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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 1  |  Page : 79-82

Leukopenia Related to Haloperidol in a Case of Chronic Untreated Schizophrenia

1 Department of Psychiatry, TNMC and BYL Nair Ch. Hospital, Mumbai, Maharashtra, India
2 Department of Psychiatry, Grant Government Medical College and JJ Hospital, Mumbai, Maharashtra, India

Date of Submission13-Jun-2020
Date of Decision05-Jul-2020
Date of Acceptance21-Jul-2020
Date of Web Publication18-Jun-2021

Correspondence Address:
Dr. Hrishikesh B Nachane
63, Sharmishtha, Tarangan, Thane – West, Thane - 400 606, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aip.aip_55_20

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Haloperidol is a commonly prescribed first-generation antipsychotic drug in psychiatric practice. It is usually well tolerated and presents with few side effects such as sedation, antiparkinsonian features, and hypotension. Few cases have been reported on leukopenia with haloperidol, none from India. We present a case where a patient with untreated schizophrenia for 9 years developed leukopenia (total leukocyte count [TLC] = 2800 cells/mm3) at 20 mg of oral haloperidol, in our inpatient setting. He chiefly presented with fever. The causality of adverse drug reaction (ADR) was attributed to haloperidol and using the Naranjo algorithm, the score recorded was 8, suggesting probable causal association. Hartwig's Severity Assessment Scale showed the severity of the ADR to be Level 4 (moderate severity). There was prompt reversal after drug discontinuation (TLC = 7000 cells/mm3 at discharge). Risk factors, possible mechanisms, and role of monitoring are discussed.

Keywords: Antipsychotics, haloperidol, leukopenia

How to cite this article:
Nachane HB, Pawar GE. Leukopenia Related to Haloperidol in a Case of Chronic Untreated Schizophrenia. Ann Indian Psychiatry 2021;5:79-82

How to cite this URL:
Nachane HB, Pawar GE. Leukopenia Related to Haloperidol in a Case of Chronic Untreated Schizophrenia. Ann Indian Psychiatry [serial online] 2021 [cited 2021 Aug 5];5:79-82. Available from: https://www.anip.co.in/text.asp?2021/5/1/86/318683

  Introduction Top

Antipsychotic medications, both first and second generation, are used for a variety of psychiatric disorders including schizophrenia.[1] Their action is primarily, but not, restricted to the dopaminergic system in the brain.[1] Several side effects of antipsychotic medications have been reported, and the common ones include sedation, extrapyramidal side effects, weight gain, hypotension, and metabolic side effects.[1] Side effect profile may vary with choice of antipsychotic and mode of administration.[1] Certain adverse effects such as neuroleptic malignant syndrome (NMS) and agranulocytosis can be life-threatening. Blood dyscrasias have been reported with antipsychotic medications, chiefly with clozapine and olanzapine.[2] Hence, they are not routinely screened with all antipsychotic use and only with clozapine. Phenothiazines among first-generation antipsychotic medications have been reported to develop neutropenia.[3] Leukopenia as such is rare, especially with haloperidol.[3] We report a case wherein a patient with long-standing untreated schizophrenia developed leukopenia with oral haloperidol.

  Case Report Top

A 33-year-old Indian male patient, Mr. R, presented to us with increased irritability, aggressive, abusive, assaultive behavior, impaired sleep and self-care, paranoid delusions, disorganized speech with neologisms, and auditory hallucinations. He had been suffering from these symptoms for the past 9 years, and they had aggravated for the last 6 months. He had never received any form of treatment, and this was his first visit to a psychiatrist. His father was his only caregiver. He had no significant history of substance abuse, seizures, head injury, or any other medical or surgical illness. A primary diagnosis of schizophrenia was made, and the patient was admitted. On admission, all his routine investigations were sent, which came back as normal. A detailed systemic examination revealed no significant abnormality. An echocardiogram and a chest X-ray were also done, which were normal. He was initially started on oral risperidone 4 mg, which was increased to 6 mg in 3 days. However, as there was no improvement in his symptoms, risperidone was stopped, and oral haloperidol 10 mg was administered on day 7 of admission. As the patient showed improvement on haloperidol, its dose was increased to 20 mg with 6-mg trihexyphenidyl. On the 10th day of admission, he started developing a fever, which was of low grade and persisted throughout the day. There were no other systemic findings. There was no evidence of tremors/rigidity or any other signs of NMS, yet a blood creatinine phosphokinase (CPK) level was done. His routine investigations were sent again, and a physician reference was sought. His complete blood count (CBC) showed severe leukopenia (3000 cells/mm3), but differential leukocyte count was undisturbed. His CBC on admission had shown a total leukocyte count (TLC) of 9000 cells/mm3. A blood smear was done to rule out any hematopathology, and empirical antibiotics were started for him. CPK levels were within normal limits. A repeat CBC 2 days later (on day 12 of admission) showed TLC to be 2800 cells/mm3. Fever still persisted but used to get temporarily relieved with an antipyretic. As no other cause was demonstrable, it was suspected that haloperidol was responsible for the leukopenia, and so it was stopped immediately. The patient was started on tablet olanzapine 5 mg and the dose was gradually increased. A repeat TLC on day 15 of admission (3 days after stopping haloperidol) was found to be 3500 cells/mm3. As the patient was showing improvement with olanzapine, its dose was increased to 20 mg. The patient showed significant improvement on this dose (symptom resolution >80%) and hence was discharged. Before discharge, his TLC was repeated and it was found to be 7000 cells/mm3.

  Discussion Top

Haloperidol, initially developed as an anesthetic agent, has been increasingly used in psychiatry as an antipsychotic agent.[4] Despite having adverse reactions in the form of sedation, lethargy, dry mouth, blurred vision, and drug-induced parkinsonism, haloperidol has been proven to be an effective and well-tolerated antipsychotic in clinical practice.[4] Haloperidol is also commonly used as a comparator in clinical trials and has served as a benchmark against which efficacy of all antipsychotics is measured.[4] Yet, there have been case reports wherein rare side effects such as blood dyscrasias with haloperidol have been reported.[3] Leukopenia is defined as a lowering of total white blood cell count below the normal range (<3000 cells/mm3).[5] Reduced neutrophil count seen in leukopenia is what predisposes a person to develop serious infections.

In the present case, the patient developed fever during his indoor stay while being on 20 mg of haloperidol. All other causes for fever were ruled out, and his TLC showed significant leukopenia. Other cases have similarly highlighted that fever and a co-occurring infection could be the only signs that can help detect leukopenia.[6] Nothing in the patient's investigations or examination revealed to be significant, so it was attributed to haloperidol. There have been reports of leukopenia with haloperidol.[3] To attribute this adverse drug reaction (ADR) to haloperidol, the Naranjo algorithm was used. The Naranjo scale or the Naranjo algorithm was developed in 1991 and is a commonly used scale for ADR.[7] The scale was primarily developed to standardize the assessment of causality for all ADRs. It has ten items and scoring on it can range from 0 to 13. In our patient, the total score came to be 8, which falls in the probable ADR range.[3] Individual item scores are presented in [Table 1]. Using the Hartwig's Severity Assessment Scale,[8] the severity was deemed to be moderate (level 4 – the ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed and leading to increase in duration of stay at the hospital by at least 1 day). Another similar case wherein neutropenia occurred with both oral and injectable haloperidol had a total score of 6 on the Naranjo algorithm and they attributed the cause of neutropenia in their patient to haloperidol.[3] Immediate stopping of haloperidol proved fruitful, and our patients' TLC picked up almost immediately [Figure 1]. As risperidone was discontinued and haloperidol was added simultaneously, it is likely that risperidone could also have contributed to the ADR. However, as temporally, the leukocyte count decreased with increment in haloperidol dosing, it is less likely that risperidone led to the ADR.
Table 1: Scoring on Naranjo algorithm for the case

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Figure 1: Change in total leukocyte count levels with haloperidol status. TLC: total leukocyte count. D denotes days post admission. Values expressed as cells/mm3

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Majority of the literature available on antipsychotic-induced leukopenia include clozapine, olanzapine, and other phenothiazines, but haloperidol is a rarity.[2] In most cases, it is a combination of antipsychotic medications that predisposes an individual to develop leukopenia, and only a handful of cases, like ours, have reported leukopenia or neutropenia with haloperidol monotherapy.[3],[9] Leukopenia or neutropenia has been reported by both oral and intravenous haloperidol.[3] It appears that it is neutrophil count that suffers while the other cell lines are usually spared.[3] In the present case, however, differential count was unchanged, implying that it may not be only neutrophils that decrease, but other cells too. Research done has highlighted that it is peripheral cells that are usually destroyed and marrow lineage is intact.[3] An immune-related mechanism has been suggested.[3] Knowledge of risk factors predisposing to leukopenia in patients is quite limited. Factors such as ethnicity (Arab, African, and Jew), age, and comorbid diagnoses have been suggested.[3] However, these were absent in our patient. Duration of untreated psychosis is known to influence treatment outcome, but whether it predisposes to more side effects is unclear.[10] This was the only significant risk factor in our patient. Many of the adverse effects of haloperidol are dose dependent, and since TLC values varied with dose in our patient, it is possible that even leukopenia may be a dose-dependent side effect.[11] More research in this area is warranted. Studies have reported that treatment with hematopoietic agents such as filgrastim resulted in normalization of leukocyte counts.[3] However, most cases, similar to ours, saw the return of normal leukocyte count upon stopping the drug.[6],[9] Monitoring of CBC has been suggested for antipsychotics such as clozapine but may also be required with other agents such as haloperidol.

In conclusion, leukopenia is a rare side effect of haloperidol that appears dose dependent and is easily reversible with stoppage of the drug. Clinicians should exercise caution and observe for this side effect in individuals on haloperidol. Monitoring of CBC in susceptible individuals may be advisable.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that their name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Miller DD, Caroff SN, Davis SM, Rosenheck RA, McEvoy JP, Saltz BL, et al. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry 2008;193:279-88.  Back to cited text no. 1
Duggal HS, Singh I. Psychotropic drug-induced neutropenia. Drugs Today (Barc) 2005;41:517-26.  Back to cited text no. 2
Sahan E. Haloperidol-related neutropenia. Indian J Psychiatry 2019;61:307-10.  Back to cited text no. 3
Ayd FJ Jr. Haloperidol: Twenty years' clinical experience. J Clin Psychiatry 1978;39:807-14.  Back to cited text no. 4
Dunk LR, Annan LJ, Andrews CD. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Br J Psychiatry 2006;188:255-63.  Back to cited text no. 5
Jurivich DA, Hanlon J, Andolsek K. Neuroleptic-induced neutropenia in the elderly. J Am Geriatr Soc 1987;35:248-50.  Back to cited text no. 6
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 7
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 8
Cutler NR, Heiser JF. Leukopenia following treatment with thiothixene and haloperidol. JAMA 1979;242:2872-3.  Back to cited text no. 9
Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: A critical review and meta-analysis. Am J Psychiatry 2005;162:1785-804.  Back to cited text no. 10
Bjørndal N, Bjerre M, Gerlach J, Kristjansen P, Magelund G, Oestrich IH, et al. High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response, side effects, serum haloperidol, and serum prolactin. Psychopharmacology (Berl) 1980;67:17-23.  Back to cited text no. 11


  [Figure 1]

  [Table 1]


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