Furious Seasons

May 30, 2008

Peter Kramer Again Defends Anti-Depressants

There was an interesting and odd article on MSN Health yesterday. Interesting because it examined the question of why different people have such wildly different responses to anti-depressants--everything from the classic "better than well" response to no response to violence and suicide. Peter Kramer of Listening to Prozac fame makes an appearance in the article which I'll untangle in a second. The response/non-response issue is one of the most ticklish and important questions in all of medicine, especially since anti-depressants are the most prescribed class of drugs in America. It's a question that the article tries to sort out, but unfortunately researchers haven't hit upon anything less than a suite of answers, so the article does end up tasting like an interesting bowl of mush by its end.

Still, it is an important question and one I'd personally love to know the answer to someday. Just for fun. Why, for example, did 10 mgs of Lexapro work so-so for me yet when I went off the drug about six months later, suffered from rebound depression and, then, went back on the drug at the same dose, it damn near exploded my heart and had me so agitated I couldn't think? Why did 20 mgs of Prozac initially work quite well for me, then later make me feel stony, then wash out altogether and then at higher doses damn near cost me my life? I don't even pretend to know the answer or answers, although my broad hunch is that it's got something to do with small strips of genetic code that some people have and some people don't. Just a guess though. Researchers have not been able to come up with a consistent, replicable set of answers to date.

Anyhow, the article references the Kirsch paper from PLoS which appeared in February and asserted that several anti-depressants were no effective than placebo based upon their approval studies that were submitted to the FDA, but remained unpublished. If I were writing the piece I would've referenced as well the Turner paper in the New England Journal of Medicine from January which reached the conclusion that non-publication of FDA approval studies with negative results for all 12 "modern" anti-depressants had led to an incredible overstatement of anti-depressant efficacy by pharma companies. In my mind, it was more damaging than the Kirsch paper since it looked at the entire class of anti-depressants.

Ever since, some researchers have gone out of their way to defend and attempt to rehabilitate anti-depressants in the media (i.e., the recent Fred Goodwin program on "The Infinite Mind" radio show), operating on what one presumes is the assumption that legitimate researchers and clinicians like Kirsch and Turner are trying to scare people off their meds. No one I know of has spoken out more on this issue than Kramer.

He first took a swing at the Turner paper on Slate back in January. Later, he defended anti-depressants again on Slate as he set about attacking Charles Barber's Comfortably Numb, in which Barber had aimed several shots at Kramer for Listening to Prozac wherein case studies of seven of Kramer's patients had all of America rushing to doctors to get their serotonin back in "balance." Perhaps, Kramer defends anti-depressants so aggressively because he has so much to answer for. In his book, for example, he's completely dismissive of the idea that SSRIs can be linked to incidents of violence. He's even defended anti-depressant efficacy to me personally and there he was yesterday in the MSN Health piece.

"Two other complications are noted by psychiatrist Peter Kramer, author of Listening to Prozac. First, early data-—of the kind included in the meta-analysis which found antidepressants no better than placebo—-often fails to show results for drugs that later prove very effective. 'We have medications that show effectiveness in post-stroke depression, in the elderly with multiple brain lesions, in people with chronic, intractable depression. Why do they only not work in the early trials?' he asks.
"Second, people get excellent care in clinical trials, which makes the placebo effect especially strong. This means it’s harder to show a difference, even if a drug works well. 'We may be losing effective substances, not approving ineffective ones,' Kramer notes."

I wonder what anti-depressants Kramer thinks are going unapproved. I cannot think of a single anti-depressant, submitted to the FDA for approval, that has been rejected in recent years. That strikes me as a baseless statement on Kramer's part and makes me wonder exactly who the hell is editing articles like this at MSN Health. It's one of those things a judicious editor would've cut.

When I interviewed Kramer for an article a few months back, he admitted that the Turner paper in the New England Journal of Medicine injured the reputation of anti-depressants, but then proceeded to criticize how clinical trials were done and told me that there were studies showing that anti-depressants worked 80 percent of the time. I asked what studies. He told me studies of anti-depressants in post-stroke depression. I was tempted to say "Whatever," but I respect Kramer too much as a writer and thinker on these issues to be dismissive. All the same, his point was moot. We were discussing anti-depressant use culture-wide not in small cohorts. I almost quoted him on this point in my article just to show the nearly-religious degree people will go to to defend anti-depressants, but I figured it was too much of a sidebar to the main point. I suppose I should've asked him what response placebo got in the same trial, so I could get a sense of what effect size he was talking about. Oh, well, it was a more hurried conversation than I would've wished for.

Still, I must begin to wonder how Kramer can use post-stroke depression to justify the efficacy of anti-depressants in non-post-stroke depression. I suspect they are entirely different animals. Perhaps, he'll write about this on his blog someday soon and enlighten us all. I'd really like to know how post-stoke depression resembles garden variety major depression and why the experiences of those patients should speak to how I--and maybe you--care for myself. It's ironic that last week Kramer's blog entry on the bipolar child article in Newsweek was entitled "Not The Politics, The Experience." It would seem that Kramer is not as open to the experiences of millions of Americans, Brits and others who've had rotten experiences on these drugs as he should be, preferring instead the politics.

I must admit that back when I first read Kramer's book in 1993 it was when I was beginning to have some serious problems with Prozac. I went to his book looking for answers and became enthralled with the response his seven patients had to the drug. I so wanted to be like them. But I never was. I stayed on the drug several months more, at increasingly higher doses until I experienced such suicidality on the drug that my then-doctor switched me to Paxil. Fifteen years later and after many bad experiences with anti-depressants, I will never take an anti-depressant again in my life absent a gun at my head and a court order in my face. And I'll appeal the court order.

I know however that anti-depressants work well for some people and I congratulate those lucky few.

Posted by Philip Dawdy at May 30, 2008 12:03 AM

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Comments

Here's my experience I guess.

I was ill for years before I sought help. It took trial and error but anti-depressants eventually worked for me.

I had to struggle so hard against my guilt complex that I wasn't ill, I was just a bad person, to get myself to take them initially.

People close to me also repeated the "you're not ill, just pull yourself together" mantra.

I then, when well, went on to project my anger at the wasted years, and the "pull yourself together" brigade, on to the critics of anti-depressants, as I saw them as invalidating my experience.

It took quite a while to realise the critics were NOT telling me not to take my meds. (Actually, this site had a large role to play in this. Thanks). They were just pointing out the other side of the story - that I was part of the lucky 30%, and that frequently, the other 70% don't get a fair hearing, and that there's a lot more to the debate than I had thought, and that I had also been unintentionally invalidating their experiences.

It's a very emotive topic. Lots of buttons to be pushed. Many participants in the debate are not really arguing with one another, but with various bozos of one type or another in their past. Me included.

Posted by: DeeDee Ramona at May 30, 2008 04:29 AM

Antidepressants, especially SSRIs, can cause homicides and that is an unacceptable risk. I believe that a person should be hospitalized if they are going to take Prozac/SSRIs. It is the only way to insure the safety of the community.

On www.SSRIstories.com there are over 2,300 tragic stories of murder, murder-suicides, school shootings, etc., involving these antidepressants.

Once the truth about the homicide risk becomes known by doctors, it should be the same issue as second-hand smoke. People didn't care if other people wanted to kill themselves by smoking but, once it became known that they themselves could be killed by another person smoking, that was the end of the tobacco era. So it is the same with the antidepressants.

I think Peter Kramer's book is a farce. Can you imagine a whole nation going on antidepressants becaue of 7 anecdotal stories? If I were Kramer, I would be ashamed and even terrified that I had encouraged this behavior.

Posted by: Rosie C at May 30, 2008 11:23 AM

When I read Kramer's book, it made me want to stop taking antidepressants. My memory is that he pretty much says that for everyone, taking ssris is like being just drunk enough all of the time. Turns out that's being overly optimistic. Of course he either played down the horrible reactions lots of people had to these drugs or didn't know about them at the time. Now he's just another creepy hack.

Posted by: Sally at May 30, 2008 05:54 PM

I didn't read his book, but I heard an interview with him on KPFA, about 7 years after his book came out. He stated that one of the less positive things about about anti-depressants was that they were being precribed for longer and longer periods of time. From reading your blog, it seems like he then chose to join the doctors he had criticised. When I started to take them 20 years ago, it was never intimated to me that I would need meds forever. It seems to me that a large shift in opinion took place, placing meds in the category of a permanent replacement for the brain's natural balance. Initially, I think it was more a temporary aid in order to look at the underlying issues which caused the depression in the first place, with emphasis on temporary. Therapists would have to actually be of some sort of help with these issues, have some belief in the patients' own ability to heal, and understand what "enough" is, if they were to avoid drug addiction.

Posted by: Sophia at June 1, 2008 01:22 PM

This is also a good article:

www.psikofarmakoloji.org/pdf/12_4_6.pdf
ABSTRACT:
MECHANISM OF ACTIONS OF ANTIDEPRESSANTS:BEYOND THE RECEPTORS

Posted by: Ana at June 1, 2008 02:21 PM

As I alluded to in my comment re: the PBS depression special thread, I really don't understand why SSRI-induced mania is considered the unmasking of pre-existing (though silent) bipolar disorder rather than a very toxic side effect of antidepressant treatment. What gives?

We'll never know the stats on this because psychiatry, on the whole, refuses to acknowledge this devastation. How many "bipolars" are actually just drug-damaged depressives? Great for Big Pharma, shits for the patient. So what else is new?

Posted by: Francesca Allan at June 1, 2008 03:25 PM

Right. Let me translate the last Kramer quote for you Phil: "We may be losing effective substances, [as opposed to, as people are implying] approving ineffective ones."

How far up your ass is your pointy head, that you think Kramer of all people doesn't know the score about the FDA and the last 15 years of psychiatric medications?

It's one of the great mysteries that you can't get a job in journalism.

Posted by: Swick at June 2, 2008 03:26 AM

Francesca,
You're right about SSRI-inducing mania.
The article I left the link raises some explanations on neuroplasticity:

www.psikofarmakoloji.org/pdf/12_4_6.pdf

ABSTRACT:
MECHANISM OF ACTIONS OF ANTIDEPRESSANTS: BEYOND THE RECEPTORS
Since the discovery of first antidepressants-monoamine oxidase inhibitors-a half century passed. There are now almost two-dozen antidepressant agents that work by nine distinct pharmacological mechanisms at the receptor evel. However, opposite to the divergence in their pharmacological mechanisms at the receptor level, antidepressant drugs probably stimulate similar pathways in subcellular level. These subcellular events or so called beyond receptor effects are named neuroplasticity, and the mechanism may be called as adaptation. These after-receptor processes, through their effects on synaptic transmission, and gene
expression are indeed capable of altering many molecular events in the brain. In this article, the mechanisms of actions of antidepressants at-and beyond-the receptors are discussed by documenting some of the evidence indicating such long-term alterations. Accordingly, the well-known effects of antidepressants on the receptor level are initiating events of antidepressant drug action, which enhance and prolong the actions of norepinephrine and/or serotonin and/or dopamine. Only if an adequate dose of an antidepressant is taken chronically, the increase in the synaptic norepinephrine and/or serotonin and/or dopamine stresses or perturbs the nervous system and the therapeutic response results from the adaptations that occur as a consequence of these chronic perturbations.
Key words :antidepressants, mechanism of action, neuroplasticity, adaptation
Bull Clin Psychopharmacol 2002;12:194-200

"SSRI-induced akathisia and agitation are hypothetically mediated by stimulating 5-HT2 receptors in the serotonin pathway that projects to the basal ganglia (11).This may be due to in part to the fact that serotonin inhibits dopamine
release there. Thus, increasing serotonin may produce a mild pseudo-dopamine deficiency state and concomitant symptoms of akathisia and agitation.
SSRI-induced anxiety and even occasional panic attacks are hypothetically mediated by stimulating 5-HT2 receptors in the serotonin pathway that projects to the hippocampus and limbic cortex (12)."

"SSRI-induced insomnia is hypothetically mediated by stimulating 5-HT2 receptors in brain stem sleep centers, particularly the serotonergic pathway that projects to the cholinergic neurons in the lateral tegmentum. Stimulation of the 5-HT3 receptors both in CNS pathways such as the brain stem vomiting center and the pathway to hypothalamus, and the gut itself appears to be responsible for various
gastrointestinal side effects of the SSRIs (13) . Disinhibition of the serotonin pathway from brain stem to hypothalamus, which mediates aspects of appetite and eating behaviors, may be responsible for the reduced appetite, nausea, and even weight loss associated with SSRIs."

"The so called synaptic plasticity or neuroplasticity is the adaptive ability of the human brain. If the right neurons are stimulated with adequate intensity within certain time constraints, a long-term change occurs, such as alterations in dendritic function, synaptic remodeling, long-term potentiation, axonal sprouting, neurite extention, synaptogenesis, and even neurogenesis (25-27). This stimulation may result from environmental events or psychotropic drugs including the antidepressants. For a long period of time, much of the biological investigations in psychiatry has focused on synaptic pharmacology, especially on neurotransmitter turnover and neurotransmitter receptors, disregarding this brain-adaptive ability (26,27).
Recently, Hyman and Nestler proposed a framework for understanding psychotropic drug action "initiation and adaptation". This framework capitalizes on recent advances in molecular neurobiology and places acute and chronic drug effects in a functional context (26)."

It's a very good article!

Posted by: Ana at June 2, 2008 04:34 AM

Don't know exactly where to put this, but know Sarah would want it:

http://www.nationalpost.com/news/canada/story.html?id=556812

Posted by: noni at June 2, 2008 09:53 AM

As a studying physician, I think antidepressants are very over prescribed.

My solution would be to have depression conditions managed by specialists, and at least by psychiatrists. Having a general practitioner dispense SSRIs with no complimentary therapy to address possible underlying issues is the biggest problem with antidepression medication, at least as I see it. I think that the condition and treatment are so nuanced that they require additional training above and beyond what a general practitioner might have.

I know that antidepressant medication is very useful for some people, but has also become a crutch for physicians that want a quick and easy way to deal with psychosocial and emotional issues that have less cut and dry treatment procedures than "prescribe medication XX." I think this is one of the manifestations of the underlying problems in medical practice, but that is another rant. I think it is a false dilemma to say that one must either accept antidepressant treatment as it exists fully or completely cease manufacture of the medication. Some simply support a smarter usage of the medication.

I will close with saying that I think it is awful that patients like my best friend's mother, who after losing her husband of over 20 years to lung cancer, was prescribed antidepressants when she still felt grief about her husband's death -one month later-. Are we such a society that any negative emotion is to immediately be considered pathological?

Posted by: Matt at June 3, 2008 07:07 PM

Matt, medical stuff isn't that straightforward either. Many drugs seem to exchange one health problem for another and doctors don't seem to pay enough attention to supplements or sometimes to special diets.
Prozac does create a quasi-drunken state sometimes. Prozac is like LSD or PCP, caffeine, and alcohol all combined in a capsule. There is also an impairment of judgment that makes the drug especially dangerous for females, young people, people with disabilities, elderly people, people in bad neighborhoods. . . I've just mentioned the majority of the population. Stay off that garbage. Prozac can also cause depression, anxiety, and obsessive-compulsive stuff.

Posted by: Jennifer at March 10, 2009 06:23 PM