Diminished GABAA Receptor-Binding Capacity and a DNA Base Substitution in a Patient with Treatment-Resistant Depression and Anxiety

Abstract

In this report, we describe the case of a caucasion male patient, aged 42 years, suffering from severe treatment-resistant generalized anxiety disorder with panic attacks and from major depression for which he was treated with a course of electroconvulsive therapy. During electroconvulsive treatment, anesthesia was difficult to induce with etomidate and, once, propofol. Bispectral indices recordings (assessing the depth of anesthesia) revealed a much shorter duration of loss of responsiveness compared to a control patient receiving also a course of electroconvulsive therapy. Since GABA A receptors with 123 I-iomazenil SPECT and found a clearly diminished binding of the radiotracer in the right frontal and orbitotemporal regions compared to the recordings in a 38-year-old healthy male control. Genetic analysis of the exons 7 and 8 of the GABRB1-3 genes coding for the1-3-subunits of the GABA A receptors revealed a silent G to A substitution in the third position of amino acid 257 of the b1-subunit. To our knowledge, this is the first report of a link between insensivity to anesthetic agents and altered GABA A receptor function in a clinical case. Whereas reduced GABA A receptor-binding capacity has been investigated in anxiety disorders, this has not been the case in depressive disorders. This case illustrates how clinical observations in psychiatry can prompt investigations by modern techniques and potentially link clinics and basic sciences. No conclusion can, however, be made about casual links in this single case.

Role of GABA in anxiety and depression

“…In contrast, chronic antidepressants upregulated a1, a3, b1, b2, and g2 genes in rat brainstem [Tanay et al, 1996[Tanay et al, , 2001, while altered anxiety and depression-related behavior was found in mutant mice lacking B1 and B2 receptors [Mombereau et al, , 2005. A recent human study showed that severe treatment-resistant depression with anxiety was linked to a mutation in the b1 subunit of GABA-A receptor [Kosel et al, 2004]. Positive genetic associations were found between polymorphism in human GABA-A receptor subunits genes and unipolar (a3, a5), bipolar (a1, a3, a5, a6) depression or neuroticism (a6) [Bell et al, 1989;Buckle et al, 1989;Oruc et al, 1997;Papadimitriou et al, 1998;Massat et al, 2002;Yamada et al, 2003;Henkel et al, 2004;Horiuchi et al, 2004;Sen et al, 2004;Korpi and Sinkkonen, 2006] as well as posttraumatic stress disorder with anxiety and depression (b3) or hormonal and autonomic stress response (a6) [Feusner et al, 2001;Uhart et al, 2004].…”

“…Reduced blood flow in inferior colliculus in several different models of depression in rats [Caldecott-Hazard et al, 1988]. While a similar phenomenon has been revealed by SPECT in patients with posttraumatic stress disorder [Bremner et al, 2000b] or severe treatment-resistant anxiety and depression [Kosel et al, 2004], numerous neuroimaging studies [MRS: Kugaya et al, 2003;Epperson et al, 2006;Sanacora et al, 2006;SPECT: Kosel et al, 2004;Mervaala et al, 2001] consistently show reduced central GABAergic function in depression and its correction by AD therapy (see Tables 2, 3 for details). Strikingly paralleling other clinical and experimental data (reviewed above), these findings further support the notion that impaired GABAergic function is directly involved in anxiety, depression, and their interplay.…”

“…Regionspecific dysregulation of allopregnanolone in OB in rats [Uzunova et al, 2003[Uzunova et al, , 2004. Reduced benzodiazepine binding in frontal and orbitotemporal cortex in a patient with treatment-resistant depression and anxiety [Kosel et al, 2004]. Increased CSF concentration of DBI [Barbaccia et al, 1986;Roy, 1991;Sandford et al, 2000], including anxiety/depressive patients [Guidotti, 1991;but see George et al, 1994] and suicide depression victims [Rochet et al, 1998].…”

“…Despite certain limitations in spatial and temporal resolution, these methods enable an in vivo real-time assessment of specific areas in these disorders with direct measurement of GABA neurochemistry and comparison of therapeutic effects of different therapies [Bremner et al, 2000a,b;Grachev and Apkarian, 2000;Kosel et al, 2004;Sanacora et al, 2006].…”

Neurobiology of Memory and Anxiety: From Genes to Behavior

“…Other studies show reduced expression of rat α 2, γ 1, or δ subunits after fear conditioning [79] and chronic unpredictable stress [120]. In humans, treatment-resistant depression with anxiety was linked to a mutant β 1 subunit gene [121], whereas positive genetic associations were found between GABA-A subunits genes and neuroticism ( α 6 [122]), posttraumatic stress disorder with anxiety and depression ( β 3 [123]), and hormonal/autonomic stress responses ( α 6 [124]).…”