Impact statement
Our results show that psychiatric patients, unlike their adherence to psychotropic agents, adhere very well to their physical illnesses medication regime in this study. Caretakers should therefore change their stigmatizing attitude toward patients with schizophrenia with regard to adherence to hypothyroidism treatment and offer them the same level of care as is offered to patients with no mental health issues.
Introduction
Schizophrenia is a chronic mental disorder with a worldwide prevalence of about 1% (Rössler et al., Reference Rössler, Salize, van Os and Riecher-Rössler2005). Illness course involves recurrent psychotic exacerbations interrupted by periods of remission with “negative” symptoms, and impairment in functionality increases gradually. Psychotic symptoms usually respond to antipsychotic medications, which are also used for long-term maintenance and prevention (Kane and Correll, Reference Kane and Correll2019). Yet, according to research, due to a multitude of factors, 34–81% of patients discontinue their antipsychotic medications with many studies putting the rate around 50% (Yang et al., Reference Yang, Ko, Paik, Lee, Han, Joe, Jung, Jung and Kim2012; El-Mallakh and Findlay, Reference El-Mallakh and Findlay2015; García et al., Reference García, Martínez-Cengotitabengoa, López-Zurbano, Zorrilla, López, Vieta and González-Pinto2016; Lafeuille et al., Reference Lafeuille, Frois, Cloutier, Duh, Lefebvre, Pesa, Clancy, Fastenau and Durkin2016; Bright, Reference Bright2017; De Las Cuevas et al., Reference De Las Cuevas, de Leon, Peñate and Betancort2017; Velligan et al., Reference Velligan, Sajatovic, Hatch, Kramata and Docherty2017).
In the general population, non-adherence to prescribed medications is a common obstacle to effective treatment of many chronic physical disorders, with rates of non-adherence reported to be 43–78% (Osterberg and Blaschke, Reference Osterberg and Blaschke2005). Reasons for non-adherence like economic difficulties, lack of awareness of the importance of treatment for the illness, cognitive deficits and poor provider–patient relationship are even more common in patients with schizophrenia (Osterberg and Blaschke, Reference Osterberg and Blaschke2005). Stigma-motivated underestimation of patients’ ability to cooperate is often involved and may lead physicians to assume that deterioration of a chronic physical disorder in a patient with schizophrenia is due to non-adherence to treatment, thus causing the physicians to refrain from searching for non-mental health-related sources of the deterioration.
Some early studies on patients with schizophrenia pointed to a trend toward lower adherence rates to prescribed medications, relative to the general population. These findings, however, were later attributed to the fact that the methods used for estimating adherence were incorrect (Cramer and Rosenheck, Reference Cramer and Rosenheck1998). More recent research has shown that patients with schizophrenia have equal or better adherence rates to antidiabetics (Dolder et al., Reference Dolder, Lacro and Jeste2003; Simard et al., Reference Simard, Presse, Roy, Dorais, White-Guay, Räkel and Perreault2015; Gorczynski et al., Reference Gorczynski, Firth, Stubbs, Rosenbaum and Vancampfort2017), antihypertensives (Dolder et al., Reference Dolder, Lacro and Jeste2003; Dolder et al., Reference Dolder, Furtek, Lacro and Jeste2005; Siegel et al., Reference Siegel, Lopez and Meier2007) and antihyperlipidemics (Dolder et al., Reference Dolder, Lacro and Jeste2003; Owen-Smith et al., Reference Owen-Smith, Stewart, Green, Ahmedani, Waitzfelder, Rossom, Copeland and Simon2016). Additionally, while mental illness, including schizophrenia, has been found to correlate with diagnostic and primary treatment delays in patients with breast cancer, most patients who initiate endocrine therapies adhere to the treatment no less than the general population (Iglay et al., Reference Iglay, Santorelli, Hirshfield, Williams, Rhoads, Lin and Demissie2017).
Some studies have found a correlation between adherence to antipsychotic medications and adherence to medications prescribed for physical disorders (Hansen et al., Reference Hansen, Maciejewski, Yu-Isenberg and Farley2012; Shafrin et al., Reference Shafrin, Silverstein, MacEwan, Lakdawalla, Hatch and Forma2019). Thus, one may assume that a patient adhering to antipsychotics will also adhere to other medications.
Previous research has shown that there is an increased rate of hypothyroidism in patients with schizophrenia (Melamed et al., Reference Melamed, Farfel, Gur, Krivoy, Weizman, Matalon, Feldhamer, Hermesh, Weizman and Meyerovitch2020). Some studies suggest an association between disorders of the thyroid hormone and mental disorders (Bono et al., Reference Bono, Fancellu, Blandini, Santoro and Mauri2004; Davis and Tremont, Reference Davis and Tremont2007; Radhakrishnan et al., Reference Radhakrishnan, Calvin, Singh, Thomas and Srinivasan2013; Remaud et al., Reference Remaud, Gothié, Morvan-Dubois and Demeneix2014; Samuels, Reference Samuels2014). A South Korean study has found that the prevalence of hypothyroidism among schizophrenia patients is 4.9% (Park et al., Reference Park, Kim and Kim2021). A large US study has found that schizophrenia is associated with hypothyroidism (OR 1.88, 95% CI 1.51–2.32) as well as other substantial chronic medical burdens (Carney et al., Reference Carney, Jones and Woolson2006).
A large-scale Israeli study has found a higher proportion of patients with hypothyroidism among schizophrenia patients than in a control group (2.01% vs. 1.25%, respectively, p < 0.0001), after adjusting for age, gender and smoking status. They, furthermore, found a robust independent association between schizophrenia and hypothyroidism (OR 1.62, p ≤ 0.001) when performing a multivariate logistic regression analysis (Sharif et al., Reference Sharif, Tiosano, Watad, Comaneshter, Cohen, Shoenfeld and Amital2018).
Three studies have found that the rate of hypothyroidism seems to rise significantly following a diagnosis of schizophrenia (Telo et al., Reference Telo, Bilgic and Karabulut2016; Melamed et al., Reference Melamed, Farfel, Gur, Krivoy, Weizman, Matalon, Feldhamer, Hermesh, Weizman and Meyerovitch2020; Launders et al., Reference Launders, Kirsh, Osborn and Hayes2022). These observations indicate that chronic antipsychotic treatment may suppress thyroid functioning (Melamed et al., Reference Melamed, Farfel, Gur, Krivoy, Weizman, Matalon, Feldhamer, Hermesh, Weizman and Meyerovitch2020).
Non-adherence is a known problem in the management of hypothyroidism, with rates of non-adherence reaching 52% (Hepp et al., Reference Hepp, Wyne, Manthena, Wang and Gossain2018), but to the best of our knowledge, our current study is the first to compare adherence to treatment and management of hypothyroidism in patients with schizophrenia to that of the general population suffering from this common endocrine disorder.
Methods
We examined the medical files of 1,252 adult patients with schizophrenia receiving treatment in the regional clinics of a large HMO in Israel, during the years 2005–2013, and of 3,756 control subjects without any mental disorder – matched for age, gender and socioeconomic status – being treated for physical health issues during the same period. These parameters were included in the model as they may affect the dependent variables. Only those under long-term (at least 5 years) care of a healthcare provider, above 18 years of age and residing in the same urban area in central Israel were included. The predefined ratio of patients to controls was 1:3. The relevant data were collected from the electronic medical database and transferred anonymously to a file, which constituted the data source for the current study. Diagnosis of schizophrenia had been done by senior psychiatrists according to ICD-10 criteria.
Exclusion criteria consisted of treatment with clozapine, which represents treatment-resistant schizophrenia, malignancy and organic brain syndrome. The records of individuals with these medical conditions were not retrieved.
Among the retrieved records, 121 patients were identified with schizophrenia and comorbid hypothyroidism and 190 controls without schizophrenia but with a registered diagnosis of hypothyroidism. Those were included in our study.
Adherence to hypothyroidism treatment was assessed by the following measures:
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• Average annual number of prescriptions of L-thyroxine (a replacement therapy for hormone deficiency in hypothyroid state).
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• Average annual number of serum thyroid stimulating hormone (TSH) level tests, which is a commonly used test for hypothyroidism.
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• Each participant’s average TSH level, which is a measure of treatment success.
Due to the retrospective nature of the study, the need for informed consent was waved by the institutional review board of the Geha Mental Health Center in Petah Tikva, Israel. The approval number is 095/2012.
Statistical analysis
Since all the variables are continuous, we used Student’s t-test to calculate the differences between groups.
Results
In our sample, 299 patients had a diagnosis of hypothyroidism corroborated by at least one result of serum TSH levels. One hundred and fifteen had a diagnosis of schizophrenia as well. The 184 with no schizophrenia constituted the control group.
The measures of adherence defined in this study (average annual number of prescriptions of L-thyroxin, average annual number of TSH level tests and average TSH level) are shown in Table 1. No statistically significant differences between the two groups were found in any of the measures.
Treatment adherence
Note: Normal range of TSH is 0.4–4.0 mIU/L.
Discussion
Several measures used in our study indicated that in patients diagnosed with comorbid schizophrenia and hypothyroidism, the adherence rate to hypothyroidism medications was as good as that of patients with hypothyroidism and no mental disorder. This is in line with previous research on the adherence of patients with schizophrenia and comorbid physical disorders (Dolder et al., Reference Dolder, Lacro and Jeste2003; Dolder et al., Reference Dolder, Furtek, Lacro and Jeste2005; Siegel et al., Reference Siegel, Lopez and Meier2007; Simard et al., Reference Simard, Presse, Roy, Dorais, White-Guay, Räkel and Perreault2015; Owen-Smith et al., Reference Owen-Smith, Stewart, Green, Ahmedani, Waitzfelder, Rossom, Copeland and Simon2016; Gorczynski et al., Reference Gorczynski, Firth, Stubbs, Rosenbaum and Vancampfort2017; Iglay et al., Reference Iglay, Santorelli, Hirshfield, Williams, Rhoads, Lin and Demissie2017).
Studies consistently demonstrated that patients with schizophrenia have higher rates of physical disorders and a shortened lifespan (Dieset et al., Reference Dieset, Andreassen and Haukvik2016; Hjorthøj et al., Reference Hjorthøj, Stürup, McGrath and Nordentoft2017). This morbidity and mortality gap has been attributed to a variety of factors, including common biological underpinnings (Crawford et al., Reference Crawford, Jayakumar, Lemmey, Zalewska, Patel, Cooper and Shiers2014), medication effects (Pillinger et al., Reference Pillinger, McCutcheon, Vano, Mizuno, Arumuham, Hindley, Beck, Natesan, Efthimiou, Cipriani and Howes2020), suicidality (Hor and Taylor, Reference Hor and Taylor2010) and non-adherence (Crawford et al., Reference Crawford, Jayakumar, Lemmey, Zalewska, Patel, Cooper and Shiers2014). As mentioned before, the results of our study indicate that non-adherence is not a significant factor in this context. This finding has implications in two main areas. One is the education of clinicians. Such information could help reduce the stigmatic view that patients with schizophrenia cannot be reliable partners in establishing and implementing a treatment plan (Chaudhry et al., Reference Chaudhry, Jordan, Cousin, Cavallaro and Mostaza2010; Briskman et al., Reference Briskman, Bar, Boaz and Shargorodsky2012; Firth et al., Reference Firth, Rosenbaum, Stubbs, Gorczynski, Yung and Vancampfort2016). The second area is resource investment. Economic resources intended to help close the morbidity–mortality gap should be directed to other factors mentioned above rather than to treatment adherence of patients with schizophrenia.
The findings of the current study clearly show that schizophrenic patients adhere to hypothyroid (and probably other) treatments no less than patients without schizophrenia. All patients, regardless of whether diagnosed with schizophrenia or not, should receive the same attention and same treatment from healthcare practitioners. Reducing such stigmatization can and should encourage more equitable and effective healthcare practices for individuals with schizophrenia, both in terms of the attitude from practitioners and the resource investment needed to provide the best available care.
In the case of hypothyroidism specifically, recent research points to the antipsychotic medications playing an important role in the etiology of the disorder (Melamed et al., Reference Melamed, Farfel, Gur, Krivoy, Weizman, Matalon, Feldhamer, Hermesh, Weizman and Meyerovitch2020).
Limitations
This study has all the limitations inherent to a retrospective study design. In addition, the study group is of relatively small size.
Some studies have found that thyroid function can be affected by early-life psychosocial factors such as childhood trauma. Early life is known to constitute a sensitive period for the long-term effects on the endocrine system, related to the functioning of the hypothalamic–pituitary–thyroid axis (Varese et al., Reference Varese, Smeets, Drukker, Lieverse, Lataster, Viechtbauer, Read, van Os and Bentall2012; Machado et al., Reference Machado, Salum, Bosa, Goldani, Meaney, Agranonik, Manfro and Silveira2015). However, neither Śmierciak et al. (Reference Śmierciak, Szwajca, Popiela, Bryll, Karcz, Donicz, Turek, Krzyściak and Pilecki2022) nor our study could find any reports explaining the dependencies or mechanisms of this relationship.
Additionally, the present study showed no evidence of a relationship between sociodemographic and cultural factors and adherence to treatment, since both the study and the control group were matched for socioeconomic status and cultural background. A future study should investigate the impact of social and cultural backgrounds, healthcare systems and their policies on treatment adherence in patients with schizophrenia. Longitudinal cohort studies are needed to clarify long-term health outcomes associated with treatment adherence or non-adherence in patients with comorbid schizophrenia and how they vary on an international scale. Such studies should also identify the effective strategies to improve adherence in psychiatric patients.
Conclusion
To the best of our knowledge, this is the first study to address the subject of adherence to hypothyroidism treatment in patients with schizophrenia. Our results boost those of previous studies of adherence in patients with schizophrenia and should help destigmatize the perception of non-adherence as a trait of schizophrenia and the unjustified blaming of these patients as being responsible for the under-treatment they receive.
Open peer review
To view the open peer review materials for this article, please visit http://doi.org/10.1017/gmh.2023.86.
Data availability statement
Due to the confidential nature of the data, it is only available on reasonable request from the corresponding author.
Author contribution
Conceptualization: S.G., S.W., A.K.; Data curation: S.G., S.W.; Formal analysis: A.K.; Funding acquisition: S.G.; Investigation: S.W., H.H., A.M., J.M.; Methodology: S.G., S.W., A.K.; Project administration: S.G.; Resources: S.G.; Supervision: A.K., J.M.; Writing – original draft: S.G., S.W.; Writing – review and editing: all authors.
Financial support
This study was supported by a specific grant to SG from the Clalit Health Services, Israel.
Competing interest
The authors declare no competing interests exist.
Ethics standard
This study was approved by the Institutional Ethics Review Board of the Geha Mental Health Center, Petah Tikva, Israel. The approval number is 095/2012. Due to the retrospective nature of the study, the need for informed consent was waved.
Open access
Comments
To
Prof. Gary Belkin
Editor-In-Chief
Cambridge Prisms: Global Mental Health
Dear Prof. Belkin,
We hereby re-submit our manuscript entitled: “Adherence of patients with schizophrenia to hypothyroidism treatment” for publication in your journal. This is an original study that used an electronic medical database to compare adherence to hypothyroidism treatment of patients with schizophrenia to the adherence to such treatment of patients without schizophrenia.
The results indicate that, contrary to often held opinions, patients with schizophrenia adhere to hypothyroidism treatment no less than patients without schizophrenia.
All the authors of this article had access to all study data, are responsible for all contents of the article, and had authority over manuscript preparation and the decision to submit the manuscript for publication. All listed authors gave their approval to the submission of the manuscript to this journal. The authors know of no other published, submitted or proposed papers reporting the same or overlapping data.
None of the authors reports any financial or other conflict of interest with regard to this study.
We hope that you will find this article suitable for publication in your journal.
Sincerely,
Dr. Shay Gur MD
On behalf of the authors