A brief history of antidepressants

Hi. I'm all better now. My exams are also done and I appear to have a summer job lined up, which means that my life has suddenly become much more simple. Hopefully this will translate into more consistent, high-quality blogging. But don't hold your breath. I appreciate your patience, now let's rock this joint.

There are a lot of things that can go wrong with your brain. Often the problem lies in a disruption of the normal levels of neurotransmitters (brain communication chemicals) present in certain parts of the brain. Take dopamine for example. Too much, you become schizophrenic. Too little, you develop Parkinson's disease. I'm grossly oversimplifying things here, but that is the essence of it.

Major depressive disorder (also known as clinical depression or unipolar disorder) is thought to have something to do with having too little norepinephrine and/or serotonin (two neurotransmitters) hanging out in the synapses in your brain. This hypothesis was initially put forward based on the fact that drugs that increase the actions of these neurotransmitters (e.g. antidepressants) help alleviate depression, while those that block their effects (e.g. reserpine) can trigger depression. Of course, there are exceptions to this, and the exact cause of depression remains hazy.

The effective pharmacological treatment of depression essentially began late 1950s, following the introduction of two classes of antidepressant drugs, the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs). The antidepressive effects of both classes were essentially discovered by accident. TCAs prevent norepinephrine and serotonin from being taken back up by neurons following their release, while MAOIs block one of the enzymes that break them down. The result in both cases is an increase in their synaptic levels, and the alleviation of depression. Both have proven to be extremely effective at treating depression, but their use has been plagued by problems. In addition to noradrenaline and serotonin, MAOIs also inhibit the breakdown of tyramine and tryptophan, two dietary monoamines that can cause a hypertensive emergency (crazy high blood pressure to the point that organ damage can occur) and serotonin syndrome (skyrocketing blood pressure and heart rate that can precipitate shock), respectively, if they accumulate to high enough levels in the body. Eating foods rich in these compounds and being on MAOIs is a bad combo, yes sir. TCAs cause unpleasant anticholinergic side effects (dry mouth, blurred vision, constipation, difficulty with peeing) and have a narrow therapeutic index, meaning that the difference between a helpful dose and a harmful dose is very small. A TCA overdose can be fatal, as it can result in deadly complications including cardiac arrhythmias and seizures.

The dangers associated with MAOI and TCA use spurred an effort to develop more tolerable and safer antidepressants, and resulted in a number of agents collectively referred to as the second- and third-generation antidepressants. Of these, the selective serotonin reuptake inhibitors (SSRIs), which include classics like fluoxetine (Prozac) and sertraline (Zoloft), have emerged as the antidepressants of choice. MAOIs and TCAs are still used when SSRIs can't do the job, but this is a fairly uncommon situation. They are considerably safer than their forebearers, although serotonin syndrome can occur with overdose and cardiovascular side effects have been observed (but are extremely rare). The biggest issue with SSRIs? Sexual dysfunction. In both sexes. We're talking incredibly frustrating things like anorgasmia (an inability to orgasm) and erectile dysfunction. This is one of the main reasons that people switch to other drugs and herbs such as St John's wort.

Other newer types of antidepressants include:

  • Dopamine reuptake inhibitors (DARIs) (example: Amineptine)
  • Norepinephrine-dopamine reuptake inhibitors (NDRI) (example: Bupropion)
  • Norepinephrine reuptake inhibitors (NRIs) (example: Reboxetine)
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) (example: Venlafaxine)
  • Selective serotonin reuptake enhancers (SSREs) (example: Tianeptine)
    • curiously these have the opposite effect of SSRIs and TCAs, serving to promote rather than block the reuptake of serotonin, yet still producing an antidepressant effect (thus pissing off pharmacologists everywhere)
  • Noradrenergic and specific serotonergic antidepressants (NaSSAs) (example: Mirtazapine)
If you suspect that your child is using drugs, some useful tips for parents can go a long way. Screening for drugs by means of urine or hair testing is a standard procedure that has been extensively studied. Screening drugs as part of their development can reveal lots of drug info, such as whether or not they are toxic to the liver.

Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.

6 chemically inspired comments:

Larry said...

Where does Wellbutrin (buproprion) fit in? It's not an SSRI, and the sexually-related side effects are actually kind of cool.

Anonymous said...

It's a norepinephrine-dopamine reuptake inhibitor.

There's also a recent class of serotonin-norepinephrine reuptake inhibitors, SNRIs.

CND said...

anonymous is correct. Bupropion is technically a second-generation antidepressant, developed just prior to the SSRIs. I'm gonna do a post on it sometime, as it's pretty darn neat.

Julian said...

There's also reboxetine and atomoxetine as (IIRC, reasonably selective) NRI's. Although having said that, atomoxetine isn't really an AD, even though I've read that it was originally intended to be one, and has instead been marketed as a non-stimulant medication for ADHD.

Besides the fact they're usually being used for different things, any idea as to the disparity in their average/starting dosages?

Ryan said...

I like the blog, great work.

julian: I don't know the details, but reboxetine inhibits an enzyme and atomoxetine blocks a channel. I would think that anything that blocks an enzymatic function might show an effect at a lower dose than something that's blocking channels (i.e. you would need more of a drug to stop an effect that utilizes many channels as opposed to stopping an effect that requires blocking a few enzymes).

also, there are probably some clearance and half-life differences, but I'm too lazy to look it up right now.

Anonymous said...

Most antidepressants are not very good drugs. In many cases a low dose of hormone replacement therapy, i.e. testosterone for men over 30, or even a low dose opiate like tylenol #3 is far superiour to trying to directly fool around with the neurotransmitters. As an organic chemist I am never surprised at the potentially dangerous drugs the FDA will approve, while safer drugs remain illegal. Its a shame more chemists can think beyond molecules and money.