A Comprehensive Objective (no BS) Summary about Antidepressant Agents

Hi, everyone.

I have some free time away from my classes so that I can write up a good informative post. I have been wanting to make this post for a long time. Antidepressants are some of the most polarizing drugs we all know of these days. Some people (especially many people who have had bad experiences with them) hate them, others find them as life-savers. The truth is that they react very uniquely with every individual. For me, they don't do much, but I DO know people with severe depression who can live a normal life.

Now, for this summary, I am talking about drugs that the FDA calls 'antidepressants.' We all know that many other drugs are antidepressants, such as a wide slew from Cannabis to Amphetamine (both of which IMO work better than the FDA antidepressants...). But I would take up too much screen-space talking about them. So I will explain how antidepressants work, some myths, and some observations. But I will keep it objective. All of my scientific claims are evidence based. I use the book "Principles of Neuropsychopharmacology" for many of my statements, so I will not use in-line citations.

Types of Antidepressants:

Selective Serotonin Reuptake Inhibitors (SSRIs): I will get this class 'out of the way' right away haha. These drugs work in a very specific way, although modern research shows they may not be as 'selective' as once thought. Examples include: Prozac, Luvox, Zoloft, Lexapro/Celexa (they are essentially the same thing), Paxil, and more.

How do they work? Well, on the most basic level, they act by 'plugging' the pre-synaptic serotonin autoreceptors. That is, on neurons which transmit serotonin, a neurotransmitter, autoreceptors exist so that excessive amounts of serotonin flow is 're-uptaked' (sucked back up) by these auto-receptors. Thus, a more consistent flow of serotonin can exist in the brain. But these drugs significantly (like up to 95%) disable the auto-receptors, allowing for higher than normal amounts of serotonin to flow from neuron to neuron. This does NOT mean that serotonin is a happy chemical NOR does it mean that the effects of these drugs is even FROM elevating serotonin levels. More on that later.

Tricyclic Antidepressants: These are 'dirty drugs' (they hit many targets) that were invented in the 1950s-1980s. They include things like: Elavil (Amitriptyline), Pamelor (Nortriptyline), Imipramine, etc.

How do they work? Well, basically, they combine the Serotonin Reuptake Inhibition from the SSRIs, but add some other properties. Importantly, the plug the Norepinephrine auto-receptors to some degree. Norepinephrine is adrenaline in the brain. Again, this doesn't mean that NOR-reuptake is the cause of their effectiveness. They also work subtly on a few receptors that are not auto-receptors. These receptors exist on POST-synaptic neurons.

First of all, many of them block 5-HT2A receptors. Doing so leads to reduced anxiety and serene behavior commonly hypothesized due to the suppression of Cortisol release (stress hormone). They also block Histamine receptors. Just like Benadryl, this means sleep induction. So if a person is anxious and depresssed and can't sleep, Tricyclics can help. Most dangerously, they are anti-cholinergics (so is Datura and Atropine), which lead to cognitive problems, memory disruptions, and muscle-tone problems. This has not effect in treating depression. It is just a side effect. But worth noting.

Serotonin and Norepinephrine Reuptake Inhibitors: These drugs were developed around 5 years after SSRIs. Examples are: Effexor (venlafaxine), Cymbalta, and Pristiq (a metabolite of Effexor that is heinously marketed as its own drug...).

As you can guess, they plug serotonin and norepinephrine auto-receptors. But unlike Tricyclics, they don't hit the problematic histamine and Acetylcholine post-synaptic receptors. They are statistically shown to be MORE effective than SSRIs in people with (this is important) SEVERE depression. In fact, Effexor is widely considered the most effective FDA approved antidepressant outside of the MAOis.

Monoamine Oxidase Inhibitors: These are the first antidepressants. They are also dirty drugs. They include things like Nardil and Selegine. They are not used too much these days due to interactions with many foods.

Like the other antidepressants, these drugs work to inhibit the work of Monamine Oxidase, an enzyme that destroys excessive amounts of Serotonin, Norepinephrine, Dopamine, Histamine, and Melatonin. So they are very dirty drugs. However, they are very effective. The likely reason for their effectiveness is the Dopamine level increase. Dopamine increase is one of the only 'proven' mechanisms for boosting one's mood.

Others: Wellbutrin (Bupropion) is a Norepinephrine and Dopamine reuptake inhibitor. So it block dopamine auto-receptors as well. This leads to very effective results since, like mentioned, dopamine is directly implicated in anti-depression.

The drug Mirtazapine (Remeron) and Trazadone work mainly as 5-HT2C antagonists. This is important, because what antagonizing 5-HT2C does is that it directly releases Dopamine and Norepinephrine in the brain. So, again, the dopamine theme is here.

How they REALLY work:

So, you may have heard the terms "chemical imbalance" and "serotonin is a happy hormone." Both are extreme over-simplifications of how antidepressants work. The real picture is more complex.

The reason that increasing serotonin levels 'works' is that after your brain gets bombarded by too much serotonin (from these drugs), the POST-synaptic serotonin (5-HT) receptors start to down-regulate. Thus, it is similar to antagonizing all of the 5-HT receptors. NOW, these 5-HT receptors have secondary effects that have NOTHING to do with serotonin. Thus it is not a happy hormone. The most prominent effects are 5-HT2C receptors, which like I said, release dopamine. And dopamine IS implicated in sense of well being (ever heard of Amphetamine, Heroin, or Cocaine...). Another effect is on the 5-HT1A receptor. This receptor, if down-regulated, allows for the suppression of hormones. So, in turn, Cortisol (the stress hormone) and adrenaline is suppressed. Interestingly, these agents also are weak 5-HT1A PARTIAL agonists, which directly releases Oxytocin which leads to calmness, anti-aggression, and empathy.

So, you can see that the real effects of SSRIs have nothing to do with serotonin.

As for agents that enhance Norepinephrine levels, there is an obvious reason that works so well. The Norepinephrine auto-receptors actually recycle not only NOR but also Dopamine! Especially in the pre-frontal cortex. So any NOR-reuptake inhibitor is also a Dopamine reuptake inhibitor (just like Ritalin and Cocaine is), and dopamine flux in the prefrontal cortex allows for more 'rational' thinking and increased confidence.

And the SSRIs aren't as selective as once thought. The most effective SSRIs tend to be Prozac and Zoloft. It was found out the Prozac antagonizes 5-HT2C (the dopamine-releasing receptor) and is a 5-HT1A agonist (the Oxytocin releaser). So that makes some sense. And Zoloft was found to actually act as a Serotonin AND Dopamine reuptake inhibitor. It just happens at a higher dose than the original product was marketed for.

And for Effexor's supreme effectiveness. Well, first of all, they discovered that it is a Dopamine reuptake inhibitor at higher doses (the very doses that work BEST for the severely depressed) AND it is a mu-opioid receptor agonist (you know, like MORPHINE and OXYCODONE!) But again, that only happens at higher doses. But guess what? Those doses are commonly used for severe depression.

Some Remarks:

The reason people 'like' antidepressants is that they boost your mood WITHOUT resorting to being 'evil' 'addictive' drugs like amphetamine, opioids, or Cannabis (which is ridiculous especially in the last case). People feel okay with the fact that they feel better in a 'legally sanctioned' way.

But the truth reveals that these drugs primarily are effective through complex indirect mechanisms that release Dopamine. Just like all of those 'evil' drugs that people eschew so much. So things like the "Serotonin Hypothesis" is partially correct: Yes, serotonin is a small part of the story. But in reality, these drugs are just legally-approved, sneaky ways to release dopamine. But they have horrible side-effects.

So why not just prescribe the direct dopamine-enhancing drugs? The fear of addictive drugs is still as widespread as ever, but the trend is changing. In my OWN case (although I have Bipolar Schizoaffective Disorder not just depression), when I was prescribed amphetamines, my depression lessened more than with any other drug in my life. And the only side effect is that I LIKE taking it. I have no tolerance. I don't abuse it. But I DO like it. When I had a small dose of Suboxone added to my regimen, I have been content with life ever since. Have I sucked dick for Suboxone? No. Have I used it all up in three days running short? Not once. I take it by mouth every day (haha- bad place to write that phrase with that dick sucking comment) and take only as much as I did the first day of treatment.

People CAN handle taking 'addictive' drugs. And if the choice is between suicide and a mild addiction, I would HOPE that people would choose the mild addiction.

So that is the story on antidepressants.

 

I know this is an older post, but still a great read. Thanks for your time and expertise. Do you happen to know why Effexor withdrawals are usually so terrible for those of us who were on 225+ mg doses? Is it because of the opoid receptor agonist? I'm not gonna lie, I abused opiates moderately during and after my divorce. I used up to 100mg of hydrocodone or 60mg of oxycodone a day. I know that's not a lot compared to a lot of people. I would have WD symptoms but nothing that compared to Effexor.