Sunday, December 2, 2012

An internet friend asked for my feedback on the following article:

Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good


Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter serotonin – an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive processes, antidepressants could have many adverse health effects. For instance, while antidepressants are modestly effective in reducing depressive symptoms, they increase the brain’s susceptibility to future episodes after they have been discontinued. Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin. However, there may be specific conditions for which their use is warranted (e.g., cancer, recovery from stroke). We conclude that altered informed consent practices and greater caution in the prescription of antidepressants are warranted.

Read the whole thing at:

It's always interesting to read and critique articles like this, because it gives me a chance to think about the Big Picture---in fact, I think I'll expand on this and make it into an extra-long blog post. I guess this article was thought-provoking; it certainly got my juices flowing, mainly because a lot of people ask me questions related to the points made in this article, and I think it’s important to answer these questions, because it’s easy to scare people away from the medical treatment they need. Some might say I'm biased, because I prescribe drugs; however, I've also done many thousands of hours of psychotherapy, too.

As an overview, this article is typical of its genre, and can be seen as part of the ongoing psychology/psychiatry turf war. It's not really just science, but also an opinion piece from people with an ax to grind, and probably some vested interest. The article is of poor quality, and the authors clearly do not understand many of the basic neuroscience topics they are purporting to review; many of the references are review articles, not original studies, and rely heavily on their own previous review articles and on those of co-authors who clearly run in the same circles. This is OK when you're in a small field, but this is not a small field. They are using a tiny fraction of the literature to support an opinion (that antidepressants do more harm than good) which is absolutely not supported by the weight of the available evidence. They also have an annoying habit of stating something non-controversial (i.e. serotonin is in platelets) and referencing that extensively, then asserting something outrageous without any reference at all---the journal reviewers shouldn’t let them get away with this, so this speaks to the quality of the journal.

It is always true in the life sciences that there is some contradictory evidence, no matter the subject. We don't know everything, and our concept of how the brain works will be evolving for a long time to come---certainly for the rest of our lives, and then some. We cannot be paralyzed by what we don't know when there is real human suffering. Depression, anxiety disorders, and other associated conditions which are commonly (and very effectively) treated with these medications exact an enormous human toll, and if we're going to wait until we understand everything about them before we start treating, we're going to be waiting for a very long time. We do the best we can with basic neuroscience research, translational research on disease mechanisms, preclinical research in animal models, and then carefully controlled clinical trials. The science is never settled, and our understanding is always subject to review (remember that when you hear other scientific issues discussed in the popular press.)

One of their main points is that there is a carefully regulated and highly evolved homeostasis in all these systems (i.e. serotonin), and that anything that perturbs it must necessarily cause dysfunction. You could say this about any medical treatment for any condition, so I guess all of modern medicine is suspect from this point of view (with the possible exception of antibiotics, but they'd probably argue that perturbing normal flora is dangerous, too.) The point they're obviously missing is that the system is already perturbed, and that's why we have a disease state. Some of the authors have previously written that depression (and by extension, just about any mental illness) is just a normal evolutionary response; that may or may not be true, but we haven't evolved much at all (genetically speaking) as a species in the last 10,000 years, while our lifestyle has changed radically. The same is true for the extensive discussion of withdrawal and discontinuation effects in the article; while it's certainly true that many patients relapse when antidepressants are discontinued, that’s also true for virtually all medical treatments of chronic (i.e. non-infectious) diseases. When patients stop taking antihypertensives, blood pressure rebounds---often higher than ever. If an epileptic patient stops taking seizure meds, more seizures are likely. If a diabetic stops taking insulin, they’re still diabetic, and their blood sugars go up. All of this is expected, yet the authors seem to proclaim that they have discredited antidepressants with this revelation.

The surprising thing is how few patients actually relapse---if it’s done right, most people are able to discontinue their antidepressants and have something like a lasting “cure”. Of course, the devil’s in the details, and it’s often not done right. It would be nice to have more research in this area, and much is underway; in the meantime, good clinicians have figured out the best methods for successful discontinuation. My clinical pearls: treat for at least a year at the optimal dose (longer if the depression is more chronic), then decrease the dose very gradually, and do it at a time of year that’s good for the individual patient (often, Spring is the best time of year.)

They really get bogged down when talking about neurogenesis; they mistakenly assert that neurogenesis is widely considered to be the mechanism of action of antidepressants; this is one theory, but not the consensus or established view by any means, so I'm not sure why they spend so much time and effort trying to poke holes in one theory of antidepressant mechanism of action. Anyone who’s ever spent any time thinking about this has come to the conclusion that the antidepressant response is essentially an alteration of gene expression (one manifestation of which might be increased neurogenesis, but it’s hard to imagine that’s the full extent of it.) All the different monoamine manipulations caused by available antidepressants are likely just means to an end, different ways of altering gene expression in the brain. It is no accident that hormonal alterations like increased cortisol or decreased thyroid hormone, which are thought to cause some cases of depression, are also known to cause widespread alterations in gene expression. There are probably many ways to get depressed or anxious, and the available treatments are just ways that we’ve found to (partially) reverse those processes.

The authors argue that the evidence for enhanced neurogenesis with SSRIs and other antidepressants is equivocal. Since there are hundreds, even thousands, of studies demonstrating this phenomenon in many different ways (not just the one they critique) and a relative handful that show a negative result, you could call that "equivocal", but I would call it a preponderance of evidence. Remember, there is always conflicting evidence in science! They speculate that if neurogenesis is increased with antidepressants, you should see more brain tumors. This is incredibly silly, and something they just made up (no reference at all, because it just isn’t true!) Neurogenesis does not lead to neoplasia (cancer) at all---those are two entirely distinct phenomena, and anyone with any medical training would know that. If neurogenesis is increased, you would expect to see more seizures with antidepressants---and you do! All known antidepressants result in a small but significant increase in seizures in trial populations; the risk isn’t great, but it’s there, and it’s probably a direct manifestation of increased neurogenesis. The interesting thing is that antidepressants vary widely in their seizure risk, but this does not correlate with antidepressant efficacy. SSRIs are low-risk, while other drugs like maprotiline (Ludiomil) and bupropion (Wellbutrin) are clearly much higher-risk. This suggests to me that neurogenesis is a sideshow, and not the primary antidepressant mechanism, but that’s just my opinion.

The article also spends a lot of time emphasizing the point that antidepressants just don’t work as well in clinical trials as most folks might imagine, and that there have been many trials (often unpublished) where the antidepressant fails to separate from placebo, or has a very small effect size. To some extent this is true, especially for those who don’t really understand drug trials, and just how difficult they are to conduct. What happens when a clinical trial isn’t properly designed and conducted? The result is that improvement on drug is not statistically superior to placebo; note that this does not mean that the trial drug doesn’t work. It could mean that, or it could mean that the trial simply wasn’t well done, for any number of reasons. However, it is exceedingly unlikely the drug would show superior efficacy compared to placebo by chance, or because of poor methodology. So, it’s a kind of one-way street: virtually all problems (other than outright fraud) lead to a result not significantly different from placebo. Positive trial results are important, and they are accorded great significance for just this reason---they are very hard to come by, because the system is heavily biased against a positive outcome in any double-blind trial. Of course, there are limits to this. If a drug goes through 20 trials, and only one shows significant efficacy compared to placebo, then it’s probably not a very effective drug. But if a drug is in 20 clinical trials, and only 12 are positive, that’s not bad (and fairly typical in psychiatry.) That is an effective drug, and the FDA understands that. It’s also important to understand that most subjects in clinical trials are chronic, difficult, treatment resistant patients; it is rare to find drug-na├»ve subjects in any psychiatric clinical trial. So, critics of antidepressants are always fond of citing big meta-analyses, where results are pooled from all the available studies, good and bad. This invariably diminishes the effect size and increases the placebo effect compared to the more successful, well-done studies. Psychiatric research is just like any other human endeavor, some of the people doing it are incompetent, and their efforts muddy the waters for everyone else.

In the real world, we tend to see much higher response rates among the general population. For example, in my practice of young and middle-age adults in a private outpatient setting, I generally found a response rate to SSRIs for depression and anxiety disorders of about 90% in patients on their first med trial---well in excess of the usual 70% response rate in most clinical trials. These were real, life-changing responses to treatment, with no “poop-out” after a while. Placebo responses never last, so I’m confident that most of these were real therapeutic effects. My success rate in discontinuing the antidepressants in this category of patients was about 60%, using my conservative methods; the unsuccessful 40% went back on the same medication, at the same dose, and virtually always did fine until the next time they wanted to attempt drug discontinuation.

This paper also includes a rather histrionic recitation of side effects of meds, focusing on SSRIs. Of course, all medications have side effects; it’s really surprising how many side effects are reported even in placebo-treated subjects. But most people on SSRIs don’t have major side effects, and many never notice anything at all; the body does adjust, so that the reported side effects usually dissipate as treatment goes on. Here again, this is not really different from what we see with any medical treatment. The authors go into gory detail about the risks of very rare side effects like hyponatremia (I’ve never seen a single case with any antidepressant---I have seen a bunch with the anticonvulsant Tegretol), and try to demonstrate that SSRIs cause cognitive impairment (there’s no evidence of it, and it has been tested directly.) Throughout, they make the most common mistake people make in this situation: they compare the rates of various problems in depressed people treated with antidepressants to the rates seen in normal untreated people. The problem is that depression causes many of these problems, like cognitive impairment, suicide, and excessive cardiac deaths. So, it’s hard to separate the symptoms of the disease from the side effects of the treatment.

I would also note that psychotherapy is not without side effects, especially since the authors seem to have the agenda of promoting psychotherapy. Now, I trained extensively in long-term, psychodynamic psychotherapy; I’ve done lots of it, and I’m very much in favor of it, as well as newer focused psychotherapy approaches. But I’ve also seen many patients (and some personal friends) devastated by poorly done or inappropriate psychotherapy. Drug side effects are usually easy to fix---just stop the drug. The kind of damage inflicted on these folks by incompetent psychotherapists can never be undone, not to mention the financial ruin and exploitation that went along with it. Most people assume psychotherapy has no side effects because they also assume it doesn’t do anything at all. Neither assumption is true.

As a final note, there have been several long-term studies of brain volume in people with depression (and similar studies in OCD). Having depression shrinks your brain on CT or MRI, and treatment with antidepressants (doesn’t seem to matter which ones, as long as they’re clinically effective) prevents this. This is a very powerful argument against most of the pseudo-biological speculation offered in this article, yet the authors gloss over these inconvenient facts entirely. Depression is very bad for your brain; antidepressants clearly help. Are they perfect? No, but their benefits clearly greatly outweigh their risks in the vast majority of people with serious Mood Disorders and Anxiety Disorders.