Introduction to Antidepressants^
Antidepressants are medications that are used to treat depression by improving symptoms such as mood, sleep, appetite and concentration. There are many different types of antidepressants, and they are classified based on how they affect the brain. Broadly, antidepressants work by increasing the amount of a certain neurotransmitter (a chemical messenger) in the brain. Most relevant to Huntington’s Disease (HD) is a class of antidepressant called SSRIs, or selective serotonin reuptake inhibitors. SSRIs increase the effect of the neurotransmitter called serotonin. Normally, serotonin transmits chemical messages to a postsynaptic cell when it is released from a presynaptic neuron into a synapse, which is the space between two nerve cells. To stop serotonin’s action, the presynaptic neuron re-absorbs the serotonin it just released. SSRIs block this re-uptake which increases the amount of serotonin present in the synapse and magnifies its effects. For more information about SSRIs, click here.
Serotonin is mostly present in intestinal membranes and the central nervous system (CNS). For more information on serotonin, click here. It has a wide range of functions in the CNS including the regulation of mood, appetite, sleep, behavior, learning, memory and muscle contraction. In the brain, there are more receptors for serotonin than any other neurotransmitter, which emphasizes the widespread effects of serotonin. Recently, researchers have been attracted to the idea of using SSRIs as a potential treatment for HD. The mutant HD gene has been found to reduce the number and activity of serotonin receptors, and SSRIs may be a way to overcome the reduction in serotonin signaling. SSRIs are also an attractive drug because they are known to have fewer side effects than other classes of antidepressants. The most common side effects of SSRIs include upset GI tract, diarrhea, restlessness, weight loss or insomnia.
Using SSRIs to treat HD may address both the psychiatric and neurological abnormalities in HD patients. HD patients have commonly exhibited psychiatric symptoms both before and after diagnosis, such as depression, hostility, obsessive–compulsiveness, anxiety, interpersonal sensitivity, phobic anxiety, and psychoticism. As stated above, SSRIs are normally used to treat depression and severe anxiety disorders. However, current research suggests that SSRIs not only can help treat depression, but also may have therapeutic potential as neuroprotective agents.
SSRIs and HD: From Animals Models to Clinical Trials^
In 2005, researchers studied the effects of a SSRI for the first time in huntingtin mutant mice. These scientists found that the administration of paroxetine, a widely prescribed antidepressant drug (and SSRI) increased serotonin levels, delayed onset of neuronal degeneration and motor dysfunction, improved energy metabolism, and increased mouse lifetime. The researchers did not investigate how paroxetine could have exerted these effects on the mice. For more information on paroxetine, click here. The researchers also observed that there were few or no side effects of the drug in mice. Most importantly, this study was the first to demonstrate the positive effects of SSRIs on neurological aspects of HD, calling for further investigation of these effects in both mice models and HD patients.
Another study conducted in 2005 investigated the relationship between SSRIs and neurogenesis, the birth of new neurons, in HD mice. In this study, researchers used another SSRI, fluoxetine (also known by the tradename Prozac), to determine whether it would promote neurogenesis and mitigate HD symptoms in a mouse model of the disease. Through extensive behavioral testing of the mice, the researchers demonstrated that flouxetine did not affect motor activity or body weight, but did improve cognitive function and “reversed” a depressive phenotype of HD mice. Furthermore, the flouxetine-treated mice displayed a considerable increase in neurogenesis and volume of the dentate gyrus. The dentate gyrus is a part of the hippocampus, which is a region of the brain thought to contribute to memory formation. The growth in the volume of the denate gyrus of the hippocampus in mice treated with flouxetine was so significant that it was comparable to the size of the denate gyrus in mice without HD.
Many recent studies have emphasized the role of the hippocampus in depression. The finding that SSRIs are able to target both neurological symptoms and those of depression implies a link between the two. In the fluoxetine study, the researchers propose a possible mechanism relating neurogenesis with the action of antidepressants in the body. They suggest that antidepressant stimulation of neurogenesis may act through the increased expression of neurotrophic factors such as BDNF, or brain-derived neurotrophic factor. BDNF is required for neurons to survive and regenerate. The loss of BDNF in the brains of HD patients and mouse models has been shown to play a crucial role in the development of the disease. For more information about BDNF click here.
Interestingly, serotonin stimulates the expression of BDNF, and BDNF enhances the growth and survival of neurons that release serotonin. Because Huntington’s patients have decreased levels of both BDNF and serotonin, this interaction could play an important role in the pathogenesis of HD. Peng and Masuda, researchers at Johns Hopkins, decided to further investigate the impact of SSRIs on BDNF levels and neurogenesis in mice. These scientists used yet another SSRI, sertraline, which has also been widely used in the treatment of depression. Their study concluded that sertraline prolongs survival, improves motor performance, and decreases brain atrophy in HD mice. Furthermore, it showed that sertraline significantly increased BDNF protein levels in HD mice, and that the effective levels of sertraline in mice are comparable in humans—providing a case for the testing of sertraline in HD patients.
Due to the evidence in HD mouse models supporting the use of SSRIs to treat HD, the University of Iowa facilitated a randomized, double-blind placebo controlled clinical trial to test the efficacy of citalopram, also an SSRI, in HD patients. This clinical trial is currently in phase II, and researchers are now recruiting more participants. For more information about clinical trials, click here.
In conclusion, many different SSRIs have consistently been shown to increase neurogenesis, motor control, cognitive ability, and brain metabolism in mouse models of HD. It is likely that SSRIs such as sertraline influence neurogenesis via increasing BDNF, a neurotrophic factor essential to neuron growth and survival that has been found in abnormally low levels in HD patients. Thus far, the data investigating the relationship between SSRIs and HD are very promising. It is also encouraging that SSRIs have been tolerated for long-term treatment in humans without significant side effects for depression—suggesting (but not proving) the safety of SSRI treatment for HD patients. Clinical trials such as the one being conducted on citalopram are necessary in order to confirm the safety and efficacy of SSRIs for HD patients. If the findings in mouse models translate to human medicine, this promising avenue of research may allow for SSRIs to be co-opted for Huntington’s Disease.
1) Visit HD drug works for specific information about different categories of antidepressants
Duan W, Peng Q, Zhao M, Ladenheim B, Masuda N, Cadet JL, Ross CA. Sertraline Retards Progression and Improves Survival in a Mouse Model of Huntington’s Disease. Society for Neuroscience.s 2005.
Duan W, Guo Z, Jiang H, Ladenheim B, Xu X, Cadet JL, Mattson MP. Paroxetine retards disease onset and progression in Huntingtin mutant mice. Ann Neurol 2004 Apr;55(4):590-4.
Lazic SE, Grote HE, Blakemore C, Hannan AJ, van Dellen A, Phillips W, Barker RA. Neurogenesis in the R6/1 transgenic mouse model of Huntington’s disease: effects of environmental enrichment. Eur J Neurosci 2006 Apr;23(7):1829-38. PubMed abstract
Grote HE, Bull ND, Howard ML, van Dellen A, Blakemore C, Bartlett PF, Hannan AJ. Cognitive disorders and neurogenesis deficits in Huntington’s disease mice are rescued by fluoxetine. Eur J Neurosci 2005 Oct;22(8):2081-8.
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