Important Terminology:
Neuron: the primary cells of the brain that are highly interconnected, communicate with each other, and are responsible for the “work” of thinking, controlling behavior, movement, and regulating bodily functions.
Synaptic cleft/space: the space between two (or more) connecting/communicating neurons. This communication is done mostly through the transmission of the neurotransmitters across the synaptic cleft/space from one “presynaptic” neuron to the “postsynaptic” neuron.
Receptor: proteins on the surface of neurons that bind to/transmit/interact with neurotransmitters (such as serotonin, dopamine, and norepinephrine, amongst many others) to facilitate the communication between neurons and lead to changes in and the actions of the neuron.
Downregulation: a decrease in the amount of receptors on the surface of a neuron, and therefore decreases opportunity for the neurotransmitter to bind and cause an effect (simply, the neuron will be less “active”).
Theories of Depression:
As we did with ADHD, we will start by discussing current understanding of the neurobiological basis of this depression which consists of two primary theories.
The first and older of the two theories is called the monoamine theory of depression. As a reminder, monoamine refers to three related neurotransmitters – serotonin, norepinephrine, and dopamine – with serotonin and norepinephrine being the most relevant to depression. To some extent, this theory originates in doctor’s observations of patient responses to various medications (used for a different condition), which then led to further research. Both animal and human research then showed decreased/impaired serotonin (and to a lesser extent norepinephrine) functioning in the relevant regions of the brain involved in mood and emotion regulation (prefrontal cortex, parts of the limbic system and midbrain) in depression. These findings led researchers and clinicians to theorize that depression may be caused by (or at least related to) impairment in serotonin and norepinephrine activity and functioning.
The second theory involves a growth factor signaling system called “brain-derived neurotrophic factor”, or BDNF. BDNF is involved in the growth, survival, and maintenance of neurons in the brain, making it vital to synaptic plasticity and our ability to regulate mood. Fittingly, studies have consistently shown a negative correlation between BDNF functioning and depressive symptoms. Hence, it is theorized that low levels of BDNF activity (specifically in a part of the brain called the hippocampus) may predispose, or at the very least contribute, to the development of depressive symptoms.
SSRIs and Depression:
Selective serotonin reuptake inhibitors (abbreviated as SSRI’s) are considered the first-line option (as well as for most anxiety disorders, more on those later). As the name suggests, SSRI’s primary mode of action is to target the serotonin system through the inhibition of the SERT transporter. SERT is a protein on the surface of a neuron that “cleans up” serotonin (and other neurotransmitters) from synaptic space resulting in increased amounts of serotonin in the synaptic space. However, this is only the beginning of the story. Over time, the increased serotonin leads to a downregulation of another type of serotonin receptor called the 5-HT1A receptor, an ““inhibitory auto-receptor”, meaning that when active, the 5HT1A receptor inhibits the activity of serotonergic neurons. So, by downregulating an inhibitory receptor (or “inhibiting inhibition), SSRIs lead to activation and an increase in overall serotonin neurotransmission! As noted, this downregulation takes time (weeks to months), which helps us understand why there is a delay in the effects of SSRIs.
Newer research has shown that SSRI’s also act by increasing BDNF levels, which, as mentioned above, may help address another pathophysiological cause of depressive symptoms. While the exact mechanism for this increase in BDNF is not fully understood, the current theory is that this occurs as a secondary result of increased serotonin, as well as the SSRI binding to a receptor that helps stabilize BDNF signaling.
In addition to their desired/targeted effects, SSRIs (as with all medications) may also cause undesired effects as well, which primarily occurs through their alteration of serotonin. The most common side effects are gastrointestinal upset (nausea/diarrhea/constipation), headaches, dizziness, insomnia, activation/anxiety, and drowsiness. These side effects, if they do occur, tend to be manageable, occur early in treatment, and often resolve as the body/brain adjusts to the medication. There are more rare and serious side effects including the black box warning regarding the risk of increased suicidality thoughts in individuals under 25yo, induction of mania/hypomania (primarily in individuals with significant risk factors for bipolar disorder), lowering of seizure threshold, and possible sexual dysfunction. These should be discussed directly with your mental health clinician to help guide you and make the decision that is best for you or your loved one’s treatment. Lastly, it is also worth noting that while all of the SSRIs share general side effect profiles, they can differ in the frequency/intensity of specific side effects
