Depression and cognitive deficits are common health issues that impact millions of people.
Scientists are testing a new drug, NSI-189, to see if it can help treat depression and improve thinking ability.
Early research shows promise that NSI-189 may be able to grow new brain cells and connections, which could potentially treat depression and boost cognition.
Key facts about NSI-189:
- It is an experimental drug not yet approved for medical use
- Appears to stimulate growth of new neurons and connections in the hippocampus, a part of the brain important for memory and emotions
- Shown to reduce depressive symptoms in an early small clinical trial in people with major depression
- Improved cognitive function related to memory, attention and thinking speed in the depression trial
- Well tolerated with minimal side effects in studies so far
How NSI-189 Works in the Brain (Mechanism of action)
NSI-189 is able to grow new neurons and neural connections by stimulating neurogenesis.
Neurogenesis is the process where stem cells in the brain divide and mature into fully functional neurons.
This takes place predominantly in two regions – the hippocampus and the subventricular zone.
The hippocampus plays key roles in forming memories and regulating mood.
Research shows NSI-189 seems to specifically stimulate neurogenesis in the dentate gyrus region of the hippocampus. It’s not yet exactly clear how NSI-189 works at the molecular level.
However, it does not interact with common neurotransmitters like serotonin that are targeted by existing antidepressants.
This means it may represent an entirely novel therapeutic mechanism.
Animal Research with NSI-189
Before testing in humans, NSI-189 was studied in mice and rats.
Rodents were given a single daily oral dose of the drug for timeframes ranging from 1 week up to 6 months.
Scientists examined the effects on various aspects like nerve cell growth, signaling, inflammation, and behaviors like learning and memory.
Findings from the animal studies:
- Increased new nerve cell growth in the hippocampus
- Improved electrical signaling and connection strength between neurons
- Reversed learning and memory deficits caused by brain injury or neurodegeneration
- Reduced nerve inflammation and damage in diabetic mice
- Increased levels of brain-derived neurotrophic factor (BDNF), which supports neuronal growth
The results suggest NSI-189 not only stimulates growth of new neurons, but also strengthens synaptic signaling between existing ones.
This may explain its cognitive enhancing effects seen in the animals.
The studies also hint at potential for treating diverse neurological conditions like stroke, Alzheimer’s disease and diabetic neuropathy.
Early Clinical Research on NSI-189
A small phase 1b clinical trial by Fava et al. studied NSI-189 in 24 adults with major depressive disorder.
This was a short 4 week study primarily looking at safety, with some initial efficacy outcomes.
Participants were given an oral dose of 40mg NSI-189 once daily, twice daily or three times daily.
For comparison, a control group was given placebo capsules.
Some key findings:
- All doses were well tolerated with no serious side effects
- Depressive symptoms improved significantly more with NSI-189 compared to placebo
- Cognitive function related to memory, concentration and processing speed was enhanced
Brain imaging and EEG scans revealed some additional interesting effects:
- Increased alpha brain wave activity in left temporal and parietal lobes with NSI-189
- Trend toward increased volume in left hippocampus, but not statistically significant
While promising, conclusions are limited due to the very small sample over a short trial length. Nonetheless, the results suggest antidepressant and pro-cognitive effects that warrant further research in larger randomized controlled studies.
Potential Benefits of NSI-189
Current antidepressant medications have limited effectiveness, with high rates of non-response and relapse.
They also take 4-6 weeks to kick in, leaving patients struggling with symptoms during that timeframe.
Cognitive problems like forgetfulness, lack of focus and mental fog are another poorly addressed symptom cluster.
Thus, there is a huge unmet need for novel, rapidly acting antidepressants and cognition enhancers.
NSI-189’s ability to stimulate new neuron growth sets it apart from conventional antidepressants that only modulate neurotransmitters like serotonin.
Growing new brain cells and connections may help reverse underlying disease processes leading to improved long-term outcomes.
The cognitive benefits demonstrated already also indicate potential to directly treat cognitive dysfunction, whether as a standalone condition or co-occurring with mood disorders.
This could be a breakthrough for individuals whose daily lives and workplace productivity are significantly impacted by impaired memory, attention and thinking speed.
Next Steps for NSI-189 Research
If future research continues yielding positive results, NSI-189 may become approved as prescription medication. However, this is likely still years away.
Next stages will involve larger, longer term clinical trials assessing efficacy and safety in people with major depressive disorder.
Testing is also needed in patients with other conditions like bipolar depression, cognitive impairment in schizophrenia, Alzheimer’s disease, and more.
Scientists still have much to uncover about NSI-189 before it can be deemed safe and effective for medical use.
- Exactly how does it stimulate neurogenesis at the molecular level?
- Does it alter dendritic spine density and morphology?
- What are the effects on inflammatory pathways and mitochondrial function?
Ongoing preclinical studies aim to address these knowledge gaps.
For now, NSI-189 remains an extremely promising investigational drug.
The neurogenic effects and preliminary antidepressant and pro-cognitive data make it an exciting potential treatment approach for a number of psychiatric and neurological conditions.
Larger clinical trials will shed more light on whether NSI-189 lives up to its early potential as a multi-domain brain health enhancing agent.
References
- Study: The neurogenic compound NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects
- Authors: Roger S McIntyre et al. (2017)
