In the world of pharmacy, mental illnesses are some of the most
difficult to understand and treat. Mechanisms that lead to these disorders are
complex, and while most drugs are designed to raise or lower the level of
certain chemicals, the exact chain of events that leads to treatment of the
disease is often unknown. In the case of Major Depressive Disorder (MDD),
inhibition of serotonin transporters (SERT) and antagonism of synaptic
serotonin receptors (5-HT receptors) have been shown to treat MDD and many
drugs on the market today have these qualities. Monoamines, synthesized from
halogenated benzenes, have demonstrated some of these qualities and have been
investigated by pharmacists as potential MDD drugs. This led to the discovery
of Vortioxetine, a molecule capable of both SERT inhibition and 5-HT binding.
The dual activity displayed by Vortioxetine was the target of an
iterative assay performed by Lundbeck that scanned all known compounds in their
database. Molecules that produced hits on SERT assays were screened for 5-HT
binding affinity. Several compounds demonstrated dual activity, but Vortioxetine
had an unexpected effect on the 5-HT receptors. Like the others, it was
antagonistic to multiple synaptic serotonin receptors. However, Vortioxetine
was agonistic of 5-HT1A, a presynaptic receptor that plays a role in
the reuptake of serotonin. It was theorized this unintended response reduced
the onset of serotonin syndrome, a condition common to antidepressant
medication that weakens the effectiveness of the drug. This effect gave it an
advantage over previous antidepressants on the market. These findings were
demonstrated in vitro and further studied in rat models. Increased serotonin
levels were found in the hippocampus and prefrontal cortex of the rats, an
indicator of predictive validity. Vortioxetine passed through clinical trials
with the help of a second company, Takeda, and has been approved in the US and
Europe since 2013.
Although the drug was not approved by the FDA until 2013, patents for
the chemical appeared in the US as early as 2000. International patents can be
seen the following year. The lineage of this compound can be traced to a previous
1980 patent referencing azacycloalkanes and their derivatives for use as
antidepressants. Lundbeck most likely incorporated these compounds into their
database based on this information, and subsequently filed a patent of their
own after synthesizing a salt incorporating one such compound. The rights to Vortioxetine
and three other compounds were shared with Takeda when the companies entered a partnership
to survive clinical trials. Takeda is a pharmaceutical company based in Tokyo
who boast a $10+ million annual revenue. Lundbeck, founded in Copenhagen, has grown
to become a $17.2 billion company. As part of their agreement, Lundbeck took over
sales operations in the US while Takeda marketed in East Asia.
Vortioxetine, like other selective serotonin reuptake inhibitors (SSRIs),
increases serotonin levels in the brain. It does this by inhibiting serotonin
reuptake from the synapse and by binding with various serotonin receptors along
the synapse. This is mostly effective for the treatment of MDD and other
psychological disorders, but the higher levels of serotonin wear down the
synaptic receptors which can lead to serotonin syndrome. This is where the
neurons lose sensitivity to serotonin, reducing the effectiveness of the
antidepressant and potentially worsening the symptoms. The ability of
Vortioxetine to modulate receptors through both agonistic and antagonistic
responses seems to eliminate the loss of sensitivity. Antagonism of serotonin
receptors 5-HT3, 5-HT1D, and 5-HT7 contribute
to the elevated levels, but agonism of the 5-HT1A receptor on the
presynaptic neuron negates the negative feedback loop triggered by the increase
in serotonin. Additionally, this may accelerate the antidepressant effect. This
combination maintains the reuptake inhibition without wearing down the
receptors that normally process the neurotransmitter.
The development of Vortioxetine moved quickly after clinical trials. It
was branded as Brintellix, rebranded as Trintellix, and had success in multiple countries. This rebranding
was approved by the FDA in July of 2015. This change was necessitated by a
popular blood thinner by the name of Brillinta.
An official safety announcement was made by the FDA regarding the change,
alerting healthcare professionals and patients to be cautious when prescribing
or taking these medications. It was recommended the generic name be included
with prescriptions and packaging to avoid confusion. This change resulted in the
chemical receiving a new National Drug Code number.
The active ingredient is delivered by film-coated tablets labeled by
color depending on the dosage. The drug should not be taken with other serotonergic
medications. Adverse reactions were uncommon, and ranged from mild effects such
as nausea, headache, and dry mouth, up to more serious effects such as
hypertensive crisis, increase rate of suicide, and pancreatitis. Although the
drug occasionally produced adverse side effects, the improvement in
effectiveness and longevity of the treatment made the drug a success.
The most compelling aspect of
Vortioxetine’s development was the company’s decision to screen for a compound
with multiple target interactions. They were able to discover a novel mechanism
of treatment that improved both effectiveness of the medication and
understanding of the disease.
References:
What is the size of the market (in dollars)? Are there any recent new patents for combination drugs or new formulations? Any warning letters for current manufacturers?
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