Lack of Beneficial Effects of L-Baclofen in Affective Disorder
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892. International Clinical Psychopharmacology
(Impact Factor: 2.46).
02/1991; 6(4):197-207. DOI: 10.1097/00004850-199100640-00001
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.
Available from: S.Hossein Fatemi
- "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). "
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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.
- "However, regarding the GABA B system, only one small study with five patients, to date, has been performed, which employed baclofen. In agreement with the recent preclinical evidence, baclofen was reported in three out of the five patients to worsen their symptoms but clearly such a small sample size means that the findings are questionable (Post et al., 1991). While studies examining the direct effect of baclofen on depressive symptomology have not been extensively performed, a number of studies have assessed the impact of acute baclofen administration on endocrine parameters in depressed patients. "
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ABSTRACT: Dysfunction of the gamma amino butyric acid (GABA)-ergic system has been purported to play a role in psychiatric disorders, including anxiety and major depression. A clear link between GABA(A) receptors and anxiety has long been established. However, despite the GABA system being the prominent inhibitory neurotransmitter in the brain, a role in depression has been less well validated. GABA(B) receptors, first characterized by Bowery and colleagues 30 years ago, have been long postulated to be involved in the etiology of depression, but a lack of selective, orally active, pharmacological compounds slowed down their assessment. From the mid-1990s, more selective pharmacological and genetic tools for examining the GABA(B) system have provided greater insight into their role in complex behavioral and molecular characteristics. The resulting literature garnered from recent behavioral studies employing selective GABA(B) receptor antagonists and knockout mice suggests in the main that the blockade, or loss of function, of GABA(B) receptors causes an antidepressant-like phenotype. The GABA(B) receptor system has been shown to have substantial interactions with the serotonergic system and neurotrophic factors, such as BDNF. We argue that the potential antidepressant properties of GABA(B) receptor antagonists may be, at least in part, mediated via these interactions. Clinical studies have repeatedly reported alterations in GABA levels, particularly in cortical areas, but studies to specifically assess GABA(B) receptors are lacking. Those available have documented differential gene expression of the GABA(B(2)) subunit but require replication. Therefore, while further research is necessary, it is suggested that GABA(B) receptor antagonists may represent a new class of antidepressant compounds.
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ABSTRACT: An algorithm is presented for computing the characteristic views
(CVs) of quadric-surfaced solids. The CVs are determined by analyzing
the characteristic-view domains of the object by relating changes in the
topology of the object's line structure to changes in the occlusion of
3D edges. The main task of the algorithm is to compute the envelope
boundaries for viewpoint regions for which the object's visible-line
projections have topologically equivalent line-junction graphs. By using
the concepts of generalized edge, generalized face, and generalized
vertex and using the techniques of order-of-visibility propagation and
edge classification, the algorithm can efficiently compute both local
and global visibility of edge segments, and therefrom compute the
required envelope boundaries. This algorithm is shown to hold for
quadric-surfaced solids in general and to treat a polyhedral object as a
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