واکنش هورمون رشد به باکلوفن در بیماران مبتلا به اختلال عاطفی فصلی: اثرات نور درمانی

There is evidence for γ-aminobutyric acid (GABA) dysfunction in the pathophysiology and treatment response of patients with major depression, but this has not been studied in seasonal affective disorder (SAD). Growth hormone (GH) response to a challenge with a GABAB receptor agonist, baclofen, is considered an in vivo index of hypothalamic GABAB receptor function in humans. To explore the role of GABAB receptor function in SAD, we compared the GH response to baclofen challenge in 15 patients with SAD and 20 matched healthy controls. Of the 15 patients with SAD, 14 had repeat baclofen challenge following 2-week treatment with light therapy. The results showed that baclofen administration led to a significant increase in GH release both in patients with SAD and normal controls. There was no significant difference in the GH response to baclofen between the two groups. Furthermore, 2-week treatment with light therapy did not significantly alter the baclofen-induced GH response in patients with SAD, in spite of a clear therapeutic effect. The results of this study suggest that hypothalamic GABAB receptor function, as measured by baclofen induced GH release, is not altered in patients with SAD or by light therapy. © 1999 Elsevier Science Ltd. All rights reserved.

Current biochemical hypotheses of depressive disorders have predominately implicated biogenic amine neurotransmitters such as serotonin (5-HT) and norepinephrine (NE), in either the pathophysiology of depression or in the mechanisms of action of antidepressant treatments. There is an ample literature to support this. However, most antidepressant treatments in clinical use affect a number of neurotransmitter receptors in addition to those of serotonin and norepinephrine (Green and Nutt, 1983). It is plausible, therefore, that other neurotransmitter systems, such as γ-aminobutyric acid (GABA) system, may be deranged in depression, and therefore could be action sites of antidepressant treatments ( Leonard, 1994). As reviewed in our recent paper (Shiah and Yatham, 1998), several lines of evidence in the literature have accumulated to support the hypothesis of low GABA function in depression. For example, four out of eight studies reported that cerebrospinal fluid (CSF) GABA levels were significantly lower in patients with major depression compared to controls (Gerner and Hare, 1981, Gerner et al., 1984, Gold et al., 1980, Joffe et al., 1986, Kasa et al., 1982, Post et al., 1980, Roy et al., 1991 and Zimmer et al., 1981). Three out of four studies showed that unipolar depressed patients have lower plasma GABA levels compared with normal controls (Petty and Schlesser, 1981, Petty and Sherman, 1984, Petty et al., 1992 and Rode et al., 1991). Petty (1994) also reported that plasma GABA levels in patients with bipolar depression had lower plasma GABA compared with matched normal controls. Furthermore, the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), in plasma was shown to be lower in patients with both unipolar and bipolar depressions (Kaiya et al., 1982), further supporting a GABA deficit in depression. Perry et al. (1977) also reported that GAD activity was significantly decreased in postmortem brain of depressed patients compared with controls. In contrast, Cheetham et al. (1988) found no alterations in frontal and temporal GAD activity in 21 depressed suicide victims compared with 21 matched controls. With regard to the contribution of GABA function to the mechanism of action of antidepressant treatments, there have been conflicting results of preclinical studies. For example, several different classes of antidepressant agents including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and electroconvulsive shock (ECS) were reported to induce an increase in GABAB receptor binding in rat frontal cortex (Gray and Green, 1987, Lloyd and Pichat, 1987, Lloyd et al., 1985, Pratt and Bowery, 1993 and Szekely et al., 1987) or hippocampus (Lloyd and Pichat, 1987) following chronic administration. However, several other studies failed to confirm the enhanced GABAB receptor binding with antidepressant treatments (Cross and Horton, 1987, Cross and Horton, 1988, Engelbrecht et al., 1994, McManus and Greenshaw, 1991 and Szekely et al., 1987). The reasons for the discrepant results relating the effects of antidepressant treatments on GABAB receptor binding remain unclear. In humans, one way to asses GABAB receptor function is to measure growth hormone (GH) release after administration of baclofen, a GABAB receptor agonist. This endocrine challenge paradigm is based on two observations: (1) that hypothalamic GABAB receptors sites are involved in the modulation of GH secretion (Gamse et al., 1980 and Muller, 1987); and (2) that the administration of baclofen induces a significant increase in GH concentrations in normal healthy humans (Koulu et al., 1979). Using this paradigm, two studies (Marchesi et al., 1991 and O'Flynn and Dinan, 1993) showed a significant reduction of GH response to baclofen in patients with major depression compared to matched normal controls, suggesting that downregulated GABAB receptor function is associated with depression. However, the other investigators (Davis et al., 1997 and Monteleone et al., 1990a) reported no significant difference in baclofen induced GH response between patients with major depression and normal controls. Furthermore, two baclofen challenge studies did not find any significant treatment effects of antidepressants on the GABAB-mediated endocrine response. Monteleone et al. (1990a) showed that 28 days of amitriptyline (100 mg/day) treatment did not significantly alter the GH response to baclofen in eight male depressed patients. A subsequent study by the same group (Monteleone et al., 1990b) reported that 15 and 35 days of treatment with amitriptyline (100 mg/day), imipramine (100 mg/day) and fluoxetine (20 mg/day) did not significantly modify this endocrine response in ten male depressed patients. Seasonal affective disorder (SAD) is a clinical subtype of recurrent major depression that occurs with a seasonal, usually winter, pattern (Rosenthal et al., 1984). It is a very common psychiatric disorder affecting up to 5–10% of the general population (Rosen et al., 1990). A significant proportion of patients with seasonal depression responds to exposure to bright artificial light therapy (Terman et al., 1989). As yet, the pathophysiology of SAD and the therapeutic mechanism of light are still unknown. Since depressive symptoms (Allen et al., 1993 and Tam et al., 1997) and the treatment response to antidepressants (Lam et al., 1995) are shared between seasonal and non-seasonal depressions, one may expect that dysregulation of GABA function also occurs in patients with seasonal depression and that the antidepressant efficacy of light therapy may be related to its capacity to restore GABA function. However, to our knowledge, no study has yet examined GABA function in patients with SAD, nor the effects of light therapy on GABA function in humans. The purposes of this study, therefore, were to: (1) compare the GABAB receptor function in patients with SAD with those in matched normal controls; and (2) examine the effect of light therapy on GABAB receptor function in patients with SAD, by measuring GH release to baclofen challenge in patients with SAD before and after light therapy and in matched healthy controls.