​Background: Cognitive impairment is a core feature of schizophrenia spectrum disorders (SSD), contributing to functional disability and reduced quality of life, yet effective treatments are lacking. Disruption of cortical excitation/inhibition balance in schizophrenia, involving dysfunction in the gamma-aminobutyric acid (GABA) system among other mechanisms, results in aberrant gamma oscillations leading to brain network dysfunction. This dysfunction may manifest as hypofrontality, which has been associated with the observed cognitive impairment. GT-002, a novel GABAA receptor partial positive allosteric modulator developed by Gabather AB, has shown promising results in preclinical models of schizophrenia and demonstrated safety and tolerability in healthy controls.

Aims: The overall objective of the TOTEMS clinical trial is to investigate the acute effects of partial GABAA-receptor modulation by GT-002 on psychophysiological measures, including event-related electroencephalography (EEG), electromyography (EMG), and resting-state EEG, in patients with SSD.​

Materials and Equipment: This single-center, double-blind, placebo- and active comparator-controlled, randomized, four-way crossover trial will recruit 20 patients with SSD and 30 healthy controls. Participants will receive GT-002 (1 mg and 2 mg), oxazepam (15 mg), and placebo across four sessions, separated by a washout period of ≥ 7 days. Psychophysiological assessments will serve as proxy measures of hypofrontality. Cognitive assessment will include the Trail Making Test and selected tests from the Brief Assessment of Cognition in Schizophrenia (BACS) and the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Anticipated Results: We hypothesize that GT-002 will improve prepulse inhibition of the startle reflex (PPI) in patients relative to placebo and oxazepam, reflecting improved sensorimotor gating. Secondary endpoints include changes in mismatch negativity, selective attention, 40-Hz auditory steady-state response, and resting-state EEG, where we also expect improvement in patients following GT-002. Exploratory endpoints include safety and tolerability of GT-002 and potential differential acute effects of GT-002 compared to oxazepam on cognition. We hypothesize that GT-002 will not affect cognitive performance, whereas oxazepam will impair it.

Perspectives: TOTEMS is the first trial to investigate acute effects of partial GABAA receptor modulation by GT-002 on brain function and cognition in SSD patients. If successful, GT-002 may offer a novel pharmacological approach to address cognitive impairment in schizophrenia.

Funding: The trial is initiated by Sponsor-investigator Bjørn H. Ebdrup in collaboration with Gabather AB. The trial is financed by a Grand Solutions grant (6.115.854 DKKR) from the Innovation Fund Denmark (IFD, grant ID: 3146-00002B) (granted to sponsor). This grant is managed by Mental Health Services in the Capital Region of Denmark.

EU CT no.: 2024-519389-28-00

Contact:

Thomas Hartwig Siebner
PhD student, MD
Email: thomas.hartwig.siebner.02@regionh.dk
Tel.: 20 27 77 25​

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