A Double-Blind, Placebo-Controlled Study of Citalopram With and Without Lithium in the Treatment of Therapy-Resistant Depressive Patients

Abstract

Sixty-nine depressive patients (DSM III criteria: 296.2, 296.3, 296.5, 300.4) were treated with 40 to 60 mg citalopram (CIT) daily for 4 weeks. Among them, 45 responded to treatment (improvement > 50% on the 21-item Hamilton Rating Scale for Depression [HAM-D]) and continued their treatment for another week before being released from the study. The 24 nonresponders were randomized and comedicated under double-blind conditions with lithium carbonate (Li) (2 x 400 mg/day) (CIT-Li group) or with placebo (CIT-Pl group) from days 29 to 35. For days 36 to 42, the patients of both subgroups were treated openly with Li (800 mg/day) in addition to the ongoing CIT treatment. On day 35, 6 of 10 patients responded to the CIT-Li combination, whereas 2 of 14 patients only responded to the CIT-Pl combination. This group difference reached significance (p < 0.05) on day 35 with lower HAM-D total scores in the CIT-Li group. No evidence was seen of a pharmacokinetic interaction between CIT and Li, and this combination was well tolerated. Patients were phenotyped with dextromethorphan and mephenytoin at baseline and at day 28. As evaluated at baseline, three patients (responders) were poor metabolizers of dextromethorphan and six patients (three responders and three nonresponders) of mephenytoin. On day 28, the ratio CIT/N-desmethylCIT (DCIT) in plasma was significantly higher in poor than in extensive metabolizers of mephenytoin (p = 0.0001), and there was a significant positive correlation between the metabolic ratio of dextromethorphan and the ratio DCIT/N-didesmethylCIT in plasma (p < 0.001). These findings illustrate the role of CYP2D6 and CYP2C19 in the metabolism of CIT. It can be concluded that Li addition to CIT is effective in patients not responding to CIT alone without any evidence of an accentuation or provocation of adverse events.

5-HT1B Receptors: A Novel Target for Lithium Possible Involvement in Mood Disorders

“…Indeed, the desensitization of 5-HT 1B autoreceptors, induced by lithium, results in a decrease of the efficacy of the negative retrocontrol of the 5-HT release at neurone terminals, leading to an increase of the release of 5-HT, and thus, to an enhancement of the availability of 5-HT in the synaptic cleft. This mechanism is in agreement with previous observations showing that lithium has the capacity to enhance 5-HT efflux at nerve terminals (Green and Grahame-Smith 1976;Treiser et al 1981;Blier and de Montigny 1985;Hotta et al 1986;Blier et al 1987;Friedman and Wang 1988;Wang and Friedman 1988;Hotta and Yamawaki 1988;Hide and Yamawaki 1989;Sharp et al 1991) and could also account for the increased benefit in the therapeutic action of antidepressant drugs when associated with lithium (de Montigny et al 1983;Cowen et al 1991;Baumann et al 1996).Antidepressants, particularly SSRIs, promote enhancement of the availability of 5-HT at the synaptic level by blocking the reuptake of the amine (Hyttel 1982;Owen et al 1997), and lithium seems to have a similar effect by reducing the 5-HT 1B auto receptor activity. Thus, a kind of synergism between lithium and antidepressants may significantly enhance the serotonergic activity in treated patients.…”

“…These interactions of lithium are likely involved in the general profile of clinical activities of the ion (Wood and Goodwin 1987;Price and Heninger 1994;Manji et al 1995;Belmaker et al 1996;Attack 1996). Focusing on the serotonergic system, whose activity is considered to be reduced in depression (Price et al 1990;Odagaki et al 1992;Siever et al 1991;GrahameSmith 1992), numerous reports have shown, in vitro as well as in vivo, that lithium has the capacity to induce an increase in the release of serotonin (5-hydroxytryptamine, 5-HT) at the synaptic level (Green and Grahame-Smith 1976;Treiser et al 1981;Blier and de Montigny 1985;Hotta et al 1986;Wood and Goodwin 1987;Blier et al 1987;Friedman and Wang 1988;Wang and Friedman 1988;Hotta and Yamawaki 1988;Hide and Yamawaki 1989;Sharp et al 1991;Price and Heninger 1994) and can also potentiate antidepressant treatments (de Montigny et al 1983;Cowen et al 1991;Baumann et al 1996). The biochemical mechanism responsible for these properties is not yet understood, although it has been suggested that 5-HT autoreceptors, and particularly 5-HT 1B, could be responsible for these effects (Blier and de Montigny 1985;Hotta et al 1986;Friedman and Wang 1988;Wang and Friedman 1988;Hotta and Yamawaki 1988;Hide and Yamawaki 1989).…”

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

“…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).…”

Evidence for the Benefits of Nonantipsychotic Pharmacological Augmentation in the Treatment of Depression

“…However, few studies were conducted on SSRI nonresponders. Most of those studies were open label, and the results confirmed that augmentation with lithium was effective in TRD (Table 2) [20][21][22][23][24][25][26][27][28][29][30].…”