Serotonin reuptake inhibitor drugs (SSRIs) treat depression and many other symptoms in Huntington's. While these actions are very important, SSRI drugs do much more. Studies show that they are neuroprotective, or able to limit HD damage to the brain. Studies also show that they promote neurogenesis or the development of new brain cells in mouse models. With all of these benefits for symptoms and neuroprotection, Dr. Goodman wonders why these drugs are underused in HD.
Serotonin and HD: Why do HD patients get psychiatric symptoms? Of course part of the reason is reactional, we're depressed and anxious because we feel sadness and fear. But the most significant reason for psychiatric symptoms is the disease itself. The HD mutation directly causes disruption of nerve circuits in parts of the brain that control emotions. The serotonin system is one of the most important systems for maintaining emotional and nerve cell health.
Serotonin and SSRIs: There are more known receptors in the brain for serotonin than any other neurotransmitter, which suggests that its action is complex and important. It is known to regulate emotions, motor activity, cognition, sleep, and cell survival. The HD mutation decreases the number and activity of serotonin receptors. SSRI drugs work by increasing serotonin levels at critical areas between brain cells. Major downstream results of this action are increases in BDNF levels, and stimulation of neurogenesis, the development of new nerve cells.
A recent review discusses other stimuli that can increase or decrease BDNF and neurogenesis [Grote HE 2007]. The positive stimuli include SSRI drugs, environmental stimulation of many sorts [Lazic SE 2006], exercise, and calorie restriction. Important to remember is that stress does the opposite. It inhibits BDNF and decreases neurogenesis to below normal levels.
HD Neurogenesis and SSRI's: Increasingly, scientists believe that SSRI drugs work in HD and other diseases by stimulating neurogenesis. Researchers from Europe and Australia have shown that fluoxetine (Prozac®), an SSRI drug, increases BDNF levels, improves cognition, and greatly enhances neurogenesis in a mouse model [Grote HE 2005]. Neurogenesis activity returned to near normal levels.
Comments: SSRIs do great things for HD; So why don't we all use them? It may be because of the linked antidepressant name. The name pushes away those who think of depression as a weakness to overcome, not a disease that can be treated. Or, much more likely it is because the name suggests that SSRIs are only helpful for depression.
If we can't change the name of SSRIs, we can change our thinking about them. They are not just antidepressants. They are first-line treatments for most of the symptoms in HD including anxiety, irritability, and depression. They help to restore healthy sleep patterns, and they improve cognition. Their use can often decrease the need for antipsychotic medications.
And importantly, they aren't just for symptoms anymore. They are neuroprotective. They promote repair of damaged nerve connections, and they stimulate the development of new nerve cells. And better yet, we can use them now. While stem cell or genomic therapies may be better options sometime in the future, we don't have to wait for SSRI neurogenesis therapy.
Grote HE, Hannan AJ. Regulators of adult neurogenesis in the healthy and diseased brain. Clin Exp Pharmacol Physiol. 2007 May-Jun;34(5-6):533-45. PubMed abstract
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. PubMed abstract