Do SSRI's Even Work? And if so, How?

Just in case you feel like reading Sunday's New York Times Magazine before it come out, over on "Post-Prozac Nation: The Science and History of Depression," Siddhartha Mukherjee will be writing about the history and efficacy of antidepressants.  Dr. Mukherjee writes:


Fast forward to 2012 and the same antidepressants that inspired such enthusiasm have become the new villains of modern psychopharmacology — overhyped, overprescribed chemicals, symptomatic of a pill-happy culture searching for quick fixes for complex mental problems. In “The Emperor’s New Drugs,” the psychologist Irving Kirsch asserted that antidepressants work no better than sugar pills and that the clinical effectiveness of the drugs is, largely, a myth. If the lodestone book of the 1990s was Peter Kramer’s near-ecstatic testimonial, “Listening to Prozac,” then the book of the 2000s is David Healy’s “Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression.”


He talks about depressed people in the 1950's being cured as a side effect of their treatment for tuberculosis (isoniazid was one of the first medicines to elevate mood in the depressed) and hyptertensive patients becoming depressed on Raudixin.


Mukherjee goes on:

In 2011, Hen and his colleagues repeated these studies with depressed primates. In monkeys, chronic stress produces a syndrome with symptoms remarkably similar to some forms of human depression. Even more strikingly than mice, stressed monkeys lose interest in pleasure and become lethargic. When Hen measured neuron birth in the hippocampi in depressed monkeys, it was low. When he gave the monkeys antidepressants, the depressed symptoms abated and neuron birth resumed. Blocking the growth of nerve cells made Prozac ineffective.

Hen’s experiments have profound implications for psychiatry and psychology. Antidepressants like Prozac and Zoloft, Hen suggested, may transiently increase serotonin in the brain, but their effect is seen only when new neurons are born. Might depression be precipitated by the death of neurons in certain parts of the brain?


He finishes off with the ideas:

The differences in responses to these drugs could also be due to variations in biological pathways. In some people, neurotransmitters other than serotonin may be involved; in yet others, there may be alterations in the brain caused by biological factors that are not neurotransmitters; in yet others, there may be no identifiable chemical or biological factors at all. The depression associated with Parkinson’s disease, for instance, seems to have little to do with serotonin. Postpartum depression is such a distinct syndrome that it is hard to imagine that neurotransmitters or hippocampal neurogenesis play a primary role in it. 

Nor does the theory explain why “talk therapies” work in some patients and not in others, and why the combination of talk and antidepressants seems to work consistently better than either alone. It is very unlikely that we can “talk” our brains into growing cells. But perhaps talking alters the way that nerve death is registered by the conscious parts of the brain. Or talking could release other chemicals, opening up parallel pathways of nerve-cell growth. 

But the most profound implications have to do with how to understand the link between the growth of neurons, the changes in mood and the alteration of behavior. Perhaps antidepressants like Prozac and Paxil primarily alter behavioral circuits in the brain — particularly the circuits deep in the hippocampus where memories and learned behaviors are stored and organized — and consequently change mood.

Fly Those Friendly Skies

We've talked before about whether having the diagnosis of a mental illness should prevent a person from pursuing certain careers. We've also mentioned that pilots, in particular, can not be on psychotropic medications. One concern is that a depressed pilot might not seek treatment because s/he fears losing her job. Is it better to have a pilot with untreated mental illness, or one on medication?

In The Wall Street Journal, Shirley S. Wang and Melanie Trottman write that the FAA has reconsidered this policy and will allow pilots to fly if they are being treated with Zoloft, Celexa, Lexapro, or Prozac. They write:

The new policy doesn't mean pilots who want to begin taking one of the medications can get in the cockpit right away. Before being granted a waiver by a physician certified by the FAA, a pilot must be considered "satisfactorily treated" for 12 months; in the meantime, he or she will be grounded.

For pilots who have been secretly taking antidepressants, the FAA is offering a grace period. The agency said it wouldn't take action against such pilots if they come forward within six months. However, pilots with a recent case of depression or who want to begin a new medication regimen will be subject to the one-year waiting period, according to FAA spokeswoman Alison Duquette. "We're really looking for stability," she said.

Grounded for 12 months? Seems like a long time. What do grounded pilots do? Do they get paid? Is this really destigmatization?

Paxil, anyone?

I ran a poll, not long ago, after reading Peter Kramer's blog post on the relative efficacy of the different SSRI's. Here's what we found:

Which SSRI is the most Effective?

Prozac 15% (22 votes)
Zoloft 14% (21 votes)
Luvox 0% (0 votes)

Paxil 5% (8 votes)
Celexa 7% (10 votes)

Lexapro 19% (28 votes)

Cymbalta (SNRI) 13% (20 votes)

Effexor (SNRI) 18% (27 votes)
Wellbutrin (neither, but it's here anyway) 9% (14 votes)

Total Votes: 150

Which Medicine Causes the Most Side Effects

Prozac 13% (17 votes)
Zoloft 7% (10 votes)
Luvox 5% (7 votes)
Paxil 31% (41 votes)
Celexa 1% (1 votes)

Lexapro 4% (6 votes)
Cymbalta 7% (10 votes)
Effexor 25% (33 votes)

Wellbutrin 7% (9 votes)

Total Votes: 134

Okay, so let's start by talking about how this 'poll' is meaningless. We don't know who took it-- patients, docs, random plumbers surfing through. We don't know what experience these people have had with antidepressants-- so the question has different meaning if it's asked to a doc who has only ever prescribed Prozac and Zoloft, then if it's asked to a patient who has been on a long trial of every medication. There's no real head-to-head here, no measures of efficacy, no controls. And I didn't even specify what the efficacy was for: Depression? Anxiety? OCD? Panic? Halitosis? Slipping behind your ear to hold your glasses in place?

Still, we had a clear loser, and I was surprised: Paxil. Few people voted for it's efficacy, many for it's side effects.

I don't start people on Paxil so much anymore: the lore is that it causes more weight gain then the others, and when I do prescribe it, I tell people to get weighed. It may cause weight gain, as an overall risk to populations, but all I care about is if it causes weight gain to my particular patient, and clearly, some people do not gain weight on it. The more concerning thing about Paxil has been the withdrawal syndrome that some people experience and so far I've found that it's manageable, especially if people come off very slowly. Still, all things being equal, these days I may start with something else.

So why was I surprised: I guess I haven't heard a lot of patients complain about side effects, and I have patients who've been on this medicine for some time. It seems to work particularly well, at least that's my impression, for Anxiety, and it seems to be well tolerated, the 'polls' would say otherwise. And for the uninsured, the generic is on Walmart's $4 list (as is Celexa).
Just my thoughts.

And to those who've read yesterday's post about does Facebook wreck your brain: If you read either the original article or the comments to our post, you'll note that the original piece is simply theories that all this computer time may re-wire people; there were no studies, no proof. And as some of our readers pointed out, On-line interactions may well be a segway into the world of Real Life encounters for people who might otherwise hesitate. I often wonder if my college experience would have been broadened by the world of the internet---

The SSRI Horse Race-- Take Our (Meaningless) Polls

This is not science, I'm just playing here, nothing random, nothing controlled, just questions for our readers.

I just read Peter Kramer's Psychology Today blog post called Lexapro and Zoloft in a Cloud of Dust. Dr. Kramer talks about the relative efficacy of SSRI's, their market share, and if the drug company's influence docs to prescribe in a way that isn't in sync with research. Lexapro, the most expensive SSRI, apparently has the biggest market with 13% of the market share. He writes:
Now comes news of a large-scale analysis of research on antidepressant efficacy. Published in The Lancet, it finds a hierarchy, with Remeron, Zoloft, Effexor, and, yes, Lexapro, leading the pack, Cymbalta and Prozac in the middle, and Luvox, Paxil, and (especially) reboxetine, which is marketed outside the US, bringing up the rear. Celexa and Wellbutrin gave statistically fuzzy efficacy results; the two drugs appeared to be about average for the group. In terms of tolerability, Zoloft, Lexapro, Celexa, and Wellbutrin led the pack. So the results give a special place to Zoloft and Lexapro.

Do read the original post.

So I thought I'd put up two polls, and again, this isn't science, it's just curiosity. Pretend you didn't read the paragraph above, and I'd like you to answer two questions: What do you think is the most Effective SSRI, and Which SSRI do you think causes the most side effects. I don't care if you're the patient or the doctor, or a non-MD therapist who's simply just heard patients talk about the meds. It's a question of perception, with the awareness that maybe you haven't seen all the horses race. Efficacy: Which med works the best (If you've only been on Prozac and that worked great, it's fine to answer that!). Side Effects: Which med makes people feel the yuckiest (now there's a scientific term).

Tell Your Doctor If You Experience Any Of The Following...

A reader writes in:

I might suggest that in some cases, the more outre side effects of SSRIs are not reported because the person taking the drug is afraid of being thought insane. I had unbelievable rage while I was taking Effexor, and never told anyone about it because I was afraid of not being believed, and also afraid that there was something else seriously wrong with me.

I am a highly intelligent and naturally moral person, and never hurt anyone despite my desire to do so, though I did put my fist through a wall at one point. But I had extremely disturbing violent impulses while on the drug, including a desire to maim or kill my beloved cats, and a strong desire to physically assault the woman I was dating at the time. All of this vanished completely when I decided to voluntarily go off the drugs, which I had been told I would need for the rest of my life. As it happened, the psycho-emotional disorder I had was consistently missed by therapists and clinicians, and SSRI drugs were not an appropriate treatment.

This may or may not account for the peculiar side effects, but at any rate -- my thought is that possibly these things go unreported due to shame and fear on the part of the patient.

So we don't give medical advise here on Shrink Rap. I borrowed this comment, however, because I'm struck with how often patients withhold critical information. If a patient tells me that since we started a medication, he's had a new symptom, if that symptom is intolerable to him, or in any way worrisome, I don't sit there thinking they are crazy. I stop the medicine. If the side effect sounds like it's a little uncomfortable but the overall quality of someone's life is better with the medication, I simply restate the facts and my thoughts about whether the good outweighs the bad, I let the patient chime in with their thoughts (I'm not in their body), and I consider the circumstances before the medication was started as well as the response to the medicine. If someone was suicidally depressed and unable to function , then maybe it's worth tolerating a dry mouth in exchange for the ability to return to work and not be sad or suicidal?

It's not just medications-- it's anything major going on in someone's life. If something huge is going on in a patient's life, the doctor needs to know. "I'm more depressed lately," has one meaning in the context of a medication change and another meaning in the setting of a recent loss.

What psychiatrists can't do is know what someone is experiencing without being told. We don't have crystal balls, we don't have ESP, we aren't mind readers, we don't "know" what you're thinking, feeling, worrying about, distressed by, unless a patient tells us in fairly precise terms.

This is Why You Need A Psychiatrist

From today's Wall Street Journal, an article on how antidepressants aren't all they were cracked up to be: Antidepressants Under Scrutiny Over Efficacy. David Armstrong and Keith Winstein write,

"Since the overwhelming amount of published data on the drugs show they are effective, doctors unaware of the unpublished data are making inappropriate prescribing decisions that aren't in the best interest of their patients, according to researchers led by Erick Turner, a psychiatrist at Oregon Health & Science University. Sales of antidepressants total about $21 billion a year, according to IMS Health."

Actually, the issue at hand is that the pharmaceutical companies don't publish or make public the studies that don't show the results that will sell their meds. It's not a news release that we've suddenly realized that antidepressants don't always work. These are two separate issues. The WSJ article is based on a report in the New England Journal of Medicine, Selective Publication of Antidepressant and Its Influence on Apparent Efficacy, and it uses data on antidepressant studies to make this point. Okay, it's also about how antidepressants aren't as effective as the drug companies say they are, but this just doesn't surprise me. The WSJ article goes on to say,

"There is a view that these drugs are effective all the time," he (Dr. Turner) said. "I would say they only work 40% to 50% of the time," based on his reviews of the research at the FDA, "and they would say, 'What are you talking about? I have never seen a negative study.'" Dr. Turner, said he knew from his time with the agency that there were negative studies that hadn't been published.

There's someone out there who thought antidepressants work all the time? This is why people need psychiatrists, not primary care docs, managing their psych meds:

1) Even at high enough doses given for long enough (6 weeks), any given antidepressant may not work on any given patient. Or it may help with some symptoms and not others.

2) If one antidepressant doesn't work, another might.

3) If one antidepressant doesn't work, augmenting with a second medication may work.

4) As a patient suffering from Bipolar Disorder, depressed, moderate in severity, recurrent, said to me recently, "I think the therapy helps as much as the medicine."

I don't think it's news that a) anyone can write a prescription for Prozac and the patient may not get better, or b) this is complicated stuff.

The issue of the pharmaceutical agencies hiding their negative data is also not news. Personally, I think the legal penalties for withholding this information should be stiff enough to stand as a deterrent. You just don't hear of drug company CEO's in the cell next to Martha Stewart.

My Three Shrinks Podcast 37: Poop-Out

[36] . . . [37] . . . [38] . . . [All]

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Sorry for the delay in getting podcasts out, folks. This one may be a bit confusing, as we recorded it prior to the new sound equipment, so it is not "new and improved". This is actually #37. So, the next one to come out will be #39 (later this week... really! :-).

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December 9, 2007: #37 Poop-Out

Topics include:

• SSRI Poop-out (a.k.a. tachyphylaxis). This is the phenomenon where a drug is working, then seems to wear off or stop working after some period of time. (see also How a Shrink Picks an Antidepressant, Family Intervention Overcomes Poop-Out, and Stassen's article on resilience.) (I also referred to the use of gestures when speaking.) Also discussed placebo response, light therapy, and Dinah's shpiel.
  
  
• Google Ads. We discuss issues about our minimal use of ads on the blog.
  
  
• Q&A from Tony. Refer back to Questions for the Doctor.
  
  
• Clink's Opera Post.
  

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Find show notes with links at: http://mythreeshrinks.com/. The address to send us your Q&A's is there, as well (mythreeshrinksATgmailDOTcom). This podcast is available on iTunes (feel free to post a review) or as an RSS feed. You can also listen to or download the .mp3 or the MPEG-4 file from mythreeshrinks.com. Thank you for listening.

How A Shrink Picks An Anti-Depressant

[Part Two of this post is here]

Midwife With A Knife wants to know how a psychiatrist chooses a medication for an SSRI-naive patient. Wow, I'd already started that post when she asked.

So a patient comes for treatment. His symptoms meet criteria for Major Depression, no question here, and he wants medication to help his condition. This is his first visit to see me.

Prozac Paxil Zoloft Lexapro Celexa Luvox Effexor Cymbalta Lamictal
Wellbutrin Remeron Serzone Pamelor Elavil Nardil Parnate Emsam Trazodone

I probably missed a few.

So how does a shrink decide what medicine to begin?

1) Past history of response. If the patient says, Oh, yeah, six years ago I felt this way, I took Paxil for six months and that helped a lot and I didn't have any side effects, then Paxil it is.
The path changes if the story is that the medication didn't work or had side effects.

2) Family history of response. This is the patient's first episode, but mom swears by Wellbutrin, it's helped her when nothing else would. This would be a good first choice.

3) Patient preference. He's here because his best friend took Celexa and became a new and wonderful person. I have no idea what friend's diagnosis is or why Celexa was chosen for friend, but if there isn't a contra-indication, then I might as well honor a patient's wishes and there's some power to believing something will help. Similarly, if patient reports that Celexa caused best friend to commit outrageous acts of horror and he wants anything but Celexa, I pick something else.

4) Other Medical Issues. I don't start with meds that interact with what the patient's already on. I don't pick meds that might exacerbate an existing medical condition. Wellbutrin is contra-indicated in patients with seizure disorders, eating disorders, or a history of CNS lesions, so I don't start with it in these patients. I save the risky stuff for after we've been at it a while, and then only with a fair amount of discussion about possible risks compared to possible benefits.

5) My Best Guess at What Will Help the Target Symptoms. Patient is tired and unmotivated...Wellbutrin is reportedly a bit energizing, so maybe that's what I use. Patient also has a lot of OCD symptoms, I might go with an SSRI. If someone has a concurrent pain syndrome, Cymbalta or a TCA might be my first choice.

6) My Best Guess at the Side Effect Profile, for better or for worse. Really, this is a guess. I actually hate this issue because patients often worry about side effects they never get, but okay, if someone is agitated, I might start something I think of as being more calming. If someone says they'll die if they gain a single pound, I pick something more weight neutral.

7) The Patient's Financial Concerns and What I have Samples of. This is only a consideration if the patient is uninsured and paying cash for the meds, but this is not a trivial thing. After that, I move to What's Cheapest that will work and won't cause intolerable side effects. If the patient has been on something and had good success, then loses their insurance, I might try something cheaper in the same class of meds, but I wouldn't recommend a switch from say a working SSRI to a cheap Tricylic-- it's not worth the risk.

Can I say a word about Weight Gain as a side effect? Some patients refuse any medication that's been associated with this. But clearly, and I'm probably repeating myself at this point, there are people who don't gain weight on medicines that are said to cause weight gain, just like there are people who don't get better with anti-anythings. People respond to meds differently. My suggestion to those who are concerned they'll gain weight-- if there's some reason to believe a medicine might help, it may be worth a try. Buy a scale. Get weighed before starting the medication. Get weighed every 2-3 days after starting it. If you gain 5 pounds (1 or 2 or 3 can be variations in fluid retention or scale flakiness), Then it's worth worrying about weight gain and addressing whether it makes sense to continue.

We've been at this blog so long, I've lost track of what I've said already, what I've thought about saying, what I want to say.

What's Your Favorite SSRI?

I like polls....something about asking questions and thinking about the answers. It started on our sidebar with Who Are You? Then, What Do You Want To Read About on Shrink Rap? Then, for lack of anything more creative to ask, What's Your Favorite Color? One day it seemed like the question should be more psychiatric to fit the Shrink Rap theme, so with little thought, I changed it to What's Your Favorite SSRI? Only I suddenly found myself tracking the answers. I didn't ask, purposely, things that might give the question some perspective: like what are you basing your answer on-- the comparison of results of your 732 patients, all of whom have been on every SSRI, or your own experience taking them--which may or may not include a comparative factor. I see lots of people who better on the first SSRI they take, swear by that med, and there's no reason to go further. Some patients are clear that one works for them while another doesn't. Tried my wife's Zoloft and it just isn't Prozac (the names have been changed to protect the innocent).

SSRI's wandered into the psychiatric scene at the start of my training, so I've watched the evolution. First let me tell you my totally random, not-particularly scientific but observational thoughts on each of the SSRI's on the poll. Then you can tell me what you think in the comment section (or Roy & Clink can hi-jack the post and add their profound thoughts if they so wish).
Prozac: It wasn't around when I was a med student, so I saw glimpses of the world before and after. This medicine clearly changed some people's lives in dramatic ways. It's easy to use-- at first the smallest pill was 20 mg and that was the therapeutic dose (though soon we were zooming it up for OCD patients). Fewer side effects than TCAs, not all that hassle with EKGs and blood levels and therapeutic windows and pretty dramatic toxicities. I worked on the inpatient units during it's earliest days where sexual side effects weren't such a big deal. Not that they weren't a big deal, but the patients would get better and go home and then they'd be a big deal, but the outpatient docs were the ones to hear about it. For the people they worked for, Prozac was a good medicine, and it opened up some people's lives.

Zoloft: It's selling point was a shorter half life, fewer side effects, less agitation, and if you don't tolerate it, it's out of your system sooner than Prozac. At first, I didn't think it worked as well-- it didn't seem to have the life-changing benefits of Zoloft. I started asking other people I worked with: Have you seen patients have great responses with Zoloft? This was an informal poll. A few said yes. A few said, "I've seen people have great responses with Prozac." It became a kind of self-fulfilling prophesy for a bit there-- I used Prozac more so of course I saw more responses to Prozac. Oh, it's been decades: I've seen a lot of patients have great responses to Zoloft, and because of the shorter half-life issue, I prescribe it a lot. Oh, the other good/bad thing about Zoloft-- the big dose range. The FDA max is 200 mg. I've seen it used up to 300mg and that patient had no side effects (at all) and the OCD experts apparently go even higher off label. While most people seem to need 100-200 mg for a good response, some people feel better on 25mg, and so for them it's nice to have the option of very low dosing. The bad is that for those who need the whole 200mg, well, it can take a while to get there.

Paxil: This was definitely good stuff, seemed to be well-tolerated, work well, my best guess was that it was more calming, or at least less agitation producing than Prozac, I've prescribed a fair amount of this stuff and still have patients on it who do very well. Time--- two bad things I've seen: a few patients complain of weight gain. I had one patient, certainly the outlier, who gained a huge amount of weight. I would have taken her off the medicine, but she didn't want to stop it. She'd been a skinny kid, she didn't like being the skinny kid, while she didn't like being so much heavier, I was shrink number 3, she'd been on lots of medicines, had lots of diagnoses, her life was a wreck. I'd stopped everything, started 10 mg of paxil, her life was better than ever, and she'd rather be heavy and happy. The years went by, it started to bother her that she was so heavy, eventually changed to Serzone, dropped a lot of the weight, and last I saw her, was still well. Oh, but then the really bad: some people had withdrawal syndrome. Most didn't. But of those who did, well there have been a few where it lingered, where the patient had this very disconcerting and distressing sense of being off balance. I still use Paxil, it still helps people, but before I start it, I tell people there is this risk, and I never just stop it, there's always a slow taper, pill breaking, and every other day dosing when it's time to come off. This helps, and I'd say it's been a while since I've heard about a withdrawal syndrome, but really, the numbers I'm dealing with are too low to be relevant.

Luvox: I've only used this a handful of times. Seems like an SSRI. It's hype is it's indication for OCD. It seems to be the least used SSRI and the poll thingy wouldn't let me have all of them as choices, so this one got dropped. By all means, write in with your Luvox experiences.

Celexa: I've worked in clinics where I get to see other people's prescribing habits, and I worked in a clinic with a doc who liked using Celexa in very high, over-the-FDA-recommended, doses. Seems like it works and is well tolerated. I have a few people on it, mostly they came to me on it. I tend to forget it exists.

Lexapro: Like the others, it seems like a good medicine. Well tolerated, and it works when it works and doesn't work when it doesn't. Same side effect profile as the others, people don't complain much about it. This was our voter's favorite and I wonder if it's because it's the newest that it's what lots of people get prescribed. I think there are now a few of people out there on Lexapro because I've thought "It's the favorite of our readers."

And the poll results, of 105 respondents:

Prozac	16 (15%)
Zoloft	25 (23%)
Celexa	16 (15%)
Paxil	14 (13%)
Lexapro	34 (32%)

Is THIS SSRI Withdrawal Syndrome???

Forgive the silly pic, I couldn't resist stealing it even if it doesn't quite fit.





This is a clinical case, but it's not my patient-- it's a little more personal than that, but still, no distinguishing characteristics, the names have been changed to protect my friends. You might ask why I'm rendering a clinical opinion on someone who is not my patient, who I haven't really examined but for pieces of a brief phone conversation, and that would be a good question. That can be it's own post, maybe one day when Roy is let out?

So I get a call from a dear friend from another state. Her father died last year shortly after being diagnosed with a terminal illness. Her mother happened to see her own GI doc and mentioned that her husband was dying. The story goes, "He told me it would be a rough time for me and prescribed paxil, it helped a lot." I personally don't prescribe medications simply for Hard Times or uncomplicated grief, and I didn't ask for a retroactive history, symptom list or mental status exam. She took paxil, it helped, time passed, she was doing better. So my friend's mother...let's call her Sally... spoke with her primary care doc who had her taper down off paxil cr 12.5 mg by taking one every other day then stopping.

The day after stopping she began to feel sick. Roughly 4-5 days later she was brought to the emergency room: she felt awful. Sally had a bad cold. She had a bad headache. She was confused, she began hallucinating. "Hallucinating? --She saw people moving, she woke someone in the middle of the night asking what a non-existent noise was, she insisted something wasn't written on a paper that was, repeatedly, until it was pointed at for her. Everyone was worried. I should mention that Sally is in her 80's, but she lives alone, drives, takes part in a number of organizations, and is the proud user of some of my favorite hair chemicals. She's not usually confused and she looks years younger than she is. She also suffers from a chronic GI problem, I don't know the rest of the medical history other than Hypertension and that med had been changed recently, too. And I don't know about past psychiatric history, but there's no psychiatrist in the story.

In the ER many tests were run, a brain CT was done. Nothing. The psychiatrist came and proclaimed "Paxil withdrawal." Relatives looked it up on the internet, all these symptoms have been described. She went home to wait it out, but she was feeling worse and worse and now developed a cough. Her primary care doctor said she could go back on Paxil but would then need to remain on it for life, and she didn't want to do this. Friend read on the internet that she could take a single dose of Prozac, which has a longer half-life than paxil, leaves the body more slowly, also increases serotonin levels, and this would help. Primary care doc agreed to call in a few prozac pills.

What did I think? Would this prozac thing work? He only called in 10 mg, was that enough?
Given that I didn't see the patient, I thought a lot, and I'll tell you my thoughts, as I told them.

1) This could be paxil withdrawal, though I personally have never seen anyone hallucinate and the hallucinations sounded a bit too close to delirium for me (Sally sounded fine on the phone). I was much more worried that something else was wrong, that an infectious process might be missed, that this could be related to her GI disease. This was my number one concern, though I was repeatedly told the ER did lots, all tests were fine, that 3 doctors had confirmed this was Paxil withdrawal.

2) Okay, so take a dose of paxil-- if it's withdrawal the symptoms should go away, soon and dramatically. Sally didn't want to do this because then she'd have to stay on paxil forever. No no no no no, I said, it would just be helpful to be sure that's what it was. She could take one dose, be sure she was okay, than happily withdraw. Or she could taper more slowly using 10mg and then 5 mg dosages.

3) Sally took the Paxil. She didn't know if she felt better-- not a good sign. The next day she took it again, she still had URI symptoms, now she had a low-grade temp. Confusion occasionally. The headache was better.

4) Friend wanted to give Sally the dose of Prozac. I said not to-- her symptoms had not resolved, I didn't think this was paxil withdrawal, adding Prozac would not help and she would be subjected to any side effects or adverse effects of the new medication.

The days went by, Sally did better, but hasn't returned to baseline. She's stayed on Paxil. She's staying alone most nights, still gets confused, and honestly, I haven't had an update in days.

The answer? I don't really know. I doubt that it was SSRI withdrawal given that some of the symptoms were not the usual and that she didn't get noticeably better after taking the Paxil. Though I do imagine this could explain part of the picture. Bronchitis (or pneumonia-- I don't know if a CXR was done)? Exacerbation of GI illness wouldn't explain headache, cold symptoms, but might explain some GI symptoms that developed after the Paxil challenge, the low grade fever, the likely delirium. Hopefully they're all doing better.
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And just in case you thought I forgot my Novel obsession, here what people are saying about Double Billing over on The Interactive Novel Project:
Parked : "Now, you have my attention! Kudos! The first chapter just didn't hit me like the second one did. "
ClinkShrink: Wow, is that an improvement over the first chapter! The first chapter was just too short and sketchy and I felt no pull for the character. This is totally different. Very cool.
emy I. nosti: Love it. I'm hooked.

Things I Wish I Knew

We come to day with day with a list of Shoulds we take at face value (--where would you like me to begin? Don't smoke, don't drink excessively, don't be overweight, exercise, take your meds, ingest enough calcium, don't shoot heroin, stay out of jail, don't quit too many jobs, get your screening colonoscopy at 50, yearly mammograms after 40, wear a condom, sunlight is good, sunlight is bad, sunscreen is good, sunscreen is bad, coffee is good, coffee is bad....) only to have them rethought time and again. Roy is now finally off his HRT or so I'm told, he still doesn't look post-menopausal to me.

A few things I find myself wishing I knew the answers to:

Will my children be damaged by all the video-game playing I allow?
Will my relationship with my children be damaged if I don't allow them to play video games and survive the inevitable fights it will cause.

If they go out to ride their bikes instead-- nice healthy exercise--will I wish they'd stayed safely home playing video games if they get hit by a truck?

Why didn't my children come with instruction manuals?
--Inspired by yesterday's snow day and my patient today who is consumed with guilt and a sense of perfectionism with regard to her parenting. Something it's easy to distance myself from during a psychotherapy session, but sometimes strikes a bit close to home.

Will some awful consequence of Gardasil (the new HPV vaccine) be discovered 20 years down the line?

If obesity is so fatal, why, since the 1950's are there so many more obese people and why is the average lifespan 10 years longer?

Why do some people seemed to be unscathed by decades of smoking marijuana?

When my patients chronically misbehave and are completely uninterested in changing (for example, young people who enjoy spending their time drinking to excess in bars, others who repeatedly and without regret sleep with strangers, those who consume large doses of prescription narcotics prescribed by someone else, or people who just won't entertain the idea of abstaining from marijuana)-- am I wrong to continue to treat them on their terms?

If I simply refused to treat them unless they get treatment for their addictions, would they a) stop coming, b) stop telling me about their bad behavior, or c) get treatment and clean up their acts?

When a patient complains of intolerable feelings of agitation or other vaguely defined distress, and gives me the "walk a mile in my shoes" talk, is it wrong that I sometimes offer a prn very low dose of an second generation anti-psychotic, along with the warnings about possible induction of diabetes and dyslipidemia, and let them make the decision about whether to take it? Is it funny that I never ask myself if I should offer that script for very low dose prn Xanax which is what they really want?

And what about the patient whose last depressive episode (of many) lasted nearly a year and who has never been able to tolerate lowering her zyprexa, should I stop it given that her risk factors for diabetes and heart disease are screaming in my face (they preceded the zyprexa, but it can't be helping)? How do we know the worst of two evils?

Were those 250 extra children who died of suicide in 2003 compared to 2004 (see Pediatrics, annual vital statistics, death figures on page 13), children who were not taken for mental health care, or not offered anti-depressants because of the Black Box Warning added to anti-depressants by the FDA?

Sometimes I wish I had a crystal ball that worked, one where I could fine tune it to ask the subtle what-ifs. When it comes to the long-term prognosis for diet Coke and hair chemical abusers, well, there are some things I just don't want to know.

What's Inside the Black Box? FDA Antidepressants Hearing, pt. 2

[posted by Roy]

A couple days ago, I reported on the results of the FDA Psychopharmacologic Drugs Advisory Committee's hearing on December 13, 2006, on the FDA's plan to add a black box warning about the increased risk of suicidality in young adults. (I tried to get this done earlier, but just didn't have the time.)

Here are some notes I made at the hearing...

Sheila Matthews, from AbleChild.org, suggested requiring MedWatch info on all pharmaceutical advertising. I think this is a great idea. MedWatch is the voluntary, side-effect reporting mechanism for the FDA. Few prescribers and fewer consumers use it to report side effects. They should go one further and make it very easy to report side effects... almost as easy as googling the side effects.

There were two out of state attorneys who brought a number of their clients to testify. There were also at least two people there testifying for the Church of Scient ology's C C H R (and making excellent points, I might add, about Lilly's reported lack of following through with their promise 15 years ago to provide additional data. There were quite a few who lost family members tragically after taking only several doses of medication. It is indeed hard to understand how a chemical can cause one to conduct such complex, planned behaviors. Yet, listening to their testimony, it was hard to wonder how their response to these antidepressants could not have contributed to their deaths.

Heidi Bryan, from the Feeling Blue Suicide Prevention Council, pointed out that a big part of the not-enough-follow-up problem was due to the lack of parity for mental health treatment. Even Medicare charges 2-1/2 times as much for co-payments for outpatient mental health diagnoses than they do for the same symptoms caused by non-psychiatric diagnoses (e.g., major depression vs hypothyroidism).

I think that managed care and pharma has so convinced folks that taking a pill is just as effective as talk therapy, that there is now a backlash that will soon require these companies to drop their discriminatory policies.

All of the voting committee members, including Wayne Goodman, Gail Griffith, George Armenteros, Andrew C. Leon, Marcia J. Slattery, Susan K. Schultz, Jean Bronstein, and the chair, Daniel S. Pine, repeatedly pointed out the importance of balancing any labeling changes with language which emphasizes the need to weigh the relative risks of nontreatment with those of treatment, even comparing the risk of treatment with that of non-treatment. In fact, when the vote came up about extending the language in the black box to include the young adults, two members voted against (Griffith and Pines), while the other six voted for it under the condition that balancing language be included as well. They told the FDA that they wanted to review the draft language prior to making a final decision.

Joe Glenmullen, who authored "Prozac Backlash", testified, as well. He and others state the the FDA has been tricked by the drug companies, by not being given complete information about all clinical trial results.

---

So, then the committee deliberated for a few hours. I must say, the committee members rather awkwardly, but repeatedly, made several important points...

• The FDA needs to make the drug companies collect and provide better data.
  
• There is inadequate data on this "activation syndrome", referring to akathisia, agitation, and anxiety apparently induced by antidepressants in some individuals.
• Collecting pharmacogenetic data might help in determining which individuals might be at higher risk of developing this and other side effects.
• The FDA is not collecting adequate data to differentiate between suicidal thoughts and suicidal behaviors and attempts. The pharmaceutical companies need to be directed to supply this type of fine-grained data. The fact that the currently reviewed data on "suicidality" makes it impossible to differentiate these two important characteristics suggests that any change in warning language needs to be carefully worded.
• The committee insisted on the FDA adding balancing language to reflect not only the increased risk of "suicidality" in young adults, but also the other side of the coin -- the increased risk associated with untreated depression. Additionally, they'd like language which refers to the apparent protective effect of these drugs in older adults, especially in seniors. It was noted that this would be the first time that the FDA has included in a black box information of a positive nature.
• They are concerned about the unintended consequences of decreased access to depression treatment as a result of the black box warning. Recent CDC information was noted, indicating that since the 2004 pediatric black box was added, prescriptions in kids are down, while suicides are up. This trend has already been noted in adults, and the fear is that it will only get worse with language that extends to young adults.
• The "25 to 30 year old" group mentioned in Part 1 was not chosen scientifically. It just fit the data. Thus, there is nothing special that happens when you turn 25 or when you turn 31to alter your risk. Because of this, they considered instead using language like "young adults", but this idea didn't seem to be too popular.
• Some of the possible explanations discussed for the biphasic nature of the data (higher risk when younger, lower risk when older) included induction of mania, late maturation of frontal lobes so impulsivity and experience improve as you get older, and greater tolerance for uncomfortable affect with age. They agreed that more data would be helpful.
• The committee also felt it was very important to emphasize the need for close follow-up when treating people of any age with depression. There was concern that it could sound like older people don't need to be followed as closely due to this "protective effect".
  
• Finally, the FDA acknowledged concern about telling doctors how to practice, and crossing the line into federal regulation of the practice of medicine. However, it was pointed out that, when the stakes are high enough, as with clozapine, the FDA has had no trouble advising things like frequency of monitoring lab tests. Telling prescribers that people with depression starting antidepressants should be followed at least weekly at first should be no different. Hopefully, they won't wimp out.

I'll leave you with two good quotes.

"Maybe we don't need a black box on antidepressants. Maybe we need a black box on Depression."

"How many will die with the black box? How many will die without it?"

technorati tags:FDA, depression, hearing, PDAC, antidepressants, suicide, suicidality, SSRIs, psychiatry, psychiatric, medication

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FDA Hearing on Antidepressants, Depression, and Suicide

[Posted by Roy]

I attended yesterday's hearing, missing the FDA's presentation in the morning, but arriving for the public comments part and the afternoon deliberations. (Check out the FDA's 150-page .pdf testimony.) I was also among the 75 people who provided testimony to the committee. The meeting lasted a total of 9.5 hours!

This is the first time I've been to an FDA Advisory Committee meeting. These are public meetings (required to be public, by law) in which the committee members discuss the issues and make decisions. The FDA presents data to them; in this case, it was data from numerous clinical trials solicited from big pharma to especially get at the question of induction of suicidal thoughts or behaviors by antidepressant medications. After the committee hears these data, they listen to public testimony. After that, they discuss what they heard, and respond to the FDA's recommendations in the form of support, opposition, or other recommendations.

The committee is advisory in nature, meaning that the FDA takes what they say into consideration, but is not bound by their recommendations. The FDA does typically follow their recommendations. Three of the committee members could not vote due to conflicts of interest (receiving industry funds for clinical research and such).

In this post, I will first cut to the chase and tell you what the committee's recommendations were. In a second post, I'll give you more details to flesh out some of the discussion points and concerns that the committee raised, and also discuss the public testimony, some of it being very gut-wrenching and impassioned.

If I had to choose one image that best describes the entire hearing, it is the one above.

What this demonstrates is that as age goes up, the relative risk of suicidal thoughts or behavior goes down. The numbers plotted are the Odds Ratios... meaning that, compared to the folks taking placebo, what are the odds that those taking antidepressants are likely to have either thoughts of suicide or actual suicidal behavior. So, an O.R.=1 means that the chances are the same, which means no difference. An O.R.=2 means your chance is doubled. An O.R.=0.5 means your chance is halved. The black square is the estimated O.R., and the gray bar represents the 95% Confidence Interval... meaning that the statistical probability of the true O.R. being within the gray bar is 95%. Thus, if the gray bar touches 1 (the vertical dashed line), then the two groups (placebo and medication) are NOT statistically significant. If they do not touch 1, then they ARE statistically significant. Got it? To put it most simply, left of the dashed line is good, right of the line is bad.

So, the pediatric Odds Ratio does not include 1; this result supports the decision made in 2004 to add a black box warning that says these medications are associated with an increase in suicidal thoughts or behavior. (As it turns out, it is just thoughts, not behavior, but I'll address that in the second post.)

The 18-24 year-old Odds Ratio does include 1 (0.91-2.70), thus we cannot say that there is an increased risk.

The 31-64 year-old Odds Ratio just includes 1, but the estimated O.R. is less than 1, meaning that we cannot say there is a decreased risk, but there almost is.

For the over 65 group, there is clearly a significantly decreased risk of suicidal thoughts or behaviors. Note that these appear to be rare events... 12 people out of 3227 taking medication, and 24 out of 2397 taking placebo reported suicidal thoughts or behaviors. Hard to believe that only 1% of people with major depression had suicidal thoughts, huh?

Okay, so here is what the committee decided:

1. There is a clear relationship between age and suicidal thoughts or behaviors in people taking antidepressants.


2. Keep the black box warning that currently exists, but be very cautious about discouraging depression treatment and attempt to include balancing language that states that the risk of suicidal thoughts or behaviors when not taking medications should be considered. (They do not have data that tells them what that number is.)


3. Encourage careful monitoring of all people being treated for depression.


4. Extend language in the black box to indicate that the increased risk of suicidal thoughts or behaviors extends to around age 25, where it starts to drop off and become a decreased risk in the 30's and up.


5. Encourage collection of data on the "activation syndrome" that some people get when taking antidepressant medications, especially SSRI's.


6. Encourage collection of data which differentiates between suicidal thoughts and suicidal behaviors.

More later this evening.

Tiihonen Suicide Study in Archives

Dinah mentioned the recent Finnish study, showing an associated protective effect of antidepressants on death and on completed suicides, but an associated increase in the number of suicide attempts. I thought I'd share, for teaching purposes (and thus subject to Fair Use), the data in the article on individual medications.

For those unskilled in looking at Relative Risks, an RR of 1.0 indicates no higher or lower risk of the outcome being measured (compared with the comparitive population... in this case, suicide survivors not on meds). An RR or 0.5 would indicate a risk that is half of expected, and an RR of, say 2.0, indicates a doubling of the risk. (Note that this is intended for a professional audience... these data should not be applied to one's own personal situation and you should discuss it with your physician if you have any questions.)

Risk of Suicide

Figure 1. Relative risk and 95% confidence interval of suicides obtained by using medication as a time-dependent variable. The relative risks were adjusted with the propensity score method, and by including sex, age, geographical location (as strata), number of suicide attempts before the index hospitalization, number of suicide attempts during follow-up, use of multiple antidepressant medications, and number of purchased antidepressant prescriptions during the previous year in the model. SNA indicates serotonergic-noradrenergic antidepressant; SSRI, selective serotonin reuptake inhibitor; and TCA, tricyclic antidepressant. Citalopram was given as citalopram hydrobromide; doxepin, as doxepin hydrochloride; fluvoxamine, as fluvoxamine maleate; mianserin, as mianserin hydrochloride; paroxetine, as paroxetine hydrochloride; and venlafaxine, as venlafaxine hydrochloride. From: Tiihonen: Arch Gen Psychiatry, Volume 63(12).December 2006.1358–1367

You can see that the only two drugs which do not touch the vertical line representing an RR=1 are fluoxetine (Prozac) and venlafaxine (Effexor). These suggest that fluoxetine use has a significantly lower associated risk of suicide, while venlafaxine has a significantly higher associated risk of suicide.

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Risk of Suicide Attempts

Figure 2. Relative risk and 95% confidence interval of suicide attempts obtained by using medication as a time-dependent variable. The relative risks were adjusted as explained in the legend to Figure 1. Abbreviations and complete drug names are also given in the legend to Figure 1.
From: Tiihonen: Arch Gen Psychiatry, Volume 63(12).December 2006.1358–1367

This one shows that anyone put on meds was more likely to have attempts (keep in mind these pts were not randomized, so it may be that those who were not placed on meds had a lower risk of future attempts).

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Risk of Death

Figure 4. Relative risk and 95% confidence interval of total mortality obtained by using medication as a time-dependent variable. The relative risks were adjusted as explained in the legend to Figure 1. Abbreviations and complete drug names are also given in the legend to Figure 1.

This one shows that there was clearly a reduction in the relative risk of death for pts on fluoxetine, citalopram (Celexa), sertraline (Zoloft), mianserin (not in US), mirtazapine (Remeron), and "other antidepressants". None were associated with an increased risk of death.

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The authors suggest that the antidepressants, especially SSRIs, may have a protective cardiovascular effect, possibly due to their mild blood-thinning effect.

Take a look at other bloggers' posts on this article:
Corpus Callosum
Armenian Medical Network
Gooznews (this one's actually on the FDA hearing, but makes some good points on conflict of interest)

I'll be at the FDA hearing later today and will report about what I heard in a follow-up post...

The Lastest On Antidepressants and Suicide

[posted by dinah, not roy]

Don't forget to listen to the MY THREE SHRINKS Podcast! See link below.

Do SSRI's cause people to become suicidal? The question feels old-- I remember when these medications first came out and there were questions about whether the medications made people violent, seems that years later we still have the same questions.

It seems like this is something we should know-- it's been a while now, two decades in fact. It's easy if everyone who takes a medication gets an unusual symptom, harder if only a few people who take a medication have an adverse reaction, and harder still if the symptom caused by the medication is the same as the symptom caused by the disease the medicine treats!

In 2004, the FDA mandated that all the newer anti-depressants carry a black box warning stating that they may cause suicidal ideation in children and adolescents. The research is convincing that a small percentage of children (1 to 2 percent) who were not having ideas about suicide before they started medications, had them after they started, generally in the first weeks of treatment. No child in any study died of suicide, though this is such a rare event that it gets difficult to look at prospectively. Sorry, no links here, I've just heard a bunch of talks. Most recently (meaning last week) I heard Mark Riddle, the Chairman of Child Psychiatry at Johns Hopkins Hospital talk about treating adolescent suicide attempters: he noted that in any given year, 2.9 percent of adolescents have a suicide attempt requiring medical treatment. Think about this, it's a general population number: in a high school of 1000 kids, 29 will have a suicide attempt requiring medical intervention, many more will have suicide gestures and not get help. Completed suicides? 6 to 8 per 100,000 .... a rare event, but given that kiddy death is pretty rare, a significant cause of childhood mortality.

This coming week, the FDA will hear testimony about whether the Black Box warning should also include adults. See: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-index.htm and press the link for the brief if you'd like to read all 140 pages in a pdf file. What will a Black Box warning mean? In my psychiatric practice, I don't think it will mean anything. Many of my patients feel helped by these medications. It may make some patients with depression less willing to try medicines, and more importantly, it may make some primary care docs afraid to prescribe them. I have to wonder why some symptoms get the dreaded Black Box warning and other's don't and why the designation has become so heated. Another post for another day.

So last week, the Archive of General Psychiatry published this amazing study on a followup of over 15,000 patients in Finland. It included all patients admitted to Finnish hospitals for suicide attempts over a 7 year period (excluding those with psychosis) and followed their future behaviors noting whether or not they took medications and which medications they took. I tried to follow the charts and the data, but it was too confusing and too overwhelming. Please, if anyone out there could follow these statistics, please help me. I was left to just read the results and the conclusions and some of the thinking about it all. This study, however, is terrific in that in includes everyone in the country who attempted suicide, and they tracked whether the patients filled their prescriptions, so they had a fairly good idea of whether the patients were actually taking them.

And the findings? People taking SSRI's/SNRI's (eg effexor) had a markedly higher rate of serious suicide attempts. Now this could be because the people given/ or taking the medications were sicker-- there's not necessarily a cause and effect here. Furthermore people taking SSRI's/SNRI's had a markedly lower rate of both completed suicide and death from cardiovascular disease (Hey, didn't Roy talk about this on our podcast???). Some of the numbers surprised me: in their avg 3.4 year follow up of 15,390 , there were 1583 deaths-- could it be that nearly 10% of their suicidal patients died? 602 were suicides. The average age of their population was just under 39. The protective factor for cardiovascular mortality was huge: 30-40% reduction in deaths.

Other interesting facts: Paroxetine (paxil) was associated with a high mortality among the 10-19 age group with 4 deaths: 1 suicide, 1 drowning, 2 unintentional injuries. Venlafaxine was the only medicine associated with increased risk of suicide and Fluoxetine (prozac) was the only one associated with decreased risk of suicide. And I didn't see bupropion (wellbutrin) mentioned anywhere at all in the article. The strongest predictor of completed suicide was number of past attempts.

My Three Shrinks Podcast 2: Roots

[1] . . . [2] . . . [3] . . . [All]

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We'd like to thank our readers and listeners for your kind comments and suggestions about our first podcast. This one's a bit longer, at about 33 minutes. I think we'll get better about the time. About 20 minutes seems to be a good balance.

This is actually the second half of the original podcast, which went long so we sliced it into two podcasts. Don't expect to get a podcast every other day... if we do one every other week, I'll be pleasantly surprised (though I'm striving for every Sunday). Maybe we can be like Digg's Kevin Rose and Alex Albrecht and drink alcohol at the beginning of each podcast... that would be interesting.
Here are the show notes for the podcast:

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December 10, 2006: Roots

Topics include:

• Dr Anonymous is again not mentioned in this podcast (but we do thank him for the idea about the musical bumpers between topics)
• Thorazine Immunity: Clink reviews a 1992 case in which a prisoner sued the on-call psychiatrist for involuntarily medicating him with chlorpromazine due to violent, self-injurious behavior... but without going through any hearing panels for forced meds [Federal Code: Civil action for deprivation of rights]
  
• Dinah brings a duck to the "Shrink Rap Studio" (my kitchen table)
• FDA hearing on December 13 about adding a black boxed warning on antidepressant labels about the possibility of increased suicidality in adults: Will this reduce access to these drugs, causing undertreatment of depression and actually INCREASE suicide rates? (Check here for background materials)
• Recent PubMed articles and Corpus Callosum post about this whole antidepressants and suicide issue. Also, Dinah mentioned this, hot-off-the-press, Finnish article, showing an increase risk of attempts and a decreased risk of deaths.
  
• Treatment of social phobia [PubMed]
• Social phobia and alcohol [PubMed]
• Paxil- and other SSRI-related withdrawal symptoms [PubMed]
• Sexual dysfunction and SSRIs [PubMed]
• Putting roots on someone
• Psilocybin mushrooms for Monk's OCD
• Maryland psychologists discuss adoptions in gay marriages
• NYT: Gender dysphoric children
  

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This podcast is available on iTunes. You can also download the .mp3 or the MPEG-4 file from mythreeshrinks.com.

technorati tags:thorazine, podcast, shrinkrap, civil, rights, duck, SSRI, antidepressants, suicide, depression, black, box, FDA, hearing, Paxil, Prozac, gay, marriage, adoption, gender, psychologist, psychiatrist, psychiatry, blog

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SSRI Antidepressants & Violence

[All three Shrink Rappers have contributed to this post]

There's an article over at PLoS Medicine about antidepressants that makes for interesting reading. The article, Antidepressants and Violence: Problems at the Interface of Medicine and Law by David Healy, Andrew Herxheimer, & David B. Menkes, reviews pharmaceutical company data regarding SSRI-induced violence, aggression, and hostility. The main antidepressant reviewed is paroxetine (Paxil, Seroxat, others), though fluoxetine/Prozac, sertraline/Zoloft, and venlafaxine/Effexor XR, are mentioned.

The three authors acknowledge that they have all served as expert witnesses supporting and opposing the role of SSRI antidepressants, which makes the article seem a bit like an advertisement for their expert witness business. Nonetheless, the review of drug company data (mostly GSK) is worth a gander.

Roy: I found most interesting the low incidence of episodes of "hostility" among both those on drug or placebo. For example there were only 55 (0.4%) reports of "aggression" or "assault" in 13,741 adverse effect monitoring reports from the UK of paroxetine, and 1 report of "murder". I'll leave it to the reader to find incidence reports in the general population, but I'm guessing it is at least this or higher.

GlaxoSmithKline's data from all of their placebo-controlled paroxetine trials showed "hostility events" (which includes mere thoughts as well as actions) in a total of 60 out 9219 paroxetine cases (0.65%) and 20 out of 6455 placebo cases (0.31%). Statistically, one appears to be twice as likely to have an "hostility event" on Paxil than on placebo.

The lawyers are lining up at the courthouse for business (Clink, feel free to pick up on that one).

The article, which anyone can view in its entirety (that's what I like about PLoS Journals), includes 9 actual case examples or folks who did bad things, like robbery and murder, after taking SSRIs (sometimes after only 2 doses).

Clink:
There's a reason why this article was not published in a standard peer-reviewed journal. It seems like an article that can't make up it's mind about what to discuss. It didn't really address the legal issues involved in drug-related criminal prosecution and it's an incomplete discussion of the clinical studies. Frankly, I left the article feeling a little bothered by the lack of focus.

Regarding the clinical issues: violence is a multifactorial behavior, and I think it's overly simplistic to reduce it to a simple medication cause-and-effect. Confounding variables are the presence of personality disorders, previous acts of violence, active affective disorder symptoms and co-existing substance abuse. We know nothing about these confounding variables from this article. While clinical trial data will be useful to identify strong associations that could be attributed to medications (eg. weight gain, increases in prolactin levels) it is less useful for low base-rate phenomena like homicide. As Roy has already pointed out, base rates of general aggression were low to begin with in the clinical monitoring data from the UK.

Regarding the legal issues: that was actually the interesting part for me, and they totally glossed over it! They only presented their own small case series. They didn't discuss diminished capacity defenses, insanity or involuntary intoxication. To keep it simple (and to minimize the length of this post) I'm only going to talk about involuntary intoxication.

When it comes to mental health defenses in crime, all jurisdictions exclude voluntary intoxication as a defense. This is done for the obvious reason that the majority of violent offenses occur under the influence of drugs and alcohol, so social policy dictates that people must be held accountable for the consequences of their choice to abuse substances. However, longterm use of some substances can cause permanent mental changes long after the person is abstinent. PCP psychosis can persist for months after chronic abusers stop using. Longterm alcohol dependence can result in permanent memory deficits. These residuals problems can be used as the basis for a legal defense.

Another legal theory that allows for substance abuse is the idea of involuntary intoxication---what I think of as the "mickey" defense---meaning that you took something without knowing it. Drinking spiked punch or accidentally taking the wrong pill might be an involuntary intoxication. Having an unusual or rare reaction to a medication---like an SSRI---could be a type of involuntary intoxication defense. Something like this would be more common with other drugs, however, with the classic one being steroids. About 15% of people prescribed prednisone have a dose-dependent affective side effect. When the first case studies were published about the psychiatric effects of anabolic steroids there was a flurry of criminal defenses based on this. Later research showed that the people who were more prone to 'roid rage' where people who also had antisocial personality disorder.

The final issue you'll hear about is the idea of paradoxical intoxication, in which a person has an extreme reaction to a small quantity of a substance. Roy mentioned the cases of homicide or robbery after only two doses of an SSRI; this would be an example of proposed paradoxical intoxication defense. (Actually, the best example of paradoxical intoxication I've seen is the movie Final Analysis. It's also a good illustration of the kind of criminal defendants who propose defenses like this.)

So that's my input. Pass the Paxil and stand back!

Dinah:
What never fails to amaze me is not that people have side effects or adverse reactions to medications, but the great variety of responses people can have to the same medication. If 70% of people will have a given response to a medication (hmm, let's say dimunition or resolution of depressive symptoms if we want to look at the cheery side of things, or sexual dysfunction if we want to look at the gloomier), well what about the other 30% of folks? Why is it that some patients have a great clinical response and there is no down side? Some people seem to be more medication-sensitive in that they are more prone to side effects or need lower doses of medicines, but there isn't necessarily carry-through from one class of drugs to another. So, we all know that Lithium may cause weight gain, but I've seen patients on high doses of lithium for years that haven't gained any weight, and we all know that zyprexa may cause weight gain (note that I say "may" because it's just not a given), so why will the same patient might tolerate one of these with no problem, and start piling on the pounds when you switch to the other?

Roy's reference gives several explanations as to why SSRI's might induce violent behavior: switch to mania (perhaps with psychosis), akathesia, activation, emotional numbing. Clinically, the question of SSRI-induced suicidal/homicidal behavior has always been a tough one: these medications aren't prescribed to people who are trooping along Just Fine. Suicidality is a very common symptom of Depression and SSRI's are prescribed for depression; we're left wondering if the SSRI caused the suicidality, began working and lifted the patient to the point of being able to act on the thoughts, shifted the patient into a bipolar mixed state, or simply was ineffective in treating the depression and was incidental to the final act.

Given the vast range of odd side effects/adverse reactions that people get from medications, the studies linking suicidal ideas in children to SSRI's and the extreme nature of the cases discussed in the PlosJournal article, it's probably reasonable to say that a very small percentage of patients given SSRI's may become violent. Still a bit of a stretch for me, because there are also people who have no history of violence who unpredictably kill someone, and it becomes hard to look at the correlation to a medication when tens of millions of Americans take that medication (kind of like I eat Twinkies and I didn't kill anyone) and only a few of them unpredictably become violent.

And what does this mean clinically? I think I'm left to say something fairly flat, like: Not Much, So Far. I don't work with children, where I believe the implications are broader-- the black box warning on SSRI's regarding suicidality may be giving pediatricians a moment's pause before prescribing them, and the latest recommendations suggest that kids be seen fairly often for the first month of treatment: probably not a bad idea, though perhaps cumbersome given the shortage of child psychiatrists.

To date, I have not seen a previously nonviolent adult become violent on an SSRI. People still enter treatment asking for these medications, and many people find they effect life-altering changes for the better. Some people have no response at all. Some people feel much calmer, less irritable, and better able to cope with what life throws them. Some simply cease to be depressed and identify that the medication makes them feel like their old, pre-depressed self. Often, people have sexual side effects and are left to make a decision. If someone were to report violent ideas on the medication, as with any distressing side effect, I would discontinue it. For an out-patient practice, the decision to take or not to take medications is ultimately the patient's; I can discuss the possible risks and the possible benefits, I can make a recommendation based on studies I've read and patient responses I've witnessed, I can strongly encourage someone to take medications, and ultimately I suppose I could refuse to treat someone who I felt I couldn't help at all without medication, but the final decision is generally an issue of team work, and often the patient comes in predisposed: "I'm never taking meds" or "Prozac made my best friend better and I want some of that stuff."

The vignettes in this story are striking. To date, I've not felt a need to warn patients that they might become violent: these cases are the exception, not the rule, not anywhere close. If I hear enough of them, I'll start warning people, until then, I'll leave it to the ever-present media, and I'll keep a close eye on my patients.