Is Depression Really Biochemical?

Direct-to-consumer ads by drug companies have been highly successful in convincing doctors as well as patients (and their families) that mental illness has biological, indeed biochemical, roots. Surprisingly few people question that depression is due to a "chemical imbalance in the brain," even though the slightest bit of questioning would lead you on a search of the literature that uncovers zero evidence supporting such a theory. Saying that because SSRIs are effective in treating depression (for a minority population of depression sufferers), therefore depression is a disease of serotonin imbalance in the brain, is like saying saying that because I have unfocused thoughts in the morning unless I drink coffee, therefore there's a disease, Morning Unfocused Thought Disorder, that's caused by a chemical imbalance of adenosine in my brain. (Caffeine is an antagonist of adenosine receptors.) From there, it's only one step away to the chocolate-imbalance theory of lovesickness, and then but another short step to the (once well accepted by doctors) masturbation theory of insanity.

The biochemical-imbalance theorists have yet to reconcile the fact that for some people (those who respond to SSRIs), depression seems to involve serotonin whereas for others (those who respond to SNRIs) it seems to involve norepinephrine and serotonin, whereas for others (those who respond to drugs like mirtazapine) it seems to involve norepinephrine and dopamine and serotonin (or dopamine and norepinephrine in the case of bupropion), whereas for others (those who respond to tricyclics) it involves an intricate combination of imbalances related to actions at the serotonin and norepinephrine and dopamine transporters (SERT and NET and DAT), the H1 histamine receptor, the 1A and 2A serotonin receptors, α1 and α2 adrinergic receptors, the D2 dopamine receptor, and the muscarinic acetylcholine receptor. That's an awful lot of different types of "chemical imbalance," for one disease. The literature shows (see, e.g., the meta-analyses by Kirsch and others, and the STAR*D study) that depressed patients respond more-or-less equally well to any of the major categories of antidepressants, basically proving that the drugs are not highly specific in their effects on patient subpopulations. If they were indeed highly specific to certain subpopulations (if some patients specifically needed an SNRI, whereas others specifically needed an SSRI, whereas others needed a tricyclic, etc.) then the patient subpopulations would add up to more than 100% of the total patient population, based on how many people tend to respond to each type of drug.

And then there's the somewhat curious fact that tianeptine, an antidepressant that has been sold for many years under the name Coaxil in Europe and South America, is actually a selective serotonin reuptake enhancer (not inhibitor). So apparently, some depression is caused by too much (rather than too little) free serotonin.

Studies that have tried to induce depressive symptoms in normal subjects by altering their neurotransmitter balances have failed to do so. (E.g., Salomon et al., "Lack of behavioral effects of monoamine depletion in healthy subjects," Biological Psychiatry, 1 January 1997, 41:1, 58–64.) This elementary result is rarely discussed.

For more on this general subject, I recommend the paper "The Chemical Imbalance Explanation for Depression: Origins, Lay Endorsement, and Clinical Implications" by Christopher M. France, Paul H. Lysaker, and Ryan P. Robinson, in Professional Psychology: Research and Practice, 2007, 38:4, 411–420 (full PDF here).

In a J Clin Psychiatry 59: 4–12, researchers from the US National Institute of Mental Health Laboratory of Clinical Science caution: "[T]he demonstrated efficacy of selective serotonin reuptake inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the pathophysiology of these disorders." Yet the medical industry (from clinicians to drug makers to advocacy groups) continues to promote a serotonin-imbalance theory of depression, as if it's accepted fact. It's not only not fact, it's a bit bizarre.

The Zoloft web site promotes Zoloft (an SSRI) as a treatment for Major Depressive Disorder (MDD), Obsessive-Compulsive Disorder (OCD), Panic Disorder, Posttraumatic Stress Disorder (PTSD), Premenstrual Dysphoric Disorder (PMDD), and Social Anxiety Disorder. As the authors of a recent (2005) paper in PLoS Medicine noted: "For the serotonin hypothesis to be correct as currently presented, serotonin regulation would need to be the cause (and remedy) of each of these disorders. This is improbable, and no one has yet proposed a cogent theory explaining how a singular putative neurochemical abnormality could result in so many wildly differing behavioral manifestations." See Lacasse, J.R., and Leo, J. (2005), "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature," PLoS Med 2(12):e392.

The Code of Federal Regulations under which direct-to-consumer drug advertising is regulated states that an advertisement may be cited as false or misleading if it "[c]ontains claims concerning the mechanism or site of drug action that are not generally regarded as established by scientific evidence by experts qualified by scientific training and experience without disclosing that the claims are not established and the limitations of the supporting evidence…" Direct-to-consumer advertisements are also forbidden to include content that "contains favorable information or opinions about a drug previously regarded as valid but which have been rendered invalid by contrary and more credible recent information." Despite this, we still find (for example) the Paxil website saying: "Paxil can help restore the balance of serotonin (a naturally occurring chemical in the brain) -- which helps reduce the symptoms of anxiety and depression." (Retrieved 24 Mar 2013.) And yet the FDA has never cited a pharmaceutical company for these sorts of falsehoods, presented over and over again in their advertising about antidepressants. There simply is no evidence that depression is caused by an imbalance of serotonin (or anything else) in the brain, any more than anxiety among smokers is caused by a lack of nicotine in the brain.

It would be easier to accept the many neurotransmitter-imbalance theories of depression if the drugs in question worked with the same high degree of efficacy that, say, aspirin works for a headache or that insulin does for diabetes, but in fact the drugs work so poorly that the number one bestselling drug in America right now is an adjunctive drug sold on the basis of helping antidepressants work better (Abilify). When I mentioned to a (non-depressed) friend of mine that the retail price of a month's worth of Abilify (5mg, 30 pills) is a thoroughly unconscionable $683 (making Abilify many times more valuable than pure gold), his comment was: "Why don't you just go lease a new Acura and see if that doesn't cheer you up? It's cheaper, and more satisfying."

Personally, I think he's right. Everybody on Medicare and Medicaid who's receiving Abilify at low or no cost right now (via government subsidy) should be offered a choice: continue to receive Abilify, or let Uncle Sam put you in a new Acura.

I wonder what people would choose?