Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression

Abstract

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine’s antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine

“…The authors suggest that following pharmacological and neurostimulatory interventions, preserving the rescued synapses may be needed to prolong remission [ 65 ]. An interesting result was found in an animal study with a TRD model where animals that did not respond to ketamine received lithium augmentation and responded with enhanced coping behavior under stress and where lithium alone was ineffective [ 66 ]. Increased insulin signaling in the augmentation group was observed.…”

“…Increased insulin signaling in the augmentation group was observed. The authors suggest that lithium augmentation of ketamine may be beneficial only in the case of a deficit in certain response moderators, such as insulin signaling, and may enable antidepressant responsivity in patients who do not respond to ketamine [ 66 ]. This kind of perspective can change the understanding of TRD and confirms the need for an individualized approach in future studies, giving hope for developing precise psychiatry strategies.…”

Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential

“…The emergence of evidence has revealed that the modulation of dopamine release via the astrocyte insulin signaling pathway, which is achieved by the regulation of ATP release, ultimately exerts depressive-anxiety-like behavioral patterns [298]. Consequently, targeting the insulin signaling pathway could potentially mitigate diabetic depression [299]. Moreover, lithium augmentation of ketamine ameliorated antidepressant-like responses to stress, peripheral insulin efflux, and region-specific PFC insulin signaling [299].…”

Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity

“…Lithium maintenance therapy has been demonstrated to reduce the risk for both types of episodes in adult populations ( Schou et al, 1954 ; Burgess et al, 2001 ; Volkmann et al, 2020 ). Lithium can also be effective as part of therapies to address depressive or manic/hypomanic symptoms in cyclothymia ( Barroilhet and Ghaemi, 2020 ), major unipolar depression ( De Montigny, 1994 ; Barroilhet and Ghaemi, 2020 ; Price et al, 2021 ), and schizophrenia ( Leucht et al, 2015 ). Furthermore, lithium therapies have been shown to reduce suicidality ( Kessing et al, 2005 ; Del Matto et al, 2020 ) and improve sleep ( Billiard, 1987 ; Geoffroy et al, 2016 ).…”