Reduced serotonin signaling
- About Huntington’s Disease and Serotonin Signaling
- Antidepressants and HD
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.
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.
Serotonin (also known as 5-HT) is a neurotransmitter used to communicate important information between nerve cells. Serotonin is sometimes referred to as the “feel good” neurotransmitter owing to its association with elevated mood levels. It also has many other functions in the central nervous system including roles in sleep, depression, memory, pain, and aggression. Recent studies on mice indicate that serotonin signaling is significantly reduced in mice models of HD compared to mice without HD. Having less serotonin and the products made from serotonin may greatly impact on the progression of HD. Because the connection between HD and serotonin signaling is a fairly new development, much more investigation needs to be done before there are clear answers. Decreased serotonin may be a contributor to the development of HD or it may simply be a result of another disease mechanism. Regardless of the cause for reduced serotonin, diminished signaling in the mouse model of HD may explain some of the common behavioral symptoms associated with HD in people. (For more information about the behavioral symptoms associated with HD, click here.)
Decreased serotonin is associated with several diseases, most notably depression. Consequently, a number of drugs are already available to help bring serotonin back to normal levels in the body. The main class of drugs for this purpose is called selective serotonin reuptake inhibitors (SSRIs). Recent research has shown that, in addition to alleviating symptoms associated with HD such as depression, SSRIs may also help delay the onset of HD and prevent the degeneration of nerve cells.
Researchers have found elevated serotonin in the brains of people with HD after death, but serotonin levels in a mouse model of HD actually have decreased levels in all different age groups. However, this discrepancy does not necessarily mean that the mouse data is wrong. First of all, it is difficult to interpret human HD samples taken after death due to the large amount of nerve cell loss that occurred in life. Most of what is known about serotonin and HD in living brains comes from mouse studies because it is easier and more ethical to experiment on mice that are made to look like they have HD than it is to study humans with HD. It is important to keep this fact in mind when discussing the findings from these studies because the results from experiments on mouse models do not always translate perfectly to people with HD. Mouse studies are an imperfect but important tool in learning about HD.
One group of researchers found that, compared to non-HD mice, HD mice had only 50% of the amount of serotonin by age 12 weeks in the striatum, hippocampus, and brainstem. They also found that a related molecule derived from serotonin called 5-hydroxyindoleacetic acid (5-HIAA) is also decreased in the brain. Decreased serotonin and 5-HIAA both before and after symptoms began to appear probably indicates that the serotonin system starts malfunctioning way before the serotonin levels are decreased.
Another group of researchers tested the hypothesis that the serotonin system starts malfunctioning before it is observable with decreased serotonin. Since serotonin levels could not be used as a marker in this experiment, they tested the rate-limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH). A rate-limiting enzyme is the slowest step in the creation of a molecule, and often the most important, because it requires additional energy and is highly regulated. The rate-limiting enzyme can have the biggest effect on the final product, so if something is wrong with it, the effect of this malfunction will translate down the chain to the end product. You can think of synthesis as a row of dominoes, with the goal to knock down the final domino. If one of the dominoes is missing or too small to reach the next one, the rest of the dominoes in the chain will not fall down and you will not achieve your goal. As a rate-limiting enzyme, TPH is essential to the overall production of serotonin. An alteration of TPH can therefore lead to decreased levels of serotonin in the brain overall.
Researchers have tested both the levels of TPH and its enzymatic activity. Despite normal levels of TPH, they found the activity of this enzyme was significantly diminished. This finding means that while the enzyme was present, it was not functioning properly. TPH activity was 62% less than normal before symptoms were present at 4 weeks and 86% less than normal in symptomatic 12 week old mice. These results indicate that TPH is severely damaged and account for the decreased levels of its product, serotonin.
Often, in order to compensate for decreased levels of a neurotransmitter like serotonin, the brain increases the number of receptors for that specific neurotransmitter. While this sort of “upregulation” of serotonin receptors occurs in Parkinson’s disease, it was not found to occur in the brains of HD mice. In fact, receptor binding was significantly decreased in several important areas of the brain.
We must now ask, “Why is TPH activity decreased?” The obvious answer might be that mutant huntingtin protein prevents TPH from doing its job; however, this appears unlikely. The researchers tested this hypothesis and found that the expanded polyglutamine section of the mutant huntingtin protein does not interact with TPH. Another possibility comes from the fact that TPH is very sensitive to free radical damage by reactive oxygen species. (For more information on free radical damage, click here.) It is already known that free radical damage plays a role in the progression of HD, so it is very possible that it contributes to decreased serotonin by interfering with TPH. More evidence about the role of free radicals comes from the decreased activity of TPH. Since TPH uses tryptophan to create certain products, when TPH doesn’t work, this pathway is disrupted. This disruption results in increased levels of 3-hydroxykynurenin (3HK), which makes free radicals. These free radicals can then go on to further damage TPH and many other molecules in the brain.
Now that researchers have an idea of the problem, they can begin to investigate ways to fix it. First, it must be determined whether TPH activity is also decreased in human brains, since so far it has only been tested in mice. If it is also decreased in humans, that could explain why depression is apparent before any of the motor symptoms of HD. If the current hypotheses from the mouse studies are correct, symptoms may be prevented or at least delayed by treating people at risk for HD with early antioxidants and SSRIs to keep TPH activity and serotonin levels normal. It has already been shown that one type of SSRI helped to increase TPH activity in rats.
Drug Summary: Fluoxetine (also known as Prozac) is part of the class of drugs known as selective serotonin reuptake inhibitors (SSRIs) . It is usually prescribed to treat depression and obsessive-compulsive disorder (OCD) in people with and without HD. While fluoxetine has traditionally been used to treat behavioral symptoms, recent observations indicate that it may also be helpful in treating other aspects of HD.
Como et al. (1997) performed a randomized, double-blind study of 30 nondepressed patients with HD. 17 subjects received fluoxetine for 4 months, while 13 received placebo. The study did not find that fluoxetine was helpful; patients receiving fluoxetine did not demonstrate improvements in motor or cognitive symptoms, and did not improve in measures of functional capacity (the ability to perform day-to-day tasks. While this study suggests that fluoxetine is not helpful for nondepressed people with HD, the researchers had previously reported that treating 8 depressed HD patients with fluoxetine helped those patients deal with symptoms much better – so fluoxetine may be useful to treat depression in HD.
DeMarchi, et al. (2001) observed two people with HD who were given fluoxetine for psychiatric issues. They tested the two patients each month using the HD motor rating scale (HDMRS) to measure movement abilities, and the mini mental state examination (MMSE) for cognitive (or thinking) abilities. These tests were also accompanied by psychiatric and neurological examinations.
The first case study was on a 60-year-old woman who had symptoms of HD beginning in her mid-forties and symptoms of OCD beginning at age 25. She had not been successfully treated for her chorea, declining cognitive functioning, or aggressive behavior. Before treatment, her symptoms were so bad that her speech could not be understood and her cognitive functioning so impaired that she could not even take the MMSE. She was given the HDMRS, and her motor functioning scored 20 on a scale of 25 (with 0 as the least impaired, and 25 as the most impaired). She began treatment with fluoxetine, and after a month she was clearly less agitated and had a better mood. Her motor performance progressively improved during treatment, scoring 12 on the HDMRS after 4-6 months. The improvement in her motor functioning allowed her to begin walking again and speak coherently. Perhaps most surprising was her improvement in cognitive functioning. Cognitive improvement began after about 4-6 months of treatment, and after about a year she could take the MMSE and scored 12 out of 25. She continues to improve 6 years after beginning treatment with fluoxetine. Additionally, her movement became worse during the two periods in which she stopped taking the medication.
The second case study was on a 55-year-old woman who had symptoms of HD for the past 8 years. Her main symptom was the involuntary movements characteristic of HD, and she mostly retained her cognitive functioning. When tested before treatment began she received a score of 13 on the HDMRS and 19 on MMSE. She began treatment with fluoxetine and another drug to treat her insomnia (since fluoxetine was making the insomnia worse). She began to improve in her motor performance after about 2 months of treatment and reached the height of her improvement after 6 months, with a score of 8 on the HDMRS. She maintained this level of motor functioning for the next year and was able to return to her job. The patient did not change significantly in cognitive functioning, maintaining a score of 20 on the MMSE for as long as she was observed. She went off of the medication for a period of 3 months after a year of treatment and her motor performance deteriorated during this time. When she started taking fluoxetine again, she regained her previous level of motor functioning.
These two case studies show that fluoxetine may be beneficial to people with HD who have not responded well to other treatments for both behavioral and movement symptoms. The motor functioning probably improved as a result of increased serotonin signaling in the brain. It is unclear how the patient in Case One had such impressive cognitive improvement; this has never been seen before and may only be partially due to the beneficial effects of serotonin. It is possible that the reason why fluoxetine was so helpful in these two cases has to do with them both having a history of OCD in their families. In other words, a possible reason for success in these cases had to do with improvements in their OCD rather than, or in addition to, HD. It is important to note that this study only represents two cases of people with HD. More research needs to be done before making assessments about fluoxetine’s effect on people with HD. However, judging by these cases, fluoxetine may at least be helpful to people with HD who also have a family history of OCD.
Grote et al. (2005) studied fluoxetine in a mouse model of HD, and found that fluoxetine might help fight some of the effects of the disease. R6/1 mice were either treated with fluoxetine or a placebo. Scientists found that there was no improvement in motor symptoms, but HD mice treated with fluoxetine had improvements in cognitive symptoms; untreated HD mice tend to repeatedly explore the same paths in a maze, and the treated HD mice behaved more like normal mice by exploring the maze more thoroughly. Treated HD mice also showed fewer symptoms of depression than untreated HD mice.
The results were more than just behavioral; when the researchers looked at the brains of these mice, they found that fluoxetine reversed many of the problems HD causes in the brain. Treated HD mice had much larger dentate gyruses than untreated HD mice, and had an increase in neurogenesis.
Altogether, research results on fluoxetine are mixed; an animal study reports some improvement, while a small clinical trial does not.
-K. Taub, 1-29-06, updated by M. Hedlin 8.9.11More
Drug Summary: Paroxetine (also known as Paxil) is part of the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). Paroxetine is a commonly prescribed drug for depression and severe anxiety in people with and without HD. While it has traditionally been used to treat psychiatric disorders, new research suggests that it may also be helpful in treating the symptoms and slowing the progression of HD.
Duan, et al. (2004) noted that SSRIs are very helpful in treating psychiatric symptoms in people with HD, yet no one had tested how they might affect neurodegeneration and the progression of the disease. These researchers created four different experimental groups of mice: transgenic (mouse models of HD) and nontransgenic mice that were injected with paroxetine, and transgenic and nontransgenic mice that were injected with a placebo. The progression of the disease was observed in the mice each day, and they were weighed each week. Their motor performance was tested by placing them on a rotating rod and recording the amount of time that they were able to stay on. Levels of different brain chemicals were measured, including serotonin and the related molecule 5-HIAA.
The mice received treatment (or placebo) starting at eight weeks of age. At 14 weeks it was found that HD mice had lower levels of serotonin and 5-HIAA in the striatum compared to the nontransgenic mice. Serotonin was increased in both transgenic and nontransgenic mice that received paroxetine. Furthermore, administration of serotonin did not affect the levels of any other important brain chemicals tested, such as dopamine.
Paroxetine also delayed the beginning of behavioral symptoms by an average of 2 weeks in the HD mice, and even helped them survive for an average of 15 days longer than the previous maximum life span (this is a significant amount of time in the life of a mouse). While weight loss is a problem both for HD mice and people with HD, paroxetine slowed the loss of weight in HD mice compared to untreated HD mice. At 16 weeks the HD mice treated with paroxetine performed significantly better than the untreated HD mice on the motor tests.
In order to assess the drug’s effect on the neurodegenerative process, the researchers examined the brains of HD mice and compared them to nontransgenic mice. While untreated HD mice showed deterioration of the brain with larger lateral ventricles and a thinner cerebral cortex, HD mice treated with paroxetine had less enlarged ventricles. Having less enlarged ventricles means that the HD mice treated with paroxetine lost fewer nerve cells in their brains. (For more information on HD and the brain, click here.)
This study suggests that paroxetine not only improves serotonin signaling in HD mice, but it also slows neurodegeneration and improves overall survival. This slowing of the neurodegenerative process may also help to slow the typical weight loss caused by HD. By using an SSRI such as paroxetine to increase serotonin in the brain, serotonin-induced signaling is increased, as is the expression of the important brain-derived neurotrophic factor (BDNF) . (For more information on BDNF, click here.) Additionally, this research found that paroxetine was helpful when given both before and after the onset of motor symptoms. This finding is important because it may indicate that paroxetine might still have beneficial effects even if it is given later in the course of the disease. SSRIs appear to be safe for long-term use in humans, so starting paroxetine early should not rule out its later use as well.
While these results are hopeful, it is important to remember that the study was conducted on mice made to look like they have HD, not on humans or people with HD themselves. Even if paroxetine is relatively safe for use in human use, it nevertheless may not help neurodegeneration in humans the same way that it is indicated in the mouse study. Overall, the use of paroxetine to treat both the symptoms and progression of HD is a promising idea that needs more investigation.
Recent research has shown that levels of serotonin in the brains of HD mice are lower than normal. A common and effective way to increase the amount of serotonin in the brain is by prescribing a class of drugs known as selective serotonin reuptake inhibitors (SSRIs).
In order to understand how SSRIs increase the amount of serotonin signaling in the brain, we must first understand how neurotransmitters like serotonin work. Neurotransmitters are important molecules in the brain that help nerve cells communicate with each other. A message is passed within a nerve cell electrically, but when it comes to the end of the nerve cell and the message must be passed to another nerve cell, the message must be converted to a chemical signal. This is where neurotransmitters come in: they are the chemicals that carry the message between nerve cells. The space between two nerve cells is called the synapse. The nerve cell that is sending the message is called the presynaptic cell and the nerve cell that is receiving the message is called the postsynaptic cell. When the presynaptic cell gets the signal to pass on the message, it releases the stored neurotransmitters into the synapse. Once in the synapse, the neurotransmitters can be taken up by receptors on the postsynaptic cell, and the message begins to be passed through the new cell. In order to prevent too much signaling, the neurotransmitter cannot stay in the synapse for too long. The presynaptic cell begins to take back the neurotransmitter, storing it for the next time that a message needs to be passed across the synapse. This recycling of neurotransmitter is called “reuptake.” (For more information on the neurobiology of HD, click here.)
When the nerve cells of the brain produce less serotonin, there is decreased serotonin signaling. Serotonin signaling is decreased simply because there are not enough serotonin molecules to interact with the receptors on the cells. Instead of figuring out how to make more serotonin, the amount of serotonin signaling can be increased by preventing the reuptake of the neurotransmitter back into the presynaptic cell. By allowing the serotonin more time in the synapse, there is a better chance that the proper amount of interactions will occur with the postsynaptic cell to pass on the message. This mechanism is where SSRIs come in: they block parts of the presynaptic cell so that less serotonin can be recycled, allowing it to spend more time in the synapse to pass on the signal.More