How Antidepressants Work Part 2: The Nitty Gritty

How Antidepressants Work Part 2: The Nitty Gritty

As explained in last week’s blog, How Antidepressants Work Part I: The Basics, antidepressants largely exert their effect (at least initially) by impacting the availability of various neurotransmitters in the synapse. The goal is to extend the amount of time neurotransmitters spend in the synapse, thereby increasing their chances of binding to receptors and causing a change in neighboring cells. Each class of antidepressant has a unique approach in terms of which individual neurotransmitters it affects and the method in which it does so. In general, there are 2 major mechanisms of action for antidepressants medication: enzyme deactivation (MAOIs) and reuptake inhibition (most other antidepressants).

Monoamine Oxidase Inhibitors (MAOIs)

Just as the name implies, MAOIs inhibit (or block) the enzyme monoamine oxidase (MAO) which is normally tasked with breaking down certain neurotransmitters in the synapse (the Pac-Man of the synapse, so to speak). Blocking MAO, therefore, delays the breakdown of these neurotransmitters, allowing them to linger in the synapse and increasing their potential to bind to neighboring receptors.

In terms of antidepressant action, MAOIs slow the breakdown of serotonin, norepinephrine, and to a lesser extent, dopamine. Unfortunately, these medications also slow the breakdown of a naturally-occurring substance known as tyramine. Too much tyramine can lead to dangerously high blood pressure, so users of MAOIs have to follow a very low-tyramine diet (say goodbye to many types of cheese, meat, beer, fruit, and various other commonly eaten products!) in order to avoid tyramine-related side-effects.

Tricyclic Antidepressants (TCAs)

TCAs are the original reuptake inhibitors that paved the way for more recently developed and commonly known options, such as Prozac (a selective serotonin reuptake inhibitor, see below). In a nutshell, reuptake is the recycling program for brain cells – it brings the neurotransmitter back to the cell that originally released it in order to repackage and store it for future use. Reuptake inhibitors, therefore, block the cell’s ability to take its neurotransmitter back from the synapse, thereby leaving it to linger in the synapse for longer periods of time (and, again, allowing more time for binding at receptors and creating change in neighboring cells).

TCAs owe much of their therapeutic effect to inhibiting reuptake of serotonin, norepinephrine, and dopamine. Similar to MAOIs, the biggest drawback to TCAs is the impact on other substances/functions in the body that do not play a role in symptom reduction. In this case, one example is the impact on histamine, which leads to side effects similar to taking an antihistamine like Benadryl (think sedated and drowsy). Some doctors cleverly use this side-effect to their advantage by prescribing their patients to take their dose at night!

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs ushered in a new era of selective antidepressants that maintain the effectiveness of earlier options (MAOIs and TCAs), but with fewer side effects and safety risks. To this day, they are the largest and most prescribed class of antidepressants, including well-known options, such as Prozac, Paxil, Zoloft. SSRIs work similarly to TCAs, but rather than blocking reuptake of many neurotransmitter families, SSRIs affect serotonin only.

While SSRIs are “cleaner” in terms of their selective impact on serotonin, they are still associated with significant side effects. As discussed in How Antidepressants Work Part I: The Basics, 95% of the serotonin in the body is actually located in the gut – this helps to explain many of the gastrointestinal side effects, such as bloating and nausea, that commonly occur during antidepressant treatment. Other common side effects, such as sexual dysfunction and insomnia, also make sense in light of serotonin’s functions in the brain and body.

Dual Reuptake Inhibitors (SNRIs & NDRIs)

The interesting thing about antidepressants is that everyone responds to them differently; one person’s successful option is another person’s dud. Serotonin and norepinephrine reuptake inhibitors (SNRIs) and norepinephrine and dopamine reuptake inhibitors (NDRIs) add to the overall success of antidepressant treatment by impacting other unique and selective combinations of neurotransmitters. They provide options in terms of therapeutic effects and side effects, allowing a more specialized fit for individuals with differing presentations, symptoms, and co-occurring conditions.

SNRIs (e.g., Cymbalta) and NDRIs (e.g., Wellbutrin) are referred to as “dual reuptake inhibitors” because they prevent the reuptake of 2 neurotransmitters each. SNRIs and NDRIs are often experienced to be more stimulating than SSRIs due to their impact on norepinephrine, particularly NDRIs due to their additional impact on dopamine. Many users appreciate this aspect of these medications, but some experience the additional stimulation as anxiety-producing.

It’s worth noting that the acronym SNRI can also refer to selective norepinephrine reuptake inhibitors often used for mild-to-moderate ADHD (e.g., Strattera), so be sure to be aware of the possibility of miscommunication if communicating with the acronym alone!

Newer Options

Many of the newest antidepressants combine standard reuptake inhibition with other more advanced and selective techniques. These medications have capitalized on findings that different receptor sub-types impact mood and cognitive processes differently than others. Serotonin, for instance, has been shown to have very different responses depending on which specific receptor it binds to; activation of sub-type 1 is more likely to cause antidepressant effects, while activation of sub-type 2 is more likely to cause side effects like insomnia and anxiety!

Trazodone (Oleptro) is an example of a newer antidepressant that essentially performs as an SSRI with the added bonus of blocking serotonin sub-type 2 receptor – in theory, the therapeutic effects of an SSRI, but with fewer side effects. Vilazodone (Viibryd) takes a different approach, working as an SSRI with additional activity at the sub-type 1 receptor, thereby theoretically enhancing therapeutic effects without increasing side effects.

But, Wait, There’s More!

Researchers have acknowledged the limitations of the simple neurotransmitter explanations of antidepressant actions in terms of explaining the 4 – 6-week time lag associated with antidepressant effectiveness and the extreme variability in terms of therapeutic and side effects. Neuroscientists have two primary explanations that account for this delay.

1. It correlates with the timing of the brain’s homeostasis mechanisms. Essentially, antidepressants cause side effects while the brain seeks to restore a new balance followed by positive, therapeutic effects only after adjusting to it.

2. Antidepressants indirectly increase proteins that act as brain fertilizer, which then encourages the development and connection of brain cells. This brain fertilizer, known as brain-derived neurotrophic factor (BDNF) can also be activated by a variety of other non-pharmacological activities and experiences.

Medications do not work for everyone and many individuals choose not to take them based on a variety of conflicting beliefs and experiences. Next week, in Part III: Nonpharmacological Approaches, we’ll explore holistic strategies for the treatment of depression that can be used with or without the concurrent use of medication.

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