of neurons and cognitive and psychotherapy (validation therapy) to slow memory loss.

To view the an extended and complete version of the original article published in the Examiner, click here.

References:

1. C Anacker,^1,2,3 P A Zunszain,¹ A Cattaneo,^1,4 L A Carvalho,¹ M J Garabedian,⁵ S Thuret,^3* J Price,³ and C M Pariante¹ Mol Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Molecular Psychiatry. 2011 July; 16(7): 738–750.

2. Wayne Chadwick,¹ Nick Mitchell,² Jenna Caroll,³ Yu Zhou,¹ Sung-Soo Park,¹ Liyun Wang,¹ Kevin G. Becker,⁴ Yongqing Zhang,⁴ Elin Lehrmann,⁴ William H. Wood, III,⁴ Bronwen Martin,⁵ and Stuart Maudsley. Amitriptyline-Mediated Cognitive Enhancement in Aged 3×Tg Alzheimer's Disease Mice Is Associated with Neurogenesis and Neurotrophic Activity PLOS One, 2011 6: (6)