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Spadin (Peptide) For Depression: A TREK-1 Inhibitor Antidepressant

Depression is a growing epidemic that affects the lives of nearly 15 million Americans.  The number of individuals diagnosed with depression will continue to grow as a result of population growth, poor diet, environmental toxins, genetic polymorphisms, and other unique neurophysiological factors.  As a result of depression, it is estimated that nearly 1 out of 10 Americans are taking pharmaceutical antidepressant drugs.

Reports suggest that 2 of 3 individuals taking antidepressant drugs actually derive significant therapeutic benefit from the medications.  However, the remaining 33% of individuals find current-market antidepressant options to be ineffective and/or worsen their depressive symptoms.  In addition, many people have noted that antidepressants cause weight gain, sexual dysfunction, and an array of other detrimental side effects.

As a result of suboptimal efficacy, debilitating side effects, and long-term risks – many individuals with depression avoid medications.  Development of new antidepressants is painstakingly slow, often leaving those with “refractory” depression without any relief.  Most developments of new antidepressants in 2014 were nothing more than “safe” permutations of older serotonergic (SSRI) and noradrenergic (SNRI) drugs.

Hypothesized newer classes of drugs include the (likely problematic) SNDRIs, the NMDA receptor modulators, and potentially safer peptidic antidepressant compounds.  One such peptide that has shown preclinical promise is referred to as “Spadin.”  Spadin has potential to serve as a model for the creation of a new class of antidepressants that are highly effective and fast-acting – with no significant side effects.

Spadin for Depression: Natural Peptidic Antidepressant (TREK-1 Antagonist)

As of 2010, researchers discovered a natural peptide called “Spadin” comprised of 17 amino acids with potent, fast-acting antidepressant properties.  Spadin is derived from the maturation of NTSR3 (neurotensin receptor 3), also known as “Sortilin.”  Sortilin is expressed in the brain, spinal cord, and muscles – and is considered a member of the “Vps10p-domain receptors.”

It is also expressed during embryogenesis in regions influenced by nerve growth factor.  Preclinical trials indicate that Spadin provides robust antidepressant efficacy within 4 days of administration.  Moreover, it appears as though administration of Spadin produces no significant adverse effects and/or side effects.

The substance elicits its effect primarily by acting as a TREK-1 potassium channel antagonist.  Meaning, it inhibits the activation of this channel, and ultimately contributes to an antidepressant effect.  Mice with knockout TREK-1 channels have been noted as being immune (or resistant) to developing depression, and among non-knockout mice, administration of Spadin elicits the same effect as a result of its antagonist effect.

While it is unclear as to whether these effects are the same in humans, targeting the TREK-1 channel similarly to Spadin may be a prime therapeutic target for engineering new antidepressants that are fast-acting with minimal side effects.  Most impressive is the fact that Spadin is considered the first natural antidepressant peptide to be scientifically identified.  Researchers have been developing Spadin-analogues that offer greater potency and a longer duration of effect than Spadin.

One study analyzed the effects of 12 Spadin-analogues to determine which offered greater benefit than Spadin.  Should these analogues prove scientifically effective in reducing depression with minimal side effects, it is estimated that one could get fast-tracked by the FDA as an antidepressant.  Thus far, it is unknown as to whether any pharmaceutical companies are considering Spadin-analogues as antidepressants.

How Spadin Works: TREK-1 Inhibitor (Mechanism of Action)

Spadin is considered a novel antidepressant peptide, and lacks sufficient research to clearly elucidate its specific mechanism of action in humans.  Thus far, most research regarding the peptide’s mechanism is derived from studies conducted in mice.  Spadin elicits a variety of effects including, acting as a TREK-1 inhibitor, altering neuronal membrane potential and signaling pathways, inducing synaptogenesis, and increasing BDNF.

  • TREK-1 antagonist: A study published in 2015 determined that Spadin functions by inhibiting the TWIK-related-potassium channel, type 1 (TREK-1). In mice, it binds to the TREK-1 channel with an affinity of 10 nM. Research documenting electrophysiological effects of Spadin demonstrated an efficient inhibition of TREK-1 activity in COS-7 cells, pyramidal neurons in the hippocampus, and CA3 hippocampal neurons.
  • MAPK / PI3K signaling pathways: Spadin activates both the MAPK and the PI3K signaling pathways. It appears as though activation of the PI3K pathway provides neuroprotective effects from brain cell death.  Hence, the peptide Spadin may serve as a neuroprotective agent.
  • BDNF increase: Evidence suggests that administration of Spadin results in increases of BDNF (brain-derived neurotrophic factor) within the hippocampus. Increases in BDNF is associated with improved cognitive function, general health, and decreased likelihood of depression.  In addition, BDNF is responsible for promoting neurogenesis or the growth of new brain cells.
  • Synaptogenesis: Treatment with Spadin resulted in enhancement of mRNA expression and 2 increased levels of 2 notable proteins: 95 kDalton (PSD-95) and synapsin. Both of these proteins are biomarkers associated with synaptogenesis, or the growth of new synapses within the brain.  Reports suggest that the quantity of mature spines within cortical neurons significantly increases upon administration of Spadin.
  • Neuronal membrane potential: Administration of Spadin was noted to increase neuronal membrane potential in mice.
  • 5-HT neuron firing: Studies have demonstrated an increase in 5-HT (serotonergic) neuronal firing rate within the medial prefrontal cortex and dorsal raphe nucleus of mice following administration of Spadin. Specifically, researchers documented that Spadin increased the firing rate of 5-HT neurons by approximately 113%.  In addition, Spadin interacted with 5-HT4 receptors.
  • Phosphorylation of CREB protein: It appears as though Spadin induces phosphorylation of CREB protein (cAMP response element-binding protein) within the hippocampus. This is regarded as a biomarker associated with therapeutic antidepressant responses.

Note:  It remains unclear as to whether the effects of Spadin in mice would be similar when tested in humans.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25598009
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25233810

Spadin For Depression (Scientific Research)

2015: It is well-established that depression is the most common mood disorder of this generation.  Despite a steadily increasing number of individuals diagnosed with depression, it is estimated that only 1/3 people successfully treat their depressive symptoms.  In 2011, researchers discovered a new target for antidepressant drug design.

They noticed that upon targeting the TWIK-related potassium channel-1 (TREK-1) potassium channel, antidepressant effects were displayed in rats.  They discovered a peptide called “Spadin” comprised of 17 amino acids with antidepressant properties.  It was noted that Spadin should be taken into consideration when designing novel antidepressant drugs.

The Spadin peptide is produced via the Sortilin-1 protein (associated with the SORT1 gene).  Perhaps the most appealing aspect of Spadin is the fact that it is regarded as a natural molecule.  In addition, preclinical research demonstrates that it produces rapid antidepressant effects without any known side effects – a seemingly utopian futuristic antidepressant.

A study was designed in 2015 to assess spadin-analogues (chemicals with a similar structure to spadin).  These analogues were engineered to elicit a greater affinity on the TREK-1 channel for an extended duration compared to spadin.  Researchers measured the effect of the spadin-analogues and documented electrophysiological functioning, behaviors, and whether they promoted neurogenesis (growth of new brain cells).

Results indicated that 2 analogs classified as “retro-inverso” peptides maintained the antidepressant effects of Spadin.  Moreover, these retro-inverso peptides were capable of increasing neurogenesis in the hippocampus after 4 days of administration.  Just like Spadin, there were no significant side effects recorded following administration.

Authors of this study concluded that retro-inverso peptides of Spadin may prove to be potent, novel antidepressant drugs.  It should be theorized that retro-inverso designs may be an effective method for designing new, more effective antidepressants with less side effects.  This research highlights the antidepressant effects of Spadin analogues and potential uses of retro-inverso peptides for the treatment of depression (and numerous other conditions).

Note: “Retro-inverso” peptides of Spadin refer to the (dextrorotatory) D-amino acids in reversed sequence.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25080852

2015: Another report published in 2015 noted that depression affects nearly 1/5th of the general population in Western countries.  Researchers note that depression is thought to occur as a result of genetics, environment, and developmental factors.  The complexity of depression (as a result of genetics, environment, development, etc.) – makes it difficult to treat.

The antidepressant market is currently saturated with SSRIs, SNRIs, and other drugs attempting to target imbalances in neurotransmitters (e.g. serotonin).  Unfortunately, most of these treatments lack efficacy and are associated with significant unwanted side effects (e.g. weight gain, sexual dysfunction, etc.).  To make matters worse, an estimated 33% of the depressed population fails to respond to current-market medications.

Authors emphasize an increased need to engineer new methodological models and drug designs for the treatment of depression.  In their 2015 report, they cite potentially novel therapeutic targets for depression based on studies with knockout model mice.  Specifically, the suggested novel therapeutic targets included: TREK-1 and TASK-3 channels.

It was hypothesized that using antagonists to target the TREK-1 and TASK-3 channels may elicit antidepressant effects.  One agent of interest remains Spadin, a peptide derived from maturation of the NTS3 (neurotensin receptor-3), commonly called “sortilin.”  Spadin functions by inhibiting activity in the TREK-1 channel and is known to provide fast-acting antidepressant effects without any side effects.

This report provides justification for further investigation of Spadin and Spadin-analogues as potential breakthroughs in the field of psychiatry.  Should a Spadin-analogue prove efficacy in humans with a high degree of safety, it has potential to dramatically reduce the incidences of refractory depression in Western countries.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25263033

2012: A study published in 2012 documented that Spadin elicits an antidepressant effect within 4 days of administration in rodents.  One major drawback associated with current-market antidepressants is that they take long to before they start working.  Often times antidepressants can take over a month before a person notices whether the drug is helping improve their mood and/or making it worse.

This means that many psychiatric patients waste significant time playing antidepressant roulette; trying one drug for 4 to 6 weeks, and immediately trying another one if the previous trial was deemed ineffective.  The problem with this strategy is that consecutive trials of antidepressants can cause a chemical imbalance, influencing the efficacy of newer medications.  This may lead to a never-ending cycle of suboptimal responses to medications in many individuals.

Even if a person does find an antidepressant that works, there are often significant side effects.  Preliminary evidence suggests that the peptidic antidepressant Spadin acts very quickly (within several days) and has no significant side effects.  It functions by inhibiting TREK-1 potassium channels, a new therapeutic target for antidepressant design.

Following 3 weeks of treatment with Spadin, the rodents had maintained the antidepressant effect.  It is unknown as to whether Spadin would be effective as a long-term therapeutic option and/or whether any adverse effects occur at supratherapeutic doses.  This research provides further motive to investigate Spadin for development of a new antidepressant class.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21807005

2011: A study published in 2011 noted that TREK-1 potassium channels are involved in a variety of neurophysiological functions including: depression, neuroprotection, and pain.  Authors suggested that the usage of molecules to strategically inhibit the TREK-1 channels may provide therapeutic benefit in the treatment of certain conditions.  Researchers studied the effects of Spadin, Fluoxetine, and Riluzole on a TREK-1 cell line.

They noted that Spadin and Fluoxetine (Prozac) inhibited the TREK-1 channel, whereas the ALS drug Riluzole opened it.  Since both Prozac and Spadin demonstrate antidepressant effects, perhaps an important mechanism responsible for these effects is TREK-1 inhibition.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22022421

2010: It was observed that knockout mice with strategic removal of the TREK-1 gene creates mice that are resistant to depression.  The mice without the TREK-1 gene were reported as displaying a “depression-resistant phenotype” similar to you’d see among those that were successfully treated with antidepressant drugs.  As a result, the TREK-1 channel has become an increasingly investigated therapeutic target for development of new antidepressants.

Researchers suggest that development of TREK-1 antagonists, or substances that inhibit activity of the TREK-1 channel.  The peptide Spadin happens to act as an inhibitor of the TREK-1 channel, making it an ideal peptide to investigate as an antidepressant.  It was reported that Spadin binds to the TREK-1 channel with an affinity of 10 nM and increased serotonergic firing rates in the dorsal raphe nucleus.

Assessments conducted in mice demonstrated that Spadin induced potent antidepressant effects.  Further, it appeared as though mice treated with Spadin were “resistant” to depression as much as those without the TREK-1 gene.  Researchers also observed that Spadin enhanced phosphorylation of CREB protein in the hippocampus and induced neurogenesis.

Authors of the research document Spadin as the first natural antidepressant peptide to be identified.  The findings from this research suggest that Spadin should be considered a novel antidepressant with rapid therapeutic effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20405001

Are other TREK-1 antagonists for depression of therapeutic interest?

A report published in 2007 suggested that TREK-1 channels may be a therapeutic target for development of antidepressants.  This is based on the fact that deletion of TREK-1 in groups of “knockout mice” results in antidepressant effects.  The mice with the deleted TREK-1 end up resistant to becoming depressed, whereas those with TREK-1 activation experience depression.

It was noted that the popular antidepressant Prozac (Fluoxetine) acts primarily as an SSRI (selective-serotonin reuptake inhibitor), but also acts as a TREK-1 (potassium channel) antagonist – possibly contributing to its antidepressant effect.  That said, not all TREK-1 inhibiting agents are known to possess antidepressant properties.  Therefore it is important to consider the complexity of Spadin’s mechanism of action in addition to its TREK-1 inhibition.

Currently it is unknown as to whether there are other TREK-1 inhibitors (besides Spadin-analogues) that are under investigation as potential antidepressants.  It is unlikely that simply inhibiting TREK-1 activity automatically will yield antidepressant effects – especially in humans.  Rather than attempting to find the latest TREK-1 antagonist, perhaps researchers should explore other natural peptides that show promise as antidepressants that could be converted into analogues.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17622574

Potential Benefits of Spadin for Depression

There are numerous potential benefits of using Spadin to treat depression.  Since it is a natural peptide comprised of 17 amino acids, it is thought to produce fewer side effects.  A notable advantage compared to other antidepressants is that it is extremely fast-acting, providing a mood-boost within days rather than weeks (like most traditional antidepressants).

  • Adjunct: There’s potential that Spadin could be used as an antidepressant augmentation strategy to enhance the efficacy of standard medications.  It appears to carry no significant side effects, and the fact that it is a natural peptide may make it safer to take with an antidepressant than other approved drug.  That said, some research has suggested that it enhances neurotransmission of 5-HT (serotonin), possibly making it riskier to combine with SSRIs.
  • Fast-Acting: Everyone wants fast results, but if you have depression, experiencing a mood improvement may take weeks or months. Current-market medications often take 4 to 8 weeks before a user notices that their mood has improved and/or been altered.  Unfortunately, not everyone can wait weeks or over a month for a mood improvement.  Spadin (and its analogues) appear to improve mood within 4 days in rodents.
  • Highly effective: Spadin appears to be highly effective in mice and rodents for alleviating depressive symptoms. Mice with depression derive clinically significant antidepressant relief from Spadin and its analogues.  It is thought that various analogues could be developed for enhanced antidepressant potency.
  • Natural peptide: This is considered the first natural peptide discovered with antidepressant properties. While natural substances are not always safer than chemically engineered drugs, Spadin is a naturally occurring biological molecule (with 17 amino acids).  The fact that it is a naturally occurring molecule should increase likelihood of its safety.
  • No side effects: Preclinical evidence suggests that Spadin carries no significant side effects. In several studies, researchers sought to determine its therapeutic value as an antidepressant, mechanisms of action, and whether any adverse reactions occurred.  It appeared as though no side effects were observed in mice and rodents following administration of Spadin.
  • Unlikely withdrawal: Since Spadin is a naturally occurring biological molecule, it is unlikely to provoke withdrawal symptoms when discontinued. Unlike antidepressants that significantly alter neurochemistry and cause a chemical imbalance upon discontinuation (with debilitating withdrawal symptoms), the likelihood of withdrawal stemming from a natural peptide is low.
  • Safety: Despite the fact that safety of Spadin is unestablished in humans, it appears extremely safe in mice and rodents. More longer-term trials are necessary to confirm preclinical safety and supratherapeutic doses should also be tested in mice.  Due to the fact that it is a natural peptide, it theoretically should be safe for most to consume.

Potential Drawbacks of Spadin for Depression

Obviously there are many drawbacks associated with using Spadin for depression.  Perhaps the biggest drawback is that pharmaceutical companies will develop Spadin-analogues, while no companies will sell Spadin as a standalone peptide.  Despite the fact that Spadin analogues may provide a more potent antidepressant effect and are patentable (meaning big pharma can cash in), a natural peptide may be a safer option.

  • Clinical trials: Spadin nor its various analogues have been registered for clinical trials. It is unknown as to whether Spadin-analogues will eventually survive to make it to preclinical trials, let alone advance to clinical trials.  Should Spadin-analogues end up in clinical trials, we will have more data to draw upon regarding efficacy, safety, and side effect profile.
  • Duration of effect: The duration of effect associated with Spadin is thought to be short-term. The research does not yet document Spadin’s duration of effect, but analogues are being developed to extend and potentiate TREK-1 antagonist properties.  Spadin may only last for an hour or so, but could perhaps be engineered into an analogue with a sustained (or extended) release.
  • Inability to patent: There is no major money to be made in natural peptides like Spadin. If there were money to be made, Spadin would’ve likely been patented and formatted into a supplement.  However, the big money will be made in the development of chemical analogues, or substances that have similar effects to Spadin.  It would be nice if someone reading this had the funds to develop Spadin, test it in humans, and market it as a dietary supplement (assuming it proves effective).
  • Lack of research: Due to the fact that Spadin is thought to be discovered within the past decade, there is limited research of the peptide and minimal research investigating its antidepressant efficacy. It should be hoped that newer research continues to investigate the potential promise of this peptide as an antidepressant.
  • Long-term effects: It is unknown as to whether there would be any long-term effects associated with taking high doses of Spadin on a regular basis. Additionally, the long-term effects associated with Spadin-analogues would be difficult to determine based on how they are designed.  Many long-term effects of current antidepressants are poorly documented and it will certainly take awhile to determine those associated with Spadin.
  • Polymorphisms: Those with polymorphisms of the TREK-1 gene and/or related compounds may experience less benefit from Spadin administration. Fortunately, services like GeneSight may eventually offer some futuristic testing protocol to determine whether a person is likely to respond and/or tolerate Spadin and its analogues.
  • Unknown efficacy in humans: As of 2015, there are no studies that have investigated the effects of Spadin administration in humans. It should be noted that despite Spadin’s efficacy as an antidepressant in mice and rodent models, research in animals does not always translate well to humans.  Spadin is hypothesized to be effective in humans, but its true efficacy cannot be determined until tested.
  • Unestablished safety of analogues: While Spadin may be relatively safe due to the fact that it is a naturally occurring biological molecule, the safety associated with analogues would be difficult to determine. Significantly more research is necessary to determine the safety profiles of various (promising) Spadin-analogues.

Do you think Spadin and its analogues sound promising as antidepressants?

A new wave of antidepressants could be engineered to target the potassium TREK-1 channel as antagonists.  Chances are that many pharmaceutical companies have looked into developing these and are waiting for another company to be the guinea pig with a Spadin-analogue to determine how well it performs.  Should one Spadin-analogue demonstrate preclinical efficacy and get fast-track status, we can expect other companies to hop on the bandwagon with other developments of TREK-1 antagonists.

It’s unfortunate that there remains significant “herd mentality” among pharmaceutical companies.  While it is certainly important to minimize risk and maximize profits when developing a new drug, it’s also important to think outside the box and really attempt to advance treatment for depression.  We are currently stuck in a generation where developers don’t know where to turn, so they are attempting to reverse engineer substances like ketamine without psychotomimetic effects.

Drug developers and researchers should really be exploring uncharted territory with hope of the next big breakthrough.  It would be nice to see greater diversification in development of new pharmaceuticals, particularly targeting novel biomarkers associated with the condition.  In this case, there is significant evidence to hypothesize that the TREK-1 channel may be one such biomarker and may spur development of an improved class of antidepressants.

Then again, it is important to avoid excess sanguinity regarding Spadin and its analogues.  Many promising substances are scrapped in the development pipeline and patents are held hostage by pharmaceutical companies for years without any application.  Feel free to share any thoughts below regarding how you feel about Spadin and (potential analogues) as antidepressants.

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