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RNAi For Depression: siRNA Targets SERT & 5-HT1A for Antidepressant Effect

It seems as though society is on the verge of ushering in a new generation of treatment modalities for depression and other psychiatric conditions.  While most people turn to pharmaceutical drugs for major depressive disorder, approximately 1 out of 3 people fail to get sufficient symptomatic relief.  To make matters worse, many end up trying an array of dangerous psychiatric drug cocktails (i.e. playing antidepressant roulette) only to exacerbate the severity of their current condition.

There are a host of problems with psychiatry, one of which is that pharmaceutical drugs are being prescribed that fail to target the underlying cause of depression.  While these drugs are effective in short-term clinical trials, they often stop working over the long-term, forcing an individual to face an onslaught of horrific discontinuation symptoms or increase their dosage (and deal with more side effects).  It’s almost as if people with depression (and other mental illnesses) are stuck between a rock and  a hard place.

Fortunately science has continued to progress and come up with new potential ways to target debilitating conditions such as depression.  A technique discovered in 1998 called RNAi or “RNA interference” is being tested in animal trials to determine whether silencing certain genes could ameliorate the severity of a person’s depression.

A Brief History of RNAi

In 1998, RNAi was demonstrated in a nematode (C. elegans) by Andrew Fire and Craig Mello. For the discovery, both were awarded the Nobel Prize in Physiology or Medicine in 2006.  After its introduction in 1998, RNAi caught the attention of Thomas Tuschl et al. at the Max Planck Institute (Germany), and they were the first to demonstrate its efficacy of silencing cells within mammals in 2001.

The silencing of mammalian cells lead many scientists to investigate RNAi techniques to inhibit expression of specific genes.  Initially, the RNAi research was applied to animal models and human cell lines.  At this point, the emergence of RNAi and its potential in the medical field quickly captured the attention of pharmaceutical companies.

By around 2005, pharmaceutical companies were pouring billions of dollars into investigational RNAi therapeutics.  This made a lot of sense because there are still countless medical conditions caused by maladaptive genetic activation without any feasible treatments.  Despite the extensive financing to the tune of billions for RNAi interventions, most early trials provoked adverse reactions and had no substantial efficacy.

Another major problem with RNAi therapeutics was that they triggered significant immune reactions.  Following early trials, many pharmaceutical companies lost hope in RNAi therapeutics and shut down their RNAi research programs, translating to significant financial losses.  However, within the past couple years, there is a resurging interest in RNAi as a result of improved modalities of delivery and targeting.

It appears as though there are various RNAi therapies in the FDA pipeline.  While it took about a decade for refinements to improve the efficacy and safety of RNAi, it appears as though the future will only look brighter.  As delivery methods and efficacy continues to improve, we may be able to expect an RNAi intervention for the treatment of a psychiatric condition (e.g. depression) within the next 20 years.

How RNAi For Depression Works (Mechanisms of Action)

Below is a synopsis of how RNAi could be effectively utilized for the treatment of various psychiatric conditions, including major depression.  The mechanisms of the example listed below specifically involve targeting the serotonergic receptor 5-HT1A, but the SERT (serotonin transporter) has also emerged as a viable target.  Understand that these specific targets may not be ideal for everyone, but have shown preclinical promise for alleviation of depression in animals.

Intro:  RNAi could be used for depression by targeting specific receptors involved in neurotransmission.  One target that has already shown some promise is the 5-HT1A autoreceptor.  This serotonergic receptor (a protein) is positioned upon the surface of serotonergic neurons with a job of binding to serotonin neurotransmitters.  When the 5-HT1A receptor binds to serotonin, it alters neurotransmission possibly by triggering the serotonergic neuron to fire at a faster or slower rate.

Targeting (5-HT1A):  The 5-HT1A autoreceptor is present throughout various regions of the brain and aids in communication of serotonergic neurons.  As a 5-HT1A autoreceptor, it is only responsive to the neurotransmitters and hormones released from the neurons upon which it sits.  A region of the brain called the “dorsal raphe” is known for manufacturing a significant amount of serotonin within the brain.

Serotonin production:  When serotonin is produced, 5-HT1A receptors bind to the serotonin and signal to the dorsal raphe when a sufficient amount has been produced.  When the 5-HT1A receptor signals that it has received adequate serotonin, the dorsal raphe reduces serotonin production.  This is an important process in the brains of most individuals, but among those taking serotonergic antidepressants, this mechanism actually decreases the speed of response to treatment.

Desensitization:  A greater quantity of serotonin lingers from the antidepressants, but the dorsal raphe releases significantly less endogenous serotonin in response.  It takes 4 to 8 weeks for the 5-HT1A receptors to become desensitized to the excess extracellular serotonin.  Upon desensitization, signaling to the dorsal raphe normalizes, and dorsal raphe serotonin production reverts back to pre-drug baseline.

RNAi (siRNA):  It is at this point when many people notice that their antidepressant medication is successfully alleviating their depressive symptoms.  While there are many drugs that modulate the 5-HT1A receptor, many of these drugs elicit a cascade of other effects across receptors and neurotransmitters.  In attempt to determine whether antidepressant responses could be expedited, researchers used a form of RNAi called “siRNA” (small interfering RNA) to immediately desensitize the 5-HT1A autoreceptor in the dorsal raphe region of the brain.

Small interfering RNA are considered short sequences of RNA that are able to inhibit the effects of specific genes, including those responsible for the 5-HT1A autoreceptor.  The siRNA can be delivered to a rodent in a viral vector that targets only one region of the rodent brain.  In other words, the effects of siRNA could be isolated to a small region.

Upon insertion of the viral vector with the siRNA, the receptors in the region become “knocked down.”  The viral vector spreads within the area upon which it is inserted and dramatically reduces the targeted (5-HT1A) receptor count.  Since 5-HT1A receptors modulate the release of serotonin via signaling to the dorsal raphe, and the siRNA knocked down the 5-HT1A receptors, there’s ultimately no signaling being sent to the dorsal raphe from these receptors.

Without signaling to the dorsal raphe to alter serotonin production, levels of serotonin remain normal upon administration of a 5-HT1A agonist drug.  On the other hand, among individuals without the RNAi, administration of a 5-HT1A agonist would temporarily decrease serotonin production because the 5-HT1A receptors would be sending signals to the dorsal raphe.

Antidepressant response: The mice with a knockdown of 5-HT1A autoreceptors in the dorsal raphe exhibited significant improvements in mood.  While their level of anxiety didn’t respond to the siRNA intervention, the mice performance on forced swim and tail suspension tests significantly improved.  This suggests that siRNA contributed to a significant antidepressant-like effect.

Moreover, it appeared as though administration of a serotonergic antidepressant bolstered the already-significant mood improvement derived from siRNA.  This enhanced antidepressant efficacy is a direct result of no signaling to the dorsal raphe from the 5-HT1A receptors, thus the serotonin production doesn’t temporarily decrease.

RNAi For Depression (Scientific Research)

Included below is some research investigating RNAi (or siRNA) for the therapeutic alteration of neurotransmission.  It seems as though targeted siRNA holds potential to treat depression, as well as a variety of other conditions.  Most exciting is the thought that mental illness could be treated with specific siRNA techniques that would carry no significant side effects.

2015: Perhaps the most exciting report of RNAi for the treatment of depression was published recently.  Researchers discussed various RNAi strategies to produce antidepressant responses in experimental models, but there were several limitations associated with the technique.  One of the major limitations is the modality of delivery for oligonucleotides (RNA molecules).

Scientists were able to use Zoloft and conjugate it with siRNA (small interfering RNA).  More specifically, the siRNA targeting the SERT (serotonin transporter) was bound to the Zoloft.  Upon insufflation (crossing the nasal cavity), the siRNA was active and transported to serotonergic neurons.

Most exciting is the fact that the responses to the siRNA were more significant than those derived from nearly a full month’s treatment of Prozac.  Assessments revealed that siRNA decreased 5-HT1A autoreceptors and enhanced neurotransmission of serotonin within the forebrain.  In addition, it increased plasticity of the hippocampus.  As expected, the short-term administration of siRNA targeting SERT attenuated depressive symptoms (and behaviors) in depressed mice.

Authors highlight the feasibility of siRNA for the treatment of depression via selective targeting of neurons.  The inhibition of the SERT protein via siRNA essentially reduced the number of transporters to “clean up” extra serotonin.  This means there was greater serotonin to be used for antidepressant processes.  The novelty of intranasal administration of siRNA could make its way to humans should researchers continue down this path.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26100539

2015: A study published in 2015 highlighted the fact that the hormone oxytocin influences social cognition and behaviors.  Several important behaviors modulated by oxytocin include: bonding, maternal nurturing, and bonding.  Researchers discussed that density of oxytocin receptors within the nucleus accumbens alters alloparental behavior.

Artificially increasing expression of oxytocin receptors within the nucleus accumbens increases alloparental behaviors and bonding in prairie voles.  Administration of an oxytocin receptor antagonist (which renders these receptors useless) decreases alloparental behavior.  To get a better understanding of the effects of oxytocin on social bonding behaviors, researchers used RNAi.

The RNAi allowed them to specifically knockdown oxytocin receptors within the nucleus accumbens of prairie voles.  The procedure involved insertion of a viral vector with shRNA (short hairpin RNA) targeting the oxytocin receptor within the nucleus accumbens.  The RNAi technique resulted in significantly reduced alloparental behavior.

While this study wasn’t related to depression, it demonstrates the effects of RNAi on psychological and behavioral functions within prairie voles.  It is clear that RNAi could be used to target a variety of behavioral and psychiatric conditions in the future.  Furthermore, it may help researchers understand how neurotransmission within specific regions influences behavior.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25874849

2014: A report published in 2014 entitled “Novel Treatment Strategies for Depression” discussed the therapeutic potential of ketamine for depression as well as RNAi.  Researchers noted that current treatments for depression involve targeting the reuptake of serotonin and/or norepinephrine with drugs like SSRIs and SNRIs.  The problematic nature of the aforementioned medications is evident when considering the fact that most people end up requiring antidepressant augmentation strategies for symptomatic relief.

A variety of potentially novel interventions were reported including deep brain stimulation (of the ventral anterior cingulate cortex) and ketamine (and other new NMDA receptor modulators).  They also mentioned the potential of various molecular strategies such as RNAi, which regulates the expression of specific genes to improve mood.  The report highlighted the fact that RNAi has already been used with success to promote antidepressant effects in laboratory animals.

Specifically, the RNAi modalities for depression tend to target the SERT (serotonin transporter) as well as the 5-HT1A receptor.  In other words, by inhibiting SERT or 5-HT1A, researchers have noted antidepressant effects in mice.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24180396

2013:  A study published in 2013 sought to determine how intranasal administration of siRNA (small interference RNA) molecules could affect mood in mice.  Researchers specifically targeted the 5-HT1A receptor in adult mice within the dorsal raphe nucleus of the brain.  The mice were then assessed with microdialysis and behavioral tests.

Results indicated that siRNA targeting the 5-HT1A receptor resulted in less immobility in tail suspension and forced swim tests.  There appeared to be greater levels of serotonin released within the prefrontal region during the tests.  Furthermore, the siRNA was able to enhance extracellular levels of serotonin following administration of Prozac.

It was concluded that suppressing 5-HT1A autoreceptors leads to significant mood improvement.  This is thought to be a result of an increase in the number of serotonergic neurons to release serotonin when faced with stress.  This evidence bolsters previous findings that document similar outcomes.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22820867

2013: Many antidepressants inhibit the serotonin transporter (SERT) to elicit a therapeutic antidepressant effect.  Most of these drugs aren’t very effective and it takes awhile (i.e. several weeks) before people notice a mood improvement.  Researchers published a study in 2013 highlighting the reduction of SERT via administration of siRNA (small interfering RNA).

Treatment with siRNA altered functioning within the mouse brain and prompted increases in BDNF levels (signifying enhanced plasticity), increased forebrain serotonin, and reduction of 5-HT1A autoreceptors.  Furthermore, it triggered neurogenesis (growth of new brain cells) within the hippocampus.  Upon comparison of the siRNA intervention to administration of Prozac, antidepressant efficacy with siRNA was established rapidly – whereas that associated with Prozac was not.

Authors documented that the siRNA to reduce SERT was an effective standalone antidepressant.  They note that the two prime targets for siRNA in depression remain: SERT and 5-HT1A.  It could be considered that a multifaceted siRNA approach targeting both SERT and 5-HT1A may be employed in the future.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23321808

2005: A study published in 2005 investigated the potential of downregulating SERT (serotonin transporters) for the treatment of depression.  Serotonergic antidepressants such as SSRIs increase levels of serotonin via inhibition of the serotonin transporter.  They are able to substantially increase serotonin levels over the short-term, but the brain eventually adapts to these increases, resulting in tolerance and decreased efficacy.

Perhaps you’ve noticed that antidepressants stop working after awhile, forcing you to either increase the dosage or opt for withdrawal to decrease your tolerance.  This is a major problem associated with administration of any pharmaceutical drug.  In this study, researchers proposed that downregulation of serotonin was responsible for the therapeutic efficacy of SSRI drugs.

To investigate this, they took adult mice and downregulated the serotonin transporter (SERT) via siRNA infusions within raphe nuclei.  As a result of the siRNA infusions, serotonin transporter (SERT) binding sites significantly decreased.  Similar decreases in SERT binding sites were also noted following administration of Celexa (an SSRI) for 2 weeks.

This suggests that despite different mechanisms, both the siRNA and the pharmaceutical drug lead to the same decreases in SERT (serotonin transporters).  Moreover, the respective antidepressant effects of each modality were similar as evidenced by forced swim tests.  Results suggest that SSRIs may combat depression by downregulating SERT.

However, it should be noted that siRNA proved to be a viable antidepressant in adult mice.  Further refinement of siRNA methods in adult mice should be investigated for the treatment of depression.  Perhaps within the not-so-distant future, RNAi techniques can be investigated in humans with depression to attain similar outcomes associated with SSRIs without side effects.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15940298

Note: Albert Ferrés-Coy, a PhD neuroscientist from the University of Barcelona (Spain) seems to be pioneering the usage of RNAi for the treatment of depression.  He’s been involved in all major studies and seems to be one step ahead of the pack.  It is hoped that more neuroscientists begin investigating the therapeutic potential of RNAi for various neurological conditions.

RNAi For Depression in Humans (Potential Advantages)

There are several major therapeutic advantages associated with using RNAi in humans for the treatment of depression.  Most preclinical research suggests that it would significantly amplify the efficacy of certain antidepressants.  In addition, RNAi modalities may work well as standalone antidepressants with minimal side effects.

  • Adjunct: Research conducted in rodents suggests that RNAi as an adjunct to serotonergic antidepressants produces a synergistic antidepressant effect with the medication. In other words, those who don’t achieve sufficient symptomatic reduction with a medication may find that by adding RNAi to the equation, depression ends up in remission.  Many speculate that RNAi will be a viable antidepressant adjunct option in forthcoming decades.
  • Antidepressant efficacy: Even among those who find antidepressants effective for reducing depression, using RNAi could enhance the efficacy. In other words, someone who experiences a little mood boost from a drug may find that adding RNAi to the mix results in a doubling or tripling of the mood improvement.  While the efficacy of RNAi isn’t well understood as an antidepressant, it may prove highly effective.
  • Comorbid conditions: It is important to consider that RNAi may not only be effective for depression, but numerous other comorbid psychiatric conditions. While the research targeting 5-HT1A knockdown via siRNA wasn’t effective for anxiety, who’s to say that a new target wouldn’t be?  It should be considered that RNAi may be used to target multiple conditions simultaneously.
  • Faster acting: Many people complain of the fact that antidepressants take a long time to work, sometimes up to 8 weeks. Those seeking treatment often aren’t able to wallow in their depressive symptoms for 8 weeks, patiently waiting with fingers crossed, hoping that their drug will work.  While companies like GeneSight are attempting to predict who will respond best to certain antidepressants, it would help if responses could be determined immediately.  RNAi could theoretically speed up antidepressant efficacy, allowing psychiatrists to determine efficacy of a drug within just one or two days (rather than weeks).  Further, it could be used as a fast-acting standalone treatment to improve mood to a greater extent than antidepressants.
  • Longer-lasting efficacy: Most people taking pharmaceuticals for depression find that antidepressants lose efficacy after awhile. Taking them for several years at the same dosage leads to tolerance, ultimately forcing a person to either increase the dosage or face a debilitating withdrawal.  RNAi holds potential to prevent tolerance as a result of mechanisms on certain receptors.  Moreover, the effects of RNAi usually last 5 to 7 days – meaning you wouldn’t need to take a drug every day.
  • Lower doses: In addition, since RNAi can function as a standalone antidepressant, increase efficacy of medications, and prevent tolerance – many people could get away with taking much smaller, minimal effective doses to reap benefits. In other words, as a result of RNAi, they’d have less side effects because they’d be taking lower doses, and would be getting something closer to a “biological free lunch” compared to the effects associated with standalone pharmaceuticals.
  • Personalized medicine: As medicine becomes more personalized, researchers will attain the ability to assess brains on an individual basis. They’ll be able to use the latest in biomarker tracking and/or neuroimaging to determine whether you have abnormalities with certain genes and/or neurotransmission.  Then they’ll be able to use RNAi to target the specific neural underpinnings of your depression (rather than assuming everyone’s depression is associated with the same neurochemistry).
  • Specific targeting: Another prominent advantage of RNAi is that it can be used to target specific regions within the brain. Researchers have already demonstrated the ability to infuse viral vectors within highly specific regions of rodent brains.  Eventually they’ll be able to complete this same process within humans.  In addition to honing in on specific regions, they’ll be able to selectively target certain receptors (e.g. 5-HT1A).  RNAi provides significantly better targeting than small drug molecules and is able to alter proteins that cannot be affected due to specific positioning within cells.
  • Standalone treatment: There is preliminary evidence suggesting that using RNAi may alleviate depressive symptoms as a standalone option. It appeared as though knockdown of 5-HT1A within the dorsal raphe of mice resulted in antidepressant effects akin to administration of the antidepressant drug Celexa.  This suggests that RNAi as a standalone could be equally effective as currently available antidepressants.
  • Withdrawal severity reduction: Using RNAi may prove to offset many of the withdrawal symptoms associated with antidepressants. Assuming researchers can determine what occurs within the brain during cessation of antidepressants (e.g. SSRIs) over a long-term, using RNAi may ameliorate the discontinuation symptoms.  Moreover, it may act as an alternative to pharmaceuticals so that withdrawal symptoms never occur in the future.

Further RNAi research for depression is warranted

While RNAi seems to be a promising intervention for a variety of medical conditions (including depression), much more research is necessary before human trials will ensue.  Specifically, researchers need to focus on maximizing safety of administering the RNAi (via a viral vector).  In addition, they will need to determine specific therapeutic targets based on previous science.

  • Animal studies: As of now there aren’t many animal studies that have investigated RNAi for the treatment of depression. Many more studies on mice and rats will be warranted before these techniques can be considered for humans.  These studies should attempt to establish specific targets for RNAi for various conditions (possibly based on specific genes).
  • Delivery of siRNA: It is important to consider the delivery of siRNA. As of now, researchers have been able to infuse mice with viral vectors in specific parts of the brain, which proved effective.  In addition, they’ve been able to engineer an intranasal form of Zoloft conjugated with siRNA to downregulate specific receptors (e.g. 5-HT1A).  Maximizing the safety of siRNA delivery is vital before human trials can be conducted.
  • Duration of effect: Generally, gene silencing resulting from siRNA can be assessed as early as 24 hours post transfection. The effect most often will last from 5-7 days. However, duration and level of knockdown are dependent on cell type and concentration of siRNA. Transfections may be repeated to maintain knockdown.
  • Preclinical human research: A major limitation of RNAi research is that no human trials have been conducted for the treatment of various mental illnesses such as major depression. As the technique is further refined and improved upon, expect preclinical human trials in the works.  RNAi has already been in trials for a variety of other medical conditions, so perhaps successful delivery methods could be used as models.
  • Specific targets: While all the buzz is about the 5-HT1A receptor and SERT (serotonin transporter) in rodent research, many other targets warrant consideration. In addition, researchers should attempt to isolate specific regions of the brain that are worth targeting compared to others.  Since the effects of RNAi are thought to last approximately 5 to 7 days, targets could be changed in rodents and effects easily observed.

Do you think RNAi will ever be used to treat depression?

Some would argue that it’s not a matter of “if” RNAi will ever be used to treat depression, but “when.”  I’m not so sure if I agree with those sentiments simply because there are a variety of other promising technologies in store for the treatment of mental illness.  Certainly RNAi seems like a relatively logical development from the perspective of pharmaceutical companies, especially considering the fact that delivery methods are getting safer and efficacy of various methods have been deemed significant in preclinical research.

Assuming RNAi was safe without any long-term effects, nearly everyone with major depression (or other mental illnesses) would be jumping at the chance to use it for symptom management.  The feasibility of the technique needs to be considered though, as well as its cost.  If it’s considered super expensive and a person requires treatment once per week – there are likely going to be some “haves” and “have nots” in the realm of psychiatric treatment.

Feel free to leave a comment mentioning whether you think RNAi holds promise for the treatment of various psychiatric conditions (e.g. depression), and how you think it could be used in the future.

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