I think it’s a very intriguing idea to try to ban haloperidol, as Dr. Henry Nasrallah, MD, suggests in his editorial in Current Psychiatry (Nasrallah, H. A., MD (2013). “Haloperidol clearly is neurotoxic. Should it be banned?” Current Psychiatry 12(7): 7-8. Why use an old and harmful antipsychotic when safer alternatives are available? Clicking the on line version link may elicit a warning by some antivirus programs that the site “contains a known threat” and will be blocked). You can view it without scary messages on the iPad app for Current Psychiatry.
He’s even started a poll about it: ban Haldol or not? My suggested alternative poll is above, but read the rest of the post before you vote. I don’t doubt that there are a number of studies showing that haloperidol is neurotoxic . My colleagues here have published about the issue. On the other hand, though I didn’t go through Dr. Nasrallah’s reference list exhaustively, I found one study that seemed to show that haloperidol is actually neuroprotective and another that showed paliperidone was protective compared to haloperidol which was obviously supported by Janssen–the maker of paliperidone [2, 3].
I couldn’t find much on a quick scan of the literature on the issue, but I found one interesting paper which indicated that haloperidol was implicated in potentiating neurotoxicity by elevating extracellular glutamate . This paper was the only one I could find right away about the clinical relevance of this issue to delirium in the critical care unit–where injectable haloperidol is still used relatively frequently. It’s not used in the high doses the authors suggest these days–at least not where I work. The multicenter feasibility study comparing haloperidol, ziprasidone, and placebo showed that both antipsychotics had similar tolerability but neither were helpful in delirium . Our hospital is part of the larger study now, The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study – Full Text View – ClinicalTrials.gov.
I don’t know if there are any studies showing that haloperidol is as neurotoxic when used in the short-term for controlling agitation of delirium as it may be over the long term in patients with schizophrenia.
I think it’s pretty well established that delirium itself is neurotoxic, http://americandeliriumsociety.org/About_Delirium.html , icudelirium.org outcomes and videos of cognitive impairment . And in the intensive care unit (ICU), intravenous haloperidol is quick and easy to administer when trying to calm delirious patients who are busy ripping out their arterial lines and endotracheal tubes. It would be logistically more challenging to try giving intramuscular injections of olanzapine, though arguably less neurotoxic.
You can try voting on Dr. Nasrallah’s on-line poll about banning haloperidol, but you’ll have to decide, depending on your antivirus software, whether you want to block or allow navigation to the site. How about voting on the alternative poll above which asks the question in a different way?
1. Mitchell, I. J., A. C. Cooper, et al. (2002). “Acute administration of haloperidol induces apoptosis of neurones in the striatum and substantia nigra in the rat.” Neuroscience 109(1): 89-99.
Chronic administration of typical neuroleptics is associated with tardive dyskinesia in some patients. This dyskinetic syndrome has been associated with loss of GABAergic markers in the basal ganglia but the cause of these GABAergic depletions remains uncertain. Haloperidol, a commonly prescribed typical neuroleptic, is known to be toxic in vitro, possibly as a consequence of its conversion to pyridinium-based metabolites and potentially by raising glutamate-mediated transmission. We report here that the in vivo, acute administration of a large dose of haloperidol resulted in a microglial response indicative of neuronal damage. This was accompanied by an increase in the number of apoptotic cells in the striatum (especially in the dorsomedial caudate putamen) and in the substantia nigra pars reticulata. These apoptotic cells were characterised by the stereotaxic injection of a retrograde neuroanatomical tracer into the projection targets of the striatum and substantia nigra pars reticulata prior to the systemic injection of haloperidol. This procedure confirmed that the dying cells were neurones and demonstrated that within the striatum the majority were striatopallidal neurones though relatively high levels of apoptotic striatoentopeduncular neurones were also seen. The possibility that chronic administration of haloperidol could induce cumulative neuronal loss in the substantia nigra pars reticulata and thereby induce the pathological changes which lead to tardive dyskinesia is discussed.
2. Keilhoff, G., G. Grecksch, et al. (2010). “Risperidone and haloperidol promote survival of stem cells in the rat hippocampus.” Eur Arch Psychiatry Clin Neurosci 260(2): 151-162.
Altered neuroplasticity contributes to the pathophysiology of schizophrenia. However, the idea that antipsychotics may act, at least in part, by normalizing neurogenesis has not been consistently supported. Our study seeks to determine whether hippocampal cell proliferation is altered in adult rats pretreated with ketamine, a validated model of schizophrenia, and whether chronic administration with neuroleptic drugs (haloperidol and risperidone) affect changes of cell genesis/survival. Ketamine per se has no effect on cell proliferation. Its withdrawal, however, significantly induced cell proliferation/survival in the hippocampus. Risperidone and haloperidol supported cell genesis/survival as well. During ketamine withdrawal, however, their application did not affect cell proliferation/survival additionally. TUNEL staining indicated a cell-protective potency of both neuroleptics with respect to a ketamine-induced cell death. As RT-PCR and Western blot revealed that the treatment effects of risperidone and haloperidol seemed to be mediated through activation of VEGF and MMP2. The mRNA expression of NGF, BDNF, and NT3 was unaffected. From the respective receptors, only TrkA was enhanced when ketamine withdrawal was combined with risperidone or haloperidol. Risperidone also induced BCL-2. Ketamine withdrawal has no effect on the expression of VEGF, MMP2, or BCL-2. It activated the expression of BDNF. This effect was normalized by risperidone or haloperidol. The findings indicate a promoting effect of risperidone and haloperidol on survival of young neurons in the hippocampus by enhancing the expression of the anti-apoptotic protein BCL-2 and by activation of VEGF/MMP2, whereby an interference with ketamine and thus a priority role of the NMDA system was not evident. CONTRADICTS HYPOTHESIS THAT HALDOL IS NEUROTOXIC.
3. Gassó, P., S. Mas, et al. (2012). “Neurotoxic/neuroprotective activity of haloperidol, risperidone and paliperidone in neuroblastoma cells.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 36(1): 71-77.
The neurotoxicity of antipsychotic (AP) drugs seems to be linked with neurological side effects like extrapyramidal symptoms (EPS). On the other hand, neuroprotective effects can mitigate or slow the progressive degenerative structural changes in the brain leading to improved outcome of schizophrenia. First and second-generation antipsychotics may differ in their neurotoxic and neuroprotective properties. The aim of this study was to compare the neurotoxic/neuroprotective activity of haloperidol, a first-generation antipsychotic, and risperidone, a second-generation one, with paliperidone, a relatively new second-generation antipsychotic, in SK-N-SH cells. Haloperidol, risperidone and paliperidone (10, 50, 100 μM) were administered, either alone or in combination with dopamine (100 μM), to human neuroblastoma SK-N-SH. We examined the effects of the drugs on cell viability (measured by alamarBlue®), caspase-3 activity (measured by fluorimetric assay) and cell death (by measuring the externalization of phosphatidylserine). Haloperidol significantly decreased cell viability and increased caspase-3 activity and cell death. Risperidone and paliperidone did not affect cell viability or cell death. Both second-generation APs decreased caspase-3 activity, especially paliperidone. In cells treated with dopamine in combination with antipsychotics, only paliperidone (10 μM) induced a slight improvement in cell viability. While haloperidol potentiated the dopamine-induced increase in caspase-3 activity, risperidone and paliperidone reduced this effect. The results indicate that haloperidol induces apoptosis, whereas risperidone and paliperidone may afford protection against it. Of the APs tested, paliperidone always showed the strongest neuroprotective effect. The different antipsychotic effects on survival and cell death might be related to differences in their capacity to induce EPS. STUDY SUPPORTED BY JANSSEN, MANUFACTURER OF PALIPERIDONE
4. Isom, A. M., G. A. Gudelsky, et al. (2013). “Antipsychotic medications, glutamate, and cell death: A hidden, but common medication side effect?” Medical Hypotheses 80(3): 252-258.
We hypothesize the interaction between antipsychotic medications and regulation of extracellular glutamate which has gone largely unnoticed in the medical community has significant clinical importance. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate because they exert antagonist effects on dopamine D2 and serotonin 5HT1A receptors. In contrast, serotonin 5HT2A receptor antagonists inhibit glutamate release. Glutamate is potentially excitotoxic through effects on ionotropic receptor channels and may exert synergistic effects with other neurotoxic pathways. In contrast to typical antipsychotic drugs, pharmacological properties of atypical antipsychotic medications at dopamine D2, serotonin 5HT1A and 5HT2A receptors limit extracellular glutamate and may theoretically be neuroprotective in certain clinical settings. In this review we discuss three common clinical settings in which typical antipsychotic medications may potentiate neurotoxicity by elevating extracellular glutamate. The most common clinical setting, hypoglycemia during combined use of antipsychotic medications and insulin, presents a theoretical risk for 35 million diabetic patients worldwide using antipsychotic medications. Antipsychotic medication treatment during hypoxic episodes in the intensive care unit and following traumatic brain injury are two other common clinical settings in which this interaction poses theoretical risk. Further study is needed to test hypothesized risk mechanisms, and determine clinical and epidemiological consequences of these exposures.
5. Girard, T. D., P. P. Pandharipande, et al. (2010). “Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial.” Crit Care Med 38(2): 428-437.
OBJECTIVE: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six tertiary care medical centers in the US. PATIENTS: One hundred one mechanically ventilated medical and surgical intensive care unit patients. INTERVENTION: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects. MEASUREMENTS AND MAIN OUTCOMES: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46). CONCLUSIONS: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.
6. Jones, S. F. and M. A. Pisani (2012). “ICU delirium: an update.” Curr Opin Crit Care 18(2): 146-151.
PURPOSE OF REVIEW: Delirium is frequently encountered in the ICU and is associated with significant adverse outcomes. The increasingly recognized consequences of ICU delirium should enhance efforts to improve recognition and management of this serious problem. We aim to review the recent literature on ICU delirium, including risk factors, detection, management and long-term impact of disease. RECENT FINDINGS: We present the most recent evidence on risk factors for ICU delirium and its persistence. In addition, we aim to clarify some of the confusion surrounding the tools for detection and their limitation in practice. The literature reflects long-term neurocognitive impairments following ICU delirium and supports efforts to reduce these negative outcomes using protocol-driven sedation and ventilator management. Although haloperidol is widely accepted as the preferred pharmacologic treatment for delirium, its use is not seeded in robust evidence. Limited studies reflect the safety of atypical antipsychotics for treatment but lack clear improvement in delirium-related outcomes. We place an emphasis on the use of protocols to reduce the use of sedatives, particularly benzodiazepines in the management of ICU delirium. SUMMARY: Delirium remains an underrecognized and underdiagnosed problem. Detection tools are readily available and easy to use. Further understanding of risk factors is needed to identify most susceptible individuals and plan management, which should include prevention and therapy based on available evidence.