Growth Hormone Studies in Psychiatric Disorders

Adrenergic input to the HPS axis is mediated primarily by the ^-adrenergic receptor. «2-Adrenergic agonism is a potent stimulus for GH secretion, the effect being blocked by corresponding antagonists (Devesa et al. 1992; Muller 1987). «-Adrenergic stimulation of GH release may also be antagonized by ^-adrenergic agonism (Devesa et al. 1992), but the H>-adrenergic-receptor-mediated influences are less well researched. In humans, the evidence suggests that the GH-releasing effect of «2-adrenergic agonism may be due primarily to inhibition of somatostatin release, with perhaps a secondary stimulation of GHRH. This is based on two main types of evidence. First, for at least 2 hours after a supramaximal dose of GHRH (200 L'g), the pituitary is refractory to a repeated dose of GHRH, but the (X 2-adrenergic agonist clonidine (Valcavi et al. 1988) or insulin-induced hypoglycemia (Shibasaki et al. 1985) will still evoke a vigorous GH response. Presumably, if the GH-releasing cells are unresponsive to GHRH, clonidine must stimulate GH release through a non-GHRH mechanism, the most likely alternative being inhibition of somatostatin release. Similarly, insulin-induced hypoglycemia is thought to stimulate noradrenergic outflow, which then suppresses somatostatin secretion (Shibasaki et al. 1985). Whereas the GH response to GHRH depends on the point in the HSR rhythm at which the GHRH is given, the response to clonidine does not (Devesa et al. 1990, 1991a, 1992), again suggesting that clonidine acts through a non-GHRH mechanism, again presumably somatostatin.

Downregulation of GH release in response to clonidine presumably occurs in response to chronic, excessive noradrenergic outflow from the locus coeruleus, which is thought to play a role in anxiety states (Uhde et al. 1992). The blunted GH response to clonidine in panic disorder has been replicated in 8 of 10 studies from 6 of 7 different clinical research groups (Abelson et al. 1991, 1992; Amsterdam et al. 1989; Charney and Heninger 1986; Coplan et al. 1993; Nutt 1989; Schittecatte et al. 1988, 1992; Uhde et al. 1986, 1991). Both failures to replicate (Schittecatte et al. 1988, 1992) were by the same group. One of those studies (Schittecatte et al. 1988) involved only seven subjects, and blunting was absent only in the female subjects, in whom birth control pills or menstrual cycle phase can obscure blunting. Blunted GH response to clonidine is seen in generalized anxiety disorder (Abelson et al. 1991) and social anxiety disorder (Uhde et al. 1991) but not in obsessive-compulsive disorder (OCD) (Hollander et al. 1991; Lee et al. 1990). It has also recently been reported in patients with PTSD (Morris et al. 2004). It is unlikely that the GH blunting seen in anxiety disorders is an artifact of tricyclic exposure, given that in our own work, 10 of 12 anxiety patients with blunted responses had no significant prior exposure to tricyclic antidepressants (Abelson et al. 1992) and our recent findings demonstrate a blunted response in subjects with anxiety (predominantly social phobia) with no tricyclic exposure (Cameron et al. 2004). The nonspecificity of the GH response to clonidine suggests that it could be a secondary response to the presence of a psychiatric disorder. However, the absence of blunting in patients with OCD (Lee et al. 1990), schizophrenia (Lal et al. 1983), or heroin abuse (Facchinetti et al. 1985) argues against this interpretation. Although the replicability of the blunted GH response to clonidine in panic disorder is well established, the mechanism remains less certain. It has been thought to reflect subsensitivity (downregulation) of postsynaptic (^-adrenergic receptors (Siever et al. 1982). Our own data support the presence of blunted GH response to clonidine in social anxiety disorder, suggesting that excessive noradrenergic tone is also present in this form of anxiety (Cameron et al. 2004). These data are consistent with the hypothesis that excessive noradrenergic outflow from the locus coeruleus plays a pivotal role in anxiety states (Charney and Heninger 1986).

Numerous studies have also demonstrated reduced GH responses to clonidine in patients with major and melancholic depression (Amsterdam and Maislin 1990; Amsterdam et al. 1989; Charney et al. 1982; Checkley et al. 1981; Corn et al. 1984; Lesch et al. 1988; Siever and Uhde 1984), but not all studies have replicated these findings (Gann et al. 1995; Katona et al. 1993; Mitchell et al. 1991; Schittecatte et al. 1989, 1994). In particular, more recent studies have not found a blunted GH response to clonidine. It is unclear whether diagnostic changes and subject selection have affected these failures to replicate, given that several investigators found differences between endogenous and nonendogenous depression, with more severe blunting in the endogenous groups (Amsterdam et al. 1989; Checkley et al. 1984; Matussek and Laakmann 1981; Matussek et al. 1980). Furthermore, most of the studies in depression were done before it was realized that menstrual status (i.e., pre- vs. postmenopausal), menstrual cycle phase, and prior tricyclic exposure affected the GH response to clonidine. In particular, patients with endogenous depression are more likely to have been older and postmenopausal, both factors that decrease the GH response. The altered GH response to clonidine is thought to result from (¡^-noradrenergic receptor downregulation, since studies using either GHRH, which acts directly at the pituitary, or apomorphine, which acts via dopamine input to the GH system, demonstrate normal GH response in depressed patients (Amsterdam and Maislin 1990; Corn et al. 1984; Krishnan et al. 1988; Lesch et al. 1988; Thomas et al. 1959). Again, this is consistent with increased central noradrenergic activation in depression, similar to that hypothesized in panic disorder. Our own recent studies (Cameron et al. 2004) found a normal GH response to clonidine in patients with "pure" depression (i.e., patients who did not meet criteria for any anxiety disorders). All of our patients had been off any psychotropic drugs for at least 6 months. Furthermore, there was no relationship between dimensional measures of anxiety or dimensional measures of depression and GH response. Patients with melancholic depression did not differ from nonmelancholic patients or control subjects. Subjects with a high Hamilton Anxiety Scale (Ham-A) score (>20, n = 13) did not differ from their matched controls. Thus, our data suggest that blunted GH response to clonidine challenge is specific to anxiety disorders and is not seen with less severe forms of anxiety or with depression in the absence of an anxiety disorder.

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