should’ve listened then…

Posted on Monday 1 July 2013

Several have written in the comments or emailed me with some "did they?…" questions and comments about the article in the last post [the mother of meta…]. I have a lot of those questions myself, but I probably didn’t convey how mega this meta really is. Besides being a long and dense article itself, it comes with a 141 page, 1+ megabyte pdf supplement. So almost every "did they?…" question imaginable can be answered "yes" [and some none of us even thought about], but I haven’t gotten there yet. If that weren’t enough, they did an earlier one [2009] on the same topic that has ten supplemental pdf’s of its own [Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis]. The drugs were mostly still "in patent" 4½ years ago, so they were focusing on cost-effectiveness as an added parameter then – not in this recent version.

I’m regularly critical of these drugs almost by reflex because they’re no great shakes; they are more toxic than advertised; and they have been massively over-prescribed, particularly off-label. But I decided to lay off of that kind of commentary for now and try to learn something from these herculean efforts. So I’ll be summarizing things down the road. But in looking, I ran across a commentary on the 2009 article that I found telling – addressing some of the questions we’re still asking:
by Peter Tyrer and Tim Kendall
The Lancet. 2009 373[9657]:4-5.

Clinicians are familiar with studies that claim to show major advances in therapy. They tend to greet early reports of such advances with a touch of scepticism and wait, usually for at least 10 years, for a raft of independent studies that show that the advance is genuine and not just another minor ripple in the treatment stream. In The Lancet today, Stefan Leucht and colleagues deviate from this pattern by suggesting that what was seen as an advance 20 years ago — when a new generation of antipsychotic drugs with additional benefits and fewer adverse effects was introduced — is now, and only now, seen as a chimera that has passed spectacularly before our eyes before disappearing and leaving puzzlement and many questions in its wake.

Leucht and colleagues’ analysis of ten outcomes from 150 randomised trials, supported by some powerful studies, shows that the name “second-generation antipsychotics” is inaccurate. This group of drugs is in fact a heterogeneous mix of compounds, with some superior to others. Antipsychotic drugs differ in their potencies and have a wide range of adverse-effect profiles, with nothing that clearly distinguishes the two major groups. Importantly, the second-generation drugs have no special atypical characteristics that separate them from the typical, or first-generation, antipsychotics. As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost eff ective. The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed. But how is it that for nearly two decades we have, as some have put it, “been beguiled” into thinking they were superior?

Leucht and co-workers provide some clues. Of 150 trials in their meta-analysis, in 95 the second- generation antipsychotic was compared with the high-potency first-generation antipsychotic haloperidol. The use of haloperidol as the first-generation anti-psychotic in these trials means that they were biased in favour of the second-generation drugs. This bias has been achieved through several routes — eg, by comparing the second-generation antipsychotic with a high-potency first-generation antipsychotic likely to be associated with a high rate of extrapyramidal side-effects. Another obvious way of favouring the second-generation drugs has been to avoid comparison with a medium-potency first-generation antipsychotic, because these drugs are likely to be just as efficacious as the second-generation drug, but less likely than haloperidol to induce Parkinsonism. The picture can be complicated further with high doses of the first-generation drug. This approach favours the second-generation antipsychotic because side-effect rates are much lower than with the first-generation antipsychotic. Moreover, there is often selective publication of trials that can skew the evidence base in favour of a drug favoured by the investigators. On present evidence from all sources it is difficult not to conclude that the trials of the second-generation antipsychotics seem to be driven more by marketing strategy than to clarify their role for clinicians and patients.

This is not to say that all antipsychotic drugs are the same, they are not. Individual responses vary, and so a range of drugs is needed for good clinical practice. So where should we go now? First, the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction. The only second-generation antipsychotic that is obviously better than other drugs in resistant schizophrenia is clozapine, and this is a very old drug indeed. Second, clinicians must remember to keep the benefit–risk ratio of each antipsychotic drug in constant perspective because all are associated in different ways with serious adverse effects, which should be important outcome measures. Finally, it is prudent to remember that although science rules during a drug’s development, the market usurps control once the drug is released for care of patients.
We should’ve listened then…
    July 1, 2013 | 5:44 PM

    I respectfully disagree. It is about generational differences, because pharmacologically Haldol is not at all like Risperdal, nor is Mellaril equivalent to Seroquel, and, let’s have a moment of candor, EPS and TD are much less a prevalent reaction with the newer antipsychotics, having had patients almost crippled with TD see much improvement with Seroquel has been quite the outcome to witness.

    But, the mistake was when Lilly let Zyprexa get marketed for this damn Bipolar indication and then got away with more off label to near full label indications. Do you know they even went after an indication for Migraine management in the early 2000s? Talk about chutzpah!!!

    No, then everyone else in the antipsychotic group said literally, “ME TOO” and all jumped on that bandwagon and then plowed into the culture with true reckless abandon. And the folly is just breathtaking in scope and atrocity to witness.

    Today the Latuda rep came in grinning to tell me it has an indication for Bipolar now. Yeah, right! Oh, and again saw at least 4 people who were at least nonverbally telling me that meds only was the treatment option they expected. None too happy to hear me reply “well, it won’t be by me hereon.”

    As I wrote in a recent post, much of what I see in CMHCs these last few years is just addiction run amok, Axis 2 mislabeled as treatment resistant mood/thought disorders, Axis 4 psychosocial stressors in bulk, or complicated tertiary care psychiatric illness not suited for primary care psychiatric clinics where I work.

    And over half just demand, not even will negotiate anymore, that there will be meds, and therapy is an afterthought.

    So, blame it on ALL the psychiatrists the process is terrible, but, care to look in the mirrors of late, antipsychiatry critics? There are no real innocents these days, sorry to have to tell you.

    July 1, 2013 | 8:48 PM

    The majority of people fully recovered (over 60%) from”schizophrenia” before any of these drugs were used (1st or 2nd generation). Their long term use impedes recovery and causes disability.

    These are facts. And all of the name calling (anti-psychiatry) will do nothing to change these facts.


    July 1, 2013 | 8:51 PM

    We are now seeing recovery rates of 85% in Lapland, Finland usinf ‘Open Dialogue’ approach – without these drugs.

    Gosh, don’t you just hate all the “damage” caused by those of us who are anxious to such share good news. Spreading hope can be so dangerous.


    July 1, 2013 | 8:53 PM

    typos -
    ‘share such good news’

    July 4, 2013 | 6:35 PM

    One of the only good things about some of the newer neuroleptics such as Seroquel over Haloperidol is that because of their receptors affinities they have kind of training wheels for doctors. Haloperidol has *potential* to block much more dopamine receptors than Seroquel, but you don’t have to give it in huge doses .. if you know what you’re doing …

    July 4, 2013 | 6:38 PM

    And there’s other “first generation” neuroleptic drugs with different receptor affinities and similar training wheels.

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