Are Antidepressants Bad for You? - Part IV

The story so far:

In his blog Mad in America, author Robert Whitaker drew attention to a recently published review article by Fava and Offidani that came to this startling conclusion:

When we prolong treatment [with antidepressants] over 6–9 months 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.

In support of their view, Fava and Offidani cite studies that show that staying on antidepressants longer than three months has no effect at reducing the risk of recurrence and may, in fact, make the illness worse. What may be occurring, they hypothesize, is "oppositional tolerance," where, over time, the brain pushes back against the antidepressant.

But the authors also note that our lack of scientific understanding of depression leaves room for interpretation.

In his book, "Anatomy of an Epidemic," Whitaker helps us out by noting that, historically, depression had been regarded as a rare illness with a good prognosis. Then antidepressants became the rage. Despite this, too many patients only seemed to be getting worse over the long haul rather than better. According to Whitaker, instead of questioning the med, psychiatry questioned the diagnosis. Overnight, the new consensus was that antidepressants are okay, but the illness is highly prevalent with a poor prognosis.

Thus, ironically, depression became an epidemic.

But what if depression is the wrong name for this epidemic? What if most of what we are observing is not clinical depression at all? And what if not all depressions are the same? These are questions I have been asking on this blog and elsewhere. 

Let's start with the obvious, with the unipolar/bipolar distinction. All too often, people with bipolar walk in the door depressed, are misdiagnosed with unipolar depression, and given an antidepressant. If they are lucky (as I was), the antidepressant will quickly flip them into mania, which will put even the dumbest clinician on notice to change both the diagnosis and treatment.

If the patient is unlucky (as many are), the antidepressant may initially make that individual feel better before feeling worse. Then that individual endures the heartbreak and frustration of being tried on one antidepressant after another, years on end. Ten or 11 years later (the time it usually takes to make an accurate bipolar II diagnosis), a smart clinician finally considers the obvious.

There is now widespread agreement that an antidepressant, even with a concomitant mood stabilizer, does nothing (as a general rule) to improve bipolar. Moreover, we know these meds run a high risk of making it worse.

There is also an emerging consensus that this may be the case for many so-called unipolar depressions, as well. These are individuals that Goodwin and Jamison in their second edition to "Manic-Depressive Illness" characterize as "highly recurrent." In other words, there is a cycling nature to the course of their illness, much like bipolar, even if the "ups" fall well short of mania or hypomania. But give these individuals an antidepressant and that may change. In effect, an antidepressant may turn an unsuspecting unipolar into a bipolar, a point that Whitaker visits in Chapter Nine of his book.

Obviously, psychiatry needs to light a match to the DSM and start over. Whether one calls highly recurrent depression a new form of depression or a new form of bipolar hardly matters, so long as clinicians are put on notice to think twice before prescribing an antidepressant. But that is not the end of the story. Four years ago, I had this to report, from a lecture delivered by Joel Paris of the University of Toronto at the 2006 APA:

In true Axis I depression, Dr Paris explained, when patients come out of a depression, they are nice people again. Individuals with personality disorders, by contrast, can come out of a depression and still have problems with life. Unfortunately, clinicians prefer not to want to hear about personality. It means trouble. They would rather throw more meds at the problem.

Dr Paris was talking about borderline personality disorder, which is often misdiagnosed as a mood disorder. With psychiatry at long last showing signs of breaking off its love affair with Pharma (thanks to psychiatric meds losing their patent protection), personality disorders are starting to get a lot more respect.

Let's take this a step further. Suppose, in some cases, that depression itself could be considered a personality disorder, as some experts are proposing (a rather controversial view) or (much less controversially) as part of one's baseline temperament? (See my January blog post on this.) In this context, depression is a natural (and possibly even healthy) part of a person's personality rather than a deviation from from one's normal healthy state.

To wrap this up for now, imagine a patient walking into a psychiatrist's office manifesting depressive symptoms. Assuming the cause is not physical (such as a thyroid condition) or neurological (such as dementia), we have five (not necessarily mutually exclusive) possibilities, namely:

1. Classic unipolar depression.
2. The depressive phase of bipolar disorder, either I or II or cyclothymia.
3. Something in between, or overlapping with, classic depression and classic bipolar.
4. A personality disorder, such as borderline.
5. A personality trait or temperament.

Five possibilities. Four chances to get it wrong. Only one chance to get it right. Is it any wonder that doctors get such bad results or that patients undergo so much misery? But even if the clinician spins the wheel correctly, we are talking numerous sub-possibilities within the one possibility that holds out promise. In other words, even more chances to get it wrong.

Stop this game of antidepressant roulette right now! one wants to cry out.

Next: The game goes on, anyway ...

Previous articles

Are Antidepressants Bad for You?
Are Antidepressants Bad for You? - Part II
Are Antidepressants Bad for You? - Part III

Are Antidepressants Bad for You? - Part III

Yesterday, we looked at a review article by Giovanni Fava and Emanuela Offidani that introduced the idea of "oppositional tolerance" in regard to long-term antidepressant use. According to the authors, the few long-term studies we have indicate a three-month limit to antidepressant treatment. Staying on these meds any longer appears to have no impact on avoiding a recurrence. Indeed, in some cases, long-term use may make our depressions worse and set us up for future episodes.

The reason for this, the authors hypothesize, is that as our brains build up a tolerance to these meds, various processes are set in motion that counteract the drug's initial effect which in turn may "propel the illness to a more malignant and treatment-unresponsive course."

The authors note, however, that oppositional tolerance needs to be considered in the broader context of psychiatry's highly suspect diagnostic criteria for mood disorders. This portion of the conversation begins in Robert Whitaker's "Anatomy of an Epidemic":

In Chapter Eight, Whitaker cites community surveys from the 1930s and 40s that found "fewer than one in a thousand adults suffered an episode of clinical depression each year." According to Charlotte Silverman, author of "The Epidemiology of Depression" (1968), and others, depression was primarily an "ailment of middle aged and older persons." Most of the "depressed-only" patients observed by Emil Kraepelin in the early twentieth century experienced just a single episode of depression and only 13 percent had three or more episodes. Even as late as 1972, Guze and Robins of Washington University (St Louis) noted that only one in ten became chronically ill.

Then came the antidepressant era in full force. For some patients, these meds proved to be magic bullets, at least in the early going. But it wasn't long before researchers began reporting on their inordinately high relapse rates (the scientific term is "Prozac poop-out"). According to Whitaker, psychiatry decided this had to do with the course of the illness rather than the effects of the drug. Overnight, psychiatry changed its party line to the effect that depression was everywhere, and that the old epidemiological studies were "flawed." In the words of the American Psychiatric Association, "depression is a highly recurrent and pernicious disorder."

Says Whitaker: "In the short span of forty years depression had been utterly transformed," going from a rare illness with good outcomes to an epidemic that kept visiting havoc its victims.

Giovanni Fava was a lone voice back in 1994 when he dared suggest in an editorial that we need to be paying attention to the man behind the curtain, wondering if meds "may actually worsen, at least in some cases, the progression of the illness which they are supposed to treat." Since Fava was merely posing this as a hypothetical he was easy to dismiss. Whitaker asserts that Fava's concerns "needed to be hushed up," but the APA is not exactly a Star Chamber.

Sixteen years later, Fava is still beating the drum, this time far less tentatively. Fittingly, it is Whitaker in his blog Mad in America who drew attention to Fava's latest contribution. Clearly Whitaker is onto something. In his book, he makes the telling point that if our meds worked as well as Pharma would have us believe, then we wouldn't have illnesses like depression to kick around anymore. Or, at the very least, thanks to treatment, depression would be very rare and relatively benign. This is a point that other commentators have raised as well, including David Healy of Cardiff University.

Instead, in the face of overwhelming evidence that depression has - defiantly, it seems - refused to yield to repeated antidepressant bombardment, psychiatry has changed its tune on the illness. Suddenly, it's everywhere and is highly malignant. Again, Whitaker and Healy and others are in harmony.

Do you see the dots starting to connect? Namely: Problematic meds to treat a vaguely defined illness advanced by those with strong monetary interests, leading to this major fallacy - If it's depression, then one must always treat it with an antidepressant.

But what if it's NOT depression, even if it looks like depression? Or what if not all depressions are the same? And who, precisely, are these people, anyway, these anomalies of psychiatry, who are put on meds that may make them worse rather than better? Why are they being lumped with everyone else?

These are questions that badly need to be asked, that hardly anyone seems to be asking.

Next: We ask the questions ...

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 ...

Are Antidepressants Bad for You?

This is the eleventh in my series based on talking points raised by Robert Whitaker's eye-opening "Anatomy of an Epidemic."

We take a slight detour. A late Oct blog entry to Robert Whitaker's "Mad in America" contained this intriguing title: Do Antidepressants Worsen the Long-term Course of Depression? ...

The piece extracted some of the main points from a review article by Giovanni Fava of the University of Bologna. Here is Whitaker's summation:

• After six months of antidepressant treatment, the drugs "generally fail to protect" against a return of depressive symptoms. (In other words, maintenance treatment is ineffective, compared to placebo.)
• Two-thirds of patients maintained on antidepressants suffer from "residual symptoms," with "anxiety, insomnia, fatigue, cognitive impairment, and irritability the most commonly reported."
• As patients are switched from one antidepressant to another or to a polypharmacy regimen, their illness may be propelled "into a refractory phase, characterized by low remission, high relapse and high intolerance."
• Antidepressants increase the risk of a "switch" into mania, and thus into bipolar illness. Antidepressants also increase the risk that bipolar patients will become rapid cyclers, and that bipolar patients will develop a syndrome dubbed "Chronic Irritable Dysphoria."

Make no mistake, right from the get-go Fava very unambiguously sounds the alarm:

It was suggested that long-term use of antidepressant drugs may increase, in some cases, the biochemical vulnerability to depression and worsen its long-term outcome and symptomatic expression, decreasing both its likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods.

In summing up, he notes:

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 there is this important qualifier:

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.

Dang! Nuances again.

Next: A look at the nuances ...