Prozac leads to testicular shrinkage of approximately 25%.

[Guest guest]

Professor Healy advises the MHRA that Prozac leads to

testicular shrinkage of approximately 25%.

Prozac and SSRIs for Children

Since I attended the SSRI review committee, the question of the use

of Prozac in children has come to the fore. Prozac is apparently

under review for children by MHRA at present and the impression

stemming from correspondence that is in the public domain from Lilly

and from other regulators in Europe is that approval by MHRA is

interestingly all but certain.

I have had a chance to review a good deal of data on Prozac given to

children and wish to make the following comments to the committee,

many of which will not come as any surprise to you.

There have been four trials of Prozac in children who are depressed.

The first by Simeon et al 1990 showed no differentiation between

Prozac and placebo.

The second by Emslie published in 1997 showed no differentiation

between Prozac and placebo on the primary outcome measure of the

study. This was a trial in which less than 100 children were

selected from over 500 children screened. This trial also used a

placebo washout period to exclude placebo responders.

The third trial was a most unusual trial. Emslie was again the first

author, and this trial was published in 2002. In addition to

extensive screening to select patients likely to be responsive to

treatment, this trial had a placebo washout phase to exclude placebo

responders, as had the previous Prozac trials, but in addition it

had a further phase, which involved children randomised into Prozac

arm of the trial being given a week of Prozac 10mg first with an

exclusion option for any children who appeared to respond adversely

to Prozac. The trial proper started after this extraordinary

manoeuvre.

Even with this extraordinary step on the primary outcome measure in

the trial as indicated in FDA medical reviews of all of these trials

Prozac did not differentiate from placebo.

The fourth trial you'll be aware of has recently been published in

JAMA with March as a first author, having first featured in the

New York Times and elsewhere extolling the virtues of Prozac. I

think rarely will the abstract of a major paper have been so at odds

with the underlying raw data.

I understand some of you in MHRA were watching the feed from the FDA

paediatric advisory committee meeting. If that is the case

presumably you will have seen Dr March present the data there and

heard him questioned. One of the most striking features of this

interchange was that Dr March was forced to admit that according to

strict FDA criteria that Prozac in his trial had not been shown to

work either.

The March group had manipulated the data in an interesting fashion,

which involved searching for responders and non-responders on scales

such as the CDRS or the clinical global impression scales, and

compared these. When this is done, the effect is to squeeze patients

into categories and under those circumstances Prozac can be shown to

be different from placebo but this squeezes the middle of the

clinical population in a manner that is methodologically

inappropriate. When the CDRS or other scales are used on a

continuous variable basis, as per FDA requirements for demonstrating

efficacy, the differences between Prozac and placebo are not

statistically significant. This point was recently brought out in a

position piece by Newman in the NEJM.

You will no doubt also be aware that the rate of suicidal acts on

Prozac in this latter trial is no less than the rate of suicidal

acts on other SSRIs, and is in fact substantially greater than in

most other SSRI trials.

It would seem therefore that there is no more evidence of efficacy

or for safety on Prozac than there is for other SSRIs, and just as

much evidence for harm.

However it is also worth noting that there is some evidence for

efficacy for Prozac, Seroxat/Paxil and Zoloft/Lustral for OCD, but

at present it is difficult for any clinician to use an SSRI for any

child or teenager in the UK, owing to MHRA's handling of the issues

thus far.

For the record it's perhaps worth adding at this point that I don't

agree that MHRA made the correct move in contraindicating SSRIs in

children. There is some evidence from trials in OCD and other

anxiety disorders that some of these drugs can be effective. The key

issue is that the treatment should come with the proper warnings for

both adult and paediatric populations.

My suspicion is that, as MHRA rarely if ever do anything without

some consultation with the market authorisation holders, it appeared

to be a better bet to the market authorisation holders to have the

drugs contraindicated in children, given that so few children in the

UK were having these drugs, rather than to have appropriate warnings

placed on the treatment, as such warnings might impact on the adult

market. But contra-indicating SSRIs and other antidepressants is the

move that seems to have set up the current quandary MHRA are in,

which appears to have all but required a licensing of Prozac for

children.

If Prozac is licensed for children, it is also worth noting that

there are other features of Prozac use in children that are of

concern. The FDA reviews of this drug make it clear that children

taking Prozac failed to grow at the rate that children taking

placebo grew. The FDA asked Lilly to undertake follow-up studies of

this effect, but as far as I know the company have not done so. No

doubt MHRA will have noticed this problem in the trial data also. If

you do intend to license Prozac, it would be good to know that the

issue of growth has been investigated properly.

There is a further potential hazard of Prozac that FDA could not

have been aware of when they reviewed the drug, but which MHRA have

a chance to familiarise themselves with. In April of this year the

US Department of Health and Human Services, National Toxicology

Programme, issued a Centre for the Evaluation of Risks to Human

Reproduction Report that focused on Fluoxetine – NTP CERHR Expert

Panel Report on the reproductive and developmental toxicity of

Fluoxetine. In this it is made clear that in male animals tested

Prozac leads to testicular shrinkage of approximately 25%. The use

of this drug in men generally must therefore be of some concern. The

use of this drug in pubertal boys would seem distinctly problematic.

[Guest guest]

Professor Healy advises the MHRA that Prozac leads to

testicular shrinkage of approximately 25%.

Prozac and SSRIs for Children

Since I attended the SSRI review committee, the question of the use

of Prozac in children has come to the fore. Prozac is apparently

under review for children by MHRA at present and the impression

stemming from correspondence that is in the public domain from Lilly

and from other regulators in Europe is that approval by MHRA is

interestingly all but certain.

I have had a chance to review a good deal of data on Prozac given to

children and wish to make the following comments to the committee,

many of which will not come as any surprise to you.

There have been four trials of Prozac in children who are depressed.

The first by Simeon et al 1990 showed no differentiation between

Prozac and placebo.

The second by Emslie published in 1997 showed no differentiation

between Prozac and placebo on the primary outcome measure of the

study. This was a trial in which less than 100 children were

selected from over 500 children screened. This trial also used a

placebo washout period to exclude placebo responders.

The third trial was a most unusual trial. Emslie was again the first

author, and this trial was published in 2002. In addition to

extensive screening to select patients likely to be responsive to

treatment, this trial had a placebo washout phase to exclude placebo

responders, as had the previous Prozac trials, but in addition it

had a further phase, which involved children randomised into Prozac

arm of the trial being given a week of Prozac 10mg first with an

exclusion option for any children who appeared to respond adversely

to Prozac. The trial proper started after this extraordinary

manoeuvre.

Even with this extraordinary step on the primary outcome measure in

the trial as indicated in FDA medical reviews of all of these trials

Prozac did not differentiate from placebo.

The fourth trial you'll be aware of has recently been published in

JAMA with March as a first author, having first featured in the

New York Times and elsewhere extolling the virtues of Prozac. I

think rarely will the abstract of a major paper have been so at odds

with the underlying raw data.

I understand some of you in MHRA were watching the feed from the FDA

paediatric advisory committee meeting. If that is the case

presumably you will have seen Dr March present the data there and

heard him questioned. One of the most striking features of this

interchange was that Dr March was forced to admit that according to

strict FDA criteria that Prozac in his trial had not been shown to

work either.

The March group had manipulated the data in an interesting fashion,

which involved searching for responders and non-responders on scales

such as the CDRS or the clinical global impression scales, and

compared these. When this is done, the effect is to squeeze patients

into categories and under those circumstances Prozac can be shown to

be different from placebo but this squeezes the middle of the

clinical population in a manner that is methodologically

inappropriate. When the CDRS or other scales are used on a

continuous variable basis, as per FDA requirements for demonstrating

efficacy, the differences between Prozac and placebo are not

statistically significant. This point was recently brought out in a

position piece by Newman in the NEJM.

You will no doubt also be aware that the rate of suicidal acts on

Prozac in this latter trial is no less than the rate of suicidal

acts on other SSRIs, and is in fact substantially greater than in

most other SSRI trials.

It would seem therefore that there is no more evidence of efficacy

or for safety on Prozac than there is for other SSRIs, and just as

much evidence for harm.

However it is also worth noting that there is some evidence for

efficacy for Prozac, Seroxat/Paxil and Zoloft/Lustral for OCD, but

at present it is difficult for any clinician to use an SSRI for any

child or teenager in the UK, owing to MHRA's handling of the issues

thus far.

For the record it's perhaps worth adding at this point that I don't

agree that MHRA made the correct move in contraindicating SSRIs in

children. There is some evidence from trials in OCD and other

anxiety disorders that some of these drugs can be effective. The key

issue is that the treatment should come with the proper warnings for

both adult and paediatric populations.

My suspicion is that, as MHRA rarely if ever do anything without

some consultation with the market authorisation holders, it appeared

to be a better bet to the market authorisation holders to have the

drugs contraindicated in children, given that so few children in the

UK were having these drugs, rather than to have appropriate warnings

placed on the treatment, as such warnings might impact on the adult

market. But contra-indicating SSRIs and other antidepressants is the

move that seems to have set up the current quandary MHRA are in,

which appears to have all but required a licensing of Prozac for

children.

If Prozac is licensed for children, it is also worth noting that

there are other features of Prozac use in children that are of

concern. The FDA reviews of this drug make it clear that children

taking Prozac failed to grow at the rate that children taking

placebo grew. The FDA asked Lilly to undertake follow-up studies of

this effect, but as far as I know the company have not done so. No

doubt MHRA will have noticed this problem in the trial data also. If

you do intend to license Prozac, it would be good to know that the

issue of growth has been investigated properly.

There is a further potential hazard of Prozac that FDA could not

have been aware of when they reviewed the drug, but which MHRA have

a chance to familiarise themselves with. In April of this year the

US Department of Health and Human Services, National Toxicology

Programme, issued a Centre for the Evaluation of Risks to Human

Reproduction Report that focused on Fluoxetine – NTP CERHR Expert

Panel Report on the reproductive and developmental toxicity of

Fluoxetine. In this it is made clear that in male animals tested

Prozac leads to testicular shrinkage of approximately 25%. The use

of this drug in men generally must therefore be of some concern. The

use of this drug in pubertal boys would seem distinctly problematic.