The “Reuptake-Plus” Antidepressants by Dr. Neal Ranen, M.D. Baltimore Psychiatrist

I previously reviewed antidepressants known as SSRI’s and SNRI’s that work as reuptake inhibitors (see June 27, 2010 blog). This mechanism of action allows serotonin and norepinephrine to remain available long after release, increasing the likelihood that they will occupy docking stations, or receptors, on surrounding neurons, and exert an effect.  There are a couple of newer antidepressants that work not only as reuptake inhibitors but also directly occupy receptors.  I reviewed one of these, vilazodone, or Viibryd, in a previous blog, and since then a newer “Reuptake-Plus” antidepressant has become available, called Trintellix.  This medication acts as a serotonin-reuptake inhibitor plus directly occupies serotonin receptors, either stimulating or inhibiting them, creating additional effects.  There are many types of serotonin receptors, and Trintellix has effects on 5 of them. As above, Trintellix activates some of these receptors but inhibits others. This may sound confusing, but the inhibitory effect can actually activate certain other chemical messenger pathways in the brain. To understand this, it is important to know a couple of pieces of information.  The first is that some chemical messengers in the brain (known as neurotransmitters) activate neurons (known as being excitatory) and some inhibit them (known as being inhibitory). They do this by having stimulating or inhibiting effects when they attach to receptors on surrounding neurons. Serotonin, for example, is an excitatory neurotransmitter.

The next layer of complexity is that serotonin neurons can connect to a second neuron that itself is either excitatory or inhibitory.  So, if serotonin attaches to a receptor on an excitatory neuron, more excitatory activity will be triggered, but if it attaches to a receptor on an inhibitory neuron then there will be more inhibition of brain pathways because it is activating the inhibition.

The next level of understanding is that there are a lot of intermediary neurons in the brain that function as connections between two other neurons.  There will be a first neuron that will connect to the intermediary neuron, known as an interneuron, which will, in turn, connect to the third neuron. These interneurons are usually inhibitory – they hold back activity in the third neuron. The first neuron is usually excitatory – the neurotransmitter it releases, like serotonin, will activate this inhibitory interneuron which results in suppressing the activity of the third neuron. So, serotonin receptors, although always excitatory, can either suppress activity if it is on an inhibitory interneuron or stimulate activity if it is on another neuron that itself is excitatory.  Now we can understand how Trintellix can increase activity in the brain even though it stimulates some and blocks other serotonin receptors: the receptors it stimulates are on neurons that are also activating, and the receptors it blocks are on neurons that are inhibitory.  In the latter case, this will prevent activation of the inhibitory neuron, thereby taking away the brake on activity in the next neuron. This may or may not be associated with certain advantages  (or disadvantages) depending on the type of symptoms of depression a person is experiencing.  For example, in addition to its overall antidepressant effect, this may result in an increase in cognitive processing speed and be less associated with weight gain, but in my experience not work as well if there is a high level of anxiety or irritability associated with the depression. So, a lot may depend on the person’s specific symptom pattern. This is why a careful psychiatric assessment is critical to determine what antidepressant might be right for any particular individual.

To learn more or to make an appointment with Dr. Neal Ranen, M.D. call 410-413-2145.

This article was originally posted on Dr. Neal Ranen