From the Editor Haloperidol clearly is neurotoxic. Should it be banned? Why use an old and harmful anti- of knowledge has emerged over the psychotic when safer alternatives past 15 years about the neurotoxicity of are available? older neuroleptics, especially haloperi- dol—knowledge that was completely Few medications remain in use 50 years unknown before.a Second-generation after they were launched. Advances in antipsychotics have been shown Henry A. Nasrallah, MD drug development often render older to be much safer for the brain than Editor-in-Chief drugs obsolete because newer drugs their older-generation counterparts are more efficacious or safer, or both. (although they are not more efficacious). Consider reserpine: Nowadays, no internist would use this drug to treat Changing awareness and hypertension, even though it was the changing practice top-selling antihypertensive 50 years I used haloperidol for 20 years, and can Second-generation ago. Why? The adverse effects profile is vouch for its unquestionable efficacy in antipsychotics have no longer acceptable, with safer alterna- treating delusions and hallucinations. tives available. But I have avoided using it over the past been shown to be Astonishingly, almost all first-genera- 15 years, as the neuroscience literature much safer for the tion psychotropics discovered 5 decades about its harmful effects on brain tissue ago (neuroleptics, tricyclic antidepres- emerged and multiplied. brain than their sants, monoamine oxidase inhibitors) In addition, I came to realize that older-generation are still on the formularies of most health most psychiatric practitioners were un- counterparts care facilities and are used by many cli- aware of the alarming deleterious neu- nicians, especially those working with rologic effects of haloperidol—largely managed care organizations. Jails and because the studies that reported those prisons in the United States, where hun- effects were published in neuroscience dreds of thousands of seriously men- journals rarely read by practicing psy- tally ill patients are incarcerated, also chiatrists and nurse practitioners, and use 50-year-old agents, without regard the pharmacists in charge of drug for- to the downside of older drugs on the mularies at hospitals. body, brain, and quality of life of those Evidence for the grave neurotoxicity incarcerated medically ill patients. of haloperidol and other older neuro- If clinicians who use these decades- leptics, compared with atypical antipsy- old drugs were to keep up with medical chotics, is substantial and multifaceted. To comment on this editorial research and advances in knowledge, or other topics of interest, aThe Clinical Antipsychotic Trials of Intervention visit www.facebook.com/ we would realize what a travesty it is Effectiveness study did not include any neurotoxicity to use a brain-unfriendly drug such biomarkers to compare older and newer antipsychotic CurrentPsychiatry, or go to choices when it was designed in 1998, because the CurrentPsychiatry.com and click on as haloperidol when we have many neurotoxic effects of the older generation were not yet the “Send Letters” link. safer alternatives. A massive volume known. continued Current Psychiatry Vol. 12, No. 7 7 Table Psychiatric Association2; a manuscript will soon be submitted for publication. Editorial Staff Molecular mechanisms of [Note: A list of the 28 published studies EDITOR John Baranowski haloperidol neurotoxicity is appended to the online version of this MANAGING EDITOR Erica Vonderheid Increase in intracellular calcium Editorial, at CurrentPsychiatry.com.] ASSOCIATE EDITOR Hina Khaliq Cytochrome c release The molecular mechanisms of neu- Art & Production Staff Increase in reactive oxygen species (free rotoxicity of older-generation antipsy- radicals) CREATIVE DIRECTOR Mary Ellen Niatas chotics, including haloperidol, fall into Decrease in the anti-oxidant glutathione ART DIRECTOR Pat Fopma several major categories: Sigma 2-receptor agonism DIRECTOR, JOURNAL MANUFACTURING • apoptosis Michael Wendt Apoptosis-inducing factor • necrosis PRODUCTION MANAGER Donna Pituras Akt (protein kinase B) inhibition • decreased cell viability Decrease in brain-derived neurotrophic Publishing Staff • inhibition of cell growth factor PUBLISHER Sharon J. Spector • increased caspase activity (the Increase in metalloproteinase inhibitor MARKETPLACE ACCOUNT MANAGER (associated with apoptosis) “death spiral”) Linda Wilson • impaired glutamate transport DIRECTOR OF NEW MEDIA Amy Park Increased Jun kinase (a protein kinase that mediates cell death) • mitochondrial damage. CONFERENCE MARKETING MANAGER Kathy Wenzler Increase in T-BOX (a transcription factor) Examples of specific mechanisms of Subscription Services: (800) 480-4851 Decrease in anti-apoptotic protein BcL-2 neurotoxicity among older-generation Increase in P53 (activates apoptosis) and antipsychotics appear in the Table. Editor-in-Chief Emeritus increased poly(ADP-ribose) polymerase With this massive evidence of the James Randolph Hillard, MD (PARP) cleavage (by caspase during serious neurotoxic effects of haloperi- apoptosis) Quadrant HealthCom Inc. dol, should it be banned? The risks Decrease in -catenin (regulates cell PRESIDENT AND CEO Marcy Holeton β growth) of the drug far exceed the benefits— EDITORIAL DIRECTOR John Baranowski Decrease in GSK-3beta phosphorylation especially given the availability of 9 VICE PRESIDENT, MULTICHANNEL CUSTOM SOLUTIONS Margo Ullmann atypical antipsychotics that have been VICE PRESIDENT, EVENTS David Small shown to exert neuroprotective prop- The FDA would never approve haloper- erties, such as inducing neurogenesis Frontline Medical Communications idol today, given the serious harm it can and increasing neurotrophic factors.3 CHAIRMAN Stephen Stoneburn do to the brain, despite its efficacy for One of our foremost duties as medi- CFO Douglas E. Grose PRESIDENT, CUSTOM SOLUTIONS psychosis. (It’s interesting how the FDA cal professionals is to protect patients JoAnn Wahl bans a drug immediately if it causes from harmful treatments that could VICE PRESIDENT, CUSTOM PROGRAMS tragic birth defects, such as thalidomide, exacerbate their disability. It’s time to Carol J. Nathan but not if a drug is destructive to the retire this aging neuroleptic. CORPORATE CIRCULATION DIRECTOR Donna Sickles brain tissue of a disabled adult patient. Do you agree? Follow the link CORPORATE DIRECTOR, MARKETING Invisible damage can be less alarming or to “Send Letters” and vote “Yes” or & RESEARCH urgent than visible damage.) “No,”on CurrentPsychiatry.com. Lori Raskin Twenty-eight studies reporting the various destructive effects of older antipsychotics (especially haloperidol) on brain tissue have been published Henry A. Nasrallah, MD 7 Century Drive, Suite 302 in prominent neuroscience journals, Editor-In-Chief Parsippany, NJ 07054 Tel: (973) 206-3434 based on work in animal models, cell References Fax: (973) 206-9378 culture, and post-mortem human tis- 1. Nasrallah HA, Rush SJ. First generation antipsychotics www.qhc.com are neurotoxic and impair neuroplasticity via sue. Multiple molecular mechanisms, multiple mechanisms. Biol Psychiatry. 2013;73:61S. pathways, and cascades are involved, 2. Rush SJ, Nasrallah HA. Neurotoxic effects of the Published through older antipsychotics: a review of several molecular an educational eventuating in neuronal death. The mechanisms of action. Paper presented at: American partnership with first review and discussion of these 28 Psychiatric Association Annual Meeting; May 18-22, 2013; San Francisco, CA. neurotoxicity studies was presented at 3. Nandra KS, Agius M. The difference between the annual meetings of the Society of typical and atypical antipsychotics: the effects on neurogenesis. Psychiatria Danub. 2012;24(supp1): Biological Psychiatry1 and the American 95-99. Current Psychiatry 8 July 2013 Bibliography 28 studies have reported the destructive effects of older antipsychotics on brain tissue Abekawa T, Ito K, Nakagawa S, et al. Effects of aripiprazole and haloperidol on progression to schizophrenia- like behavioural abnormalities and apoptosis in rodents. Schizophr Res. 2011;125(1):77-87. Brent PJ, Pang G, Little G, et al. The sigma receptor ligand, reduced haloperidol, induces apoptosis and increases intracellular-free calcium levels [Ca2+]i in colon and mammary adenocarcinoma cells. Biochem Biophys Res Commun. 1996;219(1):219-226. Crawford KW, Bowen WD. Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res. 2002;62(1):313-322. Dai Y, Wei Z, Sephton CF, et al. Haloperidol induces the nuclear translocation of phosphatidylinositol 3’-kinase to disrupt Akt phosphorylation in PC12 cells. J Psychiatry Neurosci. 2007;32(2):323-330. De Souza IE, McBean GJ, Meredith GE. Chronic haloperidol treatment impairs glutamate transport in the rat striatum. Eur J Pharmacol. 1999;382(2):139-142. Galili R, Mosberg, Gil-Ad I, et al. Haloperidol-induced neurotoxicity-possible implications for tardive dyskinesia. J Neural Transm. 2000;107(4):479-490. Gama CS, Salvador M, Andreazza AC, et al. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in schizophrenia: a study of patients treated with haloperidol or clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):512-515. Gassó P, Mas S, Molina O, et al. Neurotoxic/neuroprotective activity of haloperidol, risperidone and paliperidone in neuroblastoma cells. Prog Neuropsychopharmacol Biol