What happened to CATIE and CUtLASS?

[BobA]

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What happened to the results from CATIE and CUtLASS? From what I can tell, most people are still prescribed second-generation atypicals for new-onset schizophrenia, despite good evidence that first-gen are both as effective AND HAVE EQUAL/LESS SIDE EFFECTS.

Is it just that as a field we've been drinking the big-pharma cool-aid (or rather, big-pharma merlot) instead of looking at the evidence or am I missing something here?

Anyone know if FGA's are first line in the UK?

 

[TheWowEffect]

What happened to the results from CATIE and CUtLASS? From what I can tell, most people are still prescribed second-generation atypicals for new-onset schizophrenia, despite good evidence that first-gen are both as effective AND HAVE EQUAL/LESS SIDE EFFECTS.

Is it just that as a field we've been drinking the big-pharma cool-aid (or rather, big-pharma merlot) instead of looking at the evidence or am I missing something here?

Anyone know if FGA's are first line in the UK?

There are many things in play here but I'll touch on the side effects part of it. Metabolic side effects with atypicals can be as significant as any other but one can still monitor these and make appropriate changes as necessary. TDs, on the other hand are still a mystery and thus, many psychiatrists shy away from the typicals. Now, this arguement is not as simpe as I have made it out to be but this is indeed an important aspect of it.

 

[BobA]

There are many things in play here but I'll touch on the side effects part of it. Metabolic side effects with atypicals can be as significant as any other but one can still monitor these and make appropriate changes as necessary. TDs, on the other hand are still a mystery and thus, many psychiatrists shy away from the typicals. Now, this arguement is not as simpe as I have made it out to be but this is indeed an important aspect of it.

Can't one perform an AIMS assessment to monitor for TD?

 

[BabyPsychDoc]

I do not think it is right to say that both typicals and atypicals have "equal" side-effects. They have somewhat different side-effect profile. The choice would depend on your patient: e.g, danger of metab syndrome vs danger of parkinsonism - what they would rather, what you would be more wary of - gross oversimplification, but you get the point.

Then, from the symptoms point of view, you need to establish whether it is positive or negative symptoms that are most prominent/distressing - different drugs have slightly different "symptom profile" as well, ie some are better at alleviating positive symptoms, and others work better on negative symptoms.

If you are interested in the UK official guidelines on choosing antipsychotics, you could find them on www.nice.org.uk - go for Our Guidance > Mental Health > Schizophrenia.

From my personal experience (I worked in one of the leading departments of psychiatry in the UK), I can confidently say that I have not seen a typical antipsychotic chosen as a first-line medication for a newly diagnosed patient ONE SINGLE TIME. Depending on personal preferences of 4 attendings I worked with, the first-line choice was either aripiprazole, olanzapine, risperidone or quetiapine. If you ask my personal opinion, I would go for risperidone because it has been around for longer, has less metabolic side-effects and has been proven somewhat more effective than other atypicals.

However, if you are talking about rapid tranquilization, this is a different story altogether, and I have never used (read - have never been allowed to use) anything other than haloperidol +/-lorazepam.

 

[TheWowEffect]

Can't one perform an AIMS assessment to monitor for TD?

Yes, you can and it is routinely done. However, the slightest hint of any TD-like movements results in a switch to atypicals, thus further increasing their use. Again, this is just one aspect. There are many other things like atypicals improving negative sxs, less akathisia, dystonia, being newer and there is always fascination for new etc. Also, this is nothing unique to psychiatry. This is the way medicine works.

 

[BabyPsychDoc]

Can't one perform an AIMS assessment to monitor for TD?

Whilst you can monitor for it, you can do little to prevent it or to reverse it - so monitoring is kind of of limited value.

 

[BobA]

Yes, you can and it is routinely done. However, the slightest hint of any TD-like movements results in a switch to atypicals, thus further increasing their use. Again, this is just one aspect. There are many other things like atypicals improving negative sxs, less akathisia, dystonia, being newer and there is always fascination for new etc. Also, this is nothing unique to psychiatry. This is the way medicine works.

Isn't this why we have EBM?

In terms of +/- symptoms, I'm talking about a first-line agent. If negative symptoms from a FGA are bothersome down the road, then that agent could be switched. It just seems like the evidence overwhelmingly favors FGA's for first-line agent.

If we aren't basing our decisions on evidence, what are we basing them on? (how the drug reps make us feel?)

 

[BobA]

Whilst you can monitor for it, you can do little to prevent it or to reverse it - so monitoring is kind of of limited value.

My understanding is that the goal of using AIMS to monitor TD is to prevent the progression. So if the AIMS score reveals TD you switch agents, and in the absence of the inciting medication TD will not progress. Kind of like monitoring renal function in someone on lithium.

To be the devil's advocate - while metabolic syndrome is in theory reversible, in practice it's nearly impossible to reverse. This would be an interesting study.

Moreover, a patient on an atypical is likely to get metabolic syndrome while a patient on an FGA is unlikely to develop TD.

Finally, the costs in CATIE and CUtLASS didn't include labs to monitor metabolic syndrome, and long-term health care related costs associated with morbid obesity (esp heart disease).

 

[BabyPsychDoc]

My understanding is that the goal of using AIMS to monitor TD is to prevent the progression. So if the AIMS score reveals TD you switch agents, and in the absence of the inciting medication TD will not progress. Kind of like monitoring renal function in someone on lithium.

To be the devil's advocate - while metabolic syndrome is in theory reversible, in practice it's nearly impossible to reverse. This would be an interesting study.

Moreover, a patient on an atypical is likely to get metabolic syndrome while a patient on an FGA is unlikely to develop TD.

Finally, the costs in CATIE and CUtLASS didn't include labs to monitor metabolic syndrome, and long-term health care related costs associated with morbid obesity (esp heart disease).

TD may (and does!) get worse when you stop the typical antipsychotic. Furthermore, even if it does not progress, many patients still have to live with residual TD.

I am not entirely sure what you mean by saying that a patient on a typical antipsychotic is "unlikely to develop TD". Some estimate incidence of TD among patients treating with typicals to be about 5% per year of treatment, and even conservative estimates (eg, Goetz, 1997) say that about 1 in 3 patients on long-term typical antipsychotic will develop TD.

Ultimately, you cannot treat all patients with one wunderdrug - some people will respond better to one medication and others - to another. Some people are more concerned about being fat and dying from MI, and others - about having their tongue wriggle around like a snake. SOme people are also more prone to putting on weight than others. That's the beauty of medicine - one size does not fit all.

As Woweffect said, we are more twitchy about TD than metab syndrome, because we have more understanding about metab syndrome - and have some illusion that we can prevent it or at least minimize the likelihood of it's happening.

 

[BabyPsychDoc]

Isn't this why we have EBM?

In terms of +/- symptoms, I'm talking about a first-line agent. If negative symptoms from a FGA are bothersome down the road, then that agent could be switched. It just seems like the evidence overwhelmingly favors FGA's for first-line agent.

If we aren't basing our decisions on evidence, what are we basing them on? (how the drug reps make us feel?)

First, I think Woweffect was talking about neg sx of schizophrenia, not "negative sx from a FGA" - I am not sure what you mean by it.

Second, "The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research." Furthermore, "Without clinical expertise, practice risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient."

So, I love CATIE. It tells me that I could use either typicals or atypicals with more or less same efficacy; it tells me what I need to know about side-effects of both classes of drugs; it tells me what drugs my patients are likely to take for longer periods of time. This is the evidence it gives me. It DOES NOT tell me which drug to use for the next psychotic patient that comes through my office door - that is something for me and my patient to decide.

Oh, yes, "Evidence based medicine is not cookbook medicine". Muir Gray.

 

[TheWowEffect]

Again, this is not a simple and starightforward issue of using one class v/s another. There are many layers to it. You will learn as you treat more and more patients. Psychiatry, actually is moving towards a more individualized approach to treating patients. For this reason, it is all about balance between evidence based medicine and clinical judgement. Like BPD said, EBM does not mean cook book medicine.

Evidence is not really in favor of typicals but rather, they have the similar efficacy which every psychiatrists worth his salt knew even before CATIE o CUtLAS.

 

[BobA]

First, I think Woweffect was talking about neg sx of schizophrenia, not "negative sx from a FGA" - I am not sure what you mean by it.

So, I love CATIE. It tells me that I could use either typicals or atypicals with more or less same efficacy; it tells me what I need to know about side-effects of both classes of drugs; it tells me what drugs my patients are likely to take for longer periods of time. This is the evidence it gives me. It DOES NOT tell me which drug to use for the next psychotic patient that comes through my office door - that is something for me and my patient to decide.

I meant to say - negative symptoms persisting because of the choice of a FGA.

In terms of how long a patient will stay on a drug - there was no difference except for olanzapine.

As for the increased risk of TD in patient on perphenazine, the study showed that this risk might be over blown as there was no statistical significance between groups.

From the CATIE study (N Engl J Med 2005 353: 1209-1223)

"The dose range of perphenazine was chosen to minimize the potential for extrapyramidal symptoms that may have biased previous comparisons of first- and second-generation drugs.4,7,31

The use of low-dose perphenazine appears to have diminished the frequency of extrapyramidal side effects in patients who received the first-generation drug. In contrast to previous studies,35 the proportion of patients with extrapyramidal symptoms did not differ significantly among those who received first-generation and second-generation drugs in our study. Despite this finding, more patients discontinued perphenazine than other medications owing to extrapyramidal effects.

You'll have to forgive all my arguing. I'm an MS4 going into psych and I'm hoping to have the most sound practice I can by understanding the literature.

I'm also weary of joining a field that doesn't appear to be appropriately distanced from big pharma.

 

[masterofmonkeys]

no field is appropriately distanced from big pharma.

Looking at the trial, it doesn't appear that they looked at efficacy in positive vs. negative sx treatment and only looked at aggregated scores. While obviously continued positive symptoms are bad juju, continued negative sx in the absence of positive symptomatology contribute very heavily to the morbidity of schizophrenia.

I would think that, all else held equal, a drug that helped out more on the negative side of the equation would be preferable.

 

[BabyPsychDoc]

I meant to say - negative symptoms persisting because of the choice of a FGA.

In terms of how long a patient will stay on a drug - there was no difference except for olanzapine.

As for the increased risk of TD in patient on perphenazine, the study showed that this risk might be over blown as there was no statistical significance between groups.

From the CATIE study (N Engl J Med 2005 353: 1209-1223)

"The dose range of perphenazine was chosen to minimize the potential for extrapyramidal symptoms that may have biased previous comparisons of first- and second-generation drugs.4,7,31

The use of low-dose perphenazine appears to have diminished the frequency of extrapyramidal side effects in patients who received the first-generation drug. In contrast to previous studies,35 the proportion of patients with extrapyramidal symptoms did not differ significantly among those who received first-generation and second-generation drugs in our study. Despite this finding, more patients discontinued perphenazine than other medications owing to extrapyramidal effects.

You'll have to forgive all my arguing. I'm an MS4 going into psych and I'm hoping to have the most sound practice I can by understanding the literature.

I'm also weary of joining a field that doesn't appear to be appropriately distanced from big pharma.

BobA, there is no field in medicine that is appropriately distanced from Big Pharma.

As far as interpreting CATIE:

1) There is difference between clinical significance and statistical significance. Even if there were no statistically significant findings associated with perphenazine & TD, you have to consider the fact that most patients discontinued perphenazine owing to neurological side effects - ie, it is clinically significant.

2) Somewhere in the paper, the authors actually do mention that the statistical power of the study for comparisons involving perphenazine is 76%. What it actually means is there is 24% chance of not finding a real effect when it exists (ie, 24% chance of Type II error). IMHO, that IS significant. They essentially are saying that there is 1 in 4 chance that they did not detect real effects (eg, frequency of extrapyramidal sx, etc) related to perphenazine vs other drugs.

Thoughts?

 

[BabyPsychDoc]

no field is appropriately distanced from big pharma.

MoM, you have conspired with Woweffect to beat me to posting good points today😀. I have to deal with pretty crappy WiFi at the moment, so by the time I finalise my reply each time, one of you would already have said something similar, so it looks like I am parroting you guys.😳

Oh, well...Must be really good points I am making, if two other reasonable posters agree with me.

 

[BobA]

no field is appropriately distanced from big pharma.

Looking at the trial, it doesn't appear that they looked at efficacy in positive vs. negative sx treatment and only looked at aggregated scores. While obviously continued positive symptoms are bad juju, continued negative sx in the absence of positive symptomatology contribute very heavily to the morbidity of schizophrenia.

I would think that, all else held equal, a drug that helped out more on the negative side of the equation would be preferable.

I think all reasonable posters can agree that Big Pharma has too much influence in psych - irregardless of what goes on in other fields.

Of course the trial has it's limitations. But I think the objective measurable end-point of time to discontinuation captures all-cause treatment failure including positive and negative symptoms.

 

[BabyPsychDoc]

i think all reasonable posters can agree that big pharma has too much influence in psych - irregardless of what goes on in other fields.

Of course the trial has it's limitations. But i think the objective measurable end-point of time to discontinuation captures all-cause treatment failure including positive and negative symptoms.

huh?

 

[BobA]

Physicians and patients in the study were allowed to stop the treatment drug if it wasn't working. The amount of time that a patient was on the drug was used as the primary end point - "time to discontinuation."

This broad end point captures all reasons for treatment failures, including bad negative symptoms, or bad positive symptoms, or even, for that matter, side effects like TD and weight gain. Any reason a physician and patient might switch drugs is including in this end point. Also, this end point is objective and measurable.

 

[BabyPsychDoc]

Physicians and patients in the study were allowed to stop the treatment drug if it wasn't working. The amount of time that a patient was on the drug was used as the primary end point - "time to discontinuation."

This broad end point captures all reasons for treatment failures, including bad negative symptoms, or bad positive symptoms, or even, for that matter, side effects like TD and weight gain. Any reason a physician and patient might switch drugs is including in this end point. Also, this end point is objective and measurable.

I must be missing something here, but how is this relevant to the discussion? What I have been trying to say is that we need to individualise treatment depending on different variables - which was in response to your original question of why first generation antipsychotics are not used as first-line drugs. All my posts are simply trying to illustrate and elaborate that point.

What you are saying, is that it is good that CATIE used a single objective end-point - which sounds good, until you think through what it means. And it means that they used a whole rag bag of things as an end-point - and whilst this could be a valid approach, you need to exercise caution in interpreting the result. And it certainly goes right against the concept of individualised approach in care for the mentally ill.

Let me repeat - I think CATIE was a good trial with valuable results. But you need to read well beyond the abstract to get the most out of it.

 

[BobA]

I was responding to MoM's comment on negative and positive symptoms. I think that CATIE addressed this is a round-about way.

In terms of my need to "read beyond the abstract" - that comment is unwarranted. I've actually cited several elements of the paper in this very thread. Please let's keep this professional.

I don't think this thread is going anywhere any more.

 

[BabyPsychDoc]

I was responding to MoM's comment on negative and positive symptoms. I think that CATIE addressed this is a round-about way.

In terms of my need to "read beyond the abstract" - that comment is unwarranted. I've actually cited several elements of the paper in this very thread. Please let's keep this professional.

I don't think this thread is going anywhere any more.

Look, for somebody who wants to be guided by evidence, this comment sounds rather peculiar. I do not recall authors mentioning anything about +ve vs -ve sx anywhere in the paper. They only mention composite PANSS score. Unless you have access to the trial data, or can read minds, making inferences like that is unscientific.

So far, I have kept it rather professional, though I really do not understand where you are going at this point. You started the thread wondering about "A" and now somehow got on to "Z", picking and choosing suggestions and criticisms along the way as you see fit and getting rather sulky all of a sudden. I am sorry - you definitely read the paper, though your interpretation of it leaves me puzzled.

I do tend to agree with you that this thread is not going anywhere.

 

[TheWowEffect]

I think all reasonable posters can agree that Big Pharma has too much influence in psych - irregardless of what goes on in other fields.

I don't know how one would quantify too much. I would argue that it is not "too much." You will see this once you become a resident that there are more attendings who prescribe rationally and teach the right thing.

 

[whopper]

1 major difference noted between typicals & atypicals on CATIE showed that typicals (as represented by perphenazine) did not affect negative symptoms of psychosis, while the atypicals all treated negative symptoms.

Another major difference is all the atypicals minus Risperdal didn't cause much if any elevation of prolactin.

All the other differences all depended on the med.

(Ahem forgive me not having read CATIE in the last few weeks. I read & re-read that study all the time since its pretty much the current Bible on cross comparing atypicals).

IMHO they should do another CATIE like study on Abilify using the same exact study measures & incorporate it into CATIE.

 

[BabyPsychDoc]

1 major difference noted between typicals & atypicals on CATIE showed that typicals (as represented by perphenazine) did not affect negative symptoms of psychosis, while the atypicals all treated negative symptoms.

Another major difference is all the atypicals minus Risperdal didn't cause much if any elevation of prolactin.

All the other differences all depended on the med.

(Ahem forgive me not having read CATIE in the last few weeks. I read & re-read that study all the time since its pretty much the current Bible on cross comparing atypicals).

IMHO they should do another CATIE like study on Abilify using the same exact study measures & incorporate it into CATIE.

Sorry, whopper, I did not notice any -ve vs +ve sx distinction in CATIE. I wonder if I have missed something?
Thanks.

 

[whopper]

I don't think you missed anything. I double checked CATIE & now can't find the thing I mentioned. There was a PANSS done which tallied up their + & - sx, but it didn't discriminate them.

Sorry, happens when I haven't recently re-read the study. The technicals of this & other studies tend to blend into each other. I mentioned I haven't re-read it recently but forgot to mention the above.

 

[masterofmonkeys]

IMHO they should do another CATIE like study on Abilify using the same exact study measures & incorporate it into CATIE.

Call me a crackhead but I seem to recall that abilify was seen as having lower efficacy in several trials. To be honest I'm not sure of the dosages being used and that may have been one of the reasons. IIRC several of the atypicals show much better efficacy and maintain a reasonable side effect profile at doses higher than what they were originally studied at.

I might be pulling things out of thin air now but I kinda associated lower efficacy/potency with its use for non-psychotic disorders.

 

[whopper]

Aw nuts, I'm falling into the same trap again. I do recall reading studies showing that Abilify, while it does work, takes longer to do so. However I haven't read these studies in months, and unlike CATIE, I don't remember exactly where I put them in my collection of the articles I've found more interesting.