In 2008, a controversial meta-analysis of antidepressant trials appeared in the open-access journal PLoS that attributed more than 80% of the therapeutic benefit of antidepressants to placebo effects. Worse, there was no meaningful difference between antidepressants and placebos in the degree of clinical response as measured on a standardized depression score (HRSD). The only patients where antidepressants worked better than placebos were in those who were severely depressed at baseline. Why were the results of this review so much worse than prior reviews on the topic? Because the PLoS study wasn’t limited to just published data. In this case, the authors had taken the extra step of obtaining all the FDA trial data under the Freedom of Information Act, including the results from unpublished trials. It should surprise no one to learn that pharmaceutical companies tend to bury unfavorable results. When that extra data—almost all of it negative—was included, the overall results shifted in favor of placebos. Several subsequent reviews have reached similar conclusions. Nor do SSRI-antidepressants work any better than placebos for pediatric depression according to a just-published meta-analysis. Here, too, as in the adult literature, the benefit was merely statistical, too small to be clinically relevant. Consistent throughout all the trials, however, is that far more children and adults taking antidepressants suffer side effects compared to those receiving placebos.

It’s a little-known fact that the FDA requires just two positive efficacy trials to approve a drug. In one case, despite five negative trials, a pharmaceutical company was still able to secure approval for its antidepressant drug after the sixth and seventh trials eked out minimally positive results. Want to bet that it was tweaking the trial design—and not due to any effect of the drug—that made the difference in those last two trials? In a review of 74 antidepressant trials submitted to the FDA, more than 30% had never been published and, as expected, nearly all of the unpublished trials had negative results (22 of 23). Meanwhile, the published trials were—Surprise!—overwhelmingly positive, or at least spun by the authors to appear that way. This is something the drug companies don’t want you to know.

 

 

Here’s something else they don’t want you to know: The trials are rigged. Pharmaceutical companies are legally allowed to cherry-pick the patients used in their trials based on their response to a placebo challenge. In what is termed a “placebo washout period,” prospective study participants are given a placebo for two weeks, including before-and-after testing on standardized depression severity surveys. Those with a strong response, improving their scores by 20% or more, are excluded from the actual trial. When compared to the test drug, the placebo group will appear weaker, a priori, as the strong respondents have already been removed from the selection pool. This is no fairer than excluding patients with a strong drug response from the trial. Do you think pharmaceutical companies would be willing to do that?

 

 

There’s more: Although the trials are said to be “double-blind” (meaning that neither the patient nor the doctor knows who received the drug and who received the placebo), patients are required to be notified in advance of possible side-effects associated with active treatment. At the end of the trial, a sizable portion of patients who suffered side-effects will be able to correctly surmise that they received the test drug and not the placebo. When patients know they are receiving a therapeutic intervention it enhances the perceived effect of the drug. That is why such care is taken to blind them in the first place. (“I know that I got the drug because I gained weight just like they said I would, but I feel pretty good—that drug must work!”) Indeed, in a separate study where patients were asked to predict whether or not they had received the test drug or the placebo, 89% correctly identified their assignment.

And here’s another nail for the biologic model coffin; the most widely prescribed class of antidepressants, the SSRIs (Selective Serotonin Reuptake Inhibitors), are purported to work by increasing synaptic concentrations of serotonin through inhibition of axonal reuptake. But in France, an antidepressant drug called tianeptine worked just as well as traditional SSRIs despite the fact that it enhances the uptake of serotonin rather than inhibiting it. Either the biologic model is wrong, or the drugs work via the placebo effect, or both. Said Irving Kirsch, lead author of the PLoS meta-analysis: “What do you call pills, the effects of which are independent of their chemical composition? I call them placebos.”

Antidepressants can be thought of as “active placebos,” meaning that they do indeed possess biologic activity, but their benefit is largely unrelated to it. The side effects, however, are not. The major antidepressant classes include: SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors), TCAs (TriCyclic Antidepressants), MAOIs (Monoamine Oxidase Inhibitors), and “atypical agents.” Of these, the SSRIs (e.g. Celexa, Lexapro, Prozac, Paxil, Zoloft) and SNRIs (e.g. Cymbalta, Effexor) are the most commonly prescribed. Side effects include: sexual dysfunction, weight gain, headache, insomnia, nausea, vomiting, diarrhea/constipation, dizziness, and dry mouth. Probably the most commonly reported effect, however, is a general numbing or flattening of emotion, sometimes described by patients as feeling “like a zombie.” The SSRIs are also associated with an increased risk of GI bleeding when taken concomitantly with blood thinners or NSAIDs (e.g. naproxen, ibuprofen, or aspirin). Not only that, but antidepressants are paradoxically associated with an increased risk of suicide, particularly after a period of initial improvement.

Finally, there is a serious, rare, syndrome tied to their use when taken in excess—serotonin syndrome. This is a potentially fatal reaction characterized by high fever, agitation, muscle rigidity, rapid heart rate, elevated blood pressure, and drenching sweats that can progress to coma and death. This is the syndrome that killed an 18-year old college student by the name of Libby Zion in 1984 after taking a prescribed MAOI antidepressant. She presented to the hospital with classic symptoms of serotonin excess, but at the time, serotonin syndrome was little-known and the diagnosis went unrecognized. She was admitted instead with a presumed infection. As the night wore on, Ms. Zion’s agitation grew, and the on-call intern ordered an injection of Demerol, a potent, generally safe, opioid. Unbeknownst to the doctor, however, was that Demerol can also elevate brain levels of serotonin, and it was likely the combination of the two drugs that led to her death. Before lapsing into a coma, her temperature peaked at 107 F.  The fallout included a lawsuit that ultimately changed residency education, capping physician-in-training hours to 80 per week.

In practice, most antidepressants are safe, and the syndrome is almost never encountered in patients on standard, depression-dose SSRIs. It’s when antidepressants are inadvertently combined with other serotonin-elevating medications that the syndrome is likely to occur. For instance, say a young woman is on daily Zoloft prescribed by her PCP for depression and Imitrex prescribed by the student health center for intermittent migraines. Neither provider knows that the other has prescribed a serotonin-elevating drug. The patient develops a headache, takes her Imitrex, and soon afterward feels better. She goes out for a night of “clubbing” and, at midnight, takes a hit of Ecstasy to keep the party going. She now has 3 different drugs on board that can elevate serotonin. This is the kind of patient that winds up in my ER at 3 AM, rigid as a lead pipe with agitated delirium, and a temperature of 105 F. A surprising number of medications can precipitate the syndrome when combined with antidepressants including: migraine medicines (e.g. Imitrex, Maxalt, Zomig, Amerge), analgesics (e.g. codeine, fentanyl, Demerol, Tramadol), street drugs (e.g. cocaine, methamphetamine, Ecstasy), anti-nausea drugs (Reglan, Zofran), even cough medicines (anything with dextromethorphan—the “DM” in Robitussin DM, Vicks 44 DM etc.). The syndrome is neither common nor particularly rare. I’ve seen it more than once, and it’s always bad.

 

 

And don’t think St. John’s wort is safer just because it’s “natural.” It, too, can induce serotonin syndrome. On the plus side, a recent meta-analysis found that the supplement works as well as—but no better than—traditional antidepressants for mild to moderate depression. Side effects tend to be less severe and less frequent than those associated with traditional antidepressants and include: alterations in thyroid activity, blood pressure elevation, and, rarely, acute mania. Although available as an over-the-counter “nutritional supplement” (meaning that its effects on depression have not been evaluated by the FDA), the purity and concentration of the active ingredient isn’t standardized, so be wary if this is your go-to drug for depression.

For most, a trial of behavioral therapy should be considered before going on to medicines. Patients respond as well to behavioral therapy (“talk therapy”) as they do to antidepressants but without the side effects and less than half the relapse rate. As a general rule, psychologists utilize behavioral therapy, while psychiatrists focus more on pharmacological interventions. (Only psychiatrists are MDs with authorization to issue prescriptions.) It’s unclear how, or if, psychotherapy alters brain chemistry, but in virtually every study, it works as well as antidepressant medication. The downside to therapy is that its success is highly dependent upon the skill of the therapist. It’s also expensive and time consuming. How about spending a similar amount of time on something that works better and doesn’t cost a dime?

I’m talking about exercise. Depression is inversely related to physical activity, and the more active you are, the less likely you are to become depressed. Fit people who stop exercising are 1.5-times more likely to develop depression than those who keep exercising. A few years back, researchers at Duke University conducted a series of trials comparing exercise to medication. Collectively called the SMILE Trials (Standard Medical Intervention and Long-term Exercise), the authors found that exercise worked as well as antidepressant drugs to treat depression but with lower relapse rates. Not only that, but the likelihood of relapse decreased with increasing exercise—a 50% relative decrease for every additional 50 min per week of exercise.

A separate 2014 systematic review of 35 trials found exercise’s effects on depression to be at least equal to medication when used to treat mild to moderate depression. Somewhat surprisingly, results were better for resistance training than aerobic training. To those who say that taking a pill is easier than going to a gym, I offer the following benefits of exercise over pills:

• Antidepressants often result in weight gain; exercise promotes weight loss.
• Antidepressants frequently cause a decline in libido; exercise enhances it.
• Antidepressants foster dependency; exercise is empowering.
• The depression relapse rate is much lower with exercise than drug therapy.
• Exercise is free; antidepressants are expensive.
• Exercise offers additional health benefits that antidepressants don’t including: a decreased risk of stroke, heart attack, diabetes, dementia, falls, arthritis, and many types of cancer.
• Exercise is fun! It can be done alone or socially—try running a 10-k race with thousands of others, participating in a group ride, or joining a tennis league. There can be no such claims associated with taking a pill. It’s simply a solitary drudgery.

Exercise should be the first choice for just about everybody suffering from mild to moderate depression, followed by behavioral therapy if exercise fails. Medication should be the last choice, not the first.

For those with severe depression, a combination approach involving exercise, behavioral therapy, and medication will likely be necessary. This may also include a short-term hospitalization. If you are feeling suicidal, please seek immediate medical attention. You’ll find that if you arrive sober and sincere, emergency departments will bend over backward to help. Call your psychiatrist, your therapist, your PCP, your best friend—call someone. Choosing a permanent, life-ending solution to a transient condition—even one associated with great suffering—deprives you of everything you’ve ever had or are ever going to have, while leaving behind untold pain in those who love you. Choose life!

Finally, back to my original question from part 1 of this post: What is it about depression that makes it respond to treatment the same way that a cough responds to cough medicine? In both cases, placebo effects account for virtually all of the benefit. It’s clear that the biologic model of depression doesn’t account for this, and here is where the diabetes analogy falls apart; the correct dose of insulin works 100% of the time in diabetics to improve blood sugar, whereas treating depressed patients with antidepressants works, at best, 60% of the time. On the flip side, placebos fail altogether in the treatment of diabetes, but work quite well for depression. The biologic model is a fallacy.

Have you ever had a tickle in your throat and been in a room full of coughing people? It’s virtually impossible to not start coughing yourself. Similarly, if your workplace is surrounded by demoralized, disenfranchised, co-workers, it’s hard not to assume a similar attitude and become depressed at work. It seems that both coughing and negative attitudes are “contagious.” The likely explanation is because both are—at least in part—under volitional control and responsive to environmental cues. It is quite possible to stifle a cough if you concentrate on doing so, just as it is possible to improve your attitude by practicing positive imagery. Of course, patients with pneumonia may not be able to suppress a cough any better than a severely depressed person can cure their illness simply by thinking “happy thoughts,” but you get the idea—there are factors at work here outside the realm of the biologic.

Conditions with binary answers (e.g. Is the strep test positive or negative after treatment?) are far less susceptible to placebo effects than problems where a spectrum of response is the norm (e.g. How much pain do you have? How bad is your cough? How is your mood today?). Given an expectation of efficacy, patients with a cough report that cough medicines help irrespective of the active ingredient (or lack thereof). This is also true with depression; it’s the expectation of efficacy that counts as much, or more, than the active ingredient, and this also accounts for why all the antidepressant trials report similar efficacy irrespective of the class, agent, or dose. Knowing this, the next time you feel blue, why not call a friend and go out for a run rather than calling a doctor and heading to the pharmacy? And the next time you get a cough, try a honey-laced hot toddy rather than a swig of Robitussin. In both cases, you’ll thank me.

 

 

 

Suicide prevention resources:

National Suicide Prevention Lifeline 1-800-273-8255

American Foundation for Suicide Prevention: https://afsp.org

National Institute of Mental Health: https://www.nimh.nih.gov

 

References:

1. Irving Kirsch et al., “Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration,” PLoS Med 2008; 5 (2): 0260-68.
2. Jay Fournier et al., “Antidepressant Drug Effects and Depression Severity,” JAMA 2010; 3030 (1): 47-53.
3. Ni Khin et al., Exploratory Analysis of Efficacy Data From Major Depressive Disorder Trials Submitted to the US Food and Drug Administration in Support of New Drug Applications,” J Clin Psych 2011; 72 (4): 464-72.
4. Erik Turner et al., “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy,” NEJM 2008; 358: 252-60.
5. Cosima Locher et al., “Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-Analysis,” JAMA Psych 2017; 2432: E1-E10.
6. Irving Kirsch, “Antidepressants and the Placebo Effect,” Zeitschrift fur Psychol 2014; 222 (3): 128-34.
7. Eric Apaydin et al, “A Systematic Review of St. John’s Wort for Major Depressive Disorder,” Systematic Reviews 2016; 5: 148, DOI 10.1186/s13643-016-0325-2.
8. Sona Didjian et al., “Randomized Trial of Behavioral Activation, Cognitive Therapy, and Antidepressant Medication in the Acute Treatment of Adults With Major Depression,” J Counseling Clin Psychol 2006; 74 (4): 658-70.
9. Robert DeRubeis et al., “Cognitive Therapy vs. Medication for Depression: Treatment Outcomes and Neural Mechanisms,” Nat Rev Neurosci 2008; 9 (10): 788-96.
10. Halle Amick et al., “Comparative Benefits and Harms of Second Generation Antidepressants and Cognitive Behavioral Therapy in Initial Treatment of Major Depressive Disorder: Systematic Review and Meta-Analysis,” BMJ 2015; 351: h6019.
11. Steven Hollon et al., “Prevention and Relapse Following Cognitive Therapy vs Medications in Moderate to Severe Depression,” Arch Gen Psych 2005; 62: 417-22.
12. James Blumenthal et al., “Effects of Exercise Training on Older Patients with Major Depression,” Arch Int Med 1999; 159: 2349-56.
13. Michael Babyak et al., “Exercise Treatment for Major Depression: Maintenance of Therapeutic Benefit at 10 Months,” Psychosom Med 200; 62 (5): 633-38.
14. James Blumenthal et al., “Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder,” Psychosom Med 2007; 69 (7): 587-96.
15. Gary Cooney et al., “Exercise for Depression,” JAMA 2014; 311 (23): 2432-33.