The prognostic significance of thyroid function in mania

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<ul><li><p>J. psychiat. Res., Vol. 25, No. 1/2, pp. 1-6, 1991. 0022-3956/91 $3.00 + .00 Printed in Great Britain. 1991 Pergamon Press plc </p><p>THE PROGNOSTIC S IGNIF ICANCE OF THYROID FUNCTION IN </p><p>MANIA </p><p>PETER R . JOYCE </p><p>University Department of Psychological Medicine, Christchurch School of Medicine, P.O. Box 4345, Christchurch, New Zealand </p><p>(Received 21 February 1990; revised 5 September 1990) </p><p>Summary--Free thyroxine index (FT4I) and thyroxine (T4) levels were measured in 31 manic patients shortly after admission to a psychiatric hospital. Over one-third had elevated thyroid hormone levels, and this was largely due to increases in FT4I. Increased FT4I levels were associated with greater sleep disturbance and with being male, and were negatively associated with having had hospital admissions in the past six months. More interestingly, however, low FT4I levels prospectively predicted more hospital admissions in the 12 months from index admission, and this was not due to past admissions predicting future admissions. This adds to the growing literature on important relationships between thyroid hormones and treatment outcome in patients with affective disorders. </p><p>Introduction </p><p>A RE~ATIONSI-In" between thyroid disease and mood disturbance has long been recognized, and both hypothyroidism and hyperthyroidism are part of the differential diagnosis of depression and mania. This has resulted in the frequent evaluation of thyroid function in acutely disturbed psychiatric patients, and to the realization that many acute psychiatric patients have elevated thyroid function tests but do not have thyroid disease. This so-called euthyroid hyperthyroxinaemia occurs not only in acute psychiatric illness but also in a variety of other acute medical disorders (Borst, Eil, &amp; Burman, 1983). A number of studies (Cohen &amp; Swigar, 1979; Levy, Jensen, Laus, Agle &amp; Engel, 1981; Spratt et al., 1982) have documented that an elevated free thyroxine index (FT4I) and/or thyroxine (T4) occurs in 9-3370 of acute psychiatric admissions. These abnormalities seldom reflect thyroid disease and usually return to normal over a period of a few weeks. However, the psychiatric correlates of these abnormalities have seldom been looked at in detail, and where diagnostic information was available, all affective disorders were lumped together (e.g. Spratt et al., 1982). Very little information appears to be available on the prevalence of hyperthyroxinaemia in manic patients and whether thyroid status is related to any clinical features in manic patients. </p><p>At the opposite end of the spectrum of thyroid activity is the hypothyroid state, and there has been recent interest in the observations that sub-clinical hypothyroidism may be especially associated with rapid-cycling bipolar affective disorder (Extein, Pottash, &amp; Gold, 1982; Cowdry, Wehr, Zis, &amp; Goodwin, 1983; Alarcon, 1985; Roy-Byrne, Joffe, Uhde, &amp; Post, 1985; Tapp, 1988). Furthermore, it has been suggested that hypermetabolic doses of thyroxine may be of benefit in treating rapid-cycling bipolar affective disorder (Stancer &amp; Persad, 1982; Extein &amp; Gold, 1988). </p></li><li><p>2 PETER R. JOYCE </p><p>We were therefore interested in measuring thyroid activity in acutely admitted manic patients and documenting the prevalence of hyperthyroxinaemia, with a view to seeing whether this condition is related to certain symptoms of mania, to past history of illness, or to prospective history of readmission. </p><p>Methods </p><p>Patients aged 16-65 inclusive who were admitted from the community to an acute ward in a psychiatric hospital, with a diagnosis of mania using DSM-III criteria, were included in this study. During the first four days of hospitalization, blood was drawn for thyroid function tests; thyroxine (T4) was measured by radioimmunoassay and the free thyroxine index (FT4I) was calculated. Patients' mania was assessed on admission using the Bech- Rafaelsen mania scale (Bech, Bolwig, Kramp, &amp; Rafaelsen, 1979). Data were also collected on the duration of the manic episode prior to admission and the number of hospital admissions in the past six months, two years, five years and lifetime. </p><p>A year later, each patient's notes were checked for further admissions to this hospital. If there were any grounds for suspecting patients had been admitted to the one other hospital with an acute in-patient psychiatric ward within the region, then this was checked. In two instances, we became aware and were able to confirm that patients had been admitted to hospitals outside the region. </p><p>Results are expressed as mean 4-SD. Statistical analyses were performed using SYSTAT on an IBM PC compatible computer. </p><p>Results Prevalence of hyperthyroxinaemia </p><p>During the course of this study, complete data were collected on 31 manic patients (17 males and 14 females). The mean thyroxine (T4) level was 116 4- 23 nmol/L, and only two patients had T4 levels above the normal upper limit of 140 nmol/L" the mean free thyroxine index (FT4I) was 145 4- 40, and nine patients had FT4I levels above the normal upper limit of 160. Of the nine patients with an elevated FT4I level, six were males. FT4I levels were significantly higher in males (158 4- 42) than females (128 4- 31) (t = 2.22, p &lt; .05). Altogether, 10 manic patients (327o) had an elevated T4 and/or FT4I level. No manic patients had T4 or FT4I levels even approaching the lower limit of the normal range. </p><p>Relationship between thyroid activity and manic symptoms The majority of manic patients had been unwell in the present episode for less than one </p><p>month, and only three had had manic symptoms for over two months. The mean rating on the mania scale was 19 (4-8). T4 and FT4I levels were each correlated with 13 variables, namely duration of illness, the 11 manic symptoms, which are assessed in the mania scale, and total mania score. Only one correlation even reached a .05 level of significance, which was that FT4I did correlate with the item assessing sleep disturbance (r = 0.47, p &lt; .01). </p><p>Effect of lithium on thyroid activity Of the 31 manic patients, none of the seven first admissions, and 20 of the 24 </p><p>readmissions, had ever been prescribed lithium. Sixteen had been taking lithium in the six </p></li><li><p>Th"rROm FUNCTION IN MANIA 3 </p><p>months prior to admission, but ten of these patients had discontinued lithium at least one month prior to admission, leaving only six who had been on lithium regularly prior to admission, all of whom were still taking it when their thyroid function was assessed shortly after admission. Neither the six currently on lithium, nor the 16 who had been on lithium in the past six months, had significantly different T4 or FT4I levels to those patients not on lithium. </p><p>Relationship between thyroid activity and past admissions In this sample of manic patients, seven were having their first admission to hospital for </p><p>an affective disorder. Three had one past admission, five had two, nine had 3-10 past admissions and seven had over 10, with the greatest number being 26 past admissions. </p><p>As FT4I is calculated from T4, and as FT4I was more often elevated and was associated with sleep disturbance in mania, only FT4I was looked at in relationship to past history of admissions for affective disorder. From Table 1, which shows the Pearson correlation between FT4I and number of past admissions in the past six months, two years, five years and lifetime, it will be seen that FT4I was significantly inversely correlated with number of admissions in the past six months (r= .38, p &lt; .05). Furthermore, the FT4I was significantly lower in those who had been admitted in the past six months (120.7 24.7) than in those who had not been admitted (154.6 41.0; t= 2.82, p &lt; .01). Although the observation did not quite reach statistical significance, none of the nine patients who had had an admission within the past six months had an elevated FT4I, while nine of the patients without an elevated FT4I had been admitted within the past six months (X2= 2.85, p </p></li><li><p>4 PETER R. JOYCE </p><p>As both FT4I and numbers of past admissions were correlated with the likelihood of readmission, and as sex influenced FT4I levels, a multiple linear regression was performed, with number of readmissions as the dependent variable and FT4I, the number of admissions in the past five years, and sex as independent variables. From Table 3, it will be seen that both a low FT4I (t = -2.23, p &lt; .034), and number of admissions in the past five years (t = 2.07, p &lt; .048) significantly contribute to the prediction of readmissions. </p><p>Table 3 Multiple linear regression of number of prospective readmissions against FT41, number of past admissions over the past five years, and sex </p><p>Variable Standard Coefficient t p </p><p>FT4I -.40 -2.23 .034 Past admissions .35 2.07 .048 Sex .12 .66 .513 </p><p>Multiple R = .54, R2 = .29, F (3,27 dO = 3.67, p &lt; .024. </p><p>Discussion </p><p>The first finding from this study is that about one-third of acutely manic patients have elevated thyroid function tests, largely consisting of an elevated FT4I rather than T4. This finding is consistent with earlier reports (summarized in the Introduction) that up to one- third of acutely admitted psychiatric patients may have a euthyroid hyperthyroxinaemia. </p><p>FT4I values in these manic patients were correlated with the manic symptom of sleep disturbance but with no other individual symptom, to total manic severity or to duration of manic episode. Given that more than 20 correlations were carried out, it is possible that this is only a chance finding although, as this correlation was at the .01 level, such an interpretation on balance, is unlikely. Assuming that this is not a chance finding, it is of interest that a recent study of normal subjects found that FT4I correlates inversely with latency to REM induction by the cholinomimetic drug, arecoline, but a similar correlation was not found with T4 (Keshavan, Dube, Grabowski, &amp; Sitaram, 1988). Another study (Kaschka et al., 1989) has also reported that sleep deprivation in depression causes an increase in thyroxine and free thyroxine. Although it cannot necessarily be assumed that a similar relationship would be present in manic patients, further study of the connexion between thyroid hormones and sleep is required, as it is possible that the elevated FT4I is a consequence of the loss of sleep so often a feature of manic illness. </p><p>In these manic patients, more hospital admissions (a finding probably related to more affective episodes) within the past six months is associated with lower thyroid function. This correlation is of interest in the light of reports linking subclinical hypothyroidism with rapid cycling bipolar disorder (Extein et al., 1982; Cowdry et al., 1983). Perhaps, however, the relationship between episode frequency and lowered thyroid function is broader than just between subclinical hypothyroidism and rapid cycling, and extends to low normal thyroid function and increased episode frequency. </p><p>Although the significant correlation between admissions in the past six months and low </p></li><li><p>THYROID FUNCTION IN MAmA 5 </p><p>FT4I is of interest, it was even more notable that a low FT4I was a predictor of number of admissions in the 12 months following discharge from this index admission. This relationship between low FT4I and readmissions remained significant even when the well- known finding that past admissions predict readmissions is allowed for. Indeed, low FT4I was a stronger predictor of readmissions than number of admissions over the past five years. To confirm this finding, an analysis was also run on the relationship between FT4I and readmissions with the exclusion of those subjects with multiple past admissions (defined as two or less admissions in the past five years). In this sub-group of 21 manic patients, those readmitted had significantly lower FT4I levels than those not readmitted. Given that our sample is of limited size and that many factors contribute to readmission for bipolar patients, it is almost surprising that thyroid function alone is so predictive of readmission. Ideally, future studies should look more closely at FT4I levels and episode frequency, and not just hospital admissions. </p><p>In a recent study of thyroid function in schizophrenic and depressed patients, while many schizophrenics had an elevated T4 and/or FT4I, a finding not observed in the depressed group, among the latter, decreases in T4 and FT4I were correlated with clinical response of the depression (Baumgarter, Graf, Kurten, &amp; Meinfold, 1988). In an earlier study of carbamazepine in patients with affective illness, decreases in T4 and FT4I were greater in treatment responders than in non-responders (Roy-Byrne, Joffe, Udhe, &amp; Post, 1984). In both these studies, thyroid function was within the normal range, and yet changes in T4 and FT4I were associated with clinical improvement. A recent report describing a case of treatment-resistant mania with hypothyroidism which responded to thyroxine (Balldin, Berggren, Rybo, Kjellbo, &amp; Lindstedt, 1987) adds further weight to the possibility that variations in thyroid function are of importance in treatment response of affectively ill patients. </p><p>There is considerable evidence that thyroid function affects catecholamine metabolism and receptor activity, and it has been postulated that thyroid hormones are neuromodulators of adrenergic function (Whybrow &amp; Prange, 1981). Findings concerning the effect of thyroid hormones on central adrenergic systems suggest that they enhance alpha-adrenergic function but that effects on beta-adrenergic function are inconsistent. Given that antidepressants and other thymoleptic medications probably act via related adrenergic receptor changes, it is possible that thyroid hormones modulate the activity of such drugs. </p><p>In conclusion, this study has found that increased FT4I levels may be associated with sleep disturbance in mania and that patients with increased FT4I levels are much less likely to be readmitted to hospital after an index manic admission. When these results are combined with the others in the literature, it is possible that further studies on changes in thyroid activity at admission and during treatment may help in the prediction of outcome in affectively ill patients. </p><p>Acknowledgements--This research was supported by a grant from the Medical Research Council of New Zealand. I wish to acknowledge the help of the medical staff of Fergusson Clinic One at Sunnyside Hospital who assisted with the collection of these data and, in particular, to Drs. Paul Hobbs and Mark Oakley-Browne who shared consultant responsibility for the care of these patients. I wish to thank Mrs. Robyn Abbott for her help with collecting and collating the data. Thyroid hormone levels were measured in the Department of Nuclear Medicine at Christchurch Hospital. </p></li><li><p>6 PETER R. JOYCE </p><p>References </p><p>Alarcon, R. D. (1985). Rapid cycling affective disorders: a clinical review. Comprehensive Psychiatry, 26, 522-540. Balldin, J., Berggren, U., Rybo, E., Kjellb...</p></li></ul>

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