A Glutamate Transporter GLT1, in the Treatment of Bipolar Disorder

Bipolar affective disorder (BPD, manic-depressive illness) is a common, severe, chronic and often life-threatening illness. Increasingly, it is being recognized that it is the depressive phase of the illness, which contributes much of the morbidity and mortality. To date, only a few of the available somatic treatments have been proven to be effective for the acute phase of bipolar depression. Thus, there is a clear need to develop novel and improved therapeutics for bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Clinical data suggests that glutamatergic modulators may have antidepressant effects in humans. We first tested the glutamatergic modulator riluzole, an inhibitor of glutamate release and enhancer of glutamate reuptake in astrocytes and found it to have antidepressant properties in patients with treatment-resistant major depression and bipolar depression. In a recent study, we found that a single intravenous dose of the non-competitive NMDA antagonist ketamine produced a rapid and relatively sustained antidepressant effect in patients with treatment-resistant major depression. A recent report found that the Beta-lactam antibiotic ceftriaxone increased uptake of glutamate via increased GLT1 function (Rothstein et al 2005) and had antidepressant-like effects in animal models (Mineur et al 2006). Together, these data suggest that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents which more directly reduce glutamatergic neurotransmission may represent a novel class of antidepressants. We propose to expand our previous findings on the efficacy of glutamatergic modulators in patients with unipolar and bipolar depression by testing a specific, new mechanism where by we use ceftriaxone to chronically increase the expression of the glutamate transporter GLT1 in order to facilitate the removal of glutamate from the synaptic cleft in an effort to reduce excessive glutamate transmission and as a result produce acute antidepressant effects. The model presented here is a clinical testable one, and one that, if successful, holds the potential to develop a group of novel pharmacological treatments for major depression. Patients, ages 18 to 65, with a diagnosis of bipolar depression (without psychotic features), will be randomized to double-blind treatment to receive either ceftriaxone (1-4 g/day) or placebo intravenously for a period of 6 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 86 patients with bipolar depression will be enrolled in the study.