How is an antidepressant an antidepressant?

I recently had dinner with a fellow psychiatrist who remarked that he doesn’t use “antidepressants” anymore.  Not that he doesn’t prescribe them, but he doesn’t use the word; he has become aware of how calling something an “antidepressant” implies that it’s something it (frequently) is not.  I’ve thought about his comment for a while now, and I’ve been asking myself, what exactly is an antidepressant anyway?

At the risk of sounding facetious (but trust me, that is not my intent!), an antidepressant can be defined as “anything that makes you feel less depressed.”  Sounds simple enough.  Of course, it only begs the question of what it means to be “depressed.” I’ll return to that point at another time, but I think we can all intuitively agree that here are a number of substances/medications/drugs/activities/people/places which can have an “antidepressant” effect.  Each of us has felt depressed at some point in our lives, and each of us has been lifted from that place by something different:  the receipt of some good news, the smile of a loved one, the exhilaration from some physical activity, the pleasure of a good movie or favorite song, the intoxication from a drug, the peace and clarity of meditation or prayer, and so on.

The critical reader (and the smug clinician) will correctly argue, those are simply things that make someone feel good; what about the treatment of clinical depression?  Indeed, one aspect of clinical depression is that activities that used to be pleasurable are no longer so. This distinction between “sadness” and “depression” (similar, but not identical to, the distinction between “exogenous” and “endogenous” depression) is an important one, so how do we as mental health professionals determine what’s the best way to help a patient who asks us for help?

It’s not easy.  For one thing, the diagnostic criteria for clinical depression are broad enough (and may get even more broad) that many patients who are experiencing “the blues” or are “stressed out” are diagnosed with depression, and are prescribed medications that do little, if anything.

So can we be more scientific?  Well, it would be intellectually satisfying to be able to say, “Clinical depression is characterized by a deficiency in compound X and the treatment replaces compound X,” much like we replace insulin in diabetes or we enhance dopamine in Parkinson’s disease.  Unfortunately, despite the oft-heard statement about “chemical imbalances,” there don’t appear to be any measurable imbalances.  The pretty pictures in the drug ads— and even in the scientific literature—show how (some) antidepressants increase levels of serotonin in the brain, but there’s not much evidence for this explanation for depression, as discussed in this review.  As the authors point out, saying depression is a deficiency in serotonin because SSRIs help, is like saying a headache is a deficiency in aspirin.

In fact, many “antidepressant” drugs affect different neurotransmitters, including norepinephrine and dopamine.  Additional medications that can benefit depression include mood stabilizers, stimulants, antipsychotics, glutamate antagonists, and thyroid hormone analogues.  Do you see a pattern?  I don’t.  Finally, there are still other interventions like electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagal nerve stimulation (VNS), and others, that don’t directly affect neurotransmitters at all, but affect other structures and pathways in the brain that we’re just beginning to understand.

Each of these is a tested and “approved” therapy for depression (although the data are better for some interventions than for others), and for each intervention, there are indeed some patients who respond “miraculously.”  But there are also others who are not helped at all (and still others who are harmed); there’s little evidence to guide us in our treatment selection.

To a nonpsychiatrist, it all seems like a lot of hand-waving.  Oftentimes, it is.  But you would also think that psychiatrists, of all people, would be acutely aware that their emperor has no clothes.  Unfortunately, though, in my experience, they don’t.  With a few exceptions (like my dinner colleague, mentioned above), we psychiatrists buy the “chemical imbalance” theory and use it to guide our practice, even though it’s an inaccurate, decades-old map.  We can explain which receptors a drug is binding to, how quickly a drug is metabolized & eliminated from the body, even the target concentration of the drug in the bloodstream and cerebrospinal fluid.  The pop psychiatrist Stephen Stahl has created heuristic models of psychiatric drugs that encapsulate all these features, making prescription-writing as easy as painting by numbers.  But in the end, we still don’t know why these drugs do what they do.  (So it shouldn’t really surprise us, either, when the drugs don’t do what we want them to do.)

The great “promise” of the next era of psychiatry appears to be individualized care– in other words, performing genetic testing, imaging, or using other biological markers to predict treatment choices and improve outcomes.  Current efforts to employ such predictive techniques (like quantitative EEG) are costly, and give predictions that are not much better than chance.

Depression is indeed biological (as long as you agree that the brain has at least something to do with conscious thought, mood, and emotion!), but does it have recognizable chemical deficiencies or brain activation patterns that will respond in some predictable way to available therapies?  If so, then it bodes well for the future of our field.  But I’m afraid that too many psychiatrists are putting the cart in front of the horse, assuming that we know far more than we actually do, and suggesting treatments that “sound good,” but only according to a theoretical understanding of a disease that in no way reflects what’s really happening.  

Unfortunately, all this attention on chemicals, receptors, and putative neural pathways takes the patient out of the equation.  Sometimes we forget that the nice meal, the good friend, the beautiful sunset, or the exhilarating hike can work far better than the prescription or the pill.

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4 Responses to How is an antidepressant an antidepressant?

  1. moviedoc says:

    Depression is a mood state. Dysthymic Disorder is an illness. A number of drugs as well as ECT and rTMS have an anti-depressant effect, but I agree with your colleague that we should stop referring to anti-depressants as a category of drug. Most of the drugs we usually place in that category work as well or better for treatment of anxiety disorders, and some drugs have more anti-depressant effect than others. Who says where we should draw the line. The FDA would like us to base the category on their approval. Rubbish. If that were true, the first SSRI, fluvoxamine, would not be an antidepressant. We could also go about it backwards: Anti-depressants can precipitate mood episode switches in patients with bipolar disorder, therefor any drug that causes a mood switch is an anti-depressant. Right.

  2. Kimbriel says:

    really love the line about colleagues not realizing the emporer has no clothes. My problem is not what psych docs DO, it's with how they justify/explain it to patients. (well, and then, even when it's clear the drugs don't work for that patient, the answer is always try more, higher doses, different combos. It's never "get off them, they don't help" I thought the first SSRI was fluoxetine (Prozac)? The first antidepressant, of course, being imipramine, which is somewhat of a chemical cousin to Thorazine, the first ever psych drug, Yes, I know way too much about psychiatry. Wtf am I ever gonna do with all this useless trivia šŸ˜›

  3. moviedoc says:

    Fluoxetine was the first SSRI approved in US. Fluvoxamine came first in Europe(?). First ever psych drug? Depends on the definition. What about barbiturates? Methamphetamine? Cocaine? Morphine? Laudanum (opium)? Reserpine?Great point about what we tell patients. After a couple treatment failures I tell patients to consider whether they might be barking up the wrong tree with meds and maybe I can refer them to a good psychotherapist. Of course some are so impaired they need to keep trying even if it means ECT.

  4. Kimbriel says:

    Moviedoc: great points. So true. Opium could be considered a psych drug too šŸ˜›

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