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Serum Thyrotropin Concentrations and Bioactivity During Sleep Deprivation in Depression
David N. Orth, MD;
Richard C. Shelton, MD;
Wendell E. Nicholson, BS;
Paolo Beck-Peccoz, MD;
Andrew J. Tomarken, PhD;
Luca Persani, MD;
Peter T. Loosen, MD, PhD
Arch Gen Psychiatry. 2001;58:77-83.
ABSTRACT
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Background One night of sleep deprivation induces a brief remission in about half
of depressed patients. Subclinical hypothyroidism may be associated with depression,
and changes in hypothalamic-pituitary-thyroid function may affect the mood
response to sleep deprivation. We wished to define precisely the status of
the hypothalamic-pituitary-thyroid axis of depressed patients during sleep
deprivation and the possible relationship of hypothalamic-pituitary-thyroid
function to the mood response.
Methods We studied 18 patients with major depressive disorder and 10 normal
volunteers. We assessed mood before and after sleep. We measured serum thyrotropin
every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity,
the thyrotropin response to protirelin the next afternoon, and other indexes
of hypothalamic-pituitary-thyroid function. To determine if the changes were
limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol,
which also has a circadian secretory pattern.
Results Nocturnal serum thyrotropin concentrations were consistently higher
in responders, entirely because of elevated levels in the women reponders.
Responders had exaggerated responses to protirelin the next afternoon. The
bioactivity of thyrotropin in nonresponders was significantly greater than
in responders (F1,8.99 = 7.52; P = .02).
Other thyroid indexes and serum cortisol concentrations were similar among
groups.
Conclusions Depressed patients have mild compensated thyroid resistance to thyrotropin
action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation
responders compensate by secreting more thyrotropin with normal bioactivity;
nonresponders compensate by secreting thyrotropin with increased bioactivity.
INTRODUCTION
ONE NIGHT of sleep deprivation (SD) induces a rapid, albeit transient,
remission in about 60% of patients with major depressive disorder (MDD),1, 2 but the mechanism by which SD exerts
its antidepressant effect is unknown. Some findings suggest a relationship
between diurnal rhythm and the effects of SD: SD has been shown to alter the
sleep-wake cycle,3, 4 diurnal mood
variability predicts the antidepressant effect of SD,1, 2, 5
and phase advance and light therapy are sometimes effective in MDD.6, 7, 8, 9 Alterations
in hypothalamic-pituitary-thyroid axis (HPT) function may be involved in MDD.10, 11, 12, 13 Major
depressive disorder is common in hypothyroid patients,10
and some12, 13, 14 but
not all15, 16 studies indicate that
some patients with MDD have subclinical primary hypothyroidism. However, rather
than having the exaggerated thyrotropin response to protirelin characteristic
of hypothyroidism, about 30% of depressed euthyroid patients have blunted
responses to protirelin.10, 11 Finally,
protirelin has been shown to have antidepressant effects in some10, 17
but not all18, 19 patients. These
observations support HPT involvement in MDD, with endocrinologically distinct
MDD subgroups.20
The HPT also may be involved in the mood response to SD. Protirelin
causes acute changes in sleep electroencephalograms in normal volunteers.21, 22 Thyrotropin secretion normally demonstrates
a circadian rhythm, peaking during early sleep,23
but nocturnal serum thyrotropin level continues to rise during SD,24, 25, 26, 27 associated
with clinical improvement in some25, 26
but not all24, 27 studies. However,
most investigators measured serum thyrotropin level infrequently or only compared
hormone levels before and after SD. Therefore, little is known about detailed
thyrotropin secretion during SD in depression. Thyroxine administration during
SD can facilitate complete and sustained remission after SD,28
suggesting that altered HPT function also mediates behavioral effects of SD.
We postulated that the nocturnal pattern of serum thyrotropin concentration
in patients with MDD differs from that of normal subjects and that the clinical
response to SD correlates with this altered pattern. We analyzed HPT activity,
including serum thyrotropin bioactivity, during SD in patients with MDD and
normal subjects and measured serum concentrations of cortisol to determine
whether changes were specific to the HPT. We reexamined subjects 2 years later
to determine whether they developed overt hypothyroidism.29
SUBJECTS AND METHODS
SUBJECTS
The study protocol was approved by the Vanderbilt University Institutional
Review Board—Human Subjects (Nashville, Tenn), and written informed
consent was obtained from all subjects. We studied 8 male and 10 female outpatients
aged 28 to 62 years (mean ± 1 SD, 43.6 ± 9.31 years), diagnosed
as having MDD according to the Structured Clinical Interview for DSM-III-R—Patient Version,30 who
scored at least 18 on the first 17 items of the Hamilton Rating Scale for
Depression.31 Patients had no history of substance
abuse for 6 months and no lifetime history of psychosis or bipolar disorder.
Before SD, none had taken lithium carbonate for 3 months; fluoxetine, benzodiazepines,
or other psychotropics with long half-lives for 3 weeks; or other antidepressants
for 2 weeks. We recruited some patients from those being seen for outpatient
treatment, and other patients and all normal volunteers from advertisements
posted in the community. We studied 10 normal volunteer controls of similar
age and sex (5 men and 5 women aged 29 to 50 years [mean ± SD, 41.0
± 7.44 years]). Controls were free of Axis I mental disorders according
to the Structured Clinical Interview for DSM-III-R—Patient Version and scored less than 8 on the Hamilton Rating Scale
for Depression.31 All participants were physically
healthy as determined by clinical history, physical examination, routine serum
chemistry studies, and electrocardiogram and were able to give informed consent.
None had a personal or family history of thyroid disease or evidence of thyroid
dysfunction. We excluded any subject whose urine tested positive for illicit
drugs and any woman who was pregnant, lactating, or of childbearing potential
and not using reliable birth control. We advised patients that SD might transiently
improve their depression. We paid all participants $50.
PROCEDURES
Participants were admitted to the Vanderbilt General Clinical Research
Center during the morning of the first day. Mealtimes were 8 AM, noon, and
8 PM. Participants remained awake and ambulated and signed a record sheet
every 30 minutes for 36 hours under constant observation by the research center
staff in daytime lighting conditions.1, 4
They had no snacks, caffeinated beverages, or cigarettes. At 8 PM on the first
day, we inserted an intravenous heparin lock. At 10 PM, we began withdrawing
blood every 15 minutes for 12 hours. At 4 PM the following day, we performed
the standard protirelin stimulation test.11
We assessed severity of depression at recruitment, the day before SD,
and 1 week after SD by means of the 17-item Hamilton Rating Scale for Depression.31 We excluded subjects if they showed greater than 20%
improvement before SD. We also rated depression between 8 AM and 10 AM for
7 days before and the day after SD by means of the Sleep Deprivation Depression
Rating Scale (SDDRS), a modified Hamilton Rating Scale for Depression.32 This scale excludes insomnia, weight loss, diurnal
variation, depersonalization, paranoia, and obsessive-compulsive items and
adds elements that rate fatigue, social withdrawal, increased appetite, increased
eating, carbohydrate craving, weight gain, and hypersomnia. We defined response
to SD as 30% or more reduction in the SDDRS score the morning after SD.24, 32
Two years later, we recalled the 14 available patients with MDD and
all 10 controls for interval history, Structured Clinical Interview for DSM-III-R—Patient Version (patients with MDD), physical
examination, and thyroid function studies.
HORMONE ASSAYS
We measured serum thyrotropin with an immunoradiometric assay (Allégro;
Quest, San Juan Capistrano, Calif), and thyrotropin- and thyrotropin-ß
subunits with in-house radioimmunoassays with sensitivities of 5 and 2.8 pmol/L
of plasma, respectively. Thyrotropin cross-reacted 27% and 3.1% in the thyrotropin-
and thyrotropin-ß radioimmunoassays, respectively; thyrotropin-
cross-reacted 0.6% and 1.2% in the thyrotropin immunoradiometric assay and
thyrotropin-ß radioimmunoassay, respectively; and thyrotropin-ß
cross-reacted less than 0.0004% and less than 0.01% in the thyrotropin immunoradiometric
assay and thyrotropin- radioimmunoassay, respectively. We measured
thyrotropin bioactivity in pooled aliquots of all nocturnal samples after
immunoaffinity purification (recovery, 48% to 68%) and ultrafiltration.33, 34, 35 Results (mean ±
1 SD of 3 experiments) are expressed as the bioactivity to immunoreactivity
ratio (B/I). We measured serum free thyroxine, total triiodothyronine, anti–thyroid
peroxidase and anti–thyroglobulin antibody titers, and serum cortisol
by means of commercial kits.
STATISTICAL ANALYSES
The primary analyses compared the nocturnal serum thyrotropin levels
and thyrotropin B/I during SD and serum thyrotropin responses to protirelin
(peak level minus the mean of 2 prechallenge baseline levels) of responders,
nonresponders, and normal control subjects. We computed nocturnal serum thyrotropin
means in 4-hour sampling blocks (10 PM to 2 AM, 2:15 AM to 6 AM, and 6:15
AM to 10 AM).
Levene tests36 indicated significant between-group
heterogeneity of variance in thyrotropin B/I and protirelin response (F2,24 = 8.05; P<.005; and F2,23
= 4.27; P<.05, respectively). A likelihood ratio
test37 indicated significant between-group heterogeneity
of across-time covariance matrices in nocturnal serum thyrotropin ( 212 = 35.87; P<.001). One- and
2-way analyses of variance (ANOVAs) often demonstrate excessive type I error
rates and/or insufficient power with heterogeneous variances and unequal sample
sizes.38, 39 Consequently, we conducted
generalized Welch approximate degrees of freedom (WADF) tests40, 41, 42
to assess effects in our 3 primary measures. The WADF tests do not assume
equality of population variances across groups, and their type I error performance
and power are typically superior to those of ANOVA under variance heterogeneity.39, 43, 44
We conducted a group (responder, nonresponder, control) x time
(blocks 1-3) WADF test on nocturnal serum thyrotropin levels. Our original
intent was to assess only group effects, but inspection of cell means indicated
potential main effects or interactions involving sex. Therefore, we also conducted
group x sex x time WADF tests. We present both results because
the small numbers of subjects (ie, 3 to 7) of some group x sex x
time cells merit cautious interpretation. The main effect for group yielded
by the group x sex x time WADF test used a type III sum of squares
approach to assess differences among unweighted group means averaged across
sex.43, 45 For the repeated-measures
effects, the pattern of significant results yielded by the WADF test was identical
to that yielded by the improved general approximation test, a more conservative
alternative.46 In a parallel fashion, we conducted
group and group x sex WADF tests on responses to protirelin and thyrotropin
B/I. We set the critical level for all effects at .05, the denominator
as the number of variables analyzed. All tests were 2 tailed.
We conducted several computer simulations to test the properties of
the 2-way WADF test for sample sizes, degrees of variance heterogeneity, and
distributional shapes similar to those observed in our study. These yielded
empirical type I error rates that were consistently acceptable.43
As an additional test of the small-sample properties of our group x
sex analyses, we compared our WADF test results with those yielded by bootstrap
versions of the WADF test that yielded empirically generated sampling distributions
based on a heteroscedastic resampling model.47, 48
For all omnibus tests and planned and post hoc comparisons, the bootstrap
results and conclusions were identical to those of the theoretically based
WADF test. For brevity, we report only the latter results.
We also computed 2-tailed WADF planned comparisons ( = .05) that
compared responders and nonresponders on the 3 primary thyrotropin measures.49 We conducted post hoc WADF tests of the pairwise differences
between the control group and the other 2 groups only when omnibus WADF analyses
yielded significant main effects for group. Post hoc comparisons followed
the Fisher least significant difference strategy, which is optimal when the
group number equals 3 and only pairwise post hoc comparisons are contemplated.50, 51 Significant group x sex interactions
were followed by WADF omnibus ANOVAs that compared the 3 groups within each
category of sex. We set the critical level of these analyses at .05/2
= .025, where 2 is the number of sexes, to control familywise type I error
rates.45 Follow-up contrasts used the same critical
level.
In addition to between-group analyses, we computed Spearman correlations
to assess the relationship between pre- and post-SD SDDRS scores of the depressed
patients and each of our 3 primary thyrotropin measures.
We conducted ANOVAs (or WADF tests, when variance heterogeneity was
observed) comparing responders, nonresponders, and controls on 3 additional
thyrotropin measures during SD (thyrotropin-, thyrotropin-ß, and
the ratio of thyrotropin-ß to thyrotropin- [thyrotropin-ß/thyrotropin-]).
For brevity, we report only the group x sex analyses. We set the critical
level for each effect to .05/3 = .0167, where 3 is the number of thyrotropin
measures. We also tested for between-group differences in thyrotropin measures
at follow-up. One-way between-group tests were performed because data from
only 4 nonresponders were available. We conducted a group x sex x
time ANOVA on nocturnal serum cortisol during SD. As was true of the primary
dependent measures, resampling analyses (bootstrapping and/or permutation
tests) of each of these supplementary measures produced results and conclusions
that were identical to those of the normal-theory WADF tests and ANOVAs. For
brevity, we present only the latter results.
RESULTS
MOOD EFFECTS OF SLEEP DEPRIVATION
The mean SDDRS score of all 18 patients with MDD declined by 34% (range, -7%
to 78%), from 20.7 ± 5.2 (mean ± 1 SD) to 13.1 ± 5.5;
that of the 10 responders, by 56% (range, 38% to 78%), from 22.2 ±
5.5 to 9.8 ± 4.0; and that of the 8 nonresponders, by 6% (range, -7%
to 27%), from 18.8 ± 4.5 to 17.3 ± 4.2. The ANOVAs disclosed
no differences in baseline scores between responders and nonresponders (F1,16 = 2.07; P = .17), but a decline for the
whole MDD group (F1,16 = 69.96; P<.001)
that was greater for responders than nonresponders (F1,16 = 43.02; P<.001).
Seven of the 10 responders and 3 of the 8 nonresponders were female
(Fisher exact test, P = .34). There were no significant
age differences among the responders (43.8 ± 10.0 years), nonresponders
(43.2 ± 9.02 years), and controls (41.0 ± 7.44 years) (F2,25 = 0.29; P = .75).
NOCTURNAL SERUM THYROTROPIN CONCENTRATIONS
Responders had higher serum thyrotropin levels than the other groups
at every sampling time (Figure 1).
Eight of the 10 responders had 1 or more nocturnal thyrotropin values greater
than normal (>4.2 mU/L), as did 1 of 8 nonresponders and 2 of 10 controls.
No participant had a concentration less than normal (<0.9 mU/L). The planned
contrast indicated higher thyrotropin levels in responders than nonresponders
(F1,15.73 = 7.20; P = .02). Omnibus group
x time WADF analysis of the 4-hour pools indicated a main effect for
group (F2,15.07 = 6.64; P = .009). Post
hoc contrasts indicated that responders had higher levels than controls (F1,13.52 = 13.53; P<.001). A time effect
(F2,13.63 = 13.23; P>.001), but no group
x time interaction (F4,15.51 = 0.82; P=.53), was observed. Thyrotropin level peaked during the period from
2:15 to 6 AM (post hoc contrast F1,19.70 =25.90; P<.001).
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Figure 1. Nocturnal secretion of serum thyrotropin
in 10 depressed sleep deprivation responders, 8 depressed nonresponders, and
10 normal volunteers. Points indicate the mean of 7 to 10 values; brackets
indicate the SEM.
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The group x sex x time unweighted means WADF analysis also
indicated a main effect for group (F2,10.76 = 6.72, P = .01) and an identical pattern of between-group differences on planned
and post hoc contrasts (responders vs nonresponders, F1,9.23 =
6.50; P = .03; responders vs controls, F1,10.97 = 12.75; P = .004). However, the effects of
group were moderated by sex (group x sex interaction, F2,22
= 6.16; P = .008). Follow-up WADF analyses indicated
between-group differences for women (F2,6.34 = 18.68; P = .002), but not for men (F2,6.00 = 0.05; P = .95). Female responders had higher thyrotropin levels (6.45 ±
1.09 mU/L) than female nonresponders (3.06 ± 0.80 mU/L) (F1,5.29 = 30.02; P = .002) and female controls (2.80
± 1.19 mU/L) (F1,8.22 = 27.95; P<.001).
NOCTURNAL SERUM THYROTROPIN B/I RATIOS
Planned WADF contrasts indicated that nonresponders had higher ratios
(2.92 ± 1.36) than responders (1.50 ± 0.58) (1-way design contrast,
F1,8.99 = 7.52; P = .02; 2-way design
contrast, F1,8.18 = 6.59; P = .03). Omnibus
tests suggested a trend toward overall between-group differences (1-way design
group, F2,13.76 = 3.63; P = .054; 2-way
design group, F2,7.57 = 3.15; P = .10)
(control mean, 1.74 ± 0.45). No main effects or interactions involving
sex were found in the 2-way analyses (sex main effect, F1,9.16
= 0.006; P = .94; group x sex interaction,
F2,7.57 = 2.18; P = .18).
RESPONSE TO PROTIRELIN STIMULATION
All groups responded to protirelin (F1,11.23 = 74.45; P<.001) (Figure 2).
Eight of the 10 responders had higher than normal thyrotropin responses (>28.3
mU/L for women, >23.8 mU/L for men), as did 2 of the 6 nonresponders and 4
of the 10 controls; no participant had a less than normal response (<10.1
mU/L for women, <3.8 mU/L for men). Although 1-way omnibus WADF analysis
indicated only a trend for group (F2,13.85 = 3.41; P = .06), the planned contrast indicated that responders had greater
thyrotropin increments than nonresponders (F1,10.20 = 7.08; P = .02). The planned contrast linked to the group x
sex WADF analysis also indicated that responders had greater thyrotropin increments
than nonresponders (F1,8.80 = 8.49; P
= .02). In addition, the omnibus group x sex WADF analysis indicated
between-group differences in thyrotropin increments (group main effect, F2,12.29 = 4.04; P = .04). Follow-up contrasts
of the omnibus effect indicated that responders had greater increments than
controls (F1,9.93 = 7.42; P = .02). Nonresponders
and controls did not differ (F1,10.77 = 0.06; P = .82). Women responded more robustly than men (F1,10.89
= 9.49; P = .01). The group x sex interaction
was not significant (F2,12.29 = 2.60; P
= .11).
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Figure 2. Responses of serum thyrotropin
to administration of protirelin in 10 depressed sleep deprivation responders,
8 depressed nonresponders, and 10 normal volunteers. Points indicate the mean
of 7 to 10 values; brackets indicate the SEM.
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EFFECT SIZES
We computed Cohen's effect size index d52 to estimate the magnitude of differences between the
responders and nonresponders for the 3 thyrotropin measures. The d values for nocturnal thyrotropin, thyrotropin B/I ratios, and thyrotropin
increments in response to challenge were 1.26, 1.45, and 1.07, respectively.
In light of Cohen's stated criteria of 0.5 for a medium effect size and 0.8
for a large effect size,52 these d values underscore the magnitude of the thyrotropin differences between
responders and nonresponders.
CORRELATIONS BETWEEN PRIMARY THYROTROPIN MEASURES AND SDDRS SCORES
We computed Spearman correlations among pre- and post-SD SDDRS scores
and the 3 primary thyrotropin measures (Table 1). Post-SD SDDRS scores were significantly correlated with
all 3 thyrotropin measures despite the relatively small sample sizes: lower
post-SD SDDRS scores were associated with higher nocturnal serum thyrotropin
level, greater thyrotropin response to protirelin, and lower thyrotropin B/I.
The magnitudes of the associations indicate that thyrotropin measures accounted
for between 25% and 35% of the variance in SDDRS scores. In addition, nocturnal
serum thyrotropin level and thyrotropin B/I predicted declines in SDDRS scores
after SD. Serum thyrotropin level and thyrotropin response to protirelin were
positively correlated, while both measures were negatively correlated with
thyrotropin B/I.
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Table 1. Correlations Between SDDRS Scores and Thyrotropin Measures*
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SERUM THYROTROPIN SUBUNIT CONCENTRATIONS AND OTHER INDEXES OF HPT FUNCTION
Levene tests indicated variance heterogeneity in thyrotropin-
(F5,22 = 12.04; P<.001). The WADF and
resampling analyses of thyrotropin- indicated no significant effects
involving group (group main effect, F2,11.25 = 0.98; P = .40; group x sex interaction, F2,11.24 = 0.37; P = .70) (Table 2).
The ANOVAs and resampling analyses of thyrotropin-ß and thyrotropin-ß/thyrotropin-
indicated no significant effects involving group (thyrotropin-ß group
main effect, F2,22 = 0.28, P = .76; thyrotropin-ß
group x sex interaction, F2,22 = 0.48, P = .62; thyrotropin-ß/thyrotropin- group main effect,
F2,22 = 0.71, P = .50; thyrotropin-ß/thyrotropin-
group x sex interaction, F2,22 = 1.18; P = .33).
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Table 2. Immunoreactive Thyrotropin Subunit Measures During Sleep Deprivation*
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TWO-YEAR FOLLOW-UP EVALUATION
Five subjects were taking antidepressants and 3 (1 female and 1 male
responder and 1 female nonresponder) fulfilled MDD criteria. None had clinical
hypothyroidism, goiter, or detectable antithyroid antibodies. One male responder
had a low triiodothyronine level but a midnormal thyrotropin level. Three
patients (2 responders and 1 nonresponder) had minimally elevated serum thyrotropin
level (4.29 to 4.73 mU/L); their other thyroid indexes were normal. The serum
thyrotropin levels of responders (2.48 ± 1.15 mU/L), 4 available nonresponders
(2.92 ± 1.23 mU/L), and controls (1.53 ± 0.66 mU/L) did not
differ significantly (F2,21 = 2.74; P
= .09; responders vs nonresponders, t21
= 0.64; P = .53).
SERUM CORTISOL
Mean nocturnal serum cortisol concentrations demonstrated a normal circadian
increase in all groups (time, F2,42 = 39.72; P<.001). Cortisol levels were similar and normal in all groups (responders,
256 ± 68 nmol/L; nonresponders, 281 ± 70 nmol/L; controls, 238
± 39 nmol/L [group main effect, F2,21 = 1.65; P = .22]).
COMMENT
Consistent with previous reports,1, 2, 53
56% of our patients with MDD responded to 1 night of SD. Serum thyrotropin
level increased during SD in all 3 groups, reaching a peak between 2:15 AM
and 6 AM, confirming previous reports.54 The
elevated basal serum thyrotropin level in our SD responders increased in parallel
with that of nonresponders and controls during SD but was higher throughout
the sampling period; mean nocturnal serum thyrotropin level was above the
upper normal limit in responders, but in none of the nonresponders or controls.
The correlation of increased serum thyrotropin level with clinical response
was robust in our patients, consistent with some25, 26
but not all24, 27 studies. The changes
were limited to the HPT in our patients, since the circulating concentrations
of cortisol, which also has a circadian secretory pattern, were normal and
similar among the 3 groups. The results suggest that altered HPT function
either plays a role in MDD and the mood response to SD or is an epiphenomenon
reflecting altered HPT function in both.
The increased serum thyrotropin levels, normal thyroid hormone concentrations,
and exaggerated thyrotropin responses to protirelin stimulation in the SD
responders are consistent with subclinical primary hypothyroidism. This autoimmune
disorder occurs in about 5% of mostly postmenopausal women.55
Our patients had no evidence of autoimmune thyroiditis. Although the nocturnal
serum thyrotropin level of SD nonresponders was normal and they did not have
an exaggerated response to protirelin, their circulating thyrotropin had increased
bioactivity. Furthermore, 2 years after SD, no patient with MDD was hypothyroid.
If they had transient hypothyroidism caused by thyroiditis, it was of a kind
not previously described. Transient thyroiditis with hypothyroidism is rare
except post partum and is usually preceded by thyrotoxicosis.56, 57
However, the combination of increased serum thyrotropin level and normal serum
thyroid hormone levels may explain the proposed association between MDD and
subclinical primary hypothyroidism.12, 13, 14
Our results do not indicate central (ie, hypothalamic) hypothyroidism,
which is typified by high serum thyrotropin concentrations, low serum thyroid
hormone levels, an exaggerated response to protirelin, low thyrotropin B/I,
and high serum concentrations of free thyrotropin-ß subunit.58, 59, 60, 61 Our responders'
thyrotropin- and thyrotropin-ß subunit concentrations and thyrotropin-ß/thyrotropin-
ratios were not different from those of nonresponders or controls. Moreover,
our results are not consistent with resistance to thyroid hormone action involving
the pituitary gland, peripheral tissues, or both.62, 63
We were surprised to find that responders had normal and nonresponders
had increased thyrotropin B/I ratios; we anticipated decreased and normal
ratios, respectively. Increased thyrotropin bioactivity, caused by decreased
terminal sialic acid residues on thyrotropin carbohydrate side chains, occurs
in healthy third-trimester human fetuses and patients with thyroid hormone
resistance.64, 65 Decreased bioactivity
caused by increased sialylation is found at night in healthy subjects and
during daytime in hypothyroid patients; the latter is reversed with long-term
thyroxine administration.65, 66 Our
finding of increased thyrotropin bioactivity without evidence of thyroid hormone
resistance in an adult is unprecedented.
Sleep deprivation responders had exaggerated serum thyrotropin responses
to protirelin, and nonresponders had normal responses but greater thyrotropin
bioactivity; none had a blunted response. Previous studies, in which protirelin
usually was administered at 9 AM, report that about 30% of depressed patients
have blunted thyrotropin responses.10, 11
Some studies report higher afternoon than morning responses to protirelin
in patients with MDD.67, 68, 69
Thus, our results may reflect either the timing of the protirelin injection
or an effect of SD.
Our results suggest 2 different HPT phenomena, one associated with MDD
and the other with the mood response to SD. The thyroid gland of patients
with MDD appears to be resistant to thyrotropin action. This represents a
novel form of transient compensated primary hypothyroidism with an unknown,
but presumably central, mechanism. Although the HPT of patients with MDD appears
to respond appropriately by increasing the level of biologically active thyrotropin,
SD responders and nonresponders accomplish this by different means. Sleep
deprivation responders appear to increase their serum thyrotropin concentration
by increasing secretion of thyrotropin with normal bioactivity. In contrast,
SD nonresponders appear to increase the bioactivity of their thyrotropin without
increasing their thyrotropin secretion or serum thyrotropin concentration.
The mechanism producing this phenomenon is also unknown. Perhaps a difference
in the secretion or action of a protirelin antagonist mediates the different
pituitary thyrotropin responses in the 2 groups.
The fact that increased nocturnal serum thyrotropin concentrations were
limited to female patients with MDD is provocative. However, the small sizes
of the groups of men and women mandate that any conclusions about sex differences
be considered tentative.
The nature of the thyroid gland resistance to thyrotropin, the mechanisms
that determine why and how individual patients with MDD increase either their
thyrotropin secretion rate or their thyrotropin bioactivity to compensate
for this resistance, and the relationship of these 2 mechanisms to MDD and
SD response or nonresponse remain to be determined.
AUTHOR INFORMATION
Accepted for publication August 4, 2000.
These studies were supported in part by research grants DK33334, MH45173,
MH01741, and RR00095 from the National Institutes of Health, Bethesda, Md;
grant AA07732 from the National Institute on Alcohol Abuse and Alcoholism,
Bethesda; and Veterans Affairs Medical Research Funds from the Department
of Veterans Affairs, Washington, DC.
Presented in part at the annual meeting of American College of Neuropsychopharmacology,
San Juan, Puerto Rico, December 12, 1991, and the XVIIIth Collegium Internationale
Neuro-Psychopharmacologicum Congress, Nice, France, July 1, 1992.
We thank the National Institute of Diabetes and Digestive and Kidney
Diseases, Bethesda, and Albert F. Parlow, PhD, for human thyrotropin-
and human thyrotropin-ß radioimmunoassay reagents; William J. Kovacs,
MD, for preparing the figures; and Nosa Ekhator, Donna Burns, Bette Hawkins,
Mary Farley, Lee Allard, and the Vanderbilt General Clinical Research Center
staff for technical support.
From the Departments of Medicine (Drs Orth and Loosen and Mr Nicholson)
and Psychiatry (Drs Shelton and Loosen), Vanderbilt University Medical Center,
Nashville, Tenn; Istituto di Scienze Endocrine, Ospedale Maggiore Istituto
di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy (Dr Beck-Peccoz);
Department of Psychology, Vanderbilt University, Nashville (Dr Tomarken);
Universitá di Milano, Istituto Auxologico Italiano IRCCS, Milan (Dr
Persani); and Psychiatry Service,Veterans Affairs Hospital, Nashville (Dr
Loosen).
Corresponding author: Peter T. Loosen, MD, PhD, Psychiatry Service
(116A), Department of Veterans Affairs Medical Center, 1310 24th Ave S, Nashville,
TN 37212-2637 (e-mail: ptloosen{at}aol.com).
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