Thursday, February 18, 2010

The State of the Science on Antidepressants

In yesterday's post on grief in the DSM-V, I made a blanket statement about antidepressants being ineffective. Ronald Pies, MD, Editor in Chief of Psychiatric Times, left a comment asking readers to consider his recent article in rebuttal to Sharon Begley's Newsweek story about antidepressants being only as effective as placebos.

This is a brief quote from Begley's widely covered article:
The moral dilemma was this: oh, yes, I knew of 20-plus years of research on antidepressants, from the old tricyclics to the newer selective serotonin reuptake inhibitors (SSRIs) that target serotonin (Zoloft, Paxil, and the granddaddy of them all, Prozac, as well as their generic descendants) to even newer ones that also target norepinephrine (Effexor, Wellbutrin). The research had shown that antidepressants help about three quarters of people with depression who take them, a consistent finding that serves as the basis for the oft-repeated mantra "There is no question that the safety and efficacy of antidepressants rest on solid scientific evidence," as psychiatry professor Richard Friedman of Weill Cornell Medical College recently wrote in The New York Times. But ever since a seminal study in 1998, whose findings were reinforced by landmark research in The Journal of the American Medical Association last month, that evidence has come with a big asterisk. Yes, the drugs are effective, in that they lift depression in most patients. But that benefit is hardly more than what patients get when they, unknowingly and as part of a study, take a dummy pill—a placebo. As more and more scientists who study depression and the drugs that treat it are concluding, that suggests that antidepressants are basically expensive Tic Tacs.
This article was covered widely in the press and the blogs, with the conclusion that SSRIs do not work for anything other than severe depression. This is the article that Dr. Pies wrote in response to Begley's mainstream piece.

Newsweek’s Topsy-Turvy Take on Antidepressants

By Ronald Pies, MD, Editor in Chief | February 8, 2010

Imagine, as a psychiatrist, hearing this story from a beloved friend or relative:

“I’ve been terribly depressed for the last month—can’t focus, can’t get out of bed, and I’m barely eating. Nothing really gives me pleasure anymore. I haven’t showered in 2 weeks. Sometimes I think I’d be better off dead. I asked my family doctor if an antidepressant might help. She said I’d do just as well taking a sugar pill, and it’s a lot cheaper!”

I hope you would be both alarmed and outraged by this doctor’s dismissive attitude. Yet if the doctor—or your loved one—had read the article on antidepressants in the February 8 Newsweek (The Depressing News About Antidepressants), she might well have concluded that antidepressants are largely worthless.

Let’s credit Newsweek and the usually careful science writer, Sharon Begley, with bringing the problem of clinical depression before a wide audience. The clever cover of the magazine allows one to read either “Antidepressants Don’t Work” or “Antidepressants Do Work,” depending on which title is on top. Sadly, the article itself is a bit topsy-turvy, and may do less to educate the general public than to confuse or alarm it. (A nice rebuttal by psychiatrist Robert Klitzman, MD follows the Begley article).

Essentially, after a superficial analysis of 2 recent studies, Begley concludes that antidepressants are “basically expensive Tic Tacs” (sugar pills). Begley then struggles with whether it might be “a kindness” to keep patients “in the dark about the ineffectiveness of antidepressants, which for many are their only hope…"

The studies in question—by Kirsch and colleagues1 and Fournier and colleagues2—found that antidepressants were not substantially more effective than placebo, except for the most severe types of depression. The lay press promptly proclaimed—sometimes with barely suppressed glee—“Antidepressants No Better than Sugar Pill!”

Both the Kirsch and Fournier studies are “meta-analyses” of various individual antidepressant trials. Meta-analyses suffer from all the problems common to such “number-crunching” methods: if the individual studies are flawed, the meta-analysis is flawed. For example, the Kirsch meta-analysis looked only at studies carried out before 1999. The much-publicized Fournier study examined a total of 6 antidepressant trials (n=718) using just 2 antidepressants, paroxetine and imipramine. Two of the imipramine studies used doses that were either subtherapeutic (100 mg/day) or less than optimal (100 to 200 mg/day). Moreover, the design of the Fournier study intentionally excluded individual studies involving a “placebo washout” phase, which attempts to reduce the number of placebo-responders receiving active medication. By excluding such studies, the Fournier meta-analysis may have reduced the difference between placebo and antidepressant response rates.

The Newsweek article also misrepresented the nature of placebo controls. Begley repeatedly describes a placebo as a “dummy pill”—but subjects in the placebo group of most major antidepressant studies receive much more than a sugar pill. As research psychiatrist Dr. Sheldon Preskorn recently wrote me, “… there is much more treatment [provided] by being on a placebo in a study than most depressed patients get in routine clinical practice, particularly in the primary care setting” (personal communication, 2/03/10). Indeed, Preskorn estimates that in a typical 8-week trial, a subject in the placebo group may receive 10 to 12 hours of contact time with knowledgeable and empathic healthcare practitioners. In effect, the placebo control is a kind of substantive, supportive intervention. Furthermore, placebo group response rates in depression studies have been mysteriously and substantially rising in recent decades3—perhaps in part because less severely depressed subjects are being recruited. Since mildly depressed subjects are more likely to be placebo responders, such a recruitment artifact could be shrinking the difference between antidepressant and placebo response rates.

Moreover, the Newsweek article—like many professional journals—also ignores an important underlying reason for the diminishing drug-placebo difference, as we move from more severe to milder forms of depression. As Preskorn explains, “The ‘finding’ that antidepressants do not work as well in mild as in severe depression is a ‘floor’ effect. [One] could not show that antidepressants worked in non-depressed individuals, and the lower the severity score, the closer the participants are to the ‘floor’” (personal communication, 1/19/10).

Begley acknowledges the benefit of antidepressants in severely depressed patients, but minimizes its importance, noting that only 13% of patients meet this severity threshold. But based on a 2004 SAMHSA study,4 “only” 13% means that about 2 million adults in the United States may suffer from severe depression in a given year. Even by the lights of the Fournier study, that’s 2 million people who would probably respond well, acutely, to an antidepressant. Furthermore, as Preskorn notes, acute efficacy studies, in contrast to maintenance studies, “…overestimate the efficacy of ‘placebo’ treatment. On average, 3 out of 10 fewer patients will relapse in 1 year if they are continued on medication, as opposed to being switched to placebo.”5

Yes, antidepressants are “oversold” in those Big Pharma ads, adorned with chirping birds and fluttering butterflies—in truth, antidepressants don’t work as well or as specifically as we’d like.5 Given the frequent side effects of many antidepressants, it is usually wise to initiate treatment with psychotherapy, in cases of mild-to-moderate, non-melancholic depression.6 Alas, psychotherapy is often difficult for patients to obtain or afford.7 Despite Newsweek’s supposedly “depressing news” about antidepressants, psychiatrists have good reason to keep these medications in their armamentarium--and patients with severe unipolar depression8 have good reason to consider taking them.

Acknowledgment: My thanks to Dr Sheldon Preskorn for his helpful comments and suggestions.

1.Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5:e45.
2.Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303:47-53.
3. Walsh BT, Seidman SN, Sysko R, et al. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002;287:1840-1847.
4. NSDUH Report: Depression among adults. Accessed February 8, 2010.
5. Preskorn S. A dangerous idea. J Prac Psych Behav Health. 1996;2:231-234.
6. Brown WA. Treatment response in melancholia. Acta Psychiatr Scand Suppl. 2007;433:125-129.
7. Pies R. Antidepressants work, sort of—our system of care does not. J Clin Psychopharmacol In press; April, 2010.
8. Pies RW. Pseudoresistant bipolar depression. J Clin Psychiatry. 2009;70:1476.
I am largely in agreement with Dr. Pies in his response to the Begley article. Still, there are reasons to be skeptical of the blanket use of SSRIs. To be fair, Dr. Pies is opposed to the overuse of these drugs and would rather see therapists and psychiatrists try psychotherapy much of the time before going to drugs (with the obvious exceptions of severe depression and suicidality).

However, I have posted other articles on the issues with SSRIs, and there are reasons to question the benefits of these drugs. This is the most compelling research I have seen, from this blog, December, 2009:

Most Antidepressants Miss Key Target of Clinical Depression

Way back in what now seems like the dark ages of depression medications, the most effective and widely used drugs were MAOIs, or monoamine oxidase inhibitors. The MAOIs have some serious risks for those who do not avoid certain foods in their diets:

When ingested orally, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese syndrome"), the individual may suffer from hypertensive crisis. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual, and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

The exact mechanism by which tyramine causes a hypertensive reaction is not well understood, but it is assumed that tyramine displaces norepinephrine from the storage vesicles.[4] This may trigger a cascade in which excessive amounts of norepinephrine can lead to a hypertensive crisis. Another theory suggests that proliferation and accumulation of catecholamines causes hypertensive crises.
Here is an explanation of how the MAOIs work, from the Mayo Clinic:

How MAOIs work

Researchers believe MAOIs relieve depression by preventing the enzyme monoamine oxidase from metabolizing the neurotransmitters norepinephrine (nor-ep-ih-NEF-rin), serotonin (ser-oh-TOE-nin) and dopamine (DOE-puh-mene) in the brain. As a result, these levels remain high in the brain, boosting mood.

Antidepressants, in general, may also work by playing a neuroprotective role in how they relieve anxiety and depression. It's thought that antidepressants may increase the effects of brain receptors that help nerve cells keep sensitivity to glutamate — an organic compound of a nonessential amino acid — in check. This increased support of nerve cells decreases glutamate sensitivity, providing protection against the glutamate overwhelming and exciting key brain areas related to anxiety and depression.

Therapeutic effects of antidepressants may vary in people, due in part to each person's genetic makeup. It's thought that people's sensitivity to antidepressant effects, especially selective serotonin reuptake inhibitor effects, can vary depending on:

  • How each person's serotonin reuptake receptor function works
  • His or her alleles — the parts of chromosomes that determine inherited characteristics, such as height and hair color, that combine to make each person unique

Antidepressant medications are often the first treatment choice for adults with moderate or severe depression, sometimes along with psychotherapy. Although antidepressants may not cure depression, they can help you achieve remission — the disappearance or nearly complete reduction of depression symptoms.

Because of the risks involved with these drugs, and based on the unsupported assumption that serotonin is the most important neurotransmitter in depression, the selective serotonin reuptake inhibitors (SSRI) were developed to address this element of brain chemistry. They do not work for many people, and sometimes figuring out which one might work takes several trials. They do have fewer severe risks, but as many or more overall side effects, most notably weight gain (they interfere with glucose metabolism, i.e., cause diabetes in some people) and loss of sexual desire/function.

Turns out, according to this new study, that SSRIs might simply be making us stoned on serotonin (as argued by Peter Breggin in Medication Madness), not addressing the real issues of depression in our brain chemistry.

It seems the original idea, that the MAO inhibitors address the neuro-chemistry of depression, might be the best approach if we can make them safer.

Most Antidepressants Miss Key Target of Clinical Depression, Study Finds

ScienceDaily (Dec. 8, 2009) — A key brain protein called monoamine oxidase A (MAO-A) -- is highly elevated during clinical depression yet is unaffected by treatment with commonly used antidepressants, according to an important study published in the Archives of General Psychiatry. The study has important implications for our understanding of why antidepressants don't always work.

Researchers at the Centre for Addiction and Mental Health (CAMH) used an advanced brain imaging method to measure levels of the brain protein MAO-A. MAO-A digests multiple brain chemicals, including serotonin, that help maintain healthy mood. High MAO-A levels excessively remove these brain chemicals.

Antidepressant medications are the most commonly prescribed treatments in North America, yet 50 per cent of people do not respond adequately to antidepressant treatment. Dr. Jeffrey Meyer the lead investigator explains, "Mismatches between treatment and disease are important for understanding why treatments don't always work. Rather than reversing the problem of MAO-A breaking down several chemicals, most antidepressants only raise serotonin."

Understanding the Problem of a Persistent Illness

Depression ranks as the fourth leading cause of disability and premature death worldwide, according to the World Health Organization. Recurrent illness is a major problem. Even under the most optimal treatment circumstances, recurrence rates for clinical depression are at least 20 per cent over two years.

The new study also focused upon people who had fully recovered from past episodes of clinical depression. Some people who appeared to be in recovery actually had high levels of MAO-A. Those with high levels of MAO-A then had subsequent recurrence of their depressive episodes.

This new idea of high levels of MAO-A lowering brain chemicals (called monoamines), then falling into a clinical depression is consistent with the historical finding that medications which artificially lower monoamines can lead to clinical depression as a side effect. In the 1950's some medications to treat high blood pressure also lowered monoamines and people began to experience depressive episodes. When the medications were removed, people recovered.

From Technology to Treatment

VP of Research Dr. Bruce Pollock highlights the study's use of advanced brain imaging technology. "CAMH has the only positron emission tomography (PET) centre in the world that is dedicated solely to mental health and addiction treatment and research. As a consequence, we were able to develop this new technology to measure MAO-A levels."

Virginia Wilson knows first-hand the struggle it can be to find effective medication. After being diagnosed with depression, eight years passed before a medication was developed that worked well for her. "During this time I was on every type of antidepressant available. This process was enormously frustrating, painful -- and took a great toll on my personal life." The current research into depression gives Virginia hope for others who struggle as she did. "Understanding of the biochemical mechanisms behind depression is so important and can really improve the treatments that are available -- it can save lives."

Some early antidepressant medications did target MAO-A, but these MAO-A inhibitors fell out of favour in the 1970s due to adverse interactions with certain foods. There have been advances that overcome these problems, but the vast majority of antidepressant development and use has overlooked the MAO-A target.

According to Dr. Meyer, "Since most antidepressants miss MAO-A, we are counting on the brain to heal this process of making too much MAO-A, and that doesn't always happen. The future is to make treatments that tell the brain to make less MAO-A, even after the antidepressant treatment is over, to create better opportunities for sustained recovery."

~ Dr. Meyer is a Canada Research Chair in the Neurochemistry of Depression and the Head of the Neurochemical Imaging Program in Mood Disorders. The study was funded by the Canadian Institutes of Health Research, the Ontario Mental Health Foundation, and the Canadian Foundation for Innovation.

Journal Reference:

  1. Meyer et al. Brain Monoamine Oxidase A Binding in Major Depressive Disorder: Relationship to Selective Serotonin Reuptake Inhibitor Treatment, Recovery, and Recurrence. Archives of General Psychiatry, 2009; 66 (12): 1304 DOI: 10.1001/archgenpsychiatry.2009.156
I am not willing to disregard the SSRIs yet. For me, as someone with social anxiety disorder, Paxil (paroxetine) has been the best thing that ever happened to me - after years of therapy, mindfulness practice, meditation, and herbal approaches, I can now speak in front of people with a panic attack.

I'm sure there are many people who have felt the same relief from depression with these drugs - if they were prescribed the right one, or found the right one through trial and error. I'm waiting for the day when we can match drugs to the genetic profile of the patient - that is when we know for sure how well these drugs treat depression.


Anonymous said...

Hi, Bill--

First, many thanks for posting my rebuttal of the Begley article. For those with a more research-oriented inclination, I have a much more data-rich editorial coming out in the next (April) issue of the Journal of Clinical Psychopharmacology. So, please stay tuned!

Re: SSRIs, MAOIs, etc: first off, the SSRIs are actually a fairly heterogeneous group of agents. As I sometimes say in my lectures, "Like the Holy Roman Empire--which was neither Holy, nor Roman, nor an Empire--the so-called selective serotonin reuptake inhibitors are not entirely selective; they affect other neurotransmitters besides serotonin; and they probably work through other mechanisms beside re-uptake

For example, paroxetine has modest effects on norepinephrine reuptake, while sertraline has similar effects on dopamine. So generalizations from one or two agents are hazardous.
(That was a problem with the Fournier et al study).

That said, I am a huge fan of MAOIs, difficult though they are to
"manage" (dietary restrictions, potential for adverse drug reactions, etc.). When they work, they work very well!

As for mechanism of action, few of us in the field still believe the old "joy juice" theory of how antidepressants work; i.e., depression = too little joy juice (read: serotonin, norepinephrine, etc.)in the brain, so you just pump up these brain chemicals, and voila! The patient is well. This is probably nonsense. To the extent these agents are effective--and, to be sure, they are not fantastically effective medications--they probably work by enhancing various neurotropic factors, such as BDNF, which increases synaptic connectivity. This occurs at the level of the gene, so these are far from "cosmetic" agents.

One reason for disappointing findings in, e.g., the STAR*D study, is that the antidepressants are largely working on 2 or 3 brain chemicals, across the board. So, when you "switch" from brand A to brand B, you are largely giving the patient a "me too" experience, in terms of the pharmacology (despite the points I made earlier about subtle differences within the SSRI group).

Bottom line: these are "pretty good" medications for those patients correctly diagnosed, and the results are more and more "specific" (drug > placebo) as you move closer and closer to the "archetype" of severe, melancholic (unipolar) depression.

Thanks for the balanced coverage of this important issue. --Best regards, Ron Pies

Ronald Pies MD
Disclosure statement available on Psychiatric Times website.

WH said...

Hi Dr. Pies,

Once again, thank you so much for adding your thoughts here. I really appreciate you taking the time to offer me and my readers your perspective on this topic. For many of us, especially Buddhists, there is a serious distrust of pharmaceutical approaches to emotional issues.

But in an integral approach, there is the understanding that material brain dysfunction is connected to subjective experience - that it's not either/or but both/and.

I guess some of are struggling with the chicken/egg paradox. Which comes first - the emotional issues (trauma, etc) that change the brain; or the brain chemistry which generates the emotional issues (depression, anxiety).

Anyway, I look forward to seeing the article in the Journal of Clinical Psychopharmacology.

All best,

Anonymous said...

Thank you, Bill...very good questions to be struggling with! I have a long-standing interest in Buddhism--particularly, the distinction between dukha and tanha, and its relation to cognitive schools of psychotherapy. So, I can definitely "resonate" with some of your readers' concerns. Thanks for being open-minded and tolerant...certainly traits I associated with Buddhism! ---Best, Ron