INTRODUCTION
Hyperthyroidism is a common clinical condition with an estimated prevalence of around 1.2% and a lifetime risk of 3% and 0.5% in women and men, respectively. Graves’ disease is the most common cause accounting for 60–80% of cases. It affects patients of all age groups but is most common between 20 and 50 years.[ 1 ] Hyperthyroidism presents with a wide spectrum of well-recognized clinical manifestations affecting several systems and is associated with significant physical[2–5] and psychiatric morbidity.[ 6 ] In younger patients, it results in loss of working days, ineffective working, and reduction in productivity,[ 7 ] while in older individuals, it has an adverse impact on comorbidity and mortality risk.[ 8 , 9 ] In addition, hyperthyroidism adversely affects the quality of life (QOL).[ 10 , 11 ]
The association of hyperthyroidism with a variety of neuropsychiatric manifestations including anxiety and depression leading to impairment in QOL has long been known. As far back as 1825, Parry described these symptoms of hyperthyroidism including panic attacks in a young female;[ 12 ] and in 1835, Graves identified a similar syndrome, which identified a relationship between thyroid disorder and hysteria spherical syndrome.[ 13 ] There have been several recent reports in the literature that have demonstrated the association between hyperthyroidism and mental health impairment.[6,14–20] However, there is insufficient literature on the degree and duration of mental health symptoms, impact on patients, and their precise relationship with hyperthyroidism and its treatment which makes it difficult to establish a clinical service to support such patients.
Our aim was to determine the need to establish additional measures to support the mental health of patients with hyperthyroidism in our endocrine clinics. With a view to identifying the potential unmet service need, we closely examined the association between hyperthyroidism and mental health to determine (a) the prevalence of anxiety , depression , impairment of QOL, and the degree of functional impairment, (b) the duration of these manifestations and their relationship with the changing thyroid status after commencement of treatment, and (c) the factors linked to mental health impairment to facilitate early identification of those with the highest need.
METHODOLOGY
This project was undertaken at the Endocrine and Diabetes Centre, New Cross Hospital, Wolverhampton, which is a large district general hospital in the United Kingdom serving a population of around 300,000.
Inclusion criteria
Consecutive patients with hyperthyroidism referred by general practitioners and other departments in the hospital to the Endocrine and Diabetes Centre over 3 years from January 2016 to January 2019 were included in the study.
Exclusion criteria
Patients who declined to complete the questionnaires, or did not attend clinic appointment even after two reminders (non-adherence) were excluded. Patients with clinical features or radionuclide scan appearance of thyroiditis, amiodarone-induced thyroiditis, and subclinical hyperthyroidism were also excluded from the study.
Hyperthyroidism : Clinical definitionsPatients were considered to be hyperthyroid if they had fully suppressed serum thyroid-stimulating hormone (TSH <0.004mIU/L) along with a raised level of either free serum triiodothyronine (fT3) or free serum thyroxine (fT4) or both. Stable euthyroidism was defined as a normal serum level of TSH, fT3, and fT4 over at least two consecutive tests. Hyperthyroidism was considered severe if the level of fT4 and/or fT3 was >2 times the upper limit of the reference range. The etiology of hyperthyroidism was determined on the basis of a combination of clinical features, TSH-receptor antibodies (TRAB), and radionuclide scan.
Assessment process
At the first visit, patients were provided with a verbal explanation about the project and the associated questionnaire(s), and informed written consent for participation was obtained. Each of the questionnaires was explained to the patients, and they were requested to complete the project questionnaires at the time of the initial presentation and each of the subsequent visits until stable euthyroidism was achieved with antithyroid medication (carbimazole or propylthiouracil), radioiodine treatment, surgery, or through spontaneous remission. The standard process agreed within the directorate and supported by the NICE guidance[ 21 ] was followed in making decisions on management and frequency of follow-up of patients.
Assessment scales
We used well-established, validated, and self-reportable questionnaires to study the following parameters: anxiety , depression , QOL, and impairment in the ability to perform daily tasks. The self-report scales were chosen looking at feasibility in the endocrine clinic.
Patient Health Questionnaire 9 (PHQ-9) scale was used to screen for depression .[ 22 ] We used generalized anxiety disorder 7 (GAD-7) questionnaire to screen for anxiety .[ 23 , 24 ]
The three-level version of EuroQol group ED-5D (ED-5D-3L) was used as a measure of the QOL. It comprises a three-level descriptive scale for five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety /depression , where the levels overall suggest no problems (level 1), some problems (level 2) and extreme problems (level 3); which are presented as proportions. There is a visual analog scale (EQ-VAS) which recorded patient’s self-rated health on a vertical visual analog scale with the endpoints being “best imaginable health state” and “worst imaginable health state” scored from 0 to 100.[ 25 ]
Work and social adjustment scale (WSAS) was used as a measure of impaired functioning in performing day-to-day tasks like work, home management, social and leisure activities, and maintaining relationships. The lower is the WSAS score, the better is the functioning with WSAS scores <10, 10–20, and >20 suggesting mild, moderate, and severe functional impairment, respectively.[ 26 ]
Data analysis
Data were collected on an Excel spreadsheet and included demographic information, the use of medication including antithyroid drugs, beta-blockers and psychiatric drugs, thyroid function test and thyroid status at each visit, and the sequential data obtained from the above four questionnaires. Data entry was cross-checked for accuracy and quality by two researchers.
The final data were analyzed using SPSS (IBM Corp, Version 25.0. Armonk, NY). Results were presented as mean and standard deviation (SD), and the prevalence of various categories was given in percentages. For comparison of categorical variables, the Chi-square test was used, while mean values were compared with Student’s t-test or ANOVA. Paired t-test was used to assess the change in parameters in the same group of individuals at different periods of follow-up. With a change in thyroid function, a non-linear change in anxiety , depression , functional impairment, and QOL was expected, and therefore, Spearman’s correlation was used to measure the degree of association. Missing values were excluded from analyses. Significance was considered at the standard level of 0.05.
Ethics
The project was explained to the patients; anonymity of the data and option to withdraw anytime without assigning any reason were highlighted. Informed written consent was obtained from the patients. This project was approved by the institution. Support for their mental health was available from the local mental health services through direct referral or through patients’ GPs. The treatment decisions taken by the clinicians were not influenced by the project.
RESULTS
Sample characteristics
During the study period, 203 patients were screened of whom 27 patients were excluded (eight declined to participate, 12 were non-adherent, one had thyroiditis, two had amiodarone induced hyperthyroidism , two had subclinical hyperthyroidism , and two patients died). The final sample included 176 new hyperthyroid patients and their follow-up continued until February 2020. Baseline characteristics are in Table 1 . Mean ± SD age was 50.1 ± 15.6 years (range 16–86), and 137 (77.8%) patients were females. Most patients (156, 88.6%) had Grave’s disease, while the remaining patients had toxic nodular disease (TND) (20, 11.4%). Eighteen patients (10.2%) had recurrent hyperthyroidism .
Table 1: Baseline characteristics of the sample
At the time of recruitment, 26.7% patients were on beta-blockers and 8.5% on antidepressants (amitriptyline 3.4%, citalopram 2.3%, sertraline 1.7%, and others 1.1%). Following the initial assessment at the first visit, 85.8% (n = 151) patients received carbimazole, 4.5% (n = 8) propylthiouracil, and 9.7% (n = 17) did not receive any medications. Around one-third (31.2%) of patients had severe hyperthyroidism . Mean FT4 of the entire cohort was 29.8 pmol/L and FT3 12.8 pmol/L.
Baseline assessment
The level of anxiety , depression , functional impairment, and QOL at baseline and subsequent assessments are given in Table 2 along with thyroid parameters. A significant proportion (40.5%) of patients had moderate and severe anxiety , and a little more than half (50.6%) of the patients had moderate or severe depression . A majority of patients (72.0%) were working, and 20.8% had severe functional impairment. Their mean EQ5D score was just above the halfway mark (59.6 ± 23.5).
Table 2: Clinical status, occupational functioning , and QOL of patients at different assessment period
We examined the correlation of depression (PHQ-9 score), anxiety (GAD-7 score), functional impairment (WSAS score), and QOL (EQ5D score) between each other and with the levels of T3, T4, and TSH [Table 3 ]. The scores of anxiety , depression , and functional impairment were significantly correlated with each other; QOL was negatively correlated with anxiety , depression , and WSAS. We did not find any correlation between any of the above parameters and degree of hyperthyroidism .
Table 3: Correlation of thyroid hormone levels, mental health, functioning , and QOL at baseline
The GAD-7, PHQ-9, and WSAS scores did not differ significantly between patients with or without beta-blocker at the recruitment. However, patients on beta-blocker had significantly lower EQ5D scores (53.4 ± 23.3 v 62.0 ± 23.2 (mean ± SD), P < 0.05) compared with those who did not have beta-blockers. Those who were on antidepressants had higher GAD-7 (13.6 ± 6.5 v 8.2 ± 6.9, P < 0.01), PHQ-9 (14.2 ± 8.0 v 9.7 P < 0.05), and WSAS scores (18.7 ± 13.1 v 10.7 ± 10.7, P < 0.05) although their QOL was comparable.
In comparison with patients with TND, those with Graves’ disease were younger (mean 48.4 ± 14.7 v 63.8 ± 15.9 years, P < 0.001) and had significantly higher FT4 (30.8 ± 14.0 v 21.8 ± 8.7). Both groups of patients were comparable in terms of anxiety and depression scores, work impairment and quality of life , and on the use of beta-blockers, psychotropic drugs, and antidepressants.
Follow-up assessment
The proportion of patients with anxiety and depression gradually decreased from the initial assessment during the second and third visits (40.5%, 33.8%, 26.1% and 50.6%, 38.6%, 32.1%, respectively) and the proportion of patients working increased from 72% to 83.3% during the follow-up period [Table 2 ]. However, a considerable number of patients continued to have a clinically significant level of anxiety and depression , and after the third visit (median 163 days), it remained largely unchanged.
We assessed the impact of change in thyroid status and FT4 level on mean GAD-7, PHQ-9, WSAS, and QOL scores during the follow-up period. When patients with persistent hyperthyroidism were compared to those who were euthyroid, there was no difference (t-test) in their mean scores. We also analyzed the proportions of patients with different levels of anxiety , depression , and functional impairment in relation to their thyroid status during follow-up visits, and again there were no significant differences (Chi-square test). Thus, it appeared that a change in thyroid status did not have any influence on the scores that were used. However, in addition to a change in the overall thyroid status, we also assessed the impact of lowering of FT4 after commencement of antithyroid drugs. A reduction in FT4 not only correlated with lowering of FT3 (ρ = 0.847, P < 0.001) but also to changes in scores of anxiety (ρ = 0.119, P = 0.030), depression (ρ = 0.156, P = 0.004), QOL (ρ = -0.116, P = 0.044), and WSAS (ρ = 0.148, P = 0.041). The change in anxiety score correlated with change in scores of depression (ρ = 0.561, P < 0.001), QOL (ρ = -0.432, P < 0.001), and WSAS (ρ = 0.317, P < 0.001).
The use of beta-blocker and antidepressants came down through the study period, even though a considerable number of patients continued to have anxiety and depression .
Assessment of change in individual patients
We used paired t-test to compare the differences in studied parameters in the same individuals over the follow-up visits. There was a significant drop in GAD-7, PHQ-9, and WSAS scores at the second (p < 0.01) and third (p < 0.05) visits after which subsequent changes were not significant. Improvement in QOL was noticed to be significant only at the second visit (p < 0.01), after which there was no significant change.
DISCUSSION
We serve a population of around 300,000, and the majority of our patients are working class. Hyperthyroidism is the second most frequently encountered condition in our speciality outpatient clinics after diabetes mellitus, and we frequently come across patients with hyperthyroidism affected by mental health issues, often underlining the limited availability of psychiatry input for these patients. There is also a significant delay in acquiring mental health support when faced with acute or subacute needs. With a view to identifying and quantifying the unmet need for timely psychiatric intervention, we set up this project which is also the first naturalistic prospective study on mental health, functional status, and QOL of patients with hyperthyroidism with longitudinal follow-up.
Impairment in MH parameters, QOL, and functioning at presentation
We confirmed that patients with hyperthyroidism have a high prevalence of anxiety and depression at pre-treatment, baseline assessment.[ 27 ] Our findings are in keeping with the available literature that patients with hyperthyroidism have higher mental health morbidity.[ 28 , 29 ] One of the earlier studies demonstrated that patients with hyperthyroidism had neuropsychiatric impairment, mainly in the form of impairment of attention, memory, planning, and productivity,[ 30 ] including working memory and executive functions.[ 31 ] In another study among patients with Graves’ disease, 41.7% were diagnosed with generalized anxiety disorders, 16.7% with a mood disorder, and 16.7% with the obsessive compulsive disorder.[ 32 ] The proportion of patients with anxiety in our cohort of patients was comparable to the findings in these studies. Comparing anxiety and depression between Graves’ disease and nodular goiter, the levels were similar in both groups in our study; whereas another study found higher prevalence of depression in Grave’s disease than nodular goiter, although anxiety was similar in both groups.[ 19 ]
The high prevalence of anxiety and depression is likely to be largely responsible for 45% of patients reporting moderate to severe functional impairment.[ 31 ] This figure is highly relevant as 72% of the patients in our cohort were working at baseline, and impairment of function would have led to reduced efficiency at work or missing work altogether. This assumption was based on several reports that confirm the adverse impact of hyperthyroidism on attendance at work. This was shown in a small interview-based study,[ 33 ] as well as in a larger register-based cohort study,[ 7 ] which reported twice the risk of sickness absence within the first year of diagnosis and a lower probability of return to work during the first as well as subsequent years. A previous study also reported that 30% or more of patients with hyperthyroidism reported temporary or permanent work disabilities,[ 34 ] which were most pronounced after treatment initiation.[ 35 , 36 ] Although we did not have specific data on days of sickness absence or occupational performance, we expect a similar impact on these parameters in our patients.
In view of the significant prevalence of MH manifestations and impairment of functional state, it was not surprising to find that the QOL was reported to be as low as 59% at baseline. Anxiety , depression , and functional impairment demonstrated a statistically significant positive correlation with each other and a negative correlation with QOL, but they did not correlate with thyroid hormone level at presentation [Table 3 ]. These findings are comparable to those reported by a study using the thyroid-related patient-reported outcome (ThyPRO) questionnaire for patients with Graves’ disease.[ 37 ] It addition, literature also suggests that QOL scores in hyperthyroidism are low even though confounding influence of complications such as orbitopathy was excluded.[38–41]
Impact of treatment on parameters studied
We correlated thyroid status and FT4 values with MH symptoms during the treatment period. Euthyroid and hyperthyroid patients had comparable anxiety , depression , impairment of function, and QOL which appeared to suggest that treatment had little impact on MH. However, when correlated with a change in FT4 level from baseline, there was a significant reduction in all parameters studied with the fall in FT4. This indicates that for an individual patient, improvement of hyperthyroidism leads to improvement in anxiety , depression , QOL, and improved functioning . This correlation with FT4 as a continuous variable is more representative of the impact of treatment on an individual patient rather than categorizing patients as euthyroid and hyperthyroid, which would mask the downward trend in FT4 especially during the earlier stages of treatment and would also not account for individual patients MH status before the onset of hyperthyroidism .
However, it was also noticeable that after an initial improvement noted during the first two visits over 6 months, MH symptoms persisted well into the treatment period, and in a considerable proportion of patients, they were at moderate to severe level until the end of the study period [Table 2 ]. In some of the patients, the continued presence of anxiety and depression was noted to be longer than 12 months. However, we could not draw conclusions on the proportion of patients in this cohort, as the number of patients with such a long duration of follow-up was small. This was because, in this project, patients who achieved remission were discharged to primary care with only those with prolonged hyperthyroidism having continued follow-up in the hospital endocrine clinic which led to an obvious selection bias. The modest improvement in QOL mirrored the relief in anxiety and depression and was observed early after starting treatment. It is known that hyperthyroidism and syndromal depression –anxiety have overlapping features;[ 42 ] and any persisting symptoms after specific hormonal treatment need to be followed up in psychiatry.[ 43 ] It is reported that screening and providing timely care can improve QOL in this patient population.[ 28 ] The increase in the proportion of those in work was in line with the observation that the proportion of patients with severe functional impairment decreased during this time.
There is conflicting evidence on the relationship of treatment of hyperthyroidism and its impact on MH parameters. While some studies have shown that MH symptoms improve after thyroid hormones are normalized,[ 42 , 44–46 ] others have demonstrated persistence of these symptoms after euthyroidism was achieved.[ 10 , 30 , 34 ] Furthermore, not much is found in literature about the time it takes for these symptoms to improve after euthyroidism is achieved. The persistence of these symptoms was also demonstrated by a study at 6 months after commencement of treatment,[ 37 ] which underpins the need for further research strategies to determine the best treatment options.
It is difficult to explain why in some patients these symptoms once triggered by hyperthyroidism often persist so long, after the achievement of stable euthyroidism. One can hypothesize that within the entire cohort, there may be patients with varied previous MH status (i) previously normal MH, (ii) individuals with high vulnerability to MH manifestations, or (iii) patients with pre-existing anxiety and depression . This could explain the varied response to treatment and patients in group (i) may improve, but those in the other two groups may continue to manifest symptoms to a variable extent for longer periods, even following improvement of hyperthyroidism . This hypothesis needs to be tested in larger and appropriately designed studies.
Factors influencing mental health and functional outcome
In view of the significant variability in the degree of MH manifestations in patients with hyperthyroidism , we assessed the correlation of several clinical variables with the degree of MH involvement. These included demographic factors, concurrent use of medications (psychiatric drugs and beta-blockers), and severity of hyperthyroidism . None of these variables correlated with the degree of MH involvement other than the use of antidepressants before the diagnosis of hyperthyroidism which predicted more severe manifestations. It is likely that the patients who were on these medications had an underlying MH condition (above group (iii)) for which the medication was prescribed. It has also been shown that patients with hyperthyroidism are more likely to be on these agents as compared to the background population before the diagnosis of hyperthyroidism .[ 17 ] As there was no difference in anxiety , depression , and functional impairment between patients with or without beta-blockers, a further study to assess their effect on MH in patients with hyperthyroidism is required.
The lack of correlation of severity of biochemical hyperthyroidism with MH manifestation was difficult to explain. It is likely that the duration of hyperthyroidism is a better predictor, but this parameter was difficult to study with any degree of accuracy in our cohort of patients. Varying mental health before development of hyperthyroidism may have also had an effect but requires confirmation. There is no published literature on the impact of the degree and duration of hyperthyroidism on the specific MH parameters that we have studied. However, Graves’ disease as the etiology rather than TND and the presence of significant thyroid eye disease (TED) have been shown to have a strong influence on QOL and MH parameters.[ 6 , 33 , 37 ] However, we had a small number of patients with TND and none with significant TED; we could not study these variables.
Impact on clinical practice and service provision
This study has increased our awareness of the high prevalence and persistence of MH impairment in patients with hyperthyroidism . Anxiety and depression have a major impact on patients’ well-being and influence the management of hyperthyroidism in several ways. Most clinicians are aware of the specific communication skills required to manage patients with hyperthyroidism with significant anxiety . This study suggests that in a considerable proportion of patients with MH symptoms, impaired functioning and poor QOL may persist long term, often despite achieving biochemical euthyroidism, and the approach during subsequent consultations should continue to be supportive and empathetic. It can also explain the high prevalence of psychosomatic symptoms in successfully treated patients during the follow-up period.
MH can have an impact on the engagement of a patient with the management of hyperthyroidism and can potentially explain sub-optimal adherence to medication. It can also make it difficult for clinicians to have an early discussion on long-term treatment options required for some patients with hyperthyroidism as per the recent NICE guidance.[ 21 ] The presence of significant anxiety and depression often precludes this rather complex dialog at the initial presentation and for a few visits thereafter.
The findings of our study have also helped our understanding of the degree of service expansion required for the assessment, as well as early and extended support of these patients. Our findings support the routine use of MH screening for patients with hyperthyroidism ,[ 28 ] as a significant proportion of patients had marked (moderate and above) impairment in one or more MH parameters assessed, often not apparent in routine care. It may be possible to make a prediction of mental health of patients by assessing their functional impairment and QOL in viewing the correlation that we have demonstrated. We also highlight that patients with persisting MH concerns at second and subsequent follow-up visits should receive psychiatric support and emphasize the need for support from the local psychiatric service to establish easy and early access to MH care for these patients.
STRENGTH AND LIMITATIONS
In contrast to association of hypothyroidism and mental illness, studies on the impact of hyperthyroidism are fewer, and this study adds to the existing literature highlighting the clinical concerns in a naturalistic setting. However, there are some limitations. Sample size was not calculated a priori ; however taking into consideration the reported prevalence of depression and anxiety among patients with hyperthyroidism ,[ 19 , 32 ] a calculation based on 10% precision and 95% confidence interval suggested adequacy of the sample of this study. Exclusion of individuals with poor engagement could lead to a lower detection rate for more significant mental health issues, either pre-existing and/or worsened by hyperthyroidism , as this is one of the key reasons for non-compliance with health care. We used self-report scales for assessing anxiety and depression , and there was no further clinician assessment. Clinician-rated instruments or clinical assessment for the screen-positive patients may be considered in future projects. The study recorded only the psychopharmacological treatments, whereas some patients might be receiving psychological interventions which could be useful while designing services for these patients with anxiety and depression .
CONCLUSIONS
A considerable proportion of hyperthyroid patients had clinically significant anxiety , depression , and functional impairment. At presentation, scores of anxiety , depression , functional impairment, and QOL did not correlate with degree of hyperthyroidism . There was, however, a significant improvement in these parameters following initiation of treatment and improvement of FT4 level. A considerable proportion of patients, nonetheless, continued to have persistent symptoms. Only a minority of patients were on psychiatric drugs, possibly those with significant pre-existing anxiety and depression . The majority of the remaining patients with anxiety and depression would not have been identified or treated with usual clinical care for hyperthyroidism and were only discovered as having these issues due to participation in the study. The study emphasizes a significant unmet need for formal MH assessment of patients with hyperthyroidism and hints that easy access to psychiatry support is likely to be of benefit.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgement
All the patients who participated in the study.
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