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.