Catatonia: Clinical Overview of the Diagnosis, Treatment, and Clinical Challenges

Round 1

Reviewer 1 Report

The manuscript has improved significantly with the modifications made by the authors. I consider that at this moment it is ready to be published

Reviewer 2 Report

The paper is ready for publication

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The review is focused on catatonia causes, presentation and treatment. The topic is important, nevertheless the paper is in the current form not suitable for publication.

Abstract: the Authors provide examples of medical states inducing catatonia. I believe that for the educational purposes malignant neuroleptic syndrome and NMDA encephalitis - which are the condition that should be taken into consideration in the differential diagnosis - should also be named in the abstract.

Introduction:

This section should be rephrased. The Authors do not provide clear definition of catatonia. (Symptoms summary, provided in lines 96 - 98 is not a definition). The Authors mention some psychiatric and some medical conditions which may be associated with catatonia which (in my opinion) are not those most clinically significant. It is not clear why the Authors mention Bush-Francis Catation Scale. Although I, of course, agree, that autonomic instability is one of the major problems in this condition, introducing this idea in the line 105 is not preceded by sufficient explanation.

In the section "Causes" the Authors provide some percentage data. This is difficult to interpret, as the definition is - still - not provided.

Similar vagueness characterises the section "Presentation". The Authors inform, that "In general, catatonia can be behavior that is either increased, decreased, or abnormal compared to baseline". In general that may be true for catatonia as well as for many, many other conditions. In the following paragraphs the Authors enlist numerous symptoms. "Presentation" is much more than an enumeration of symptoms. In psychiatry, not only symptoms, but also time-frame and functioning disturbances are important in the diagnostic process. Although the Authors refer to autonomic instability in the Introduction section, they do not mention this problem in the "Presentation" part. Why?

Section "Pathophysiology". Lines 194 - 195. "Further evidence of the connection 193 between NMDARs and catatonia is that ketamine and phencyclidine are both NMDAR 194 antagonists and have both been shown to cause catatonia". The sentence should be clarified - usually ketamine and phencyclidine do not cause catatonia.

Section "Treatment". At the beginning the Authors mention risk associated with catatonia starting from venous thrombosis or pulmonary embolism. The main risk associated with catatonia is that the patient may die due to autonomic instability or undiagnosed medical condition. Differentiating between more and less important issues is necessary in this section as well as in other parts of manuscript.

In the line 225 the Authors recommend zolpidem in children and adolescents in case od lorazepam inefficacy. The cited case series (50, 51, 52) ARE NOT a recommendations. Numerous papers review treatment options in catatonia and I recommend analysing and dicussing some of them.

The section "clinical challenges" is definitely unclear for me. Why just those challenges? In this section the Authors mention a woman with catatonia in the course of schizophrenia. That seems rather typical situation, not challenge.

In the lines 272 - 281 the Authors discuss the legal and ethical issues associated with treatment consent. This must be specified which country lenational law is discussed.

Section "Clinical Studies" do not provide information how the literature search was performed.

In the section "Diagnosis" not only diagnosis, but also the course and some treatment issues are discussed. Regarding the disgnosis, the definition of catatonia is still not provided.

In the section "Complications and risk factors" the Authors discuss the association between NMS and catatonia. From the provided information I do not understand what the discussed study was about. It seems that the study presents rather historical point of view: now 1. we believe NMS to be a form of organic catatonia, 2. we do not treat catatonia with neuroleptics because of the risk of developing NMS. Similarily, regarding the citation 88,  administering zuclopentixol (Accuphase!) in catatonia is recently definitely not recommended. If the Authors decide to cite this paper, some commentary regarding currently recommended and contraindicated treatment options is necessary.

In the section "Conclusion" the Authors declare that "Catatonic symptoms are often associated with various psychological (..) disorders". Psychological problems are not associated with catatonia, psychiatric disorders are. Why the Authors mention in the conclusion nodding syndrome which is rare desease not discussed in the previous parts of the paper?

Author Response

Abstract: the Authors provide examples of medical states inducing catatonia. I believe that for the educational purposes malignant neuroleptic syndrome and NMDA encephalitis - which are the condition that should be taken into consideration in the differential diagnosis - should also be named in the abstract.

Answer: This is a good point. It was in the original one and then edited. This has been added back in.

Introduction:

This section should be rephrased. The Authors do not provide clear definition of catatonia. (Symptoms summary, provided in lines 96 - 98 is not a definition). The Authors mention some psychiatric and some medical conditions which may be associated with catatonia which (in my opinion) are not those most clinically significant. It is not clear why the Authors mention Bush-Francis Catation Scale. Although I, of course, agree, that autonomic instability is one of the major problems in this condition, introducing this idea in the line 105 is not preceded by sufficient explanation.

Answer: Thank you for this point. This has been rephrased to provide a clear definition of catatonia. The Bush-Francis Catatonia Scale is one scale that can be used to diagnosed catatonia since it has been reliable and that is why it was included but we can see how that could be confusing to put it in the introduction so it has been removed.

In the section "Causes" the Authors provide some percentage data. This is difficult to interpret, as the definition is - still - not provided.

Answer: Percentages were important to note as it gives a way to show the reader that this isn’t as uncommon as they could think. Some explanation was added.

Similar vagueness characterises the section "Presentation". The Authors inform, that "In general, catatonia can be behavior that is either increased, decreased, or abnormal compared to baseline". In general that may be true for catatonia as well as for many, many other conditions. In the following paragraphs the Authors enlist numerous symptoms. "Presentation" is much more than an enumeration of symptoms. In psychiatry, not only symptoms, but also time-frame and functioning disturbances are important in the diagnostic process. Although the Authors refer to autonomic instability in the Introduction section, they do not mention this problem in the "Presentation" part. Why?

Answer: A short paragraph regarding autonomic instability as this could be life threatening.

Section "Pathophysiology". Lines 194 - 195. "Further evidence of the connection 193 between NMDARs and catatonia is that ketamine and phencyclidine are both NMDAR 194 antagonists and have both been shown to cause catatonia". The sentence should be clarified - usually ketamine and phencyclidine do not cause catatonia.

Answer: This section was edited

Section "Treatment". At the beginning the Authors mention risk associated with catatonia starting from venous thrombosis or pulmonary embolism. The main risk associated with catatonia is that the patient may die due to autonomic instability or undiagnosed medical condition. Differentiating between more and less important issues is necessary in this section as well as in other parts of manuscript.

Answer: This section has been added with these points in mind with some further clarifications of points.

In the line 225 the Authors recommend zolpidem in children and adolescents in case od lorazepam inefficacy. The cited case series (50, 51, 52) ARE NOT a recommendations. Numerous papers review treatment options in catatonia and I recommend analysing and dicussing some of them.

Answer: This section has been edited with these points in mind

The section "clinical challenges" is definitely unclear for me. Why just those challenges? In this section the Authors mention a woman with catatonia in the course of schizophrenia. That seems rather typical situation, not challenge.

Answer: This section has been edited with these points in mind

In the lines 272 - 281 the Authors discuss the legal and ethical issues associated with treatment consent. This must be specified which country lenational law is discussed.

Answer: This section has been edited with these points in mind

Section "Clinical Studies" do not provide information how the literature search was performed.

Answer: This section has been edited with these points in mind

In the section "Diagnosis" not only diagnosis, but also the course and some treatment issues are discussed. Regarding the disgnosis, the definition of catatonia is still not provided.

Answer: This was already added earlier in the manuscript and not placed here for conciseness

In the section "Complications and risk factors" the Authors discuss the association between NMS and catatonia. From the provided information I do not understand what the discussed study was about. It seems that the study presents rather historical point of view: now 1. we believe NMS to be a form of organic catatonia, 2. we do not treat catatonia with neuroleptics because of the risk of developing NMS. Similarily, regarding the citation 88,  administering zuclopentixol (Accuphase!) in catatonia is recently definitely not recommended. If the Authors decide to cite this paper, some commentary regarding currently recommended and contraindicated treatment options is necessary.

Answer: This section has been edited with these points in mind

In the section "Conclusion" the Authors declare that "Catatonic symptoms are often associated with various psychological (..) disorders". Psychological problems are not associated with catatonia, psychiatric disorders are. Why the Authors mention in the conclusion nodding syndrome which is rare desease not discussed in the previous parts of the paper?

Answer: This section has been edited with these points in mind

Reviewer 2 Report

I reviewed the manuscript "Catatonia: Clinical Overview of the Diagnosis, Treatment, and Clinical Challenges" The authors' aims were to review and synthesize diagnosis, treatment and clinical challenges of catatonia syndrome.  Their study corroborates that catatonia is a complex condition with varying presentations and that is associated with  multiple disorders, which can make recognition, diagnosis, and treatment a challenging process for healthcare professionals.

This work contributes to the literature on parsing physiopathology, diagnosis and treatment of catatonia and its relationship to psychiatric and medical conditions. This study provides a synthesis of case clinics that helps to better understand catatonia.

Please see my comments below for my suggestions and questions.

• In introduction section. Line 79: Although it was often previously categorized with schizophrenia or associated with other mental health disorders and neurological disorders. I would suggest adding that it was Krapelin's vision, and later confirmed by Bleuler's, that caused catatonia to be associated with schizophrenia. It was not categorized with other psychiatric disorders until the appearance of DSM-IV. Line 102: The Bush-Francis Catatonia Rating Scale (BFCRS) is a validate. Please reference: Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia. I. Rating scale and standardized examination. Acta Psychiatr Scand. 1996;93:129-36. Line 115: DSM-IV instead of DSM-4.

• In Catatonia Causes, Presentation, and Pathophysiology section. At this point, it would be interesting to report the hypothesis of fear as a possible etiology of the catatonic syndrome. Please consider including the two following references: Moskowitz AK. «Scared stiff»: catatonia as an evolutionary-based fear response. Psychol Rev. 2004;111:984-1002.  Cuevas-Esteban J, Iglesias-González M, Serra-Mestres J, Butjosa A, Canal-Rivero M, Serrano-Blanco A, et al. Catatonia in elderly psychiatric inpatients is not always associated with intense anxiety: Factor analysis and correlation with psychopathology. Int J Geriatr Psychiatry. 2020;35:1409-17.

• In Catatonia Causes, Presentation, and Pathophysiology section. Line 196: both NMDAR and GABA-A receptors has been implicated in the pathogenesis of catatonia. I think it would be of great interest to introduce the pathophysiological hypothesis of the dysregulation of the immune system. Please check the following reference: Rogers JP, Pollak TA, Blackman G, David AS. Catatonia and the immune system: a review. The Lancet Psychiatry. 2019;0366:1-11.

• In Catatonia Current Treatment section. In this section treatments for the treatment of catatonia that may be useful, such as NMDA receptor antagonists and antiepileptic drugs, are not mentioned. It is important to reflect these treatments as well as the risks and benefits of the use of antipsychotics. Line 229: It must be noted that ECT is a first line treatment in special forms of catatonia: neuroleptic malignant syndrome, malignant catatonia, deliurous mania.

• In Clinical Challenges section. Line 264:  It is important to note that, in addition to the difficulty involved in the differential diagnosis of catatonia-delirium, treatment of catatonia with benzodizepines can worsen delirium and treatment of delirium with antipsychotics can worsen catatonia. In that sense, there is the alternative of treatment with NMDA receptor antagonists. Please see: Roy K, Warnick SJ, Balon R. Catatonia Delirium: 3 Cases Treated With Memantine. Psychosomatics. 2016;57:645-650. doi: 10.1016/j.psym.2016.08.001.

• In Clinical Challenges section. I suggest adding the diagnosis and treatment of catatonia in the elderly as a clinical challenge. They are usually associated with greater comorbidity and cognitive impairment. In addition, they present a worse response to the usual treatments. Catatonia in the elderly is very prevalent so it is essential to reflect it in studies. Please check the following references. Cuevas-Esteban J, Iglesias-González M, Rubio-Valera M, Serra-Mestres J, Serrano-Blanco A, Baladon L. Prevalence and characteristics of catatonia on admission to an acute geriatric psychiatry ward. Prog Neuro-Psychopharmacology Biol Psychiatry. 2017;78:27-33. doi: 10.1016/j.pnpbp.2017.05.013.  Jaimes-Albornoz W, Serra-Mestres J. Prevalence and clinical correlations of catatonia in older adults referred to a liaison psychiatry service in a general hospital. Gen Hosp Psychiatry. 2013;35:512-6. doi: 10.1016/j.genhosppsych.2013.04.009.  Sharma P, Sawhney I, Jaimes-Albornoz W, Serra-Mestres J. Catatonia in Patients with Dementia Admitted to a Geriatric Psychiatry Ward. J Neurosci Rural Pract. 2017;8:S103-S105. doi: 10.4103/jnrp.jnrp_47_17.

Author Response

• In introduction section. Line 79: Although it was often previously categorized with schizophrenia or associated with other mental health disorders and neurological disorders. I would suggest adding that it was Krapelin's vision, and later confirmed by Bleuler's, that caused catatonia to be associated with schizophrenia. It was not categorized with other psychiatric disorders until the appearance of DSM-IV. Line 102: The Bush-Francis Catatonia Rating Scale (BFCRS) is a validate. Please reference: Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia. I. Rating scale and standardized examination. Acta Psychiatr Scand. 1996;93:129-36. Line 115: DSM-IV instead of DSM-4.
• Answer: This is a great point and the section was edited.

• In Catatonia Causes, Presentation, and Pathophysiology section. At this point, it would be interesting to report the hypothesis of fear as a possible etiology of the catatonic syndrome. Please consider including the two following references: Moskowitz AK. «Scared stiff»: catatonia as an evolutionary-based fear response. Psychol Rev. 2004;111:984-1002.  Cuevas-Esteban J, Iglesias-González M, Serra-Mestres J, Butjosa A, Canal-Rivero M, Serrano-Blanco A, et al. Catatonia in elderly psychiatric inpatients is not always associated with intense anxiety: Factor analysis and correlation with psychopathology. Int J Geriatr Psychiatry. 2020;35:1409-17.
• Answer: This is a great point and the section was edited.

• In Catatonia Causes, Presentation, and Pathophysiology section. Line 196: both NMDAR and GABA-A receptors has been implicated in the pathogenesis of catatonia. I think it would be of great interest to introduce the pathophysiological hypothesis of the dysregulation of the immune system. Please check the following reference: Rogers JP, Pollak TA, Blackman G, David AS. Catatonia and the immune system: a review. The Lancet Psychiatry. 2019;0366:1-11.
• Answer: This was edited to be briefly touched on.

• In Catatonia Current Treatment section. In this section treatments for the treatment of catatonia that may be useful, such as NMDA receptor antagonists and antiepileptic drugs, are not mentioned. It is important to reflect these treatments as well as the risks and benefits of the use of antipsychotics. Line 229: It must be noted that ECT is a first line treatment in special forms of catatonia: neuroleptic malignant syndrome, malignant catatonia, deliurous mania.
• Answer: This was excluded as of now because there are more risks than benefits so the authors felt this was best left out of the discussion. The point on ECT was added into the manuscript

• In Clinical Challenges section. Line 264:  It is important to note that, in addition to the difficulty involved in the differential diagnosis of catatonia-delirium, treatment of catatonia with benzodizepines can worsen delirium and treatment of delirium with antipsychotics can worsen catatonia. In that sense, there is the alternative of treatment with NMDA receptor antagonists. Please see: Roy K, Warnick SJ, Balon R. Catatonia Delirium: 3 Cases Treated With Memantine. Psychosomatics. 2016;57:645-650. doi: 10.1016/j.psym.2016.08.001.
• Answer: This was actually edited out with the first reviewers comments

• In Clinical Challenges section. I suggest adding the diagnosis and treatment of catatonia in the elderly as a clinical challenge. They are usually associated with greater comorbidity and cognitive impairment. In addition, they present a worse response to the usual treatments. Catatonia in the elderly is very prevalent so it is essential to reflect it in studies. Please check the following references. Cuevas-Esteban J, Iglesias-González M, Rubio-Valera M, Serra-Mestres J, Serrano-Blanco A, Baladon L. Prevalence and characteristics of catatonia on admission to an acute geriatric psychiatry ward. Prog Neuro-Psychopharmacology Biol Psychiatry. 2017;78:27-33. doi: 10.1016/j.pnpbp.2017.05.013.  Jaimes-Albornoz W, Serra-Mestres J. Prevalence and clinical correlations of catatonia in older adults referred to a liaison psychiatry service in a general hospital. Gen Hosp Psychiatry. 2013;35:512-6. doi: 10.1016/j.genhosppsych.2013.04.009.  Sharma P, Sawhney I, Jaimes-Albornoz W, Serra-Mestres J. Catatonia in Patients with Dementia Admitted to a Geriatric Psychiatry Ward. J Neurosci Rural Pract. 2017;8:S103-S105. doi: 10.4103/jnrp.jnrp_47_17.
• Answer: This was actually edited out with the first reviewers comments