A Systematic Review of Clozapine for Catatonia

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RESEARCH UPDATE

CASE VIGNETTE

“Mrs Brick” is a 56-year-old Caucasian female with a history of chronic schizophrenia. She has been stable on a medication regimen of risperidone 4 mg at bedtime and citalopram 20 mg in the morning. However, in the past 6 months, she experienced the loss of both her mother due to cardiovascular disease and her brother, who died within 2 months of a cancer diagnosis. Mrs Brick was brought into the emergency department by her husband, due to self-care deficits. She has not been eating well, with a 15-pound weight loss in the past 2 months. She has low energy and poor concentration. She has been isolating in bed most of the time, and requires significant prompting to attend to personal hygiene. On exam, she has profound psychomotor retardation, poverty of speech, and increased latency of response. She also exhibited some mild posturing.

Mrs Brick was admitted to the inpatient psychiatric unit. Laboratory studies were unremarkable. She was started on lorazepam 1 mg three times daily for catatonia and her risperidone was increased to 6 mg. After 3 days, her condition remained largely unchanged. Subsequently, her psychiatrist decided to start her on clozapine, which was titrated to a dose of 200 mg at bedtime over the next week. This was associated with improvement in symptoms of catatonia. Mrs Brick was able to articulate feeling depressed about her recent losses, as well as suspiciousness that someone in her neighborhood was plotting to kill her. Her mood and paranoia also improved with clozapine. She was discharged home on hospital day 14 in the care of her husband.

Catatonia is a group of symptoms characterized by abnormalities in movement, speech, and behavior. The prevalence of catatonia is 9% in acute psychiatric patient populations.¹ Catatonia was classically tied to schizophrenia, but it is associated with other psychiatric and medical disorders. The usual first-line treatment for catatonia, beyond addressing underlying causes and complications, is benzodiazepines.² Electroconvulsive therapy (ECT) also plays an important role in the treatment of catatonia, particularly if resistant to benzodiazepines or in emergencies.³ Several other psychotropic medications, including atypical antipsychotics, have been used off-label for treatment-resistant catatonia.

The atypical antipsychotic clozapine with its unique pharmacologic profile, including relatively weaker dopamine D₂ receptor antagonism, represents a potential treatment for both catatonia and underlying psychosis. There is also evidence for catatonia following clozapine withdrawal.⁴ However, evidence for clozapine as a potential treatment for catatonia has not been systematically reviewed.

The Current Study

Saini and colleagues performed a systematic review of clozapine in the treatment of catatonia.⁵ The authors used the NICE Healthcare Databases to search Medline, EMBASE, PubMed, PsycINFO, and CINHAL from inception through June 2021. They included English-language original full-text studies in peer-reviewed journals. They included all study designs with at least 1 patient with catatonia treated with clozapine, although case reports and case series were grouped separately. They excluded studies where catatonia was not identified by a clinician or catatonia occurring in the context of neuroleptic malignant syndrome, or where maintenance clozapine was used only for secondary prophylaxis of catatonia. Data on demographic and clinical characteristics were collected for each study. Quantitative review (ie, meta-analysis) was not possible, as most studies were case reports or case series. The authors assessed the methodological quality of the case reports and case series using a published tool.⁶

The authors identified 849 studies from initial searches, of which 93 were included. This consisted of 79 case reports, 8 case series, and 6 cohort studies. The final sample treated with clozapine consisted of 182 patients, including 101 from case reports or case series and 81 from cohort studies. In the cohort studies, the only specified diagnosis was schizophrenia, which was present in at least 68% of patients. The outcome was reported as complete remission in 10%, partial remission in 74%, and no change in 7%. Reporting of adverse effects was limited. Other clinical data were limited across the cohort studies.

In the case reports and case series, mean age was 35 (but the age range was broad), 65% were male, and 63% had schizophrenia or related psychosis. Benzodiazepines, other antipsychotics, and ECT were commonly used. Complete remission occurred in 63%, partial remission in 18%, and no change in 19%, after a mean of 54, 72, and 41 days between clozapine initiation and outcome assessment. Only a minority of catatonia diagnoses (24%) were reported to follow clozapine withdrawal. The majority of included studies were deemed to be of moderate quality.

Study Conclusions

The authors identified 182 patients treated with clozapine for catatonia. Full or partial remission rates were 84% in cohort studies and 81% in case reports or case series, with treatment over a period of weeks to months. The mean peak dose of clozapine was 322 mg. A major limitation is the absence of any controlled treatment trials, which precluded the use of meta-analysis. Another limitation is that data on blood clozapine levels was not available for the vast majority of patients. There may have been potential confounding by other psychotropic medications. The main study strength is that this is the first systematic review of clozapine for the treatment of catatonia.

The Bottom Line

There is very modest evidence that clozapine may be associated with improvement of catatonia. Clozapine represent a potential second-line treatment for catatonia, following failure of benzodiazepines or ECT, or if precipitated by clozapine withdrawal. Future research should use large health care databases to assess whether clozapine is associated with better outcomes in catatonia. Further support could justify a clinical trial in this area.

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times™. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Sienaert P, Dhossche DM, Vancampfort D, et al. A clinical review of the treatment of catatonia. Front Psychiatry. 2014;5:181.

2. Solmi M, Pigato GG, Roiter B, et al. Prevalence of catatonia and its moderators in clinical samples: results from a meta-analysis and meta-regression analysis. Schizophr Bull. 2018;44(5):1133-1150.

3. Guidance on the use of electroconvulsive therapy. National Institute for Health and Care Excellence. April 26, 2003. Accessed December 13, 2022. https://www.nice.org.uk/guidance/ta59

4. Lander M, Bastiampillai T, Sareen J. Review of withdrawal catatonia: what does this reveal about clozapine? Transl Psychiatry. 2018;8(1):139.

5. Saini A, Begum N, Matti J, et al. Clozapine as a treatment for catatonia: a systematic review. Schizophr Res. 2022;S0920-9964(22)00363-2.

6. Murad MH, Sultam S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018;23(2):60-63.