Another Option for Aggression and Self-Injury,Alternative Benzodiazepines for Catatonia in Profound Autism

Abstract

Introduction:

Individuals with profound autism often present for inpatient care due to aggression. Diagnostic and treatment options are limited. Agitated catatonia is a treatable comorbidity in autism, which should be considered in cases of aggression. Preliminary data report high clinical response rates of catatonia in autism when treated with electroconvulsive therapy (ECT), with poor response to lorazepam. However, access to ECT is often limited, especially in pediatric populations.

Methods:

We conducted a retrospective chart review to identify cases of hyperactive catatonia with partial response to lorazepam in profoundly autistic children presenting to the pediatric medical hospital. Five cases were identified, all of whom were followed by the child and adolescent psychiatry consult-liaison service during admission and treated without the use of ECT. Data from the medical record were obtained after institutional review board (IRB) approval including the following: (1) treatment course, (2) Bush-Francis Catatonia Rating Scale (BFCRS) scores, and (3) Kanner Catatonia Rating Scale (KCRS) severity scores. The Clinical Global Impressions–Improvement (CGI-I) Scale was applied retrospectively to each case.

Results:

All five patients demonstrated clinically significant improvements. The average CGI-I score was 1.2. The average percentage reduction in the BFCRS and KCRS severity scores was 63% and 59%, respectively. Two of five patients were first stabilized with infusions midazolam and dexmedetomidine due to the symptom severity and then transitioned to long-acting oral benzodiazepines. Overall, four of five patients were stabilized with oral clonazepam and one of five with oral diazepam. Notably, four of five patients experienced an acute worsening of aggression, self-injury, and other catatonic symptoms with escalating dosages of antipsychotic treatment, which occurred before inpatient admission. All patients experienced resolution of physical aggression toward self and/or others, experienced improvement in their communicative abilities, and were able to return home or enter residential level of care upon discharge.

Conclusions:

Given the limited availability of ECT and the unclear utility of lorazepam for hyperactive catatonia in autism, the use of long-acting benzodiazepines and/or midazolam infusion may offer a safe and readily available treatment alternative.

Introduction

Autism is a heterogeneous neurodevelopmental disorder (NDD), which presents with restricted behaviors/interests and deficits in social interactions (Mottron and Bzdok, 2020). Per the 2022 Lancet Commission, profound autism (PA), defined as autism with intellectual disability (AID) and language impairment, is the most severe phenotype of autism (Lord et al., 2022). PA is prevalent (Lord et al., 2022) and associated with frequent medical and psychiatric inpatient admissions for externalizing behaviors, including aggression as well as severe and recurrent self-injury (Becker et al., 2020; Siegel et al., 2015; Wachtel et al., 2018).

Clinical care of aggression and self-injury in PA can be challenging due to limited treatment options and a complex range of contributing factors including but not limited to challenges in social relatedness, external pressure to deviate from topics of restricted interest, low adaptive functioning skills, cognitive impairment, and possible conflict with caregivers (Fitzpatrick et al., 2016; Henneberry et al., 2021; Langenfeld et al., 2021). Under such circumstances, consideration of catatonia as a potential cause of aggression and self-injury in PA is warranted.

Catatonia is a psychomotor syndrome with affective domains and distinct physical examination findings. While classically reported in schizophrenia, affective disorders, and medical illness (Wachtel et al., 2011), interest in catatonia presenting in autism has risen (Billstedt et al., 2005; Wing and Shah, 2000). A recent meta-analysis by Vaquerizo-Serrano et al. found that 20.2% of autistic individuals had features of catatonia, with 10.4% having a diagnosis of catatonia. The most common symptoms of autism in catatonia were new onset speech impairment, negativism, and aggression (Vaquerizo-Serrano et al., 2021). Moreover, recent literature has suggested that recurrent self-injury is a symptom along the catatonia spectrum for PA individuals (Wachtel et al., 2018). Thus, while traditionally described catatonic symptoms do occur in autism, an excited and agitated phenotype with accompanying recurrent self-injury may be more common.

The agitated phenotype also increases the difficulty in conducting a comprehensive physical examination, which is of clinical significance as abnormal physical examination findings are key in differentiating catatonia from baseline PA symptomology. Deficits in communication, hyperactivity, irritability, stereotypies, mannerisms, grimacing, echolalia, and echopraxia are symptoms that are often present in both autism and catatonia. However, the following components of the catatonia physical examination are not observed in autism and are instrumental in determining if comorbid catatonia is present: posturing, waxy flexibility, ambitendency, and catalepsy (Carroll et al., 2008; Vaquerizo-Serrano et al., 2021).

For pediatric patients with autism and comorbid catatonia, the following symptoms can be used to differentiate acute catatonia from autism: new onset urinary incontinence, acrocyanosis, and schizophasia (Benarous et al., 2016). Individuals with PA and comorbid catatonia are also at an increased risk for having catatonic symptoms, especially in the setting of the agitated phenotype, attributed to psychological distress, pain, or caregiver conflict. In summary, there are multiple factors that may contribute to underrecognition and treatment delay of catatonia in this patient population (Vaquerizo-Serrano et al., 2021).

A missed diagnosis of catatonia is of concern as it may result in worsening/ongoing aggression, and/or progression to malignant catatonia, a condition associated autonomic instability and rates of mortality as high as 10%–20% if left untreated (Walther et al., 2019). Encouragingly, treatment of catatonia with electroconvulsive therapy (ECT) and lorazepam has been associated with high clinical response rates in affective and psychotic disorders (Beach et al., 2017). Overall, research has shown that ECT is associated with the highest rate of clinical efficacy in catatonia for adult patients, regardless of associated disorder (Bush et al., 1996; Fink, 2013). Preliminary research also reports high clinical response rates of catatonia for adults and children with autism when treated with ECT, whereas the efficacy and tolerability of lorazepam have been called into question (Park et al., 2020; Smith et al., 2022b; Vaquerizo-Serrano et al., 2021; Wachtel, 2019).

For persons of any age, the use of ECT in the United States is limited due to a lack of provider availability, stigma, and underutilization, especially in rural settings (Espinoza and Kellner, 2022; Ong et al., 2023). For persons younger than 18 years, state-dependent legislation often determines ECT availability, even in emergent and life-threatening cases. Inconsistent, although legally mandated, age cutoffs for ECT treatment in minors are present in the following states: California, Colorado, Georgia, Tennessee, New York, Ohio, and Texas (Miller et al., 2022; Ong et al., 2023). Thus, consideration of other emergent treatment options is critical.

In this article, we report the safe and efficacious use of midazolam infusion and/or long-acting benzodiazepines (LABZDs) in the treatment of agitated catatonia for five minimally verbal children with PA presenting with new onset aggression. LABZDs were used after patients failed a lorazepam challenge or demonstrated breakthrough symptoms of catatonia when the next dose of lorazepam was due. We aim to present the use of LABZDs in the treatment of agitated catatonia as a viable diagnostic and therapeutic consideration in PA presenting with intractable aggression and self-injury.

Methods

All patients were identified upon presentation to the emergency department between August 1, 2021, and August 1, 2022. All patients carried historic diagnoses of autism spectrum disorder and met the criteria for the disorder based on the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association, 2013). Acutely, all patients presented with intractable aggression, recurrent self-injury, profound negativism, impulsivity, frenzied psychomotor activity, increased frequency of baseline stereotyped movements, reduced oral intake, hypertension, tachycardia, frequent disrobing, and a reduction in their baseline ability to communicate verbally or nonverbally.

No acute stressors were identified, although all patients did present during the COVID-19 pandemic and experienced social disruption/routine change secondary to the pandemic. All cases were admitted to pediatric medicine and underwent a comprehensive medical evaluation, which did not identify a medical cause of the patients' symptoms. All presented with aggression that was too severe and persistent to evaluate via functional behavioral assessments and/or manage with behavioral interventions. They were evaluated by the child and adolescent psychiatry consult liaison service who identified catatonia and began treatment with lorazepam. Four of five patients had a negative response to a lorazepam challenge of ≥1 mg. Patient 3 experienced a positive response to a 0.5 mg oral lorazepam challenge. However, patient 3 then experienced breakthrough symptomology after catatonic symptoms stabilized with lorazepam.

The use of ECT was considered in all cases. The patients received care in Tennessee where by law, with the exception of acutely life-threatening presentations requiring emergent ECT treatment, individuals younger than 14 years require the following steps for ECT authorization: (1) informed consent from guardians to pursue ECT; (2) consultation with two psychiatrists who have not been providing clinical care to the patient at the time of consultation, one of whom must be board certified in child and adolescent psychiatry and have no financial incentive in recommending ECT; (3) conduct a meeting of multiple clinical providers from various fields of clinical care who must all agree that ECT is warranted; (4) attend a hearing with a judge, state legal representative, and a guardian ad litem assigned to the child; and (5) at the end of the hearing, the judge must agree that ECT is warranted.

For individuals older than 14 years, steps 1 and 2 as above are required. Thus, given the inherent delay in pursuing ECT authorization, emergent symptoms of all patients in this report, as well as family hesitancy in pursuing ECT after learning of current legislation, ECT was not pursued.

Data regarding presenting symptoms, diagnosis, treatment, and clinical outcomes were obtained retrospectively. Additionally, the Clinical Global Impressions–Improvement (CGI-I) Scale was applied to retrospectively to each case (Busner and Targum, 2007). This report was approved and overseen by the institutional review board (No. 220898). The purpose of this study was to investigate the effectiveness and safety of midazolam infusion and/or LABZDs at high dosages for individuals under the following inclusion criteria: (1) had a diagnosis of PA with comorbid catatonia, (2) presented with hyperactive catatonia that did not entirely resolve with lorazepam, (3) presented with symptoms severe enough to warrant inpatient level of care, (4) were unable to obtain ECT for acute stabilization of catatonia, and (5) were clinically assessed with both the Bush-Francis Catatonia Rating Scale (BFCRS) (Bush et al., 1996) and the Kanner Catatonia Rating Scale (KCRS) (Carroll et al., 2008).

Notably, the KCRS includes a severity assessment and standardized physical examination. The severity assessment was reported in all cases. However, the KCRS examination was unable to be safely completed in multiple cases and is not reported in this article. Therefore, all KCRS scores reported include the severity assessment only. For ease of comparison between the BFCRS and KCRS, Figure 1 contains the average-adjusted KCRS severity and BFCRS scores (current score/total possible score) across the course of treatment for all cases.

FIG. 1.

Catatonia rating measures in response to long-acting benzodiazepines.

Results

Table 1 contains a summary of all data obtained. Four of five patients in our study were white and biologically male. Patient number 2 was black and biologically female. The age range of patients included in our study was 7 to 16 years. All patients presented with new acute symptoms of aggression and recurrent self-injury, and three of five patients experienced an acute loss of previously acquired communication ability (singing or using sign language). All patients presented with symptomology warranting inpatient level of care, were diagnosed with catatonia, and underwent the lorazepam challenge. Notably, there is little literature that systematically addresses the dose of lorazepam, which constitutes a challenge (Suchandra et al., 2021), especially in pediatric cases (Ridgeway et al., 2021).

Table 1.

Treatment of Hyperactive Catatonia in Profound Autism

No.	Age (years)	Biological sex and ancestry	Relevant history and unique presenting symptoms	Unique presenting symptoms	Catatonia treatment course Medication doses are reported as the total dose administered within a 24-hour period	Changes to medication regimen at discharge or clinic follow-up Medication doses are reported as the total dose administered within a 24-hour period	CGI-I scores, percent reduction in catatonia measures	Additional notes and retrospective CGI-I scores
(1)	16	Male, White	Failed trials of aripiprazole, risperidone, and olanzapine in the treatment of aggression, self-injury, and irritability.	Three days before admission, experienced significant worsening of self-injury and aggression. Experienced a loss in previously acquired signing ability to communicate needs.	Lorazepam 4 mg IV once dose, no change in catatonia scores. PICU admission with continuous infusions of midazolam (4 mg/h) and dexmedetomidine [0.3 μg/(kg·h)]. Acute worsening of agitation and self-injury was noted after receiving a total of haloperidol 4.5 mg IM PRN in a 24-hour period.	The patient was cross-tapered from midazolam to clonazepam PO. Clonazepam was uptitrated to 6 mg before discharge. Haloperidol was reduced from 15 to 10 mg daily.	CGI-I: 1 BFCRS: 73% KCRS: 61%	Admitted to medical pediatric hospital for 4 days, discharged to residential facility for long-term care. Resolution of all presenting symptoms, including vital sign instability.
(2)	9	Female, Black	Six months before evaluation, developed aggression toward peers at school, other patients at medical appointments, family at home, and shoppers at grocery stores.	Two weeks before admission, experienced regression in previous acquired and enjoyed skill (singing) after increase in risperidone from 1.5 to 2 mg total daily dose.	Lorazepam 1 mg IM once dose, no change in catatonia scores. PICU admission with infusions of midazolam (3 mg/h) and dexmedetomidine [0.3 μg/(kg·h)]. Acute worsening of agitation and self-injury was noted after receiving a total of haloperidol 10 mg IM PRN in a 24-hour period.	The patient was cross-tapered from midazolam to diazepam PO. Diazepam uptitrated to 180 mg before discharge. Memantine initiated and uptitrated to 5 mg. Valproic acid initiated and uptitrated to 700 mg. Risperidone reduced from 2 to 1 mg daily.	CGI-I: 1 BFCRS: 55% KCRS: 31%	Admitted to medical pediatric hospital for 10 days, discharged home with family. Resolution of presenting symptoms and return of singing ability.
(3)	7	Male, White	Had a discrete episode 2 years prior aggression, lack of sleep, and urinating in usual places. Was prescribed aripiprazole without benefit. Family self discontinued and symptoms resolved over the course of months.	Lack of interest in previously enjoyed toys and games, urinating on the carpet and corners of the home, and inability to sleep.	Positive initial lorazepam challenge at 0.5 mg PO. Dose increased to 0.75 mg total daily dose (0.25 mg three times daily) without further improvements in catatonia symptoms.	Transitioned to a total daily dose of clonazepam 1.5 mg in neurodevelopmental psychiatry outpatient clinic due to breakthrough symptoms occurring at the time the next lorazepam dose was due. Clonazepam was then uptitrated to 4.5 mg total daily dose.	CGI-I: 1 BFCRS: 56% KCRS: 82%	Admitted to medical pediatric hospital for 5 days. Now followed in neurodevelopmental psychiatry clinic. Able to return to school after receiving homebound learning for an extended period of time.
(4)	16	Male, White	History of head banging, which resulted in retinal detachment and epilepsy. Historically, failed trials of olanzapine, risperidone, aripiprazole, and chlorpromazine in the treatment of aggression, self-injury, and irritability.	Discharged from a residential level of care 6 months before evaluation. Was treated for impulsivity and aggression with haloperidol.	Lorazepam 8 mg IM was administered over a 24-hour period with no change in catatonia scores. Clonazepam 1.5 mg total daily dose was initiated after failed lorazepam trial.	Clonazepam was uptitrated to 3 mg, and haloperidol was reduced to 10 mg during inpatient admission before discharge. Haloperidol was discontinued during neurodevelopmental psychiatry outpatient clinic follow-up.	CGI-I: 1 BFCRS: 55% KCRS: 59%	Admitted to medical pediatric hospital for 3 days, discharged home with family. Able to return to school, participate in special education programming, and regularly attend his siblings' baseball games; all of which he was previously unable to accomplish.
(5)^*	16	Male, White	Failed trails of risperidone, haloperidol, aripiprazole, and ziprasidone in the treatment of aggression, self-injury, and irritability.	Hospitalization 1: Presented after severe head banging, resulting in breaking glass and arterial bleed requiring surgical intervention. Experienced a loss in previously acquired signing ability to communicate needs.	Hospitalization 1: Lorazepam 8 mg PO was administered over a 24-hour period, no changes in catatonia scores. Clonazepam initiated at 1 mg total daily dose and olanzapine reduction initiated; patient transferred to inpatient psychiatry.	Clonazepam initiated and uptitrated to 1.5 mg. Memantine initiated and uptitrated to 12.5 mg. Olanzapine reduced from 22.5 mg to 10 mg daily.	CGI-I: 3 BFCRS: 50% KCRS: 40%	Before transfer to inpatient psychiatry, was able to spontaneously communicate needs via signing. Inpatient admission pursued due to ongoing concerns by family for aggression and self-injury at home.
(5)	—	—	Hospitalization 2: Returned to the hospital 2 weeks after discharge from inpatient psychiatry due to ongoing difficulties with recurrent self-injury via head banging.	Since first hospitalization: Dose of olanzapine increased to 15 mg total daily dose, started on chlorpromazine 300 mg daily. Dose of clonazepam remained 1.5 mg total daily dose, memantine was discontinued.	Hospitalization 2: Clonazepam uptitrated from 1.5 to 4.5 mg, and Olanzapine was discontinued	Clonazepam uptitrated to 4.5 mg. Olanzapine discontinued. Memantine not resumed given clinical improvement.	Compared with measures from first hospitalization CGI-I: 2 BFCRS: 77% KCRS: 60%	Admitted to medical pediatric hospital for 3 days and then discharged home with family. Now followed in neurodevelopmental psychiatry clinic.

indicates the patient's second hospitalization.

BFCRS, Bush-Francis Catatonia Rating Scale; CGI-I, Clinical Global Impressions–Improvement; IM, intramuscular administration; IV, intravenous administration; KCRS, Kanner Catatonia Rating Scale; PICU, pediatric intensive care unit; PO, oral administration.

Similar to previous research in the field, parameters of the lorazepam challenge were heterogeneous in both total dosage and route of administration (Ridgeway et al., 2021; Suchandra et al., 2021). Three of five patients underwent a lorazepam challenge via intramuscular or intravenous administration of lorazepam; two of five were challenged orally. Four of five patients had a negative lorazepam challenge, with no improvement in catatonic symptoms appreciated after lorazepam administration. The average single dose of lorazepam administered to individuals with a negative lorazepam challenge was 2.75 mg. Patients 1 and 2 had a single dose of lorazepam as part of the challenge, although both were rapidly transferred to the pediatric intensive care unit (PICU) after undergoing the lorazepam challenge due to their risk of harm to self and others in the setting of hyperactive catatonia.

Patient 4 had two doses of lorazepam 4 mg via intramuscular administration without improvement in catatonic symptoms. Patient 5 had four doses of lorazepam 2 mg via oral administration without improvement in catatonic symptoms. Patient 3 was the only patient to respond positively to the lorazepam challenge at an oral dose of 0.5 mg. Patient 3's symptoms were stable for 6 weeks on lorazepam 0.25 mg three times per day. However, he began to experience catatonic symptom breakthrough at the time the next dose of lorazepam was scheduled. Thus, he was transitioned to clonazepam for longer acting coverage.

As discussed above, two of five required intravenous treatment due to acuity and concern for injury if not rapidly addressed; this was provided in the PICU. The patients requiring PICU level of care were treated with infusions of both midazolam and dexmedetomidine with significant therapeutic benefit. After leaving the PICU, both patients were successfully transitioned to oral LABZDs at equivalent dosages to the midazolam infusion and neither required ongoing alpha agonist treatment. Four of five patients were acutely stabilized within 10 days or less and were able to either return home with their families or transfer to a residential level of care. Patient 5 was admitted medically, transferred to inpatient psychiatry, and then was readmitted to pediatric medicine soon after discharge from inpatient psychiatry. However, patient 5's symptoms were acutely stabilized during this second hospitalization within a 3-day period.

Regarding pharmacology, four of five patients were stabilized on clonazepam: with an average total daily dose of 4.5 mg. The remaining patient was stabilized on 180 mg of diazepam. No side effects were observed or reported by caregivers or clinical providers, despite the high dose of benzodiazepines administered. All five patients presented with aggression and self-injury, which was refractory to treatment with antipsychotics. Four of five patients experienced an acute worsening of aggression, self-injury, and other catatonic symptoms with escalating dosages of antipsychotic treatment, which occurred before inpatient admission. These same patients also experienced improvement in symptomology with antipsychotic reduction and/or discontinuation while receiving treatment with benzodiazepines. We note that antipsychotics were not rapidly tapered due the potentially elevated risk of withdrawal dyskinesia in this patient population (Campbell et al., 1997; Kumar et al., 2018).

Two of five patients were started on memantine and one of five on valproic acid as augmenting treatment in hyperactive catatonia (Beach et al., 2017). For all cases, the average percentage reduction in the BFCRS and KCRS severity scores was 63% and 59%, respectively. Four of five patients had CGI-I score of 1 = very much improved applied retrospectively. Patient 5 scored a CGI-I of 3 = minimally improved at the end of the first pediatric medicine hospitalization, and a 2 = much improved at the end of the second hospitalization. The average CGI-I for all five patients was 1.2. All patients experienced significant improvement in their acute symptomology, were able to return home with family or enter into residential level of care, and had improvement in their abilities to engage academically and socially.

Discussion

One current theory regarding the neurobiology of autism is that of an excitatory:inhibitory (E:I) imbalance. Per this hypothesis, cortical hyperactivity is present in autism, which may represent GABAergic dysfunction and/or hyperplasticity due to impairment of long-term cortical plasticity mechanisms (Casanova et al., 2020; Rojas, 2014; Smith et al., 2022a). Recent diagnostic work in transcranial magnetic stimulation of intellectually capable persons with autism (AIC) has reported enhanced cortical modulation, indicative of cortical hyperplasticity (Jannati et al., 2022; Smith et al., 2022a). Furthermore, recent preliminary magnetoencephalographic research has reported greater E:I imbalance in biologically male AID persons compared with AIC (Manyukhina et al., 2022), indicative of a direct correlation between the degree of E:I imbalance and cognitive impairment.

These findings, coupled with the potential role of GABAergic signaling dysfunction in catatonia (Walther et al., 2019), may explain the elevated rates of catatonia observed in this population and suggest that the risk of catatonia may be elevated in PA individuals compared with AIC persons. Moreover, a direct correlation between E:I imbalance and symptom severity offers a possible rationale for lorazepam partial response in cases of catatonia occurring in autism (Smith et al., 2022a; Vaquerizo-Serrano et al., 2021). Specifically, that a hyperplastic cortex may rapidly acclimate to a relatively short-acting benzodiazepine such as lorazepam leading to inadequately managed catatonic symptomology (Smith et al., 2022a; Vaquerizo-Serrano et al., 2021). Indeed, in our study, the only short-acting benzodiazepine that resulted in sustained clinical improvement was midazolam. We hypothesize that midazolam delivered as an hourly infusion may treat catatonic symptoms before the cortex is allowed to acclimate.

Conclusions

In our study, clinical response to lorazepam and lower dosages of clonazepam were inadequate, suggestive of possible rapid acclimation to lorazepam and low-dose LABZD. Additionally, access to ECT was limited by restrictive legislation in the state where the patients received care (Miller et al., 2022). However, all patients demonstrated a robust clinical response to higher relative dosing of LABZDs. Acute stabilization in the most severe of cases was safely and effectively implemented via PICU admission and accompanying midazolam and dexmedetomidine infusions. Thus, we suggest that consideration of catatonia as a potential cause of new onset aggression and recurrent self-injury in PA patients offers alternative diagnostic considerations and treatment options in a clinical population with few of either.

At present, there are no FDA-approved treatments for core features of autism (Henneberry et al., 2021). Moreover, aripiprazole and risperidone are the only FDA-approved treatments for irritability in autism (Henneberry et al., 2021). Such limited treatment options are of concern given the elevated catatonia prevalence rates reported in autism (Vaquerizo-Serrano et al., 2021), the risk of clinical decompensation when antipsychotics are administered to catatonic individuals as evidenced by our report and other research (Beach et al., 2017), as well as the increased prevalence of antipsychotic side effect burden in autistic persons (DeFilippis and Wagner, 2016; Henneberry et al., 2021; Smith and Pierce, 2022). Our report offers preliminary data demonstrating safety and efficacy of high-dose LABZDs for PA individuals experiencing acute catatonic symptoms of new onset aggression and recurrent self-injury, including in the setting of a negative lorazepam challenge.

Clinical Significance

Our findings are of clinical importance given the high prevalence of PA (Lord et al., 2022), limited treatment options (Henneberry et al., 2021), long-standing exclusion of PA individuals from clinical research (Russell et al., 2019), greatly elevated risk of poor outcomes and/or long-term residential placement in this patient population (Lord et al., 2022), and heterogeneous data on treatment, diagnosis, and use of lorazepam challenge in catatonia (Ridgeway et al., 2021; Suchandra et al., 2021; Vaquerizo-Serrano et al., 2021). While more research is needed, we recommend clinicians consider the use of LABZDs in the management of catatonia in autism if an individual with autism and catatonia has a negative lorazepam challenge, or a partial and/or limited response to lorazepam. Also, in cases of suspected hyperactive catatonia complicated by lorazepam nonresponsive aggression, and if oral medications are unable to be consistently administered, we recommend consideration of midazolam infusion for rapid benzodiazepine titration, followed by transition to oral LABZD once stability is achieved.

Overall, there are multiple limitations in our study. Diagnostically, in this article, we have utilized the KCRS and BFCRS for catatonia assessment (Carroll et al., 2008). The BFCRS is not designed for individuals with NDDs. The KCRS is not validated and does not include acrocyanosis, a finding reported in the validated pediatric catatonia rating scale (Benarous et al., 2016). Pharmacologically, we are unable to determine the clinical impact of antipsychotic continuation and/or reduction may have on catatonia in these cases due to slow tapering of antipsychotics in four of five cases.

Additionally, possible side effects of high-dose LABZDs were difficult to appreciate given the patients' baseline communication challenges. Future research should address the following: continued investigation of LABZDs in the treatment of catatonia in autism, the impact of antipsychotic use and/or reduction in catatonia, possible correlation between E:I imbalance and PA symptom severity, disparity of ECT access, and measurement-based care optimization of catatonia. Overall, progress in our understanding of catatonia in PA can lead to improvements in quality of life with an accompanying reduction of hospital burden following treatment of catatonia in this population.

Footnotes

Authors' Contributions

J.R.S.: Conceptualization, investigation, writing—original draft, supervision. T.Y.: Conceptualization, investigation, writing—original draft. S.W. and D.B.: Conceptualization and investigation. D.L.P.: Conceptualization, writing—review and editing, supervision. D.C.F.: Conceptualization, investigation, writing—review and editing, supervision.

Disclosure

No competing financial interests exist.

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