Lesson 3: Antidepressants
In this lesson we will learn how antidepressants work, what to expect from your antidepressant, and how to cope with side effects.
Introduction and Types of Antidepressants
Let's start with the bad news, first. Antidepressants are not magic bullets. Success is measured in terms of a 50 percent response, which would be unacceptable for any other illness. Only seventy percent of patients achieve a response, and of these only 30 percent actually achieve remission (ie nearly symptom-free). In addition, the Prozac class of antidepressants poop out on as many as fifty percent of their users, bringing on perhaps their second major depressive episode in the space of a year - a situation about as acceptable as two by-pass operations in twelve months. Consequently, you should regard antidepressants as but one small part of your wellness program, along with talking therapy, support groups, and right lifestyle choices such as diet, exercise, and sleep.
Older Generation Meds
Antidepressants are classified by their chemical structure and how they act. MAO inhibitors arrived on the scene back in the nineteen fifties, but the first of these drugs were quickly taken off the market. The holdovers from this era are mainly used as a medication of last resort, after the newer varieties have failed. Nardil and Parnate are the best known. MAO inhibitors can be as subtle as the proverbial 800-pound gorilla. Possible side-effects range from nausea to weight gain or loss to insomnia to sexual dysfunction to just about everything in between.
The tricyclic antidepressants were introduced about the same time as the MAO inhibitors. Imipramine (Tofranil) can claim to be the oldest antidepressant still in service. Desipramine (Norpramin), Nortriptyline (Pamelor, Aventyl), and Amitriptyline (Elavil) also fall into this category. They work by preventing two neurotransmitters - norepinephrine and serotonin - from being absorbed by the brain's receptors, and can be a life-saver where other medications have failed. Overdoses can be fatal and side effects can be as pronounced as the MAO inhibitors.
Prozac and its Cousins
The SSRIs (selective serotonin reuptake inhibitors) work in a similar fashion to the tricyclics (ie preventing serotonin from being reabsorbed), but without many of the side effects, tending to make them the medication of first choice. Celexa and Luvox were the first of these drugs, introduced in Europe in the mid-eighties, but it was Prozac's debut in America in 1988 that attracted all the attention and helped eliminate much of the ignorance and stigma surrounding depression. Zoloft and Paxil followed in the early nineties. The hype that followed on the release of these drugs is finally dying down, and the public is at last beginning to see them for what they truly are - if not the proverbial 800-pound gorilla, then perhaps one that weighs in at 400 pounds.
Moreover, compared to earlier generations of antidepressants, SSRIs are no more efficacious in treating depression. Their one advantage continues to remain their moderately more benign side effect profile.
Contrary to popular belief, depression is not caused by a deficiency in the brain's serotonin. A patient will not get better simply by boosting his system with serotonin. If only life were that simple. An SSRI's function, rather, is to keep existing serotonin in circulation by blocking some of its escape routes.
There is only one problem with this conventional explanation for how SSRIs work - namely science can't explain why it takes several weeks for these pills to have any effect. The recent discovery that antidepressants stimulate nerve cell growth in the hippocampus has scientists theorizing this may be how antidepressants actually operate, which would also account for their lag effect.
Serotonin, as you may have guessed, is involved in mood and emotions, but it also plays a role in sleep and digestive functions. Norepinephrine (targeted by Effexor and Remeron) is associated with the flight or fight response, and dopamine (a secondary target of Wellbutrin) is identified with pleasure and reward.
Novel Antidepressants
Some of the newer drugs - Effexor, Wellbutrin, Remeron, Serzone, and others - technically belong in unique classes of their own, but are generally mentioned in the same breath as the SSRIs. Effexor has a reuptake inhibitor action similar to the SSRIs, but also works on norepinephrine, while Wellbutrin works mainly on norepinephrine and to a lesser extent on dopamine. Remeron and Serzone both operate on the brain's alpha-adrenergic-receptors (which affect norepinephrine) and serotonin. The point to be made here is that there exists a sufficient variety of newer medications to offer hope to even the hardest cases, however unsuccessful previous attempts may have been.
Drugs in the pipeline include:
- A substance P antagonist, aprepitant, by manufacturer Merck. Among other things, substance P and the receptor NK1 it acts on are present in the brain's hypothalamus and amygdala, associated with emotional behavior.
- CRF agonists and antagonists, which work on stress-induced depression. Several companies have these drugs in development.
- A 5HT-1A agonist, meaning it triggers a response in one of the serotonin receptors. Organon filed for FDA approval in 2001.
- Eli Lilly's duloxetine, which targets serotonin and norepinephine (noradrenaline), with FDA approval expected later this year.
- A combination Prozac-Zyprexa pill for treatment-resistant depression, possibly on the market in 2003.
- Lexapro, a cleaner version of Celexa - final approval expected any time.
- A transdermal MAOI patch by Somerset that promises to have no side effects.
