Neuroleptic malignant syndrome (NMS) is a rare, life-threatening condition traditionally associated with antipsychotic medications or the abrupt withdrawal of dopamine receptor agonists [1]. While NMS may occur across all age groups and sexes, a predilection for young adult males has been consistently documented, suggesting a sex-specific susceptibility to dopaminergic pathway modulation [2]. Clinically, NMS manifests as a tetrad of hyperthermia (>38 °C), severe muscle rigidity, autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis), and altered mental status, which may progress from delirium to stupor or coma [2,3].

Diagnostic challenges arise when hallmark features, particularly rigidity, are absent, as the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for NMS remain insufficiently sensitive to atypical presentations [3]. This report describes an atypical case of NMS occurring after abrupt discontinuation of long-acting depot flupentixol. We present the case of a woman in her sixties who developed NMS without the hallmark feature of muscle rigidity, a presentation rarely reported in the literature. This case illustrates the diagnostic challenges of atypical NMS and highlights the need for increased clinical vigilance, especially in older female patients who may not exhibit classic signs such as muscle rigidity.

A 61-year-old female with a documented history of schizophrenia was admitted to the intensive care unit (ICU) with respiratory infection, hypotension (systolic blood pressure, 70 mm Hg; diastolic blood pressure, 50 mm Hg), metabolic acidosis, hypoglycemia (serum glucose, 52 mg/dL), and acute hypoxemic respiratory failure requiring invasive mechanical ventilation under continuous sedation. Initial management included discontinuation of all psychotropic medications and initiation of empiric broad-spectrum antimicrobial therapy, along with aggressive intravenous fluid resuscitation and vasopressor support for hemodynamic stabilization.

NMS is a life-threatening hypermetabolic condition that is primarily attributed to central D2 receptor antagonism [2]. Although rare, its incidence is estimated to range between 0.02% and 3% among patients exposed to antipsychotics [1], and mortality can be significant without prompt treatment [3-5]. Classically, NMS is more common in young males [2]; however, our case involving a woman in her sixties underscores the broad demographic variability and associated diagnostic challenges [6].

Two pathophysiological hypotheses have been proposed: (1) central D2 receptor blockade in the hypothalamus and basal ganglia leads to thermoregulatory, motor control, and autonomic dysfunction, underlying hallmark features such as hyperthermia, muscle rigidity, and altered mental status; and (2) direct neuroleptic toxicity in skeletal muscle induces calcium dysregulation [6].

Common risk factors include high-potency first-generation antipsychotics (especially parenteral forms), abrupt withdrawal of dopaminergic agents, environmental factors (e.g., heat), dehydration, or catatonia [6-8]. In our case, inconsistent depot antipsychotic use, abrupt cessation of flupentixol, and concurrent tryptophan intake were likely contributing factors. In pathophysiologic hypothesis, despite drug discontinuation, long-acting flupentixol may sustain clinically relevant D2 receptor occupancy for several weeks, thereby maintaining dopaminergic hypoactivity. Exogenous L-tryptophan may further shift the monoaminergic balance toward serotonergic tone, and 5-HT2C–mediated inhibition of midbrain dopaminergic firing can exacerbate functional dopamine deficiency—collectively lowering the threshold for NMS in predisposed individuals [9,10]

Although NMS typically presents with hyperthermia, generalized muscle rigidity, altered mental status, and autonomic dysfunction, our patient's course differed significantly [1,6] . Autonomic instability—manifested by persistent tachycardia, blood pressure fluctuations >30 mm Hg), episodic hyperthermia, and profuse diaphoresis—fulfilled DSM-5 criteria for NMS [11]. This supports a diagnosis of dysautonomia, even in the presence of hypotension due to systemic illness.

Notably, the patient lacked rigidity and instead exhibited generalized tremors and hyporeflexia, a rare neuromuscular pattern [4,11]. Although such variations have been sporadically reported [4], the combination of advanced age, female sex, and absence of rigidity renders this case particularly atypical. Although her initial altered mental status was attributed to hypoglycemia and hypotension amid suspected septicemia, persistent stupor raised the suspicion of NMS. Autonomic instability could not be fully explained by sepsis, and multiorgan involvement with delayed symptom onset post-antipsychotic withdrawal further complicated the diagnosis [3,6,12].

A striking feature is the absence of CK elevation despite significant autonomic dysfunction, highlighting the limitations of CK as a diagnostic marker [4]. According to the DSM-5, the diagnosis of NMS requires exposure to dopamine-blocking agents, severe muscular rigidity, fever, and at least two of the following: diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, or elevated serum CK levels [1].

In this case, the patient received a long-acting intramuscular dopamine antagonist (flupentixol) and presented with high-grade fever (39 °C), decreased consciousness, tachycardia, hypotension, and normal CK levels. Table 1 summarizes the DSM-5 criteria and corresponding clinical findings. Most clinical guidelines consider muscle rigidity a cardinal feature in differential diagnosis, and all diagnostic frameworks emphasize the need to exclude other conditions with similar symptom profiles [2,6]. Initial brain computed tomography and cerebrospinal fluid analyses were unremarkable. Despite the temporal association with tryptophan, the patient did not meet the Hunter Serotonin Toxicity Criteria, the standard for diagnosing serotonin syndrome. Spontaneous or inducible clonus, hyperreflexia, and neuromuscular hyperactivity were absent during the clinical course [13]. The distinct onset, progression, and resolution of the symptoms further differentiated this case from the serotonin syndrome [13]. Serotonin syndrome typically emerges within 24 hours of serotonergic exposure or dosage escalation, whereas NMS has a more insidious onset, developing days to weeks after antipsychotic exposure [13]. Moreover, serotonin syndrome often resolves rapidly after discontinuation of the offending agent, without specific intervention. In contrast, NMS follows a more protracted course, with symptom resolution requiring several days to weeks, even with appropriate treatment [13].

Neuromuscular manifestations also differ: serotonin syndrome is characterized by hyperactivity (tremors, clonus, and hyperreflexia), while NMS is characterized by hypoactivity (rigidity, hypokinesia, and bradykinesia)—all observed in our patient [13]. Serotonin syndrome, critical illness neuropathy, and ICU-acquired weakness were considered in the differential diagnosis. However, the absence of hallmark features, such as hyperreflexia, clonus, or serotoninergic overdose, combined with the clinical context, favored a diagnosis of atypical NMS. Furthermore, the patient's recovery was notably slow, with significant clinical improvement only after approximately 4 weeks of treatment, including bromocriptine initiation. This highlights the absence of a single pathognomonic laboratory marker for NMS. Patients may exhibit metabolic acidosis or hypoxia in approximately 75% of cases, leukocytosis (with or without a left shift), elevated serum creatine phosphokinase in up to 95% of cases originating from the skeletal muscle, and myoglobinuria in approximately 67%.

Acute renal failure may result from muscle necrosis due to ischemia, hyperthermia, or rigidity [2,14]. Our patient initially developed metabolic acidosis and respiratory insufficiency, which progressed to respiratory acidosis secondary to muscular weakness. Despite normal CK levels, renal function remained preserved, and acute kidney injury did not occur. Ultimately, multidisciplinary collaboration among the ICU, neurology, and psychiatry teams was essential in managing this atypical NMS case, demonstrating the expanding clinical spectrum of the syndrome [12].

Treatment strategies for NMS are based on expert consensus and case series [2,6]. Benzodiazepines, such as lorazepam or clonazepam, can alleviate catatonia, mutism, fever, and rigidity within 24–48 hours [2,6]. In our patient, clonazepam (0.5 mg nightly) improved mutism. Dopaminergic agents, including amantadine and bromocriptine, are known to reverse parkinsonian symptoms and reduce mortality [2,6]. Bromocriptine was initiated at 2.5 mg BID, resulting in significant resolution of fever and tremor, and was continued for 10 days to prevent relapse. Dantrolene may be considered for rigidity and hyperthermia, although it was not employed in this case because of the absence of rigidity [2,6]. Electroconvulsive therapy is generally reserved for pharmacoresistant or catatonic cases but was unnecessary in this patient, given her clinical improvement with medical therapy [1,2,6].

This case exemplifies the diagnostic complexity of atypical NMS and highlights the importance of clinical vigilance when hallmark features, such as rigidity or extreme hyperthermia, are absent. Despite normal CK levels and lack of rigidity, the patient’s constellation of autonomic instability and encephalopathy underscores the evolving clinical spectrum of NMS. Multidisciplinary coordination remains critical for accurate diagnosis and effective recovery. Heightened awareness of atypical presentations, particularly in elderly female patients receiving depot antipsychotics, is essential for timely intervention and improved clinical outcomes.