Saturday, June 7, 2014

Dangerous Medications 3: No - New IS Better Than Old

People certainly know how to spin drug studies.  The debate over "old" versus "new" or typical versus atypical antipsychotics always seems to contain an element of marketing and somebody pushing an agenda.  Reality in those analyses is always lacking and the spin on the issue of older antipsychotics (haloperidol and fluphenazine) versus the newer (risperidone and paliperidone) is problematic especially when the conclusion is that there is no reason to use newer second or third generation antipsychotics.  It also points out the difference between clinical experience and clinical trials.  Clinical experience is often minimized as being "anecdotal" but at some point anecdotal becomes statistically significant.  That has been my experience with typical or first generation antipsychotics and neurological side effects.

In looking at the results of the drug trials it might be interesting to look at the agendas of various parties involved.  Certainly the pharmaceutical manufacturers want their products to look as good as possible.  But there are also clear agendas on the part of the investigators, even when the financial conflict of interest is eliminated.  Investigators with the view that schizophrenia is largely a disorder that can be adequately treated with an antipsychotic medication and that medication adherence is a big part of that treatment is certainly one interest.  The idea that intramuscular injections is the best way to do this is another.  I recall listening to some of these investigators talk about how this is good for the patient, not that painful and there why wouldn't a psychiatrist recommend an injectable medication as soon as it was shown that the medication was tolerated in the oral form.  They seem to suggest that the patient would actually want the injection.  In my experience, nobody does.  Who would want to take monthly painful intramuscular (IM) injections for the foreseeable future?  I have seen people come to that conclusion, but they need to accumulate a significant amount of equally painful evidence related to missing oral doses of medication.

The argument about long acting injectables has take on a new dimension with the availability of long acting naltrexone (Vivitrol) injections.  This medication is one approach to the treatment of opioid use disorders and it is very effective for some some people.  If opioids do not produce the expected euphoria there is no incentive to keep taking them.  It also reduces the rate of accidental opioid overdose.  Following detoxification, many people are taken off the medications that they were using in high doses.  At the time of discharge, there is a real risk that many will attempt to go back to using the amount of opioids that they were using.  If their tolerance is gone that creates the potential for opioid overdose and death.  The nature of addiction prevent many people from using substitution therapies like buprenorphine or methadone.  Long acting naltrexone injections can be painful, but many people with opioid addiction realize it is their best chance to stop their ongoing addiction and avoid the complications of overdose including death.  In the treatment of schizophrenia spectrum disorders, many patients never get to that level of risk/benefit analysis  and that translates to an even lower likelihood of appreciating the advantages of a long acting injectable medication.

The neurological side effects of older antipsychotics are usually ignored or minimized in the debate of old versus new medications.  They were the largest single side effect problem facing psychiatrists 20-30 years ago.   It would be common to look at a group of hospitalized patients and notice that 20-30% had tardive dyskinesia the commonest movement disorder caused by older antipsychotic medications.  I can recall the experience of stabilizing people with severe bipolar disorder on an antipsychotic medication and a mood stabilizer and by the time they came back to see me in clinic they had developed tardive dyskinesia or some other movement disorder like akathisia or drug induced Parkinson's syndrome.  In the worst case scenario the movement disorder would not completely resolve with modification of the therapy or discontinuation of the antipsychotic medication.  The treatment of tardive dyskinesia after it has developed is problematic.For anyone who continues to need the medication clozapine is the treatment of choice.  Clozapine is highly regarded by experts treating schizophrenia because of its use in treatment resistant cases, protective effects against suicide, and use with movement disorders.  Those same experts often suggest that it is not used soon enough by front line clinicians, but it does have a unique set of liabilities in terms of metabolic and cardiac side effects and the need for white blood cell monitoring for the duration of use.  Technically, the medication should not be dispensed to the patient unless their absolute neutrophil count is known at the exact days suggested in the protocol.

Drug induced movement disorders can be much more than a cosmetic problem depending on your sensitivity to the medication.  Although it rarely happens, I have treated patients with psychosis who had severe drug induced tardive syndromes that were identical to severe Parkinson's disease and who continued to have severe symptoms of psychosis.  I would typically see patients with movement disorders because of my interest in the area, so I was seeing a large number of severe cases, but even rare cases of movement disorder related disability leave an impression.  I have low threshold for discontinuing antipsychotic medication and would not use an antipsychotic medication when there is another option available.  The best case in point is the current practice of augmenting antidepressant medications with an atypical antipsychotic.  I have used these augmentation strategies, but only after other options were exhausted and the patient was educated about the potential problems.  Even then, there is the risk that the pateint will not follow through with reporting the problems or stopping the medication does not have an effect on the movements.

The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study published in the New England Journal of Medicine in 2005 is as responsible as any for the minimization of the fact that newer antipsychotic agents have a much better neurological side effect profile and that is a major therapeutic advance.  My read of this study is that the authors were sensitive to the issue of comparison studies between atypical antipsychotics and doses of the typical antipsychotic haloperidol that were designed to bias the neurological side effect results toward the newer medications.  Haloperidol is a potent antipsychotic medication with significant neurological side effects even at low doses.  In this study the authors chose perphenazine as the older antipsychotic medication because of its more moderate side effect profile.  Perphenazine also received special treatment in this study as indicated by the following 6 excerpts from the body of the paper:

"Patients were initially randomly assigned to receive olanzapine, perphenazine, quetiapine, or risperidone under double-blind conditions and followed for up to 18 months or until treatment was discontinued for any reason (phase 1)."

"Patients with current tardive dyskinesia could enroll, but the randomization scheme prevented their assignment to treatment with perphenazine."

"Two hundred thirty-one patients with tardive dyskinesia were excluded from random assignment to perphenazine."

"Moreover, more patients discontinued olanzapine owing to weight gain or metabolic effects (9 percent vs. 1 percent to 4 percent with the other four drugs, P<0.001) and more patients discontinued perphenazine owing to extrapyramidal effects (8 percent vs. 2 percent to 4 percent, P=0.002)"

"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."

"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, 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."

Effectiveness in this study was measured as time to medication discontinuation (primary measure) and Clinincal Global Impression (CGI) scale and Positive and Negative Syndrome Scale (PANSS).  On the time to medication discontinuation olanzapine was significantly better than perphenazine.  There were no differences on what are admittedly crude secondary measures and on those measures and efficacy perphenazine appeared to be as good as questiapine, ziprasidone and risperidone.  The actual study results of CATIE were widely interpreted as older antipsychotics "being as good as" newer antipsychotics.  The usual conspiracy theories about pharmaceutical companies making billions from new drugs that were "no better" than the old drugs was in play.  Grist for the popular press with the subtext that the gullible (or greedy) psychiatrists have been duped again.  More  concerning  is that it did lead to prescriptions of perpehanazine and some pharmaceutical beneift managers used it s an opportunity to suggest that newer antipsychotics should be used only if typical antipsychotic medications have bee tried.

Even a cursory reading of the CATIE excerpts should suggest that the researchers here attempted to compensate for the tendency of perphenazine to cause neurological side effects and even then they could not prevent it.  They clearly did not want anyone with tardive dyskinesia to take perphenazine.  Having personally practiced during that time both of those statements make perfect sense to me.  The people with no expertise and no experience can always come up with a sensational theory of headline for one reason or another.  Nobody should doubt that newer antipsychotic agents are a significant therapeutic advance in terms of neurological side effects.  As an expert, I cannot think of a reason why I would prescribe a first generation antipsychotic.  I still see some opinions about using chlorpromazine for sleep, or other psychiatric conditions.  There are some first generation antipsychotics that should not be prescribed to human beings.  Only their low frequency of use keeps the FDA from pulling them off the market.

I digressed on the issue of neurological side effects because it is one of the main contentions of the Goff editorial on typical versus atypical long acting injections.  He describes the difference in akathisia and tardive dyskinesia (15% haoloperidol versus 11% paliperidone) between both groups and despite ample qualifiers does suggest that side effect profiles should guide medication selection.  In the actual study by McEvoy, haloperidol at the low end of the dosing spectrum did lead to significantly more neurological side effects:

"Treatment discontinuations due to neurologic adverse effects according to clinician judgment were as follows: 2 patients (1.4%) in the haloperidol decanoate group vs 1 (0.7%) in the paliperidone palmitate group due to akathisia; 3 (2.0%) in haloperidol decanoate group vs 1 (0.7%) in the paliperidone palmitate group due to parkinsonism; and 4 (2.7%) in the haloperidol decanoate group vs 1 (0.7%) in the paliperidone palmitate group due to tardive dyskinesia."

The study also borrows some of the logic from the CATIE study in discussing neurological side effects:

"Contrary to expectations, there was no statistically significant advantage for paliperidone palmitate when compared with haloperidol decanoate in ratings of the severity of abnormal involuntary movements and parkinsonism, or in the incidence of tardive dyskinesia. However, ratings of the severity of akathisia increased more for haloperidol decanoate, and more medications to manage akathisia and parkinsonism were started for patients in the haloperidol decanoate group, partially confirming that paliperidone palmitate has a lower propensity to cause extrapyramidal symptoms than haloperidol decanoate."

How might statistical significance be relevant here?

The other interesting aspect of the McEvoy paper is that it references randomized clinical trials showing that long acting injectable medications add nothing in terms of reducing the frequency of hospitalization.  That is a useful fact compared with some experts who claim otherwise.  This study and the CATIE study highlight a couple of problems with medication focused research.  First, the medication focus is not that intense.  The researcher stake an approach to prescribing that is about as rigorous as the average clinician.  Average clinicians do check prolactin levels but usually only when there is an indication and that will typically call for a more intensive intervention to treat the side effect.  Whenever I look at samples of hundreds of people, I know that the metabolism of the drug in that sample is not going to be uniform and that accounts for a lot of the neurological side effects.  Given the reasonable costs of therapeutic drug monitoring, it is curious that is never done in these trials.  Unlike observation of prolactin levels, it could result in something actually being done like lowering the dose of a medication.  Second, now that we have interventions to prevent complications should they be incorporated into the clinical trials?  In the McEvoy study, should all of the patients have been coached on metabolic syndrome and strategies to prevent weight gain?  Are we past the point where informed consent and the idea that we are observing the effect of a medication alone enough these days?  Should Human Subjects Committees start introducing that idea?  After all the neurological side effects were treated with a medication.  What about the metabolic side effects?

The bottom line for me is that there is no reason for prescribing first generation antipsychotics, unless a person has been stable on them for years and is not experiencing side effects.  Comparisons for academic purposes are interesting, but they lead to misinterpretations by both the media and managed care entities.  Psychopharmacology trials remain fairly primitive and they are a blunt instrument compared with clinical experience dealing with the neurological side effects of first generation antipsychotics.

George Dawson, MD, DFAPA

1:  Goff DC. Maintenance Treatment With Long-Acting Injectable Antipsychotics: Comparing Old With New. JAMA. 2014;311(19):1973-1974. doi:10.1001/jama.2014.4311

2:  Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209-23. Epub 2005 Sep 19. Erratum in: N Engl J Med. 2010 Sep 9;363(11):1092-3. PubMed PMID: 16172203.

3:  McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.4310.

4: Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999 Apr;122 ( Pt 4):593-624. Review. PubMed PMID: 10219775.

5:  Iritani S. Neuropathology of schizophrenia: a mini review. Neuropathology  2007 Dec;27(6):604-8. Review. PubMed PMID: 18021384.

Supplementary 1:  I had an interesting thought about when the anecdotal becomes the statistical.  I would say - probably when you have personally treated thousands of patients more than are in any clinical trial you are reading about - across multiple settings.  At that point, your clinical experience and the conclusions that you draw from it are probably more valid than PANNS, extrapyramidal side effects and CGI ratings.


  1. I know this article focused on antipsychotics, but I wondered about your take on experience with antidepressant augmentation.

    Some of the studies on L-methyl-folate I find deeply flawed because of the use of the PHQ-9 which is a joke for research. However, in practice I find that it works very well at the 15 mg for partial responders and for the overweight/obese depressed. Conceding limited sample size, anecdotal, all of that.

    The good news is that it's incredibly safe, the bad news is the cost.

  2. I did some extensive research on L-methylfolate some years ago for a colleague. If I can find that e-mail I will post it later. I seem to recall that the purported genotypes supporting this approach were rare and that made me a skeptic of the research at the time. That said, I have had people tell me that they tried all sorts of augmentation strategies on their own with good to great results. The most unusual was 5 Hour Energy drinks that totally eradicated low energy and depression at the same time (just 1-2 drinks per day). My preferred strategy has been buspirone and I think that works pretty well. I have consulted on a lot of people using aripiprazole including some who clearly developed TD from it. I use it only in special circumstances.

    Maybe a good study would be L-methylfolate versus buspirone as augmentation?

  3. My experience is similar to that of Stahl...I like everything about Buspar except efficacy.

    I almost never use antipsychotics for this purpose.

    In the last couple years LMTF has expanded beyond MTHFR polymorphism into waist size as a biomarker. I think there is an article on this by a research from Alabama Birmingham on this.

  4. I make my own antidepressants at home. Have you looked into the components of 5 hr energy? I think it may be the tyrosine that has worked for some where caffeine alone didn't work.

    Also, have you ever not augmented an antidepressant and instead replaced it?

  5. I looked into the 5 Hour Energy and concluded it was a placebo - except for the caffeine which would not be sustained.

    Most of what I do these days is stop or replace antidepressants, typically for either the wrong diagnosis and side effects. There are a significant number of people who do not tolerate SSRIs and should not take them. I use the augmentation only if the antidepressant is well tolerated (no detectable side effects) and there is evidence of some partial response.

    1. I hate to switch meds unless its bothersome side effects. Two months, costs, and dropout problems. I'll at least give LMTF a shot before doing that. Here's another link in the form of summary article:

  6. Oh, and one other area where new is better: sleepers, specifically Lunesta which is now off patent (not a fan of Ambien). However, i don't get the FDAs latest recc on dosage, which is ridiculously low in my experience.

    The UAB researcher is Shelton. Here's one of his newer articles on LMTF and biomarkers (subs req).

  7. What about the weight gain, and diabetes, associated with the second generation anti-psychotics?

    I remember hearing a podcast where Robin Murray (a British psychiatrist) commenting that even though Tardive Dyskinesia is associated with the first generation antipsychotics, second generation ones are associated with significant weight gain, increase in blood cholesterol, triglyercide levels, etc. And the important thing to note is a lot of patients with schizophrenia live sedentary lifestyles, which can be attributed to negative affect, just counselling them on how to avoid weight gain (when we know that anhedonia, avolition, etc.) could very well prevent these patients from exercising. Likewise, studies in Canada show that, due to the excess weight gain caused by second generation antipsychotics (and combine that with the sedentary lifestyle most patients with schizophrenia have....) Also, the drugs themselves cause raised glucose, triglycerides and cholesterol by themselves, in fact one of Olazapine's potential side effects is glucose in urine, due to the hyperglycemia, and again, I think you too are aware in your practice (and the many other psychiatrists note) patients with schizophrenia tend to live more sedentary lifestyles. I think just educating them on the risks of weight gain won't do too much because, again, negative affect, and there is no real proven treatment for that (yet) is there?

    Also, clozapine isn't prescribed as a first line treatment, in fact I recall that the reason why it only is used in treatment resistant schizophrenia is because of the chance of agranulocytosis, and the economic cost for the monitoring to make sure that does not happen.

    In fact, I remember clozapine was initially rejected because of the high rate of death, it wasn't only until investigators observed its effects in the treatment resistant population that it was *cautiously* used again.That is why it is not used as front line treatment.

    Also the CATIE study was not the first study to show that the first generation antipsychotics were on par with the second generation antipsychotics, it was the CUTLASS study done in the UK, where clozapine was judged to be the only superior second generation antipsychotic, but with the risk of agranulocytosis, it is a drug of last resort ( real term by the way).

    In fact, here in Canada, we only prescribe clozapine if (at least) two other antipsychotics have failed,and why it is only used for treatment resistant cases.
    Also, the CATIE study wasn't the first one that demonstrated second generation antipsychotics were not superior to the first generation ones, it was the CUTLASS study done in the UK where only clozapine was judged to be superior out of the second generation bunch. And again, the British too view it as a drug of last resort.

    I say there is no clinical justification to view the second generation antipsychotics (aside from clozapine) as more effective than first generation antipsychotics, and coincidentally the non drug company funded studies (such as CATIE and CUTLASS) showing no significant advantage between first and second generation antipsychotics, whereas (purely coincidental) it's the drug companies' studies that show the "superior" advantages of *their* drugs means psychiatrists should take a more personalized approach to the treatment of our patients.

    Also, SGAs such as haloperidol are associated with inducing mania. Again, personalized approaches to patients, I'm sure some patients benefit more from SGAs than FGAs, but the opposite is true as well. Which is why the British don't prescribes SGAs: FGAs in 9:1 ratios like the Americans, but more of a 50/50 (if I recall correctly) and I think their CUTLASS study, along with America's subsequent CATIE study, support their claims.

    1. Haloperidol is an FGA. Clozapine was the original SGA.

      The only thing that matters in clinical practice is the outcomes of individual practitioners. There is no clinical trial that predicts that and as I have pointed out the CATIE technology is incredibly crude. The ratio of prescribing FGAs and SGAs is fairly meaningless.

      Prescribing SGAs does require a lot more effort on the part of the psychiatrist and close monitoring and intervention to prevent weight gain. Apart from the biases that is about all the CATIE study meant to me.

  8. And a lot of the psychiatrists do notice a lot more obese schizophrenics in the psychiatric wards than when the FGAs were around, I side with NIH and the UK's CUTLASS study, SGAs, though less associated with extra pyramidal symptoms, the weight gain is significant and, overall, that FGAs are on par with the SGAs.

    And I agree with the NIH statement that " (the CATIE study) will provide valuable information to help physicians and patients choose the most appropriate medication for them" and the added negative effects--again diabetes and obesity, compensates for the slight advantages that the SGAs deliver.

    So, in summary, I think there is no real reason for your belief that the SGAs should be more prescribed than the FGAs, they are, at the very least, roughly equivalent and a *personalized* approach (what treatment is best for the *individual* patient , FGA or SGA) must be taken.

    And I recall that one of the psychiatrists who was involved with the CUTLASS study (that preceded America's CATIE study) looked forward to "Americans eating their own words" when CATIE's results were published. And eat their own words many American psychiatrists did, I remember reading some go as far as saying that the perceived advantages of the SGAs were just a result of drug companies marketing their products. Also, CATIE was , if I recall correctly, the largest follow up study that was *not* funded by the drug companies, and combine that with the consistent findings the similar (long term) follow up study the British conducted( CUTLASS), I saw there is little evidence supporting your claims that there is more reason to prescribe SGAs more commonly than the first generation ones.

    And I conclude with saying that, from my experience, that your opinion that the CATIE studies (and the CUTLASS study you failed to mention) are no reason to view Second generation antipsychotics as inherently superior is a minority view, even in America (the land of the drug company funded studies).

    1. Obviously I disagree. If you read through my post - you can see the biases in the CATIE study and they are significant. The other issue with the CATIE study was time to drug discontinuation as the primary outcome measure. If anything it proves how crude clinical trials are. I guess if my goals was to treat people for 18 months it might apply. If you have treated as many people with disabling movement disorders as I have and you know how to manage metabolic side effects that is a reason to prescribe SGAs first. The other clinical issue is that most patients prefer olanzapine over other antipsychotics and that was probably why it was the "most effective" int he CATIE study.

      Your quote of the British psychiatrist saying that the Americans would eat their own words seems strangely biased to me. The goal here is patient care not some kind of political argument. If you feel strongly about first generation antipsychotics - feel free to use them as first line agents. Just have a movement disorder specialist that you can refer patients to who predictably develop tardive dyskinesia and other movement disorders.

  9. I have a question about these drugs.

    What happens to patients today who have been made sick by anti-psychotics, specifically in the case of "dopamine super-sensitivity psychosis"?

    In the past, persistent drug-induced psychosis was usually treated with dangerous doses of the same drugs that caused it, or ablative treatments. Is this still the case today?

  10. I think that there is scant evidence that supersensitivity psychosis occurs. The diagnostic criteria for this disorder are so vague that they could basically include anybody with increased symptoms and a movement disorder. In many of the studies of this phenomenon - low to moderate doses of antipsychotics are used. The only condition I have seen that resembles a supersensitivity psychosis is a person with a severe movement disorder typically from first generation antipsychotics who also has psychotic symptoms. In that case the dose of the medication is not necessarily the factor that leads to problems it is probably the genetics of the person taking the medication.

    That is the message of this post - it is currently possible to determine who is sensitive on a clinical basis by a person who knows what to look for. There is no one size fits all approach and people have to be carefully monitored for the first signs of toxicity. With regard to CNS effects - second generation drugs are less toxic.

  11. I would disagree that the newer drugs are necessarily less toxic. They do after-all have the same mechanism of action to produce sedation as the old. Some of the anti-psychotic side effects appear to be unique to blocking dopamine, such as brain volume reduction. There are about 13 'placebo' controlled studies on brain shrinkage with anti-psychotics drugs published. Their quality is higher then those without placebo groups (maybe, some used automated voxel imaging). Interestingly, none found brain volume changes in untreated schizophrenics.

    But, would it not make more sense to just introduce routine MRI scans every so many months? Brain shrinkage is very significant with these drugs, and that would provide a means to falsify an anecdotal observation concerning neurotoxicity. Then again, I'm aware the APA is trying to sell brain shrinkage as 'schizophrenia' itself... I guess there's a reason these tests have not been made available for this purpose in the first place, possibly the same reason placebo groups are not included in studies like CATIE.

    None the less, I'm not sure how "knowing what to look for" could be realistically applied to many physicians who clearly do not and probably never will either. Maybe there's no solution?

    I mean, since the FDA refuses to take these drugs off the market in the first place.

    Happy independence day, btw

    1. Well I guess you would be wrong then Clark.

      Ionnadides paper on most published research being false clearly applies to practically all research studies involving brain volumes in psychiatric disorders and they go back at least 30 years. And keep in mind that I am not somebody who just reads about it in the papers. For those 30 years I actually went down and looked at all of the brain scans I ordered and did the measurements. I think what most people fail to realize is that differences are subtle and that schizophrenia is a very heterogenous disorder. I am not aware of any brain volume studies stratified on endophenotypes, but I can easily find out.

      As far as your remark about unmedicated schizophrenia goes, there are many neuropathological studies from before the time of medications and there are many studies that disagree with your statement. I reference one at the end here. Serial MRI scans looking a volumetric analysis would produce what you expect them to. A percentage of people with "cortical atrophy"and everyone else with normal scans. If you talk with any neuroradiologist (as I have) they will tell you it is a nonspecific finding. That is the reason the studies were not included in CATIE (at least in addition to the fact that the researchers did not seem capable of keeping anyone in the study to image them a second time) and why they are not done clinically.

      As far as the APA "selling" some idea about medications - you have not been paying attention. They don't seem to be able to sell the idea that it might be reasonable to increase psychiatric services. Selling an idea about medications is not even on their agenda.

      Harrison PJ. The neuropathology of schizophrenia. A critical review of the
      data and their interpretation. Brain. 1999 Apr;122 ( Pt 4):593-624. Review.
      PubMed PMID: 10219775.

  12. I suppose it's possible that that was Dr. Lieberman's agenda alone, and i confused it with the organization he was president of. He has been very active to promote "early innervation and prevention" of a schizophrenia for decades.

    Thank you for the link, I have actually read that paper.
    Here was a paper I was referring to, reviewing 13 more recent voxel MRI studies to compare FGAs and SGAs:

    It was published in a chemistry journal called "Current Medical Chemistry" in the Netherlands. The full paper is available for free. There is a minor conflict of interest declared; Eli-Lilly has an anti-psychotic called Zyprexa on the market.