Treatment of Catatonia with Benzodiazepine, Electroconvulsive Therapy and Memantine in an Adolescent: a Case Report

Abstract

Catatonia is a severe psychomotor syndrome that can be life-threatening if not promptly diagnosed and treated. While benzodiazepines and electroconvulsive therapy (ECT) are established treatments for catatonia in adults, there is limited literature on their efficacy and safety in adolescents. Additionally, the use of N-methyl-D-aspartate (NMDA) antagonists, such as memantine, has been explored as a potential treatment option; however, there is a lack of extensive research in the pediatric population. We report the case of a 16-year-old boy who presented with refractory catatonia. The patient initially appeared to respond to lorazepam but experienced adverse effects, necessitating a switch to clonazepam. Despite some improvement, his condition deteriorated, leading to the initiation of ECT, which was associated with significant improvements. However, stagnation in clinical progress prompted the introduction of memantine, an NMDA antagonist. Memantine was well tolerated and appeared to contribute to further symptom resolution. The patient achieved full remission of catatonia in approximately 2 months and sustained well-being 19 weeks post-discharge with a treatment regimen of olanzapine, memantine and clonazepam. This case highlights the potential efficacy of combining benzodiazepines, ECT, and NMDA antagonists in treating refractory catatonia in adolescents. Our findings support considering NMDA antagonists in treatment protocols, particularly when conventional therapies are ineffective or inaccessible. Further research is needed to validate these results and establish comprehensive guidelines for managing pediatric catatonia.

Introduction

According to the DSM-5 (1), catatonia is characterised by the presence of at least three of the following psychomotor disturbances: catalepsy, waxy flexibility, stupor, agitation, mutism, negativism, posturing, mannerisms, stereotypies, grimacing, echolalia and echopraxia. The pathophysiology of catatonia remains unknown, although several hypotheses have been proposed, including dysfunction of neurotransmitters. It is postulated that catatonia could be secondary to dopamine hypoactivity, low GABA-A receptor binding, and glutamate hyperactivity (2).

There is no known prevalence rate of catatonia in the general population, as it is a rare clinical syndrome (3). Reported prevalence rates in children and adolescents in clinical settings vary (4). One study found a prevalence of 0.6% in a general pediatric inpatient population (5). At the same time, another reported a prevalence of 18% among patients with affective and nonaffective psychotic disorders referred to a child psychiatry outpatient clinic (6). In children and adolescents, catatonia occurs more frequently in boys, with the most prevalent underlying disease being schizophrenia (7–12). Moreover, in more than 20% of cases, catatonia is due to an underlying medical condition (3, 8, 13). Those medical conditions generally include infectious diseases, neurological and genetic conditions, and intoxications. Therefore, it is mandatory to conduct a thorough workup (14). Catatonia can be life-threatening. When compared with the general population matched for age and gender, the risk of premature mortality in the catatonia population is increased by 60-fold (15, 16). Regarding the suicide risk, it is estimated to be 500-fold higher than in the general population (17, 18). Despite this notable morbidity, catatonia remains underdiagnosed and undertreated in children and adolescents (3, 15, 19–21).

The Bush-Francis Catatonia Rating Scale (BFCRS) is a 23-item rating scale that includes a 14-item screening instrument (22). The presence of catatonia is defined by a score of 2 or more on the 14-item scale within the last 24 hours. Sum scores of the 23-item rating scale quantify the severity of catatonia, with a possible maximum score of 69 (23). The BFCRS is the only scale validated for a lorazepam challenge and is the most widely used scale worldwide (24).

The first-line treatment for catatonia is benzodiazepines. The response rate to benzodiazepines was found to be around 65% in a naturalistic study involving 66 children and adolescents (3, 9). In the event of inadequate response to benzodiazepines, bilateral electroconvulsive therapy is recommended as a second line (25–27). According to the American Academy of Child and Adolescent Psychiatry practice parameters (28), electroconvulsive therapy (ECT) may be considered for patients diagnosed with catatonia with a symptom severity that is persistently disabling or life-threatening, and a failure to at least two adequate prior treatment regimens, unless the symptom severity precludes waiting for a response to pharmacological treatment (29, 30). In cases involving adolescents with life-threatening conditions or exhibiting an imminent risk of harming themselves or others, acute ECT may be justified with the aim of reducing symptomatology, facilitating faster recovery, and mitigating impact on development (29, 31). In adolescents, ECT has been found to be safe, useful, and comparably efficient to that in adults (32). The efficacy appears comparable to that observed in adults suffering from catatonia, with response rates ranging from 80% to 100% (18, 33). One study reported a 91.6% response rate to ECT in pediatric catatonia, while another reported an 80% response (16, 34–36). Despite the available data on efficacy and safety, many doctors appear unwilling and hesitant to use ECT in adolescents. This could be attributed to societal stigma; concerns about memory loss; and lack of knowledge, training, and experience with ECT (33, 37–40).

In some parts of the world, factors such as accessibility, legislation, and ethical concerns contribute to the underuse of ECT (32, 39, 41). These limitations, combined with refractory cases, have prompted a search for alternative treatments such as N-methyl-D-aspartate (NMDA) antagonists (42–44). The distinctive feature of the case we present is the safe use of memantine, an NMDA antagonist, to treat refractory catatonia in an adolescent.

Case report

A 16-year-old male was referred for hospitalisation from a peripheral center due to catatonia, as diagnosed by a child and adolescent psychiatrist. The episode is reported to have started a few months earlier and had been more clearly deteriorating for two weeks. Over the previous few months, the family had sought consultation a few times, and a diagnosis of depression had been made based on symptoms of psychomotor retardation. Trazodone was initially started, followed by citalopram up to 15 mg daily. Eventually, due to a lack of efficacy, citalopram was discontinued and replaced by sertraline. Upon admission, the patient was receiving a daily dosage of sertraline 50 mg and trazodone 25 mg nightly.

The patient, who is the eldest of four siblings, presented a developmental history of significant speech delays and some motor delays. The patient exhibited academic struggles, resulting in his failure in his fourth year of high school. In terms of medical history, the patient has a known congenital shoulder malformation, a language disorder, and verbal and motor dyspraxia. Additionally, he was diagnosed with Lyme disease two months before the admission and underwent a two-week course of antibiotic treatment. Family history reveals a paternal cousin with schizophrenia stemming from substance abuse and a paternal uncle with anxiety managed with sertraline.

The patient had a history of regular nicotine vaping and weekly alcohol use. Cannabis use commenced during his third year of high school, escalating to daily use for the past year until two months prior to admission, when he reduced consumption to weekends only. At the time of admission, three weeks had passed since his last cannabis use. Additionally, the patient reported three instances of psilocybin (magic mushrooms) ingestion, with the most recent occurrence four months prior to admission. According to the patient’s mother, the latest occurrence was associated with visual and potentially auditory hallucinations lasting two weeks, accompanied by anxiety and cognitive symptoms, including persistent passivity.

Upon his admission, the patient exhibited significant passivity with stupor, immobility, hypersalivation, and a fixed gaze, accompanied by near muteness. He had experienced urinary and faecal incontinence in the preceding days. Significant stimulation and assistance were necessary to facilitate the patient’s self-care, feeding, and use of the bathroom. The patient scored 12/69 on the BFCRS. He underwent assessments by several medical specialities, including general paediatrics, pediatric neurology, pediatric infectious diseases, adolescent psychiatry, and genetics. A comprehensive workup was conducted to rule out medical causes. The results of the metabolic panel, complete blood count, thyroid function tests, C-reactive protein, creatine kinase, urinalysis, ammonia, blood lead level, ferritin, ceruloplasmin, homocysteine, and vitamins B9, B12 and D were within normal limits. Urine toxicology was negative. Antinuclear antibody and anti-dsDNA antibody tests were negative. Infectious serologies were unremarkable, except for a false-positive result for arbovirus. Cerebral magnetic resonance imaging and electroencephalogram findings were also within normal limits. The results of the lumbar puncture were negative for infectious, autoimmune, and metabolic processes. Lastly, all genetic tests yielded normal results.

On day 1, a trial of intravenous lorazepam 2 mg was initiated, followed by a 9-point improvement on the BFCRS. The patient exhibited increased responsiveness, ocular motility, and ambulation. Subsequently, the patient was prescribed lorazepam 1 mg orally four times daily, with additional doses administered as needed. Over the following days, the lorazepam dosage was titrated up to a total of 8 mg daily (2 mg four times daily) by day 6. The route of administration was modified from oral to intravenous and subsequently to intramuscular. Despite some apparent therapeutic response to lorazepam, the patient experienced persistent hypotension and frequent episodes of vomiting occurring approximately thirty minutes post-administration of lorazepam. After consultation with the institutional pharmacist, a decision was made to transition to clonazepam due to these rare adverse effects associated with lorazepam. On the sixth day of treatment, the BFCRS score was 6, and the patient’s medication was switched from lorazepam to clonazepam 1 mg, administered three times daily (totalling 3 mg daily). The following day, his BFCRS score increased to 8. By day 11, the patient’s condition remained unchanged, with a BFCRS score of 8, despite an increase in clonazepam up to a total of 7 mg daily. From day 11 onward, the patient’s clinical condition deteriorated, culminating in a BFCRS score of 17 on day 14.

Given the patient’s deteriorating condition (including difficulty in eating and drinking) and resistance to treatment, ECT was selected as the next intervention. In accordance with AACAP guidelines (28), a second opinion was obtained from another child and adolescent psychiatrist. Both parents provided consent for the treatment, and the patient, despite being unfit, also gave their assent. Consultations with the anesthesiology and psychiatry ECT clinics were conducted, and a cognitive assessment was performed prior to treatment.

The patient received his first ECT treatment on day 16. Over seven and a half weeks, the patient underwent a total of 20 bilateral ECT treatments, administered using a MECTA Spectrum 5000Q device. The treatment parameters included a pulse width of 0.5 to 1 millisecond, a current of 0.8 A, a duration of 1.0 to 1.25 seconds, and a frequency ranging from 25 to 30 Hz. These settings ensured a clinical convulsion duration exceeding 20 seconds per session. ECT treatments were generally well tolerated, with the primary side effects being headaches and fatigue on the day following treatment. Improvements were observed after the initial treatment, including a gradual decrease in BFCRS scores. By day 17, a 6-point decrease in BFCRS score was achieved after a single ECT session (from 17 to 11). The patient exhibited decreased psychomotor retardation, increased cooperation, improved communication (using both words and sounds), and enhanced responsiveness to stimuli. A noticeable improvement in reaction time was also observed. However, clinical stagnation was observed around the tenth ECT treatment.

While the symptoms of catatonia improved, some mixed mood symptoms emerged, including suicidal ideation, guilt, and disinhibition, The patient also reported auditory hallucinations, describing sounds of babies crying and people screaming. In this context, and given the absence of any signs suggesting malignant catatonia, a cautious use of an atypical antipsychotic appeared to offer potential benefits (45). A trial of risperidone 0.5 mg was attempted at day 34 but resulted in a deterioration of the patient’s condition. The patient became more irritable, exhibited a fixed gaze, abrupt gestures, and a light tremor. Consequently, risperidone was stopped at day 38. Given the poor tolerance to an atypical antipsychotic and the persistence of catatonia symptoms, memantine was initiated at 5 mg twice daily on day 39. The dosage was adjusted to 5 mg in the morning and 10 mg in the evening on day 48, and subsequently to 10 mg twice a day on day 54. Memantine was well tolerated, with no reported adverse effects. The BFCRS score remained below two from day 40 onward. Olanzapine was introduced at 2.5 mg daily on day 43 to address the underlying psychosis. The dose was gradually increased in 2.5 mg increments, reaching 12.5 mg/day by day 76, allowing time for fatigue to improve between adjustments.

Treatment Timeline With BFCRS scores for Catatonia Case Study

A complete resolution of catatonia was observed approximately two months after the initiation of hospitalisation, allowing for the gradual tapering of ECT over a two-week period. Clonazepam was subsequently reduced by 10% decrements per week over a three-week duration without recurrence of symptoms. Multiple temporary home leaves (therapeutic passes) were trialled, all of which were successful. The patient also underwent a trial return to school, attending for two half-days with favourable outcomes. At discharge on day 90, the patient was clinically stable and euthymic, with no psychotic symptoms, catatonic features, or suicidal ideation. Discharge medications were memantine 10 mg twice daily, olanzapine 12.5 mg at night and a total dose of clonazepam 4.75 mg daily.

Approximately nineteen weeks post-discharge (day 222), the patient remained in a stable condition without any relapse. He was attending school three days a week within an adapted educational setting and continued to receive psychiatric follow-up. At this time, the patient was taking memantine 10 mg twice a day, olanzapine 12.5 mg daily, and a total dose of clonazepam 1.75 mg daily. The reduction of clonazepam was well tolerated. An attempt to decrease olanzapine due to fatigue led to re-emergence of mood symptoms, necessitating an increase in the olanzapine dose.

Discussion

We report the case of a 16-year-old male presenting with catatonia in the context of a potential first episode of bipolar disorder, who recovered following a course of treatments that included clonazepam, ECT, the NMDA antagonist memantine, and olanzapine. A notable strength of our approach was the comprehensive and multidisciplinary diagnostic workup, which ensured a thorough investigation of potential underlying causes. Furthermore, the use of a combination of treatments facilitated a tailored and flexible treatment plan.

Recent studies have explored the potential of NMDA antagonists for treating catatonia. Amantadine and memantine, both noncompetitive antagonists, are believed to exert their effects by inhibiting glutamate activity, which may, in turn, enhance GABA-A and dopamine levels in deficient areas(46, 47). Memantine specifically acts as an antagonist at the NMDA receptor subtype of glutamate receptors, preventing over-activation of glutamine receptors while allowing normal activity (46, 47). Studies in the pediatric population suggest that these two medications are generally well-tolerated, with the most commonly reported side effects being decreased appetite, nausea, headache, insomnia, irritability, and behavioural changes (47–56).

In 2017, Beach et al. (43) conducted a literature review on alternative treatment strategies for catatonia in adult patients, leading to the proposal of a new treatment algorithm that included NMDA antagonists, which was subsequently supported by Theibert et al. (57). They recommended that NMDA antagonists be used as a third-line treatment in case of non-response to benzodiazepines and ECT or as a second-line option when ECT is inaccessible or refused (43). Additionally, the evidence-based consensus guidelines for the management of catatonia by the British Association for Psychopharmacology recommend a trial of an NMDA antagonist when first-line therapies are unavailable, contraindicated, ineffective, or only regarding suggested that NMDA antagonists, with or without atypical neuroleptics, should be considered in cases where benzodiazepines are not tolerated, ECT is inaccessible, or symptoms worsen.

A 2023 review of the literature (24) reported significant clinical improvement in 58 cases where amantadine and memantine were used to treat catatonia of various etiologies in adult patients, with one adolescent case included. Data on children and adolescents remain limited, and the optimal dosage and treatment duration for NMDA antagonists have not been clearly defined due to the scarcity of comprehensive studies. Regarding the use of amantadine as an adjunctive treatment in patients under 18 years of age, only four case reports have been published, three of which support the efficacy of amantadine in the resolution of catatonia (16, 35, 47, 58). In these cases, amantadine was used in combination with ECT and/or lorazepam. For memantine, one case reports a 16-year-old girl with catatonia who was successfully treated with a combination of lorazepam and memantine 10 mg daily (59). Another article, in which three adolescents received memantine 20 mg daily, suggests a role for memantine in catatonia refractory to lorazepam or ECT and for relapse prevention of catatonia (60). A retrospective study of pediatric patients with catatonia who received psychopharmacologic treatment with an agent other than lorazepam reported that the mean daily dose of memantine used for the 12 cases included was 17.7 (SD: 6.2) mg (42). Systematic reviews of adult patients suggest that improvement with memantine can be observed within 1–2 days, although responses can also take several weeks (43). Additionally, treatment duration should be tailored to the patient’s response (44).

The use of ECT and multiple medications to treat this patient complicates the specific assessment of memantine’s contribution. It is possible that the resolution of catatonia was a result of the continuation of ECT, despite the stagnation observed after ten sessions, or the initiation of olanzapine. The concomitant use of first-line treatments introduces potential bias in evaluating efficacy, as highlighted by Theibert et al. (61). Other authors have highlighted the importance of considering biases related to unreported negative outcomes, and the absence of randomised controlled trials (RCTs) and other controlled studies as significant limitations (24). Despite these limitations, several articles suggest incorporating NMDA antagonists into the treatment algorithm for catatonia (16, 24, 43, 46, 47, 59, 61–63).

It was in consideration of the previously cited literature, the favourable adverse effect profile of memantine, the partial response to clonazepam and ECT, and the aim of accelerating recovery and minimising developmental impacts, that we initiated a trial of memantine. Despite the previously cited limitations, we believe that this combination may have facilitated the resolution of catatonia in the patient, allowing for the resumption of basic functioning, including a transition to outpatient psychiatric care and a return to school.

Patient’s perspective and informed consent

According to the patient’s parents, ECT was considered the most effective treatment, despite its potentially intimidating nature. They expressed their willingness to recommend ECT to others in similar situations. In contrast, the parents were uncertain about the role of memantine in their son’s recovery. The patient, however, had limited recollection of ECT but acknowledged that all his medications, including memantine, were beneficial and well tolerated. Both the patient and his parents provided consent for the publication of this article detailing their experiences.

Conclusion

In conclusion, the combination of clonazepam, ECT, memantine, and olanzapine was used to treat catatonia in our patient, highlighting the potential of this therapeutic approach for similar cases. This case emphasises the importance of recognising and appropriately treating catatonia in child and adolescent patients. It also reinforces the legitimacy of using ECT in young patients. Additionally, this case raises questions about the role of NMDA antagonists in our therapeutic arsenal. These drugs show significant potential and could be considered adjunctively when ECT is not available or when consent is not obtained. Further studies are necessary to clarify the role of NMDA antagonists in child and adolescent psychiatry. The seeming benefits observed in this case report support their use. Future research should focus on conducting RCTs to further assess the efficacy and safety of NMDA antagonists in the treatment of catatonia in children and adolescents, as well as exploring the long-term outcomes to establish more comprehensive therapeutic guidelines.