Catatonia – Pathophysiology, Diagnosis and Management

The term catatonia (from Greek kata=down+tonos=tension) was coined in 1874 by a German psychiatrist, Karl Ludwig Kahlbaum.

Current clinical rating scales for catatonia, with few exceptions (e.g., Northoff Catatonia Rating Scale), predominantly assess motor signs at the expense of affective symptoms.

The widely used Bush Francis Catatonia Rating Scale (BFCRS) reflects this bias.

Thus, rather than using catatonia scales, psychiatrists may be more familiar with motor symptoms like flexibilitas cerea and posturing, often overlooking affective and cognitive and behavioural aspects. Incorporating these dimensions is crucial as patients frequently describe their catatonic symptoms in affective terms. [Hirjak et al., 2022]

A study using principal component analysis identified three components of catatonia: [Dawkins et al, 2022].

1. Parakinetic:

• Posturing/catalepsy, grimacing, echopraxia/echolalia, stereotypy, and mannerisms
• Linked to women, neurodevelopmental disorders, and longer hospital stays.

2. Hypokinetic:

• Immobility/stupor, mutism, rigidity, negativism, and waxy flexibility
• Associated with catatonia relapse

3. Withdrawal:

• Withdrawal
• Linked to men and mood disorders

Among 68 patients, 35% expressed fear, but 72% provided narrative explanations involving hallucinations, delusions, and non-psychotic rationales. These findings highlight the diverse phenomenology of catatonia, emphasising the importance of understanding both affective and cognitive-behavioural dimensions.

Catatonia as a Fear Response: 

Contemporary perspectives suggest catatonia may be better understood as a fear response similar to the animal defence mechanism of tonic immobility, or “death feint”. [Moskowitz,2004]

It is postulated that catatonia originated from ancestral encounters with predators, with modern manifestations triggered by different threats. Read more about the fear cascade and its parallels with dissociation, especially the flag and faint stage of the fear cascade. 

This hypothesis aligns with Kahlbaum’s original conception, emphasising the parallels between catatonia and tonic immobility.

Similarly, Northoff et al. retrospectively asked 24 patients about their experiences following recovery from an episode of catatonia, and half of them reported uncontrollable and overwhelming emotions, particularly fear. [Northoff et al, 1996]

The study identified two catatonia subgroups:

• Emotive (high anxiety and intense emotions)
• Non-emotive (predominant ambivalence).

Emotive patients responded better to lorazepam, suggesting benzodiazepines’ effectiveness may be due to their anxiolytic effects.

Cohen proposed three phenomenological groups in paediatric catatonia: [Cohen, 2006]

1. The hyperanxious who are “frightened stiff.”
2. Those with adherence to delusional ideas, such as a belief that a repetitive action was necessary.
3. Those with resistance to delusional thinking, such as when an individual resists an impulse by holding still.

Neuroimaging Findings

• Evidence suggests a combination of cortical and subcortical dysfunctions contribute to the pathophysiology of catatonia.
• Patients with catatonia exhibit significantly lower Iomazenil (a SPECT agent for the central benzodiazepine receptor system binding),) with notable right-left asymmetries in the sensorimotor cortex.
• Reduced regional cerebral blood flow (rCBF) and significant right-left alterations have been observed in the right lower prefrontal and parietal cortex. [Hirjak et al, 2020]
• The neurodevelopmental hypothesis of catatonia is supported by recent MRI studies identifying structural brain abnormalities, such as reduced surface area in the right medial OFC and left superior parietal gyrus and hypergyrification in the left medial OFC and rostral anterior cingulate cortex. These findings suggest a link between early cortical development markers and catatonia. [Hirjak et al., 2022]

The Role of the Orbitofrontal Cortex in Catatonia 

• The OFC plays a crucial role in decision-making, mood regulation, and impulse control. It is connected to the amygdala, hippocampus, thalamus, cingulate/medial prefrontal, premotor, and parietal areas.
• Aberrant OFC activation and disrupted connectivity to the premotor cortex are observed in catatonia during emotional states. [Northoff, et al, 2004]
• Similar abnormalities are seen in schizophrenia and bipolar disorder patients, with lorazepam reducing the OFC signal, suggesting it compensates for OFC dysfunction.
• Disrupted OFC connectivity impairs cortico-cortical modulation, leading to emotional dysregulation, impulsive behaviour, and aggression.
• Neuroimaging studies show decreased GABA-A receptor density in the left sensorimotor cortex and intrinsic neural activity abnormalities in the frontoparietal network, implicating the OFC in catatonia’s pathophysiology.

Neurotransmitter Abnormalities: 

The neurobiology of catatonia is believed to originate in disturbances in GABA, glutamate, and dopamine signalling, which are hypothesised to underlie the behavioural, motor, cognitive, and affective symptoms of catatonia [Northoff 2002],  [Hirjak et al., 2020]

Motor symptoms in catatonia seem to be modulated by changes in dopamine, whereas affective symptoms may be mainly associated with GABA and glutamate changes.

For example, GABA is a major inhibitory neurotransmitter within the motor cortex (M1), and the administration of lorazepam or electroconvulsive therapy (ECT) may enhance the excitability of GABA-related inhibitory circuits, thereby alleviating catatonic symptoms via intracortical inhibition (ICI).

• Reduced GABA-A receptor activity is found in the right lateral orbitofrontal and right posterior parietal cortex, which would explain the motor and affective symptoms but not behavioural catatonic symptoms. Furthermore, this explains the efficacy of benzodiazepines, which increase GABA activity and are therapeutically effective in up to 70% of patients. [Northoff 2002]
• Glutamate is an excitatory neurotransmitter, and glutamatergic abnormalities in the basal ganglia have been suggested to be a driver of catatonia-related glutamate hyperactivity. Therapeutic recovery with the NMDA antagonist, amantadine, is gradual, and therefore, NMDA receptors are likely to be a secondary mechanism (unlike GABA-A receptors)
• Dysfunctional dopamine metabolism was originally hypothesised to be linked to catatonia during the 1970’s; however, the data is inconsistent. Evidence of sudden and massive dopamine blockade in the striatal dopaminergic system does, however, explain why antipsychotics such as haloperidol can exacerbate the syndrome (i.e. neuroleptic-induced catatonia).

Immunological Dysfunction in Catatonia: 

Neuroinflammatory, autoimmune, and infectious etiologies contribute to catatonia, with immune cell activation impairing CSTC loop systems.

72% of autoimmune catatonia cases are due to NMDAR encephalitis, which disrupts synaptic connectivity through glutamate dysregulation.  [Ariza-Salamanca et al., 2022]

Anti-NMDA Encephalitis (Brain on Fire) – Clinical Symptoms and Management

Psychosocial or environmental stress (including infections) initiates a cascade of events that can lead to catatonia.

When the body experiences stress, catecholamines such as noradrenaline are released from activated sympathetic nervous system fibres.

This response stimulates the bone marrow to produce myeloid cells (e.g., monocytes), which then enter the periphery.

These monocytes encounter stress-induced damage-associated molecular patterns (DAMPs) and microbial-associated molecular patterns (MAMPs).

DAMPs and MAMPs include various substances such as bacteria, LPS, flagellin, HSPs, glucose, HMGB1, uric acid, and ATP.

Upon encountering these patterns, the monocytes activate inflammatory signalling pathways, including NF-κB.

This activation releases pro-inflammatory cytokines such as TNF, IL-1, and IL-6, which can access the brain through both humoral and neural routes.

Psychosocial stress also activates microglia in the brain to adopt a pro-inflammatory phenotype, releasing chemokines like CCL2 that attract more myeloid cells to the brain.

Once in the brain, these activated macrophages perpetuate central inflammatory responses, further activating inflammatory pathways.

Immunoactivation affects several critical brain regions and circuits, including the anterior cingulate cortex (ACC), mid-cingulate cortex (MCC), medial prefrontal cortex (mPFC), and paralimbic cortico-striato-thalamo-cortical (CSTC) circuits.

These regions are crucial for controlling motivation and movement. [Beach et al., 2024]

Environmental stressors that activate amygdala threat signalling enhance vulnerability to catatonia through these pro-inflammatory processes.

Cytokines activate circuits regulating anxiety, arousal, alarm and fear, including the amygdala, hippocampus, ACC and insula.

Cytokines also affect dopaminergic, GABAergic and glutamatergic systems.

Neuroinflammation and Depression – A Simplified Guide

Chronic stress exacerbates this vulnerability by increasing pro-inflammatory gene expression and disrupting T-helper cell balance, leading to autoimmune disorders.

This creates a fertile ground for neuroinflammatory, autoimmune, and infectious aetiologies to contribute to catatonia.

Pro-inflammatory microglial activation can further impair connectivity and synaptic stability, contributing to the neurovegetative features of catatonia, such as mutism and psychomotor retardation.

While GABAergic modulation can reduce pro-inflammatory cytokines and potentially alleviate catatonia, glutamatergic hypofunction, particularly involving NMDA receptors, plays a crucial role, especially in autoimmune catatonia. [Rogers et al., 2019]

In conclusion, the cascade triggered by stress and immune activation leads to catatonia through a complex interplay of pro-inflammatory processes, impaired connectivity, and neurotransmitter dysregulation.

The classical clinical feature of catatonia is stupor, which is characterised by immobility and mutism. Another classic symptom is posturing, whereby the patient positions themselves in an uncomfortable position against gravity with complete akinesia.

Catatonia is an identifiable syndrome that is well-characterised and defined in the DSM-V as a separate clinical diagnosis from schizophrenia.[APA 2013]

Although the catatonic subtype of schizophrenia has been deleted from the DSM, catatonia is still included as a specifier for schizophrenia and major mood disorders (bipolar disorder, major depressive disorder, and other mental and neurodevelopmental disorders).

Catatonia is also a specifier for brief psychotic disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.

A new residual diagnostic category of catatonia not otherwise specified (NOS) is added in patients with psychiatric conditions other than schizophrenia or mood disorders or when the general medical condition is not immediately recognised. [Luchini et al. 2015]

The ICD-11 framework conceptualises catatonia as an episodic diagnosis, emphasising psychomotor disturbances as the primary clinical feature during its course. Catatonia is recognised as a distinct diagnostic category, separate from psychotic and mood disorders. [Reed et al., 2019]

Despite over 150 years in psychiatric literature, catatonia’s etiopathogenesis, phenomenology, diagnostic criteria, and treatment remain fraught with gaps and controversies.

The ICD-11 and DSM-5 require the identification of any three of 15 (ICD-11) or 12 (DSM-5) signs for a diagnosis. Catalepsy and waxy flexibility are highly specific motor features.

A bi-axial classification framework akin to those for dystonia and tremor has been proposed, which could facilitate the evaluation of underlying etiologies and guide therapeutic decisions, improving patient outcomes. [Lenka et al., 2024]

For example, in tremor, the two axes include:

1. Axis 1- Emphasising the clinical features, history, and tremor characteristics
2. Axis 2- Emphasising the potential etiologies of tremor

Types of Catatonia:  [Rogers et al, 2023]

1. Medication-induced catatonia:

• Induced by administration or withdrawal of prescribed medications.

2. Substance-induced catatonia:

• Induced by administration or withdrawal of psychotropic substances.

3. Malignant (pernicious/febrile/lethal) catatonia:

• Life-threatening form with pronounced autonomic abnormalities.
• Can cause elevated blood pressure, heart rate, and body temperature.
• Occurs in a small fraction of patients with catatonia.

4. Catatonia in critical illness:

• Occurs in patients needing medical ICUs (e.g., intubation, ventilation, vasopressors).
• Some may meet criteria for both catatonia and delirium and benefit from treatment for both.

5. Periodic catatonia:

• Rare, highly heritable form characterized by alternation between stupor and excitement.

6. Catatonic schizophrenia:

• Historical subtype of schizophrenia with predominant psychomotor disorders.
• May also include hallucinations, delusions, and thought disorder.

7. Organic catatonic disorder:

• Described in ICD-10 as a syndrome due to a known physiological condition.
• Requires exclusion of catatonic schizophrenia, delirium, and stupor.
• Listed as ‘secondary catatonia syndrome’ in ICD-11 and ‘catatonic disorder due to another medical condition’ in DSM-5-TR.

8. Psychomotor concept of catatonia:

• Clinical/neurobiological concept viewing catatonia as a psychomotor syndrome.
• Defined by motor, affective, and behavioural domains with associated brain networks.

9. Motor concept of catatonia:

• Clinical/neurobiological concept viewing catatonia as primarily a motor syndrome.
• Defined mainly by motor and behavioural features with associated brain networks.

Classification of Catatonia

There are several proposed classifications of catatonia. For further reading, please refer to [Luchini F et al., 2015]

Taylor and Fink proposed that catatonia should be classified as an independent entity with three subtypes:[Taylor and Fink, 2003]

1. Non-malignant (Kahlbaum syndrome): the most frequent form of catatonia, which has a positive response to treatment with benzodiazepines (lorazepam 6-20 mg IV)
2. Delirious catatonia: defined by the presence of excitement, altered states of consciousness and delirium requiring higher doses of BZDs, worsens with antipsychotics (APs) and often requires adjunctive ECT.
3. Malignant catatonia: acute onset, fever, autonomic instability, leucocytosis, increased CK. This type responds to ECT. Due to the similarity with the presentation of neuroleptic malignant syndrome, Fink suggested that malignant catatonia and NMS should be considered the same disorder.

One key difference highlighted between NMS and catatonia is that malignant catatonia starts with psychotic excitement, while NMS starts with severe extrapyramidal muscular rigidity.

The alternative clinical classification includes:

1. Retarded catatonia: characterised by immobility, mutism, staring, rigidity,

2. Excited catatonia: less common presentation in which patients develop prolonged periods of psychomotor agitation

The Wernicke-Kleist-Leonhard (WKL) school distinguishes seven chronic catatonic subtypes within the spectrum of schizophrenia spectrum disorders, each characterised by a distinct course and prognosis.

Karl Leonhard meticulously documented these subtypes over decades, using clinical observations, patient interviews, and long-term follow-ups, resulting in the following classifications: [Leonhard, 1979]

1.Periodic Catatonia:

• Characterised by a mix of hyperkinetic and akinetic states, with stiff, ungraceful movements. Remissions are common, and prognosis is relatively positive.

2.Parakinetic Catatonia:

• Defined by choppy, disjointed movements following stimulation. Speech is often fragmented and ungrammatical, reflecting the disorder in motion and communication.

3. Affected Catatonia:

• Increasing rigidity and stereotypical movements dominate, leading to a severe lack of motion and requiring assistance with basic needs.

4. Proskinetic Catatonia:

• Patients show responsiveness in facial expressions but remain largely uncommunicative. Stimuli trigger repetitive behaviours like grasping or mumbling.

5. Negativistic Catatonia:

• Marked by resistance and refusal to follow instructions, often expressed as ambivalence. Friendly interaction can reduce resistance partially.

6. Voluble Catatonia:

• Characterised by evasive speech, patients may answer simple questions but avoid complex ones. Responses are often brief, incoherent, and may include neologisms.

7. Sluggish Catatonia:

• Defined by slow responses and distractibility, with occasional bursts of lively movement or speech. Hallucinations are common, but motivation and affect are severely diminished.

A recent study attempted to explore the heterogeneity within schizophrenia spectrum disorders (SSD) by comparing clinical and neuropsychological profiles across distinct catatonic subtypes, specifically progressive periodic catatonia (PPC) and chronic system catatonia (CSC), as classified by the Wernicke-Kleist-Leonhard (WKL) framework. [Schorr et al, 2024]

Findings revealed that PPC is marked by more frequent schizoaffective presentation, higher levels of depression, less positive psychotic symptoms, a higher familial predisposition, and specific biomarkers. Two biomarkers strongly associated with progressive periodic catatonia (PPC) include a genetic linkage on chromosome 15q found in over two-thirds of PPC cases and hyper-perfusion in the lateral premotor cortex and supplementary motor area, demonstrating 82% sensitivity and 95% specificity for PPC.

CSC is characterised by early-onset psychomotor deficits, significant cognitive impairment, and minimal response to antipsychotic treatment.

The study highlights substantial clinical heterogeneity within catatonia in SSD, indicating that differentiating chronic catatonic subtypes, such as PPC and CSC, is crucial for better understanding and addressing this complexity. [Schorr et al, 2024]

Rating Scales

1. Bush- Francis Catatonia Rating Scale (BCFRS)
2. Modified Rogers Scale (MRS)

It is essential to rule out organic causes: 

A systematic review showed: [Oldham MA, 2018]

• Hospital-wide, 20% of catatonia was medical.
• In acute medical and surgical settings, medical catatonia comprised more than half of the cases.
• At least 80% of older adults seen by consult psychiatry and critically ill patients had a medical cause.
• Two-thirds of medical catatonia involved CNS-specific disease, including encephalitis, neural injury, developmental disorders, structural brain pathology, or seizures.

Catatonia presents with a range of clinical signs that are relatively non-specific.

They can be divided as follows: [Rogers et al., 2023]

Motor Signs:

• Mannerisms
• Stereotypy
• Festination
• Athetotic movements
• Dyskinesias
• Gegenhalten
• Posturing
• Catalepsy
• Waxy flexibility (flexibilitas cerea)
• Rigidity
• Muscular hypotonus
• Sudden muscular tone alterations
• Akinesia

Affective Features:

• Compulsive emotions
• Emotional lability
• Impulsivity
• Aggression
• Excitement
• Affect-related behaviour
• Flat affect
• Affective latency
• Anxiety
• Ambivalence
• Staring
• Agitation

Cognitive-Behavioral Features:

• Grimacing
• Verbigeration
• Perseveration
• Aprosodic speech
• Abnormal speech
• Automatic obedience
• Echolalia/Echopraxia
• Mitgehen/Mitmachen
• Compulsive behaviour
• Negativism
• Autism/withdrawal
• Mutism
• Stupor
• Loss of initiative
• Vegetative abnormalities

The video below shows the signs of waxy flexibility, forced grasping, opposition, negativism and aversion.

1. Stupor – The classic and most striking catatonic sign. It is a combination of immobility and mutism, although both can occur independently.
2. Automatic obedience – the subject does whatever is asked of him or her despite being told not to.
3. Ambitendence – alternating cooperation and opposition; the patient makes a movement, but before completing it, starts the opposite movement
4. Aversion – The patient turns away from the examiner when
   addressed.
5. Echopraxia – subject imitates the movements of the interviewer
6. Echolalia – words or phrases are imitated
7. Perseveration – senseless repetition of previously requested movement, i.e. the repetition of a response after the withdrawal of stimulus (palilalia – the perseverated word is repeated with increasing frequency;  logoclonia – perseveration of the last syllable of the last word seen in organic disorders and occasionally in catatonia)
8. Forced grasping – the offered hand is repeatedly grasped and shaken, despite requests not to do so. Seen in frontal lobe lesions
9. Mitmachen – the body can be put into any posture, despite instructions to resist
10. Mitgehen – an extreme form of mitmachen in which very slight pressure leads to movement in any direction; the ‘anglepoise’ effect, despite being told to resist the pressure; often associated with forced grasping
11. Mannerisms – repetitive goal-directed movements
12. Posturing –Active maintenance of a posture against gravity. Strange and abnormal postures adopted habitually.
13. Perseveration of posture or catalepsy –Passive induction of a posture held against gravity. If the subject’s body is placed in an awkward posture and left, the posture is held for a period before slowly relaxing, despite asking the patient to relax
14. Waxy flexibility –Slight, even resistance to positioning.
    Smooth resistant muscle tone is felt to initial movement (.flexibilitas cerea), e.g. ‘psychological pillow’
15. Negativism – A disorder of volition in which patients do the reverse of whatever is asked of them, e.g. resist attempts to stand when asked to stand up
16. Gegenhalten or opposition (‘against hold’) – A form of negativism in which the springy resistance to passive movement increases with the force exerted.
17. Obstruction – The patient stops suddenly in the course of a movement and is generally unable to give a reason. This appears to be the motor counterpart of thought block.
18. Positivism – includes echopraxia and mitgehen and automatic obedience

Waxy Flexibility

Psychological Pillow

Clinical Assessment:

• Diagnosis is typically made on clinical assessment alone.
• Initial assessment and treatment should be conducted within secondary care.
• Collateral history should be sought to clarify potential explanations and time course.
• Gather detailed medical, neurological, and psychiatric history.
• Assess exposure to or withdrawal from medications, recreational substances, and infections.

Family History:

• Obtain detailed family medical, neurological, and psychiatric history to identify specific biological vulnerabilities.

Physical Examination:

• Essential for assessing catatonic signs and related medical conditions.
• Include signs of medical complications of catatonia.

Mental Capacity:

• Do not assume non-engagement is willful.
• Assess mental capacity to engage in assessment and act in the individual’s best interests if lacking.

Rating Scales:

• Use validated instruments like the Bush-Francis Catatonia Rating Scale (BFCRS) or the Northoff Catatonia Rating Scale (NCRS).
• BFCRS is widely used, validated by a lorazepam challenge, and assesses all DSM-5-TR and ICD-11 criteria.
• NCRS offers comprehensive evaluation and uniquely emphasises affective features.

Investigations:

First-line

• Full blood count
• Renal function tests
• Liver function tests
• Thyroid function tests
• Blood glucose measurement
• Creatine phosphokinase measurement
• Drug screen of urine

Further investigations (depending on findings on physical examination)

• Electrocardiography
• Computed tomography
• Magnetic resonance imaging
• Electroencephalography
• Urine culture
• Blood culture
• Test for syphilis
• Test for HIV
• Heavy-metal screen
• Auto-antibody screen
• Lumbar puncture
• Based on history and examination findings, consider blood tests, a urine drug screen, lumbar puncture, electroencephalography, and neuroimaging.
• Consider CT or MRI of the brain for first episodes or unclear diagnoses.
• Assess for NMDA receptor antibodies and other relevant autoantibodies in serum and CSF.
• For seizure risk factors or evidence of encephalitis, consider performing an EEG.

Challenge Tests:

Catatonia is often confused with a variety of other conditions that have signs that are similar to catatonia, although the full clinical picture is normally distinguishable: [Bahti et al. 2007; Rasmussen et al. 2016]

• Parkinson’s disease –Akinesia and rigidity are commonly associated with Parkinson’s disease; however, catatonia also has strong affective and behavioural abnormalities that do not generally occur in cases of Parkinson’s disease. Tremor is also notably absent in catatonia.
• Extra-pyramidal side-effects (EPSE) – Adverse events commonly observed with antipsychotics that can present with immobility, rigidity, and staring. Postural instability can be exacerbated by benzodiazepines, and so the distinction between EPS and catatonia is important.
• Neuroleptic malignant syndrome – A serious adverse event associated with antipsychotics that is characterised by rigidity and mutism however, autonomic instability differentiates this syndrome from catatonia.
• Nonconvulsive status epilepticus – Often indistinguishable from catatonia however, an electroencephalogram (EEG) can assist in making the correct diagnosis.
• Abulia or akinetic mutism – Moderate or severely diminished motivation that can result in the absence of speech or movement; however, visual tracking is preserved. It does not present with negativism or echophenomena.
• Locked-in syndrome – Complete paralysis caused by ventral pontine lesions, which may be detectable by MRI or by brainstem potential examination.
• Vegetative state – Often a secondary feature of severe cerebral injury that can be distinguished from catatonia by an abnormal EEG.
• Stiff-person syndrome – An autoimmune disorder characterised by lower extremity stiffness and spasms that are very painful, and as such patients are generally not mute like catatonic patients. A GAD65 antibody seropositive result is indicative of stiff-person syndrome.
• Organic Disorders – metabolic disorders (hyponatraemia, Tay-Sachs disease, Wilson’s disease), infections, drugs.
• Subarachnoid haemorrhages
• Antiphospholipid syndrome
• Systemic Lupus Erythematosus

Risk factors for Catatonia

1. Affective disorders
2. Increasing age
3. Postpartum disorders
4. Low Serum Iron
5. Abrupt cessation of clozapine
6. Thrombotic thrombocytopenic purpura
7. History of severe infectious disease in childhood, including rheumatic fever, is associated with an increased risk of catatonia
   in adult life
8. Prior brain injury
9. Physical illness at onset of psychosis

First Line Treatments: [Rogers et al., 2023]

• Benzodiazepines and ECT have the most evidence in Catatonia.
• Response rates: 59–100% for ECT and 66–100% in Western studies of benzodiazepines.

Below is the algorithm from the British Association for Psychopharmacology Recommendations [Rogers et al., 2023]

The below algorithm is derived from a combination of 3 sources as outlined in the references:

Early treatment is important, and clinical research has shown that electroconvulsive therapy (ECT) and/or benzodiazepines are the recommended first-line choices for treating catatonia. Combination therapy is clinically advantageous for increasing GABA neurotransmission. [Escobar et al. 2000]

Benzodiazepines

• Lorazepam is particularly effective following a positive Lorazepam Challenge Test (1–2 mg in adults and 0.5–1 mg in children and geriatric patients delivered orally, IM, or IV).
• The typical dose is 1–4 mg/day, up to 16 mg/day; a maximum of 24 mg/day may be used.
• The dose may need to be kept high (up to <30 mg/day) and treatment prolonged for complete resolution of catatonic symptoms.
• An adequate trial may be considered complete when catatonia is adequately treated, titration has been stopped due to side effects, or the dose has reached at least 16 mg per day.
• Overall response rate of 66%-100% in acute catatonia.
• The therapeutic response is strongest in acute catatonia, where the patient presents with a rapid-onset catatonic state, especially in bipolar disorder and major depressive disorder.
• Patients with chronic catatonia, especially in the context of schizophrenia, show a less strong response to lorazepam and are more likely to receive ECT.
• Benzodiazepines should be tapered down to avoid withdrawal symptoms and dependence.
• If catatonia relapses on withdrawal of benzodiazepines, a clinician should ensure that any underlying condition has been adequately treated, and a slower taper may be tried.
• Oxazepam, diazepam, clonazepam, and flurazepam have been used.
• Diazepam and zolpidem are alternatives to lorazepam; however, much higher doses are required.

Zolpidem: 

• Selective positive modulator of the GABA-A alpha-1 subunit; selective for the gamma-2 subunit of the GABA-A receptor.
• The recommended dose is 10 mg orally; 5 mg may be used in older patients.
• Available in oral and sublingual preparations, no parenteral preparation limits its use.
• The response is usually observed for 3–6 hours, consistent with zolpidem’s short elimination half-life of 1–4 hours.
• Dramatic response to 10 mg oral zolpidem in a woman with subcortical stroke unresponsive to lorazepam or ECT has been shown. [Mastain et al., 1995]
• Effective in improving verbal fluency in catatonia.
• Two adolescent patients diagnosed with catatonia, unresponsive to lorazepam and olanzapine, showed marked improvement within days when treated with zolpidem 30 mg/day in divided doses. Both patients were successfully discharged on zolpidem extended-release (ER) three times a day and maintained well over two months, suggesting zolpidem is a viable alternative for resistant catatonia in children and adolescents. [Kumar et al., 2020]

Electroconvulsive therapy

• ECT has been used since 1934, with efficacy ranging from 59% to 100%. Right unilateral ECT has even been reported to be effective after one treatment. [Kugler et al 2015; Medda et al 2015]
• NICE advises using ECT for severe depression and prolonged or severe mania in specific situations.
• Studies show ECT has high success rates when benzodiazepines fail.
• ECT should be considered when benzodiazepines are ineffective.
• Restarting clozapine or using ECT is more effective than benzodiazepines for clozapine-withdrawal catatonia.
• Often reserved for patients with treatment-resistant malignant catatonia
• Treatment of choice in malignant catatonia (85 % response), which is less likely to respond to BZDs (40%)
• Bilateral ECT is recommended at least two times weekly for acute catatonia, and sessions should be considered close to each other.

BZD and ECT combined can have a synergistic effect. [Rogers et al., 2023]

Predictors of Response to ECT in Catatonia : [Luchini et al., 2015]

Other Treatments:

1. NMDA Receptor Antagonists

Amantadine and Memantine:

• Postulated to address dopamine and GABA dysregulation in CSTC circuits by modulating NMDA receptors on PFC GABA-A parvalbumin interneurons and decreasing NMDA action in the striatum. [Fricchione & Beach, 2019]
• Amantadine is known to enhance central dopamine release.
• Substantial improvement was reported with amantadine and memantine in 58 published cases with various (aetiologies) within a 7-day window. [Sienaert et al, 2014]
• Oral doses ranged from 100 to 600mg daily; most patients received 200mg daily.
• Daily IV doses ranged from 400–600mg.

2. Dopamine Precursors, Agonists, and Reuptake Inhibitors [Rogers et al., 2023]

• Postulated to treat catatonia by increasing dopamine modulation in the striatal direct pathway, with subsequent thalamic activation of cortical regions.
• Levodopa: Marked improvement in catatonia reported.
• Bromocriptine: Successfully used in a 16-year-old girl with catatonia.
• Methylphenidate: Successful use has been reported in five cases, mostly mood disorders.

Dopamine Receptor Antagonists and Partial Agonists

• Antipsychotics can induce or worsen catatonia and thus should be used with caution, particularly in malignant catatonia. [Sienaert et al, 2014]
• High-potency antipsychotics should be avoided. However, second-generation antipsychotics may be used to treat comorbid psychosis, which has also been shown to be effective in treating acute catatonia.[Hesslinger et al 2001]
• Second-generation antipsychotics (SGAs) are potentially safer adjunctive treatments compared to FGAs.
• Aripiprazole (partial dopamine agonist) has the potential to be marginally effective; however, more research is required as most of the data is based on case reports.[Muneoka et al. 2017]
• Antipsychotics should be co-administered with benzodiazepines when necessary.

Recommendations from the British Association for Psychopharmacology for alternative treatments: [Rogers et al., 2023]

• When first-line therapies for catatonia are unavailable, cautioned, ineffective, or only partially effective, consider a trial of an NMDA receptor antagonist, such as amantadine or memantine.

Alternative Medications:

• If first-line therapies and NMDA receptor antagonists are unavailable, cautioned, ineffective, or only partially effective, consider a trial of levodopa, a dopamine agonist, carbamazepine, valproate, topiramate, or a second-generation antipsychotic (SGA).

Use of Antipsychotic Medications:

• Antipsychotic medications should be avoided where there is no underlying psychotic disorder.
• If antipsychotic medications are used, a second-generation antipsychotic (SGA) should be preferred, with gradual titration, and the co-administration of a benzodiazepine should be considered.

Below is the algorithm by Beach S et al., 2017

Below is another clinical algorithm by Dr Tyler Black. 

1. Dehydration and starvation
2. Increased risk of Deep vein thrombosis and death due to pulmonary embolism in patients with persistent catatonia
3. Significant risk of harm to self or others in the phase of catatonic excitement
4. Progression to NMS with high mortality if untreated