University Department of Psychiatry, Oxford
Correspondence: Professor P.J. Cowen, University Department of Psychiatry, Warneford Hospital, Oxford OC37JX
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ABSTRACT |
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Aims The aim of the study was to use the 5-HT1D receptor agonist, zolmitriptan, to test the sensitivity of 5-HT1D receptors in patients with depression before and after treatment with selective serotonin reuptake inhibitors (SSRIs).
Method We measured the growth hormone response to zolmitriptan (5 mg orally) in patients with major depression before and after SSRI treatment. A matched sample of healthy subjects acted as a control group.
Results The growth hormone response to zolmitriptan was blunted in patients with a melancholic depressive syndrome. SSRI treatment produced a marked reduction in zolmitriptan-induced growth hormone release.
Conclusions Patients with melancholic depression have impaired sensitivity of the post-synaptic 5-HT1D receptors that mediate growth hormone release. The reduction in 5-HT1D receptor sensitivity following SSRI treatment is probably an adaptive response to increased levels of synaptic 5-HT.
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INTRODUCTION |
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METHOD |
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A group of 25 healthy controls were selected from a volunteer register, and matched to the patient group for gender, including menstrual status (stage of the menstrual cycle or postmenopausal), age, weight and hormonal medication. This group consisted of nine men and 16 women with mean age 39.9 years (range 23-54) and mean weight 71.5 kg (range 56-102 kg). Controls had been free of psychotropic medication for at least 3 months. The SCID interview was used to ensure that none met criteria for any Axis 1 disorder on DSM-IV. All subjects gave informed consent to the study, which was approved by the local ethics committee.
Neuroendocrine testing and antidepressant treatment
Subjects were brought to the laboratory in the morning, having fasted for
at least 4 hours. An indwelling venous cannula was inserted and a 30-minute
rest period allowed to elapse before zolmitriptan (5 mg orally) was
administered. Blood samples were then removed at 15-minute intervals for a
further 180 minutes. Subjects remained at rest throughout the test procedure.
Following the neuroendocrine test, antidepressant medication was prescribed as
clinically appropriate by the patient's treating clinician. A subgroup of 12
patients (three men, nine women) were re-challenged with zolmitriptan (5 mg
orally) following a trial of SSRI treatment of mean duration 33.9 days (range
27-76 days). Of this group, seven patients received fluoxetine (20 mg daily
except one subject who took 20 mg on alternate days), three paroxetine (20
mg), one venlafaxine (150 mg daily) and one citalopram (20 mg). Six healthy
controls (four men, two women) were also challenged twice with zolmitriptan (5
mg orally). The mean inverval between these two tests was 28.2 days (range
23-35 days). In both these studies female subjects received the second
zolmitriptan challenge at the same stage of the menstrual cycle as the
first.
Biochemical measurements
Following blood collection, plasma was separated by centrifugation and
stored at -20°C. Plasma growth hormone was measured using standard
immunoradiometric assays (reagents provided by Netria, London). The inter- and
intra-assay coefficients of variation of the growth hormone assays over the
range encompassed by the standard curve were 4.1% and 2.6%. Because growth
hormone can inhibit its own secretion, we excluded subjects whose tests
demonstrated elevated baseline growth hormone secretion (>15 mIU/l) at Time
0. Plasma cortisol was determined by radio-immunoassay. The intra- and
inter-assay coefficients of variation over the range encompassed by the
standard curve were 4.3% and 5.8%. Plasma zolmitriptan levels were measured by
a high-performance liquid chromatography (HPLC) procedure which utilised
coulometric end-point detection, and solid phase extraction.
Statistical analysis
Analyses were carried out using SSPS for Windows (version 9.0). Growth
hormone responses were analysed as peak change from baseline and also area
under the curve (AUC), measured by the trapezoid method with extrapolation of
baseline secretion measured from Time 0. These two measures were highly
correlated (r=0.94, P<0.001). Baseline cortisol was
measured as mean concentration from the three baseline sample levels. Plasma
zolmitriptan levels were calculated as AUC. Differences between patients and
controls were examined with Student's unpaired t-test (two-tailed).
Within-group comparisons were made using Student's paired t-test
(two-tailed). Correlations were carried out using Pearson's product
moment.
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RESULTS |
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In the 12 patients who were re-challenged with zolmitriptan after SSRI treatment the mean (s.e.m.) peak growth hormone response was significantly attenuated (14.2 (4.8) v. 1.9 (0.7) mIU/l, P=0.024). The AUC of growth hormone secretion after zolmitriptan was also significantly less following SSRI treatment (675 (355) v. -368 (173) mIU x min/l, P=0.005) (see Fig. 2). The mean (s.e.m.) AUC of zolmitriptan was not significantly altered by SSRI treatment (588 (83) v. 649 (87), P=0.45). The mean fall in HRSD was 7.9. Five of the patients were responders as judged by a 50% decline in HRSD score. There was no correlation between fall in HRSD and change in peak or AUC growth hormone response to zolmitriptan (r=0.18, P=0.57 and r=-0.10, P=0.98, respectively).
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In the group of healthy controls who were tested on two occasions there was no significant difference between the mean (s.e.m.) peak growth hormone response to the first zolmitriptan challenge and the second (16.9 (7.6) v. 17.3 (8.9) mIU/l, P=0.81). The AUC growth hormone values on the two occasions were also similar (943 (597) and 1189 (854) mIU x min/l, P=0.42).
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DISCUSSION |
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Growth hormone response to zolmitriptan
A number of triptan drugs, including sumatriptan, rizatriptan and
zolmitriptan, increase plasma growth hormone in humans (see
Whale & Cowen, 1998).
Zolmitriptan is the only one of these agents with good bloodbrain
barrier permeability and its ability to stimulate growth hormone release
appears more robust than that of sumatriptan
(Whale et al,
1999).
All the triptans have a high affinity for both the 5-HT1D receptors and the closely related 5-HT1B receptors, and, in the absence of selective antagonists, it is not possible at present to state with certainty which receptor subtype mediates the growth hormone response. However, we recently found that zolmitriptan-induced growth hormone release is attenuated by the 5-HT receptor antagonist, ketanserin, which has some preference for the 5-HT1D receptor over the 5-HT1B receptor (Whale et al, 1999). In addition, because 5-HT pathways stimulate growth hormone secretion, we assume that the 5-HT receptors mediating zolmitriptan-induced growth hormone release are located post-synaptically to 5-HT neurons and do not function as inhibitory 5-HT1D autoreceptors (Barnes & Sharp, 1999).
Growth hormone response to zolmitriptan in depression
Our data suggest that patients with melancholic depression have blunted
growth hormone responses to zolmitriptan. In this respect our findings are
similar to those of challenge studies using 5-HT1A receptor
ligands, where blunted endocrine and thermic responses are particularly
apparent in subjects with melancholic depression
(Lesch, 1992;
Cowen et al, 1994).
Two other studies have reported blunted growth hormone responses to
sumatriptan in patients with major depression
(Yatham et al, 1997;
Cleare et al, 1998), although results of sumatriptan challenge are difficult to interpret because
of the number of healthy subjects who fail to produce useful growth hormone
responses. While these data appear to suggest a fairly reliable blunting of
growth hormone responses to 5-HT1D receptor challenge in patients
with depression, it is worth noting that this abnormality could reflect
decreased growth hormone release at pituitary level. However, studies with
growth hormone releasing hormone do not consistently support this
interpretation (Skare et al,
1994).
The current results from challenge studies with directly acting 5-HT receptor agonists in patients with depression differ from those obtained with the 5-HT precursor, tryptophan, where endocrine responses are blunted both in subjects with melancholic and non-melancholic depression (Cowen & Charig, 1987). This suggests that whereas patients with depression in general may have impaired pre-synaptic release of 5-HT, patients with melancholia may additionally exhibit impaired sensitivity of post-synaptic 5-HT receptors. This would be expected to result in a larger decrement in overall 5-HT neurotransmission. This could explain why SSRIs may not be as effective as less selective antidepressants in patients with severe depressive illness (Anderson, 2000). Where brain 5-HT function is particularly compromised the therapeutic effect of SSRIs could be impaired.
It seems paradoxical that impaired presynaptic 5-HT release should be associated with diminished post-synaptic receptor sensitivity. Normally a compensatory up-regulation in post-synaptic receptor responsiveness would be expected. This makes it likely that in patients with depression some other factor is overriding this normal compensatory response. For example, in the case of the 5-HT1A receptor there is a possible role of cortisol hypersecretion to decrease 5-HT1A receptor expression (see Dinan, 1994). Conceivably cortisol could exert a similar effect on the 5-HT1D receptor. In addition we have recently shown that patients who have recovered from depression have impaired up-regulation of post-synaptic 5-HT receptor sensitivity when exposed to dietary-induced tryptophan deficit (Smith et al, 2000). It is, therefore, also possible that people prone to depression have a trait abnormality in 5-HT receptor regulation.
The possible contribution of impaired post-synaptic 5-HT1D receptor sensitivity to the depressive syndrome is unclear because there are few known functional correlates of 5-HT1D receptor activation in animals or humans. Higher concentrations of post-synaptic 5-HT1D receptors are found in basal ganglia which might indicate involvement in depression-associated psychomotor changes (Barnes & Sharp, 1999). In addition, 5-HT1D receptors in the cortex modulate glutamate release, which might suggest a role in the memory impairments experienced by patients with depression (Maura et al, 1998).
Effect of SSRIs on 5-HT1D receptor sensitivity
In patients treated with SSRIs the growth hormone response to zolmitriptan
was markedly decreased. This suggests that SSRIs produce a down-regulation of
post-synaptic 5-HT1D receptors. There is also evidence that
repeated SSRI treatment can down-regulate post-synaptic 5-HT1A and
5-HT2 receptors, in both healthy subjects and patients with
depression (Lesch, 1992;
Quested et al, 1997;
Sargent et al,
1997).
Despite these effects of SSRIs on post-synaptic 5-HT receptors, it is likely that overall, SSRIs increase 5-HT neurotransmission because procedures such as tryptophan depletion, which lower synaptic 5-HT availability, reverse the antidepressant effects of SSRIs in patients who have recovered from depression (Delgado et al, 1999). From this point of view the down-regulation of post-synaptic receptors seen during SSRI treatment is presumably an adaptive response which limits, but does not remove, the increase in 5-HT neurotransmission produced by chronic 5-HT reuptake blockade and increased levels of synaptic 5-HT. This may explain the apparently paradoxical finding that some unmedicated patients with major depression have impaired post-synaptic 5-HT1D receptor function which is further diminished by effective treatment.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication April 19, 2000. Revision received October 23, 2000. Accepted for publication October 27, 2000.