Lithium Monotherapy Increases ACTH and Cortisol Response in the Dex/CRH Test in Unipolar Depressed Subjects. A Study with 30 Treatment-Naive Patients

Abstract

BackgroundDistorted activity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the most robustly documented biological abnormalities in major depression. Lithium is central to the treatment of affective disorders, but little is known about its effects on the HPA system of depressed subjects.ObjectiveTo assess the effects of lithium monotherapy on the HPA system of patients with major depression by means of the combined DEX/CRH test.MethodThirty drug-naive outpatients with major depression (single episode or unipolar recurrent; SCID I- and II-confirmed) were treated with lithium monotherapy for four weeks. The DEX/CRH test was conducted directly before intake of the first lithium tablet and four weeks thereafter. Weekly ratings with the HDRS21 were used to determine response (≥50% symptom reduction) and remission (HDRS ≤7).ResultsLithium levels within the therapeutic range were achieved rapidly. Tolerability was good; no patient terminated the treatment prematurely. Response and remission rates were 50% and 33% respectively. Compared to the DEX/CRH test before the start of the treatment, a considerable and significant increase in all CRH-stimulated ACTH and cortisol parameters could be detected in the second DEX/CRH test. When analysed with particular regard to responders and non-responders, that significant increase was only present in the responders.ConclusionsWe were able to demonstrate that lithium leads to a significant activation of the HPA system. This is possibly connected to stimulation of hypothalamic arginine vasoporessin (AVP), to direct intracellular effects of lithium on pituitary cells and to an induction of gene expression.Trial Registrationdrks-nue.uniklinik-freiburg.de DRKS00003185

Lithium ameliorates sleep deprivation‐induced mania‐like behavior, hypothalamic‐pituitary‐adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice

“…On the other hand, previous studies have demonstrated that Li administration increased the levels of ACTH and corticosterone in the plasma of rats . Wood and colleagues demonstrated that 36 days of Li treatment did not significantly alter corticosterone levels. The effects of Li on the HPA axis are therefore somewhat controversial.…”

Stress, Schizophrenia and Bipolar Disorder

“…Other studies have identified an increase in cortisol from baseline after a 12-day period of withdrawal from psychotropic treatment (Naber et al 1985;Albus et al 1985). Unlike antipsychotics, mood stabilisers, including lithium carbonate, have been shown to increase cortisol levels in a dose dependent manner (Platman and Fieve 1968;Bschor et al 2011;Eroglu et al 1979).…”

Exploring Genetic Variability at PI, GSK3, HPA, and Glutamatergic Pathways in Lithium Response

“…11 Moreover, it has been demonstrated that Li leads to a significant activation of the hypothalamic-pituitary-adrenal (HPA) system in patients with major depression, rising CRH-stimulated parameters in the DEX/CRH test. 12 Identifying such a Li-responsive gene network in the brain would allow us to distinguish between subsets of genes underlying therapeutic and nontherapeutic actions of Li. The aim of this study was to investigate the potential association of genetic variability at 16 candidate genes related to PI (INPP1, MARCKS, IMPA1, IMPA2, ITPKC, PLCG1), GSK3 (GSK3B, GSK3A, CREB1), HPA (FKBP5, CRHR2, CRHR1), and glutamatergic (GRIA2, GABRB2, GRIK2, GRIK5) systems with Li response in BP.…”