Growth hormone response to baclofen in patients with seasonal affective disorder: effects of light therapy

Psychoneuroendocrinology 24 (1999) 143–153

Growth hormone response to baclofen inpatients with seasonal affective disorder: effects

of light therapy

I-Shin Shiah a,b, Heather A. Robertson a,Raymond W. Lam a,*, Lakshmi N. Yatham a,

Edwin M. Tam a, Athanasios P. Zis a

a Di6ision of Mood Disorders, Department of Psychiatry, The Uni6ersity of British Columbia, Vancou6er,British Columbia, BC, V6T 2A1, Canada

b Department of Psychiatry, Tri-Ser6ice General Hospital, National Defense Medical Center,Taipei, Taiwan, ROC

Received 20 May 1998; received in revised form 5 August 1998

Abstract

There is evidence for g-aminobutyric acid (GABA) dysfunction in the pathophysiologyand treatment response of patients with major depression, but this has not been studied inseasonal affective disorder (SAD). Growth hormone (GH) response to a challenge with aGABAB 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, wecompared the GH response to baclofen challenge in 15 patients with SAD and 20 matchedhealthy controls. Of the 15 patients with SAD, 14 had repeat baclofen challenge following2-week treatment with light therapy. The results showed that baclofen administration led toa significant increase in GH release both in patients with SAD and normal controls. Therewas 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-in-duced GH response in patients with SAD, in spite of a clear therapeutic effect. The resultsof this study suggest that hypothalamic GABAB receptor function, as measured by baclofeninduced GH release, is not altered in patients with SAD or by light therapy. © 1999 ElsevierScience Ltd. All rights reserved. © 1999 Elsevier Science Ltd. All rights reserved.

Keywords: GABA; GABAB receptor; Baclofen; Growth hormone; Seasonal affective disor-der; Winter depression; Light therapy

* Corresponding author. Tel.: +1-604-822-7325; fax: +1-604-822-7922; e-mail: [email protected].

0306-4530/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.PII S0306-4530(98)00066-3

144 I.-S. Shiah et al. / Psychoneuroendocrinology 24 (1999) 143–153

1. Introduction

Current biochemical hypotheses of depressive disorders have predominatelyimplicated biogenic amine neurotransmitters such as serotonin (5-HT) and nore-pinephrine (NE), in either the pathophysiology of depression or in the mechanismsof action of antidepressant treatments. There is an ample literature to support this.However, most antidepressant treatments in clinical use affect a number of neuro-transmitter receptors in addition to those of serotonin and norepinephrine (Greenand Nutt, 1983). It is plausible, therefore, that other neurotransmitter systems, suchas g-aminobutyric acid (GABA) system, may be deranged in depression, andtherefore could be action sites of antidepressant treatments (Leonard, 1994).

As reviewed in our recent paper (Shiah and Yatham, 1998), several lines ofevidence in the literature have accumulated to support the hypothesis of low GABAfunction in depression. For example, four out of eight studies reported thatcerebrospinal fluid (CSF) GABA levels were significantly lower in patients withmajor 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; Royet al., 1991; Zimmer et al., 1981). Three out of four studies showed that unipolardepressed patients have lower plasma GABA levels compared with normal controls(Petty and Schlesser, 1981; Petty and Sherman, 1984; Petty et al., 1992; Rode et al.,1991). Petty (1994) also reported that plasma GABA levels in patients with bipolardepression 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 bipolardepressions (Kaiya et al., 1982), further supporting a GABA deficit in depression.Perry et al. (1977) also reported that GAD activity was significantly decreased inpostmortem brain of depressed patients compared with controls. In contrast,Cheetham et al. (1988) found no alterations in frontal and temporal GAD activityin 21 depressed suicide victims compared with 21 matched controls.

With regard to the contribution of GABA function to the mechanism of actionof antidepressant treatments, there have been conflicting results of preclinicalstudies. For example, several different classes of antidepressant agents includingtricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selectiveserotonin reuptake inhibitors (SSRIs), and electroconvulsive shock (ECS) werereported 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 andBowery, 1993; Szekely et al., 1987) or hippocampus (Lloyd and Pichat, 1987)following chronic administration. However, several other studies failed to confirmthe enhanced GABAB receptor binding with antidepressant treatments (Cross andHorton, 1987, 1988; Engelbrecht et al., 1994; McManus and Greenshaw, 1991;Szekely et al., 1987). The reasons for the discrepant results relating the effects ofantidepressant treatments on GABAB receptor binding remain unclear.

In humans, one way to asses GABAB receptor function is to measure growthhormone (GH) release after administration of baclofen, a GABAB receptor agonist.This endocrine challenge paradigm is based on two observations: (1) that hypotha-

145I.-S. Shiah et al. / Psychoneuroendocrinology 24 (1999) 143–153

lamic GABAB receptors sites are involved in the modulation of GH secretion(Gamse et al., 1980; Muller, 1987); and (2) that the administration of baclofeninduces a significant increase in GH concentrations in normal healthy humans(Koulu et al., 1979). Using this paradigm, two studies (Marchesi et al., 1991;O’Flynn and Dinan, 1993) showed a significant reduction of GH response tobaclofen in patients with major depression compared to matched normal controls,suggesting that downregulated GABAB receptor function is associated with depres-sion. However, the other investigators (Davis et al., 1997; Monteleone et al., 1990a)reported no significant difference in baclofen induced GH response between pa-tients with major depression and normal controls. Furthermore, two baclofenchallenge studies did not find any significant treatment effects of antidepressants onthe GABAB-mediated endocrine response. Monteleone et al. (1990a) showed that28 days of amitriptyline (100 mg/day) treatment did not significantly alter the GHresponse to baclofen in eight male depressed patients. A subsequent study by thesame group (Monteleone et al., 1990b) reported that 15 and 35 days of treatmentwith amitriptyline (100 mg/day), imipramine (100 mg/day) and fluoxetine (20mg/day) did not significantly modify this endocrine response in ten male depressedpatients.

Seasonal affective disorder (SAD) is a clinical subtype of recurrent majordepression 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 thegeneral population (Rosen et al., 1990). A significant proportion of patients withseasonal depression responds to exposure to bright artificial light therapy (Termanet al., 1989). As yet, the pathophysiology of SAD and the therapeutic mechanismof light are still unknown. Since depressive symptoms (Allen et al., 1993; Tam et al.,1997) and the treatment response to antidepressants (Lam et al., 1995) are sharedbetween seasonal and non-seasonal depressions, one may expect that dysregulationof GABA function also occurs in patients with seasonal depression and that theantidepressant efficacy of light therapy may be related to its capacity to restoreGABA function. However, to our knowledge, no study has yet examined GABAfunction in patients with SAD, nor the effects of light therapy on GABA functionin 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 withSAD, by measuring GH release to baclofen challenge in patients with SAD beforeand after light therapy and in matched healthy controls.

2. Methods

Fifteen patients (six women and nine men; mean age9SD=35.398.8) who metDSM-IV criteria for recurrent major depressive episodes with a seasonal pattern(American Psychiatric Association, 1994) as well as Rosenthal et al. (1984) criteriafor a diagnosis of SAD participated in the study. Those that met criteria for otheraxis I diagnoses were excluded. The patients were recruited by newspaper advertise-


ments and referral from family physicians and psychiatrists. They were screened bya routine clinical interview, as well as a structured clinical interview for DSM-III-R(SCID) diagnosis (Spitzer et al., 1990). All female patients were premenopausal andwere menstruating regularly. The patients had a mean9SD 21-item depressionscore of 19.691.7, and a mean9SD eight-item atypical depression score of11.492.7 on the Hamilton Depression Rating Scale-SAD version (SIGH-SAD)(Williams et al., 1991).

Twenty healthy controls (seven women and 13 men; mean age9SD=32.498.8)were also studied. They had no lifetime history of psychiatric illness as determinedby SCID-non-patient version (Spitzer et al., 1992) and were free of a family historyof an Axis I psychiatric disorder in their first-degree relatives.

All study subjects were physically healthy and gave written informed consent forparticipation in the study, which had been approved by the Clinical Research EthicsCommittee of the University of British Columbia. All study subjects were drug freefor at least 2 weeks prior to baclofen challenge test and none had taken fluoxetinein the preceding 8 weeks.

The patients with seasonal depression were tested during fall/winter depressionbetween November and March, and the normal controls were also tested during thesame season. The baclofen challenge test was carried out during the follicular phasein both female patients and healthy female controls. The subjects, having fastedfrom midnight, presented for testing between 0800 and 0830h. An intravenouscannula was inserted in a forearm vein at 0830h and subjects were allowed to restbut not to sleep, smoke or eat until the challenge procedure was completed. Thefirst blood sample for baseline GH level was taken at 1000h (time ‘0’). Baclofen 20mg was given orally at this time, and further blood samples were obtained at30-min intervals for the following 3 h. The blood was immediately centrifuged andserum stored at −80°C until analysis.

Patients with seasonal depression were treated with light therapy on an outpa-tient basis. They took home a light box that delivered 10000 lux of cool-whitefluorescent light with an ultraviolet filter. Exposure time was set for 30 min between0700 and 0900h each morning. Fourteen out of 15 patients had the baclofenchallenge test repeated after 2 weeks of treatment with light therapy.

GH was assayed by Quantitope HGH Radioimmunoassay (Kallestad diagnos-tics). The samples were assayed blind to the diagnostic status of subjects. Allsamples from each subject were assayed in the same batch. The sensitivity of GHwas 0.2 mg/l. The interassay coefficients of variation were 10.8% for GH pool of 2.6ng/ml, 6.6% for GH pool of 5.8 ng/ml, and 5.7% for GH pool of 11.3 ng/ml. Theintraassay coefficients for GH were 6.8, 5 and 9.1% for GH pools of 2.5, 5.4, and35.2 ng/ml, respectively.

Chi-square test and Student’s t-test were used to compute differences in sex, age,baseline GH level between patients with SAD and normal controls. Paired t-testwas used to compute differences in baseline GH levels within patients before andafter light therapy. An analysis of variance (ANOVA) with repeated measures wasused to compare the difference in GH response to baclofen challenge betweenpatients with SAD and normal controls. The effect of treatment with light therapy


on GH response in patients with SAD was determined by ANOVA with repeatedmeasures. GH response to baclofen was also calculated as: (1) the net area underthe time curve (labeled as AUC GH), using trapezoidal method with subtraction ofthe baseline values; and (2) the net maximal response (labeled as Dmax GH), thatis, the peak response minus baseline. Student’s t-test was used to compare the AUCGH or Dmax GH between patients with SAD and normal controls. Paired t-testwas used to compare the AUC GH or Dmax GH within patients with SAD beforeand after light therapy. Relationships between variables were assessed by means ofPearson’s correlation coefficient. Kolmogorov–Smirnov test was used to ascertainnormality of data distribution, and those not approximating satisfactorily tonormality were log10 transformed before statistical calculation. Values reported aremeans9SD, unless otherwise specified. All tests were two-tailed, with significanceset at pB .05.

3. Results

Of the 15 patients with SAD, one was noncompliant with treatment and did nothave the repeated baclofen test; another one had a posttreatment baseline GH levelabove 5 mg/l. The two patients were included when comparing GH responses with20 normal controls but were excluded when comparing GH responses withinpatients with SAD before and after light therapy. The exclusion of subjects withlarge baseline GH levels is standard practice because after a GH secretory episode,the pituitary is relatively refractory (Vance et al., 1985).

There was no significant difference in sex (x2=0.09, d.f.=1, p= .76) or age(t=0.97, d.f.=33, p= .33) between the 15 patients with SAD and 20 normalcontrols. The baseline GH levels in patient with SAD (1.1290.73 mg/l, n=15)were similar to those (1.3091.25 mg/l, n=20) in normal controls (t= −0.51,d.f.=33, p= .60). As shown in Fig. 1, there was a significant increase in GH releasefollowing baclofen administration at time ‘0’ both in patients with SAD and normalcontrols. ANOVA with repeated measures on log10 GH data showed a significanttime effect (F=10.95, d.f.=6, 198, pB .001), but no significant group effect(F=0.17, d.f.=6,198, p= .98) or an effect for time x group interaction (F=0.00,d.f.=1,33, p= .96). Similarly, there was no significant difference in baclofeninduced GH response measured as AUC GH between patients with SAD (245.629294.12 mg×min/l, n=15) and normal controls (191.379268.97 mg×min/l, n=20) (t=0.61, d.f.=43, p= .54). Furthermore, the GH response to baclofenmeasured as Dmax GH in patients with SAD (4.1494.43 mg/l, n=15) also did notdiffer from that in normal controls (3.8893.26 mg/l, n=20) (t=0.21, d.f.=33,p=0.84).

Of the fourteen patients with SAD that had baclofen test repeated following 2weeks of treatment with light therapy, one had high baseline GH level posttreat-ment as previously stated and therefore, was excluded from the analysis. Theremaining 13 patients with SAD had a mean9SD baseline 29-item SIGH-SADscore of 31.095.9 and post-treatment SIGH-SAD score of 10.994.8. All 13


Fig. 1. Mean (9SEM) growth hormone (GH) responses following baclofen administration in 15patients with seasonal affective disorder (SAD) and 20 normal controls. The GH responses to baclofenwere similar between the two groups (Repeated measures of ANOVA, time effect: pB .001, treatmenteffect: p= .98, time× treatment interaction effect: p= .96).

patients improved with light therapy and nine out of 13 had ]50% reduction inSIGH-SAD score post-treatment compared to baseline. Within patients with SAD,the baseline GH level did not differ between before (1.1090.73 mg/l, n=13) andafter light therapy (0.9390.34, n=13) (t= −0.32, d.f.=13, p= .75). As shown inFig. 2, the GH release following baclofen administration at time ‘0’ within 13

Fig. 2. Mean (9SEM) growth hormone (GH) responses following baclofen administration in 13patients with seasonal affective disorder (SAD) before and after 2-week of treatment with light therapy.The GH responses to baclofen were similar between before and after treatment (Repeated measures ofANOVA, time effect: pB .001, treatment effect: p= .94, time× treatment interaction effect: p= .57).


patients with SAD were similar between before and after 2-week of treatment withlight therapy. Repeated measures ANOVA on log10 GH data showed a significanttime effect (F=9.71, d.f.=6,72, pB .001), but no significant treatment effect(F=0.00, d.f.=1,12, p= .94) or an effect for time× treatment interaction effect(F=0.80, d.f.=6,72, p= .57). Similarly, there was no significant difference in thebaclofen induced GH response measured as AUC GH between before (254.109311.37 mg×min/l, n=13) and after (215.319158.87 mg×min/l, n=13) lighttherapy (t=0.58, d.f.=12, p= .56). The GH response to baclofen measured asDmax GH in patients with SAD (4.3694.69 mg/l, n=13) was also not altered bythe light therapy (3.4292.41 mg/l, n=13) (t=0.96, d.f.=12, p= .36).

When patients with SAD and normal controls were pooled together, there was nosignificant difference in GH response to baclofen measured as AUC GH betweenfemales (171.879425.74 mg×min/l, n=13) and males (234.909201.84 mg×min/l, n=22) (t=0.50, d.f.=15.24, p= .62). Furthermore, there was no significantcorrelation between AUC GH and gender (Pearson’s r= − .10, p= .55, n=35), orbetween AUC GH and age (Pearson’s r=0.07, p= .65, n=35). No significantcorrelation was found between pretreatment AUC GH and SIGH-SAD depressionscores in patients with SAD (Pearson’s r= −0.07, p= .78, n=15). There was nosignificant correlation between the change in AUC GH (pretreatment AUC GHminus posttreatment AUC GH) and the change in SIGH-SAD scores (pretreatmentSIGH-SAD minus posttreatment SIGH-SAD scores) in patients with SAD (Pear-son’s r=0.11, p= .71, n=13).

4. Discussion

The major findings of the present study included that: (1) administration ofbaclofen, a GABAB receptor agonist, significantly increased plasma GH levels bothin patients with SAD and matched normal controls; (2) there was no significantdifference in the endocrine response between the two groups; (3) 2 weeks oftreatment with light therapy did not significantly alter the GH response to baclofenin patients with SAD.

Our finding of an increase in GH release in normal controls after administrationof baclofen is consistent with previous studies (Davis et al., 1996; Lucey et al., 1994;Monteleone et al., 1990a,b; O’Flynn and Dinan, 1993) and further supports a roleof GABAB receptors in regulating GH release in humans. It is of interest to notethat the baclofen induced GH response also occurred in patients with SAD, andwas not altered after 2 week of treatment with light therapy, in spite of a cleartherapeutic effect.

Several potential limitations need to be considered for the negative findings in thepresent study. First, since we did not use a placebo control condition to minimizethe effects of confounding variables such as nonspecific stress effects, we can notexclude the possibility of a type II error of inference (Thompson et al., 1994). Such,however, is unlikely because previous neuroendocrine placebo controlled studieshave shown that GH responses to placebo did not differ between patients with


SAD and normal controls (Jacobsen et al., 1987; Schwartz et al., 1997) suggestingthat SAD patients do not respond differently in GH responses to nonspecificaspects of test procedure. Second, although one could argue that longer duration oflight therapy may have yielded positive results, it must be pointed out that patientswith SAD usually respond to light therapy within 2 weeks of treatment (Wessonand Levitt, 1998). Third, a failure to detect a significant difference in GH responsebetween patients with SAD and normal controls, or an effect of light therapy onGABAB receptors could be due to a type II error because of small sample size.However, when we examined our results using sample size nomogram (Young etal., 1983), we found an extremely large sample would be needed to demonstrate adifference between the two diagnostic groups if one does in fact exist. Furthermore,we were able to demonstrate an attenuating effect of divalproex sodium, a moodstabilizer, on the baclofen-induced GH response in ten healthy humans (Shiah etal., 1998), which is the number of subjects less than that in the present study. Onthe basis of our data, a significant difference in GH response between or withingroups does not seem likely.

In addition to the GABAB receptor-mediated GH response reported in thepresent study, the GH responses to serotonergic challenging agents have also beenused to investigate the pathophysiology of SAD and/or the mechanism of action oflight therapy in two neuroendocrine studies. Yatham et al. (1997) reported ablunted GH response to sumatriptan, a 5-HT10 receptor agonist, in patients withSAD compared with healthy controls. The GH response normalized followingtreatment with light therapy to similar levels in normal controls. Their findingssupport the involvement of serotonin function in SAD and light therapy. Incontrast, Jacobsen et al. (1987) reported that 5-hydroxytryptophan (5-HTP), the5-HT precursor, had no effect on GH release in either patients with SAD or normalcontrols. The discrepant findings between the two studies are likely to be due to theinherent differences in pharmacology of sumatriptan and 5-HTP. To our knowl-edge, the GH responses to noradrenergic drugs such as clonidine and desipramine,dopaminergic drugs such as apomorphine, or cholinergic drugs such as pyridostig-mine, have not been studied in patients with SAD. Further studies using the GHresponses to the different classes of challenging agents may be useful to enhance ourunderstanding of the roles for different neurotransmitters in the pathophysiology ofSAD and in the mechanism of action of light therapy.

In summary, this study did not find any differences in GH response to baclofenbetween patients with SAD and normal controls. Two weeks of treatment with lighttherapy did not modify the GH response in patients with SAD, in spite of a cleartherapeutic effect. Our findings suggest that hypothalamic GABAB receptor func-tion, as measured by baclofen induced GH release, is not altered in patients withSAD or by light therapy.

Acknowledgements

The authors would like to thank Arvinder Grewal for her technical assistance. Apreliminary report of these data was presented at the 10th Annual Meeting, Society


for Light Treatment and Biological Rhythms, Amelia Island Plantation, Florida,May, 1998.

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Growth hormone response to baclofen in patients with seasonal affective disorder: effects of light therapy