Monday, 20 May 2013

Vortioxetine, a new antidepressant in the process of being approved in the US and the EU

Definitions of some terms used: 

Placebo - a drug, that despite having no therapeutic efficacy with respect to the action being tested, is designed to trick patients into improving due to the whole mind over matter situation.
Placebo-controlled, double blind clinical trial - a clinical trial in of which some study participants are given placebos and others are given the drug that is being tested in the clinical trial and neither the person giving the patient the drug, nor the patient, know which one the patient is receiving.

Post:

A new antidepressant is currently in the process of being approved in various countries, unfortunately, at the moment, from what I can tell, at least, Australia isn't one of them, but the US is. It's known as vortioxetine and is truly unique among antidepressants. Albeit it still works based on the monoamine hypothesis of depression, just as all, currently approved in Australia, antidepressants, except one, agomelatine, which works partly based on this hypothesis. The monoamine hypothesis of depression states that certain neurotransmitters, known as monoamine neurotransmitters that include serotonin, norepinephrine and dopamine are deficient (i.e. present in abnormally low quantities) in the brains of patients with depression.

It works, or so it appears, by a combination of actions: selective serotonin reuptake inhibition, agonism of the 5-HT1A receptor, partial agonism of the 5-HT1B receptor, antagonism of the 5-HT3 receptor and antagonism of the 5-HT7 receptor.

Selective serotonin reuptake inhibition is a mechanism of action vortioxetine shares with a class of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs) that include, sertraline (Zoloft), fluoxetine (Prozac), escitalopram (Lexapro), citalopram (Celexa, Cipramil), fluvoxamine (Luvox) and paroxetine (Aropax, Paxil).

5-HT, in the context of these receptors, is an acronym for 5-hydroxytryptamine, the chemical name for serotonin, that is, these receptors that vortioxetine interacts with are all serotonin receptors. 5-HT1A receptors regulate, among other things, the release and synthesis of serotonin in the brain (skip until the next paragraph if you understand the concept of a synapse from my last blog post or other sources). See expressed on neurons (the electrically and chemically signalling cells of the brain and spinal cord) there are two types of receptors: presynaptic and postsynaptic receptors, they are expressed pre- and post- synaptically respectively. See each neuron is joined to other neurons at something known as a synapse. Synapses are where one neuron (the presynaptic neuron this is known as) propagate signals, in the form of neurotransmitter release, to the next neuron (or the postsynaptic neuron). The receptors are called pre- and post- synaptic based on which of these neurons they are expressed in a particular synapse.

5-HT1A receptors are located both pre- and post- synaptically. Presynaptically they serve as autoreceptors, that is they are the receptors that send back negative feedback to the presynaptic neuron. That is, upon binding with serotonin they send back signals to the presynaptic neuron that tell it to reduce the amount of serotonin it is synthesising (serotonin synthesis only occurs in one region of the brain, the raphe nucleus, which is one place that the 5-HT1A receptor is highly expressed) and/or releasing. Over time, with repeat exposure to the neurotransmitter serotonin or other ligands (drugs that bind to it) these presynaptic 5-HT1A receptors becomes downregulated. This means there are fewer of this particular type of receptor, thus leading to reduced negative feedback to the presynaptic neuron. Additionally it has been found that postsynaptic 5-HT1A receptor agonism (activation) leads to lifting of depression and anxiety. It also appears to leads to pain relief and some cognitive (memory and learning) effects [there's some evidence saying it is a positive [enhancing] effect while other evidence suggests the reverse].

5-HT1B receptors also serve as autoreceptors but in other parts of the body. They also appear to play a key role in vasoconstriction (constriction of blood vessels) and as of such 5-HT1B receptor agonists are used in the treatment of migraines. Their effects on mood are unclear.

5-HT3 receptors appear to play roles in schizophrenia (5-HT3 receptor antagonists are known to improve the symptoms of schizophrenia) and emesis (nausea and vomiting). In fact 5-HT3 receptor antagonists are among the most well-tolerated (i.e. the best with respect to fewer side effects) antiemetics we have.

5-HT7 receptors on the other hand also appear to be primarily located presynaptically. 5-HT7 receptors serve as both auto- and hetero- receptors. Heteroreceptors, similarly to autoreceptors, are receptors located presynaptically that regulate the release of neurotransmitter from the neurons they're located on. Heteroreceptors, however, instead of regulating the release of the neurotransmitters that activate them, regulate the release of other neurotransmitters.

At the moment there are only one indication (i.e. conditions for it to be used to treat) for which approval of vortioxetine is being sort by its developers: major depressive disorder (MDD; also known as unipolar or clinical depression). Four placebo-controlled, double blind clinical trials have been conducted to ascertain the efficacy of vortioxetine in treating MDD with conflicting results. Two found a statistically significant improvement in MDD patients receiving vortioxetine over placebo. One found no such improvement, whereas the other had an exceptionally high placebo response rate that clouded the results. Despite these conflicting results the drug's developers filed for approval in September 2012 in the US and October 2012 in the EU market. Another indication for which vortioxetine was being investigated was generalised anxiety disorder or GAD. There were two clinical trials conducted into its use in treating GAD, one managed to show a statistically significant improvement over placebo while the other failed to find such an improvement.


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