¹Centro Hospital e Universitário de Coimbra, Psychiatry, Coimbra, Portugal

Background: Catatonia is a severe neuropsychiatric syndrome characterized by behavioral, motor, and autonomic disturbances. It is associated with mood, psychotic disorders, encephalitis, thyroid disease, or delirium, but is often underdiagnosed, particularly in autism spectrum disorder. Its pathophysiology may involve dysregulation of GABA, dopamine, and glutamate. First-line treatment includes benzodiazepines (e.g., lorazepam) and electroconvulsive therapy. However, refractory cases may require atypical antipsychotics, NMDA receptor antagonists, or mood stabilizers.

Aims & Objectives: This review aims to explore therapeutic alternatives for cases of resistant catatonia.

Method: We conducted a non-systematic literature review, searching PubMed databases, using the keywords “catatonia”; “therapeutic use” and “resistant”.

Results: Studies on alternative therapeutic strategies for treatment-resistant catatonia are still limited. First-line treatment typically consists of high doses of benzodiazepines, followed by electroconvulsive therapy (ECT). However, some patients do not respond to these approaches. Therefore, exploring alternative therapies is essential. NMDA receptor antagonists, such as amantadine (100–600 mg/day), have shown promising results, as catatonia is associated with excessive NMDA receptor activity in the striato-thalamic-cortical circuit, leading to reduced GABAergic and dopaminergic signaling. Amantadine’s dopaminergic and antiglutamatergic effects may thus be beneficial. Similarly, ketamine and esketamine, also NMDA receptor antagonists, may help normalize NMDA signaling and reduce excessive glutamate activity. Atypical antipsychotics, such as clozapine (150–800 mg/day), may play an important role in treatment-resistant catatonia due to their modulation of glutamatergic neurotransmission through NMDA receptor antagonism and potential effects on the GABAergic system. Aripiprazole, another atypical antipsychotic, exerts beneficial effects as a partial agonist of D2 receptors. Finally, cariprazine has been investigated as an adjunct to electroconvulsive therapy (ECT). Studies suggest that combining cariprazine with ECT may help prevent catatonic relapses in patients unresponsive to other treatments. Its selectivity for D3 receptors may offer additional benefits in these cases. The use of antipsychotics in these cases remains limited and requires careful monitoring to avoid worsening catatonia, such as progression to neuroleptic malignant syndrome. Therefore, antipsychotic treatment is generally reserved for cases in which a primary psychotic disorder is suspected.

Discussion & Conclusions: The treatment of catatonia can be challenging, and standard therapies, such as lorazepam and electroconvulsive therapy (ECT), may not always produce complete responses. In such cases, alternative third-line therapies may be considered when there is no response to benzodiazepines and ECT, or second-line therapies when ECT is unavailable or contraindicated. Further studies are needed to better understand and consolidate the use of these alternative strategies in treatment-resistant catatonia.