Agomelatine (Valdoxan) Potential Uses & Side Effects

Agomelatine is a melatonin analog, developed under the premise that an abnormal circadian rhythm can contribute to depression. But this theory remains unproven. Read about its possible uses and side effects in this informative article.

Disclaimer: Agomelatine Isn’t accepted in the United States. The development of the US marketplace was discontinued in October 2011. The major concern was that efficiency had not been satisfactorily shown. This medication was approved in Europe in 2009 and Australia in 2010, in which it can simply be used with a doctor’s prescription. Discuss your symptoms with your health care provider. He or she will diagnose and treat your health issues.

What is Agomelatine?

Overview

Agomelatine (Valdoxan) was developed as an atypical antidepressant on the basis that abnormal circadian rhythms may contribute to depression. This theory requires further human trials to be adequately verified.

A Major group of antidepressant drugs is selective serotonin reuptake inhibitors (SSRIs). Unlike SSRIs, agomelatine likely activates melatonin (MT1 and MT2) receptors and blocks the 5-HT2C dopamine receptor.

Agomelatine is not approved for use in the United States.

This Medication was undergoing several stage III clinical trials in the US. Until late 2011, agomelatine was listed as scheduled for submission to the Food Drug Administration (FDA). However, the development for the US market was discontinued and withdrawn in October 2011, when the newest clinical trial results became available.

Presently, agomelatine is approved in the European Union for the treatment of big depression.

Mechanism of Action

Agomelatine activates melatonergic M1 and M2 receptors and inhibits serotonergic 5-HT2C receptors.

Although agomelatine is molecularly very similar to melatonin, it’s a longer half-life.

The Half-life of agomelatine is 2.3 hours, whilst melatonin has a half-life of 50 minutes. Agomelatine may also bind to nitric oxide stronger than melatonin.

By obstructing 5-HT2C receptors on dopaminergic and noradrenergic Pathways, agomelatine may increase dopamine and norepinephrine levels in the mind (in the adrenal gland but not in the limbic system). Scientists hypothesize this might improve mood and supply nootropic cognitive enhancement.

Investigators Also imply that agomelatine can improve the number of spontaneously-active neurons as well as the bursting activity of dopaminergic neurons in the ventral tegmental brain area.

Research Depression & Other disorders

According To some notions, depression is connected to certain abnormalities in the limbic system (part of their brain involved in memory and emotions ) and circadian rhythms. Scientists are researching how the subsequent changes may be linked with melancholy:

• HPA Axis dysfunction, elevated CRH, elevated cortisol, and “cortisol resistance” in the brain.
• Unhealthy sleep habits and circadian rhythm problems that might lead to individuals to stay up and wake up later.
• Brain inflammation, gut inflammation, “sickness behavior,” and tryptophan and serotonin manufacturing.
  Reduced BDNF levels.

However, Additional high-quality studies are essential to ascertain how valid these hypotheses and potential biomarkers are. Not one of them has been confirmed in large scale studies.

Potential Uses of Agomelatine

Agomelatine Is not approved in America. Discuss your symptoms with your doctor who should recommend approved medical care for your situation.

Mood Disorders

By stimulating melatonin receptors, Agomelatine is hypothesized to synchronize the circadian rhythm with the outside atmosphere. In animal studies, agomelatine revived tubal sleep/wake cycles, represented with an improved length of REM and slow-wave sleep following acute oral treatment.

Back in Europe, agomelatine has been approved for the treatment of major depressive episodes in adults.

In humans, limited research indicates that adjunctive agomelatine might also be useful in the treatment of acute bipolar depression.

One open-label study suggests that agomelatine as monotherapy May enhance seasonal affective disorder (SAD). However, bigger double-blind, randomized, placebo-controlled trials are still needed to further specify the clinical significance of agomelatine for SAD.

Additionally, Current evidence indicates that agomelatine alone may not be effective as a monotherapy for the treatment of unipolar or bipolar depression or schizoaffective depression, likely due to its distinctive mechanism of action.

Anxiety Disorders

Clinical Studies suggest that agomelatine could possibly be utilized as an adjunctive treatment for depression-related anxiety symptoms. In clinical trials, agomelatine showed the capability to boost anxiety symptoms of major depression.

According To restricted clinical research, agomelatine can also improve generalized anxiety disorders (GAD) in people who don’t have depression.

One research (double-blind randomized controlled research ) involving over 400 patients over the course of 12 weeks, agomelatine was proven to be as successful as escitalopram in mitigating stress symptoms.

A Couple of different trials had favorable results. However, people with GAD frequently have other medical and psychiatric conditions. Therefore, future studies should explore the effects of agomelatine on anxiety from the real-world, general patient population.

Fibromyalgia

Melatonin, Serotonin, and norepinephrine play a major role in neuropathic pain ailments. Agomelatine can reduce neuropathic pain in fibromyalgia instances which have previously been unresponsive to medical treatment, perhaps by blocking the serotonergic receptor 5-HT2C.

However, The existing studies had many limitations: small sample sizes, short duration, lacking control groups. Additionally, patients with fibromyalgia have a higher prevalence of depressive and anxiety disorders. For that reason, it’s hard to tease apart fibromyalgia developments from agomelatine because of its antidepressant effects.

Added Research

The Effects of agomelatine on BDNF, neurotransmitter balance, muscle and bone health, and inflammation have yet to be set in large-scale clinical trials.

Hence, the research outlined below should Guide further research, but we can not draw any conclusions about additional agomelatine indications and/or utilizes based on them.

Agomelatine Should only be used under medical supervision in countries where it has been accepted by the governing regulatory agency.

Outcomes on BDNF

Researchers Think hippocampal BDNF might improve synaptic plasticity, which may theoretically improve the brain’s capacity to learn, store, and access new info.

Ongoing Research is exploring whether agomelatine raises BDNF levels in the hippocampus, thereby enhancing the survival of present neurons and synapses as well as the growth and creation of newly-generated ones.

According to a hypothesis, elevated BDNF might help prevent stress-induced impairment of visual memory and spatial learning.

Some Researchers believe agomelatine may affect long-term behavioral reactions to anxiety to mitigate symptoms of mood disorders and physiologically boost the brain’s ability to cope with stressful conditions. Their hypotheses remain unproven.

Other Research factors are wanting to ascertain if agomelatine raises CREB (cAMP response element-binding protein), which can be posited to prevent the degenerative impact of environmental stressors on the hippocampus.

Outcomes on Neurotransmitter Release

By Obstructing the serotonergic receptor 5-HT2C, agomelatine likely increases norepinephrine and dopamine release in the frontal cortex. Researchers believe this might enhance daytime motivation and help fight the physical and mental effects of mood disorders, though their stance remains badly investigated.

Effects on Bones and Muscles

Inflammatory cytokines are produced by cells to initiate localized inflammation and immune responses and keep bone equilibrium.

Uncontrolled levels of inflammatory cytokines can impair the balance between osteoblast and osteoclast activity, which can be included with bone recovery and maintenance.

High Amounts of IL-1β, IL-6, and TNF-α may even weaken bones; the connection between these cytokines and osteoporosis, arthritis, bone erosion, cartilage degradation, and even gum disease are being investigated.

Additionally, Scientists are investigating whether agomelatine reduces the levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6.

By Suppressing these possibly harmful cytokines, agomelatine would theoretically affect bone health. On the other hand, the consequences of agomelatine on bone health in humans are unknown.

Some researchers hypothesize that agomelatine increases both IGF-1 and growth hormone levels by stimulating nitric oxide, which modulates hormone secretion during sleep.

Another Potential region of agomelatine research is its effects on muscle strength. Rodents medicated with agomelatine demonstrated an increase in muscle strength and density, but clinical data are completely lacking.

Inflammation

Lipopolysaccharides (LPS) is a bacterial poison. It may leak into the blood in people with increased gastrointestinal permeability or “leaky gut” It has been linked with inflammation and metabolic issues like insulin resistance, diabetes, obesity, and heart ailments, though most of these associations remain inconclusive.

In rats, agomelatine reduces the inflammatory cytokines IL-1beta and IL-6 triggered by LPS. In precisely the exact same study, agomelatine deactivated NF-kB, a protein that turns on inflammatory responses in the immune system.

Side Effects and Dangers of Agomelatine

Side Effects

The possible side effects of agomelatine include:

• Anxiety
• Back pain
• Constipation
• Diarrhea
• Dizziness
• Drowsiness
• Excessive sweating
• Fatigue
• Insomnia
• Migraines and headaches
• Nausea

Importantly, agomelatine can raise liver enzyme levels and may damage the liver.

During Treatment, transaminases should be periodically monitored and treatment discontinued if transaminases exceed three times the upper limit of normal.

Risks

Liver Damage

Physicians Ought to perform liver function tests in all patients before beginning treatment. Treatment shouldn’t be initiated if transaminases exceed three times the upper limit of normal.

Additional Receptor screening ought to be carried out after 3, 6, 12, and 24 weeks. If the dose is raised, the screening period should restart. A final screening after the treatment is also recommended.

The Usage of agomelatine should be stopped if liver enzyme screening indicates that a 3X increase of blood transaminases. Beware of symptoms that may indicate potential liver damage, like dark urine, light-colored stool, yellowing eyes or skin, stomach pain, or new/worsening fatigue.

Overdose

The data on agomelatine overdose is restricted however, symptoms of an overdose might contain:

• Agitation
• Stress
• Dizziness
• Drowsiness
• Infection
• Malaise
• Tension

In a situation report, a person exerts on 2,450 mg but managed to recuperate.

Risk of Suicide

With all antidepressants, there is a possible risk of suicide. Individuals at high risk of suicide should be carefully monitored by their doctor.

Agomelatine Dosage

Pharmaceutical Agomelatine is prescribed (as Valdoxan) in 25-mg pills, typically taken once per day at bedtime. Dosage can be adjusted for 50 mg (2 x 25 mg tablets) taken at bedtime if agomelatine treatment has no effect after fourteen days.

Antidepressant treatment utilizing agomelatine generally lasts at least six months.

Agomelatine shouldn’t be prescribed to older individuals (75+ years).