Schizophrenia is known to affect over 2 million adults in America and over 300,000 adults in Canada.(1,2)  The life-time prevalence of schizophrenia in the United States has been estimated to be 0.2% - 1.5%.(3,4)  The DSM diagnostic manual presents schizophrenia as a major psychiatric disorder commonly associated with a various combination of symptoms that are categorized into being either positive, negative or disorganized symptoms.(3)  Positive symptoms include hallucinations and delusions, whereas negative symptoms include having a flat affect (no emotional expression), alogia (reduced thought and speech productivity), and avolition (decreased initiation of goal directed behavior).  Disorganized symptoms include disorganized speech, behavior, and poor attention.(3)  The approach to treatment of this disorder has historically centered around the modulation of the dopaminergic and serotonergic pathways in the central nervous system.(4)  In particular, it is known that the selective inhibition of the nigrostriatal dopamine pathways by conventional (or typical) antipsychotics (chlorpromazine, fluphenazine, haloperidol, and thioridazine) can improve the positive symptoms associated with schizophrenia.(5)   Unfortunately, conventional (or typical) antipsychotics are also known to cause a hyperkinetic movement disorder called tardive dyskinesia (TD), especially with long-term use.(5,6)

What is TD and how prevalent is it?

• Tardive dyskinesia is characterized by involuntary and repetitive movement of the face, tongue and extremities in a choreiform motion.6 
  
• In patients maintained on conventional antipsychotics, about 5% will develop TD for every year while on therapy.  This means that after only 5 years of treatment, approximately 25% of patients will develop TD, which can be irreversible.(5) 
  
• This is the main reason why the use of atypical antipsychotics such as aripiprazole, olanzapine, paliperidone, risperidone, and ziprasidone are now considered first line therapy.(7)  These agents not only inhibit dopamine receptors, but can also modulate the serotonergic system as well and have been associated with less incidence in TD. 

What is the mechanism or cause of TD?

• The exact mechanism by which conventional antipsychotics result in the development of TD is not fully known, but one finding commonly reported is the increase in the number and the affinity of antipsychotics that are selective inhibitors dopamine-2 (D2) receptors.(5,8)  In addition, patients with a genetic polymorphism to the dopamine D3 receptor gene (DRD3) may further increase the susceptibility to TD.(9)  The influence one particular antipsychotic may have over another may also contribute to the risk.  In particular, the use of haloperidol may result in the formation of a neurotoxic metabolite that affects the dopaminergic function.(10-14)
• The basis of this later hypothesis comes from data on the potent and selective dopaminergic neurotoxicant N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is a byproduct formed when drug dealers or abusers synthesize the reverse ester of N-methyl-4-propionoxy-4-phenylpiperidine (MPPP; "designer heroin" or "synthetic heroin").(15)  This was determined when a 23 year old college student developed sudden Parkinson's like symptoms (bradykinesia, rigidity, and mutism) after he used illicit drugs that were later determined to have MPTP.   

Why is MPTP so neurotoxic?

• In the brain, MPTP is metabolized by monoamine oxidase (MAO)-B enzymes to form an unstable metabolite called MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium).(16-18) 
  
• This unstable MPDP+ is then metabolized to MPP+ where it will accumulate in transporters within the dopamine producing cells and dopamine nerve terminales of cells in the substantia nigra resulting in metabolic changes to dopamine and norepinephrine. 
  
• In addition, MPP+ will begin to bind to the neuromelanin in these same cells that disrupts mitochondrial respiration.  This disruption of mitochondrial respiration can result in neuronal cell death and has been implicated in the cause of idiopathic Parkinson's disease.(19) 
  
• Animal studies using a MAO-B inhibitor were able to prevent MPTP-induced parkinsonism thus helping to further validate this neurotoxic effect on cell bodies in the substantia nigra.(20,21)

What relationship does haloperidol have to MPTP and neurotoxicity?

• The microsomal-catalyzed dehydration of haloperidol results in the formation of HPTP (1,2,3,6-tetrahydropyridine) which is close to the analogue to MPTP just described above.(22)  In addition, HPTP is further oxidized to HPP+, similar to the oxidation of MPTP to MPP+.(22) 
  
• In rats, HPP+ has also been shown to be neurotoxic to both dopaminergic and serotonergic neurons.(10,12)  As it relates to TD, additional animal studies found that those treated chronically with HPTP developed orofacial dyskinesia and had histological evidence of neuronal cell toxicity.(11)  In addition, a study in humans suggested that increased ratios of blood HPP+:haloperidol concentrations was associated with the severity of parkinsonism and TD.(14)
• While more data is needed to fully elucidate the mechanism for TD, the above information about the neurotoxicity of the metabolites for both haloperidol and MPTP ("designer heroin") help to shed light on one component that maybe contributing.  Due to the improved efficacy and lower incidence of TD with atypical antipsychotics, they should be used first line in most patients.  When haloperidol is needed or used for certain patients, the risk for TD and neurotoxicity risk should be kept in mind with particular attention being paid towards the development of TD.

1. National Alliance of Mental Illness.  Schizophrenia.  February 2007.  Last accessed on 8/3/2009.  
   
2. Schizophrenia Society of Canada.  What is Schizophrenia?  An Information Guide.  Last accessed 8/3/2009.  
   
3. American Psychiatric Society.  Practice Guideline for the Treatment of Patients with Schizophrenia Second Edition.  Last accessed on 8/3/2009.  
   
4. Kendler KS, Gallagher TJ, Abelson JM et al.  Lifetime prevalence, demographic risk factors, and diagnostic validity of nonaffective psychosis as assessed in a US community sample.  The National Comorbidity Survey.  Arch Gen Psychiatry  1996;53:1022-31.  
   
5. Stahl SM.  Antipsychotic Agents.  In: Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications.  3^rd ed.  Stahl SM eds.  Cambridge University Press. New York, NY.  2008:327-342. 
6. Soares-Weiser K, Fernandez HH.  Tardive dyskinesia.  Semin Neurol  2007;27:159-69.  
   
7. Moore TA, Buchanan RW, Buckley PF et al.  The Texas Medication Algorithm Project antipsychotic for schizophrenia: 2006 update.  J Clin Psychiatry  2007;68:1751-62.  
   
8. Hitri A, Weiner WJ, Borison RL et al.  Dopamine binding following prolonged haloperidol pretreatment.  Ann Neurol  1978;3:134-40.  
   
9. Steen VM, Lovlie R, MacEwan T et al.  Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients.  Mol Psychiatry  1997;2:139-45.  
   
10. Subramanyam B, Pnd SM, Eyles DW et al.  Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol.  Biochem Biophys Res Commun  1991;181:573-8.  
    
11. Halliday GM, Pond SM, Cartwright H et al.  Clinical and neuropathological abnormalities in baboons treated with HPTP, the tetrahydropyridine analog of haloperidol.  Exp Neurol  1999;158:155-63.  
    
12. Igarashi K, Matsubara K, Kasuya F et al.  Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats.  Neurosci Lett  1996;214:183-6.  
13. Rollema H, Skolnik M, D'Engelbronner J et al.  MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies.  J Pharmacol Exp Ther  1994;268:380-7.  
    
14. Ulrich S, Sandmann U, Genz A.  Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients.  Pharmacopsychiatry  2005;38:171-7.  
    
15. Booth RG.  Drugs used to treat neuromuscular disorders: antiparkinsonian and spasmolytic agents.  In: Foye's Principles of Medicinal Chemistry. 6^th Ed.  Lemke TL, Williams DA, Roche VF, Zito SW.  eds.  Wolters Kluwer|Lippincott Williams & Wilkins.  Philadelphia, PA.  2008:679-84. 
16. Chiba K, Trevor A, Castagnoli N Jr.  Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase.  Biochem Biophys Res Commun  1984;120:574-8.  
    
17. Salach JI, Singer TP, Castagnoli N Jr et al.  Oxidation of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monamine oxidase A and B and suicide inactivation of the enzymes by MPTP.  Biochem Biohphys Res Commun  1984;125:831-5.  
    
18. Peterson LA, Caldera PS, Trevor A et al.  Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).  J Med Chem  1985;28:1432-6.  
    
19. Schapira AH, Mann VM, Cooper JM et al.  Mitochondrial function in Parkinson's disease.  The Royal Kings and Queens Parkinson's Disease Research Group.  Ann Neurol  1992;32 Suppl:S116-24.  
    
20. Langston JW, Irwin I, Langston EB et al.  Pargyline prevents MPTP-induced parkinsonism in primates.  Science  1984;225:1480-2.  
    
21. Watanabe H, Muramatsu Y, Kurosaki R et al.  Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity: an immunohistological study.  Eur Neuropsychopharmacol  2004;14:93-104. 
    
22. Booth RG.  Antipsychotic Drugs: Antipsychotic and Anxiolytic Agents.  In:Foye's Principles of Medicinal Chemistry. 6^th Ed.  Lemke TL, Williams DA, Roche VF, Zito SW.  eds.  Wolters Kluwer|Lippincott Williams & Wilkins.  Philadelphia, PA.  2008:612-13.

Haldol, Haloperidol, Antipsychotic, Tardive dyskinesia