Thursday, September 21, 2006

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.

17 comments:

foofoo5 said...

I mentioned this example, though I can't seem to remember where...

You may recall Jeff Weise, a Native American adolescent who killed nine fellow-stundents and himself in March, 2005. A follow-up article by the New York Times headlined his family's concern as to the possible contribution of Prozac in this extreme act of violence. Notably, the Times stated, "The effects of antidepressants on young people remain a topic of fierce debate among scientists and doctors." I was not aware of the ferocity of the debate (and then again, I am not a lawyer), and I took exception to this article's focus, as its premise - even if only implied by the presenting the "concern of the family" - is fiercely unfounded.

I agree with Clink: violence is a multi-variable act. I wrote the Times pointing out the observation that the young man appeared to be wearing Doc Marten-style boots (as did the Columbine killers & the recent Montreal killer). Does this warrant a "black-box warning" on Doc Marten products, suggesting that they may correlate with extreme violence? Could they be the "final straw" in an already disturbed life? In anomalous behaviour, it seems to me that contributory variables are virtually indistinguishable, given that we have so little data about these individuals.

I recall the previous disscussion: Dr. A.'s.

By the way, nice graphic...

Sarebear said...

I like reading three perspectives at once!

On a couple points, you've put into words, crystallized some half-formed thoughts I've had for awhile but hadn't really fleshed out.

jw said...

I think part of this is that we do not sufficiently understand violent behavior.

We can state the person most likely to be violent:

- younger male
- mother is/was primary parent (1)
- bad attachment to both parents
- low serotonin levels
- no healthy male mentor

Yah ... these men account for 80% or so of all violence. It's the other 20% or so that we simply do not understand.

How then can we predict what part of violence comes from a drug and what part comes from the non-understood portion of violence?

1: The FBI profiling will soon be adding this as the sons of lone fathers do not appear to show up in the profiled population. NOTE: As the children of lone fathers are more likely than the children of two parent families & lone mothers to show up in accidental injury populations there appears to be a gender factor at play, cause as of yet unknown.

DrivingMissMolly said...

As a PT I can say that during the very brief time I took Effexor, i noticed feelings of hostility and anger. Usually I tend to be suicidal and not homicidal so my abnormal thinking really got my attention.

At the time I was walking my dog and, as usual, I felt resentful of the many homeless people in the area of my expensive apartment.

However, beyond eing bothered, my thoughts extended to this; "I wish they were all dead. I bet I could kill them and get away with it because they're homeless and noone would care anyway."

Not Normal for me. Luckily, side effects from the Effexor enabled me to get off it.

Also, I will chime in about my little sister who took paroxetine ain junion high. This was before the black box warning. My mother told me that the medication caused her to lose it at school where she was provoking fights and being violent.

People are all so different. I was told I am very sensitive to medications.

The weirdest side effects I have had: Severe blurred vision from Effexor, breast tenderness from Zoloft, and upset stomach and diarhea from Cleocin (topical antibiotic for acne I could take one dose and be OK, but after that second dose, all bets were off).

Lilt

DrivingMissMolly said...

My appologies for my errors in typing. I seem to be having a hard time today.

Sarebear said...

I don't know if suicidality is violence or not (I don't think of it as such, tho), but ever since starting Effexor XR, I went from not having been suicidal in many years, to frequent episodes, and alot of thinking about it, even when I wasn't sad or depressed.

Within the first month of starting it, and it's been that way ever since . . . from 0 to a ton.

Then again, I started therapy two-three months after, and I've been told, that as defenses start to come down, it's not uncommon that one actually gets worse, because the defenses you used to rely on are coming down. Alot of stressful life events since starting the med, too.

If all I said was, 0 before, to 1000% more after starting it, one would think the med was completely behind it. With the other things I said, though, that definitely changes things. I can't eliminate the possibility of a link, though, but it's complicated.

Fat Doctor said...

I'm always curious about those links to side effects and whether people get the side effects because they read every word in the pharmacy handouts. I've had a lot of patients report the most bizarre side effects from whatever drugs, most of these side effects not painful or irritating in any way, and when I ask them, yes, they always read the little drug info sheet before they took the medicine.

I like it when you all contribute like that. :)

SSRI-Research said...

It's really very simple... Eli Lilly knew about Prozac Induced Suicidality, Mania and psychosis before the drug came on the market... Here is legal testimony on this subject:
http://www.baumhedlundlaw.com/
media/timeline.html

and...

"Suicidality, violence and mania caused by selective serotonin reuptake inhibitors (SSRIs): A review and analysis"
Peter R. Breggin MD
http://www.breggin.com/31-49.pdf"

School Shootings & Antidepressants" - Fox News
http://www.youtube.com/watch?v=Ifbjy-YKgRI

not to mention that...

Approximately half of all Americans have genetic defects that affect how they process these drugs."
http://www.healthanddna.com:80/
labelmesaneorderformdetail.htm

Add insult to injury... Prozac, et al, is no more effective than placebo and infinitely more dangerous/lethal... There should be no question as to the role these drugs play in current and regular violence.

"'I do not think I could explain to the BGA, a judge, to a reporter or even to my family why we would do this especially on the sensitive issue of suicide and suicidal ideation.’ — Memo from Bouchy C to L Thompson Re: Adverse Drug Event Reporting – Suicide Fluoxetine. November 13th 1990. Exhibit 117 in Forsyth vs Eli Lilly." - www.healyprozac.com

ssristories said...

For a list of 1,650 criminal acts involving SSRIs which have appeared in the media, go to www.ssristories.com

By going into the Index, you can read the actual media articles.

Psychiatrists have not picked up on the harm that antidepressants are doing to their patients because the patients never tell them. The patients go to their psychiatrist and say they are feeling great, just fine or something along these lines and then they are going home and acting in a crazy manner. Some kind of study really needs to be done on the bizarre behavior these people exhibit once they are on their SSRI. It is a National Tragedy.

NastyPredator said...

Lifetime of antidepressants: diabetics need insulin their whole lives; ppl with thyroid disorders have to take their thyroid meds for a lifetime. same same same, no shame.

Anonymous said...

Please forgive my horrible spelling and bad typing skills. Im actually going to college for this now.
I dont know if this will help anyone but I was recently taking paxil for anxiety.I was on 20mgs once a day. At first it made me a bit drowsey but the doctors made sure to tell me i had to let it get into my system for the full affect. The first month of taking this drug I felt great. No aniety attacks at all and in fact i was even happy. There is no "high " or any thing like that. However, as the second and third months came around I became cold, emotionless, with no sex drive, no humor, no personality and i seemed like a robot to my then boyfriend.
I still functioned and did what I had to in life but started to feel down for no reason , almost like i had this hurt in my heart and i didnt even no why it was there. It was a familiar feeling, ive suffered from it my whole life, bu usualoly a good hug from some one will ake it go away. Any how, the worse this got the more withdrawn I became and the more moody I was as well. I started to argue with every one, and I didnt even no why I was arguing with them, and my reasons made absolutely no sense.
So I started drinking with it . after about 2 weeks of drinking with this medication i started to get nasty. Then one night I just blacked out on some one who didnt in a million years deserve it. I just snapped for no reason and probley would have even gotten physical if some one hadnt had yelled my name to snap me out of it.. It was like a rage had taken over me and coming out of it i scared my self and was very confused. This was not in my character at all. Evry one was angry with me and i felt even worse. So I decided to stop taking it. I slowly went back to normal mentaly and didnt feel any with drawl symptons except for my mind feelig like it was just empty. i had no thoughts.
So a few months went by and I began to get anxiety attacks again. Normaly In hot humid climate with no air flow sets them off but they are horrible to deal with. So with out every knowing, I started to take what was left of my script. Again the same exact things happened but every one thought I was just becoming a b_tch! I didnt want to tell them i was back on it and I really wanted to see if this medication really is what caused me to be so nasty. So we had friends over and being that im in college ,thats a fairly normal thing. So Im not much of a drinker and hadnt drank since that last black out. I drank again, and i ended up flipping on my bf at the time. i even slappe him in the face and didnt have any recollection of doing this. Well I can tell you that ruined 3 years and my relationship ended over it. That 6 months of paxil took a tull on every one in my life. I havent touched it since and im fine. i still have anxiety but not often any more.
So i then started dating a new guy. And he happened to have some form of depression and the doctors prescribed him paxil.. I tried to warn him but he said he owuld be fine.. he slowly started to become the same way i was. very numb and secluded and absolutely no sex drive.. He drank twice on it.. the fiorst time resulted inhim snapping and beating up my friend.. This time he is now in jail for being drunk and violent and on paxil.. This is totaly out of his character as well for 37 years old. He doesnt remember alot of what happened, but he does remember at one point he couldnt stop the violence during the rage.
So now he is losing almost 5 years of his life for taking paxil and drinking with it.. He also admitted that as the months past, he 2 began to feel depressed like he had never felt in his life. to the point he questioned why he was even alive and didnt want to wake up.. I wasnt to that point but medication effects every one differently..
So please, if you are told not to drink with a medication, dont!! Theres a reason for it and your not a doctor!

David Rochester said...

FWIW --

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 psychoemotional 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.

Anonymous said...

I think that SSRI's, especially newer ones under patent, are prescribed when older, less expensive drugs would be more appropriate. There is too much drug company influence upon medical schools and medical associations that set guidelines for doctors.

Interestingly, Dr. Amy Bishop published this research about SSRI's causing nerve cell damage about the time the efforts to deny her tenure began last year.


http://www.dovepress.com/effects-of-selective-serotonin-reuptake-inhibitors-on-motor-neuron-sur-peer-reviewed-article-IJGM

matt said...

I kicked a hole in the wall and choked my dad my 1st day on effexor. I'm normally very mellow so it was very obvious what the problem was. Never took it again and never had that problem. I think it should be withdrawn from the market.

leonie said...

I can only tell you the truth about my son(shane clancy) who was on cipramil (celexa)for 3 weeks when he killed himself and another young man.I can honestly say he was the kindest and most well rounded person that you are ever likely to meet. He had no underlying issues and was loved by everyone.He was the last person in the world to do something like this!Please be careful if you are contemplating going on anti-depressants..because the drug companies will do anything to keep the adverse side effects from the public! If you think im just a sad mother trying to make some sense of this then read on...
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2004/celexa_hpc-cps-eng.php
Lundbeck (the makers of cipramil) already knew that their drug could cause self harm and harm to others.
Pity myself and Shane didn,t.
Leonie Fennell

Roy.Pradhan said...

SSRI stands for selective serotonin re-uptake inhibitor. That means that it makes neurotransmitters released into the space between neurons hang out in that space longer - normally the neuron that released the neurotransmitters into that space will absorb the neurotransmitters that are not immediately absorbed by the neuron on the other side of the space between them (the space between them is called 'the synapse' of them). When the originating neuron absorbs the neurotransmitters that are not immediately absorbed by the neuron on the other side of the space between them it is called 're-uptake'. By calling a drug an SSRI the manufacturer says it inhibits the re-uptake of serotonin neurotransmitters.

Excessive serotonin in the brain causes serotonin syndrome, a medically recognized syndrome in which too much serotonin in the body causes one or a number of physical and/or mental syndromes including nausea, palpitations, agitation and hallucinations. The body will make serotonin from tryptophan, a substance found in protein, pretty much as long as it has a supply of it; so the body uses an enzyme to control serotonin levels - monoamine oxidase breaks down serotonin. But it only breaks down the serotonin it comes into contact with through diffusion in synapses. The longer a serotonin molecule spends in the synapse the greater the probability it will be destroyed by encountering a monoamine oxidase molecule. So the re-uptake of serotonin actually conserves serotonin - we can conclude from this that selective serotonin re-uptake inhibitors make the brain burn through its serotonin supply faster than normal, eventually causing depletion.

It is known that low serotonin levels are linked to hostility:

http://www.dana.org/news/brainwork/detail.aspx?id=13182: "Now, researchers at Cambridge University and UCLA have found that serotonin also plays a critical role in regulating emotions such as impulsive aggression during social decision making. Impulsive aggression is the tendency to respond with hostility or aggression when faced with serious frustration.

The researchers believe their results suggest that serotonin plays a critical role in social decision making by normally keeping aggressive social responses in check.

By manipulating diet, the researchers were able to lower serotonin levels in the brains of healthy volunteers. Tryptophan, the essential amino acid necessary for the body to produce serotonin, can be obtained only through diet. Twenty healthy volunteers fasted overnight and were then given a protein drink, receiving drinks with tryptophan one day and without it the next.

On both days, the study participants played the “Ultimatum Game,” in which one player poses a way to split a sum of money with a partner. If the partner accepts the offer, both players are paid accordingly. If the offer is rejected, however, neither player is paid. Some of the offers were considered “fair” (45 percent of the cash), while others were considered “unfair” (18 percent of the cash). When the players’ serotonin levels were low they showed increased aggression toward the offers they perceived to be unfair.

The findings highlight why some people become aggressive or act impulsively when they have not eaten, says lead researcher Molly Crockett of the University of Cambridge Behavioral and Clinical Neuroscience Institute."

http://www.time.com/time/magazine/article/0,9171,980153-1,00.html: "What, you may ask, is impulsivity? The standard answer tends to involve people who can't control their emotions or who get into bar fights. A study conducted in Finland found that men so characterized tend to be deficient in the brain hormone serotonin -- one of several chemical messengers that transmit signals between nerve cells."

Anonymous said...

Right. Multi-variable, difficult to correlate. http://news.yahoo.com/mo-teen-gets-life-possible-parole-killing-141938731.html