Do thyroid hormones mediate the effects of starvation on mood in adolescent girls with eating disorders?

Psychoneuroendocrinology (2010) 35, 1517—1524

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n

Do thyroid hormones mediate the effects of starvation on mood in adolescent girls with eating disorders? Ingemar Swenne a,*, Agneta Rosling b a b

Dept. of Women’s and Children’s Health, Uppsala University Children’s Hospital, S-751 85 Uppsala, Sweden Dept. of Neuroscience, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden

Received 25 January 2010; received in revised form 18 May 2010; accepted 19 May 2010

KEYWORDS Eating disorder; Anorexia nervosa; Depression; Thyroxine; Triiodothyronine; Thyroid-stimulating hormone

Summary In the eating disorders (ED) comorbid depression is common and clinical experience suggests that it is partly related to starvation. Starvation affects thyroid hormone status and thyroid hypofunction is in turn associated with depressed mood. We have therefore investigated the possibility that thyroid hormones and starvation are associated with mood in ED. Two-hundred and thirty-nine adolescent girls were examined at presentation of an ED. Analyses of thyroid hormones, documentation of weight and weight changes, self-reports of depressive symptomatology and clinical diagnoses of ED and depression were used in the analyses. Of the 239 girls 100 were diagnosed with depression. The girls with and without depression did not differ in age, weight, height, body mass index (BMI), weight loss or duration of disease. Plasma free thyroxine concentrations were lower in depressed girls (11.9  1.7 versus 12.8  1.9 pmol/L; p < 0.01). Plasma triodothyronine and thyroid-stimulating hormone concentrations did not differ between groups. In a logistic regression analysis the odds ratio for depression was 41.1 (95% confidence interval 4.18—405; p = 0.001) for a 10 pmol/L change of plasma free thyroxine after correction for BMI, weight loss, duration of disease, rate of weight loss, plasma triodothyronine and an interaction between BMI and plasma free thyroxine. BMI did not predict depression. Low circulating thyroxine concentrations may provide a link between starvation and depression in adolescent girls with ED. # 2010 Elsevier Ltd. All rights reserved.

In the eating disorders (ED) depression is a common comorbid condition (Hudson et al., 2006; Godart et al., 2007). Starvation depresses mood in healthy individuals (Keys et al., 1950) and extensive clinical experience suggests that depression is related to restricted eating and weight loss in ED. This is

* Corresponding author. Tel.: +46 18 6115892; fax: +46 18 6115853. E-mail address: [email protected] (I. Swenne).

supported by the observation that in patients with ED malnutrition and weight loss exaggerates depressive mood and anxiety and that there is a reduction, although often a persistence, of such symptoms following nutritional rehabilitation. However, direct relationships between mood and a parameter assessing nutritional status, such as body mass index (BMI) or weight loss, have only occasionally been reported (Eckert et al., 1982; Miyasaka et al., 2003; Konstantynowicz et al., 2005).

0306-4530/$ — see front matter # 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2010.05.005

1518 Thyroid hormone status has been related to depression by several lines of evidence. Hypothyroidism, even marginal subclinical hypothyroidism, is associated with an increased risk of depression (Haggarty et al., 1993; Larisch et al., 2004; Bono et al., 2004; Konstantinos et al., 2006). In established depression low circulating thyroid hormones and elevated TSH are related to poor response to treatment, poor outcome and increased risk of relapse (Joffe and Marriot, 2000; Gitlin et al., 2004; Abulseoud et al., 2007). Finally, pharmacological antidepressive therapy has in several studies been augmented by addition of triiodothyronine (T3) medication (DeBattista and Lembke, 2005; Lifschytz et al., 2006; Nierenberg et al., 2006; Abraham et al., 2006). A body of experimental evidence showing how thyroid hormone action influences brain metabolism (Iosifescu et al., 2008) and serotoninergic transmission (Bauer et al., 2002) unifies these observations. Circulating thyroid hormones are sensitive to nutritional status. In ED with weight loss there is typically low T3, low/ normal thyroxine (T4) and normal thyroid-stimulating hormone (TSH) (Moshang et al., 1975; Miyai et al., 1975; Croxson and Ibbertsson, 1977; Leslie et al., 1978; DeRosa et al., 1983; Tamai et al., 1986; Bannai et al., 1988; Kiyohara et al., 1989; Støving et al., 2001; Onur et al., 2005; Swenne et al., 2009). This is a configuration commonly seen in different non-thyroidal illnesses (McIver and Gorman, 1997) and has also been observed in depressed patients (Premachandra et al., 2006). The circulating concentrations of T3 and to some extent T4 are related to weight and weight changes (Leslie et al., 1978; Swenne et al., 2009) which raises the possibility that effects of starvation on mood could be mediated by thyroid hormones (Brambilla et al., 2006). We have investigated the relationship between mood, weight changes and thyroid hormone status in a large group of adolescent girls presenting with ED.

1. Method

I. Swenne, A. Rosling lyses of thyroid hormones, growth charts, the self-report ˚ sberg Depression Rating Scaleinstrument Montgomery—A ˚ sberg, 2001) and clinSelf-Report (MADRS-S) (Svanborg and A ical diagnoses were available for 239/257 (93%) of the remaining girls. MADRS-S is an easily used and well-validated self-rating instrument for depression. It consists of nine items each scored 0—6, the higher scores indicating more severe depressive symptomatology. With a maximum score of 54 a healthy reference population scores <10 and those with a moderate— ˚ sberg, 2001). severe depression usually >20 (Svanborg and A In departmental routines a MADRS-S score > 18 has been taken to indicate a mood depressed to a degree which warrants clinical psychiatric assessment of a putative depression. MADRS-S scores were therefore categorised as ‘‘not depressed’’ (score  18) or ‘‘depressed’’ (score > 18). Depression was diagnosed according to DSM-IV (American Psychiatric Association, 1994) criteria for a ‘‘major depressive episode’’ except for that criterion D, ‘‘symptoms are not due to the direct physiological effects of a general medical condition’’ (i.e. in this case starvation), was not applied in the assessment. ED was diagnosed according to DSM-IV criteria. The weight criterion for anorexia nervosa (AN) in adults is a body mass index (BMI) below 17.5. This corresponds to a BMI standard deviation score (SDS) below —2.00 (Lindgren et al., 1995). This BMI SDS was used as the weight criterion for the growing teenagers presently assessed (Hebebrand et al., 2004). In a 16-year-old girl BMI SDS below —2.00 would correspond to approximately BMI 16.5, in 14-year-old girl approximately BMI 15.5 and in 12-year-old girl approximately BMI 14.3. The Eating Disorders Not Otherwise Specified (EDNOS) group of DSM-IV was further subdivided. EDNOSA represents an ED with features of AN but with one of the criteria, most often the weight criterion, not fulfilled. EDNOSB represents an ED with features of bulimia nervosa (BN) but with one of the criteria, usually the frequency of bingeing, not fulfilled. The remaining ED were denoted EDNOS.

1.1. Assessment of new patients 1.2. Analysis of growth charts The Child and Adolescent Eating Disorders Unit at the Uppsala University Hospital treats all patients under the age of 18 of the county (population 270 000) with eating disorders. Patients were first subject to a careful medical history and physical examination. At this first assessment blood sampling was performed to exclude somatic disease and to evaluate to what extent starvation had compromised metabolism and organ function. Copies of growth charts from the school health services provided information on previous growth and helped to establish the course of weight change, which in most cases was what prompted the first consultation. Psychiatric diagnoses were established at subsequent clinical interviews with patients and parents by a child and adolescent psychiatrist. They were performed without the use of structured instruments but supported by self-report instruments. During the period 2004—2007 a total 282 patients were assessed. Sixteen boys and nine patients with chronic somatic diseases (three with coeliac disease, two with hypothyroidism, two with rheumatoid arthritis and two with type 1 diabetes) were not included in the present analysis. Eleven of the patients were on antidepressant medication, usually fluoxetine. No patient had any other medication, which could influence thyroid function. Data including ana-

From the growth charts a recorded maximal weight could be obtained. It had been reached less than a year before the first assessment for 138 (54%) of the patients. Timing of menarche was established by patients/parents recall and often corroborated by notes on the growth charts. Weight loss was calculated as the difference between maximal recorded weight and weight at assessment. Duration of weight loss was calculated as the difference in time between the maximal recorded weight and the assessment. Rate of weight loss was calculated as weight loss divided by duration. BMI was calculated as weight/length2 (kg/m2). Measures of weight, stature and BMI were recalculated into standard deviation scores (Lindgren et al., 1995). The rationale for using SDS is to compensate for differences in age and height of growing individuals. Weight SDS could then be regarded as weight corrected for age and BMI SDS as weight corrected for age and height.

1.3. Analyses of thyroid hormones Non-fasting blood samples were analysed for plasma T3, plasma free T4 (fT4) and plasma TSH by the immunoassays in use for routine analysis at the Department of Clinical

Do thyroid hormones mediate the effects of starvation on mood in adolescent girls with eating disorders? Chemistry at the time of sampling. For analysis of TSH this was up to January 2005 Advia Centaur TSH-3 and from January 2005 Abbot Architect. For fT4 it was up to January 2005 Advia Centaur and from January 2005 Abbot Architect. For T3 it was up to January 2005 Advia Centaur and from January 2005 Abbot Architect. The correlation and stability of the assays were continuously reviewed. The total assay variation in the individual assays was less than 5% (total CV < 5). The reference range for T3 was 1.2—1.8 nmol/L, for fT4 9—18 pmol/L and for TSH 0.3—4.0 mIU/L.

1.4. Ethics The protocol was approved by the Ethics committee of the Faculty of Medicine of Uppsala University.

1.5. Statistical analysis All data were analysed using SPSS version 15.0.1. Values are means  SD. Predictors of depression were analysed using a logistic regression analysis.

2. Results Of the 239 patients with ED 100 (42%) were diagnosed with depression and had higher MADRS-S scores (Table 1). Forty had AN and 18 (45%) of these were depressed. Nine patients Table 1 Weight, weight changes, serum thyroid hormones and MADRS-S score in adolescent girls presenting with eating disorders. Depressed (n = 100)

Not depressed (n = 139)

Age (years)

15.4  1.5

15.1  1.7

Weight (kg) Height (m) BMI (kg/m2)

49.6  8.6 1.64  0.08 18.5  2.8

49.2  8.9 1.64  0.08 18.1  2.6

0.69  1.09 0.09  1.10 0.84  1.30

0.61  1.12 0.17  1.03 0.95  1.25

Weight (SDS) Height (SDS) BMI (SDS) Weight loss (kg) Duration (days) Rate of weight loss (g/day)

6.8  6,4 402  331 26  34

6.6  5.6 358  313 31  32

1.49  0.51

1.39  0,47

Plasma triiodothyronine (nmol/L) Plasma free thyroxine (pmol/L) Plasma TSH (mIU/L)

11.9  1.7

12.8  1.9 **

1.42  0.85

1.37  0.74

MADRS-S score

26.3  6.8

10.6  6.2 ***

Values are means  SD for the number of assessments indicated. BMI, body mass index; SDS, standard deviation score; MADRS-S, ˚sberg Depression Rating Scale-Self-Report. Montgomery—A ** p < 0.01 (significance of difference between depressed and not depressed patients). *** p < 0.001 (significance of difference between depressed and not depressed patients).

1519

had BN of whom seven (76%) were depressed. A majority of the patients were in the EDNOS groups: EDNOSA 24/63 (38%) patients were depressed, EDNOSB 5/12 (42%) patients were depressed and EDNOS 44/115 (39%) patients were depressed. The documented top weight was registered approximately a year before assessment. Average weight loss was just below 7 kg and did not differ between depressed and not depressed patients. At assessment patients were underweight but of average stature as evidenced by height SDS around zero and weight SDS and BMI SDS significantly ( p < 0.001) below zero. In these measurements there were no differences between depressed and not depressed patients. Of the 239 girls 28 had not reached menarche at assessment, 7 (25%) of these were depressed. Of postmenarcheal girls 76 had secondary amenorrhea defined as absence of menstruations for at least three months, 31 (41%) of these were depressed. One-hundred sixteen did not have amenorrhea by this definition, 53 (46%) were depressed. A further 19 were on hormonal contraceptives and nine (47%) were depressed. Plasma T3 concentrations were in the lower end of the reference range or below it. Seventy-five (31%) of the patients had T3 concentrations below the reference range but there was no difference between depressed and not depressed patients (Table 1). Plasma fT4 concentrations were in the lower two-thirds of the reference range but only one of the patients was below it (Fig. 1). FT4 concentrations were lower in the depressed patients ( p < 0.01). Plasma TSH concentrations were within the reference range for all patients and did not differ between groups. Depression was entered as the dependent variable in a logistic regression analysis against the independent variables plasma fT4 and BMI SDS, the latter being a measure of leanness corrected for age and height. Odds ratios (OR) were calculated for one-unit changes of BMI SDS. In a 165 cm tall 15-year-old girl a weight loss from +1 BMI SDS to —1 BMI SDS would correspond to a loss of 13.3 kg. OR were calculated for 10-unit changes of fT4, approximately corresponding to the full span of the reference range of this hormone. There was a relationship between depression and low fT4 (OR 10.4; confidence interval (CI) 2.14—50.5; p = 0.004) but no relationship between depression and BMI SDS (Table 2). BMI SDS is a point measure of leanness and does not take into account the magnitude of weight loss, the duration of weight loss or the rate of weight loss. Correction of the model for these variables, however, did not alter the OR. It is furthermore conceivable that there could be an interaction between fT4 and BMI SDS, i.e. fT4 would have different relationships with depression at different BMI SDS. When the model was corrected for such an interaction fT4 remained the significant predictor and the relationship with depression was strengthened (OR 19.2; CI 2.24—164; p = 0.007). When, in addition to this, the model was corrected for T3 the relationship between fT4 and depression was further strengthened (OR 41.1; CI 4.18—405; p = 0.001). Self-reported depressive symptoms were analysed in a similar manner. MADRS-S scores were categorised as ‘‘not depressed’’ (score  18) or ‘‘depressed’’ (score > 18) and entered as the dependent variable in the logistic regression. When fT4 and BMI SDS were entered as independent variables there was a positive relationship between fT4 and high MADRS-S scores (OR 6.89; CI 1.59—33.1; p < 0.012) (Table 2). Correction for weight changes, for an interaction

1520 [(Figure_1)TD$IG]

I. Swenne, A. Rosling

Figure 1 Plasma free thyroxine concentrations in adolescent girls presenting with an eating disorder and weight loss. The presence (*) or absence (*) of comorbid depression is indicated. Dashed lines indicate the reference range of the thyroxine assay.

between fT4 and BMI SDS and for T3 strengthened this relationship (OR 24.8; CI 2.76—222; p = 0.004). If the cutoff score for depression was changed in the interval 15—22 the outcome of the analysis was only little altered. When similar analyses were performed with T3 or TSH as dependent variables no significant relationships with depression or MADRS-S scores could be demonstrated.

3. Discussion The present data confirm the association between thyroid hormone status and depression (Konstantinos et al., 2006). Of the hormones analysed circulating TSH and T3 concentrations were, however, not associated with depression or selfreported symptoms associated with depressed mood. In non-thyroidal illness circulating T3 and T4 concentrations decrease but there is not an increase of TSH although the inhibiting feedback of the peripheral hormones is diminished. This could indicate that circulating T3 and T4 are appropriate for the prevailing condition, if not, TSH would have increased (McIver and Gorman, 1997; Danforth and Burger, 1989). An alternative interpretation of the present data would be that there is a central effect on TSH secretion (Bianco and Kim, 2006). This would obviate the use of TSH concentrations to evaluate thyroid hypofunction during starvation and explain why an association between circulating TSH and depression could not be demonstrated. At variance with a previous investigation (Brambilla et al., 2006) circulating T3 concentrations were not related to depressed mood. However, circulating T3 concentrations increase rapidly, within days, during refeeding but decrease instantly during periods of negative energy balance (O’Brian et al., 1980; Hugues et al., 1984; Jahreis et al., 1991; Loucks and Heath, 1994 Swenne et al., 2009). A depressed mood recovers more slowly and may therefore be difficult to relate the rapidly changing circulating T3 concentrations. More-

over, in view of that 80% of circulating T3 is derived from deiodination of T4 in the liver it cannot be expected to reflect the intracerebral T3 concentration and its effects (Hulbert, 2000). The largest proportion of brain T3 is produced by local deiodination of T4 by the type 2 iodothyronine deiodinase (D2), the only enzyme of its kind present in the human brain (Bianco et al., 2002). The association between fT4 and depression would be understood if it were assumed that circulating fT4 concentrations represent a measure of T4 supplied to the brain for local deiodination into T3 which, in turn, would exert its effects locally in the central nervous system. A low supply of T4 would then generate lower intracerebral concentrations of T3. There is indeed evidence to support that the availability of T4 influences the tissue concentration of T3 (Escobar-Morreale et al., 1995; CamposBarros et al., 1996; Kester et al., 2004; Peeters et al., 2005a). Moreover, if deiodination of T4 by D2 is reduced in nonthyroidal illness (Bianco et al., 2002; Maia et al., 2005) this would further decrease intracerebral T3. The present observation of that a correction for an interaction between fT4 and BMI SDS strengthens the relation between fT4 and depression supports the view that T4 has different effects on mood at different degrees of leanness, i.e. that less T4 is converted when BMI is low. It is furthermore conceivable that circulating T3 may supplement T3 derived from local conversion of T4. T3 was not independently related to depressed mood but correction of the model for T3 strengthened the relationship between T4 and depression. This is suggestive of that preformed, circulating T3 has a minor role for thyroid hormone status in the central nervous system and may explain why in a previous report a relationship between T3 and mood could be demonstrated (Brambilla et al., 2006). It is in this context noteworthy that in patients on replacement therapy with thyroxine psychological well-being is related to circulating fT4 but not to fT3 (Saravanan et al., 2006). This supports the

Do thyroid hormones mediate the effects of starvation on mood in adolescent girls with eating disorders?

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Table 2 Odds ratio for depression/self-reported depressive symptoms in relation to leanness and plasma free thyroxine concentration in adolescent girls presenting with an eating disorder. Dependent variable

Independent variables

Corrections

OR

Depression

Plasma free thyroxine BMI SDS

—

10.4 0.90

2.14—50.5 0.73—1.11

0.004 0.328

Depression

Plasma free thyroxine

Weight loss, duration, rate of weight loss

10.0

2.05—48.9

0.004

0.72—1.11

0.317

2.24—164

0.007

0.07—2.36

0.306

4.18—405

0.001

0.54

0.087—3.37

0.511

BMI SDS Depression

Plasma free thyroxine

0.89 Weight loss, duration, rate of weight loss Interaction between BMI SDS and free plasma thyroxine

BMI SDS Depression

Plasma free thyroxine

19.2

0.392 Weight loss, duration, rate of weight loss Interaction between BMI SDS and free plasma thyroxine Serum triiodothyronine

BMI SDS

41.1

95% CI

P

MADRS-S > 18

Plasma free thyroxine BMI SDS

—

6.89 0.90

1.52—31.2 0.73—1.11

0.012 0.309

MADRS-S > 18

Plasma free thyroxine

Weight loss, duration, rate of weight loss

7.37

1.61—33.7

0.010

0.91

0.74—1.13

0.396

1.33—80.5

0.026

0.10—3.37

0.556

2.76—222

0.004

0.15—5.22

0.390

BMI SDS MADRS-S > 18

Plasma free thyroxine

Weight loss, duration, rate of weight loss Interaction between BMI SDS and free plasma thyroxine

BMI SDS MADRS-S > 18

Plasma free thyroxine

10.3

0.59 Weight loss, duration, rate of weight loss Interaction between BMI SDS and free plasma thyroxine Serum triiodothyronine

BMI SDS

24.8

0.910

˚ sberg Depression OR, odds ratio; CI, confidence interval; BMI, body mass index; SDS, standard deviation score; MADRS-S, Montgomery—A Rating Scale-Self-Report.

view that systemic provision of T4 for local use in the central nervous system is important for mood and that circulating T3 may not reflect intracerebral thyroid hormone status. This notion is not entirely uncontroversial since there is some evidence to indicate an association between depression and total T4 in the high normal range in healthy adult populations (Bunevicˇius, 2009). The relationship between thyroid function and mood may, however, be different in healthy individuals compared to those with an ED and evidence of starvation. Clinical experience and also experiments in volunteers (Franklin et al., 1948) indicate that undernutrition and weight loss depresses mood. There are, however, only occasional reports to demonstrate a direct relationship between measures of body weight/BMI and mood in patients with ED (Eckert et al., 1982; Miyasaka et al., 2003; Konstantynowicz et al., 2005). Restrictive eating behaviour may, however, influence thyroid hormone status and mood even if body

weight changes only little (Laessle et al., 1996). Indeed, the intermittent restrictive eating behaviour in bulimia nervosa decreases circulating T3 and T4 concentrations even though an average weight in the normal range is maintained (Pirke et al., 1985; Laessle et al., 1988; Kiyohara et al., 1988; Altemus et al., 1996; Gendall et al., 2003). It is therefore conceivable that thyroid hormones form a link between disturbed eating, starvation and depression even though a direct relationship between mood and weight changes is not always apparent. Although the relationship between fT4 and depressed mood presently demonstrated is highly significant the difference in plasma fT4 concentrations between the depressed and non-depressed groups is small. This considerable overlap of plasma fT4 concentrations indicates a mechanism not accounted for in the present investigation. One such possibility would be a difference in the ability of the D2 enzyme to convert T4 into T3. There are indeed polymorphisms in the D2

1522 gene, which confer a reduced enzymatic velocity to the gene product and influence circulating T4 concentrations (Peeters et al., 2005b; Canani et al., 2005). If such a gene would reduce D2 activity in the brain less intracerebral T3 would be produced (Bunevic ˇius and Prange, 2010). This would be evident especially when T4 supply is reduced, as it is during starvation, and would explain why mood is influenced during weight loss. The polymorphism would thus confer an increased risk of developing depression, which would not be apparent until challenged by starvation. An alternative or complementary explanation would be alterations in the ability to transport thyroid hormones into the cells. There are polymorphisms of the human thyroid hormone transporter gene MCT8 but little is known as to how they influence circulating thyroid hormone concentrations and intracerebral T3 availability (Van der Deure et al., 2010; Bunevic ˇius and Prange, 2010). Again, when challenged by starvation and reduced availability of circulating thyroid hormones minor alterations in this transport capacity may become clinically significant. The unresponsiveness of depression to pharmacological treatment in starving patients can be understood against the background of a diminished T4 supply. A decreased local production of T3 is likely to diminish the effect of selective serotonin reuptake inhibitors (Bauer et al., 2002; Lifschytz et al., 2006). A sustained normalisation of eating behaviour and restoration of body weight may therefore be the most important first step in the treatment of an eating disorder with comorbid depression. Once achieved, thyroid hormone status would be expected to have improved and the patient would be accessible to pharmacological and other treatments of both the ED and the depression.

Role of funding sources This work was supported by HRH Crown Princess Lovisas Fund for Child Health Care, the Gillbergska Foundation, the First of May Flower Annual Campaign, professor Bror Gadelius Memorial Foundation, the Sven Jerring Foundation and Uppsala University. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in writing the report; or in the decision to submit the paper for publication.

Contributors The authors planned and performed data collection together. The first author performed the statistical analyses and wrote the manuscript. The second authors read all manuscript drafts and made comments to forward the finalisation of the paper. Both authors have thus contributed to and approved of the final manuscript.

Conflict of interest The authors reported no biomedical financial interests or other potential conflicts of interest.

Acknowledgement The authors do not wish to state any specific acknowledgements.

I. Swenne, A. Rosling

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