Medically Reviewed by Jacque Parker, RN
It took nearly an entire century for the medical and psychiatric professions to come around to the obvious: namely that depression is not simply a condition of the mind. Rather, it is a disorder of the brain. Whereas the mind does not exist in space, the brain occupies all three dimensions and responds to physical intervention, not unlike the heart or liver, though certainly in a far more complicated manner.
The advent of Prozac and its sister antidepressants in the 1980s blew the lid off decades of wrong thinking once and for all. All this business about depression being all in the mind went right out the window as patients by the millions streamed in from the cold to have the mechanisms in their brains repaired rather than their heads examined.
The psychiatric profession, in turn, responded by becoming a pharmaceutical dating service or sorts, matching patient to medication. There was still a place for therapy of the talking kind, but the task was largely taken over by a different class of professional using approaches that left Freud and his couch far behind.
The first thing to know is that while the right medication can be a godsend, there is no one-drug-fits-all, and the process of finding the one that works for you can sometimes turn into a nightmarish game of hit and miss.
Antidepressants are classified by their chemical structure and how they act. Even the experts do not know exactly how these medications operate, other than they optimize neurotransmitter activity in the brain.
MAO Inhibitors
Which class of antidepressant came first is a question lost in time. 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 (phenelzine) and Parnate (tranylcypromine) are the best known. They operate by blocking out the enzyme, monomine oxidase, which gives the neurotransmitters serotonin, norepinephrine, and dopamine a chance to do their work. Because of their action on other chemicals in the body, users must severely restrict their diets, at the risk of an extreme reaction. In addition, 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.
Nevertheless, MAOIs are considered especially effective for treating atypical depression. The development of a transdermal patch and of a different class of MAOIs called RIMAs promise much greater tolerability (see article).
Tricyclic Antidepressants
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 cell’s receptors, and can be a life-saver where other medications have failed. Overdoses can be fatal, and though users don’t face the same diet restrictions as the MAO inhibitors, the other side effects can be just as bad.
SSRIs
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 (citalopram) and Luvox (fluvoxamine) were the first of these drugs, introduced in Europe in the mid-eighties, but it was Prozac’s debut in America in 1987 that attracted all the attention and helped eliminate much of the ignorance and stigma surrounding depression. Zoloft and Paxil followed in the mid-nineties. A cleaner version of Celexa, Lexapro (escitalopram), with less side effects, was approved by the FDA in 2002. The hype that followed on the release of these drugs has now died 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.
Test subjects who are depleted of tryptophan, an amino acid precursor of serotonin, will get depressed, and a case can be made for tryptophan therapy to get serotonin back in circulation. SSRIs are more complicated, working on the brain’s serotonin system rather than the serotonin itself, by blocking off certain escape routes so the available serotonin stays in circulation.
There is only one problem with the conventional explanation for how SSRIs work – namely, science can’t explain why it takes several weeks for these pills to achieve their therapeutic effect. One theory is that impulse flow inside the neuron is initially dampened by the antidepressant, but once the current is turned back on serotonin is released across a synapse (divide) and absorbed by the post-synaptic cell. The presynaptic neuron than acts as a vacuum to clear what’s left of the serotonin from the synapse in preparation for the next round of serotonin release. According to long-held belief, it was the SSRIs’ (and tricyclics’) ability to bind to certain receptors and block serotonin’s “reuptake” that resulted in these drugs’ antidepressant action.
Exciting new research now indicates that antidepressants may simply kickstart neurotransmitters, which in turn set in motion molecular cascades involving processes critical to cell maintenance and survival (see article). One or more of these downstream effects, such as perhaps the growth of new cells in the brain’s hippocampus (with a lag of several weeks), may either be the cause of the antidepressant’s clinical effect or something that must happen before the neurotransmitters can do their work.
Side effects result from antidepressants binding to more types of receptors outside the neuron than intended. Identify the exact targets inside the neuron (ie where these molecular cascades take place), the thinking goes, formulate compounds that will zero in on these targets, and – voila! – your perfect magic bullet, tailor-made for different types of depression, with no side effects. But we’re light years away from making that happen.
Serotonin, as you may have guessed, is involved in mood and emotions, but it also plays a role in sleep and digestive functions and pain. Norepinephrine (targeted by Effexor, Cymbalta, Remeron, and Wellbutrin) is associated with the flight or fight response and pain, and dopamine (targeted by Wellbutrin) is identified with pleasure and reward.
Surprisingly, even though SSRIs are more expensive, an Oregon Health Sciences University study has found that this class of drugs cost less to treat patients in the long term than the TCAs. Reasons include lower dose adjustments, single tablet regimens, and often shorter duration of treatment.
Other Medications
Some other drugs – Effexor (venlafaxine), Wellbutrin (buproprion), Remeron (mirtazapine), Serzone (nefazadone), and Cymbalta (duloxetine) – technically belong in unique classes of their own, but are generally mentioned in the same breath as the SSRIs. Effexor and Cymbalta both have dual reuptake action of serotonin and norepinephrine, not unlike the tricyclics, while Wellbutrin works mainly on both the neurotransmitter dopamine and norepinephrine. 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.
Treatment Strategies
Published studies indicate that antidepressants result in a response (ie a 50 percent reduction in depression scores) in two-thirds of subjects over the course of a usual four to eight week trial. Going off the FDA database, however, which includes studies not published, the success rate is more like 50 percent.
Fifty percent of patients getting only fifty percent well is not exactly encouraging. Add to that the phenomenon of Prozac poop-out and the prospect of high relapse, and one is entitled to question whether the side effects are worth trying an antidepressant in the first place.
Fifty-fifty odds of achieving fifty percent improvement, however, is misleading. In one sense, the real world odds can be even worse, as the primary care physicians who prescribe most of the antidepressants do so under less than ideal conditions. But you can dramatically turn the tables in your favor by not giving up. The American Psychiatric Association in its Practice Guidelines for the treatment of depression recommends switching to another antidepressant if the first one does not work and to a different class of antidepressant if the second one fails.
Other strategies include combining your antidepressant with another antidepressant or augmenting your antidepressant with a different class of drug such as a thyroid drug or lithium.
You also improve your chances by not quitting on your medication. Still, even the most persevering can be frustrated by a long and drawn out game of pill roulette that can take months or (in rare cases) even years to resolve, that is if they don’t give up in despair, first.
But even the lucky ones are in for a difficult initial several weeks, for antidepressants have a perverse way of making their side effects known almost at once, weeks before their healing power kicks in, when the depression is raging at its fiercest. The side effects tend to diminish over time, but too late for many distressed patients who have given up long before then. Here – and this is tough – you must have faith. Barring some extreme side effect or medical emergency, you need to give your prescription a full eight weeks to work.
And another eight weeks, should you have to switch medications. And again, another eight weeks, if necessary. These heartbreaking searches for the right drug can cause as much despair as one’s actual depression, but with one important difference: Those past struggles against depression were all in vain. This time you are battling for your own healing, a fight you have an excellent chance of winning.
The Future
The introduction of Prozac and its chemical cousins Zoloft, Paxil, Celexa, and Luvox promised a bright new day for people suffering from depression. In contrast to their predecessor medications, these selective serotonin reuptake inhibitors (SSRIs) plus other newer drugs such as Wellbutrin, Serzone, Effexor, and Remeron were supposed to be the smart bombs of pharmacology, delivering surgical strikes exactly where they were needed in the brain, with little in the way of collateral damage to the rest of the system.
Perhaps we should start with the bad news about these antidepressants: First, the SSRIs and other newer medications have only a two-thirds success rate or lower, where 50 percent response is regarded as success – the type of recovery neither you nor I would find tolerable. In addition, SSRIs 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.
Also, don’t expect an antidepressant to make your miserable life bearable. If the underlying cause of your depression is a toxic relationship or abusive working situation or something similar, at best an antidepressant will perk you up enough to help you resolve it. Doing nothing invites depression back in.
Side Effects
Then there are the side effects. Far from operating with laser precision deep inside the brain as many of us were initially led to believe, SSRIs have a bit more in common with the massive sledge-hammers of those earlier generations of medications than perhaps the pharmaceutical companies would like to let on. The most notorious side effect of the SSRIs is sexual dysfunction (found by one study to be as high as 40 percent, including women). Other side effects may include increased anxiety, loss of strength/fatigue, diarrhea dry mouth, insomnia, nausea, somnolence, and sexual dysfunction. Side effects can be reduced by lowering the dose, but patients on lower doses face a greater risk of relapse.
Antidepressant therapy is long term, possibly for life. You don’t get rid of your antidepressants if you’re feeling well anymore than a heart patient would throw out his heart pills or a diabetic his insulin. Even if all goes well, there are bound to be adjustments along the way.
Depression is a long-term, if not lifetime condition, lasting nine months on average, and usually requiring much longer medications regimes to reduce the likelihood of relapse. If your drugs don’t quit on you in that time, your body is almost certainly bound to change, and with it, your ability to respond to your current medication. Consider your brain an organ every bit as important as your heart, together with a quality of life free from permanent side effects, and find a doctor or psychiatrist who feels the same way.
Things To Consider
If early in your treatment you begin to feel agitated hyper, or anxious, notify your physician at once. The anxiety usually goes away in a few days, but if you are an undiagnosed manic depressive, an antidepressant without a mood stabilizer can send you into orbit. Others who do not have manic depression can have these reactions as well.
The flip side of agitation is the drowsy feeling many users experience, particularly in the early phases of taking the drug, when the body has not yet adjusted. All antidepressants come with the warning to be careful about operating heavy machinery, and this includes your car.
Other substances that affect your mood, be it alcohol, legal or illegal drugs, caffeine, or foods rich in sugars or carbohydrates. Alcohol and recreational drugs should be regarded as taboo, caffeine should be taken advisedly, and junk foods should be only an occasional indulgence.
Let your doctor know what other drugs you are taking, as some drugs affect the metabolism of the other. This includes herbal supplements, as well.
Access To Medications
Lack of disposable income should not prevent you from seeking antidepressant therapy. True, each pill retails in the neighborhood of $2.00 in the US, but few individuals wind up paying the full price. Private health plans and state welfare usually pick up the tab or most of the tab, and for those who otherwise do not qualify, the best-kept secret in America is that pharmaceutical companies have patient assistance programs that give away drugs to those in need.
You need to work through your prescribing physician to take advantage of these programs. The drug companies have 1-800 numbers for your physicianandrsquo;s office manager to call. Once the paperwork is completed, you will be able to pick up your medications at your doctorandrsquo;s office.
Good News
The last bit of good news is that there are better medications just over the horizon, some in trials even as you read this. By now we know better than to expect the equivalent of a cure for polio. The mind is simply too complex to allow that to happen. But we all possess the wisdom to work with what is available to us. And we are getting smarter every day.
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John McManamy took up writing about mental health in response to his diagnosis of bipolar disorder. You can visit his web site at http://www.mcmanweb.com/.
