Lithium Augmentation Increases the ACTH and Cortisol Response in the Combined DEX/CRH Test in Unipolar Major Depression,

Abstract

Lithium augmentation is a well established strategy for treatment-resistant depression. The exact mode of its action is unknown, but an enhancement of serotonergic transmission is hypothesized. The authors investigated changes in the hypothalamic-pituitary-adrenocortical (HPA) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test (DEX/CRH test). Thirty patients with unipolar major depressive episodes (DSM IV) who had not responded to an adequate trial with an antidepressantwere assessed on the day before lithium augmentation (baseline) with the DEX/CRH test (pretreatment with 1.5 mg dexamethasone p.o. at 11 P . M . and CRH stimulation at 3 P . M . on the next day). Twenty-four patients were reassessed after response was determined or, in cases of nonresponse, four weeks after initiation of lithium augmentation. Response to lithium augmentation was measured by weekly ratings on the Hamilton DepressionRating Scale Regardless of the initial choice of antidepressant, about 30 to 40% of patients with major depressive disorder will not respond sufficiently (Thase and Rush 1995 Among the various treatment options that have been proposed for non-responding depressed patients, lithium augmentation has been recommended as a first-line strategy . The efficacy of lithium augmentation has been well documented in placebo-controlled acute (Joffe et al. 1993;Katona et al. 1995;Baumann et al. 1996) and continuation treatment trials (Bauer et al. 2000;Bschor et al. 2002) using different classes of antidepressants. A recent meta-analysis confirmed the evidence that lithium augmentation is superior to placebo augmentation for the treatment of unipolar major depression, with a median response rate of 50% across double-blind studies (Bauer and Döpfmer 1999). Severity of depression was recently identified as a clinical predictor of response to lithium augmentation (Bschor et al. 2001). Better knowledge of the neurobiological mechanisms of lithium augmentation would help to identify patients who will respond favorably to this treatment intervention. However, to date, the mode of action of lithium augmentation is unknown. Shortly after the initial report on its efficacy (de Montigny et al. 1981), it was postulated by de Montigny et al. (1983) that a pharmacodynamic action mediated via the serotonergic systems might account for the synergistic effect of lithium when added to a tricyclic antidepressant.Another system potentially involved in its mechanism of action is the hypothalamic-pituitary-adrenocortical (HPA) system, putatively the best studied biological system in affective disorders (Dinan 1997). The most sensitive challenge test of the HPA system is the combined dexamethasone/CRH test (DEX/CRH test) (Heuser 1998). A dysfunction in the regulation of the HPA system, especially an overstimulation of ACTH and cortisol in the DEX/CRH test, was repeatedly shown in depressed patients (for a review see Steckler et al. 1999;Holsboer 2000). In treatment studies with ...

Pharmacological and Nonpharmacological Factors Influencing Hypothalamic–Pituitary–Adrenocortical Axis Reactivity in Acutely Depressed Psychiatric In-patients, Measured by the Dex-CRH Test

“…Treatment history was obtained from medical records and from questioning the patients and included the number and type of antidepressant treatment attempts overall and in the present episode and whether the episode exacerbated under an established pharmacotherapy or not. It was also recorded whether patients were treated with mood stabilizers or not, especially lithium and carbamazepine as these drugs have been previously shown to influence the Dex-CRH test (Bschor et al, 2002;von Bardeleben et al, 1988). The presence of benzodiazepine treatment at the time of the Dex-CRH test was also noted.…”

“…These observations may be explained by the fact that this drug induces CYP3A3/4 (a member of the cytochrome P450 family) activity leading to an increased metabolism and clearance of dexamethasone via CYP3A3/4 and thus to lower dexamethasone plasma concentrations and insufficient suppression of the HPA-axis in the test (Guthrie, 1991;Wang and Ketter, 2002). Lithium has also been shown to independently increase HPA-axis activity (Bschor et al, 2002). In our sample, patients treated with lithium showed nonsignificantly higher responses in the Dex-CRH test than patients not receiving any mood stabilizers, so that we cannot fully confirm the effects observed by Bschor et al (2002) in this sample.…”

“…Lithium has also been shown to independently increase HPA-axis activity (Bschor et al, 2002). In our sample, patients treated with lithium showed nonsignificantly higher responses in the Dex-CRH test than patients not receiving any mood stabilizers, so that we cannot fully confirm the effects observed by Bschor et al (2002) in this sample. It has to be pointed out, however, that we investigated only 21 patients treated with lithium at the time of the Dex-CRH test.…”

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

“…Patients with concomitant treatment with mood stabilizers, such as lithium or carbamazepine, were excluded from the analysis because of the potential of these drugs to influence the outcome of the dex/CRH test (Bschor et al, 2002;Kunzel et al, 2003). The procedure of the combined dex/CRH test has been described in detail elsewhere (Heuser et al, 1994;Kunzel et al, 2003).…”

Higher 5-HT1A Receptor Binding Potential During a Major Depressive Episode Predicts Poor Treatment Response: Preliminary Data from a Naturalistic Study

“…Six of these depressed subjects did not receive 1-year post-treatment ratings; five were lost to follow-up and one missed the 1-year follow-up. Remission was defined as at least a 50% decrease from HAM-D 24 baseline score and a score of p10 at the 1-year assessment (Bschor et al, 2002;Bschor et al, 2003;Keller, 2004;Lin et al, 1998;Paykel et al, 1995;Roose and Suthers, 1998;Smith et al, 2002). All subjects were treated with antidepressant medications during the year.…”