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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 7 of 7. This is the beginning of the thread.
Posted by Larry Hoover on August 26, 2004, at 13:32:28
One of the problems plaguing the interpretation of clinical studies involving adolescent and pediatric use of SSRIs is that the standardized reporting of potentially suicidal acts fell under the general heading "emotional lability", and some other things that fell under that same heading had nothing to do with suicidality at all. As a result, some reports linked SSRIs to suicidality when the evidence did not show that. In order to make sense out of this mess, the FDA commissioned two studies which "re-scored" the suicidal acts, using more explicit terms of reference. The new analyses do show an increase of suicidality for some drugs, but at a far lower extent than has been reported in the "shock media".
http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-11-TAB09a-Mosholder-review.pdf
Also, for the first time, suicidality is used as a primary outcome measure in a clinical trial of pediatric Prozac (fluoxetine). When suicidality is scored in this way, it is now clear that Prozac (at least) is not associated with an increase in suicidal thinking or acts. Quite the contrary.
Lar
JAMA. 2004 Aug 18;292(7):807-20.Comment in:
JAMA. 2004 Aug 18;292(7):861-3.
Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial.March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J; Treatment for Adolescents With Depression Study (TADS) Team.
Duke Clinical Research Institute, Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. jsmarch@acpub.duke.edu
CONTEXT: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. OBJECTIVE: To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. INTERVENTIONS: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. MAIN OUTCOME MEASURES: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. RESULTS: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P =.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P =.02) and CBT alone (P =.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P =.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P =.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. CONCLUSION: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.
Posted by Ilene on August 26, 2004, at 17:01:07
In reply to pediatric suicidality and SSRIs, posted by Larry Hoover on August 26, 2004, at 13:32:28
My understanding is that there were no suicides. In other words, there is no evidence that SSRIs increase the risk of completed suicides in adolescents. I believe the suicide rate in adolescents is going down, but I don't know to what that is attributed.
Posted by jay on August 27, 2004, at 18:01:47
In reply to pediatric suicidality and SSRIs, posted by Larry Hoover on August 26, 2004, at 13:32:28
Hey Lar....
Good points...but I really have to wonder as there are numerous cases that have shown up over the past few years, where so-called 'normal' or 'non-clinically depressed' people have taken the meds (SSRI') and reported suicidal ideation and rumination. These number of reports came from clinicians in France and England, and some had even taken the drug themselves. (They used other co-workers to double blind the studies.) I'll see what I can find. I really *don't* think this is limited to kids. Most a.d.'s cause some pretty hefty chemical shifts at first when taken..and it seems that it is during this begining phase when most of the reports (including the many with kids)indicate there was suicidal rumination or behaviour.
There is a *very* simple sollution to this. First off, doctors should monitor new patients say weekly if not sooner, and start on as low a dose as possible. If that means liquid meds...or cutting into fours...whatever it takes! If agitation seems to be a possible problem, a heavy dose of a good benzo and a few days away from work/school may help. It's just using common sense, and I don't see why doctors shouldn't be held somewhat responsible, especially in the early care, for this. My old pdoc saw me every week for a year, then every two for the next.
Anyhow...just IMHO .02 (CAN) cents. ;-)
Jay
Posted by Larry Hoover on August 28, 2004, at 7:57:12
In reply to Re: pediatric suicidality and SSRIs, posted by Ilene on August 26, 2004, at 17:01:07
> My understanding is that there were no suicides. In other words, there is no evidence that SSRIs increase the risk of completed suicides in adolescents. I believe the suicide rate in adolescents is going down, but I don't know to what that is attributed.
Glaxo (GSK) put complete documentation for their pediatric trials online. I only reviewed one, but it was one from which the press was publishing headlines such as "paxil causes 700% increase in suicidal behaviour in adolescents" or such like.
The complete documentation for each incident of serious emotional lability was given in the appendices, so I read them. Turns out that the only serious suicide attempt was in the placebo group. For that individual, the blind was broken, as the attempt was so serious they needed to know what (if any) medication she was taking. There were no serious suicide attempts in the paxil group. There was no parasuicidal behaviour attributed to the med in the paxil group. (There were two incidents, but the blind was not broken, and the incidents were attributed to non-drug circumstances.)
It kind of gets my back up when data are misrepresented so. The study showed that paxil was superior to placebo at every point in the study, but it was not significantly better at the a priori cut-off point of 40% better than placebo. It was significantly better at 10, 20, 30, and 50 percent cutoffs, but not at 40, so they couldn't say it was better. All the press did was trumpet that it was not only not significantly better, but that it caused a seven-fold increase in suicide. Bollocks.
Lar
Posted by Larry Hoover on August 28, 2004, at 8:08:12
In reply to Re: pediatric suicidality and SSRIs » Larry Hoover, posted by jay on August 27, 2004, at 18:01:47
> Hey Lar....
>
> Good points...but I really have to wonder as there are numerous cases that have shown up over the past few years, where so-called 'normal' or 'non-clinically depressed' people have taken the meds (SSRI') and reported suicidal ideation and rumination. These number of reports came from clinicians in France and England, and some had even taken the drug themselves. (They used other co-workers to double blind the studies.) I'll see what I can find. I really *don't* think this is limited to kids. Most a.d.'s cause some pretty hefty chemical shifts at first when taken..and it seems that it is during this begining phase when most of the reports (including the many with kids)indicate there was suicidal rumination or behaviour.I certainly agree with you that there is a treatment-emergent risk of suicidal rumination and actions. In fact, I think the effect is more pronounced when the drugs are given to non-depressed subjects. I've been following the subject closely, as there is far too much hyperbole and too little critical thinking, for my taste.
> There is a *very* simple sollution to this. First off, doctors should monitor new patients say weekly if not sooner, and start on as low a dose as possible. If that means liquid meds...or cutting into fours...whatever it takes! If agitation seems to be a possible problem, a heavy dose of a good benzo and a few days away from work/school may help. It's just using common sense, and I don't see why doctors shouldn't be held somewhat responsible, especially in the early care, for this. My old pdoc saw me every week for a year, then every two for the next.
>
> Anyhow...just IMHO .02 (CAN) cents. ;-)
>
> JayI agree with you, absolutely, Jay. I'll add my own .02 Canadian to your two, and maybe we'll have .02 U.S. between us?
The SSRIs are serious meds. They have been prescribed fairly loosely, and have been very poorly managed by the prescribing physicians. This is a drug management issue, IMHO, not a drug issue. Recent comparisons with e.g. TCAs have shown that the incidence of suicidal induction during the early treatment phase is about the same for both classes of drugs. In fact, one of the prime motives for developing the SSRIs was to find an antidepressant which was not lethal in overdose. It was a bit ironic to prescibe a drug (e.g. a tricyclic) which was to treat major depression, which simultaneously gave the patient the tool to end their misery.
The European Union has recently brought down restrictive prescribing guidelines for the SSRIs, and strongly suggested monitoring protocols. It is also recommended that the risk of suicidality is overtly discussed, and that family and associates (as appropriate) are made aware of the risk, as well.
I don't know how we came to believe these drugs were so benign, and I'm not laying that on the drug companies. We've all been willfully blind to what is going on around us.
Lar
Posted by SLS on August 28, 2004, at 10:11:17
In reply to Re: pediatric suicidality and SSRIs » Ilene, posted by Larry Hoover on August 28, 2004, at 7:57:12
Dear Larry,
Thanks for taking the time to review the published material on Paxil. I never would have been able to get through it, much less interpret it. Your conclusions are reassuring. I only hope that they are to be concurred with by others and make headlines in the media to the same extent as were the alarmist accusations.
- Scott
Posted by Larry Hoover on August 28, 2004, at 11:07:43
In reply to Re: pediatric suicidality and SSRIs » Larry Hoover, posted by SLS on August 28, 2004, at 10:11:17
> Dear Larry,
>
> Thanks for taking the time to review the published material on Paxil. I never would have been able to get through it, much less interpret it. Your conclusions are reassuring.I'm thrilled that the raw data are being published. There is a new target for the anti-drug press, Cymbalta. I understand the full study data will be online by the end of the year.
> I only hope that they are to be concurred with by others and make headlines in the media to the same extent as were the alarmist accusations.
>
>
> - ScottYou're not going to see the retraction headlines, Scott. That won't sell newpapers.
I'll give you an example of an incidence of "serious emotional lability" in the pediatric Paxil arm of the study I reviewed. Using a priori reporting guidelines, it had to be reported this way.....
Each subject was given those foil-bubble packs of drugs, enough for 10 days intake, at twice-a-day dosing. This allowed for a little flexibility around the intended weekly monitoring meeting, at which a new set of drugs was dispensed. The old drug packs were returned, and counted, to ensure some measure of compliance to the protocol.
One subject took a little bit too much medication. She was supposed to take 14 capsules over the week-long period, but she three times took either 15 or 16 capsules. Under the study protocol, doing so two or more weeks in a row, was to be scored as "intentional overdose, severe emotional lability". If she had done so with a single week between each mistaken dosing pattern, it wouldn't have been scored at all.
Give me a break. The subject was warned to pay closer attention to her dosing schedule, and she then complied completely. No adverse side-effects of any sort were reported. She later went on to the long-term maintenance arm of the study, and did not ever again mistakenly take too many pills. She could have been in the placebo arm, for all anybody knew. Her blind was not broken.
The loony press reported this as a suicide attempt in the Paxil arm of the study.
Lar
This is the end of the thread.
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