Lack of Beneficial Effects of L-Baclofen in Affective Disorder

ArticleinInternational Clinical Psychopharmacology 6(4):197-207 · February 1991with2 Reads
DOI: 10.1097/00004850-199100640-00001 · Source: PubMed
Abstract
GABAB mechanisms have been implicated in the antinociceptive, but not anticonvulsant effects of carbamazepine. A variety of antidepressants have been reported to upregulate GABAB receptors after chronic administration. The GABAB agonist l-baclofen was studied in depressed patients based on two separate rationales. l-Baclofen, in doses ranging from 10-55 mg/day, was administered to five patients with primary affective disorder. No patient showed a positive clinical response, while three patients showed a pattern of increasing depression or cycling during treatment and improvement during withdrawal. These preliminary data suggest that GABAB agonism is unlikely to produce antidepressant effects and may be unrelated to the mechanism of carbamazepine's antidepressant action. These data, taken with a reinterpretation of other findings that antidepressant modalities upregulate GABAB receptors in brain following chronic administration, suggest that GABAB antagonism rather than agonism may be a fruitful clinical strategy to explore in depression.
    • "The efficacy of GABA B antagonist, baclofen, and GABA A agonist, diazepam, was shown to be equal to amitryptiline in the treatment of affective disturbances in alcoholic patients (Krupitsky et al., 1993). Other studies showed that baclofen worsens the symptoms of depression (Post et al., 1991). A study published in 2004 revealed the efficacy of SGS742 (CGP36742) in patients with mild cognitive impairment and opened the possibility for the compound to be investigated in humans (Froestl et al., 2004). "
    Full-text · Chapter · Feb 2012 · British Journal of Pharmacology
    • "GABA B receptor antagonists have been found to produce antidepressant properties in animal models, as have GABBR1 deletion studies (Nakagawa et al., 1999; Heese et al., 2000; Mombereau et al., 2005). Moreover, a study found that treatment of subjects with major depression with baclofen resulted in a worsening of symptoms (Post et al., 1991). These findings have led some to believe that an overactive GABA system contributes to major depression (Ghose et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Postmortem and genetic studies have clearly demonstrated changes in GABA(B) receptors in neuropsychiatric disorders such as autism, bipolar disorder, major depression, and schizophrenia. Moreover, a number of recent studies have stressed the importance of cerebellar dysfunction in these same disorders. In the current study, we examined protein levels of the two GABA(B) receptor subunits GABBR1 and GABBR2 in lateral cerebella from a well-characterized cohort of subjects with schizophrenia (n=15), bipolar disorder (n=14), major depression (n=13) and healthy controls (n=12). We found significant reductions in protein for both GABBR1 and GABBR2 in lateral cerebella from subjects with schizophrenia, bipolar disorder and major depression when compared with controls. These results provide further evidence of GABAergic dysfunction in these three disorders as well as identify potential targets for therapeutic intervention.
    Full-text · Article · Feb 2011
    • "The latter possibility is consistent with the discovery that GABAB receptor antagonists display an antidepressant profile in animal models of this condition (Nakagawa et al., 1999; Froestl et al., 2004; Slattery et al., 2005; Nowak et al., 2006). The findings that baclofen, a GABAB receptor agonist, worsens the symptoms of depression (Post et al., 1991 ) and, like depression, prolongs the cortical silent period in humans (Levinson et al., 2010), and that mice lacking functional GABAB receptors behave as though they have been administered an antidepressant, all support the notion that an overactive GABA system contributes to the symptoms of this disorder. They also argue strongly against the idea that the antidepressant response to GABAB receptor antagonists might be due to an enhancement in GABA release secondary to the blockade of GABAB autoreceptors. "
    [Show abstract] [Hide abstract] ABSTRACT: Preclinical and clinical data suggest that a modification in GABA(B) receptor expression and function may contribute to the symptoms of major depression and the response to antidepressants. This includes laboratory animal experiments demonstrating that antidepressants modify brain GABA(B) receptor expression and function and that GABA(B) receptor antagonists display antidepressant potential in animal models of this condition. Clinical and post-mortem studies reveal changes in GABAergic transmission associated with depression as well as depression-related changes in GABA(B) subunit expression that are localized to the cortical depression network. Detailed in this review are the preclinical and clinical data implicating a role for the GABA(B) receptor system in mediating symptoms of this disorder and its possible involvement in the response to antidepressants. Particular emphasis is placed on clinical and post-mortem studies, including previously unpublished work demonstrating regionally-selective modifications in GABA(B) receptor subunit expression in brain samples obtained from depressed subjects. Together with the earlier preclinical studies, these new data point to a role for the GABA(B) system in major depression and support the antidepressant potential of GABA(B) receptor antagonists.
    Full-text · Article · Jan 2011
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