Authors: Lu Liu, Zhi-Rong Zhang, Chun-Feng Chen
Categories: Case Report, Serotonin syndrome, Neuroleptic malignant syndrome, Quetiapine, Sertraline, Adolescent
Source: BMC Psychiatry
Authors: Lu Liu, Zhi-Rong Zhang, Chun-Feng Chen
Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) are more likely to occur in psychiatric patients. Both conditions have a low incidence rate but can be life-threatening in severe cases.they are easily overlooked, misdiagnosed, or missed in clinical practice.
A case of a girl who ingested 700 mg of sertraline,350 mg of quetiapine and 90 mg of oxazepam, presenting with altered consciousness, hallucinations, muscle rigidity, and rhabdomyolysis. Laboratory results showed a creatine phosphokinase (CPK) concentration of 20,930 U/L, lactate dehydrogenase (LDH) of 593 U/L, and white blood cell (WBC) count of 15.1 × 10^9/L. The patient met the diagnostic criteria for both Serotonin Syndrome and Neuroleptic Malignant Syndrome, possibly exhibiting both adverse drug reactions closely spaced. Treatment involved discontinuing the implicated drugs, providing tracheal intubation, ventilatory support, continuous renal replacement therapy (CRRT), cardiac protection, anti-inflammatory treatment, norepinephrine to maintain blood pressure, and other treatments to support organ function. The patient recovered after one month.
This article analyzes the clinical data and reviews the literature to discuss the management of severe complications caused by antipsychotic drugs and antidepressant drugs, aimed to improve awareness of these two adverse reactions. Guardians should strictly monitor the patient’s medication usage to prevent the child from freely accessing medications, thereby avoiding self-medication or overdose.
Serotonin Syndrome(SS) is a rare, potentially life-threatening syndrome caused by adverse reactions to serotonergic drugs. SS can occur with an overdose of serotonergic drugs,or monoamine oxidase inhibitors(MAOIs) appeared after combined with 5-HTergic drugs [1].The typical clinical features of SS are changes in mental status (anxiety, agitation, and confusion), autonomic instability (tachycardia, sweating, high fever, etc.), neuromuscular dystonia(hyperkinesia, myoclonus, tremors, etc.) [2]. Neuroleptic malignant syndrome (NMS) is another rare and severe drug side effect, mainly caused by antipsychotics. The main clinical manifestations include high fever, disturbance of consciousness, extrapyramidal reactions (such as muscle rigidity,), elevated creatine phosphokinase (CPK) levels (at least 4 times higher than normal upper limits), and autonomic nerve dysfunction[3]. It occurs when the drug is stopped suddenly, when the psychotics are changed, when the antipsychotics are used in large doses, or a rapid increase in the doses [4, 5]. The clinical symptoms of SS and NMS are very similar.With the increasing trend of combining serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics(SGAs) [6], it is difficult to distinguish between SS and NMS in patients with altered mental status, high fever, muscle stiffness, and hyperautonomic nervous system.
There is a case report of SS and NMS occurring with the combined use of antidepressants and antipsychotic drugs, where the patient was older, had multiple underlying diseases, and the condition was caused by a combination of various medications [7]. Cases of SS caused by overdose on sertraline or NMS caused by quetiapine have been reported [8, 9]. However, there have been no reports of SS and NMS occurring in adolescents with the sole use of sertraline combined with quetiapine. Here, we report a case of an adolescent who ingested an overdose of sertraline and quetiapine, showing characteristic clinical features of both SS and MNS. The case presented with alteration of mental status, autonomic instability and neuromuscular hyperexcitability. Based on the characteristic clinical features, laboratory findings and clinical course, diagnise serotonin syndrome and neuroleptic malignant syndrome. It is worth pointing out that no similar case has been reported. This case report aims to raise awareness and medication regulations for adolescents with depression. Raising awareness and alerting patients to the fact that rapid increases in drug doses in patients with depression while using antidepressants in combination with antipsychotics may significantly increase the risk of serious adverse reactions.
A 15-year-old junior high school girl was admitted to the Emergency Department of a University Hospital because of symptoms including changes in consciousness, hallucinations, rigidity in muscle tonus, unsteady gait, nausea and vomiting, and fever. Prior to her first depressive episode approximately 12 months ago, she had no history of mental disorders or physical illnesses. The onset was precipitated by academic stress and parental conflict, manifesting as symptoms including depressed mood,marked anhedonia,decreased energy, irritability,insomnia,social withdrawal and impaired concentration, resulting in a sharp decline in academic performance and frequent absenteeism. Initially misinterpreted by her parents as malingering, she did not receive timely medical attention.
The patient subsequently developed headaches, palpitations, chest tightness, anorexia with significant weight loss, and psychotic features including auditory hallucinations of derogatory content. The progression of these severe symptoms ultimately prompted her parents to take her to the hospital. Following medical evaluation excluding organic etiologies, she was diagnosed with major depressive disorder with psychotic features. Pharmacotherapy was initiated with sertraline (50 mg/day) and quetiapine (25 mg/day).
Approximately one month prior to the current admission, the patient’s depressive symptoms worsened following perceived failure in her school physical-fitness examination, characterized by persistently low mood.Two days prior to admission, severe agitation and insomnia led her to self-administer 6 tablets of oxazepam (90 mg). One day before admission, following an argument with her mother, she attempted suicide by ingesting 14 tablets of sertraline (700 mg) and 14 tablets of quetiapine (350 mg) at 30 p.m. By 00 a.m. the next morning(day of admission), the patient experienced confusion, hallucinations, fever, muscle rigidity, nausea,vomiting, and tachycardia.
She was admitted to the hospital at 30 a.m.Physical Temperature 38.9 °C, heart rate 110 beats/minute, blood pressure 127/72 mmHg, height 155 cm, weight 33 kg, Body Mass Index (BMI) 13.7 kg/m^2^, she wan consciousness clouded and scored 11/15 on the Glasgow Coma Scale (GCS),mentally exhausted, pale complexion,sweating, tachypnea(RR 26 bpm), generalized paroxysmal muscle tremor manifestations,bilateral inducible ankle clonus. The Electrocardiogram (ECG) demonstrated sinus tachycardia.The laboratory results at admission were as white blood cell (WBC) count 15.1 × 10^9/L, alanine transaminase (ALT) 48 U/L, aspartate transaminase (AST) 313 U/L, creatine phosphokinase (CPK) 20,930 U/L, lactate dehydrogenase(LDH)593 U/L, amylase 237 U/L (Table1). Brain Magnetic Resonance Imaging(MRI) was performed to rule out organic causes of psychosis, with normal findings.The Chest Computed Tomography (Chest CT) scan was normal.Over the next 24 h, the patient presented with a decrease in blood pressure(94/50 mmHg), coma(GCS 6), seizure, muscular hypertonia, respiratory distress(RR 35 bpm, 91% on room air) and an anuric phase of acute renal failure. Preliminary 1. Neuroleptic malignant syndrome? 2. Serotonin syndrome ?3. Rhabdomyolysis 4. Nutritional risk 5. Acute kidney failure. Considering the patient’s critical condition, she was transferred to the Intensive Care Unit (ICU).The initial treatment includes stop the antidepressant and antipsychotic medications;Airway tracheal intubation(Day 2 00),sedation:Propofol (50 mg/h) and Fentanyl (50 μg/h),neuromuscular Rocuronium (5 mg/h);Temperature control was managed with a combination of aggressive physical cooling and administration of chlorpromazine and promethazine;ventilator-assisted breathing;Remal continuous renal replacement therapy (CRRT),include Plasma Exchange,Hemoperfusion,Continuous Veno-Venous Hemofiltration(CVVH); cardioprotective, antiepileptic treatment (Valproate sodium,20 mg/kg/day IV), broad-spectrum antibiotics for anti-inflammatory purposes (Piperacillin-tazobactam 3.375 g q6h); Nutritional Initiated enteral nutrition at 25 kcal/kg/day on ICU day 2;Norepinephrine to maintain blood pressure, and other treatments to maintain organ function.Such as Hepatoprotection: N-acetylcysteine infusion.GI Pantoprazole 40 mg qd.Metabolic Electrolyte repletion.Renal Strict fluid balance monitoring and electrolyte correction protocol.Table 1Evolution of key clinical and laboratory parameters during treatmentFootnote: PH, potential of hydrogen; AST, alanine aminotransferase(U/L);ALT,aspartate aminotransferase(U/L);Creatine phosphokinase (CPK);CREA, creatinine(µmol/L); LDH, lactate dehydrogenase (IU/L); WBC, white blood cell(× 10^9/L);BNP, B-type natriuretic peptide(ng/L) ;TNT, troponin T(µg/L);AMY, amylase (IU/L); Ca, K(mmol/L);
Reference PH:7.35-7.45;AST:13-35U/L;ALT:7-40U/L;CREA:45-84µmol/L;CPK:40-200U/L;LDH:120-250U/L;WBC: 3.5-9.5 × 10^9/L; BNP:0-100ng/L;TNT:0-0.026µg/L;AMY:35-135IU/L;Ca:2.11-2.52mmol/L;K:3.5-5.3mmol/L.
On hospital day 6, the patient’s condition worsened, and the ECG indicated ventricular tachycardia; The Chest CT scan showed scattered inflammatory changes in both lower lungs. Sputum Klebsiella pneumoniae (MDR, ESBL+);Blood Methicillin-resistant Staphylococcus aureus (MRSA).CPK was very higher (26384 U/L), LDH 723 U/L, BNP383.8 U/L,INT 0.008 µg/L (Table 1), muscle rigidity and the condition was critically ill.
The therapeutic strategy involved controlling the ventricular rate with amiodarone along with maintaining electrolyte balance; continue enteral nutrition and CRRT treatment. Antimicrobial therapy was escalated Linezolid 600 mg IV q12combined with Piperacillin-tazobactam 3.375 g IV q8h.Dual coverage was maintained for 7 days until clinical improvement, then de-escalated to piperacillin-tazobactam monotherapy per antimicrobial stewardship protocol.
On day 21, the patient’s condition improved and she was transferred to the general ward of the Neurology Department for further treatment. Subsequently, on day 30, she was transferred to the Rehabilitation Department for intensive rehabilitation therapy, and she was discharged home from the Rehabilitation Department on day 50.At discharge,the patient had achieved a significant weight gain, reaching 38 kg (BMI: 15.8 kg/m^2^), marking a substantial improvement from her admission nutritional status despite remaining underweight.She resumed taking sertraline, starting from 25 mg/day and gradually increasing the dosage up to 100 mg/day, and was started olanzapine (1.25 mg/day). To date, no adverse reactions have been reported.
Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) are more likely to occur in psychiatric patients. Both conditions have a low incidence rate but can be life-threatening in severe cases [1, 3]. Due to their diverse and nonspecific presentations, they are easily overlooked, misdiagnosed, or undiagnosed in clinical practice.[2, 10].
Serotonin Syndrome is a syndrome caused by serotonergic drugs, resulting in acute toxic reactions due to excessive activation of 5-Hydroxytryptamine(5-HT) receptors in the central and peripheral nervous systems [1].While most commonly precipitated by pharmacodynamic interactions between multiple serotonergic agents (e.g., SSRIs, SNRIs), it may also follow an overdose of a single drug [11]. With the increasing global use of antidepressants, the incidence of this adverse reaction is likely to rise. The onset and progression of SS are highly dependent on the underlying an acute overdose typically triggers a rapid onset of symptoms (often within hours), whereas cases arising from therapeutic dose increments or drug interactions may exhibit a more insidious onset over several days[12].
Currently, there is no gold standard for the diagnosis of SS. The Hunter criteria, established by Dunkley et al. [13], which is commonly used, operates on a diagnostic algorithm. A patient must have recently taken a serotonergic agent and meet one of the following ①Spontaneous clonus;②Inducible clonus plus agitation or diaphoresis;③Ocular clonus plus agitation or diaphoresis;④ Tremor plus hyperreflexia;Hypertonia plus hyperthermia ( > 38°C) plus ocular clonus or inducible clonus.Exclusion of other potential causes (e.g., infection, metabolic disorders, substance withdrawal).In this case, the patient developed confusion, sweating, tachycardia, fever, tremors,and seizures after an overdose of sertraline and quetiapine.This case meets the Hunter criteria, leading to a clinical diagnosis.
SS can be classified into mild, moderate, and severe levels based on symptom severity. Mild cases often present with anxiety, tachycardia, sweating, hypertension, tremors, and hyperreflexia; moderate cases may have irritability, clonus, hyperthermia, delirium, horizontal nystagmus, and increased bowel sounds on top of mild symptoms; severe cases can present with severe hypertension, hyperthermia, rhabdomyolysis, seizures, respiratory failure, renal failure, coma, and death. [1, 13]Previous studies have found that high fever, seizures, and high CK activity may be associated with severe SS[14].
The patient presented with coma, high fever, seizures, progressive rhabdomyolysis, and very high creatine kinase activity, which was considered as severe SS. There have been reports of severe SS in an 8-year old child who was admitted to ICU after taking 1500 mg of sertraline [8].
On the other hand, there is a considerable overlap in the clinical manifestations and laboratory findings of SS, NMS and Malignant Hyperthermia(MH), such as fever, elevated white blood cell count, and increased creatine kinase levels.However,MH is a clinical syndrome primarily inherited in an autosomal dominant pattern. Its typical clinical manifestations often occur follow the use of volatile inhalational anesthetics, such as halothane, isoflurane, sevoflurane, and/or the depolarizing neuromuscular blocking agent succinylcholine [15]. Given that the patient has not used inhalational anesthetics and lacks a family history of MH, the condition can be ruled out.
The adolescent in this case was extremely underweight and malnourished, with a BMI of only 13.7. The rapid intake of 350 mg of quetiapine in a short period led to a sharp increase in the concentration of quetiapine in the body, and clinical symptoms such as altered mental status, fever, autonomic dysregulation, rhabdomyolysis, and muscle rigidity appeared, suggesting the need to consider NMS. Malnutrition can lead to muscle metabolic abnormalities, which increase the risk of developing NMS. [16]NMS is an idiosyncratic reaction to medication, which is not dose-dependent, a rapid increase in the dosage of medication, a single dose, and therapeutic doses can also trigger it.[17]
NMS is a rare but serious psychiatric complication that often occurs when antipsychotics are changed, dosages are increased, or medications are combined [18]. The incidence of NMS ranges from 0.02% to 3.23%, with a fatality rate of 20% [19]. The main clinical manifestations of NMS include muscle rigidity, hyperpyrexia, altered consciousness, and unstable autonomic nerve dysfunctions. Laboratory test results revealed increased leukocyte and creatine phosphokinase levels[3]. Severe patients often suffer from various physical complications, including pneumonia, renal failure, heart failure, sepsis, pulmonary embolism, and even death[20].
In clinical work,International Expert Consensus on NMS diagnostic criteria include [21]:1. Exposure to a dopamine antagonist within the past 72 hours, or withdrawal from a dopamine agonist0.2.Hyperthermia ( > 100.4°F or > 38.0 °C on at least two occasions, measured orally)0.3.Rigidity0.4.Altered mental status (reduced or fluctuating level of consciousness)0.5.Creatine kinase elevation (at least four times the upper limit of normal).
6.Sympathetic nervous system lability0.7.Hypermetabolism0.8.Negative work-up for infectious, toxic, metabolic, or neurological causes.On the basis of the patient’s medical history and clinical symptoms the patient met the diagnostic criteria for NMS.
The pathogenic mechanism of NMS remains unclear. However, it may be caused by decreased dopaminergic activity in the central nervous system and dysregulation of autonomic nervous system activity [22–24]. Quetiapine is an atypical antipsychotic agent that is metabolized in the liver and discharged in urine. Compared to other antipsychotic agents, such as olanzapine, risperidone, aripiprazole, clozapine, and haloperidol, quetiapine has the lowest binding affinity to the D2 receptor, with an antagonistic effect [25] Patients treated with quetiapine had a lower risk of developing NMS than those treated with antipsychotics did. However, almost all antipsychotics are associated with the risk of NMS, especially large doses, and a rapid increase in drug dosage is a risk factor for NMS [26, 27].
Considering that the patient meets the diagnostic criteria of SS and NMS, combined with clinical characteristics, laboratory examination results and clinical course.We considered that the patient may have two toxidromes occurring in close succession.Research have shown that cyproheptadine has non-selective 5-HT antagonism, which can relieve SS symptoms by antagonizing 5-HT 1A and 5-HT 2A receptors, and is the most commonly used specific drug for SS treatment in clinical practice [14].However, we did not choose cyproheptadine in treatment, because the patient’s condition was critical and combined with gastrointestinal dysfunction, cyproheptadine was only available in oral preparation, its absorption is unstable after oral administration, and its onset of action is relatively slow. Considering the patient’s toxic side effects from both SS and NMS, we did not use dantrolene, which is used to treat malignant syndrome.
Research has established benzodiazepines as the first-line therapeutic agent for SS [2]. In the present case, however, the patient’s pre-hospital self-administration of a substantial 90 mg dose of oxazepam led to the clinical judgment that additional benzodiazepines posed an unacceptable risk of compounded respiratory depression and oversedation. Consequently, it was decided to avoid administering additional benzodiazepines.This cautious approach extended to temperature control. The management consisted of aggressive physical cooling supplemented with chlorpromazine and promethazine. Meperidine, a component of the traditional “lytic cocktail,” was deliberately omitted due to its well-documented serotonergic activity and potential to exacerbate SS [28]. A key limitation was the use of chlorpromazine, a dopamine antagonist, which carries a risk of inducing or worsening NMS [29]. This decision, made during the initial diagnostic uncertainty between SS and NMS.This case reinforces the principle that when faced with such a diagnostic dilemma, first of all, immediately stop all suspected drugs.Secondly, before a clear diagnosis is made, be careful to avoid using any drugs that may worsen the condition, whether it is serotonin or dopamine.Finally, adhering to this principle is crucial for the safe treatment of complex neurotoxic syndromes.
In recent years, the incidence of depression among children and adolescents has been increasingly recognized as a serious public health issue. The use of SSRIs and atypical antipsychotic medications among children and adolescents has risen [30]. SS and NMS are both potentially life-threatening drug effects. However, SS and NMS are still not fully recognized by doctors, especially in children and adolescents, which are easy to be misdiagnosed [31].
In this case, an early diagnosis was made due to a clear history of medication use, as well as the triad of psychiatric, muscular, and autonomic signs. Discontinuing serotonergic and antipsychotic medications and providing supportive care remain the pillars of treatment. Adolescent depression is often associated with impulsive suicidal behaviors. During the treatment period, guardians should strictly monitor the patient’s medication usage to prevent the child from freely accessing medications, thereby avoiding self-medication or overdose. Students living on campus can be managed by teachers or dormitory staff members.
This case highlights a life-threatening presentation following intentional overdose of sertraline and quetiapine in an adolescent with depression, manifesting overlapping features of SS and NMS.Clinicians should maintain a high index of suspicion for both entities whenever an adolescent presents with fever, altered mental status, dystonia, autonomic instability, or markedly elevated creatine kinase after psychotropic ingestion. Immediate drug discontinuation, aggressive supportive care (including continuous renal replacement therapy/CRRT), and early intensive monitoring are all essential for survival.
Families must recognise the severity of adolescent depression and the lethal potential of seemingly “safe” medications. Therefore, secure storage and direct supervision of every dose constitute the simplest, yet most effective, preventive measures. From a therapeutic perspective, non-essential polypharmacy should be avoided; when combination therapy is unavoidable, an ultra-low initial dose with careful up-titration is recommended. Furthermore, comprehensive education of both patient and caregivers regarding medication safety and early warning signs of toxicity is not only advised but imperative.