Local and global effects of sedation in resting-state fMRI: a randomized, placebo-controlled comparison between etifoxine and alprazolam.

TSPO ligands are promising alternatives to benzodiazepines in the treatment of anxiety, as they display less pronounced side effects such as sedation, cognitive impairment, tolerance development and abuse potential. In a randomized double-blind repeated-measures study we compare a benzodiazepine (alprazolam) to a TSPO ligand (etifoxine) by assessing side effects and acquiring resting-state fMRI data from 34 healthy participants after 5 days of taking alprazolam, etifoxine or a placebo. To study the effects of the pharmacological interventions in fMRI in detail and across different scales, we combine in our study complementary analysis strategies related to whole-brain functional network connectivity, local connectivity analysis expressed in regional homogeneity, fluctuations in low-frequency BOLD amplitudes and coherency of independent resting-state networks. Participants reported considerable adverse effects such as fatigue, sleepiness and concentration impairments, related to the administration of alprazolam compared to placebo. In resting-state fMRI we found a significant decrease in functional connection density, network efficiency and a decrease in the networks rich-club coefficient related to alprazolam. While observing a general decrease in regional homogeneity in high-level brain networks in the alprazolam condition, we simultaneously could detect an increase in regional homogeneity and resting-state network coherence in low-level sensory regions. Further we found a general increase in the low-frequency compartment of the BOLD signal. In the etifoxine condition, participants did not report any significant side effects compared to the placebo, and we did not observe any corresponding modulations in our fMRI metrics. Our results are consistent with the idea that sedation globally disconnects low-level functional networks, but simultaneously increases their within-connectivity. Further, our results point towards the potential of TSPO ligands in the treatment of anxiety and depression.

The translocator protein 18kDa ligand etifoxine in the treatment of depressive disorders-a double-blind, randomized, placebo-controlled proof-of-concept study.

BACKGROUND: Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects. METHODS: This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10-20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg. DISCUSSION: This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders. TRIAL REGISTRATION: Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023).

Neurosteroids and translocator protein 18 kDa (TSPO) in depression: implications for synaptic plasticity, cognition, and treatment options.

There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABAA receptors and target also extrasynaptic receptors. Their synthesis is mediated by the translocator protein 18 kDa (TSPO). TSPO ligands not only promote endogenous neurosteroidogenesis, but also exert a broad spectrum of functions involving modulation of mitochondrial activity and acting as anti-inflammatory and neuroregenerative agents. Besides affective symptoms, in depression cognitive impairment can be frequently observed, which may be ameliorated through targeting of extrasynaptic GABAA receptors either via TSPO ligands or exogenously administered 3α-reduced neurosteroids. Interestingly, recent findings indicate an enhanced activation of the complement system, e.g., enhanced expression of C1q, both in depression and dementia. It is of note that benzodiazepines have been shown to reduce long-term potentiation and to cause cognitive decline. Intriguingly, TSPO may be crucial in mediating the effects of benzodiazepines on synaptic pruning. Here, we discuss how benzodiazepines and TSPO may interfere with synaptic pruning. Moreover, we highlight recent developments of TSPO ligands and 3α-reduced neurosteroids as therapeutic agents. Etifoxine is the only clinically available TSPO ligand so far and has been studied in anxiety disorders. Regarding 3α-reduced neurosteroids, brexanolone, an intravenous formulation of allopregnanolone, has been approved for the treatment of postpartum depression and zuranolone, an orally available 3α-reduced neurosteroid, is currently being studied in major depressive disorder and postpartum depression. As such, 3α-reduced neurosteroids and TSPO ligands may constitute promising treatment approaches for affective disorders.

Differential effects of the translocator protein 18 kDa (TSPO) ligand etifoxine and the benzodiazepine alprazolam on startle response to predictable threat in a NPU-threat task after acute and short-term treatment.

RATIONALE: Benzodiazepines have been extensively investigated in experimental settings especially after single administration, which mostly revealed effects on unpredictable threat (U-threat) rather than predictable threat (P-threat). Given the need for pharmacological alternatives with a preferable side-effect profile and to better represent clinical conditions, research should cover also other anxiolytics and longer application times. OBJECTIVES: The present study compared the acute and short-term effects of the translocator protein 18 kDa (TSPO) ligand etifoxine and the benzodiazepine alprazolam on P-threat and U-threat while controlling for sedation. METHODS: Sixty healthy male volunteers, aged between 18 and 55 years, were randomly assigned to receive a daily dose of either 150 mg etifoxine, 1.5 mg alprazolam, or placebo for 5 days. On days 1 and 5 of intake, they performed a NPU-threat task including neutral (N), predictable (P), and unpredictable (U) conditions, while startle responsivity and self-reports were studied. Sedative effects were assessed using a continuous performance test. RESULTS: Neither alprazolam nor etifoxine affected startle responsivity to U-threat on any of the testing days. While etifoxine reduced the startle response to P-threat on day 1 of treatment for transformed data, a contrary effect of alprazolam was found for raw values. No effects on self-reports and no evidence of sedation could be observed for either drug. CONCLUSIONS: None of the anxiolytic substances had an impact on startle potentiation to U-threat even after several days of intake. The effects of the anxiolytics on startle responsivity to P-threat as well as implications for future studies are discussed.