Journal Article Annotations
2023, 1st Quarter

Catatonia

Annotations by Samuel Kohrman, MD
April, 2023

Clozapine as a treatment for catatonia: A systematic review.
The role of the electroencephalogram (EEG) in determining the aetiology of catatonia: a systematic review and meta-analysis of diagnostic test accuracy.

PUBLICATION #1 — Catatonia

Clozapine as a treatment for catatonia: A systematic review.

Aman Saini, Nazifa Begum, James Matti, Dory Anthony Ghanem, Laurie Fripp, Thomas A Pollak, Michael S Zandi, Anthony David, Glyn Lewis, Jonathan Rogers

Abstract: Schizophr Res. 2022 Sep 15;S0920-9964(22)00363-2. doi: 10.1016/j.schres.2022.09.021. Online ahead of print.

Catatonia is a neuropsychiatric disorder characterised by altered movement, speech, and behaviour. Clozapine is an established therapy for treatment-resistant schizophrenia, but its role in catatonia has not been systematically examined. In this systematic review, we aimed to assess the evidence for clozapine as a treatment for catatonia. Full text original research articles in English where at least one patient with catatonia was treated with clozapine were included, provided catatonia did not occur solely in the context of neuroleptic malignant syndrome. Results were tabulated with calculations of summary statistics presented. Risk of bias was assessed with the Tool for Evaluating the Methodological Quality of Case Reports and Case Series. 182 patients were included, 81 from cohort studies and 101 from case reports or case series. 119/182 patients (65 %) had a specified underlying diagnosis of schizophrenia. Over 80 % of reported patients with catatonia had at least partial remission following treatment with clozapine across both cohort studies and case reports and case series. Among the case reports and series, 24/101 patients (23.8 %) followed clozapine withdrawal. Overall, 25 studies were of low quality, 60 of moderate quality and 8 of high quality. Our findings should be interpreted with caution, as the reliance on case reports, case series and small cohort studies is susceptible to reporting biases, regression to the mean and confounding by other treatments. Future research could use large healthcare databases to ascertain outcomes in those on clozapine with a history of catatonia given the difficulty and expense of conducting randomised controlled trials.

Annotation

The finding:
From the combined six observational cohort studies, eight case series and 79 case reports, 119 of 182 (>80%) patients with catatonia reached a partial or full remission of catatonic symptoms following clozapine treatment. Of the 81 patients from cohort studies, 74% of patients reached partial and 10% reached full remission; 55 patients (68%) were diagnosed with schizophrenia while the remaining patients had unspecified diagnoses. From the case reports and case series, 81% of patients combined reached either partial remission (18%) or full remission (63%); 24 patients (24%) had clozapine withdrawal catatonia, 64 patients (63%) were diagnosed with a schizophrenia or related disorder. Concurrent treatment for catatonia included benzodiazepines (61%),antipsychotics (72%), and/or ECT (41%). In case reports and case series, clozapine took weeks to lead to resolution in partial responders (mean 41 days) and in complete responders (mean 54 days).

Strength and weaknesses:
This is the first systematic review to specifically investigate clozapine usage to treat catatonia. As a systematic review of observational studies, only an associative relationship can be drawn and findings should be interpreted with caution given the overall low and moderate quality of studies used. Cohort studies demonstrated more of a partial response finding than did the case reports and case series, which suggests in the latter likely confirmation and publication biases towards publishing positive outcomes. We cannot draw direct conclusions on the effect of clozapine on catatonia as more than half of patients received one or a combination of concurrent treatments (benzodiazepine, antipsychotic, and/or ECT) rather than clozapine alone. Additionally, there were no included head-to-head comparisons of clozapine to other treatments.

Relevance:
With a low to perhaps a cautiously low-to-medium level of evidence, it is reasonable to consider clozapine as part of the armamentarium of non-first line agents for treating catatonia. Given the overall challenges of treating catatonia, clozapine may be helpful in treating catatonia in cases of co-existing psychosis, in undifferentiated aetiology, or in clozapine withdrawal catatonia particularly if first line therapies of benzodiazepines and or ECT are ineffective, partially effective, or not fully feasible. Further studies are surely warranted.

PUBLICATION #2 — Catatonia

The role of the electroencephalogram (EEG) in determining the aetiology of catatonia: a systematic review and meta-analysis of diagnostic test accuracy.

Paris Hosseini, Rebecca Whincup, Karrish Devan, Dory Anthony Ghanem, Jack B Fanshawe, Aman Saini, Benjamin Cross, Apoorva Vijay, Tomas Mastellari, Umesh Vivekananda, Steven White, Franz Brunnhuber, Michael S Zandi, Anthony S David, Ben Carter, Dominic Oliver, Glyn Lewis, Charles Fry, Puja R Mehta, Biba Stanton, Jonathan P Rogers.

Abstract: EClinicalMedicine. 2023 Jan 5;56:101808. doi: 10.1016/j.eclinm.2022.101808. eCollection 2023 Feb.

Background:
Catatonia is a psychomotor syndrome that has a wide range of aetiologies. Determining whether catatonia is due to a medical or psychiatric cause is important for directing treatment but is clinically challenging. We aimed to ascertain the performance of the electroencephalogram (EEG) in determining whether catatonia has a medical or psychiatric cause, conventionally defined.

Methods:
In this systematic review and meta-analysis of diagnostic test accuracy (PROSPERO CRD42021239027), Medline, EMBASE, PsycInfo, and AMED were searched from inception to May 11, 2022 for articles published in peer-reviewed journals that reported EEG findings in catatonia of a medical or psychiatric origin and were reported in English, French, or Italian. Eligible study types were clinical trials, cohort studies, case-control studies, cross-sectional studies, case series, and case reports. The reference standard was the final clinical diagnosis. Data extraction was conducted using individual patient-level data, where available, by two authors. We prespecified two types of studies to overcome the limitations anticipated in the data: larger studies (n ≥ 5), which were suitable for formal meta-analytic methods but generally lacked detailed information about participants, and smaller studies (n < 5), which were unsuitable for formal meta-analytic methods but had detailed individual patient level data, enabling additional sensitivity analyses. Risk of bias and applicability were assessed with the QUADAS-2 tool for larger studies, and with a published tool designed for case reports and series for smaller studies. The primary outcomes were sensitivity and specificity, which were derived using a bivariate mixed-effects regression model.

Findings:
355 studies were included, spanning 707 patients. Of the 12 larger studies (5 cohort studies and 7 case series), 308 patients were included with a mean age of 48.2 (SD = 8.9) years. 85 (52.8%) were reported as male and 99 had catatonia due to a general medical condition. In the larger studies, we found that an abnormal EEG predicted a medical cause of catatonia with a sensitivity of 0.82 (95% CI 0.67-0.91) and a specificity of 0.66 (95% CI 0.45-0.82) with an I ² of 74% (95% CI 42-100%). The area under the summary ROC curve offered excellent discrimination (AUC = 0.83). The positive likelihood ratio was 2.4 (95% CI 1.4-4.1) and the negative likelihood ratio was 0.28 (95% CI 0.15-0.51). Only 5 studies had low concerns in terms of risk of bias and applicability, but a sensitivity analysis limited to these studies was similar to the main analysis. Among the 343 smaller studies, 399 patients were included, resulting in a sensitivity of 0.76 (95% CI 0.71-0.81), specificity of 0.67 (0.57-0.76) and AUC = 0.71 (95% CI 0.67-0.76). In multiple sensitivity analyses, the results were robust to the exclusion of reports of studies and individuals considered at high risk of bias. Features of limbic encephalitis, epileptiform discharges, focal abnormality, or status epilepticus were highly specific to medical catatonia, but features of encephalopathy had only moderate specificity and occurred in 23% of the cases of psychiatric catatonia in smaller studies.

Interpretation: In cases of diagnostic uncertainty, the EEG should be used alongside other investigations to ascertain whether the underlying cause of catatonia is medical. The main limitation of this review is the differing thresholds for considering an EEG abnormal between studies.

Annotation

The finding:
Out of 335 studies included in this systematic review, 707 patients were included to determine the accuracy of EEGs in discerning between neuropathological processes and primary mental disorders as aetiologies for catatonia. Large studies showed that an abnormal EEG could predict medical causes of catatonia with sensitivity of 0.82 and specificity of 0.66, as compared to smaller studies with sensitivity of 0.76 and specificity of 0.67. Limbic encephalitis, epileptiform discharges, focal abnormalities and status epilepticus were highly specificfor medical causes, even though with varying sensitivity. Interestingly, features of encephalopathy were found in both medical and psychiatric proposed aetiologies of catatonia; a significant minority (23%) of patients with a presumed psychiatric cause for catatonia had an abnormal EEG, most often with signs of encephalopathy.

Strength and weaknesses:
This is the first systematic review and meta-analysis investigating the test accuracy of EEGs in determining aetiology of catatonia. All studies included were observational and the threshold for classifying an EEG as abnormal differed between studies. Selection bias and reporting bias may have played a role in findings; only patients whose clinical presentation justified use of an EEG were included in this study.

Relevance:
As recommendations vary about when to use EEGs in the workup of catatonia, this study can guide C-L psychiatrists to utilize EEGs as a component of the medical workup in cases of catatonia with diagnostic uncertainty, including when there is uncertainty regarding a possible neuropathologic cause. Given the broad aetiologies of catatonia, C–L psychiatrists encounter a large majority of cases in a general medical setting. Thus, for hospital-based C-L psychiatrists, the question of utilizing EEGs in the workup of diagnostically uncertain catatonia may be less of a question of clinical utility and more of a question of availability of resources and timing as it could delay treatment. Furthermore, the state of catatonia can be considered as a neuropathological process, whether its aetiology is a primary mental disorder, a medical process or a combination of the two.