Comment
I have received speakers’ fees from Lundbeck and Servier. 5 Khan A, Khan SR, Walens G, Kolts R, Giller EL. Frequency of positive studies
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY 4.0 license.
1 Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G.
Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and
mirtazapine in major depression: systematic review and dose-response
meta-analysis. Lancet Psychiatry 2019; published online June 6.
http://dx.doi.org/10.1016/S2215-0366(19)30217-2.
2 Papakostas GI, Charles D, Fava M. Are typical starting doses of the selective
serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized,
double-blind, placebo-controlled, dose-finding studies in major depressive
disorder. World J Biol Psychiatry 2010; 11: 300–07.
3 Jakubovski E, Varigonda AL, Freemantle N, Taylor MJ, Bloch MH.
Systematic review and meta-analysis: dose-response relationship of
selective serotonin reuptake inhibitors in major depressive disorder.
Am J Psychiatry 2016; 173: 174–83.
4 Hieronymus F, Nilsson S, Eriksson E. A mega-analysis of fixed-dose trials
reveals dose-dependency and a rapid onset of action for the antidepressant
effect of three selective serotonin reuptake inhibitors. Transl Psychiatry 2016;
6: e834.
A diversified theory of catatonia
Published Online As the 150-year anniversary of Kahlbaum’s seminal 1874
June 10, 2019
http://dx.doi.org/10.1016/
monograph Die Katatonie: oder das Spannungsirresein
S2215-0366(19)30212-3 (which translates to The Catatonia: or the Tension
See Series pages 610 and 620 Insanity)1 approaches, fundamental questions remain
about the nature of catatonia and its phenotype. In
The Lancet Psychiatry, two Series papers bring further
clarity to these issues and aim to bolster scientific and
clinical advance.
Catatonia deserves attention foremost as an end in
itself, both for the arresting disruption of life it causes
and for its potential medical complications including
risk of death.2 The syndrome also merits consideration
as a means to exploring conation and the association
between brain and behaviour because it involves stark
behavioural changes at the cusp of voluntariness. Further,
among its curiosities, catatonia might be the presenting
H-P Haack / Wikimedia Commons
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among fixed and flexible dose antidepressant clinical trials: an analysis of
the food and drug administration summary basis of approval reports.
Neuropsychopharmacology 2003; 28: 552–57.
6 Huezo-Diaz P, Perroud N, Spencer EP, et al. CYP2C19 genotype predicts steady
state escitalopram concentration in GENDEP. J Psychopharmacol 2012;
26: 398–407.
7 Dold M, Bartova L, Rupprecht R, Kasper S. Dose escalation of antidepressants
in unipolar depression: a meta-analysis of double-blind, randomized
controlled trials. Psychother Psychosom 2017; 86: 283–291.
8 Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and
acceptability of 21 antidepressant drugs for the acute treatment of adults
with major depressive disorder: a systematic review and network
meta-analysis. Lancet 2018; 91: 1357–66.
9 Montgomery S, Hansen T, Kasper S. Efficacy of escitalopram compared to
citalopram: a meta-analysis. Int J Neuropsychopharmacol 2011; 14: 261–68.
10 Papakostas GI, Ostergaard SD, Iovieno N. The nature of placebo response in
clinical studies of major depressive disorder. J Clin Psychiatry 2015; 76: 456–66.
11 Salanti G, Chaimani A, Furukawa TA, et al. Impact of placebo arms on
outcomes in antidepressant trials: systematic review and meta-regression
analysis. Int J Epidemiol 2018; 47: 1454–64.
syndrome of several primary psychiatric disorders,
medical conditions, or substance-induced states.
In catatonia, disturbances of will and motoric
expression are intertwined such that even experienced
clinicians might occasionally wonder about the extent
to which certain behaviours are voluntary, such as
when a patient gives negativistic responses that
appear pseudovolitional. Along these lines, Sebastian
Walther and colleagues3 provide a modern appraisal
of catatonia as a psychomotor syndrome, a model
with a long tradition in catatonia research. In their
review of cerebral motor network dysfunction, the
authors outline convergent evidence that points to
abnormal hyperactivity in the supplementary and
pre-supplementary motor areas. The studies cited
in support of this model mostly involve akinetic
catatonia and might oversample patients with catatonic
schizophrenia; this situation probably reflects an artifact
of earlier literature, which overemphasised catatonia
as a subtype of schizophrenia. Though this model’s
predictions are intuitive, further study is needed to
understand how well it reflects the full spectrum of
catatonia types.
In the second paper, Jonathan Rogers and colleagues4
assemble two immune-related perspectives of
catatonia. The authors consider the catatonia-like
neurovegetative symptoms that occur with innate
immune system activation and how autoimmunity
might cause the full catatonic syndrome. In their novel

synthesis, the authors theorise that immune activation
in response to infections and that which occurs in
a variety of autoimmune conditions might lead to
catatonic symptoms due to downstream glutamatergic
or γ-aminobutyric-acid (GABA)ergic modulation.
Although this hypothesis remains to be tested, it
suggests a potential role for medications that modulate
not only GABA or glutamate activity but also immune
targets in catatonia—or at least in a subset of cases.
These Series papers conceptualise catatonia as a
single entity defined by its syndrome comprising three
motoric subtypes: increased, decreased, or abnormal
activity. This idea might be considered the unified
theory of catatonia, akin to Lipowski’s5 unified theory of
delirium that also incorporates three motoric variants.
Whereas this unified theory remains the prevailing
view, I wonder whether physiologically distinct types
of catatonia—catatonias—might yet be identified and
whether the models presented in these papers might
help to parse these out.
At the very least, the diversity of catatonia’s
phenotype3 and the diversity across biological indices4
suggest a spectrum of catatonic states. The DSM-5
approach to catatonia stands out for being entirely
polythetic: none of its 12 symptoms take priority and
no specific criteria must be present.6 Mathematically,
4017 unique symptom combinations exist that would
yield a catatonia diagnosis. Among these combinations,
many will have no symptom in common with a host
of other diagnosable combinations: for instance, any
presentation fulfilling exactly three diagnostic criteria
will share no symptom with 466 other diagnosable
combinations. The sheer combinatorial complexity of
catatonia’s phenotype and the diversity of potentially
non-overlapping syndromes as currently defined pose a
formidable barrier to achieving clarity in diagnosis and
to deciphering catatonia’s underlying structure.7
Differential response rates to lorazepam would also
reasonably suggest physiological distinctions among
catatonia subtypes and might even serve as a modern
means of pharmacological dissection.8 Catatonia
associated with primary mood disorders responds
more favourably to lorazepam than does catatonic
schizophrenia9 or certain medical catatonias.10 The
only double-blind randomised controlled trial (RCT)
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Comment
of lorazepam for catatonia to date was in individuals
with chronic catatonic schizophrenia and failed to find
improvement when compared with placebo.11
Broadly, these papers3,4 might be seen as a call to
combat widespread under-recognition of catatonia.
The inclusion of unspecified catatonia in DSM-5
should encourage clinicians to consider catatonia
in any context.3,12 Next, catatonia’s diagnostic
structure needs refinement. Should certain features
serve as index criteria? Are specific features properly
pathognomonic? Likewise, as illustrated by the many
unanswered questions highlighted in these papers,
further investigation on the nature of catatonia is
warranted. Is all catatonia created equal? Finally, the
most pressing gap in the literature regards treatment:
the field awaits even its first double-blind RCT on the
efficacy of any medication for acute catatonia. Even
less clear is how clinicians should manage chronic
catatonia or catatonic features that persist beyond an
acute presentation.
Mark Oldham
University of Rochester Medical Center, Rochester, NY 14642, USA
mark_oldham@urmc.rochester.edu
I declare no competing interests.
1 Kahlbaum K. Die Katatonie oder das Spannungsirresein. Eine klinische form
psychischer Krankheit. Berlin: A Hirschwald, 1874.
2 Gross AF, Smith FA, Stern TA. Dread complications of catatonia: a case
discussion and review of the literature. Prim Care Companion J Clin Psychiatry
2008; 10: 153–55.
3 Walther S, Stegmayer K, Wilson JE, Heckers S. Structure and neural
mechanisms of catatonia. Lancet Psychiatry 2019; published online June 10.
http://dx.doi.org/10.1016/S2215-0366(18)30474-7.
4 Rogers JP, Pollak TA, Blackman G, David AS. Catatonia and the immune
system: a review. Lancet Psychiatry 2019; published online June 10.
http://dx.doi.org/10.1016/S2215-0366(19)30190-7.
5 Lipowski ZJ. Delirium: acute brain failure in man. Springfield, IL:
Charles C Thomas, 1980.
6 American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders. Washington, DC: American Psychiatric Association, 2013.
7 Wilson JE, Niu K, Nicolson SE, Levine SZ, Heckers S. The diagnostic criteria
and structure of catatonia. Schizophr Res 2015; 164: 256–62.
8 Klein DF, Fink M. Psychiatric reaction patterns to imipramine. Am J Psychiatry
1962; 119: 432–38.
9 Rasmussen SA, Mazurek MF, Rosebush PI. Catatonia: our current
understanding of its diagnosis, treatment and pathophysiology.
World J Psychiatry 2016; 6: 391–98.
10 Smith JH, Smith VD, Philbrick KL, Kumar N. Catatonic disorder due to a
general medical or psychiatric condition. J Neuropsychiatry Clin Neurosci 2012;
24: 198–207.
11 Ungvari GS, Chiu HF, Chow LY, Lau BS, Tang WK. Lorazepam for chronic
catatonia: a randomized, double-blind, placebo-controlled cross-over
study. Psychopharmacology (Berl) 1999; 142: 393–98.
12 Tandon R, Heckers S, Bustillo J, et al. Catatonia in DSM-5. Schizophr Res 2013;
150: 26–30.