youngsters and antidepressants

[animas]

Why is there an increased risk of suicidality when children and adolescents are initially placed on antidepressant therapy?

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[billypilgrim37]

It's not clear that SSRIs increase suicidality in children or adolescents, for many reasons.

1) When you run a clinical trial and you start someone on an antidepressant, you start monitoring them closely for suicidality. If they are depressed, they have a good chance of being suicidal. They have a higher chance of being suicidal before their treatment is effective. If they are suicidal before the study, they wouldn't be in the study to begin with.

1a) In said studies, there was not a risk of suicidal acts, just suicidal thoughts. If you look for it, you might find it.

2) When the black box warnings came out, pediatricians stopped prescribing SSRIs. Suicide rates in adolescents went up.

3) Mechanistically, some wonder if early in treatment whether some of the neurovegetative symptoms (being sleepy, having no energy) abate before the existential angst and death wish do. If all the sudden you now have the get-up-and-go to kill yourself, you might think about it more.

4) We don't well understand suicide or suicidal behavior, and the way DSM deals with suicidality probably prevents some research questions from being addressed the way we might want to.

5) SSRIs themselves have side effects. One of those side effects is some level of akathisia. Feeling restless and agitated is a risk factor for suicidality.

 

[OldPsychDoc]

It's not clear that SSRIs increase suicidality in children or adolescents, for many reasons.

1) When you run a clinical trial and you start someone on an antidepressant, you start monitoring them closely for suicidality. If they are depressed, they have a good chance of being suicidal. They have a higher chance of being suicidal before their treatment is effective. If they are suicidal before the study, they wouldn't be in the study to begin with.

1a) In said studies, there was not a risk of suicidal acts, just suicidal thoughts. If you look for it, you might find it.

2) When the black box warnings came out, pediatricians stopped prescribing SSRIs. Suicide rates in adolescents went up.

3) Mechanistically, some wonder if early in treatment whether some of the neurovegetative symptoms (being sleepy, having no energy) abate before the existential angst and death wish do. If all the sudden you now have the get-up-and-go to kill yourself, you might think about it more.

4) We don't well understand suicide or suicidal behavior, and the way DSM deals with suicidality probably prevents some research questions from being addressed the way we might want to.

5) SSRIs themselves have side effects. One of those side effects is some level of akathisia. Feeling restless and agitated is a risk factor for suicidality.

I'd just add to the above that pre-1988, it was much less common to put a patient of any age, but particularly a "youngster", on a psychotropic. When the SSRI era began, we (as in the entire medical community) may have adopted an attitude of complacency regarding these "safe" meds.

 

[masterofmonkeys]

3) Mechanistically, some wonder if early in treatment whether some of the neurovegetative symptoms (being sleepy, having no energy) abate before the existential angst and death wish do. If all the sudden you now have the get-up-and-go to kill yourself, you might think about it more.

4) We don't well understand suicide or suicidal behavior, and the way DSM deals with suicidality probably prevents some research questions from being addressed the way we might want to.

5) SSRIs themselves have side effects. One of those side effects is some level of akathisia. Feeling restless and agitated is a risk factor for suicidality.

I tend to put more money on these, with 3>5>4. No evidence for it though.

 

[DrRazberrySwirl]

we just had a big grand rounds on this, and the conclusion was no. i dont have the presentation in front of me, so i can't give you the specifics, but the presenter went through all the recent/relevent studies, and was able to show how the research did not support this.

 

[billypilgrim37]

I tend to put more money on these, with 3>5>4. No evidence for it though.

3 is sexy, but I like 5. 5 just sounds more miserable, ya know?

 

[kugel]

I have a pet theory for which I have NO evidence:
Many people experience a positive placebo effect when starting an antidepressant, in part because of the hope that "this person understands that I'm miserable and at least didn't just say, 'you shouldn't feel that way.'" Also, there is the hope that this medicine will help. Perhaps this placebo effect is greater in adolescents (regardless of the field of medicine being treated); I don't know.

But when the placebo effect wears off in a few days, it would be easy to think "well even that didn't work. I guess now there's no hope left." And this time before the meds have a chance to kick in (2-8 weeks) could easily feel even worse than before the meds were prescribed. And that may lead to SI if you don't understand what's going on and why you feel "worse" shortly after starting an antidepressant.

So does the time difference between how long the placebo response lasts vs when the medicine effect kicks in "cause" the perceived increase in SI after starting an AD?

On another note entirely, wasn't it an aphorism even before SSRI's came to market that "pt's may have INcreased suicide risk in the first 2 weeks after starting an antidepressant?" If this phenomenon is similar no matter what type of antidepressant used, doesn't that argue that it is a phenomenon of the illness, and not the treatment?

 

[maranatha]

we just had a big grand rounds on this, and the conclusion was no. i dont have the presentation in front of me, so i can't give you the specifics, but the presenter went through all the recent/relevent studies, and was able to show how the research did not support this.

Yes, the most recent evidence suggests that an increase in SI with adolescents starting an anti-depressant is NOT the case. In fact, there was a study that concluded adolscents who take anti-depressants are a 1/3rd less likely to attempt suicide then those not treated with an anti-depressant. There is a big push to have the FDA remove that black box warning.

 

[animas]

It's not clear that SSRIs increase suicidality in children or adolescents, for many reasons.

3) Mechanistically, some wonder if early in treatment whether some of the neurovegetative symptoms (being sleepy, having no energy) abate before the existential angst and death wish do. If all the sudden you now have the get-up-and-go to kill yourself, you might think about it more.

Yes, the most recent evidence suggests that an increase in SI with adolescents starting an anti-depressant is NOT the case. In fact, there was a study that concluded adolscents who take anti-depressants are a 1/3rd less likely to attempt suicide then those not treated with an anti-depressant. There is a big push to have the FDA remove that black box warning.

Very interesting responses for me as a medical student.

I asked this question because I was working on a presentation on adolescent depression for my elective in adolescent medicine (quick aside: highly recommend doing this elective to students interested in C&A psychiatry!!!).

Anyhow, my sources on this topic were pretty much UpToDate. a few C&A psych textbooks in the hospital library, and a few websites... I didn't come across this "most recent recent evidence" but am glad to be made aware now.

What I am confused about, however, is that intuitively it would still make sense to me there is an increased risk of SA in BOTH adolescents and adults, (increased energy, etc, to carry out a previous plan as the depression begins to lift away)... but, more in adolescents because they as a group are more impulsive? I.e. when the FDA did issue that black box warning why didn't they issue it for everyone, regardless of age?

Another question: Is it true 70% of depressed adolescents never get treatment? Pretty big figure.

 

[Regnvejr]

.....There is a big push to have the FDA remove that black box warning.

Not going to happen. They will immediately face a class-action suit of the families of kids who killed themselves after being taken off the antidepressants.

 

[animas]

Going off on a tangent, but what do you think of this:

http://www.nytimes.com/2010/03/30/us/30bully.html

http://community.nytimes.com/commen...html?permid=3&scp=2&sq=suicide cornell&st=cse

http://www.nytimes.com/aponline/201...lding-Death.html?scp=1&sq=yale suicide&st=cse

When it comes to depression, young people are underdiagnosed and undertreated. Young students--whether depressed, stressed, bullied--are comitting suicide... an epidemic? Not right.

 

[psychpsych]

This is a sore spot for me, so I apologize if the tone of this post is harsh. For the record, I am a child and adolescent psychiatry fellow, and I have prescribed plenty to antidepressants to kids. I've likewise heard the gamut of rationalizations for continuing to do so.

In all of the formal presentations I have heard on this topic, I have been disturbed by the frequency of flawed explanations. This thread is no exception. Again, I am not saying there aren't good explanations, but the bad explanations do nothing but make us look like sloppy scientists that are interpreting data based on what we want to be true.

Example: If you look for it, you'll find it; the kids are depressed and already at risk for suicide. Fair enough, but that does not explain why you would find it more than in those taking placebo. Remember, the black box warning is not b/c of more SI compared to pre-trial; it is for more (double) the rate of SI during the trial compared to placebo.

Example: Kugel, same goes for your explanation. It doesn't make sense that the kids taking placebo wouldn't experience the same phenomenon.

Example: This phenomenon is a product of flawed conceptualizations/paradigms. Another distractor. To effectively utilize this argument, one would then have to actually demonstrate why the paradigm as it is would lead to inflated rates of "SI" in treatment group over placebo AND why that increased rate (even if flawed in its measurement/definition/etc) isn't a cause for concern.

Here are some answers to the original poster's question that respect the data and do not try to distract or detract from it.

-As already mentioned, "activation" and side effects are more likely than with placebo and might lead to increased SI. This doesn't mean that those particular kids couldn't be switched or that over time (more time than the clinical trials), the benefits wouldn't counterbalance the risks. As further support for the use of SSRIs, one could cite some of the population studies that others alluded to here. However, I *think* there is evidence on both sides, e.g., I *think* the suicide rate in people under 25 has dropped since 2004.

-First mood episode in bipolar patients is usually depression. In fact, the average bipolar patient will have multiple episodes of depression before being diagnosed as bipolar. Thus, these depressed kids may in fact be "bipolar." I don't mean this hazy Bipolar NOS stuff, but that they will end up later in life having true manic/hypomanic episodes that simply haven't been observed yet. The SSRIs may be "switching" them into a more mixed state with increased SI risk. (Yes, I know the SSRI switching issue is another debatable one, but if you accept that it does happen to some people, then here's a vulnerable group.) These same patients would have been screened out in adult clinical trials because of history of mania/hypomania.

- Children may be more sensitive to SSRI "withdrawal." This may explain why short half-lived Paxil and Effexor seem to be worse w/ regard to SI in kids, while long half-lived Prozac seems best. (I'm blanking on the Effexor XR data, but I *think* it is relatively bad, too, which doesn't fit as well with this model.)

I'm not saying don't presribe SSRIs. I'm saying, 1) understand what you are doing, 2) minimize risks, 3) try to explain the data, rather than EXPLAIN AWAY the data to maintain the status quo.

 

[Regnvejr]

..Example: If you look for it, you'll find it; the kids are depressed and already at risk for suicide. Fair enough, but that does not explain why you would find it more than in those taking placebo. Remember, the black box warning is not b/c of more SI compared to pre-trial; it is for more (double) the rate of SI during the trial compared to placebo.

In Paxil, mainly.

 

[BobA]

I'm a PGY1, and I don't feel comfortable yet even in diagnosing depression in the under 18 population. I mean, how do you tell the difference between a child who's acting out because of terrible parenting vs. a child who's "depressed"? How does one determine between healthy teenage angst/the struggle for establishing an independent identity and endogenous "depression" in an adolescent?

I CERTAINLY don't feel I'm able to reassure the parents of a child/adolescent that an SSRI would be "safe" for their child.

We see children & adolescents in the ED when we're on call, and I ALWAYS push psychotherapy with the parents, and then either admit the youngster or get them follow up with a C & A psych Fellow the next day.

 

[maranatha]

I'm a PGY1, and I don't feel comfortable yet even in diagnosing depression in the under 18 population. I mean, how do you tell the difference between a child who's acting out because of terrible parenting vs. a child who's "depressed"? How does one determine between healthy teenage angst/the struggle for establishing an independent identity and endogenous "depression" in an adolescent?

I CERTAINLY don't feel I'm able to reassure the parents of a child/adolescent that an SSRI would be "safe" for their child.

We see children & adolescents in the ED when we're on call, and I ALWAYS push psychotherapy with the parents, and then either admit the youngster or get them follow up with a C & A psych Fellow the next day.

Fair enough. But even if you believe the studies that show an increase in SI with adolescents, it has still been establised that the risk of taking antidepressant outweighs the risk of SI. Psychotherapy should always be recommended, but antidepressants can be very effective. Your concern has been reflected in the prescribing practices since the black box warning and this is very unfortunate.

Also, if I'm not mistaken, those studies that drove the black box warning showed an increase in suicidal ideation, not attempts.

 

[AbbyNormal]

Psychology/psychiatry is not my thing so I may be wrong but it was my understanding that when people are severely depressed they may have suicidal ideation but often lack energy to carry through. Then when they start taking antidepressants they are still depressed but not so severely as they were and then they have more energy and that combination makes them more likely to attempt suicide. Or so I have been told by a psychologist friend.

 

[psychpsych]

Also, if I'm not mistaken, those studies that drove the black box warning showed an increase in suicidal ideation, not attempts.

Ideation and attempts (but no completed suicides) in the pooled studies precipitating the black box warning.

 

[BabyPsychDoc]

I'm a PGY1, and I don't feel comfortable yet even in diagnosing depression in the under 18 population. I mean, how do you tell the difference between a child who's acting out because of terrible parenting vs. a child who's "depressed"? How does one determine between healthy teenage angst/the struggle for establishing an independent identity and endogenous "depression" in an adolescent?

I CERTAINLY don't feel I'm able to reassure the parents of a child/adolescent that an SSRI would be "safe" for their child.

We see children & adolescents in the ED when we're on call, and I ALWAYS push psychotherapy with the parents, and then either admit the youngster or get them follow up with a C & A psych Fellow the next day.

"Healthy teenage angst" does not normally bring you to the ED?

 

[kugel]

Example: Kugel, same goes for your explanation. It doesn't make sense that the kids taking placebo wouldn't experience the same phenomenon.

Absolutely fair criticism of my explanation.
I do think something like my version happens in practice, where pt's know they are getting active medication - but it's only part of the picture. The side effects are at least as important - probably more so.
I will be much more careful about how I word that.

So, it looks like the best explanations for the data set prompting the BlackBox are:
1) activation/akathesia/anxiety induced by the medication
2) "accidental" treatment of undiagnosed bipolar with antidepressant monotherapy, thereby causing emergence of some manic symptoms.

Makes good sense to me.
Did I understand you correctly, Psychpsych?

 

[mishavrach]

The suggested mechanism has to do with serotonin receptors. During low serotonin states, there is up-regulation of receptors (in other words post-synaptic membrane makes extra receptors in response to paucity of serotonin - 5HT). There are different types of 5HT receptors. 5HT1A leads to reduction in anxiety and elevation of mood, 5HT2A - agitation and possibly some change of reality testing (LSD is believed to act via 5HT2A)

When an SSRI blocks serotonin re-uptake, those with proportionally higher ratio of 5HT2A have initial tendency toward agitation , decrease of rational thinking, and in some cases suicidality. Eventually receptors down-regulate and activation subsides, but the first few weeks might be unpleasant to say the least.

Gradual titration, and/or concomitant use of benzos or atypicals (when indicated) might help. FWIW

 

[whopper]

I've read data showing that the benefits of antidepressants to children is actually far less than that of adults. The studies I've seen gave me an impression that perhaps in children, depression is more situationally-based than it is for adults, and perhaps the depression, because it was not as long, may have not caused as much pharmacological changes in their brains.

If someone asks, I'll fish for the data. I generally try to put a link to this data, but as of right now I'm burned out!

Antidepressants should be considered, but the feeling I got from the studies were that psychosocial treatment was more important.

Anyone with C&A training please feel free to drop in and correct me if I'm wrong.

 

[mishavrach]

I've read data showing that the benefits of antidepressants to children is actually far less than that of adults. The studies I've seen gave me an impression that perhaps in children, depression is more situationally-based than it is for adults, and perhaps the depression, because it was not as long, may have not caused as much pharmacological changes in their brains.

If someone asks, I'll fish for the data. I generally try to put a link to this data, but as of right now I'm burned out!

Antidepressants should be considered, but the feeling I got from the studies were that psychosocial treatment was more important.

Anyone with C&A training please feel free to drop in and correct me if I'm wrong.

It is more complex than it looks. First, there are no agreed upon criteria for pediatric depression.Second, there are different types of depression (not only clinically but also neurochemically). Third, the studies have major limitations - you'll need a separate thread just to list them. Next, there are dev. milestones, hormones, parental biases, depression vs. demoralization, definition of pediatric dysfunctionality from depression, etc.

BTW, pediatric depression is less a function of the length of duration, but biological (read inherited) predisposition. It's much harder to diagnoses depression in kids as everything at this age looks like disruptive and inattentive behavior. Quoting "Niccolo Machiavelli:

."...at the beginning a disease is easy to cure but difficult to diagnose; but as time passes, not having been treated or recognized at the outset, it becomes easy to diagnose but difficult to cure." ..circa 1550.
.Bottom line: Pediatric depression is uncommon but real; antidepressants work in skillful hands. Psycho-social treatment (try to define it) for peds depression is ineffective at bes,t except in cases of neglect and abuse (psychoanalysts would argue that any life experience can tentatively lead to depression, but this is not the only thing they are wrong about) .
Parenting works better. FWIW

 

[kugel]

How Do Antidepressants Increase Suicide Risk in the Young?

This animal study finds a possible answer in the locus ceruleus.
The small but real risk for suicide in youth taking selective serotonin reuptake inhibitors is well documented but still poorly understood. These researchers administered 1.25, 2.50, or 5.00 mg/kg/day of paroxetine for 2, 4, 8, and 14 days to adult and young rats and measured its ability to reduce activity in the locus ceruleus (LC), the main noradrenergic center. This reduction, observed in depressed humans treated with antidepressants, is thought to underlie their therapeutic effect.

A fourth dose (0.625 mg/kg/day) was also studied but showed no effect on any test. Adult rats showed the expected effects in the LC. However, in young rats, paradoxical LC activity increases occurred at days 2 and 4 at 1.25 and 2.50 mg/kg/day doses (but not at 5.00 mg/kg/day) and corresponded to increased depression-like behavior in the forced-swim test. Young rats had 2- to 10-fold lower paroxetine blood levels than adult rats on the same dose, even when LC activity was at its peak in the young rats (days 2 and 4).
Comment: In this study, an SSRI had counter-therapeutic effects in young rats (increased locus ceruleus activity), which seems to correspond with worsening "depression" in the swim test. The effects appear to occur only at lower doses and with low drug blood levels. Increased central noradrenergic activity has also been associated with increases in anxiety and agitation, which are thought to underlie suicidal risk. If these findings translate to humans, one possible strategy to prevent this effect might be to give higher SSRI doses, although this theory requires testing before anyone adopts such a recommendation.
— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry August 2, 2010

CITATION(S):
West CHK et al. Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: Implication of a countertherapeutic effect of an antidepressant. Neuropsychopharmacology 2010 Jul; 35:1653.

 

[Regnvejr]

How Do Antidepressants Increase Suicide Risk in the Young?

This animal study finds a possible answer in the locus ceruleus.
The small but real risk for suicide in youth taking selective serotonin reuptake inhibitors is well documented but still poorly understood. These researchers administered 1.25, 2.50, or 5.00 mg/kg/day of paroxetine for 2, 4, 8, and 14 days to adult and young rats and measured its ability to reduce activity in the locus ceruleus (LC), the main noradrenergic center. This reduction, observed in depressed humans treated with antidepressants, is thought to underlie their therapeutic effect.

A fourth dose (0.625 mg/kg/day) was also studied but showed no effect on any test. Adult rats showed the expected effects in the LC. However, in young rats, paradoxical LC activity increases occurred at days 2 and 4 at 1.25 and 2.50 mg/kg/day doses (but not at 5.00 mg/kg/day) and corresponded to increased depression-like behavior in the forced-swim test. Young rats had 2- to 10-fold lower paroxetine blood levels than adult rats on the same dose, even when LC activity was at its peak in the young rats (days 2 and 4).
Comment: In this study, an SSRI had counter-therapeutic effects in young rats (increased locus ceruleus activity), which seems to correspond with worsening "depression" in the swim test. The effects appear to occur only at lower doses and with low drug blood levels. Increased central noradrenergic activity has also been associated with increases in anxiety and agitation, which are thought to underlie suicidal risk. If these findings translate to humans, one possible strategy to prevent this effect might be to give higher SSRI doses, although this theory requires testing before anyone adopts such a recommendation.
— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry August 2, 2010

CITATION(S):
West CHK et al. Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: Implication of a countertherapeutic effect of an antidepressant. Neuropsychopharmacology 2010 Jul; 35:1653.

Hmm, Paroxetine is supposed to be decidedly non-noradrenergic. So now there is another proposed mechanism, one not dealing with reuptake inibition, but rather with enhancing the LC NE? Perhaps I am getting old and gray early, but I don't remember much about the SSRIs affecting NE other than as a rather delayed response? If we see SI in kids within weeks, can the LC and NE at all be involved

 

[markglt]

cause they activate the suicide center in the brain....not just in kids...in everybody..
just like high dose dopaminergics activate the god/religon center in the brain...


doesn't get more technical than that

 

[billypilgrim37]

cause they activate the suicide center in the brain....not just in kids...in everybody..
just like high dose dopaminergics activate the god/religon center in the brain...


doesn't get more technical than that

Is that next to the Homicide Pavillion?