Is Abrupt Withdrawal of Benzodiazepines a Risk Factor for Neuroleptic Malignant Syndrome? A Case Report With Single‐Dose Haloperidol

ABSTRACT

Neuroleptic malignant syndrome (NMS) is a rare but life‐threatening reaction associated with the use of dopamine‐modulating agents, which presents with symptoms like high fever, muscle rigidity, and autonomic instability. It is known that both the use of dopamine receptor antagonists and the sudden withdrawal of dopamine receptor agonists can trigger NMS. Benzodiazepine withdrawal can create a GABA‐deficient state, linked to catatonia and possibly predisposing individuals to NMS. The case was a 53‐year‐old male patient with a history of high‐dose benzodiazepine dependency, who developed NMS after the abrupt withdrawal of alprazolam and the single‐dose intramuscular (IM) haloperidol. He presented with the symptoms of stupor, generalized rigidity, and fever, requiring admission to the Respiratory Care Unit. His medical history included long‐term use of clonazepam, alprazolam, and methadone maintenance therapy (MMT). The laboratory findings also demonstrated elevated creatine phosphokinase (CPK) levels, peaking at 7896 IU/L. The treatments with bromocriptine and lorazepam further led to gradual improvement, and the patient was discharged after 11 days following the resolution of NMS symptoms. This case highlights the potential role of benzodiazepine withdrawal as a risk factor for NMS, especially when combined with antipsychotic medication like haloperidol. The shared mechanisms between the pathophysiology of NMS and benzodiazepine withdrawal suggest that the abrupt cessation of GABAergic agents may lower dopaminergic activity, contributing to the onset of NMS. Clinicians must be accordingly cautious in distinguishing benzodiazepine withdrawal from other causes of delirium and then option for appropriate treatment approaches to mitigate risks.

Summary.

• Benzodiazepine withdrawal may act as a risk factor for NMS development.

1. Introduction

Neuroleptic malignant syndrome (NMS), as a rare life‐threatening idiosyncratic reaction, is generally associated with the dose‐independent use of dopamine‐modulating pharmacologic agents, including typical and atypical antipsychotics, metoclopramides, and anti‐Parkinson's disease medications. This condition presents with a selection of symptoms, such as high fever, features of Parkinsonism, autonomic instability, mental state changes, leukocytosis, and increased levels of creatinine phosphokinase (CPK) accompanied by altered level of consciousness [1, 2]. As widely accepted, disruptions in dopaminergic transmission within the central nervous system (CNS), linked to pharmaceutical treatments, play a key role in NMS development. They often occur either as a result of taking dopamine receptor antagonists or stopping dopamine receptor agonists [3]. Besides, the abrupt withdrawal of benzodiazepines is likely to create a gamma‐aminobutyric acid (GABA)‐deficient state, manifesting catatonic symptoms [4]. Benzodiazepine withdrawal symptoms can further range from mild anxiety to severe and life‐threatening conditions, such as delirium or seizures. In individuals with particular vulnerabilities, particularly those with mood disorders, withdrawal from benzodiazepines may accordingly cause catatonia [5]. Both catatonia and NMS are thus believed to share a pathophysiology involving decreased dopaminergic transmission in the basal ganglia‐thalamocortical circuits, accounting for their overlapping clinical manifestations. This commonality further supports the idea that NMS may be viewed as a drug‐induced form of malignant catatonia [6]. In this case, NMS occurrence with no prior history, following single‐dose use of haloperidol, may suggest benzodiazepine withdrawal as an important predisposing factor.

2. Case Presentation

2.1. Case History/Examination

The patient was a 53‐year‐old man, presenting the symptoms of stupor and mutism, admitted to the Emergency Ward of a general teaching hospital in northern Iran. Due to tachypnea, aspiration pneumonia, and atelectasis on the chest computed tomography (CT) (Figure 1A,B) scans, 93% oxygen saturation, and a partial pressure of carbon dioxide (pCO₂) of 62 mm/Hg, he was admitted to the Respiratory Care Unit of the Internal Medicine Ward. Then treatment was started with intravenous (Iv) antibiotics. Given his history of alprazolam dependency, methadone maintenance therapy (MMT), and delirium during his last admission, consultation with the Liaison‐Consultation Psychiatry Service was requested. All through the examinations, stupor, generalized upper/lower limb rigidity, neck stiffness, sweating along with fever (axillary temperature: 39.8°C) were noted. The psychiatric history also revealed that the patient had suffered from high‐dose benzodiazepine dependency for 13 years. In addition, he had taken clonazepam up to 10 mg/day for 10 years, and alprazolam at 10–15 mg/day for 3 years. Of note, the patient had been treated with levodopa after visiting the neurologist 3 years earlier, but had no signs of Parkinson's disease. In the past year, he had further exhibited aggression, suspiciousness, and jealousy toward his wife, and he had suddenly discontinued alprazolam 1 week before admission. Later, he showed delirium accompanied by psychotic episodes as well as verbal and physical aggression. Two days before the most recent hospitalization, he had been referred to another general hospital in his place of residence and received intramuscular (IM) haloperidol (5 mg). A few hours after the injection, he had presented symptoms of mutism, rigidity, stupor, and posturing, but discharged upon receiving his family's consent after being diagnosed with catatonia and recommended to go to a psychiatric hospital.

FIGURE 1.

(A and B) Lung CT scan.

2.2. Differential Diagnosis, Investigations, and Treatment

Following the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5‐TR) and the +9 score in the Naranjo Algorithm [7], as the adverse drug reaction probability scale, NMS was diagnosed. The case also meets the diagnostic criteria of NMS according to Levenson's major criteria, which include fever, rigidity, and elevated CPK [8]. The initial CPK level was also 3422 IU/L, which increased to 7896 IU/L during the second day of hospitalization. The changes in CPK, lactate dehydrogenase (LDH), and serum glutamic‐oxaloacetic transaminase (SGOT) levels are illustrated in (Figures 2 and 3). Likewise, C‐reactive protein (CRP) level rose from 2 to 58 mg/dL, which is markedly elevated, reflecting an inflammatory response that may contribute to the pathophysiology of NMS (Figure 4) and the serum iron was 23 mcg/dL.

FIGURE 2.

Laboratory data: Creatine phosphokinase/lactate dehydrogenase.

FIGURE 3.

Liver function tests‐serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transferase.

FIGURE 4.

CRP (mg/dL) (Up to 6).

2.3. Conclusion and Results (Outcome and Follow‐Up)

The patient was accordingly treated using gavage bromocriptine (2.5 mg) three times a day, IM lorazepam (10 mg/day), and oral methadone (40 mg/day). Considering his hypercapnia and respiratory conditions together with alprazolam discontinuation from a week ago, a dose lower than that of the alprazolam equivalent was prescribed. In the days ahead, the bromocriptine dose was augmented to five tablets (2.5 mg/day), and the IM lorazepam dose was reduced to 9 mg/day. All through the neurological consultation, levodopa was not started due to the unclear reason for its administration and no acute pathological evidence on the brain CT scans (Figure 5). The fever correspondingly terminated on the second day of hospitalization. In the following days, rigidity and CPK levels further subsided. Ultimately, the level of consciousness and verbal communication improved, even though the patient provided meaningless answers to some questions on the third day of hospitalization. On the eleventh day of hospitalization, the NMS symptoms resolved, and bromocriptine was discontinued. At this point, the IV antibiotics were switched to oral ones, and the patient was referred to receive electroconvulsive therapy (ECT) with regard to the remaining psychotic disorder.

FIGURE 5.

Brain CT scan.

3. Discussion

The case report here was a male patient who experienced NMS following the abrupt withdrawal of alprazolam, in conjunction with the administration of the single‐dose IM haloperidol (5 mg). Although cases of NMS following antipsychotic administration have been reported, its occurrence after a single dose of haloperidol without any predisposing factor is rare. It is mentioned that high dose, rapid titration, and parenteral routes of antipsychotics are related to higher incidence of NMS [9] rather than single intramuscular dose. On the other hand, studies have shown that abrupt benzodiazepine withdrawal can lead to a GABA‐deficient state, increasing the risk of catatonia; in this case, given the onset of initial symptoms of restlessness and agitation that began after discontinuing alprazolam and before hospital admission, the diagnosis of NMS with triggering of alprazolam discontinuation is likely. However, the role of haloperidol as a causing factor cannot be ruled out, and it appears that the combination of both factors, benzodiazepine withdrawal and antipsychotic exposure, may have contributed to the development of NMS. There are few cases of catatonia occurring after the discontinuation of benzodiazepines [10]. In 2018, Iyengar et al. presented a case that developed symptoms of catatonia and rigidity after discontinuing alprazolam [10]; however, the symptoms of fever and elevated CPK were absent. Another study by Majumder et al. in 2022 [11] reported two cases of catatonia that begins after discontinuation of long‐term benzodiazepines use even at lower doses. They associated the condition with mechanisms related to GABA deficiency. Given the absence of other catatonic symptoms, along with the presence of rigidity and elevated CPK levels and presence of temporal relationship between neuroleptic administrations, the diagnosis of NMS is more likely. This is while acknowledging that NMS is a variant of catatonia [12]. The patient showed significant improvement after IM lorazepam and oral bromocriptine treatments. Although other contributing factors, such as age and delirium, could play important roles, the shared mechanisms between the pathophysiology and benzodiazepine withdrawal, along with the timing of NMS onset following a single dose of haloperidol suggested that the discontinuation of benzodiazepines could serve as a risk factor for triggering NMS.

As NMS pathophysiology was complex and not fully understood, most of its symptoms were believed to result from a sudden decrease in central dopaminergic activity, either due to the blockage of D2 receptors or the abrupt cessation of D2 receptor stimulation [13]. Additionally, the musculoskeletal fiber toxicity hypothesis suggested that the toxic effects of antipsychotic medications on calcium regulation within muscle fibers could contribute to the sustained muscle contractions and rigidity observed in NMS. This was supported by similarities between NMS and malignant hyperthermia, a condition linked to calcium dysregulation in skeletal muscle. Inflammatory responses, such as elevated acute phase reactants and low iron levels, have also been implicated in the pathophysiology, though it has remained unclear whether these are primary causes or secondary consequences of the given syndrome [14]. In this case, there was a progressive increase in CRP levels accompanied by low serum iron that could impact the course of NMS. Of note, benzodiazepines are known to multiply dopamine levels in the nigrostriatal and mesolimbic regions, as GABA has been linked to enhanced firing of dopamine neurons in the ventral tegmental area and greater dopamine metabolism in the striatum [15]. Chronic benzodiazepine use induces long‐lasting changes in the mesolimbic dopamine system by modulating GABA A receptor activity in the ventral tegmental area. These adaptations may increase sensitivity to dopamine‐blocking agents [16]. In this case, the abrupt withdrawal of benzodiazepines likely created a priming effect, leading to excessive dopaminergic suppression upon exposure to haloperidol, ultimately triggering NMS and better response to bromocriptine, a dopamine agonist. As pointed out in some studies, the long‐term use of benzodiazepines could reduce hippocampal volume and impair neuroplasticity associated with the changes in dopamine activity [11]. Additionally, long‐term use might induce alterations in the dopaminergic system, potentially lowering dopamine levels, which could influence mood regulation and cognitive functions. Structural changes, such as brain atrophy, have additionally been observed in cases of prolonged benzodiazepine use, particularly in regions like the frontal cortex [17]. The changes in GABAergic activity could also play a leading role in NMS development. In cases of abrupt withdrawal from GABAergic agents like benzodiazepines, the resulting decrease in GABA activity could further lower dopamine levels. This reduction in dopaminergic signaling might contribute to the onset by disturbing the balance between dopamine and acetylcholine, thereby promoting motor rigidity and autonomic dysfunction [18].

4. Conclusion

This case highlights the risk of abrupt benzodiazepine withdrawal in triggering NMS. Clinicians should cautiously taper benzodiazepines in long‐term users and consider alternative strategies for managing benzodiazepine withdrawal and avoid the administration of antipsychotics to prevent severe complications. Additionally, clinicians should be mindful to distinguish benzodiazepine withdrawal delirium from other forms of delirium and prioritize the use of benzodiazepines, rather than antipsychotics, in treating withdrawal complications.

Author Contributions

Behnam Abbasi: validation, writing – original draft, writing – review and editing. Forouzan Elyasi: conceptualization, data curation, investigation, supervision, validation, writing – original draft, writing – review and editing. Masoud Aliyali: investigation.

Ethics Statement

The research protocols were conformed to the tenets of the Declaration of Helsinki. The research proposal was approved by the Ethics Committee affiliated with Mazandaran University of Medical Sciences [IR.MAZUMS.REC.1403.370].

Consent

Written informed consent for the publication of this manuscript was obtained from the patient and his spouse.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbasi B., Elyasi F., and Aliyali M., “Is Abrupt Withdrawal of Benzodiazepines a Risk Factor for Neuroleptic Malignant Syndrome? A Case Report With Single‐Dose Haloperidol,” Clinical Case Reports 13, no. 7 (2025): e70632, 10.1002/ccr3.70632.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.