A study of thyroid profile in patients suffering from the first episode of mania: A cross-sectional study.

BACKGROUND: Thyroid function is commonly considered in the assessment of mood disorders. Reports of thyroid dysregulation in patients with mania are associated with several confounding factors. To eliminate confounding factors, studies of first-episode mania are desirable. This study tried to find out any relationship between thyroid disorders and mania. AIM: The aim of this study is to assess and compare the thyroid profile between first-episode mania and healthy controls and to ascertain the correlation between severity and duration of the manic episode with FT3, FT4, and thyroid-stimulating hormone (TSH) levels.
MATERIALS AND METHODS: This was a cross-sectional study conducted in the psychiatry department of a tertiary care hospital. Forty consecutive drug-naïve patients with first-episode mania, diagnosed according to the International Classification of Disease-10 (study group), were matched with 40 healthy controls (control group). Both the groups were compared on the basis of thyroid profile and thyroid levels were correlated with duration and severity of illness in the study group.
RESULTS: Nearly 7.5% of cases in the study group had hyperthyroidism, whereas 5% had subclinical hyperthyroidism. In contrast, normal controls showed 5% and 10% prevalence of hypothyroidism and subclinical hypothyroidism, respectively. A statistically significant lower level of TSH was observed in the study group (P < 0.001), whereas the mean serum levels of FT3 and FT4 were higher in the study group, but the difference was statistically nonsignificant. No significant correlation of thyroid hormones level with duration and severity of illness was noted.
CONCLUSION: Our findings highlight a higher prevalence of hyperthyroidism in patients with mania and suggest the role of thyroid hormones in mania. Copyright:

INTRODUCTION

Mania, such as depression, anxiety, and schizophrenia, is thought to be a disorder of unknown etiology.[1] Many studies have also found that drugs, metabolic disturbances, infection, neoplasm, and epilepsy could cause secondary mania.[23] In the Diagnostic and Statistical Manual of Mental Disorders-5, secondary mania is included in the category of “bipolar and related disorder due to another medical condition.” According to DSM-5 it is characterized by an episode of mania that should be attributable to a medical condition and should not chronologically precede the organic illness and the causal relationship between the symptoms and the condition should be plausible.[4]

For assessment of organic cause of mood disorders, thyroid hormone functions are commonly considered as these hormones can affect the developing brain. Advancement in biotechnology helps to get a better insight into their effects on the mature brain.[5] Thyroid disorders are commonly associated with various neuropsychiatric symptoms, such as affective and cognitive disturbances. Symptoms of depression, mood liability, anxiety, and sleep disturbances are usually associated with thyrotoxicosis or hyperthyroidism. However, overt psychiatric disorders are said to occur in approximately 10% of the patients.[56] Most of the studies were conducted on the relationship between thyroid functions and depressive disorders, and less attention was given to any association between thyroid disorder and mania. It has been suggested that mania is associated with hyperthyroidism with a prevalence between 2% and 5%.[7] Few studies have demonstrated an increased level of free thyroxin index and/or thyroxin in patients with bipolar mania.[89] Some case reports are also available that highlight the relationship between mania-like episodes and thyroid disorders.[101112]

The reports of thyroid dysregulation in patients with mania are associated with several confounding factors, including long-term effects of psychiatric illness, psychotropic drug treatment, substance abuse, and comorbid medical illness.[13] To eliminate many of these confounding factors, studies of first-episode mania are needed. Therefore, to find out any relationship between thyroid disorders and mania, this study was conducted in psychotropic drug-naïve patients suffering from first-episode mania who were matched against the normal population.

The term first-episode mania is used, which is synonymous with manic episode (F30) of International Classification of Disease (ICD) 10. This is characterized by episode of mania, which is not preceded by any depressive, manic, or hypomanic episode.[14]

The aim of the study was to evaluate and then compare the thyroid profile of patients with first-episode mania and healthy controls and also to ascertain the correlation between severity and duration of the manic episode with FT3, FT4, and thyroid-stimulating hormone (TSH) levels.

MATERIALS AND METHODS

Sample size is calculated at 80% study power and 0.05 α error, assuming minimum difference of means to be detected in TSH of bipolar I and control groups with combined standard deviation 1 ± 1.5 as per the result of reference article.[15] For minimum detectable mean difference in TSH of bipolar I and control, 35 participants are required in each group as sample size which is further rounded off as 40 participants in each group. Permission was taken from the research review board of the institute to conduct study.

Forty consecutive drug-naive patients with manic episode (F30, first-episode mania), diagnosed according to the ICD 10 (study group) presenting in the psychiatric center of a tertiary care hospital, were matched with 40 healthy controls, preferably person who accompanied the patient (control group). Willing participants in both groups were recruited after taking written informed consent and fulfilling inclusion and exclusion criteria. The severity of mania in the study group was assessed by Young Mania Rating Scale (YMRS). Blood samples were collected by a vacutainer from antecubital vein of all the participants after taking proper aseptic measures. Samples were collected in the morning hours (8–11 am) after an overnight fast and sent to the laboratory for the assessment of thyroid profile (FT3, FT4, and TSH). The reference range that was used: FT3 = 2.3–4.2 pg/ml, FT4 = 0.89–1.76 ng/dl, TSH = 0.35–5.5 uIU/ml. This was the reference range used by the laboratory while analyzing the samples.

Definition of thyroid disorders

Hyperthyroidism - Higher T3, T4 and lower TSH level from normal range[16]

Subclinical hyperthyroidism - Normal T3, T4 and lower TSH level from normal range[17]

Hypothyroidism - Lower T3, T4 and higher TSH level from normal range[18]

Subclinical hypothyroidism - Normal T3, T4 and higher TSH level from normal range.[19]

Inclusion criteria for case

Age between 10 and 60 years

Both gender

First episode of mania.

Exclusion criteria for case

Any past history of psychiatric illness and treatment

Any history of taking psychotropic drug for other reasons

Any history of chronic medical illness, and treatment

Known case of thyroid disorder

Substance use except for tobacco

Pregnant women.

Inclusion criteria for controls

Controls were matched on the basis of age and gender (preferably person who accompanied the patient, otherwise chosen from attendant of other patient).

Exclusion criteria for controls

Any history of psychiatric illness and treatment

Any history of taking psychotropic drug for other reasons

Any history of chronic medical illness and treatment

Known case of thyroid disorder

Substance use except for tobacco

Pregnant women.

The exclusion of thyroid disorder, psychiatric illness, and chronic medical illness was done on the basis of information provided by informants and participants.

Statistical analysis

Study and control groups were compared on the basis of data obtained. Kolmogorov–Smirnov test was used to determine whether the data were normally distributed. For nominal variables, mean ± standard deviation and percentage were used as the descriptive statistics. To assess the significance of the difference among mean values, Student's t-test was applied, and for nominal variables, Pearson's Chi-square was used. Spearman's correlation test was used to find any relationship between the continuous variables.

RESULTS

Both the groups had comparable sociodemographic characteristics.

Among a total of 40 patients of mania, 7.5% were found to be of hyperthyroidism while 5% had subclinical hyperthyroidism. In contrast, normal controls showed 5% and 10% prevalence of hypothyroidism and subclinical hypothyroidism, respectively.

The mean serum levels of FT3 (3.58 ± 2.79) and FT4 (1.64 ± 1.21) were higher in the study group, but the difference was statistically nonsignificant. Interestingly, a significantly lower level of TSH (1.51 ± 0.99) was observed in the study group (P < 0.001).

The mean YMRS score was 35.85 ± 7.15 (range 24–48). Serum levels of FT3 and FT4 had positive, while TSH had a negative correlation with YMRS score, but these correlations were nonsignificant statistically.

The mean duration of illness was 19.03 ± 13.65 (range 7–75) days. A nonsignificant negative correlation of FT3 and FT4 and nonsignificant positive correlation of TSH with the duration of illness were observed.

DISCUSSION

In our study, the sociodemographic profile of both the groups was comparable based on their age, sex, religion, residence, education, occupation, and marital status [Table 1].

Table 1

Comparison of sociodemographic characteristics between the two groups

Variables	Study group, n (%)	Control group, n (%)	P*
Age, mean±SD	24.88±6.10	27.23±5.59	t (df)=−1.797 (78)
			P=0.076†
Sex
Male	25 (62.50)	25 (62.50)	1.000
Female	15 (37.50)	15 (37.50)
Religion
Hindu	37 (92.50)	38 (95)	1.000
Muslim	3 (7.50)	2 (5)
Residence
Rural	34 (85)	35 (87.50)	1.000
Urban	6 (15)	5 (12.50)
Education
Illiterate	3 (7.50)	6 (15)	0.321
Up to secondary	24 (60)	26 (65)
Up to graduate	13 (32.50)	8 (20)
Occupation
Unemployed	4 (10)	3 (7.50)	0.505
Employed	18 (45)	16 (40)
Student	14 (35)	12 (30)
Homemaker	4 (10)	9 (22.50)
Marital status
Married	21 (52.50)	25 (62.50)	0.498
Unmarried	19 (47.50)	15 (37.50)

*Chi-square test; †Independent sample t-test. SD – Standard deviation

The prevalence of thyroid disorder in the study group was 12.5% which included hyperthyroidism in 7.5% along with subclinical hyperthyroidism in 5%. Not a single case in the study group was found to be of either hypothyroid or subclinical hypothyroid state [Table 2]. This finding is similar to a previous study that showed supranormal thyroid function in 9.2% of patients with mania.[20] Few other studies also report hyperthyroidism in patients suffering from bipolar disorder with varying prevalence of 0.7%–32%.[814] On the other hand, many studies have reported a higher prevalence of hypothyroidism that may range from 9.2% to 65% in patients with bipolar disorder.[1520212223]

Table 2

Prevalence of thyroid abnormality

Thyroid abnormality	Study group, n (%)	Control group, n (%)
Hyperthyroidism	3 (7.50)	0
Subclinical hyperthyroidism	2 (5)	0
Hypothyroidism	0	2 (5)
Subclinical hypothyroidism	0	4 (10)

In the control group, a higher prevalence of hypothyroidism (5%) and subclinical hypothyroidism (10%) was found. These findings are similar to the thyroid disorder prevalence reported in studies done on the general population of India.[24252627]

Mean serum TSH level was lower in the study group that was statistically significant (P < 0.001). Although the serum FT3 and FT4 levels were higher in study group, the difference was not significant [Table 3]. In the past, an Indian study was done to find out thyroid function in various psychiatric disorders, which found a higher prevalence of hyperthyroid in patients with bipolar mania.[28] On the contrary, another study that compared the thyroid level between patients with bipolar disorder and healthy controls found a significantly higher level of serum TSH and nonsignificantly lower level of T4 in patients with bipolar disorder,[15] but participants for these studies were bipolar and not psychotropic drug naïve unlike us. Although a study was done, in the past, on the patients with first-episode bipolar mania, it did not involve control group, and the subjects were not completely psychotropic drug naive.[13] Several studies have reported that thyroid hormone levels or their functioning can be altered by many psychotropic medicines.[15293031323334] Antipsychotics can also cause obesity,[35] and there are few studies available that suggest a possible mechanism of altered TSH level in an obese person,[36] especially leptin can alter the hypothalamic–pituitary–thyroid (HPT) axis.[3738]

Table 3

Comparison of thyroid profile between the two groups (independent sample t-test)

Variables	Mean±SD		t (df)	P
	Study group (n=40)	Control group (n=40)
FT3	3.58±2.79	3.06±0.48	1.152 (78)	0.253
FT4	1.64±1.21	1.34±0.25	1.546 (78)	0.126
TSH	1.51±0.99	4.16±3.21	−4.994 (78)	<0.001***

***Significant at <0.001 level. TSH – Thyroid-stimulating hormone; SD – Standard deviation; FT – Free thyroxin

The present study also evaluated if any correlation of severity and duration of first-episode mania with thyroid hormones. The score of YMRS showed positive correlation with serum FT3 and FT4 levels and negative correlation with serum TSH level [Table 4], but these correlations were nonsignificant statistically, suggesting that mania severity is not related to thyroid profile of the patients. There has been only a single study done in the past that tried to correlate individual illness symptoms with thyroid function by using Bech–Rafaelsen Mania Scale and found a significant correlation between FT4 and sleep disturbance only.[8] Similarly, thyroid hormone levels did not have a significant correlation with a duration of illness [Table 4]. Previous studies on patients with bipolar disorder that included past episodes of depression and mania also suggested no significant association between thyroid hormone level and duration of illness.[1520]

Table 4

Correlation of variables of study group with thyroid levels

Variables	FT3	FT4	TSH
YMRS
Rho	0.235	0.281	−0.208
P	0.145	0.079	0.198
Duration of illness
Rho	−0.166	−0.254	0.025
P	0.306	0.114	0.878

YMRS – Young Mania Rating Scale; Rho – Spearman correlation; TSH – Thyroid-stimulating hormone; FT – Free thyroxin

All the above findings suggest a presumptive role of thyroid hormones as a risk factor of mania, although the exact mechanism is still unknown. Earlier, it was hypothesized that central adrenergic response to catecholamines can be modified by thyroid hormones in a way that is similar to their action on the peripheral tissues. Hyperthyroidism is thought to augment the sensitivity of beta-adrenergic receptors to noradrenalin, which predisposes an individual to mania in accordance with the catecholamine theory of mood disorders.[3940]

Apart from this, there is a great role of HPT axis in mood disorder. Bipolar disorder-related symptoms can be deteriorated by an acute change in the levels of thyroid hormones. The HPT axis plays a significant role in neuropsychiatric disorders, for example, in hyperthyroidism, emotional irritability, increased activity, and sleep deprivation occur,[39] similar to mania symptoms. The theory of the classical neuroendocrine feedback suggests that physiological feedback systems are, in most instances, modulated by negative feedback and self-protection. The self-regulatory mechanism of bipolar disorder-mania serves at relieving symptoms by decreasing the levels of thyroid hormones, thus reducing its physiological affective symptoms, and stimulates the regulation of the pituitary axis by negative feedback mechanism. Therefore, the process increases not only the TSH secretion[4142] but also the sensitivity of the anterior pituitary.[43] Compensatory enhancement of the pituitary function is developed in the process of spontaneous hyposecretion of hormones during the remission of symptoms.

The present study has some limitations such as the sample size was small, so the results cannot be generalized. Exclusion of past psychiatric and chronic medical illness was done only on the basis of information provided by informants and participants, and no standard screening tool was applied. Another limitation is that this is a cross-sectional study, so cause and effect is not established between thyroid hormones and mania.

CONCLUSION

This study is unique in the sense that it included only drug-naïve patients with first-episode mania, making it free from various confounding factors that were present in the past studies. Our findings highlight a higher prevalence of hyperthyroidism in patients suffering from mania in comparison to controls. Even mean TSH level is significantly lower in patients suffering from mania in relation to controls. Hence, it is worthwhile to screen for thyroid profile in every patient that present with manic illness, to achieve better disease management.

Future direction

The longitudinal study with greater sample size is needed to confirm the causal relationship between thyroid profile and mania.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.