There’s an editorial by Henry Nasrallah, MD, in last month’s edition of Current Psychiatry. Dr. Nasrallah is the journal’s editor-in-chief. The title of the article is Haloperidol clearly is neurotoxic. Should it be banned? Haloperidol is marketed under the brand name Haldol, but its patent has long expired, and a generic version is available and inexpensive.
Here’s a quote from Dr. Nasrallah’s article:
“If clinicians who use these decades old drugs were to keep up with medical research and advances in knowledge, we would realize what a travesty it is to use a brain-unfriendly drug such as haloperidol when we have many safer alternatives. A massive volume of knowledge has emerged over the past 15 years about the neurotoxicity of older neuroleptics, especially haloperidol—knowledge that was completely unknown before. Second-generation antipsychotics have been shown to be much safer for the brain than their older-generation counterparts (although they are not more efficacious).”
When the second-generation drugs were launched in 1989, it was widely claimed by psychiatrists (who got their “info” from drug reps), that the severe neurological side effects of the older drugs (e.g. tardive dyskinesia, akathisia, etc.) did not occur with the newer products. After a few years of prescribing, however, it was clear that the neurological damage did occur with the newer drugs, and that there’s not much difference between old and new in terms of frequency or intensity of these effects. The CATIE study, for instance, found:
“There were no significant differences among the groups in the incidence of extrapyramidal side effects, akathisia, or movement disorders as reflected by rating scale measures of severity.”
Dr. Nasrallah, however, anticipates this objection with a footnote:
“The Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE] study did not include any neurotoxicity biomarkers to compare older and newer antipsychotic choices when it was designed in 1998, because the neurotoxic effects of the older generation were not yet known.”
This is psychiatric spin. Neurotoxicity biomarkers are not the only way to assess neurological damage. CATIE used three separate rating scales to assess for neurological effects: AIM global severity score (equal to or above 2); Barnes Akathisia Rating Scale (global score equal to or greater than 3); Simpson-Angus Extrapyramidal Signs Scale (equal to or above 1).
The message that Dr. Nasrallah is trying to promote is: don’t use haloperidol; use one of the newer neuroleptics. The CATIE findings pose a problem, so he uses the neurotoxicity biomarkers as a distraction to push CATIE to the sidelines.
Here’s another quote:
“Evidence for the grave neurotoxicity of haloperidol and other older neuroleptics, compared with atypical antipsychotics, is substantial and multifaceted.”
Dr. Nasrallah provides 28 references in support of the neurotoxicity of haloperidol and other first-generation neuroleptics. I don’t think anybody is arguing with him there.
But he provides only one reference to support his assertion that the newer products are free from this defect:
Nandra KS, Agius M. The difference between typical and atypical antipsychotics: the effects on neurogenesis. Psychiatria Danub. 2012;24(supp1): 95-99.
This study is a literature review, and cites several papers from the neuroscience field. But Nandra and Agius don’t just say that the newer drugs aren’t neurotoxic. They go a good deal further – they say, or at least suggest, that the second-generation neuroleptics are neuroprotective, and that they promote neurogenesis. In other words – the second-generation neuroleptics are not only not harmful to the brain, they are actually good for the brain; they promote the regeneration of neural tissue, and actually help repair the damage done by drugs like haloperidol.
Nandra and Agius cite three papers in support of the neuroprotective assertion.
Nasrallah HA, Hopkins T, Pixley SK. Differential effects of antipsychotic and antidepressant drugs on neurogenic regions in rats. Brain Res 2010; 1354:23-9. Epub 2010 Aug 1.
Parikh V, Khan MM, Terry A, Mahadik SP. Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats. J Psychiatr Res 2004; 38: 521-9.
Wakade CG, Mahadik SP, Waller JL, Chiu FC. Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 2002; 69:72-9.
All of these trials are rat studies, and their conclusions are stated rather guardedly.
Nasrallah et al:
“These results show that psychotropic drug-induced cell proliferation occurs in the OE [olfactory-epithelium] and parallels changes in the SVZ [subventricular zone] but not DG [dentate gyrus]. Thus, the peripheral OE can serve as a proxy for certain psychotropic drug-induced actions on SVZ brain cell proliferation. This olfactory model can be employed in human research as a method to explore the neurogenesis effects of various pharmacologic treatments of neuropsychiatric disorders.”
Parikh et al:
“The crossover data further suggest that certain atypical antipsychotic drugs (e.g., clozapine) may have the potential to prevent or reverse the deleterious effects of HAL [Haldol] on important neurochemical substrates of cognitive function.” (Emphasis added)
Wakade et al:
“Our results indicate that atypical neuroleptics have a mechanism of action other than the previously proposed mechanisms, which might explain their role in improved cognition in animal and in schizophrenic patients. If substantiated by future studies, our findings may lead to an expanded use of atypical neuroleptics in other neurodegenerative diseases to stimulate neuronal replacement and repair.” (Emphasis added)
Nevertheless, Dr. Nasrallah concludes his Current Psychiatry editorial by endorsing without reservations the neuroprotective hypothesis, with regards to the newer neuroleptics
“The risks of the drug [haloperidol] far exceed the benefits—especially given the availability of atypical antipsychotics that have been shown to exert neuroprotective properties, such as inducing neurogenesis and increasing neurotrophic factors. One of our foremost duties as medical professionals is to protect patients from harmful treatments that could exacerbate their disability. It’s time to retire this aging neuroleptic.”
Not everyone agrees that the newer drugs are easier on the brain. Joanna Moncrieff, a UK psychiatrist, in a 2011 article in the British Journal of Psychiatry (Questioning the ‘neuroprotective’ hypotheses: does drug treatment prevent brain damage in early psychosis or schizophrenia?) states:
“I argue that there is little evidence to support the view that old- or new-generation antipsychotics are ‘neuroprotective’, and some evidence that the drugs themselves may be responsible for the decline in brain matter observed in some studies.”
Similarly, Peluso et al, in Extrapyramidal motor side-effects of first-and second-generation antipsychotic drugs:
“The expected improvement in EPS profiles for participants randomised to second-generation drugs was not found; the prognosis over 1 year of those in the first-generation arm was no worse in these terms.”
(EPS stands for the extrapyramidal system. This is the system of neurons that enables us to exercise fine motor movements. Tardive dyskinesia results from drug-induced damage to the EPS.)
Keefe et al, working with the CATIE data and focusing on neurocogitive effects, found that the newer neuroleptics were no safer in this regard than perphenazine, an older neuroleptic that has been in use for decades.
The big question in all of this is: why is an eminent psychiatrist like Dr. Nasrallah calling for a ban on haloperidol and endorsing, without reservation, the neuroprotective claims for the newer drugs, even though this latter claim is, at the very least, still a matter for debate?
I don’t know the answer to this question, but here are some clues that may be relevant.
1. According to Dollars for Docs, Dr. Nasrallah received $897,079 from various pharmaceutical companies between 2009 and 2012. In fact, Dollars for Docs lists Dr. Nasrallah as the seventh highest earner in their list of Top Earners, doctors who received money for speaking and consulting for pharmaceutical companies.
2. Other members of Current Psychiatry’s editorial staff also received substantial sums of money from pharmaceutical companies (Also per Pro Publica’s Dollars for Docs):
$169,324 Joseph Goldberg MD, Deputy Editor, 2009-12
$17,303 Robert A. Kowatch MD, PhD, Section Editor, 2010
$80,178 George Grossberg MD, Section Editor, 2010-12
$298,738 Sheldon Preskorn MD, PhD, Section Editor, 2009-12
$401,278 Robert Anthenelli MD, Section Editor, 2009-12
$46,423 Dale D’Mello,MD, Dept. Editor, 2010-11
$394,376 Leslie Lundt MD, Dept. Editor, 2009-12
$134,037 Robert McCarron DO, Section Editor, 2009-12
3. Current Psychiatry carries advertizing from pharmaceutical companies. They charge $7,200 for a 4-color, full page, single run ad. In the issue in question, (July 2013), there is an ad for Abilify above the table of contents. Abilify (aripiprazole) is a second-generation neuroleptic.
4. A 30-day supply of haloperidol tablets (5 mg per day) costs about $4. A 30-day supply of aripiprazole tablets (10mg per day) costs about $1424. [GoodRx]
Could it be – could it possibly be – that the real problem with haloperidol is not its neurotoxicity (which apparently didn’t bother Dr. Nasrallah too much in the old days), but rather its price? It’s too cheap! Every time a psychiatrist writes a prescription for haloperidol, it’s $1420 down the drain.
But I’m sure that an eminent psychiatrist like Dr. Nasrallah wouldn’t be swayed by such tawdry considerations. It is noteworthy, however, that he has received “consulting fees” from Lundbeck, the manufacturer of aripiprazole (Abilify).
At the bottom of Current Psychiatry’s masthead it says:
“Published through an educational partnership with University of Cincinnati.”
To which I can only say: if this is education, I’d hate to see propaganda.
The purpose of this post is to draw attention to conflicts of interest in this matter. I am not defending haloperidol. In my view, all neuroleptics – old and new – are neurotoxic.
Incidentally, Sandra Steingard, MD, has also written a post, (Haloperidol is Neurotoxic) on Dr. Nasrallah’s article. It’s on Mad in America. There is some overlap between our two articles, though Dr. Steingard raises some issues that hadn’t occurred to me, and her post is well worth reading.