PS118. Single administration of ketamine and Pregnenolone-Methyl-Ether (3ß-Methoxy-Pregnenolone) has antidepressant efficacy in a preclinical model of treatment resistant depression: identification of a plasma biomarker of pharmacological efficacy
P. Jack, B. Massimiliano, Grazia di Capua, M. Conor, R. Jennifer
The International Journal of Neuropsychopharmacology May 27, 2016 DOI: 10.1093/ijnp/pyw043.118 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Wistar Kyoto (WKY) rats, a model of treatment-resistant depression, compared with Sprague Dawley rats |
| Interventions | Fluoxetine Ketamine |
| Dose | Fluoxetine 10 mg/kg i.p.; Ketamine 5 mg/kg i.p.; PME 10 mg/kg s.c. |
| Duration | Effects assessed acutely and at 24 hours post-administration, with ketamine effects persisting for 7 days |
| Measures | Forced swimming test (FST), plasma acetylated alpha-tubulin (Acet-Tub) |
| Topics | 5-MeO-DMT Depression Esketamine Ketamine |
| Key points | WKY rats displayed depressive-like behaviour (increased immobility) and elevated plasma acetylated alpha-tubulin relative to Sprague Dawley rats. Fluoxetine had no effect on immobility, whereas ketamine and PME showed rapid antidepressant efficacy, with ketamine's effect lasting 7 days; both drugs reduced plasma acetylated alpha-tubulin only when antidepressant efficacy was evident. The authors conclude that WKY rats are suitable for screening treatments for treatment-resistant depression and that microtubules may be a target for future drug development. |
Abstract
Abstract
Objective: One third of major depressive disorder (MDD) patients are unresponsive to antidepressant drugs, a sub-type known as treatment resistant depression (TRD). Acute intravenous administration of ketamine at sub-anaesthetic dosage is the only efficacious pharmacological treatment in TRD. Development of TRD preclinical assays to screen for more efficacious antidepressant drugs and identification of diagnostic biomarkers is therefore of immediate importance. The neuronal microtubule modulator Pregnenolone-Methyl-Ether (PME; also known as 3β-Methoxy-Pregnenolone) has been shown to have antidepressant efficacy.
Methods: The Wistar Kyoto (WKY) rat was used as a model of TRD to investigate the effectiveness of fluoxetine (10mg/kg, i.p.), ketamine (5mg/kg, i.p.) and PME (10mg/kg, s.c.) in the forced swimming test (FST). Hippocampal acetylated α-tubulin (Acet-Tub) was previously shown increased in preclinical models of depression and was here investigated as a potential plasma biomarker.
Results: WKY rats demonstrated depressive-like behaviour indicated by increased immobility in the FST associated with overexpression of plasma Acet-Tub compared to Sprague Dawley rats. Acute treatment with the selective serotonin inhibitor (SSRI) fluoxetine had no effect on FST immobility but increased plasma Acet-Tub in WKY rats. Acute administration of ketamine or PME demonstrated rapid antidepressant efficacy in the FST with the effects of ketamine persisting for 7 days. Ketamine and PME demonstrated long-lasting antidepressant efficacy in the FST 24h post-administration. Furthermore, both drugs decreased plasma Acet-Tub overexpression only when their antidepressant efficacy was evident.
Conclusion: WKY rats are a suitable model for screening of novel pharmacological treatments for TRD due to their sensitivity to ketamine and lack thereof to SSRIs. PME demonstrates antidepressant efficacy in this model of TRD while plasma Acet-Tub represents a potential biomarker of disease progression and pharmacological efficacy. Therefore, microtubules represent a potential target for future drug development in TRD.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.