Understanding Antidepressants

Posted by James Driver, With 0 Comments, Category: medication, Tags: , ,

I figured it made sense to start a detailed discussion about psychotropic medications by beginning with antidepressants since they’re probably the most common.  Apparently, as of 2014 one in nine adults and one in six women are taking antidepressants.  I want to briefly discuss the four most commonly used types of antidepressants in New Zealand (SNRIs, SSRIs, MAOIs, and TCAs – you’ll get used to the acronyms, psychiatry is full of them) but first of all start with a brief and really important overview of how these things work in the brain.

This gets a little technical, but it’s also really important in understanding how most antidepressants (and atypical anti-psychotics) work, so put on your best thinking hat and read on.  Each antidepressant is made up of molecules that bind themselves to various receptors and systems in our brain, and affect those systems in some way.  Most antidepressants we use tend to work because of the ways in which they affect specific systems and neurotransmitters in our brain, most notably serotonin, norepinephrine and dopamine.  However, and this is the important bit, these are not the only neurotransmitters and receptors in our brain that are affected.  Each antidepressant has what are called ‘affinities’, which are basically preferences of where it will go in the brain once it gets into your bloodstream.

Imagine a parking garage made up of multiple floors.  Each floor represents one of the systems or receptors in your brain, and has a limited number of parks.  A molecule of an antidepressant works kind of like a car that comes to the parking garage looking for a park.  In this case, let’s imagine that the car is Amitriptyline, a particular antidepressant.  Amitriptyline’s first preference is to bind to the H1 receptors in your brain, so in our parking-garage analogy this would be the first floor of the garage.  The first molecule comes along, finds a park in the first floor and all is well.  The next molecule does the same, and so on.  Eventually though, this floor of the garage fills up and the next molecule that comes along can’t find a park – what happens then?  Well, then it looks for the next most preferred place to park, in this case probably the serotonin transporter protein.  The next few molecules do the same until this floor is filled up, and then subsequent molecules have to find a park somewhere else.  This continues on until all possible ‘parks’ in the parking garage are full.

The reason this is important to understand is that these different receptors in the brain/levels in our parking garage do very different things.  In the case of the H1 receptor in the brain, the effect of Amitriptyline on this receptor is to make you sleepy.  The effect of Amitriptyline on the serotonin transporter protein is to make you feel better (hopefully).  So what this means is, if you take a really low dose of Amitriptyline, all of it will just fill up the parks at the bottom of the parking garage (the H1 receptor) and all you’ll get is that you feel sleepy.  It’s not that you don’t get much antidepressant effect, it’s that you get absolutely no antidepressant effect because all the molecules of the drug are going first of all to a receptor in the brain that influences sedation.  If you then increase the dose, you’ll start to get an antidepressant effect.  If you continue to increase the dose past a certain point, you won’t get any more antidepressant effect because that level of the parking garage is now full, and subsequent molecules will bind to receptors that create different side effects (or do nothing).  This is why getting dosing right with antidepressants is so important, because increasing or decreasing the dosage can be less about increasing/decreasing the effect of the drug and more about introducing completely different effects.  It also means that you won’t get more of an existing effect beyond a certain point – which means just because you’re experiencing a side effect from a particular drug does not mean you will experience more of that side effect if you increase the dosage.

So what do all these drugs do then?  Well, starting with the most common:


Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants are the most commonly prescribed antidepressants in New Zealand (including Fluoxetine, Citalopram, Escitalopram, Paroxetine and Sertraline).  These work by affecting the serotonin receptors and transport systems in the brain in ways that are far too complicated for me to get my head around, and which are still not fully understood even to psychiatrists working specifically in this area.  We know that serotonin is somehow involved in some forms of depression, but exactly how is unknown – it’s not as simple as ‘not having enough’ when it comes to levels of specific neurotransmitters in the brain.

These are generally tried first before any other antidepressants due to their generally lower risk of side-effects.  However, there are some very common side effects experienced with these drugs including (with reported rate of likelihood):

56% decreased sexual functioning (reduced libido, anorgasmia, delayed ejaculation)
53% drowsiness
49% weight gain
19% dry mouth
16% insomnia
14% fatigue
14% nausea
13% light-headedness
12% tremor


These numbers are averaged across multiple SSRIs, so may vary from one drug to the next.  The ‘selective’ part of SSRI refers to the fact that these drugs are more selective about binding to the receptors in the brain associated with their antidepressant effect.  If we go back to the parking garage analogy, they look for the parking spaces that have to do with serotonin (which affects mood) more than the spaces to do with other effects.  The fact that some of these side effects still occur for a majority of people relates to the fact that they’re not perfectly selective, so some binding to other receptors in the brain still occurs.  However, the idea is that they’re more selective than older antidepressants like tricyclics.

One other common feature of SSRIs that is worth being aware of, particularly if you’re taking them for the first time, is that they usually take up to six weeks to take full effect.  During this time it is not uncommon to experience increased anxiety, including racing thoughts, increased heart-rate, jitteriness or trouble sleeping.  These symptoms often subside after the initial period, but can lead to people stopping taking the medication before it has a chance to create a positive effect.



Another reasonably common class of antidepressants are Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs).  These work on the serotonin transporter proteins (the same as SSRIs) but also affect the norepinephrine transporter protein which is also indicated in affecting our mood.  In New Zealand, the most common SNRIs I’m aware of being prescribed are venlafaxine and duloxetine.  SNRIs tend to create very similar side-effects to SSRIs due to very similar mechanisms of action.


Tricyclic Antidepressants

Tricyclic Antidepressants (TCAs) are older antidepressants and were some of the first to be used to treat major depressive disorder.  These medications include things like nortriptyline, amitriptyline and imipramine.  TCAs have usually been shown to be just as effective as more modern SSRIs and SNRIs, but are typically used less often due to increased side effects.  This increase is due to the fact that tricyclic antidepressants bind preferentially to a lot more receptors and systems in the brain than SSRIs do – that is, they’ll fill up the parks to do with sleepiness/sedation before you get an antidepressant effect, which is why they are sometimes used as sleep aids in low doses.

Some studies have shown TCAs to be more effective than SSRIs in the treatment of melancholic depression  (a particularly serious and debilitating form of depressive disorder), and some people find that they do not particularly notice or are not affected by the sedative effect of TCAs.  For this reason, they are still quite commonly used.  If you suffer from severe depression and have tried a range of SSRIs without any effect, then it can definitely be worth trying a tricyclic antidepressant as it may be that you are more responsive to these than to SSRIs.



The last type of antidepressant I’ll talk about and probably the least prescribed in New Zealand are Monoamine Oxidase Inhibitors (MAOIs).  The most common MAOI I’m aware of being used in NZ is moclobomide, but there may be others.  In a different way, MAOIs also have an affect on serotonin, dopamine and norepinephrine in the brain – all antidepressants tend to work on these systems, but in different ways and with different degrees of preference.  MAOIs tend to be used infrequently in the treatment of depression due to the fact that they have potentially lethal interactions with certain foods and other medications, although recent research has called this into question and shown that at least some of these interactions have been over-stated and are less dangerous then previously thought.

MAOIs have been shown to be effective in the treatment of depression, and are sometimes prescribed for this reason when SSRIs and TCAs have been tried without effect.  Due to a somewhat different mechanism of action, they can be effective when other medications have not been.  As long as people taking them are mindful of the dietary restrictions and other potential interactions, MAOIs can be a useful treatment option and for some people produce fewer side effects than other medications.



Hopefully this gives you a bit of an idea about what to expect and the options available in terms of antidepressants in New Zealand.  There are a few other medications available including atypical antidepressants like Buproprion which I haven’t mentioned as these are generally not used unless other treatments have been ineffective, but I’ve covered the major types that are used in treatment.  As I stated in my first article about psychotropic medication, these medications can be both enormously helpful for some people, and worthless or problematic for others.  The general principle of ‘what can help can harm’ applies here – particularly since as discussed, these medications affect other systems in the brain apart from those that are just to do with mood.  I really encourage anyone taking or thinking of taking antidepressant medication to research how it works, the side effects for that particular medication, and to record for yourself what you notice in terms of both positive and negative changes.  The more you can become aware of your own responses to medication, the more you will be able to help your prescriber make choices about what best to prescribe if the first things you try are not effective.