Pharmacotherapies for Depression

Now I’m FINALLY starting the second part in the series on Depression.  Sorry it took so long!  I really think this might be easier if my posts weren’t always over 1000 words…

As I covered in the last depression post, depression can come in many flavors.  But no matter which type, depression can make life a living hell and cause suffering both to the patient and the people around them.  Doctors have been trying to treat depression for a long time, with treatments from trepanation with many holes or cross-shaped holes (which you can find lots of info about over at Neurophilosophy) to bloodletting, though some doctors, particularly in Muslim countries, tried to treat it with soothing environments and music. 

However, since about the 1950’s, an assortment of drugs to treat depression has come on to the market.  I’m only going to cover the four most common categories, but keep in mind that there are many more types of drugs and treatments out there, especially as research has progressed.  Also keep in mind that I am NOT the expert on this topic, it’s merely a subject that I find exceedingly interesting, and which I would like to study some day, but I will not say I know everything about it right now.

The Tricyclic Antidepressants

The first group of antidepressants to come into use were the tricyclics (TCAs), with Imipramine (Tofranil) as the original, and Amitryptiline (Elavil) as perhaps the most well known.  Studies were first done with imipramine, when Dr. Kuhn noticed that, though the drug had no effects in psychotic patients, it worked wonders with some of his patients with severe depression.  For the next 30 years, TCAs became the drug of choice for treating unipolar depression, though their side-effect profile means that they have somewhat limited efficacy. 

Image via picasa from

The TCAs are norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors.  These chemicals are two kinds of neurotransmitters in your brain, that play a large role in the communication between neurons.  When one neuron fires, it releases a neurotransmitter, such as NE, into a small space in between the first neuron and its neighbor.  The transmitter crosses the space, and gets bound to receptors that are specific for it on the other side, stimulating the neighboring neuron to pass on the message.  However, you don’t want your neurotransmitters hanging around and stimulating, you want a short, brief pulse to get the message across.  So the releasing neuron has transporters that reuptake and recycle the NE, or 5-HT, once it is released, which allows for a short signal, and also allows your brain to save energy by recycling the neurotransmitter to use again.

What TCAs do is inhibit the transporters that do the recycling, and this allows NE and 5-HT to build up in the synapse.  Although the original drug itself is effective, it also has active metabolites.  For example, imipramine, which has activity at both NE and 5-HT transporters is broken down to desipramine (itself a drug on the market as Norpramin), which has activity specific for NE transporters.

So when you first take a TCA, you get increases in neurotransmitters in the synapse.  But this overstimulation doesn’t last.  Due to the high levels of neurotransmitters, your receptors on the neighboring neurons will desensitize, making them less sensitive to the high levels of neurotransmitters around. You also get a decrease in firing of NE and 5-HT neurons.  However, after about three weeks of treatment, firing returns to normal levels, and this is about the time when patients begin to see results (though not everyone does see results, and differences in responsiveness may be due to genetic or other variables).  

Note: Scientists first thought that levels of neurotransmitters account for depressive symptoms and the effects of antidepressant medications, but now there is a new theory that anti depressant medications have long term downstream effects on neuronal growth in the brain.  I’m not going to cover that here, that’s for the next post.  If you want some insight RIGHT NOW, check out “how prozac really works” from The Frontal Cortex).

Although TCAs were the first set of drugs discovered to treat depression, they have a significant side effect profile, so now are reserved as a secondary or tertiary line of treatment if other methods fail.  Side effects include: postural hypotension (when you sit up you get dizzy), dry mouth, constipation, dizziness, sleepiness, and weight gain.   Also these drugs should not be mixed with other antidepressant drugs which can increase side effects, or even other protein bound drugs (such as asprin or barbiturates) because that can interfere with their breakdown in the liver and result in potentially toxic effects. 

The Monoamine Oxidase Inhibitors

The monoamine oxidase inhibitors (MAOIs, which always reminds me of M.O.A.I. in the ‘love poem’ from Twelfth Night, say it softly! “If I could make that resemble something in me,–Softly! M, O, A, I,–“) were originally discovered in 1951, when isoniazid was developed as a treatment for tuberculosis, of all things.  They found that, not only does it help the symptoms of TB, but it puts the patients in an awfully good mood, in fact causing the caretakers some trouble with discipline.  It turned out that the metabolite of isoniazid, iproniazid, inhibited monoamine oxidase. 

What is monoamine oxidase?  Well, as you know by now, to send signals, cells release neurotransmitters into the synapse, which activate receptors on the neighboring cell and lead to the transmission of a message.  Most of the neurotransmitters that are released get taken back up by transporters, but a certain number of them also get broken down into inactive parts by monoamine oxidase.  Monoamine oxidase comes in two flavors, A and B, with monoamine oxidase A preferring to breakdown NE and 5-HT, while B has more of a preference for dopamine (DA). 

Monoamine Oxidase, image via

The clinical effects appear to mostly be due to the inhibition of MAO-A, which is selective for NE and 5-HT.  Since these compounds are no longer being broken down, you get more of them in the synapse, then selective desensitization of synaptic receptors, decreases in firing, and then a return to homeostasis, much like with the TCAs.  MAOIs are still on the market today, mostly as Nardil, Parmate, or Marplan.  They are most often prescribed for treatment-resistant depression, because of their side effect profile and some interesting changes that have to be made to your diet.

Side effects of MAOIs include inhibitation of ejaculation, fatigue, dry mouth, hallucinations (at high doses), and excessive central stimulation (NE in particular) which can result in tremors, insomnia, agitation, and dizziness.  Not only that, MAOIs have toxic interaction with compounds that contain phenylephrine or tyramine.  This means that if you’re on them you cannot eat: cheese, bananas, yeast, liver, smoked or pickled fish, avacados, beer, wine, or chocolate.  So you can see why this drug might be a last resort.

Finally, MAOIs should not be mixed with other drugs that have an effect on the serotonin system, because really high levels of serotonin in your body can result in something called serotonin syndrome.  It’s a pretty rare conditioned characterized by restlessness, tremors, hyperreflexia, mental effects, myoclonus, seizures, and coma.  So they cannot be mixed with TCAs or with SSRIs (which are the next topic!)

Selective Serotonin Reuptake Inhibitors

As you can tell, TCAs and MAOIs have some pretty interesting side effects associated with them, and so, though they are often effective, they can be difficult for outpatient treatment.  So when the selective serotonin reuptake inhibitors (SSRIs) came on to the scene, with their low side effect profile, they skyrocketed in sales, and were soon one of the best selling drug classes in the United States.  And they still are.  Everyone’s heard of Prozac (fluoxetine), Celexa, Lexapro (citalopram), and Zoloft (sertraline).

The Zoloft Rock (at least I think it’s a rock, otherwise it’s some sort of depressed marshmallow) from

What’s so great about SSRIs?  As you can tell by their name, they inhibit the uptake of 5-HT from the synapse, in a manner similar to the TCAs.  However, SSRIs are much more selective for serotonin instead of NE, and so you avoid many of the side effects associated with the TCAs.  However, just because they have a safer side effect profile, doesn’t mean that they are better at treating depression.  Long term effects of the drug include changes in 5-HT receptors, as you would expect, though they may also include changes in brain-derived neurotrophic factor (BDNF), and changes in neurogenesis in the hippocampus.

The most common side effects of the SSRIs are highly variable, but can include nausea, headaches, sexual dysfuction, weight gain, and seizures at really high doses.  There are also some indications of suicide, but I’m going to leave that part alone for right now.  Also note that SSRIs increase liver microsomal oxidases, so drugs that are metabolized by liver microsomal oxidases may build up in the blood more than normal.

Until recently, the SSRIs were the gold standard in antidepressant treatment.  In many cases, they still are.  But some doctors are now showing a preference for even newer drugs: the atypical antidepressants.

The Atypical Antidepressants

For a while recently, the name on everyone’s lips was Wellbutrin (buproprion).  Closely following Wellbutrin was Buspar (buspirone), as well as Remeron (mirtazepine).  What were these new drugs?

These are they atypical antidepressants.  They are called atypical because they don’t work in any of the ways we associate with traditional antidepressants, and yet they score well on animal tests for anti-depressant efficacy (which I may go into in one of the later posts), and also score well among patients.  They are also atypical in that no single one works the same way as another. 

For example, Wellbutrin is more of a stimulant than an antidepressnat, and inhibits the reuptake of DA and NE.  Its metabolites may also be active.  This is very different from the typical antidepressants because it does not focus on the serotonin system.  In contrast, Buspar and Remeron are both agonists that stimulate specific 5-HT receptors on the neuron, increasing the effects of 5-HT at these particular receptors. 

Because they are atypical, none of these drugs will have the same side effect profile, though Wellbutrin has side effects associated with stimulants (such as insomnia, weight loss, and anxiety), while Buspar and Remeron may have side effects associated with the more typical antidepressants.  They may not be better antidepressants, but they often are associated with a better side effect profile and toleration. 

Although all of none of these drugs may be effective, depending on the patient, they are all known to do better when the patient also has a support group and talk therapy.  Combination of talk therapy and pharmacology appear to produce the best results. 

Also keep in mind that after a patient has been on the drugs for a long period of time, going off them may result in withdrawal.  Your body and brain have gotten used to the presence of the drugs.  This does NOT mean that they are addictive, you aren’t going to feel a huge drive to take them and a tendancy to sell your child for your next Prozac hit.  But your body and brain will need time to adjust, so it’s always best to discuss a taper off the drugs with your doctor if you want to quit.  Some of the drugs are very long acting (such as Prozac, which can have a half life of several days), so decreasing over several weeks on a taper can prevent problems associated with going full turkey.  When people go off antidepressant medications they can suffer depression, anxiety, headaches, nausea, weight loss or gain, and even a possibility of seizures if you’ve previously been on a high dose. 

So that’s what I know on the current pharmacotherapies.  If I’ve said anything blatantly untrue, or if anyone has more up to date knowledge or new information, please comment!  I can’t learn new stuff unless I know where to find it.

Next up will be current methods of studying depression and antidepressants in the lab!  But since this was a LONG post, let’s wait until my fingers recover, yeah?

4 Responses

  1. Hey, thanks for the interesting write-up. I would like to stress that Wellbutrin (Bupropion) can increase the risk of seizures in epilepsy patients at the higher end of its therapeutic dose. It is also prescribed to aid smoking cessation.

    I also think it is important to note that many Anti-depressants are prescribed for several other psychiatric disorders, like OCD, anxiety disorders, etc..

    Stopping SSRIs is associated with a condition called discontinuation syndrome. Which is not, as you said, technically a withdrawal.

    SSRIs were blamed for increasing adolescent suicidal ideation. However, it didn’t increase the levels of suicide in the said population. Sorry, I don’t have a link to back up this though.

    Regarding the MAOI it’s name is Parnate and not Parmate.

    Thanks again for the informative post.

  2. On tyramine. There is a lot of pseudo-information out there that gets passed around, especially on the internet. Worth knowing what the actual scientific evidence is – here are two studies based on laboratory analysis:

    Click to access IND43817287.pdf

    As you’ll see, lab tests show no tyramine in bananas (the pulp, that is – a little in the skins, but only a little, and most of us don’t eat the skins. As for avocadoes, the only case that suggested caution was one person who ate a whole quart of over-ripe guacamole and got ill (how surprising!).

  3. My friend on Orkut shared this link and I’m not dissapointed that I came to your blog.

  4. […] chemistry drastically. SSRI stands for "selective serotonin reuptake inhibitor", which I've written a bit about in my various posts on depression over at my old site. There is a serotonin theory of depression, […]

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: