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Collected data from the Anxiety and Depression Association of America (ADAA) suggests that upwards of 40 million adults are affected by anxiety, or approximately 18% of the United States population.  Among the 40 million adults who are affected by anxiety, it is estimated that approximately: 19 million suffer from specific phobias; 15 million suffer from social anxiety disorder; 7 million suffer from generalized anxiety disorder (GAD); and 7.7 million suffer from post-traumatic stress disorder; and 2.2 million suffer from obsessive-compulsive disorder (OCD).

Though anxiety can be crippling for many, individualized treatments often alleviate anxious symptoms and improve quality of life for persons with anxiety.  Some individuals may find it possible to manage anxious symptoms with “natural cures for anxiety” (i.e. lifestyle modifications) such as: regularly engaging in aerobic exercise, practicing stress reduction on a daily basis (e.g. meditating), avoiding high-stress situations, eating a specific type of diet, and/or adhering to a sleep regimen.

That said, many persons with longstanding anxiety disorders derive inadequate symptom relief from lifestyle modifications.  Medically-recommended first-line interventions for anxiety consist of: anxiolytic medications (e.g. SSRIs) and cognitive behavioral therapy (CBT).  While many people with anxiety disorders benefit from anxiety medications, not everyone responds well to these drugs or can tolerate the side effects they cause.

A subset of individuals with anxiety disorders find current-market anxiety medications to be ineffective, suboptimally effective and/or difficult to tolerate.  These individuals are hoping that new anxiety medications in clinical trials [with novel mechanisms of action] might help to manage their anxious symptoms.

New Anxiety Medications (2018): Drugs In Clinical Trials

Listed below are new substances currently undergoing investigation for the treatment of anxiety disorders as of Q1 (first-quarter) 2018.  While writing this article, I reevaluated an older article in which I outlined the anxiety medications being developed in 2015 clinical trials.

As was expected, several of the prospective anxiolytic agents from the 2015 article are still undergoing clinical trial evaluation in 2018 – however, several substances from the 2015 article are no longer being developed.  Nonetheless, there seem to be a variety of new anxiolytic agents in the developmental pipeline that were not undergoing investigation in 2015.

  1. AVN-101

  • Mechanism: Serotonin receptor modulator
  • Status: Phase II clinical trials
  • Developer: Avineuro Pharmaceuticals

AVN-101 is a substance undergoing investigation by Avineuro Pharmaceuticals as a treatment for anxiety disorders – and Alzheimer’s disease.  According to the developer, AVN-101 is intended to be a safe, orally bioavailable, multi-target medication aimed to treat generalized anxiety – and CNS diseases associated with cognitive dysfunction.  It is thought that the serotonergic action of AVN-101 will facilitate a therapeutic anxiolytic effect while simultaneously reversing cognitive deficits such as memory loss.

Researchers speculate that AVN-101 might also combat depressive symptoms and counteract neurodegeneration by acting as a neuroprotective agent.  AVN-101 is known to be a close structural analogue to the drug Latrepirdine (sold under the name Dimebon), an antihistamine medication used primarily in Russia with neuroprotective properties.  Pharmacodynamically, AVN-101 exhibits highest affinity for the 5-HT7 receptor, but also interacts with other serotonergic receptors, including: 5-HT6; 5-HT2A; and 5-HT2C.

Moreover, AVN-101 exhibits a high affinity for H1 histamine receptors and adrenergic receptors (2A; 2B; 2C).  Preliminary results from phase I clinical trials indicate that AVN-101 is very well-tolerated at dosages up to 20 mg per day – and that it possesses an excellent toxicology profile.  As of February 2018, AVN-101 remains in phase II clinical trials – a phase it originally entered ~5 years ago (in 2013).

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/27232215
  • Source: http://www.avineuro.com/pipeline/
  1. FKW00GA

  • Mechanism: 5-HT1A partial agonist & 5-HT2A antagonist
  • Status: Phase II clinical trials (complete)
  • Developer: Fabre-Kramer Pharmaceuticals

FKW00GA is a substance undergoing initial investigation by Fabre-Kramer Pharmaceuticals for the treatment of social phobia (i.e. social anxiety disorder).  According to the developer, FKW00GA may eventually be tested for the treatment of: additional anxiety disorder subtypes (beyond social phobia) and sexual dysfunction.  The mechanism of FKW00GA’s action involves partial agonism of the 5-HT1A receptor and antagonism of the 5-HT2A receptor.

In Phase I clinical trials, FKW00GA appeared safe and tolerable at doses up to 180 mg – and multiple doses of 60 mg (t.i.d.) for 7 days.  Side effects of treatment were relatively modest, but included: lightheadedness and nausea.  Following Phase II trials, developers of FKW00GA noted that “signals indicating efficacy” were observed.

Based on Phase II results, Fabre-Kramer Pharmaceuticals has submitted Phase III protocol information to the FDA.  Developers intend to manufacture an extended-release format of FKW00GA for better patient compliance and reduced likelihood of side effects.  Though its mechanism of action may not be exciting, one potential upside is that this medication should counteract sexual dysfunction – or enhance sexual performance.

  • Source: http://www.fabrekramer.com/?page_id=70
  1. JNJ-42165279

  • Mechanism: FAAH inhibitor
  • Status: Phase II clinical trials (suspended)
  • Developer: Janssen Research & Development

JNJ-42165279 is a substance developed by Janssen Research & Development (a subsidiary of Johnson & Johnson) for the treatment of anxiety disorders.  It functions as a selective inhibitor of the enzyme known as FAAH (fatty acid amide hydrolase).  Inhibition of FAAH enzymes may generate rapid anxiolytic (anti-anxiety) effects by inducing long-term depression (LTD) at prefrontal cortex-basolateral amygdala synapses whereby basolateral amygdala neurons become suppressed.

As of 2016, Janssen temporarily suspended Phase II clinical trials of JNJ-42165279 due to the finding that another FAAH inhibitor referenced as “BIA (10-2474)” caused severe adverse reactions – including one death.  Janssen has stated that trials of JNJ-42165279 were suspended as a precautionary measure.  That said, there were no serious adverse effects observed among users of JNJ-42165279 to date.

Basically, Janssen wants to find out more information about why BIA 10-2474, another FAAH inhibitor, caused adverse reactions.  Until more information is discovered, JNJ-42165279 development will be suspended.  Because its action as an FAAH inhibitor is novel compared to most current-market anxiolytics, let’s hope that JNJ-42165279 turns out to be safe and trials can eventually resume.

  • Source: https://clinicaltrials.gov/ct2/show/NCT02432703
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/26713105
  1. NBTX-001 (Xenon)

  • Mechanism: NMDA receptor antagonist
  • Status: Phase I
  • Developer: Nobilis Therapeutics

NBTX-001 is a medication developed by Nobilis Therapeutics, containing the noble gas xenon as its primary active ingredient.  According to the developer, xenon exerts unique biological effects, is very safe, has been utilized extensively in imaging technology, and is occasionally administered some places for general anesthesia.  Xenon is devoid of psychotomimetic properties, meaning it won’t provoke hallucinations (e.g. hearing voices) or delusions.

What’s more, NBTX-001 is said to be non-addictive and non-flammable – plus it isn’t a greenhouse gas.  Preliminary research indicates that NBTX-001 is highly bioavailable and rapidly absorbed.  After ingested, the xenon atoms within NBTX-001 interact with aromatic amino-acid residues on NMDA receptors to exert a highly selective and controlled antagonist effect.

NBTX-001 appears to decrease excitatory neurotransmission via blockade of AMPA, nACh (Alpha-4-beta-2), 5-HT3, Ca2+ ATPase – yet increases inhibitory neurotransmission via stimulation of GlyR1 and TREK-1 potassium channels.  Interestingly, NBTX-001 also decreases inflammation via downregulation of cytokines (TNF-alpha, IL-beta) to upregulate growth factors (e.g. BDNF and IGF), possibly yielding neurogenesis.  Considering the unique mechanism of NBTX-001’s action and its safety profile, this is a relatively exciting development.

  • Source: http://www.nobilistx.com/science-behind-nbtx-001/
  1. Aloradine (PH94B)

  • Mechanism: GABAA receptor modulator
  • Status: Phase III clinical trials
  • Developer: Pherin Pharmaceuticals

Aloradine (PH94B) is a pherine or synthetic pheromone developed by Pherin Pharmaceuticals for the treatment of social anxiety disorder.  It is formatted as a nasal spray to be administered on an “as-needed” basis (i.e. p.r.n.) to help reduce symptoms of social anxiety, primarily in women; it is unknown as to whether effects will also prove therapeutic in men.  Pharmacodynamic evaluations of Aloradine indicate that it activates vomeronasal receptors and functions as a positive allosteric modulator of the GABAA receptor.

It has been suggested that GABAA receptor modulation is probably the principal means by which Aloradine attenuates anxious symptoms.  Aloradine has been in Phase III clinical trials since 2015 and thus far seems to be a safe and effective substance.  Though Aloradine is manufactured in a unique format (nasal spray) and is a synthetic pheromone, its mechanism of action isn’t markedly different than many current current-market anxiolytics.

It’ll be interesting to determine if Aloradine treatment results in rapid tolerance onset, psychological dependence, and/or severe withdrawal symptoms.  If Aloradine is associated with rapid tolerance onset, there’s a chance that it may be abused or misused for the sake of psychological intoxication.  Moreover, withdrawals from Aloradine could be severe among frequent users – as a result of GABAA modulation.

  • Source: http://www.pherin.com/products.html
  1. SRX246

  • Mechanism: Vasopressin (1A) receptor antagonist
  • Status: Phase II (PTSD); Phase I (anxiety)
  • Developer: Azevan Pharmaceuticals

SRX246 (also known as API-246) is a substance under development by Azevan Pharmaceuticals for the treatment of PTSD and anxiety disorders.  Preliminary evidence suggests that SRX246 is a small-molecule that functions centrally as a highly-selective vasopressin-1A (V1A) receptor antagonist.  It is thought that SRX246 may prove efficacious in the treatment of PTSD, generalized anxiety disorder, and anger disorders (e.g. intermittent explosive disorder).

SRX246 is classified as an azetidinone-derivative and was engineered by using LY-307174 as a principal lead compound.  As of 2018, SRX246 is in Phase II clinical trials for PTSD, Phase I clinical trials for generalized anxiety, and Phase II clinical trials for adults with intermittent explosive disorder.  It is believed that SRX246’s action upon V1A receptors may counteract stress or anxiety-induced dysregulation of neural circuitry, particularly in the limbic system and cortex.

Developers state that SRX246 will be administered orally and is highly bioavailable.  In animal model and neuroimaging research, SRX246 decreases aggression, anxiety, depression, fear, and stress.  Thus far, it seems as though SRX246 has been well-tolerated and successfully met all of its primary endpoints in clinical trials.

  • Source: http://azevan.com/index.php/pages/clinical-candidates-2/
  • Source: https://clinicaltrials.gov/ct2/show/NCT03036397
  1. Tonmya (Cyclobenzaprine)

  • Mechanism: 5-HT2A; Alpha-1; H1 receptor modulator
  • Status: Phase III clinical trials
  • Developer: Tonix Pharmaceuticals

Tonmya is a medication under development by Tonix Pharmaceuticals for the treatment of PTSD (post-traumatic stress disorder).  The medication is formatted as small, rapidly-disintegrating sublingual tablets that contain 5.6 mg cyclobenzaprine hydrochloride – and is intended to be administered once per day before bed.  Tonmya is also formatted with a lower 2.8 mg dose that may prove helpful for insomnia, sleep disturbances, and other forms of anxiety.

The FDA considers Tonmya to be a “breakthrough therapy” such that it’s development may be fast-tracked through Phase III of clinical trials.  In preliminary trials, Tonmya 5.6 mg administered before bed significantly reduced CAP-5 scores, indicating that it decreased symptoms of PTSD.  Additionally, preliminary trials suggest that Tonmya 5.6 is safe, well-tolerated and enhances deep sleep among persons with military-related PTSD.

According to the developer, Tonmya targets and treats irregular neural activation implicated in sleep disturbances and nightmares.  Researchers speculate that restoration of deep stage sleep (e.g. delta brain waves) might aid in natural recovery from severe trauma and reverse hyperarousal.  The low-dose cyclobenzaprine in Tonmya: inhibits 5-HT2A receptor (to enhance sleep); inhibits Alpha-1 adrenergic receptor to counteract trauma-related nightmares, and inhibits H1 receptors to reverse stress-induced rapid eye movement (REM).

  • Source: https://www.tonixpharma.com/research-development/tonmya-for-ptsd
  1. Travivo (Gepirone ER)

  • Mechanism: 5-HT1A selective partial agonist
  • Status: Phase II clinical trials
  • Developer: Fabre-Kramer Pharmaceuticals

Travivo (or extended-release Gepirone) is a medication being developed by Fabre-Kramer Pharmaceuticals for the treatment of depression and anxiety disorders – as well as anxiodepressive symptoms (i.e. comorbid anxiety and depression).  The medication was originally synthesized in 1986 and has been rejected on multiple occasions by the FDA as a treatment for depression.

That said, the FDA reversed its rejection of Travivo in 2016 and, as of January 2018, the medication is in a pre-registration phase for major depressive disorder.  Travivo is currently in Phase II clinical trials for the treatment of generalized anxiety disorder.  As a 5-HT1A selective partial agonist of the azapirone classification, Travivo is believed to reduce anxiety, enhance mood, and improve sexual function (possibly reversing sexual dysfunction associated with SSRIs).

Though similar to the medication buspirone, Travivo exerts a stronger effect upon 5-HT1A receptors and minimal interaction with D2 receptors. I’ve already documented the therapeutic potential of Travivo for anxiety disorders – and depression.  There’s a chance that Travivo might be like an upgraded version of Buspar – with an extended-release formula.  I’m expecting the medication to hit the market relatively soon for the treatment of depression.

  • Source: http://www.fabrekramer.com/?page_id=409
  1. Rexulti (Brexpiprazole)

  • Mechanism: 5-HT1A; D2; D3 partial agonist
  • Status: Phase II (PTSD)
  • Developer: Otsuka

Rexulti (Brexpiprazole) is a medication that’s been FDA approved for the treatment of schizophrenia since 2015.  It functions as a partial agonist at various receptor sites, including: 5-HT1A (serotonin); D2 (dopamine); and D3 (dopamine) receptors.  Some consider Rexulti to be like an upgraded version of Abilify with fewer severe side effects and greater therapeutic efficacy.

Though the medication functions primarily as an antipsychotic, it is believed to exhibit antidepressant, anxiolytic, and anti-aggressive properties.  For this reason, Rexulti is being investigated as a potential treatment for PTSD and agitation associated with Alzheimer’s disease.  Rexulti is currently in Phase II clinical trials for PTSD and Phase III clinical trials for Alzheimer’s-related agitation.

Because the medication acts in a way consisted with most antipsychotics, it’s probably not something that most individuals will want to use as a first-line anxiolytic.  Furthermore, there’s evidence that Rexulti may cause weight gain – and other unwanted side effects.  It’ll be interesting to determine how efficacious Rexulti ends up being among persons with PTSD.

  • Source: https://www.rexulti.com/us/mdd

Thoughts on new anxiolytics in clinical trials (2018)

There are a variety of intriguing anxiolytics in development, including: Tonmya (low-dose cyclobenzaprine), SRX246, Aloradine, NBTX-001, and JNJ-42165279.  Several of these agents exhibit unique mechanisms of action when compared to current-market anxiolytics.  Examples of novel mechanisms of action include: vasopressin receptor modulation (by SRX246); NMDA receptor modulation (by NBTX-001); and FAAH inhibition (by JNJ-42165279).

Tonmya is thought to reduce symptoms of PTSD and/or aid in recovery from PTSD by modulating a combination of neurochemical receptors, including: 5-HT2A (to improve sleep), Alpha-1 (to prevent nightmares associated with trauma), and H1 receptors (to decrease REM sleep).  Additionally, while Aloradine is novel in its mode of administration, it may be less novel in its mechanism of action (modulation of GABAA receptor activation) compared to current-market medications.

In any regard, I’m of the mindset that the greater the total number of anxiolytics with novel mechanisms of action (that are safe and effective enough to survive clinical trials) – the better the odds will be of finding an effective anxiety medication.  Currently, mainstream treatments for anxiety principally include: serotonin modulators (SSRIs, SNRIs, TCAs, Buspar etc.) and GABAergic modulators (e.g. benzodiazepines).

There are some problems with these interventions, including: unwanted side effects (sexual dysfunction, weight gain, etc.), long-term effects (benzodiazepines are linked to dementia), and discontinuation symptoms (most have harsh withdrawal symptoms).  Off-label interventions for anxiety may include: antihypertensive medications (i.e. beta blockers for anxiety – including: clonidine (read: “clonidine for anxiety” OR hydroxyzine (read: “hydroxyzine for anxiety“), ion channel modulators (e.g. gabapentin for anxiety), or counterintuitively, psychostimulants (e.g. Adderall for anxiety).

That said, persons with treatment-resistant or refractory anxiety disorders may not respond well to any of the aforementioned conventional interventions – and desperately await new therapies.  In addition to the new anxiolytics in development mentioned above, there are a host of new antidepressants in 2018 trials.  Some of the newer antidepressant medications being tested may exert potent anxiolytic effects such that they prove effective in managing symptoms of anxiety disorders.

Which new anxiety medications (2018) are you most excited about?

If you’ve reviewed the new anxiety medications in development (2018) that were mentioned above, leave a comment below with your thoughts.  Which new anxiety medications are you most excited about?  Are there any medications in development that you think have greater therapeutic potential than others?  Are there any medications in development that you aren’t excited about?

Personally, I’m most intrigued by NBTX-001 which consists of the noble gas xenon and acts as an NMDA receptor antagonist.  I suspect that action on the NMDA receptor could yield rapid-acting and protracted anxiolytic effects (at least in some cases).  I’m also interested in following SRX246 which function as a vasopressin 1A receptor antagonist.  Moreover, I’m curious as to whether Janssen will reinstate JNJ-42165279 trials – or if the development will end up permanently shelved.

The Aloradine nasal spray comprised of a synthetic pheromone seems great on the surface, but its action is similar to many available medications (GABAA modulation), possibly resulting in rapid tolerance onset and/or deleterious long-term effects akin to benzodiazepine treatment.  Nevertheless, both Aloradine and Tonmya are already in Phase III clinical trials and could hit the market sooner than expected.

In the near future (or within the next ~20 years), it is hoped that anxiolytic medications will be developed that avert or bypass physiologic tolerance mechanisms.  This would allow the medications to remain effective indefinitely at a stable dose (without the need for dosage increases over a long-term).  In the far future, it is hoped that anxiety disorders can be prevented and/or cured via biomedical engineering.

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