Treatment

When Your First Antidepressant Fails

Thinking of quitting? Think again.

We know our antidepressants leave much to be desired. A "successful" clinical trial is one that gets 50 percent of us 50 percent better. A lucky one third may reach the Promised Land, but the overwhelming majority of us are left struggling on our first try in various states of debilitating half-life.

The APA, in its 2000 Practice Guideline for the Treatment of Major Depressive Disorder, recognizes that initial disappointment is a fact of life, and suggests a range of second and third options that include switching to another antidepressant or augmenting an antidepressant with another medication or with talking therapy. Unfortunately, the APA cites little supporting evidence, such is our lack of knowledge.

The next edition of the Practice Guideline will have a bit more to go on, thanks to an NIMH-underwritten project called STAR*D. Several years ago, STAR*D (Sequenced Treatment Alternatives to Relieve Depression) began enrolling 4,041 outpatients with nonpsychotic major depression in 41 real world clinical settings. Unlike clinical trials funded by pharmaceutical companies, the trial included patients with co-occurring mental and physical illnesses. No placebos were used for comparison, and patients knew which drugs they were receiving.

The project was headed up by A John Rush MD of the University of Texas Southwestern Medical Center at Dallas.

The first phase of the study was published in January 2006 in the American Journal of Psychiatry, with Dr Rush’s university colleague Madhukar Trivedi MD as lead author. All the patients - most with highly recurrent depressions - were placed on flexible doses of the SSRI antidepressant Celexa. After 12 weeks, 47 percent responded to the drug (ie a 50 percent reduction in symptoms or better) and 28 percent remitted (ie virtual elimination of symptoms), similar to the findings in most placebo-controlled, double-blinded drug trials.

You don’t find pharmaceutical companies advertising these kinds of results in their TV commercials, and a cynical public is catching on. The LA Times reports antidepressant sales were down 14 percent from last year. In the same journal issue as the STAR*D study, a Columbia University and other centers survey of 829 adults on antidepressants found only 27.6 percent stayed on their meds for more than 90 days. Four in ten of all the patients quit in the first month.

But don’t antidepressants deserve a little more love, or at least a second chance?

Switching to a Different Antidepressant

The second phase of STAR*D involved patients who experienced less than satisfactory results on the Celexa. Of these, 1,439 opted to stay in the study. Two of their options included either switching to another antidepressant or augmenting their Celexa with another drug. The results were published in two articles in the March 2006 New England Journal of Medicine (the switch study with Dr Rush as lead author, the augmentation study with Dr Trivedi as lead author).

Those who chose to switch antidepressants had experienced virtually no clinical benefit on their Celexa. Fifty-six percent were not able to tolerate this medication.

So would they have better luck on a different class of drug altogether, say a non-SSRI such as Wellbutrin or Effexor? After 14 weeks on one or the other of these meds, a quarter of these patients got completely better. (The study measured for remission rather than response.) Those on Effexor did about the same as those on Wellbutrin.

The success rate was lower than those of much smaller studies. The authors of the study attribute this to the inclusion of more difficult to treat "real world" patients in STAR*D.

Okay, how about substituting an SSRI with another SSRI, then, say Zoloft? In theory, if you can’t stand the taste of Coke you’re not going to be happy with Pepsi, either. The results didn’t turn out that way. Those on the Zoloft did as well as those on the Wellbutrin or Effexor, leading the authors of the study to observe that "intolerance to or the lack of efficacy of one SSRI seems not to imply intolerance or lack of efficacy of another SSRI." Various small studies had already borne this out, but now we have something that passes for evidence in our "evidence-based" medicine.

Some Background on Antidepressant Augmentation

Augmentation - supplementing an antidepressant with a different type of drug - is meant to either kickstart an antidepressant or enhance its effect, though there is precious little data to go on. At the 2002 APA annual meeting, Andrew Nierenberg MD of Harvard alluded to the phenomenon of the "augmentation of the month club" where once you have a study involving five patients, "everyone does it."

Augmenters include:

Lithium - A 2003 meta-analysis of 10 placebo-controlled trials of treatment-resistant patients found 45 percent responded to the addition of lithium.
Thyroid (T3) - Mixed results from small studies.
Buspar - Very little data, may improve sexual dysfunction, may speed up response of SSRI.
Pindolol - Positive results from a University Hospital Lewisham (London) study of 78 patients to speed up antidepressant action.
Viagra - May counter SSRI sexual dysfunction side effect.
Stimulant and Dopamine Agonists (Mirapex, etc) - A University of Pisa study of 31 non-responders to antidepressants (both unipolar and bipolar depressed) found that the Parkinson's drug pramipexole (Mirapex) added to their meds resulted in 21 responding after 16 weeks.
Anticonvulsants - Evidence for bipolar depression.
Provigil - Novel psychostimulant, three studies finding the drug useful as an adjunct.
Ritalin - Some psychiatrists are treating their geriatric patients with low doses of Ritalin to augment their antidepressants. Ritalin can have an energizing effect in 72 hours, but its benefit is short-lived. By then, hopefully, the antidepressant is beginning to kick in. It is also being used to clear up the thinking and concentration difficulties that occur with depression
Antipsychotics - Eli Lilly has a combo Prozac-Zyprexa med marketed as Symbyax for bipolar depression, but potential side effects limit its use. Psychiatrists may also recommend their own SSRI-antipsychotics combos.
Estrogen - Case reports of women responding.
Inositol - A Massachusetts General Hospital study of 16 depressed bipolar patients found a 33 percent response in those who augmented their lithium or Depakote with the simple carbohydrate, inositol, vs zero in the placebo group. Inositol naturally occurs in the body, is necessary for the formation of lecithin, and may reverse desensitization of serotonin receptors.
Potential augmenters - SAMe, EPA (found in omega-3), folate.

Some Background on Antidepressant Combinations

Combinations tend to involve two different classes of antidepressants, such as an SSRI with an antidepressant that works on norepinephrine (such as Effexor, with a dual serotonin-norepinephrine action, plus a weaker dopamine action). One controlled study of patients who had not responded to an SSRI showed a 64 percent response when treated with an SSRI-Remeron combination (Remeron has a unique action that works on both serotonin and norepinephrine).

Essential Pharmacology of Depression and Bipolar Disorder by Stephen Stahl of the University of California at San Diego describes "California rocket fuel," a combo of Remeron and Effexor which can give a triple boost to the serotonin system, a double boost to the norephinephrine system, and a single boost to the dopamine system.

With triple combinations, Dr Nierenberg reported at the 2002 APA meeting, "we’re in No Man’s Land," with no data. "A lot of time I make my patients better by getting rid of the drugs [the pharmaceutical companies] give out."

Augmenting the Original Antidepressant

Back to STAR*D:

Those who chose to augment their Celexa with another med were in slightly better shape than the patients who switched meds. Nevertheless, more than half these patients had experienced side effects they found intolerable. The doctors in the study were given the flexibility to lower the Celexa doses if side effects occurred.

Half the patients in this study were assigned Wellbutrin, increased over four weeks to a full clinical dose (300 mg) and to 400 mg at week six. The drug is an obvious choice in any combination or augmentation strategy with an SSRI. This is because the two meds together can enhance the activity of the three neurotransmitters we know best – serotonin, norepinephrine, and dopamine. (And also because the Wellbutrin can counteract the sexual side effects of SSRIs.) At the end of 14 weeks, nearly a third of the Celexa-Wellbutrin patients achieved remission.

What about a different strategy? Instead of targeting three neurotransmitters, try instead turbocharging just the serotonin. Buspar is a novel anti-anxiety med that, according to the authors of the study, "enhances the activity of SSRIs through the [serotonin] 5HT1A receptors." The drug is not used as an antidepressant. The patients in the study received the maximum dose of the drug (60 mg) by week six.

At the end of 14 weeks those on the Celexa-Buspar combo achieved the same outcome as those on Celexa-Wellbutrin, though the authors of the study noted the Celexa-Wellbutrin group experienced lower drop-out rates.

What to Make of These Findings

Clearly, STAR*D demonstrates the value in trying another antidepressant or antidepressant combo if your first one fails. The catch is we don’t know in advance which ones.

Celexa is typical of all those one-size-fits-all medications that the pharmaceutical companies love to produce. Unfortunately, one size fits very few. In an article in the June 2004 Australian and New Zealand Journal of Psychiatry, Gordon Parker MD, PhD of the University of New South Wales pointed out that drug trials typically view depression as a single entity varying only by severity, with no regard to distinguishing symptoms or causes.

Predictably, taking a drug such as Celexa is a lottery, and STAR*D shed no light on taking some of the guesswork out of choosing our first antidepressant. We are similarly in the dark about second choices. Another SSRI or another class of drug? Who knows? Try one; you may get lucky.

The augmentation studies tell us a little more. Probably go with the Wellbutrin first because of the side effects issues. Otherwise, pick a number, any number.

What about the higher success rate among the augmenters as opposed to the switchers? Can we make anything of that? Probably not. Apples and oranges. The augmenters had slightly better depression scores going into stage two of the study.

Okay. So now we know a little bit about what to do if your first antidepressant fails. What about if your second antidepressant fails? Houston, we have a problem

Updated Feb 10, 2008