Individuals diagnosed with major depression often are found to have reduced volume within their hippocampus. The hippocampus is a small region of the brain that is responsible for regulating various memory and spatial navigation functions. It is also believed to play a pivotal role in the regulation of mood. Modern day antidepressants such as SSRIs tend to improve functioning within the hippocampus and are capable of prompting a process called “neurogenesis,” allowing for the growth of new brain cells.
A biotech company named Neuralstem is taking a different approach towards developing a new antidepressant. Their goal is to develop a medication that actually stimulates growth of various regions within the brain. They are attempting to essentially treat depression, and potentially a variety of other conditions (e.g. Alzheimer’s disease) with a experimental drug called “NSI-189.”
Unlike traditional antidepressants, NSI-189 doesn’t function by solely altering neurotransmitter levels. Rather, it attempts to increase hippocampus volume, neurons, and change neurotransmitter functions. The company’s CEO believes that depression is largely influenced by hippocampal size and by increasing its overall volume, many cases can be reversed or cured.
What is NSI-189?
NSI-189 is an experimental medication that is currently being investigated for the treatment of major depression. It is being developed by a company called Neuralstem, Inc. and is funded by DARPA (Defense Advanced Research Projects Agency) and the NIH (National Institute of Health). Based on the fact that DARPA is invested in this particular drug, it is thought to be relatively promising for the treatment of a variety of conditions including: depression, Alzheimer’s disease, PTSD, and age-related cognitive decline.
How does NSI-189 work?
From a pharmacological standpoint, administration of NSI-189 tends to stimulate neurogenesis (growth of new brain cells) and increase overall volume in the hippocampus. It is thought that this drug may result in improvements in both short and long-term memory functions as well as with spatial navigation. It is believed that targeting the hippocampus is how the drug helps regulate mood and elicit an antidepressant response.
The goal of Neuralstem is to essentially treat what they consider to be three major aspects of depression including:
- Hippocampal volume: The primary target of this drug appears to be increasing volume within the hippocampus. It is thought that by increasing the size of the hippocampus as well as the density of healthy neurons, this will improve mood and cognition.
- Neurogenesis: The developers have suggested that this drug will improve the functionality of neurons. It will obviously help grow new brain cells and repair damaged regions. Based on preliminary statements from Neuralstem, it could be speculated that neuronal functioning will improve.
- Neurotransmission: The developers have not yet indicated how the drug will affect neurotransmitter levels. They do state that it does affect neurotransmitters, but the particular ones that it affects are currently undocumented.
Potential benefits of NSI-189…
There are a few potential benefits of this experimental drug including: antidepressant effects, potential to “cure” certain conditions, its mechanism of action, and the fact that it increases brain volume in certain regions of the brain with a targeted approach.
- Brain volume increase: It has the potential to increase overall brain volume in areas that have shrunken as a result of disease or stress. This is significantly different from other current-market medications that attempt to solely address neurotransmitter levels. Increasing the brain volume would allow patients to actually see size differences on an MRI. A direct quote from the CEO: “If we can show by MRI that we’ve increased hippocampus volume and at the same time reversed depression symptoms for six months after patients have stopped taking the drug, then we’ll have a cure.” Ironically, using an MRI has been one of my suggestions to improve psychiatric treatment outcomes.
- “Cure” potential: Dr. Karl Johe (CEO of Neuralstem) has implied that this drug may have the potential to “cure” people with conditions related to reduced hippocampal volume. In other words, taking the drug will elicit neurogenesis and initiate growth of certain regions within the brain. When a person stops taking the drug, these regions will have already grown to healthier sizes and functions will be maintained.
- Hippocampus-targeted: This particular drug appears to target the hippocampus, suggesting that it will improve memory-related functions. It may also help improve performance at tasks that require a high level of spatial navigation. The primary reason for targeting the hippocampus is due to the fact that a major contributor to certain conditions is a shrunken or undersized hippocampus.
- Improves brain functioning: The drug may prove to enhance or improve overall brain functioning including mental speed, dexterity, and performance, particularly in the hippocampus. This could result in improved ability to retrieve memories (both short and long-term).
- Mechanism of action: At this time NSI-189’s mechanism of action remains a mystery. As clinical trials progress, more data will surface discussing how the drug elicits its neurogenesis, growth-oriented response upon the hippocampal region of the brain.
- Neuroprotective / Nootropic potential: Some would surmise that it may carry neuroprotective and/or nootropic properties. It seems relatively obvious that if it works to increase hippocampal volume and functionality, it will improve memory and cognitive functions. It may also help prevent age-related cognitive decline and/or development of neurodegenerative disorders.
- Neurotransmitter adjustments: Based on preliminary statements from the developers, it is thought that this drug will affect levels of various neurotransmitters. It may affect the speed and/or processing of neurotransmission as well as various receptors. As of now, the mechanism by which it accomplishes this is unknown.
Neuralstem’s Theory: Reduced Hippocampal Volume Contributes to Depression
Among rodents and animals, smaller than average size of the hippocampus has been shown to be a cause of depression. In humans, this is somewhat of an unverified theory, but researchers do know that if NSI-189 is capable of instating growth of the hippocampus, and depression significantly improves, the theory will gain more credibility. Creators of this drug first tested it thoroughly in the lab to determine how well it worked.
They utilized neural stem cells and began administering various compounds that they thought may contribute to growth. Many of these substances had promise, but the company couldn’t afford to invest in all seven as it would’ve been too costly. So they chose one substance of the seven (NSI-189) which they believed would have the best chance of working in humans.
Prior to initiating clinical trials, the substance was tested in mice. Results indicated that the mice had significantly increased the size of their hippocampi following administration. A small sample size of human participants were recruited to try this drug and no major adverse effects were observed. Following this, the FDA granted Neuralstem approval to test their drug in those who suffer from major depression.
NSI-189 Clinical Trials / Research
At the moment, research is too early to determine whether this substance guaranteed to be a safe, effective treatment for major depression. It has completed Phase I clinical trials in 2011 with a sample size of 41 people, and Phase I(B) clinical trials that finished in 2014 with a sample size of 24 people. Therefore at the moment, the drug has only been tested on a sum total of 65 individuals which should be considered a very small sample size.
Based on results from the trials though, participants’ depression improved when administered 40 mg to 80 mg per day of NSI-189. Higher dosages were tested , but no noticeable improvements were noted at doses exceeding 120 mg per day. Therefore one can assume that Neuralstem and other cohorts are trying to determine the ideal dosages to administer moving forward.
The interesting aspect of the NSI-189 drug is that it is unlikely to be limited solely to treating depression. Neuralstem plans to initiate additional clinical trials of the drug to determine whether it effectively helps individuals with traumatic brain injuries, neurodegenerative disorders, PTSD, stroke, and age-related cognitive decline. Due to small sample sizes and insufficient evidence, bold claims cannot yet be made regarding using this drug for the treatment of any condition.
The first Phase of the clinical trials was conducted primarily to evaluate the drug’s safety and calibrate the dosing. Sometime in 2015 the company should be able to advance to Phase II of the trials, assuming no adverse reactions. If results indicate that the drug is helpful and that it is safe in larger populations, the FDA may eventually grant “fast track” status to the developers, allowing for quicker approval.
Final thoughts on NSI-189 as an antidepressant
It is impressive that Neuralstem (cool name by the way) is attempting to get creative and come up with a treatment that differs from modern day antidepressants. The drug seems to work solely by affecting growth in the hippocampal region of the brain. It is however unclear as to whether this “growth” is targeted to this particular region and whether taking the drug could potentially trigger unwanted growth (e.g. a tumor).
From an objective standpoint, it could be hypothesized that the drug will have major potential to help repair broken structures within the brain. However, other data including adverse effects, side effects, and average efficacy are unavailable to the public. This drug will certainly be a project to monitor in forthcoming years as biotechnology and pharmaceutical developments continue to progress.
On the surface, this treatment seems to be unique. We just don’t know whether it is affecting various neurotransmitters and creating neurochemical changes in addition to the growth that it is inducing. It should also be noted that its ability to “grow new brain cells” sounds exciting, but really shouldn’t be considering the fact that SSRIs are capable of the exact same feat. Feel free to share your thoughts on NSI-189 in the comments section below.