Karl Ludwig Kahlbaum (1828-1899) was the first to conceptualize and describe the main clinical features of a novel psychiatric illness, which he termed catatonia in his groundbreaking monograph published 150 years ago. Although Kahlbaum postulated catatonia as a separate disease entity characterized by psychomotor symptoms and a cyclical course, a close examination of his 26 cases reveals that most of them presented with motor symptom complexes or syndromes associated with various psychiatric and medical conditions. In his classification system, Kraepelin categorized catatonic motor symptoms that occur in combination with psychotic symptoms and typically have a poor prognosis within his dementia praecox (schizophrenia) disease entity. Because of the substantial influence of Kraepelin’s classification, catatonia was predominantly perceived as a component of schizophrenia for most of the 20^th century. However, with the advent of the psychopharmacotherapy era starting from the early 1950s, interest in catatonia in both clinical practice and research subsided until the early 2000s. The past two decades have witnessed a resurgence of interest in catatonia. The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, marked a paradigmatic shift by acknowledging that catatonia can occur secondary to various psychiatric and medical conditions. The introduction of an independent diagnostic category termed “Catatonia Not Otherwise Specified” significantly stimulated research in this field. The authors briefly review the history and findings of recent catatonia research and highlight promising directions for future exploration.

Over the past 150 years, the definition, clinical assessment, and diagnosis of catatonia have followed a long and winding path. The 150^th anniversary of the first scientific description of catatonia by Kahlbaum provides an excellent opportunity to summarize the evolution of the concept and current understanding of its myriad manifestations and neurobiological correlates, emphasizing its clinical importance and exploring future directions for catatonia research.

Kahlbaum[1] (1828-1899) was the first to conceptualize and describe the main clinical features of a new psychiatric illness, which he termed catatonia in his groundbreaking monograph published in 1874. He defined catatonia as “a brain disease with a cyclical, fluctuating course, in which successive mental symptoms are melancholia, mania, stupor, confusion, and finally dementia. In addition to mental symptoms, motor nervous (systemic) processes also appear, the typical symptoms of which are usually epileptic in nature”. He described 17 motor and psychomotor abnormalities, collectively designated as “movement stereotypes” and unified them into a new clinical entity. In addition, Kahlbaum was a pioneer of psychiatric nosology, being the first to emphasize the fundamental importance of longitudinal observations and disease outcomes and to distinguish the disease process (Krankheitsprozess) from the cross-sectional presentation (Zustandsbild), effectively separating the presenting syndrome from the presumed underlying disease entity. Although Kahlbaum postulated catatonia as a separate disease entity characterized by psychomotor symptoms and a cyclical course, a close examination of his 26 cases reveals that most of them presented with motor symptom complexes or syndromes associated with various psychiatric and medical conditions.

Kraepelin[2] sought to establish the position of catatonia in psychiatric nosology in a different way. He postulated that psychiatric illnesses primarily result from biological and genetic disorders. Kraepelin[2] introduced the concept of dementia praecox, defining it as “a semi-acute development of a peculiar state of mental weakness occurring at a young age”. In his initial presentation of this concept in 1893 in the fourth German edition of his “Compendium der Psychiatrie”[3], he placed it alongside degenerative disorders but separately from catatonia and paranoid dementia. However, in 1899, in the sixth edition of the Compendium, Kraepelin[4] treated all three clinical types (hebephrenia, catatonia, and paranoid dementia praecox) as different expressions of a single disease, dementia praecox. According to Kraepelin’s description, catatonia did not follow a sequential course; it exhibited an acute onset and was primarily defined by prominent positive psychotic symptoms, such as delusional preoccupations and hallucinations. Furthermore, it often culminated in dementia for over half of his patients, whereas others displayed varying degrees of lasting behavioral and/or motor “peculiarities”. Although acknowledging that catatonic signs and symptoms can manifest in various psychiatric disorders, it was Kraepelin, according to Kendler[5], who positioned catatonia primarily as a subtype of his newly proposed diagnostic entity, dementia praecox, a form of acute onset psychosis in young individuals that rapidly progressed toward dementia.

Because of the substantial influence of Kraepelin’s classification, catatonia was predominantly viewed as a component of schizophrenia for most of the 20^th century. Catatonic manifestations unrelated to schizophrenia, although recognized, were absent from international diagnostic classifications[6]. The contribution of the Wernicke-Kleist-Leonhard school to the description and classification of catatonia has received scant attention in the international literature. Following the neuropathological and clinical traditions established by Carl Wernicke (1856-1906) and Karl Kleist (1879-1960), Karl Leonhard (1904-1988) devised a comprehensive description and nosology of catatonia based on painstakingly meticulous and dispassionate observation of patients over several decades. Drawing on personally conducted interviews, long-term follow up and family genetic studies of mostly chronic psychotic patients, Leonhard delineated seven sharply circumscribed catatonia subtypes, each with prognostic implications[7,8]. Yet, in spite of its great heuristic value, Leonhard’s classification has always been pursued only by a small group of devotees and up to very recently, has never been subjected to vigorous scientific scrutiny exploring its validity apart from its periodic catatonia category[9,10].

In his 1934 review, Karl Heinz Stauder (1905-1969) described 27 cases of catatonia emerging in the context of acute febrile states[11]. These cases typically began with sudden and purposeless excitation, which then evolved into an exhausted stuporous state with severe confusion and key catatonic symptoms, such as hypertonic hypokinesia, posturing, and mutism. If untreated, patients remained in this final stuporous state for a maximum of 4 d, wherein cardiovascular and/or respiratory failure resulted in coma and eventually death. This variant of catatonia is referred to as Stauder’s lethal catatonia[12] or pernicious or malignant catatonia[13]. This condition can also have iatrogenic origins, such as neuroleptic-induced catatonia, neuroleptic malignant syndrome, toxic serotonergic syndrome, or, as a more recently discovered cause, autoimmune [e.g., anti-N-methyl-D-aspartate (NMDA) receptor] encephalitis[14].

With the advent of the psychopharmacotherapy era starting from the early 1950s, interest in catatonia subsided in clinical practice and research until the early 2000s. Most American psychiatrists mainly relied on Kraepelin’s and Bleuler’s concepts of catatonia. In the first three editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM)[15-17] published by the American Psychiatric Association, catatonia only appeared as a subtype of schizophrenia; this approach likely resulted in significant neglect, underdiagnosis and inadequate treatment of catatonia[18,19].

Two seminal studies by American authors[20,21] reshaped the understanding of catatonia in American psychiatry. In a prospective 14-month study involving 55 patients with catatonia, only a quarter of the patients met the DSM criteria for schizophrenia, whereas approximately two-thirds of them developed affective disorders, predominantly mania, and nine of the patients were diagnosed with a neurological condition[20]. Catatonic signs and symptoms were present in similar proportions across all three groups. Gelenberg took the findings of Abrams and Taylor one step further by offering a well-researched and poignant appeal to the scientific community. In a seminal review, Gelenberg[21] documented the occurrence of catatonia across diverse etiological conditions essentially challenging the narrow general understanding of catatonia as subtype of schizophrenia and establishing it as a syndrome that extended across diagnostic boundaries. This shift in the conceptualization of catatonia was reflected in the fourth edition of the DSM[22], leading to the inclusion of two new categories: (1) Catatonia secondary to a general medical condition; and (2) catatonic features as specifiers of mood disorders. The classification of catatonia as a subtype of schizophrenia remained unchanged. The presence of a minimum of 2 out of a total of 12 catatonic signs and symptoms was required to make a diagnosis of catatonia. Further refinement in DSM-5 led to the subdivision of catatonia into acute, chronic, cyclic, excited, retarded, and malignant forms[23]. It was also suggested that the etiology of catatonic symptoms, specifically the primary psychiatric or medical diagnosis, should be reflected in the diagnostic scheme, given their therapeutic and prognostic implications[23].

The past two decades witnessed a resurgence of interest in catatonia. In the DSM-5[24], there was a notable change in the paradigm regarding catatonia. It was recognized that catatonia can be secondary and can occur within a wide range of psychiatric and medical conditions. The manual no longer listed catatonia as a form of schizophrenia. Instead, catatonia is classified as a syndrome occurring in three major settings: (1) Catatonic disorder due to a general medical condition; (2) catatonia as a specifier for 10 mood and psychotic disorders (including schizophrenia); and (3) catatonia not otherwise specified. The introduction of the last category opened the possibility of considering catatonia as an independent, separate entity, significantly stimulating research in this field[18]. To establish a diagnosis, clinicians must observe 3 out of the 12 catatonic signs or symptoms within a month, potentially yielding thousands of possible combinations of symptoms and signs that all lead to the same general unitary diagnosis of catatonia, without distinguishing between different phenotypical or clinical variants of catatonia.

Over the past two decades, the number of publications reporting results of studies on catatonia and the number of articles published following the release of DSM-5 have increased dramatically. Despite these efforts, many questions regarding catatonia remain unanswered.

Since 1991, seven catatonia rating scales have been developed: the Modified Rogers Scale, Rogers Catatonia Scale Revised, Bush-Francis Catatonia Rating Scale, Northoff Catatonia Rating Scale, Catatonia Rating Scale, Braunig Catatonia Rating Scale and Kanner Scale[25]. All of these are generic scales based on the assumption that the composition and time frame of the catatonic syndrome remain the same irrespective of the underlying primary medical or psychiatric conditions. The aforementioned seven scales differ from each other in terms of the definitions and number of catatonic signs and symptoms they incorporate. Thus, the frequencies of catatonia cases measured using these different rating scales can vary substantially, ranging from 3.4% to 10.3%[26]. Given that various theoretical frameworks, nosological concepts, and rating scales/criteria used to diagnose catatonia have changed over time, comparing results using different scales is challenging. Comparisons are further complicated by the lack of a uniform procedure or definition for the time frame over which ratings are recorded, although some of the diagnostic criteria and the measurement scales also contain temporal and longitudinal factors.

Biological research in this field has a rich history. For instance, Rolv Gjessing and Leiv Gjessing described nitrogen disturbances and serum glucose and white blood cell abnormalities in phases of periodic catatonia and highlighted the therapeutic effect of thyroid extracts in some patients[27].

More recently, studies have explored the neurobiological underpinnings of catatonia using advanced imaging techniques[28-30]. Structural magnetic resonance imaging studies have revealed that catatonia was associated with widespread reductions in gray-matter volume, including in the orbitofrontal, cingulate, and visual cortices and the insula when compared with healthy individuals. Patients with catatonia demonstrated hypergyrification in the motor, premotor, and somatosensory cortices compared with controls; however, no differences in cortical thickness were observed between patients with catatonia and controls[29]. In addition, patients with catatonia were found to have significantly smaller volumes in the anterior inferior hypothalamus, the cortical nucleus of the amygdala, and the hippocampal fimbria[30]. Furthermore, patients with catatonia exhibited poor functional activation of the supplementary motor area, primary and secondary motor cortices, inferior parietal cortex, and basal ganglia during self-initiated movements[31,32]. Studies have observed reduced cerebral blood flow in the right prefrontal and parietal cortices[33] and reduced GABA-A-receptor density in the left sensorimotor cortex[34]. Dysfunction in the orbitofrontal cortex could contribute to poor connectivity in the medial prefrontal cortices[35]. An arterial spin labeling study showed that patients with schizophrenia exhibited increased cerebral blood flow in the left primary motor cortex and supplementary motor area during a catatonic episode[36]. In addition, a transcranial magnetic stimulation (TMS) study of a patient with acute catatonia and echolalia revealed a “hyper-imitative” state that may account for echo-phenomenon observed in catatonia. TMS-induced hand muscle evoked potentials were higher when the subject watched hand movements involving those muscle groups compared to the resting state. However, this effect disappeared after the resolution of catatonia and echolalia, suggesting that specialized “mirror” neurons of motor and premotor cortices that fire during both action performance and action observation are disinhibited during a catatonic episode. Observations in this case report have raised intriguing questions and require further research[37]. At present, imaging techniques are research tools only and not of practical use for identifying catatonia other than excluding underlying structural brain lesions that are suspected based on clinical findings.

In genetic studies, the lifetime morbidity risk of catatonia in the first-degree relatives of patients with periodic catatonia was found to be 27%, with an autosomal dominant linkage to chromosome 15q15 and a heterogeneous linkage to chromosome 22q13[38,39]. Preliminary evidence indicates that a more severe catatonic syndrome in patients with schizophrenia is associated with a loss-of-function allele of a myelin-specific gene[40]. In animal studies, D2-receptor-deficient mice showed severe motor abnormalities, including aberrant locomotor initiation and spontaneous catatonia[41,42]. While no chromosomal variants have been consistently tied to catatonia, further studies may prove informative in identifying pathophysiology, enabling targeted treatment development, and identifying patients at risk.

In epidemiological studies, the incidence of catatonia in adult inpatients with psychiatric conditions was estimated to be approximately 10%[43-45]. However, the prevalence of catatonia varied substantially based on underlying or comorbid conditions, ranging from 4% to 67% in schizophrenia, from 14% to 71% in mood disorders, from 4% to 46% in medical conditions[46], and from 6% to 20.2% in neurodevelopmental disabilities[47]. Among hospitalized children, the incidence of catatonia was 4%[48].

Patients with catatonia exhibited decreased serum iron levels and increased creatine kinase and NMDA-receptor antibodies[49]. Iron levels serve as a negative acute phase reactant and tend to be low in acute inflammatory states and numerous autoimmune disorders. Thus, it is hypothesized that catatonia is associated with central and peripheral inflammation[50].

Several studies have focused on catatonia in specific populations, including children[47], adolescents[51], older individuals[52,53], and women in the peripartum period[54,55].

Advances in the management of catatonia remain primarily based on clinical and observational evidence rather than controlled trials. Nevertheless, the lorazepam challenge test is accepted as a useful tool not only to treat catatonia, but also to confirm its diagnosis. The gold standard for the treatment of catatonic symptoms is still lorazepam or other benzodiazepines. If benzodiazepines proved to be ineffective, then electroconvulsive therapy (ECT) is the second option[56]. If psychosis is the underlying cause of catatonia, second generation antipsychotics could be used with caution due to the risk of inducing neuroleptic malignant syndrome[57]. If the patient does not respond to the above-mentioned therapeutic interventions, then an NMDA-receptor antagonist could be a possible choice. When ECT is not available, new neurostimulation techniques, e.g., TMS or direct current stimulation could be alternatives for pharmacotherapy-resistant cases[56].

The first and most important research imperative involves achieving a consensus-based harmonization of the concept and symptoms of catatonia. This harmonization is necessary to improve the diagnostic process and standardize results between studies to enable systematic comparisons and meta-analyses. In addition, it is important to determine the longitudinal course of diverse catatonic phenotypes and the time frame in which the presence of catatonic symptoms is required for a diagnosis. Neural mechanisms underlying catatonia remain unknown. Advances in genetics as well as structural and functional imaging techniques can provide a deeper understanding of the neurobiological correlates of catatonia[28]. Furthermore, research on experimental animal models of catatonia is still in its initial stages, and their development appears to be a promising avenue for further research that is unique in research of behavioral conditions[47]. In addition, investigations and research into innovative pharmacological and neuromodulatory treatments are still in their early stages[58,59].

Catatonia has garnered substantial renewed interest in psychiatry over the past two decades, with a notable surge following the publication of DSM-5. The development of the concept and diagnosis of catatonia has undergone a remarkable journey over the last 150 years, and this journey is still ongoing. Several international research groups are actively investigating the theoretical, diagnostic, and neurobiological aspects of catatonia. Their aim is to translate research findings into clinical practice to improve the rate and speed of recovery and the quality of life of patients with catatonia.