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GABAB receptor, clozapine, and catatonia—a complex triad

Molecular Psychiatry volume 26, pages 2683–2684 (2021)Cite this article

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We were very pleased to read the article by Nair et al. [1], who rightly highlighted the pharmacological uniqueness of clozapine and hypothesized its action as a modulator of the gamma-aminobutyric acid B receptor (GABAB). Such mechanisms may not only be relevant for treatment-resistant schizophrenia (SZ), but also for catatonia. We suggest that besides positive symptoms (e.g., delusions, hallucinations, and first-rank symptoms), catatonia can also be considered as one of the paradigmatic examples of aberrant fluctuation of GABAA+B activity [2]. Here, we will refer to three main reasons in support of our claim:

First, catatonia is a psychomotor syndrome (occurring in 9–17% of acute mental disorders) characterized by motor, affective, and behavioral anomalies [3,4,5]. Affective symptoms on the perceptual-experiential level such as anxiety (fear), aggression, flat affect, negative affect, and affect incontinence are intrinsic to catatonia, but can also occur in a variety of mental disorders such as SZ, bipolar disorder (BD), and major depressive disorder (MDD). We agree with Nair et al. that SZ patients, whether catatonic or not, might misinterpret environmental stimuli [1]. Furthermore, the inability to control emotions and affects has a strong impact on behavioral and motor functions [6]. For this reason, in DSM-5, catatonia can be used as a specifier to characterize an underlying mental disorder in more clinical detail. In ICD-11, catatonia will be recognized as an independent diagnostic entity [7]. Despite these developments, patients with typical catatonic symptoms might still be diagnosed with solely SZ, BD, or MDD, and not as having catatonia (as an independent diagnostic entity). The fact that all three diagnostic groups benefit from clozapine (complex neuropharmacological properties), benzodiazepines (e.g., lorazepam as a GABAA agonist), and electroconvulsive therapy [ECT; increase of GABA concentration in the medial prefrontal cortex (mPFC) [8]] suggests a trans-diagnosis mechanism of action with respect to the GABAergic system. Since there is convincing evidence from human studies that benzodiazepines and ECT modulate the GABAergic system, patients with SZ, BD and MDD may suffer from catatonia and GABAergic dysregulation. However, we are aware that the idea of one neurotransmitter as the basis for catatonia is oversimplified.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Dusan Hirjak

  2. Mind, Brain Imaging and Neuroethics Research Unit, The Royal’s Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

    Georg Northoff

  3. Department of Psychiatry, University of Michigan, Rachel Upjohn Building, Ann Arbor, MI, USA

    Stephan F. Taylor

  4. Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany

    Robert Christian Wolf

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Correspondence to Dusan Hirjak.

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Hirjak, D., Northoff, G., Taylor, S.F. et al. GABAB receptor, clozapine, and catatonia—a complex triad. Mol Psychiatry 26, 2683–2684 (2021). https://doi.org/10.1038/s41380-020-00889-y

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