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Clinical Trials

Into the Numbers

I want to recommend this analysis (at the Mind the Brain blog) of a new paper in PLOS Medicine. The paper is an analysis from a very large Swedish data set of possible links between SSRI antidepressant use and violent crime, which is a contentious topic. As the post by James Coyne notes, there are plenty of groups on both sides of this issue with axes to grind, and very quickly you find yourself knee-deep in conflicting claims from trial lawyers, drug companies, Scientologists (and other opponents of psychiatry), gun-control advocates (and opponents), public health administrators, and more.

The study itself looks to be the best of its kind that we’re likely to get, in both size and quality of data: individual medical and criminal records on more than 850,000 patients (out of Sweden’s total population of about 8 million, 15 and over). Coyne does an excellent job of digging into this paper, and illustrating how it tries to deal with the many confounding variables. For example, right up front, the medical conditions that lead to prescriptions for SSRI drugs are likely to affect an individual’s likelihood of being arrested for violent acts. And there are plenty of more subtle effects: one analysis of this same data set suggests that individuals with a sibling diagnosed with depression are themselves statistically slightly more likely to have committed a violent crime, even after controlling for sex, age, income level and so on.

The paper itself, when everything has been worked through, finds a small association between SSRI use and violent crime, but only in one age group (15 to 24 years old), and only in the lowest-dose group (i.e., no dose-response). This could be an actual causal relationship, but looks equally likely to be the result of something else:

In the age bracket for which this association between antidepressant use and conviction of a violent crime was significant, antidepressant use was also associated with an increased risk of violent crime arrests, non-violent crime convictions, and non-violent crime arrests, using emergency inpatient and or outpatient treatment for alcohol intoxication or misuse. . .

. . .Perhaps one of the greatest weaknesses of this data set is its limited assessment of alcohol and substance use and abuse. For alcohol, we are limited to emergency inpatient or outpatient treatment for alcohol intoxication or misuse. For substance abuse, we have only convictions designated as substance-related. These are poor proxies for more common actual alcohol and substance use, which for a variety of reasons may not show up in these administrative data.

There’s also the problem that SSRIs are prescribed for a variety of heterogeneous conditions: unipolar depressive disorders, certainly, but also the depressive phase of bipolar disorder and others. On the behavioral end, we have only arrests as a proxy for violent acts – useful, but imperfect as well. So the answer to the question “Is there an association between SSRI use and violent crime?” could be (at different levels of detail): “Yes” “Possibly” “Nothing that stands out much” and “Maybe just in one particular age group, but maybe not, too”.

The authors of the PLOS Medicine paper have done an excellent job laying out all these issues, but I’m willing to bet that this doesn’t translate very well to a short headline. The various axe-grinders involved with this issue will find no reason to stop grinding, and no doubt all sides will cite this study as proving their points. And I bring this up on this site as an example of how to approach medical statistics in general, such as data from large clinical studies. Those are certainly more controlled than population-level statistics, even ones as comprehensive as those collected by the Swedish authorities. But they have plenty of confounding variables of their own, still. We set up these trials, from the beginning, to try to provide definitive answers (a big difference from observational studies such as this one), but even tying things down in this fashion still leaves plenty of room for the numbers to thrash around.

And this work also illustrates the trickiness of observational studies themselves. This is as large and granular a data set as you could possibly wish to see here in the real world, and there are still all sorts of things that aren’t accounted for. Keep that in mind next time you see a headline (especially a headline) about an association between wearing plaid and being diagnosed with psoriasis or whatever. Observational studies are very blunt tools with which to carve fine distinctions, and the great majority of them are probably reporting either noise or the effect of confounding variables.

12 comments on “Into the Numbers”

  1. drunken sailor says:

    Another recent study using the Swedish health data showed a very significant correlation between low blood pressure at age 18 and likelihood to die in an accident or be incarcerated for a crime. Do you know if they looked at blood pressure as a confounding variable?

  2. julien says:

    Swedes have quite a broad definition of “violence” and a slightly distorted vision of “drugs”
    (eg “drugs are not swedish”, never mind they are the world’s heaviest coffee drinkers).

  3. a.nonymaus says:

    Further, it may be that SSRIs have an association with being arrested and/or convicted for violent acts but not with committing violence.

  4. CMCguy says:

    Gosh I had a friend in high school that developed psoriasis and he used to always wear plaid just never made the connection.

    Actually nice overview on this type issue and I also believe you have previously discussed problems with correlations vs. causation where can be confounded and an example where people will misinterpret or misuse data analysis.

  5. Wile E. Coyote, Genius says:

    I think it could be argued that the violent behavior leads to the SSRI prescription than the other way around. As a society, we are quick to prescribe. Addicts and alcoholics are likely to have a poor outlook on life, and wouldn’t that then lead to depression? Those are groups that are also likely to commit crimes, to be able to afford their addiction(s). Correlation vs causation is very important here.

  6. luyii says:

    Back in the day the FDA put a black box label on SSRIs warning about suicidal ideation in adolescents on them. The following year prescriptions for them decreased by 25% and adolescent suicides rose by the same amount. That’s old news, I’m mercifully retired from the fray. Does anyone know what happened subsequently.

    For details, and more problems with psychiatry see

  7. Anon says:

    As one who has attended many support groups for sufferers of mental health disorders my understanding is that coming off ssri inhibitors is associated with violent outbursts.

    So it seems likely that the 15-24 year old age group is less likely to taper off the drug and they are probably more likely to engage in violent behavior from the start.

  8. Old Pump Kicker says:

    Many (all?) SSRIs can cause withdrawal (including an “overshoot” of depression or anxiety symptoms) if discontinued abruptly.
    My first thought when the FDA announced the black box warning was that the affected patients should be checked for whether a few missed doses pushed them over the top from depression to suicidal ideation.
    Therefore, we should also consider “SSRI use” or “has been prescribed an SSRI” as mere proxies for “medication compliant”.

  9. Sisyphus says:

    Oct 1st and no mention of Nobel Prize nominations?

  10. tangent says:

    I’m just done with observational studies. People give it a good honest try to correct for this and that, it just doesn’t hold up worth a damn when randomized-trial evidence finally comes in.

    I wish we as a society could
    1) acknowledge that any A/B treatment decision occurs on a continuum from “definitely A” to “definitely B” through “we just don’t know.”
    2) routinely randomize some of the people who are in the gray middle.

    But physicians are actively trained to be sure even when they don’t know, and none of us feel good about being in the randomization group; maybe because we know that whatever’s the best treatment group to be in, that’s not it. And so we blunder on, killing ourselves blindly.

  11. MoMo says:

    Forget about the violent crime in the 15-24 cohort group- the most impulsive of the bunch. That group is probably pissed that they are on neuromodulating drugs to begin with instead of self-medicating.
    Its the fact that 1 in 10 Americans (10%) are on antidepressant SSRIs and 10.8 % in Sweden. Most startling is the violent crime rate per capita is 0.2% in the US and 1% in Sweden!
    What’s going on Sweden? You are 5xs more violent than us, and we have way more guns than you!
    Get a grip Swedes, and thanks for buying the megatons and using our SSRIs, an experiment in large scale neurobehavioral engineering that will someday make us look absolutely ridiculous if not Medieval!

  12. Been There, Done That... says:

    I was prescribed Cymbalta (SNRI) as an adjunct therapy for ADD by a hack psychiatrist. I was not depressed. Stimulants did not work so his normative psychiatric tactic was psychotropic mind bombing. The only effect the garbage drug Cymbalta induced was metabolic disorder. (I gained 35 pounds in 9 months.)

    What I went off it, I was a crazed lunatic for 6 weeks, including wanting to do a beat down on my hack psychiatrist for writing those scripts without warning me. I had to essentially barricade myself in my apartment. The internet is saturated with similar anecdotes of off the wall psychological lability resulting from SSRI / SNRI discontinuation.

    Whenever I read about a college kid committing suicide I wonder what their SSRI / SNRI drug history was. And why no one, (especially the reporters) ever seem to ask.

    Of course the psychiatrists sweep those sad cases under the rug. Given how they make their money, they’d rather not know…

    BTW, about Cymbalta, do a web search on “Cymbalta AND Traci Johnson”

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