Wednesday, November 10, 2010

Are Antidepressants Bad for You? - Part II

Yesterday focused on an important review article by Giovanni Fava of the University of Bologna (Emanuela Offidani, co-author), brought to my attention by Robert Whitaker on his blog, Mad in America. In the review article, Fava and Offidani indicate that long-term use of antidepressant drugs in some cases may actually worsen the outcome of depression. But they also suggest that bad outcomes may have a lot to do with our simplistic notion of depression, which only encourages equally simplistic treatments.

Let's start at the beginning ...

According to Fava and Offidani, antidepressants are much better suited to treating the episode rather than the illness. Thus, if you are feeling depressed, there is a reasonable chance that your antidepressant may boot you out of your current state - for a little while, anyway. The evidence that antidepressants will keep another depression from occurring, however, is far more problematic.

For instance, a 1998 study found that patients on Prozac fared nearly twice as well as those in the placebo group (26 percent relapse vs 48 percent), but only at the 24-week point. After 62 weeks the two groups relapsed about equally. Other studies show relapse rates in the 46 to 65 percent range over one year.

Meanwhile, in some individuals (30 percent in one study, 7 percent in another), depression scores went up among those on an antidepressant rather than down. Also, studies have found that antidepressants appear to increase - not decrease - the frequency of recurrences, and that they increase depression symptoms in those being treated for anxiety.

We know there is a high risk of antidepressants causing bipolar patients to flip into mania or speeding up cycling, but there is also the possibility that these meds may also increase the rate of depressive relapse in this same population.

What is going on?

In their review article, Fava and Offadani devote a lot of attention to the tolerance factor. Thus, in a 1995 study conducted by Fava, patients who relapsed on Prozac at 20 mg responded to Prozac at 40 mg. A related phenomena is "resistance," when a med doesn't work when restarted after it had previously been effective. Percentages from various resistance studies range from 4 to 38 percent. Then there is "discontinuation syndrome," such as headache or sleep disturbance soon after the med is withdrawn. This occurs with far greater frequency in the shorter half-life meds such as Paxil.

The unifying theme, the authors suggest is "oppositional tolerance." In their own words:

According to this model, continued drug treatment may recruit processes that oppose the initial acute effects of a drug or of receptor alterations ... Use of antidepressant drugs may also propel the illness to a more malignant and treatment-unresponsive course ...

We're entering the realm of hypothesis here, but what may be happening, according to the authors, is that the therapeutic modulations that antidepressants induce in the 5HT1A, 5HT1B, and 5HT2 serotonin receptors may, in certain cases, be triggering downstream effects inside the neuron "that are likely to affect the balance of serotonin receptors."

Or a similar result may occur via the HPA axis (the neuroendocrine loop that mediates fight-or-flight). In this scenario, enhanced 5HT1 neurotransmission may activate the HPA axis, which in turn may disturb serotonin receptor function. Stress figures mightily in depression, and while antidepressants may have a protective effect, in some cases there is the possibility of heightened sensitization.

The authors acknowledge there are no studies that prove oppositional tolerance, but the NIMH-underwritten STAR-D trials, they maintain, sheds light on the theory. In STAR-D, 3,600 patients were first tried on Celexa. Of these, 37 percent remitted. Those who didn't recover were tried on other antidepressants or various meds combinations in four successive stages. Sixty-seven percent of those who remained in the study eventually remitted, but owing to relapse the true figure was 43 percent. Thus, the very best that medicine could accomplish was squeeze out a measly 6 percent improvement in the initial recovery rate. Moreover, remission rates decreased after each treatment while relapse rates increased.

STAR-D most convincingly demonstrated that when the first or second antidepressant fails, there is little prospect of the third or fourth one proving to be the magic bullet. But was this due to a predisposition on the part of the individual patient or to the cumulative effects of repeated antidepressant administration? Fava and Offadani raise the possibility of the latter, saying that switching or augmenting meds "may propel depressive illness into a refractory phase, characterized by low remission, high relapse and high intolerance."

This sets up their conclusion:

When we prolong treatment over 6–9months we may recruit processes that oppose the initial acute effects of antidepressant drugs (loss of clinical effects). We may also propel the illness to a malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration. When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible. The more we switch or potentiate antidepressant drugs the more likely is oppositional tolerance to take place.

But they also pull their punch with this final sentence: 

The phenomena we have described, however, are difficult to interpret unless a precise diagnostic categorization of mood disturbances is made, taking into consideration both their longitudinal course, the unipolar/bipolar distinction and their subtypes.

Here, of course, is where the real discussion begins.

Next: The real discussion begins ...


Tony Previte said...

Isn't it peculiar that studies on these medications beyond 90 days are hard, or nearly impossible to find?

Why is it that our caregivers always throw out the "Prevention" aspect of using these medications in the long term, when there is little to no data to support that notion?

Why did it have to come to me telling my last Psychiatrist that he was "full of shit" when he assertively told me that going off my meds would land me in a hospital within 2 weeks and be harder to treat?

I had to point out to him that my history said something different and pointed to my rather thick file on his desk that I had painstakingly spent 2 days going over with various intake specialists to ensure something like this wouldn't happen. It happened anyway and it took me having to literally "shock" him with facts and call him out for not paying attention. Our interactions from that point forward were much different and we laid out a plan to taper off my medications as a team.

John McManamy said...

Hey, Tony. Unfortunately, shit is in much greater supply than evidence. The evidence for long-term treatment simply isn't there. Psychiatry is making unwarranted assumptions that a med that got you out of a crisis (often by over-sedating you) is somehow going to get you well. The whole concept of maintenance treatment is fundamentally flawed. It is based on relapse prevention (ie keeping you out of the hospital, even if your basic functioning is severely compromised) rather than returning you to your pre-illness well state.

I could go on and on - and I will in future blogs.

Erica said...

Hi John! I hear you that staying on anti-depressants long term may be harmful to the course of the disease (more info needed, of course). But do you know anything about long-term mood stabilizers? Any research suggesting that they might only be needed short term? I'd love the excuse to ask my doctor for a break off my meds. Thanks!