Serotonin, Violence and Prozac

A lot has been written in the past week guessing as to whether Prozac, a commonly-prescribed 20-year-old antidepressant, had any connection to the violence that Steven Kazmierczak (the NIU murderer) perpetrated. Kazmierczak was reportedly previously taking Prozac (usually prescribed for depression), but had stopped taking it 3 weeks prior to the murders.

USA Today has some commentary in an article in yesterday’s paper:

Stopping antidepressants abruptly can be dangerous, says John Greden, executive director of the Depression Center at the University of Michigan. Prozac, designed to increase serotonin, a “feel-good” brain chemical, lingers in the body longer than similar medicines, he says.

But serotonin can plummet if the pills are stopped, and the brain chemical often reaches a low point about three weeks after discontinuing, Greden says — just the time of the killing rampage, according to Baty’s timetable.

That’s an interesting observation, so let’s look at the research on serotonin levels and fluoxetine discontinuation…

It should first be noted that amongst this class of antidepressants, fluoxetine (the generic name for Prozac) has the longest half-life. That is, the remnants of the medication would be in a person’s system longer than in most other SSRI antidepressants. Because of this, the emergence of “SSRI discontinuation syndrome” generally is less evident than in people taking other SSRI antidepressants (see, for instance, Tint et. al., 2008; Calil, 2001; Rosenbaum et. al., 1998). Fluoxetine has a half-life of less than 2 days in most people, but remains in our plasma much longer — a plasma half-life of about 10 days. That means that we would expect to see virtually all of the drug out of a person’s system online after 3 weeks or so. Prozac also has been associated with an increase in anger or aggression while taking it (see, for example, Fisher et. al., 1995, but not while discontinuing it).

So if the drug is out of a person’s system within 3 weeks, could it still have an effect on other brain chemicals or hormones long after that? It appears the answer may be “yes.”

Oxytocin is a hormone that is secreted within the brain and other tissues and is involved in a fair amount of maternal and sexual behaviors. But Raap et. al. (1999), in a study of rats, found that even 60 days after discontinuation of fluoxetine, oxytocin levels still weren’t back to normal:

During further withdrawal from fluoxetine, there was a gradual increase in the oxytocin response toward control levels. However, even 60 days after discontinuation of fluoxetine, the oxytocin response was still significantly reduced by 26% compared with controls. In contrast, the suppressed ACTH response to 8 OH DPAT (a less-sensitive indicator of desensitization) gradually returned to control levels by day 14 of withdrawal from fluoxetine.

There are other rat studies that have shown various effects on different neurochemicals and hormones, but their generalizability to humans is limited. I could find no similar studies done on humans.

In a study examining the effects of Prozac on sleep, Feige et. al. (2002) found:

After discontinuation from subchronic administration, sleep quality indices normalized quickly (within 2-4 days), whereas REM latency and spectral power effects correlated with total SSRI plasma concentration and normalized more slowly, corresponding to the drug plasma half-life of about 10 days.

Meaning that REM sleep recovered more slowly from the discontinuation of Prozac, but not substantially so much it interfered with a person’s general sleep quality.

On the other side, in a 10th anniversary love letter to Prozac, Stokes & Holtz (1997) wrote:

Rapid discontinuation or missed doses of short-half-life selective serotonin reuptake inhibitors, TCAs, and heterocyclic antidepressants are associated with withdrawal symptoms of a somatic and psychological nature, which cannot only be disruptive, but can also be suggestive of relapse or recurrence of depression.

In striking contrast to these short-half-life antidepressants, fluoxetine is rarely associated with such sequelae on sudden discontinuation or missed doses. This preventive effect against withdrawal symptoms on discontinuation of fluoxetine is attributed to the unique extended half-life of this antidepressant.

A randomized, placebo-controlled study found no ill effects in the sudden discontinuation of Prozac (Zajecka, et. al., 1998):

No cluster of symptoms suggestive of a discontinuation syndrome was observed. Abrupt discontinuation of fluoxetine treatment was well tolerated and did not seem to be associated with significant clinical risk.

We also found a case study describing someone who experienced delirum after discontinuing Prozac suddenly (Blum et. al, 2008).

There is also an entire body of research examining the effects of acute tryptophan depletion (ATD), and the ensuing reduction of central nervous system levels of serotonin. This could occur in someone who discontinues an SSRI like Prozac, but most of the research into ATD is again at the rat level, and it’s very mixed in its findings (and we could find no research that has examined tryptophan depletion in relation to the discontinuation of fluoxetine).

The conclusion drawn from this quick research review? That Prozac is actually one of the better-tolerated drugs when discontinued suddenly, but problems can still arise. The effects of these types of medications on the brain and in the body in general are still not well understood by researchers.

Could any of this have been related to the NIU case? It’s still a possibility, but it’s doubtful we will ever know the answer for certain.

Read more about this controversy over at Furious Seasons, as well as Philip’s own take.

References:

Blum D, Maldonado J, Meyer E, Lansberg M. (2008). Delirium following abrupt discontinuation of fluoxetine. Clin Neurol Neurosurg., 110(1):69-70.

Calil HM. (2001). Fluoxetine: a suitable long-term treatment. J Clin Psychiatry, 62 Suppl 22:24-9.

Feige B, Voderholzer U, Riemann D, Dittmann R, Hohagen F, Berger M.
(2002). Fluoxetine and sleep EEG: effects of a single dose, subchronic treatment, and discontinuation in healthy subjects. Neuropsychopharmacology, 26(2):246-58.

Fisher S, Kent TA, Bryant SG. (1995). Postmarketing surveillance by patient self-monitoring: preliminary data for sertraline versus fluoxetine. J Clin Psychiatry, 56(7):288-96.

Raap DK, Garcia F, Muma NA, Wolf WA, Battaglia G, van de Kar LD. (1999). Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z proteins. J Pharmacol Exp Ther., 288(2):561-7.

Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. (1998). Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry., 44(2):77-87.

Stokes PE, & Holtz A. (1997). Fluoxetine tenth anniversary update: the progress continues. Clin Ther., 19(5):1135-250.

Tint A, Haddad P, Anderson IM. (2008). The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms:a randomised study. J Psychopharmacol.

Zajecka J, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaum J, Michelson D, Beasley C. (1998). Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study. J Clin Psychopharmacol., 18(3):193-7.