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Knowledge is Necessity

If your second antidepressant fails, it's time to rethink your options.

"So what went wrong?"

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Admitting You Need Help

Antidepressants - Part I

Antidepressants - Part II

Med Combos

When Your First Antidepressant Fails

Treating to Remission

Antidepressants for the Long Haul

Bipolar Meds - Introduction

Bipolar Meds - Mood Stabilizers

Bipolar Meds - Antipsychotics

Algorithms For Meds Treatment

TIMA Algorithm

APA Bipolar Guidelines

BAP Bipolar Guidelines

Long Haul Bipolar Treatment

Treating Hypomania

Treating BP Depression

Remission for Bipolar

Drug Metabolism

Meds and Pregnancy

FDA Antidepressant Suicide Warning

Three Paxil Studies

Prozac Mania

Pax-Ills

Worthless?

Talking Therapy Turbocharge

Cognitive Therapy

Long-Term Talking Therapy

Psycho-Battle

On the Couch

Screen Saver

Warning - Family Physician

ECT

Electroboy

Vagus Nerve Stimulation, etc

 When Your Second Antidepressant Fails

The previous article reported on the second round findings of the NIMH-underwritten STAR*D trials. Four thousand patients with major depression, most of them with recurrent depression, were tried on Celexa under real world conditions. Forty-seven percent responded and 28 percent remitted, not exactly spectacular results but fairly predictable.

In round two, the 1,439 who did not fare well on Celexa and who elected to remain in the study were tried on either one of three antidepressants (Wellbutrin or Effexor or Zoloft) or one of two combinations (Celexa with Wellbutrin or Celexa with Buspar). The results were nothing to write home about (between a quarter and a third remitting) but were sufficiently encouraging to indicate the wisdom in trying a second antidepressant after your first one has failed.

The third round results in July 2006, a few months after the first round results, and the findings indicate that a serious rethinking about antidepressant treatment is in order. Serious as in Code Red, stop the presses, Defcon One, Junior go straight to your room right now.

In round three, 235 STAR*D patients who had not achieved satisfactory results were tried on flexible doses of either the novel action antidepressant Remeron or the old generation tricyclic nortryptyline for 12 weeks under real world conditions. Twelve percent of those on Remeron achieved remission (as measured on the HAM-D) vs one in five for those on nortriptyline. On the QIDS-SR, remission was eight and 12 percent, respectively for Remeron and nortriptyline.

The QIDS-SR response rates were equally dismal, 13 and 17 percent, respectively, for Remeron and nortryptyline.

The study authors did not attempt any positive spin. Instead, they noted:

"Contrary to previous efficacy trials in major depressive disorder, study results suggest that switching antidepressants … after two consecutive antidepressant medication trials have failed provides only a modest chance of producing remission in major depressive disorder."

So what went wrong? Was there something going on that STAR*D did not anticipate? Funny you should ask.

The Kraepelin Factor

When I initially reported on the STAR*D second round results, Frederick Goodwin MD, co-author (with Kay Jamison PhD) of "Manic-Depressive Illness" got back to me with this observation:

"I noticed that the cohort they studied had a mean of six previous episodes; this means that they were relatively highly recurrent unipolar patients, which was included in Kraepelin's description of manic depressive illness (a term which is not synonymous with bipolar disorder)."

Those with recurrent depressions in the study also had an earlier age of onset than those with just one depressive episode (23 years vs 34 years).

To liberally interpret Dr Goodwin, there may have been patients in the study whose so-called unipolar depressions perhaps resembled bipolar depressions. Dr Goodwin, with S Nassir Ghaemi MD of Emory University, has proposed the new diagnosis of "Bipolar Spectrum Disorder" (BSD) that would acknowledge the clinical reality of many of these patients. One of the criteria for BSD would include brief recurrent episodes (more than five), early onset, and non-response to three antidepressants. A 2005 study found that 37 percent of those with unipolar disorder could conceivably be rediagnosed with BSD.

It is important to note that BSD also contains other criteria that would exclude many patients with highly recurrent depressions. The point is there may be a good many people who are not getting well because their unipolar depressions are not exactly conforming to whatever is meant by "uni."

In his correspondence to me, and in a talk at the recent American Psychiatric Association annual meeting in Toronto in May 2006, Dr Goodwin referred to early studies that found lithium had some effect for both bipolar depression and "cyclic" unipolar depression, and for preventing depression in these populations.

In his 2006 book "Why Am I Still Depressed?" Oregon psychiatrist Jim Phelps MD stresses the importance of "treating the cycle" for highly recurrent depressions (which also includes bipolar depressions) rather than the "symptom du jour." The emphasis is on getting the cycle under control, usually with a mood stabilizer (but also employing smart talking therapy and scrupulous life style management).

In other words, the way to go might be treating certain highly recurring unipolar depressions as if they were bipolar depressions. The catch is we haven’t enjoyed much success treating bipolar depression. The unfortunate consensus among the experts is that bringing a patient down from mania and stabilizing this individual is a piece of cake, by comparison.

Making Sense

So what have we learned from the third round of STAR*D? It appears that after two failed antidepressant trials, clinicians need to be rethinking their options. With a second trial the odds of success are somewhat less than the first, but third time out we are starting to look at the falling off the edge of the cliff phenomenon. The success rates drop off significantly.

The results should not be interpreted as two strikes and you’re out. It’s more like two strikes and let’s start rethinking. This is a crucial distinction. Going with a different antidepressant or antidepressant combo may be justified after two or even three or more failures.. But after the second failure, the clinician needs to be aware that he or she may have passed the point of diminishing returns.

Should the patient be informed of the situation? On one hand the patient has a right to know. On the other, the bitter truth may act as a reverse placebo.

At this stage, the clinician needs to be looking far more closely at the patient’s depression. Highly recurrent? Early onset? Family history of bipolar? First-degree relative with bipolar? Mixed states? Co-occurring illnesses? Personality issues? Arguably, this should have happened at the very beginning of treatment, but better late than never.

It’s easy to say STAR*D should have included various lithium, Lamictal, and Seroquel options in rounds two and three, but we know a lot more now than back seven years ago when STAR*D was on the drawing board. One thing we learned from round three is there is a crying need for fresh trials with mood stabilizer options, but we won’t learn anything more if the NIMH pulls the plug on STAR*D.

The infrastructure for STAR*D is already in place – 41 treatment centers throughout the US, trained personnel, protocols, data collection, institutional wisdom, everything. This is no time to wrap up the program. Fresh funding, fresh patients, new insights, new treatment options – let’s get started.

Final Word

The people who put together STAR*D felt very strongly that remission rather than response should be the goal of antidepressant treatment, and used this much higher standard as the criterion for success in their trials. But we know antidepressants leave a lot to be desired, and that true recovery typically involves active measures on the part of the patient, as well, such as good lifestyle regimens, coping techniques, support, effective stress management, and cognitive skills.

The paradox: Perhaps if we don’t expect much of our antidepressant, we can get much better results.

For free online issues of McMan's Depression and Bipolar Weekly, email me and put "Sample" in the heading and your email address in the body.

July 11, 2006

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