Haloperidol

Brand Names: Haldol, Haldol Decanoate, Halperon

Clinical Names: Haloperidol

Summary

generic name: Haloperidol

trade names: Haldol®, Haldol Decanoate®, Halperon®

type of drug: Antipsychotic; a dopamine receptor antagonist and sigma-receptor-active neuroleptic drug.

used to treat: Psychotic disorders, including schizophrenia; psychosis associated with dementia, depression, or mania; Gilles de la Tourette syndrome; acute behavioural disturbances.

adverse effects: Even in therapeutic doses haloperidol commonly causes extrapyramidal movement disorders, especially parkinsonism, acute dyskinesias, and akathisia (motorial excitation).

overview of interactions:
• nutrient affecting drug performance: Vitamin C (Ascorbate)

• nutrient affecting drug performance: Vitamin E

• nutrient affected by drug: Iron

• nutrient affected by drug: Potassium

• nutrient affected by drug: Sodium

• substance affected by drug: Glutathione (GSH)

• nutrients affecting drug toxicity: Alpha Lipoic Acid (Thioctic Acid) and Glutathione (GSH)

• herb affecting drug toxicity: Silybum marianum (Milk Thistle)

• food/herb affecting drug performance: Coffea arabica (Coffee) and Camellia sinensis (Tea)

• food/herb affecting drug toxicity: Alcohol



Interactions

nutrient affecting drug performance: Vitamin C (Ascorbate)

• mechanism: Some evidence indicates that ascorbate modulates dopamine transmission in the portion of the brain called the striatum and increases the activity of haloperidol.

• research: Straw et al gave oral doses of ascorbic acid, 4.5 grams daily, to patients taking haloperidol for 2 weeks in an open trial. They found that the addition of ascorbic acid was not associated with any change in psychopathology in this group of patients, nor was there any apparent pharmacokinetic interaction with haloperidol. More recent research by Gulley and Rebec supports the findings of an antidopaminergic action of ascorbate on striatal function, but suggests that this effect requires relatively high systemic doses.
(Rebec GV, et al. Science. 1985 Jan 25;227(4685):438-440; Straw GM, et al. J Clin Psychopharmacol 1989 Apr;9(2):130-132; Pierce RC, et al. Neuroscience. 1991;45(2):373-378; Pierce RC, et al. Psychopharmacology (Berl). 1994 Sep;116(1):103-109; Gulley JM, Rebec GV. Pharmacol Biochem Behav 1999 May;63(1):125-129.)

nutrient affecting drug performance: Vitamin E

• mechanism: Haloperidol is cytotoxic to numerous parts of the brain, specifically the primary hippocampal neurons, C6 glioma cells and NCB20 cells. Researchers have investigated the possibility that various activities of vitamin E, particularly as a free radical scavenger, might reduce the toxic side effects associated with use of the drug.

• research: In vitro research indicates that chronic haloperidol administration can reduce striatal vitamin E levels. In other test tube studies looking at haloperidol-induced toxicity Behl et al determined that vitamin E (alpha-tocopherol), a lipophilic free radical scavenger, prevented DNA fragmentation and ultimately cell death. Based upon their research involving rats Gattaz et al suggested that the concomitant administration of vitamin E to neuroleptics might prevent the development of tardive dyskinesia in humans. However, in human studies supplementation with vitamin E neither provides protective effect against haloperidol-induced symptoms nor does it interfere with the therapeutic efficacy of the drug.
(VonVoigtlander PF, et al. Res Commun Chem Pathol Pharmacol. 1990 Jun;68(3):343-352;
Gattaz WF, et al. J Neural Transm Gen Sect 1993;92(2-3):197-201; Behl C, et al. Neuroreport 1995 Dec 29;7(1):360-364; Eranti VS, et al. Psychopharmacology (Berl). 1998 Dec;140(4):418-420.)

nutrient affected by drug: Iron

• mechanism: Decreased blood levels of iron are associated with use of haloperidol, especially when liver iron stores were initially inadequate. Further, Ben-Shachar and Youdim have observed that rats with nutritionally-induced iron deficiency exhibit reduced brain iron content, resulting in dopamine D2 receptor subsensitivity.
(Ben-Shachar D, Youdim MB. J Neurochem 1990 Apr;54(4):1136-1141.)

• nutritional concerns: No definitive research has emerged to clarify and confirm the clinical significance of this interaction between haloperidol and iron. Individuals taking haloperidol should avoid supplements containing iron unless they have consulted with their prescribing physician and iron deficiency has been tested for and diagnosed.

nutrient affected by drug: Potassium

• research: Haloperidol has variously been observed to induce both hyperkalemia and hypokalemia, i.e., high and low blood levels of potassium, respectively.
(Aunsholt NA. Acta Psychiatr Scand. 1989 Apr;79(4):411-412; Mathe V, et al. Int Pharmacopsychiatry. 1971;6(2):111-130.)

• nutritional concerns: The clinical significance of changes in potassium levels due to haloperidol remains unclear. Individuals concerned about this aspect of haloperidol intoxication's side effects should consult their prescribing physician and/or pharmacist. Serum potassium levels are commonly measured as part of standard lab tests.

nutrient affected by drug: Sodium

• mechanism: The use of haloperidol is associated with hyponatremia, i.e., low blood levels of sodium. The dopamine system seems to be relatively more important in promoting excretion of sodium at the lower (physiological) range of hypervolemia whereas in the high range other factors have a greater impact.
(Cuche JL, et al. Nephrologie. 1983;4(3):103-105; Hansell P, et al. Acta Physiol Scand. 1987 Jul;130(3):401-407; Hansell P, et al. Kidney Int. 1991 Feb;39(2):253-258.)

• nutritional concerns: The clinical significance of changes in sodium levels due to haloperidol remains unclear. Individuals concerned about this aspect of haloperidol intoxications side effects should consult their prescribing physician and/or pharmacist. Serum sodium levels are commonly measured as part of standard lab tests.

substance affected by drug: Glutathione (GSH)
nutrients affecting drug toxicity: Alpha Lipoic Acid (Thioctic Acid) and Glutathione (GSH)

• mechanism: Haloperidol acts through blockade of dopamine receptors leading to increased turnover of dopamine. Increased turnover of dopamine could lead to excessive production of hydrogen peroxide and, thus, generate oxidative stress. Haloperidol administration also appears to result in a loss of glutathione (GSH), a key antioxidant substance naturally occurring in the body.
(Shivakumar BR, et al. J Pharmacol Exp Ther. 1993 Jun;265(3):1137-1141; Rabinovic AD, Hastings TG. Neurochem. 1998 Nov;71(5):2071-2078.)

• research: Balijepalli et al examined the effects of a variety of classical and atypical neuroleptic drugs and found that haloperidol was the most potent inhibitor of mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. They found that in vitro treatment of mouse brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity.
(Balijepalli S, et al. Neuropharmacology 1999 Apr;38(4):567-577.)

• nutritional support: Preliminary evidence indicates that supplementation with alpha-lipoic acid and/or glutathione could potentially reduce depletion of naturally occurring glutathione and other adverse side effects due to use of haloperidol. No definitive advise or dosage recommendations can be offered given the lack of clinical trials. However, physicians experienced in nutritional therapies often suggest 20-50 mg of alpha-lipoic acid per day for general antioxidant protection while prescribing dosages of 800 mg per day and 150 mg per day, respectively, in the treatment of diabetic neuropathies and glaucoma. Likewise, l-glutathione (reduced) is typically prescribed at a dosage of 100-200 mg per day for a variety of conditions, including general protective activity. Individuals concerned about preventing the damaging effects of haloperidol should consult their prescribing physician and/or a nutritionally trained healthcare professional about possible benefits of supplementing with alpha-lipoic acid and/or glutathione (GSH). Neither substance has known toxic effects at commonly used dosages and neither has been shown to inhibit the therapeutic efficacy of haloperidol.

herb affecting drug toxicity: Silybum marianum (Milk Thistle)

• adverse effect due to drug: Haloperidol is known to induce liver damage.

• mechanism: Silymarin, an extract of Silybum marianum, has been used in a variety of settings for its antioxidant function as well as its ability to protect the liver against a wide range of toxic influences, including those due to pharmaceutical agents.
(Carrescia O, et al. Clin Ter. 1980 Oct 31;95(2):157-164.)

• research: In a double-blind study involving sixty women taking psychotropic drugs, including haloperidol, Palasciano et al found that 800 mg daily of silymarin, an extract of Silybum marianum, was associated with a significant decrease in free radicals among those taking silymarin as compared to controls.
(Palasciano G, et al. Curr Ther Res 1994;55:537-545.)

food/herb affecting drug performance: Coffea arabica (Coffee) and Camellia sinensis (Tea)

• mechanism: Various reports and in vitro studies have observed that coffee and tea can cause precipitation of haloperidol. Such an interaction, were it to similarly occur in human patients, could potentially reduce absorption of haloperidol and its subsequent therapeutic efficacy. Other animal studies on chlorpromazine, another antipsychotic drug, found that drug's cataleptic effects were abolished when administered with tea, most likely due to its precipitation (in vitro) by non-caffeine constituents. Based on this, and similar, evidence speculation has been raised that the methylxanthines in coffee and tea may act as dopamine agonists.
(Hirsch SR. Lancet. 1979 Nov 24;2(8152):1130-1131; Kulhanek F, et al. Lancet. 1979 Nov 24;2(8152):1130; Cheeseman HJ, Neal MJ. Br J Clin Pharmacol. 1981 Aug;12(2):165-169; Lasswell WL Jr, et al. J Pharm Sci. 1984 Aug;73(8):1056-1058.)

• dietary concerns: Pending definitive research individuals taking haloperidol should avoid consuming coffee and tea within one hour prior to or two hours after taking the drug. Some authors have cautioned that this warning should be extended to include cola drinks.

food/herb affecting drug toxicity: Alcohol

• mechanism: Drowsiness and decreased coordination are common side effects of haloperidol. The consumption of alcohol by individuals taking haloperidol increases the risk of accidents and should be avoided. Furthermore, research with rat hearts indicates that ethanol potentiates haloperidol-induced electromechanical cardiac depression. It is interesting to note that haloperidol (and lorazepam) are commonly used to sedate ethanol-intoxicated patients in emergency rooms.
(Risinger FO, et al. Psychopharmacology (Berl). 1992;107(2-3):453-456; Broadbent J, et al. Psychopharmacology (Berl) 1995 Aug;120(4):475-482; Medlin RP Jr, et al. J Cardiovasc Pharmacol 1996 Dec;28(6):792-798.)

• dietary concerns: Individuals taking haloperidol should avoid consuming alcohol, alcohol-containing products, in order to minimize risk of adverse effects or accidents.

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References

Aunsholt NA. Prolonged Q-T interval and hypokalemia caused by haloperidol. Acta Psychiatr Scand. 1989 Apr;79(4):411-412.
Abstract: A patient is described who developed hypokalemia and cardiac arrhythmia after acute intoxication with haloperidol.

Balijepalli S, Boyd MR, Ravindranath V. Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropharmacology 1999 Apr;38(4):567-577.
Abstract: We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.

Behl C, Rupprecht R, Skutella T, Holsboer F. Haloperidol-induced cell death--mechanism and protection with vitamin E in vitro. Neuroreport 1995 Dec 29;7(1):360-364.
Abstract: Haloperidol, a dopamine receptor antagonist and sigma-receptor-active neuroleptic drug, is cytotoxic to primary hippocampal neurones, C6 glioma cells and NCB20 cells. A 24 h challenge of these cells with haloperidol resulted in reduced cell viability and ultimately cell lysis. The most dramatic changes in cellular morphology were the retraction of cellular extensions, development of membrane blebs, and finally cell detachment from the culture dish. DNA isolated from haloperidol-treated cells was randomly degraded, indicating a necrotic rather than an apoptotic pathway of cell death. Vitamin E (alpha-tocopherol), a lipophilic free radical scavenger, prevented haloperidol-induced DNA fragmentation and ultimately cell death. These findings suggest that haloperidol induces necrotic cell death in which free radicals play a major role.

Ben-Shachar D, Youdim MB. Neuroleptic-induced supersensitivity and brain iron: I. Iron deficiency and neuroleptic-induced dopamine D2 receptor supersensitivity. J Neurochem 1990 Apr;54(4):1136-1141.
Abstract: Previous studies have shown that nutritional iron deficiency in rats reduces brain iron content, resulting in dopamine D2 receptor subsensitivity, as indicated by a decrease in [3H]spiperone binding in caudate nucleus and in behavioral responses to apomorphine. Both phenomena can be reversed by iron supplementation. The possibility that neuroleptic-induced dopamine D2 receptor supersensitivity involves an alteration in brain iron content was investigated in nutritionally iron-deficient and control rats chronically treated with haloperidol (5 mg/kg daily for 14 or 21 days). Neuroleptic treatment was initiated either (a) concurrently with iron deficiency or (b) 2 weeks after the start of iron deficiency. The results show that dopamine D2 receptor subsensitivity, a feature of iron deficiency, is absent in haloperidol-treated, iron-deficient groups. On the contrary, these animals demonstrated biochemical and behavioral dopamine D2 receptor supersensitivity that is relatively greater than that observed with control, haloperidol-treated animals. Haloperidol (5 mg/kg daily for 21 days) as well as chlorpromazine (10 mg/kg daily for 21 days) caused a significant reduction (20-25%) in liver nonheme iron stores as compared with values in control rats. However, in iron-deficient rats, in which liver iron stores were almost totally depleted, haloperidol had no effect. The ability of chronic haloperidol treatment to prevent the reduction of dopamine D2 receptor number during iron deficiency may be associated with alteration of body iron status. Thus, less iron may result in an increase in free haloperidol available to the dopamine D2 receptor.

Broadbent J, Grahame NJ, Cunningham C. Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization. Psychopharmacology (Berl) 1995 Aug;120(4):475-482.

Carrescia O, Benelli L, Saraceni F, Braga PC, Cagnetta G, Copponi V.  [Silymarin in the prevention of hepatic damage by psychopharmacologic drugs. Experimental premises and clinical evaluations]. Clin Ter. 1980 Oct 31;95(2):157-164. [Article in Italian]

Cheeseman HJ, Neal MJ. Interaction of chlorpromazine with tea and coffee. Br J Clin Pharmacol. 1981 Aug;12(2):165-169.
Abstract: 1 The interaction between phenothiazine neuroleptics with tea and coffee was studied in vitro. 2 Filtered infusions of tea and coffee caused precipitation of all the neuroleptics studied. Tea always caused a heavier precipitate than coffee. 3 The constituent or constituents of tea and coffee responsible for precipitating the neuroleptics was not identified. Solutions of caffeine, caffeine citrate and sodium chloride did not form a precipitate with chlorpromazine but precipitates were formed by sodium salicylate, sodium benzoate and trisodium citrate. 4 The interaction between chlorpromazine (CPZ) and tea was studied quantitatively using radiolabelled drug and it was found that the precipitation of [3H]-CPZ with a given quantity of tea was 'saturable'. The proportion of CPZ precipitated by a 'standard cup of tea' was 80% at low doses of the drug (10-40 mg) whilst at high doses (800 mg), the proportion of the drug precipitated was approximately 20%. 5 The interaction was further studied in vivo by the oral administration of tea and CPZ to rats. The cataleptic effect of CPZ was significantly reduced by the simultaneous administration of tea and this was apparently not due to the caffeine present in tea. 6 The results suggest that a substantial proportion of orally administered neuroleptic may be precipitated as a highly insoluble compound if coffee, or more especially tea, is taken close to drug administration. This interaction might affect the absorption of phenothiazines given orally to patients.

Cuche JL, Prinseau J, Baglin A, Guedon J. [Natriuretic effect of haloperidol in dogs]. Nephrologie. 1983;4(3):103-105. [Article in French]
Abstract: A 0.5 microM/kg/min infusion of haloperidol in the renal artery of 20 sodium-loaded dogs undergoing water diuresis is showed to induce the following net effects: a statistically significant reduction of both clearance of PAH (-18.1 +/- 6.6 ml/min), and glomerular filtration rate (-4.3 +/- 1.5 ml/min), an increase of both fractional excretion of sodium (+ 6.8 +/- 1.1%) and potassium (+ 55.1 +/- 5.5%), a decrease of fractional excretion of phosphate (-5.3 +/- 1.5%), and a lack of change of free water clearance (infused minus controlateral kidney difference).

Eranti VS, Gangadhar BN, Janakiramaiah N.  Haloperidol-induced extrapyramidal reaction: lack of protective effect by vitamin E. Psychopharmacology (Berl). 1998 Dec;140(4):418-420.
Abstract: Haloperidol treatment has been shown to produce oxidative stress in patients with acute psychosis. Oxidative stress has also been implicated in the extrapyramidal symptoms (EPS) produced by haloperidol. Supporting the oxidative stress hypothesis, vitamin E (antioxidant) has demonstrated therapeutic efficacy in idiopathic parkinsonism. The prophylactic efficacy of vitamin E (antioxidant) on haloperidol-induced EPS was examined in a randomized controlled trial. The sample consisted of 24 acute psychotic patients hospitalized for a 2-week trial. All patients received oral haloperidol 10 mg/day. The sample was equally randomized to receive either haloperidol alone or haloperidol + vitamin E (3200 IU/day). EPS was rated at recruitment, both live and with video records, and on days 3, 7, 10 and 14. Psychopathology was rated at recruitment and weekly thereafter. Vitamin E had no prophylactic effect on drug-induced EPS, though it did not interfere with the therapeutic efficacy of haloperidol.

Gattaz WF, Emrich A, Behrens S. Vitamin E attenuates the development of haloperidol-induced dopaminergic hypersensitivity in rats: possible implications for tardive dyskinesia. J Neural Transm Gen Sect 1993;92(2-3):197-201.
Abstract: Chronic haloperidol treatment in rats results in behavioural supersensitivity to dopamine agonists. This mechanism has been suggested as a possible animal model for tardive dyskinesia. In the present study the simultaneous administration of vitamin E to chronic haloperidol treatment in rats prevented the development of behavioural supersensitivity to apomorphine. This finding suggest that the concomitant administration of vitamin E to neuroleptics might prevent the development of tardive dyskinesia in humans.

Gulley JM, Rebec GV. Modulatory effects of ascorbate, alone or with haloperidol, on a lever-release conditioned avoidance response task. Pharmacol Biochem Behav 1999 May;63(1):125-129.
Abstract: Pretreatment with ascorbate, a modulator of dopamine transmission in the striatum, enhances the ability of haloperidol, a dopamine antagonist, to induce catalepsy and block the motor-activating effects of amphetamine. The present study extended this line of work to a lever-release version of the conditioned avoidance response (CAR) task, which is highly sensitive to changes in striatal dopamine. Adult male rats were trained to avoid footshock by releasing a lever within 500 ms of tone onset. Ascorbate (100 and 1000 mg/kg, IP) or vehicle was tested either alone or in conjunction with haloperidol (0.01 and 0.05 mg/kg, SC). Compared to vehicle pretreatment, 1000 mg/kg ascorbate alone or in combination with haloperidol impaired CAR performance by increasing avoidance latency. Latency to escape footshock was not impaired, ruling out a generalized motor deficit. In contrast, 100 mg/kg ascorbate alone or in combination with haloperidol had no consistent effects on CAR performance, even at a haloperidol dose (0.005 mg/kg, SC) known to potentiate dopamine transmission by preferentially blocking autoreceptors. Collectively, these results support an antidopaminergic action of ascorbate on striatal function, but suggest that this effect requires relatively high systemic doses.

Hansell P, Fasching A, Sjoquist M, Anden NE, Ulfendahl HR. The dopamine receptor antagonist haloperidol blocks natriuretic but not hypotensive effects of the atrial natriuretic factor. Acta Physiol Scand. 1987 Jul;130(3):401-407.

Hansell P, Fasching A. The effect of dopamine receptor blockade on natriuresis is dependent on the degree of hypervolemia. Kidney Int. 1991 Feb;39(2):253-258.
Abstract: A number of different physiological factors and systems have been suggested to be responsible for the natriuretic effect following acute isotonic volume expansion (VE). The variation in suggestions may depend on the prevailing status of the systems governing fluid and electrolyte balance before VE, on the expansion medium and on the rate and degree of VE. A study was performed to determine whether the previously documented attenuating effect of dopamine receptor blockade on natriuresis induced by VE is dependent on the degree of hypervolemia. Anesthetized rats were pretreated with the dopamine receptor blockers haloperidol (1 mg.kg-1 body weight, i.p.), SCH 23390 (30 micrograms.hr-1.kg-1 i.v.) or vehicle and then subjected to VE at 2, 5 or 10% of body weight per hour. VE at 2, 5 and 10% increased sodium excretion in vehicle-pretreated animals 6-, 29- and 130-fold, respectively. In the haloperidol-pretreated animals the natriuretic response (accumulated sodium excretion) to VE was attenuated by 67% (P less than 0.05), 46% (P less than 0.05) and 22% (NS) at the three degrees of expansion, respectively. The corresponding attenuation in SCH 23390-treated animals were 60% (P less than 0.05), 56% (P less than 0.05) and 19% (NS), respectively. The gradual decrease in attenuation indicates that at varying degrees of hypervolemia, different physiological systems contribute differently to the renal natriuretic response. The dopamine system seems to be relatively more important in promoting natriuresis at the lower (physiological) range of hypervolemia whereas in the high range other factors have a greater impact.

Hirsch SR. Precipitation of antipsychotic drugs in interaction with coffee or tea. Lancet. 1979 Nov 24;2(8152):1130-1131. (Letter )

Kenyon-David D. Haloperidol intoxication. N Z Med J. 1981 Mar 11;93(679):165.

Kulhanek F, et al. Kulhanek F, Linde OK, Meisenberg G. Precipitation of antipsychotic drugs in interaction with coffee or tea. Lancet. 1979 Nov 24;2(8152):1130. (Letter)

Lasswell WL Jr, Weber SS, Wilkins JM. In vitro interaction of neuroleptics and tricylic antidepressants with coffee, tea, and gallotannic acid. J Pharm Sci 1984 Aug;73(8):1056-1058.
Abstract: The in vitro interaction of selected drugs with coffee, tea, gallic acid, and gallotannic acid was examined by mixing solutions of drug with each of these four preparations. Results of these experiments indicate that significant precipitation occurs for a variety of agents, including several phenothiazines, amitriptyline, haloperidol, imipramine, and loxapine. The strong complex which is formed between these drugs and tannins is probably the basis of the interaction of these drugs with coffee and tea. Although precipitates did occur with a number of neuroleptics, two members of this drug class, thiothixene and molindone, failed to interact with the solutions used.

Mathe V, Kassay G, Tuske M. [Results of glucose tolerance tests and changes in inorganic serum phosphate and potassium levels in schizophrenic patients responding to treatment with psychotropic drugs]. Int Pharmacopsychiatry. 1971;6(2):111-130. [Article in German]

McElvain JS, Schenk JO. Blockade of dopamine autoreceptors by haloperidol and the apparent dynamics of potassium-stimulated endogenous release of dopamine from and reuptake into striatal suspensions in the rat. Neuropharmacology. 1992 Jul;31(7):649-59.

Medlin RP Jr, Ransom MM, Watts JA, Kline JA. Effect of ethanol, haloperidol, and lorazepam on cardiac conduction and contraction. J Cardiovasc Pharmacol 1996 Dec;28(6):792-798.
Abstract: Haloperidol and lorazepam are commonly used to sedate ethanol (E)-intoxicated patients in emergency departments. This study was conducted to explore the role of ethanol in altering the potency of haloperidol and lorazepam with respect to cardiac conduction and contraction. For mechanical studies, isolated rat hearts were studied under isovolumetric conditions by using standard Langendorff technique. Hearts were perfused with Krebs-Heinseleit-Bicarbonate buffer containing haloperidol or lorazepam in concentrations ranging from 100 to 750 ng/ml (one heart per drug concentration). For both haloperidol and lorazepam individually, significant reductions in Left ventricular-generated pressure (LVGP) were observed at a concentration of 750 ng/ml (haloperidol = 2,250 nM and lorazepam = 2,000 nM). The addition of 20 and 65 mM ethanol shifted the concentration-response effect of haloperidol such that LVGP was significantly reduced at haloperidol = 500 and 300 ng/ml, respectively (p < 0.05 vs. basal control; paired t test). Ethanol produced no observable shift on the lorazepam concentration-response for LVGP. For electrophysiologic studies, hearts were perfused with haloperidol and lorazepam (300 ng/ml) +/- 65 mM ethanol. Compared with basal control, E + H significantly decreased heart rate (-74 +/- 12 beats/min) and increased His-ventricular conduction time (+7.6 +/- 1.5 ms vs. +1.7 +/- 0.6 ms for control hearts). Both haloperidol and EH significantly increased atrioventricular (AV) effective refractory period and the atrioventricular-His (AH) conduction interval. No significant changes in any electrophysiologic parameter were observed with ethanol or lorazepam perfused individually or with the combination of ethanol and lorazepam. Ethanol potentiates haloperidol-induced electromechanical depression of isolated rat hearts. Ethanol had no such effect on lorazepam.

Palasciano G, Portincasa P, Palmier V, Ciani D, Vendemiale G, Altomare E. The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res 1994;55:537-545.
Abstract: The efficacy of the antioxidant silymarin in preventing psychotropic drug-induced hepatic damage was evaluated in a double-blind, placebo-controlled study. Sixty patients receiving chronic psychotropic drug therapy were randomly divided into four groups and were treated for 90 days with silymarin or placebo as follows: group IA - treatment with psychotropic drugs and silymarin, 800 mg/d; group IB - treatment with psychotropic drugs and placebo; group IIA - suspension of psychotropic drugs plus treatment with silymarin, 800 mg/d; and group IIB - suspension of psychotropic drugs plus treatment with placebo. Serum levels of malon-dialdehyde (the end product of the oxidation of polyunsaturated fatty acids} and the indices of hepatocellular function were assessed in each patient at baseline (day 0), on days 15, 30, 60, and 90, and 1 month after the completion of treatment. Our data show that silymarin, when used at submaximal doses, reduces the lipoperoxidative hepatic damage that occurs during treatment with butyrophenones or phenothiazines. The study results also suggest that increased lipoperoxidation may contribute to psychotropic drug-induced hepatotoxicity.

Pierce RC, Rowlett JK, Bardo MT, Rebec GV. Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor binding. Neuroscience. 1991;45(2):373-378.
Abstract: Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [3H]spiperone saturation studies showed, as expected, an up-regulation of striatal D2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density (Bmax) but not affinity (KD). Ascorbate treatment, however, had no effect on D2 receptor density or the distribution of [3H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [3H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

Pierce RC, Clemens AJ, Shapiro LA, Rebec GV. Repeated treatment with ascorbate or haloperidol, but not clozapine, elevates extracellular ascorbate in the neostriatum of freely moving rats. Psychopharmacology (Berl). 1994 Sep;116(1):103-109.

Rabinovic AD, Hastings TG. Role of endogenous glutathione in the oxidation of dopamine. J Neurochem. 1998 Nov;71(5):2071-2078.
Abstract: Intrastriatal injection of dopamine causes the selective degeneration of tyrosine hydroxylase-containing terminals and an increase in content of cysteinyl-catechols, an index of dopamine oxidation. Both of these effects can be attenuated by coadministration of antioxidants such as glutathione. Therefore, we investigated the effects of decreased endogenous glutathione on the neurotoxic potential of dopamine. We observed that pretreatment with either L-buthionine sulfoximine, a specific inhibitor of glutathione synthesis, or diethyl maleate, which forms adducts with glutathione, caused significant decreases in endogenous glutathione levels at the time of dopamine injection. Pretreatment with L-buthionine sulfoximine potentiated the formation of protein cysteinyl-dopamine after intrastriatal injection of 1.0 micromol of dopamine. We also observed that intrastriatal injection of 1.0 micromol of dopamine decreased striatal glutathione content in all pretreatment conditions. However, injection of a low dose (0.05 micromol of dopamine) caused a decrease in striatal glutathione levels only in the L-buthionine sulfoximine-pretreated rats. Diethyl maleate pretreatment was not effective in potentiating either cysteinyl-catechol formation or glutathione loss after dopamine injection. We conclude that dopamine contributes to cellular oxidative stress and that this can be exacerbated, or at least unmasked, if glutathione synthesis is compromised.

Rebec GV, Centore JM, White LK, Alloway KD. Ascorbic acid and the behavioral response to haloperidol: implications for the action of antipsychotic drugs. Science. 1985 Jan 25;227(4685):438-440.
Abstract: Haloperidol, a widely used antipsychotic drug, was tested for its ability to block the behavioral response to amphetamine and to elicit catalepsy in rats treated with saline or ascorbic acid (1000 milligrams per kilogram of body weight). By itself, ascorbic acid failed to exert significant behavioral effects, but it enhanced the antiamphetamine and cataleptogenic effects of haloperidol (0.1 or 0.5 milligrams per kilogram). These results, combined with a growing body of biochemical evidence, suggest that ascorbic acid plays an important role in modulating the behavioral effects of haloperidol and related antipsychotic drugs.

Risinger FO, Dickinson SD, Cunningham CL.  Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference. Psychopharmacology (Berl). 1992;107(2-3):453-456.
Abstract: This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP)+ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.

Shivakumar BR, Ravindranath V. Shivakumar BR, et al. Oxidative stress and thiol modification induced by chronic administration of haloperidol. J Pharmacol Exp Ther. 1993 Jun;265(3):1137-1141.
Abstract: Haloperidol, a widely used neuroleptic, acts through blockade of dopamine receptors leading to increased turnover of dopamine. Increased turnover of dopamine could lead to excessive production of hydrogen peroxide and, thus, generate oxidative stress. The effect of chronic administration of haloperidol on glutathione (GSH)-protein thiol homeostasis and lipid peroxidation was examined in rat brain regions. The oxidized GSH levels increased significantly, though not substantially, in cortex (CT, 15%), striatum (ST, 28%) and midbrain (MB, 27%). Maximal decreases in GSH levels were noted in CT (23%), ST (28%) and MB (20%) after 1 month of haloperidol administration. The GSH levels recovered thereafter, and after 6 months of haloperidol treatment, the GSH levels were not significantly different from control in ST and MB. The depleted GSH was recovered essentially as protein-GSH mixed disulfide with a concomitant decrease in the protein thiol concentration in all the three regions of the brain. The increase in oxidized GSH concentration represented only 1.8, 2.0 and 3.5% of the depleted GSH in the CT, ST and MB after 1 month of haloperidol administration. The concentration of thiobarbituric acid-reactive products increased significantly up to 3 months of haloperidol treatment, but at the end of 6 months, the levels were substantially decreased. The present study demonstrates that haloperidol administration for 1 month results in significant oxidative stress in CT, ST and MB regions of the brain, as demonstrated by alterations in GSH-protein thiol homeostasis and increased lipid peroxidation products. However, after prolonged administration of haloperidol for 6 months, the GSH-protein thiol homeostasis is restored to a large extent, concomitant with the decrease in the concentration of lipid peroxidation products. Administration of haloperidol leads to development of tolerance (supersensitivity of the dopamine autoreceptors) to neuroleptics, which is associated with decreased turnover of dopamine; this may result in overcoming the oxidative stress generated initially due to increased dopamine turnover.

Straw GM, Bigelow LB, Kirch DG. Haloperidol and reduced haloperidol concentrations and psychiatric ratings in schizophrenic patients treated with ascorbic acid. J Clin Psychopharmacol 1989 Apr;9(2):130-132.
Abstract: Recent reports have suggested an augmentation by ascorbic acid of haloperidol treatment of schizophrenic patients. This study was designed to examine whether pharmacokinetic interactions between ascorbic acid and haloperidol occur in this population. Eight male inpatients diagnosed as having chronic schizophrenia by DSM-III-R criteria and stabilized on a fixed dose of haloperidol were given oral doses of ascorbic acid, 4.5 grams daily, for 2 weeks in an open trial. Serum concentrations of haloperidol and is metabolite, reduced haloperidol, were measured by high performance liquid chromatography. Psychiatric symptoms were monitored using the Psychiatric Symptom Assessment Scale performed by nursing staff blind to the haloperidol status but not to the ascorbic acid dosage. The addition of ascorbic acid was not associated with any change in psychopathology in this group of patients, nor was there any apparent pharmacokinetic interaction with haloperidol.

Threlkeld DS, ed. Central Nervous System Drugs, Antipsychotic Agents. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, May 1998.

VonVoigtlander PF, Burian MA, Althaus JS, Williams LR. Effects of chronic haloperidol on vitamin E levels and monoamine metabolism in rats fed normal and vitamin E deficient diets. Res Commun Chem Pathol Pharmacol. 1990 Jun;68(3):343-352.
Abstract: Experiments were conducted to study the effects of chronic haloperidol treatment on brain catechols and indoles in rats fed vitamin E deficient diets. Rats were fed basal diet or vitamin E deficient diet and injected with saline or haloperidol (1 mg/kg/day x 28 days i.p.). Tissue levels of catechols, indoles and vitamin E were measured using HPLC-EC techniques. Chronic haloperidol reduced striatal vitamin E levels. Activity in the striatal dopaminergic systems was also reduced, as, shown by reduced 3,4-dihydrophenylanine (DOPA), homovanillic acid (HVA), 3-methoxytyramine (3-MT), and dopamine (DA) levels. In addition, serotonergic activity was reduced, as indicated by lowered 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA), and 5-hydroxytryptamine (5-HT) levels. In the substantia nigra, only 5-HIAA levels were reduced by treatment with haloperidol. These effects of haloperidol on monoamine metabolism were noted in both the vitamin E deficient and basal diet treated rats. However, vitamin E deficiency alone resulted in reduced DOPA and dopamine in the striatum. The vitamin E deficient diets resulted in markedly lowered vitamin E levels in the striatum and substantia nigra. All of these effects were more profound in rats that had been maintained on a vitamin E deficient diet for 7 weeks than those that were so treated for 5 weeks. These results suggest that alterations in dopamine metabolism and endogenous antioxidant systems may interact. Neuroleptics such as haloperidol that acutely accelerate dopamine synthesis and metabolism may cause peroxidative stress as indicated by depletions of vitamin E. Such depletions are capable of reducing dopamine levels and synthesis. The possibility that this and the effect of chronic haloperidol are mediated by peroxidative damage to dopamine neurons must be considered.