دمای کند و واکنش های کورتیزول به آیپساپیرون در افسردگی اساسی: عدم افزایش الکتروشوک درمانی

Depression has been shown in some studies to be associated with a reduction in hypothalamic 5-HT1A receptor function, as indicated by reduced hormone and/or hypothermic responses to 5-HT1A agonists such as ipsapirone. The hypothermic response to ipsapirone was reduced in depressed patients treated with amitriptyline. Hormone and hypothermic responses to 5-HT1A agonists were reduced in normal subjects administered specific serotonin reuptake inhibitors. Effects of electroconvulsive therapy (ECT) on 5-HT1A receptor-mediated responses in humans have not been reported. In the present work, ten depressed patients and 15 control subjects were challenged with placebo and with 0.3 mg/kg ipsapirone, administered 48 h apart in a randomised double blind design. Hypothermic, growth hormone (GH) and cortisol responses were measured. Seven of the depressed patients were treated with a course of ECT, and placebo and ipsapirone challenges were repeated 24 and 72 h after the last treatment. The cortisol response to ipsapirone was significantly reduced in the depressed patients compared with controls. The hypothermic response to ipsapirone was totally abolished in the depressed patients. When tested after a course of ECT, the seven depressed patients again showed reduced or blunted responses. We conclude that hypothalamic 5-HT1A receptor function is reduced in depression. In contrast to the effects of electroconvulsive shock (ECS) on post-synaptic 5-HT1A receptor function in animals, which have chiefly been measured in the hippocampus using electrophysiological techniques, ECT in humans does not induce an increase in sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus.

Although there is much evidence for a dysfunction of brain serotonergic systems in major depression, most of this is indirect (Maes and Meltzer, 1995). One of the most fruitful approaches to study neurotransmitter receptor function in depressed patients has been the use of neuroendocrine challenge tests. Results obtained with the fenfluramine challenge test (reviewed by Newman et al., 1998) have in general indicated blunting of prolactin and cortisol responses in depressed patients, although some recent studies (Park et al., 1996 and Kavoussi et al., 1998) have failed to show this. The exact mechanism of fenfluramine-induced hormone release is still uncertain and may involve either release of 5-HT, in which case its mechanism is essentially pre-synaptic, or direct stimulation of post-synaptic serotonin 5-HT2A/2C receptors. Neuroendocrine challenge tests with other agents such as l-tryptophan (Heninger et al., 1984 and Cowen and Charig, 1987) or clomipramine (Golden et al., 1992; for review see Power and Cowen, 1992) have shown essentially similar results with blunting of the prolactin and/or growth hormone (GH) responses in depression. The ACTH and cortisol responses to the 5-HT precursors tryptophan and l-5-hydroxytryptophan (l-5-HTP) were however increased in depressed patients compared with control subjects in some studies (Meltzer et al., 1984 and Maes et al., 1989). More specific information about serotonergic function can be obtained using 5-HT1A receptor agonists, of which several are available. The effects of 5-HT1A receptor agonists on temperature regulation and hormone release provide a useful avenue for evaluating the functional sensitivity of 5-HT1A receptors in animals and man. The effect of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to induce hypothermia has been shown in several animal studies. Although a pre-synaptic mechanism has been suggested ( Goodwin et al., 1985a, Goodwin et al., 1987a and Hillegaart, 1991), the bulk of the evidence indicates that the hypothermic effect of 8-OH-DPAT is mediated via post-synaptic 5-HT1A receptors in the hypothalamus ( Hjorth, 1985, Hutson et al., 1987, O’Connell et al., 1992 and Millan et al., 1993). 5-HT1A receptor stimulation also evokes ACTH and corticosterone release in rodents, via an effect on corticotrophin releasing factor in the paraventricular nucleus of the hypothalamus ( Koenig et al., 1987, Gilbert et al., 1988, Haleem et al., 1989 and Bagdy and Makara, 1994). Ipsapirone, a centrally acting pyrimidinylpiperazine derivative, (Traber and Glaser, 1987), has a radioligand binding profile very similar to that of 8-OH-DPAT (Peroutka, 1988). Iipsapirone (0.3 mg/kg PO) induces a hypothermic response in normal human subjects (Lesch et al., 1990a and Gelfin et al., 1995). The hypothermia is dose-related, attenuated by the non-selective 5-HT receptor antagonist, metergoline, completely antagonized by the non-selective β adrenoceptor but selective 5-HT1A/5-HT1B receptor antagonist, pindolol, and not affected by the selective β1 adrenoceptor antagonist, betaxolol (Lesch et al., 1990a). Ipsapirone-induced hypothermia is negatively related to age with no difference between males and females (Gelfin et al., 1995). Ipsapirone also induces release of ACTH, cortisol (Lesch et al., 1989, Lesch et al., 1990b, Gelfin et al., 1995 and Cleare et al., 1998) and GH (Lesch et al., 1989, Cleare et al., 1998 and Newman et al., 1999) in normal human subjects. The effects of age and gender on ipsapirone-induced ACTH and cortisol release are complex; whereas both responses diminished with age in male subjects, they increased with age in females (Gelfin et al., 1995). Ipsapirone-induced GH release, however, was greater in male than in female subjects, with no apparent effect of age (Newman et al., 1999). Hypothalamic-pituitary-adrenal (HPA) activation by ipsapirone is dose-related and pharmacologically attributable to 5-HT1A receptor activation, as indicated by the attenuating effect of metergoline, complete antagonism of the response by pindolol and absence of an effect of betaxolol (Lesch et al., 1990b). 5-HT1A receptor function in depression has been examined in several studies. Lesch et al., 1990c and Lesch et al., 1990d observed reductions in the hypothermic, ACTH and cortisol responses to ipsapirone in 12 depressed patients (all inpatients, all unipolar), although in subsequent studies these results were only partially replicated. Meltzer and Maes (1994) observed no change in the cortisol or prolactin responses to buspirone in 45 depressed patients (all outpatients, all unipolar, 32 melancholic, 13 non-melancholic). In a second study (Meltzer and Maes, 1995) the cortisol response to ipsapirone was decreased in a group of 12 patients (seven inpatients, five outpatients, three bipolar, nine unipolar, eight melancholic, four non-melancholic) but there was no change in the hypothermic response. Cowen et al. (1994) observed a reduced hypothermic response to buspirone in 20 depressed patients (11 inpatients, nine outpatients, all unipolar, 12 melancholic, eight non-melancholic), with a greater effect in males, while the GH and ACTH responses were not significantly different from controls. Price et al. (1997) observed no change in hypothermic, GH, ACTH or cortisol responses to ipsapirone in their group of 15 depressed patients (eight outpatients, seven inpatients, all unipolar, four melancholic; 11 non-melancholic), possibly because of the preponderance of non-melancholic patients in their study. Similarly, Shin-Shiah et al. (1998) found no difference from controls in the hypothermic and cortisol responses to ipsapirone in eight depressed bipolar patients (all inpatients), although there was a correlation between blunting of the hypothermic response and the severity of depression as determined by the Hamilton Depression Scale (HAM-D) scores. Although it might be expected that the reduced serotonergic responses seen in depression would return to normal levels after treatment with antidepressant drugs, such an effect has not been observed in the case of the 5-HT1A receptor. In the only study of 5-HT1A function in depressed patients after treatment, Lesch et al. (1990e) observed a further reduction of the hypothermic response to ipsapirone after administration of amitriptyline, although ACTH and cortisol reponses were unchanged (Lesch, 1991). In normal subjects, administration of the SSRI drugs fluvoxamine, paroxetine and fluoxetine has been observed to induce subsensitivity of the hormone responses to the 5-HT1A receptor agonists buspirone, gepirone and ipsapirone respectively in three studies (Anderson et al., 1996, Sargent et al., 1997 and Lerer et al., 1999). The hypothermic response was also reduced in the two studies in which it was measured (by Sargent et al. (1997) using gepirone challenge and by Lerer et al. (1999) using ipsapirone challenge). In patients with obsessive-compulsive disorder, Lesch et al. (1991) also observed reductions in the hypothermic, ACTH and cortisol responses to ipsapirone after chronic treatment with fluoxetine. These results contrast with the increased prolactin responses to fenfluramine in depressed patients observed in a number of studies after treatment with antidepressant drugs (reviewed by Newman et al., 1998). An increased prolactin response to fenfluramine after treatment with electroconvulsive therapy (ECT) was observed by Shapira et al. (1992), although this was not confirmed in a smaller study (O’Keane et al., 1992). The effects of ECT on the tryptophan challenge test do not appear to have been studied, although antidepressant drugs in general induce an increased prolactin response to tryptophan (Charney et al., 1984, Cowen et al., 1986 and Price et al., 1989). ECT was shown not to alter ACTH and prolactin responses to clomipramine challenge (Manji et al., 1992). Animal studies using electrophysiological methods have shown increased sensitivity of post-synaptic 5-HT1A receptors after chronic administration of ECS (de Montigny, 1984, Chaput et al., 1991 and Mongeau et al., 1994; reviewed by Blier and de Montigny, 1994). These findings were not always supported, however, when binding studies were performed to determine the density of 5-HT1A receptors in distinct brain areas (Pandey et al., 1991 and Stockmeier et al., 1992). Biochemical measures of post-synaptic 5-HT1A receptor function, such as inhibition by 5-HT of forskolin-activated adenylate cyclase in hippocampal membranes, have shown reduced responses after ECS administration (Newman and Lerer, 1988 and Varrault et al., 1991). Hypothermic responses to 8-OH-DPAT have also been shown to be reduced after chronic ECS administration to mice (Goodwin et al., 1985b) and rats (Goodwin et al., 1987b, Blier and Bouchard, 1992 and Stockmeier et al., 1992). In the present work we report cortisol, GH and hypothermic responses to ipsapirone challenge in a group of ten depressed patients in comparison with 15 age- and sex-matched controls, and also the effects of ECT on these responses to ipsapirone in seven of the depressed patients.