The pharmacology of antidepressants: depression is a major cause of morbidity worldwide.
The lifetime prevalence of depression varies greatly but it is estimated that between 8
and 12 percent of people will suffer from depression at some point in their lives.
Some of the classes of antidepressant medications we will be discussing are Noradrenaline uptake
inhibitors, Monoamine Oxidase A inhibitors, or MAO-A inhibitors for short, tricyclic antidepressants
and Selective serotonin reuptake inhibitors or SSRIs.
In this tutorial we will be concerned with both noradrenergic and serotonergic nerve
endings.
To begin with we have a representation of a noradrenergic nerve ending, with the neurotransmitter
noradrenaline stored inside a vesicle, and a noradrenaline transporter on its surface.
Noradrenaline is moved to the presynaptic terminal within its vesicle, where it fuses,
releasing noradrenaline into the synaptic cleft.
Here some is free to be taken up by a post-synaptic adrenoreceptor.
However, some noradrenaline is taken back into the presynaptic noradrenergic nerve via
the noradrenaline transporter.
Here it is broken down by the enzyme Monoamine Oxidase A, or MAO-A for short, into noradrenaline
aldehyde.
This reduces the amount of noradrenaline available to travel to the post synaptic adrenoreceptor,
and in individuals with depression there is a greater reduction in the availability of
noradrenaline than usual which underpins one of the proposed mechanisms for depression
– a reduced amount of noradrenaline available to be taken up by the post-synaptic adrenergic
nerve.
Therefore in order to treat depression, it would be helpful to increase the amount of
noradrenaline available to the post-synaptic adrenergic nerve- we will now discuss methods
for doing this.
Again, noradrenaline is released and some makes its way to the post-synaptic noradrenergic
nerve, while some makes its way towards the noradrenaline uptake transporter.
However, by the addition of a noradrenaline uptake inhibitor, such as maprotiline, a conformational
change in the shape of the noradrenaline binding site on the transporter occurs which stops
noradrenaline from being taken back into the presynaptic nerve – and so there is now
more available to act at the post-synaptic adrenergic nerve.
This increase the amount of noradrenaline available to the post-synaptic adrenergic
nerve helps to reduce the severity of depression.
Tricyclic anti-depressants such as imipramine and amitriptyline also bind to the noradrenaline
transporter, blocking noradrenaline from binding and so reducing the amount taken back into
the pre-synaptic nerve.
Again, this increases the amount of noradrenaline available to act at the post-synaptic adrenergic
nerve, improving symptoms of depression.
Another method of increasing the amount of noradrenaline available in the synaptic cleft
to act at the post synaptic adrenergic nerve is through the use of an MAO-A Inhibitor such
as Phenelzine or Isocarboxazid.
These bind to the enzyme MAO-A preventing it from breaking noradrenaline down into noradrenaline
aldehyde, thereby increasing the amount of noradrenaline available for transport via
vesicles to the synaptic cleft and ultimately to the post-synaptic adrenergic nerve – which
helps to reduce the symptoms of depression.
Now if we look to a serotonergic nerve, we can see that the principles are similar.
Here we have a representation of a serotonergic nerve ending, with the neurotransmitter serotonin
stored inside a vesicle, and a serotonin transporter on its surface.
Serotonin is moved to the presynaptic terminal within its vesicle, where it fuses, releasing
it into the synaptic cleft.
Here some is free to be taken up by a post-synaptic serotonin receptor.
However, some serotonin is taken back into the presynaptic serotonergic nerve via the
serotonergic transporter.
Here it is broken down by the enzyme Monoamine Oxidase A, or MAO-A for short, into serotonin
aldehyde.
This reduces the amount of serotonin available to travel to the post synaptic serotonin receptor,
and in individuals with depression there is a greater reduction in the availability of
serotonin than usual which underpins one of the other proposed mechanisms for depression
– a reduced amount of serotonin available to be taken up by the post-synaptic serotonin
receptor.
Therefore in order to treat depression, it would be helpful to increase the amount of
serotonin available to the post-synaptic serotonin receptor- we will now discuss methods for
doing this.
Again, serotonin is released and some makes its way to the post-synaptic serotonin receptor,
while some makes its way towards the serotonin uptake transporter.
However, by the addition of a selective serotonin reuptake inhibitor, or SSRI, such as fluoxetine
and paroxetine, binding site stopping serotonin from being taken back into the presynaptic
nerve – and so there is now more available to act at the post-synaptic serotonergic receptor.
This increase the amount of serotonin available to the post-synaptic adrenergic nerve helps
to reduce the severity of depression.
Tricyclic anti-depressants such as imipramine and amitriptyline also bind to the serotonin
transporter in much the same way as they bind to the noradrenaline transporter as discussed
previously.
This blocks serotonin from binding and so reduces the amount taken back into the pre-synaptic
nerve.
Again, this increases the amount of serotonin available to act at the post-synaptic serotonin
receptor, improving symptoms of depression.
Another method of increasing the amount of serotonin available in the synaptic cleft
to act at the post synaptic serotonergic nerve is through the use of an MAO-A Inhibitor such
as Phenelzine or Isocarboxazid.
These bind to the enzyme MAO-A preventing it from breaking serotonin down into serotonin
aldehyde, thereby increasing the amount of serotonin available for transport via vesicles
to the synaptic cleft and ultimately to the post-synaptic serotonin receptor – which
reduces the severity of the depression.