An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression
ABSTRACT Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression.
This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of >/=20 received riluzole (50-200 mg/day) for 8 weeks.
Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated.
Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.
- SourceAvailable from: Lisa Chang
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- "Recent studies indicated that LTG reduced brain glutamine levels in depressed BD patients (Frye et al., 2007), and that memantine, a NMDAR antagonist, was beneficial in BD patients (Koukopoulos et al., 2010; Teng and Demetrio, 2006). As a rationale for applying agents that modulate the glutamatergic system in treating patients with BD, riluzole, an inhibitor of glutamate release, has been reported to be effective alone (Brennan et al., 2010) or in combination with lithium in open-label trials for the treatment of bipolar depression (Zarate et al., 2005). In healthy subjects, LTG decreased perceptual abnormalities induced by ketamine, an NMDAR antagonist (Anand et al., 2000). "
ABSTRACT: An up-regulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-d-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signalling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanaesthetized rats that had been treated p.o. daily for 42 d with vehicle or a therapeutically relevant dose of LTG (10 mg/kg.d). Regional brain AA incorporation coefficients k* and rates J in, and AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and J in in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signalling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signalling are up-regulated in the post-mortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade.The International Journal of Neuropsychopharmacology 06/2011; 15(7):931-43. DOI:10.1017/S1461145711001003 · 5.26 Impact Factor
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- "24 A. M. Kanner MDD (Zarate et al., 2004). Riluzole has been tested in open trials as add-on therapy; in one study of eight patients with bipolar depression, combination with lithium for 8 weeks significantly improved depressive symptoms (Zarate et al., 2005). Another trial of 10 patients with treatment-resistant MDD with Riluzole as add-on therapy to antidepressant drugs therapy resulted in a significant improvement in depressive symptoms after 6–12 weeks of treatment (Sanacora et al., 2007). "
ABSTRACT: A bidirectional relation between depressive disorders and epilepsy has been suggested by several population-based studies and is supported by experimental studies. This article reviews the potential pathogenic mechanisms operant in both disorders that may explain such a relation. These mechanisms include a hyperactive hypothalamic-pituitary-adrenal (HPA) axis and its neuroanatomic and neuropathologic complications, as well as disturbances in serotonergic, noradrenergic, γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmitter systems, all of which may be interrelated.Epilepsia 01/2011; 52 Suppl 1:21-7. DOI:10.1111/j.1528-1167.2010.02907.x · 4.58 Impact Factor
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- "The cholinesterase inhibitor, physostigmine, and the cholinergic agonist, RS86, have mooddepressing effects in bipolar mania, as well as in schizophrenic and healthy subjects (Berger et al., 1989). Consistent with increased glutamate signaling in BD, memantine (1-amino-3,5- dimethyl-adamantane), an NMDA receptor antagonist approved for treating moderate to severe Alzheimer disease (FDA, 2009), was found beneficial in bipolar depression (Davis et al., 1978; Janowsky and Overstreet, 1995; Teng and Demetrio, 2006), and Riluzole (2-amino-6- trifluoromethoxybenzothiazole), an inhibitor of glutamate release, was reported effective in combination with lithium in an open label trial in BD patients (Zarate et al., 2005). "
ABSTRACT: Bipolar disorder (BD) is a major medical and social burden, whose cause, pathophysiology and treatment are not agreed on. It is characterized by recurrent periods of mania and depression (Bipolar I) or of hypomania and depression (Bipolar II). Its inheritance is polygenic, with evidence of a neurotransmission imbalance and disease progression. Patients often take multiple agents concurrently, with incomplete therapeutic success, particularly with regard to depression. Suicide is common. Of the hypotheses regarding the action of mood stabilizers in BD, the "arachidonic acid (AA) cascade" hypothesis is presented in detail in this review. It is based on evidence that chronic administration of lithium, carbamazepine, sodium valproate, or lamotrigine to rats downregulated AA turnover in brain phospholipids, formation of prostaglandin E(2), and/or expression of AA cascade enzymes, including cytosolic phospholipase A(2), cyclooxygenase-2 and/or acyl-CoA synthetase. The changes were selective for AA, since brain docosahexaenoic or palmitic acid metabolism, when measured, was unaffected, and topiramate, ineffective in BD, did not modify the rat brain AA cascade. Downregulation of the cascade by the mood stabilizers corresponded to inhibition of AA neurotransmission via dopaminergic D(2)-like and glutamatergic NMDA receptors. Unlike the mood stabilizers, antidepressants that increase switching of bipolar depression to mania upregulated the rat brain AA cascade. These observations suggest that the brain AA cascade is a common target of mood stabilizers, and that bipolar symptoms, particularly mania, are associated with an upregulated cascade and excess AA signaling via D(2)-like and NMDA receptors. This review presents ways to test these suggestions.Brain Research Reviews 07/2009; 61(2):185-209. DOI:10.1016/j.brainresrev.2009.06.003 · 5.93 Impact Factor