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A New Pharmacological Drug Target in Anxiety and Depression Therapy

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A New Pharmacological Drug Target in Anxiety and Depression Therapy

Despite recent progress in developing new antidepressants and neuromodulators for anxiety, there remains a pressing need to enhance existing pharmacotherapeutic approaches. Some anxiety disorders and related conditions remain resistant to approved first-line treatments (like selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors) while others show poor response to current therapies.

Current investigations for anxiety disorders involve glutamatergic, GABAergic and serotonergic agents that come either from nature or are chemical modifications of naturally occurring compounds.

Anxiety is a global public health concern, estimated that about 10% of the global population suffers from some form of anxiety disorder at any given time. Generalized anxiety disorder (GAD), social anxiety disorder (SAD), and posttraumatic stress disorder (PTSD) are the three most prevalent disorders; they all feature excessive and pervasive anxiety which impacts daily life for those affected.

Pharmacological treatments for these disorders typically involve serotonergic or GABAergic antidepressants and benzodiazepines. The latter act on the central nervous system (CNS) by slowing brain activity and relieving anxiety and agitation. The sedative effects of benzodiazepines last hours or days, often used in combination with other drugs to address more serious anxiety conditions.

Serotonin and melatonin receptor agonists may provide anxiolytic benefits. For instance, various 5-HT1A agonists have been developed and tested for their potential anxiolytic effects, such as buspirone, nefazodone, and mirtazapine.

Some of these agonists can be taken orally, and their effectiveness has been demonstrated in phase 3 randomized controlled trials (RCTs). Mifepristone has also been studied on patients with late-life anxiety; it was found to reduce cognitive impairment associated with anxiety when combined with benzodiazepine medication (NCT01333098).

Ketamine is an addictive drug of abuse known to produce rapid antidepressant effects, though it can be difficult to administer in a controlled setting. A number of studies have examined the anxiolytic effects of ketamine on patients suffering from depression and anxiety, with promising results. A small randomized study comparing IV ketamine with midazolam found that it was superior at relieving PTSD symptoms among subjects with PTSD while an open-label open-label study found it could reduce anxiety and social phobia in an OCD sample (26).

Tiagabine is an anticonvulsant that blocks voltage-dependent sodium channels, thus inhibiting glutamate release and decreasing gamma-aminobutyric acid (GABA) production. It has been approved for treating partial seizures, with animal models showing it to have anxiolytic properties as well. An open label study comparing tiagabine with gabapentin for generalized anxiety disorder found both drugs effective at relieving anxiety symptoms.

Corticotrophin-releasing factor (CRF) receptor antagonists are currently being researched for anxiety treatment. Animal models of CRF antagonists have demonstrated that they reduce hypercortisolemia, although limited data exists regarding their anxiolytic effectiveness in human trials. Pexacerfont (BMS-562086) and Verucerfont (GSK561679), two CRF antagonists available currently, both completed phase 2 RCTs with positive outcomes in Parkinson’s Disease (PD) and Generalized Anxiety Disorder (GAD).

Other novel drug targets under investigation for anxiety include kava, an NMDA receptor agonist; oxytocin, a neuropeptide; tetrahydrocannabinol (THC), an cannabinoid; and prazosin, an alpha-adrenergic receptor agonist being studied for PTSD nightmares and possible daytime anxiolytic effects in PTSD. Unfortunately, these agents have yet to undergo double-blind randomized studies so cannot yet be recommended for immediate use.

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- Welcome, SoundTherapy.com lowers anxiety 86%, pain 77%, and boosts memory 11-29%. Click on the brain to sign up or share with buttons below to help others:
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