Hyperthyroidism and antithyroid medications: a friend and an enemy of psychosis

Keywords::

• antithyroid medications
• carbimazole
• encephalopathy
• hyperthyroidism
• methimazole
• propylthiouracil
• psychosis

1. Introduction

Since the middle of the past century three classes of antithyroid medications, namely thionamides (carbimazole, methimazole and propylthiouracil), anion inhibitors (potassium perchlorate) and iodides (potassium iodide), are used for the pharmacological treatment of hyperthyroidism [1,2]. Their use has had a fundamental therapeutic impact in the management of patients with overactive thyroid function and these medications are largely used worldwide, though with some geographical differences in the use of one rather than another drug of the thionamide class and with some selective indications or restrictions with regard to the use of potassium perchlorate and potassium iodide.

The possible impact of thyroid hormone abnormalities on the development of a new onset or the worsening of a pre-existing neurological or psychiatric disorder, including psychosis, is historically well defined. On the contrary, the safety profile of antithyroid medications in connection with the risk of occurrence of a neurological or psychiatric illness has never been precisely documented, with the exception of only few sporadic reports raising a doubtful and uncertain warning. In the current issue of Expert Opinion on Drug Safety, Vita et al. have reviewed the relationship between the administration of antithyroid drugs and the development of psychosis [3]. Interestingly, the review of the literature led the authors to explore such issue deep back in the past as most of the reports of a suspicious manifestation of psychosis following the use of antithyroid medications are just historical. Though the universal clinical experience and the routine practice induce the physicians to safely prescribe antithyroid drugs for the treatment of hyperthyroidism without any specific concern regarding the risk of occurrence of iatrogenic psychosis, an evidence-based conclusion supported by the analysis of the reported cases has never been done so far. Following a careful review of the literature, the authors have now put a stone in favor of the safe use of antithyroid medications against the hypothetical and never confirmed risk of development of psychosis when managing patients with hyperthyroidism.

2. Side effects of antithyroid medications

The administration of thionamides is associated with a number of possible side effects and adverse reactions, ranging from minor events, such as transient skin rash, urticaria and mild symptoms of gastrointestinal discomfort, which usually do not require drug withdrawal, to more severe events such as granulocytopenia, vasculitis, arthralgia, cholestasis and liver impairment and finally to potentially fatal events such as agranulocytosis and acute hepatitis [4,5]. The risk of hepatotoxicity is an issue relevant in particular to propylthiouracil [6,7]. Currently, the prescription of propylthiouracil is reserved to those patients who are intolerant to carbimazole or methimazole and to hyperthyroid women in their first trimester of pregnancy [8].

3. Is there any clinically relevant effect of antithyroid medications on the functions of the central nervous system?

With the only exception of some minor olfaction disorder exceptionally occurring in patients taking thionamides, this class of medications is thought to be free from unwanted effects on the functions of the nervous system both from a neurological and a psychiatric perspective [5,8]. Antithyroid medications have been suspected to very rarely trigger acute psychosis in patients with no history of psychiatric disturbances [3]. The few historical reports of occurrence of psychosis following the administration of antithyroid drugs were mostly affected by an incomplete biochemical assessment of the patient and missed the substantiation of a clear cause–effect link between the intake of the drug and the clinical manifestation of psychosis. Even in the event of a very rapid biochemical response to the administration of antithyroid drugs leading suddenly from a condition of hyperthyroidism to the opposite condition of hypothyroidism, it is unconvincing to figure out that a change of the bioavailable concentration of the thyroid hormones at the level of the tissues, such as the brain, could occur in such fast parallel course to acutely impair the psychiatric functions and maybe induce the occurrence of psychosis. Till date, there is not any substantial evidence in the literature showing a direct clinically relevant effect of the currently available antithyroid medications, when prescribed at the appropriate therapeutic doses, on the functions of the central nervous system, including the psychiatric balance. Though science requires evidence to support a thesis, the lack of evidence of a suspicion (thesis) after many decades of observation (use of antithyroid medications in the clinical practice) might somehow support the idea that such suspicion is actually not based on any solid foundation (antithesis).

4. Thyroid dysfunction and central nervous system: here comes trouble

A number of neurological or psychiatric alterations, including psychosis, can appear as clinical manifestations of abnormal thyroid hormone levels. Also a subclinical thyroid dysfunction can determine some abnormalities in the function of the central nervous system [9]. Both hyperthyroidism and hypothyroidism may lead to the exacerbation of some forms of psychosis, though depression represents the most classical psychiatric manifestation of hypothyroidism [10]. Hyperthyroid patients are more likely to manifest psychotic symptoms. However, the effects of abnormal thyroid hormone levels on the function of the central nervous system are well known and deeply characterized and do not require any additional mention or comment in this space.

There are an increasing number of reports of patients with an autoimmune thyroid disease, either Hashimoto's thyroiditis or Graves' disease, and concomitant neurological or psychiatric symptoms occurring regardless of the thyroid hormone status [11]. In these patients, the concentration of the thyroid hormones is usually normal or, anyway, not so abnormal to provide an explanation for the neurological or psychiatric manifestations. Such condition was historically defined as Hashimoto's encephalopathy [12]. Nowadays, more precise denominations such as encephalopathy associated with autoimmune thyroid disease [13] or steroid-responsive encephalopathy associated with autoimmune thyroiditis [14] are preferred, though there is still no concordance among authors with regard to the most appropriate definition. Further basic and clinical research will hopefully help and clarify the pathophysiology of this clinical condition and, subsequently, a precise and universally accepted denomination of the same could be possible.

5. Expert opinion

Till date, there is no evidence of univocal, well defined and clearly documented reports of psychosis due to the administration of antithyroid medications. Only a few historical reports, which are only partially reliable because of obvious limitations derived from an incomplete hormonal assessment or a poorly defined nosological characterization of the patients, have raised the suspicion that the antithyroid medications currently in use might induce the onset of psychosis. Moreover, very large use of these medications for the clinical management of patients with hyperthyroidism worldwide has allowed the development of a huge, deep and well-established expertise among the prescribers. As far as the author knows and as far as it concerns to the author's personal practice, it is thought that there is no actual solid concern about the risk of developing psychosis when prescribing an antithyroid drug to a patient with hyperthyroidism. On the contrary, other than psychiatric side effects of these medications can possibly occur and a reasonable degree of caution together with specifically addressed warnings must always take place. The comprehensive review of the literature done by Vita et al. has noticeably defined the current state of the knowledge on such matter and the author believes that the outcome finally reached may also help and reassure the most suspicious among the physicians. Of course, in the case that future research will show new and currently unexpected findings suggesting an association between the use of antithyroid drugs and the onset of psychosis, the concern should lift up again and the whole matter should be re-thought and carefully re-evaluated.

At the moment, it is probably much more pertinent from a clinical point of view to concentrate the interest on the neurological and psychiatric disorders, including psychosis, which can appear as manifestations of or in association with a thyroid disease. The attempt to optimize the strategies for the management of patients with abnormal thyroid hormone levels with the goal of achieving a clinically euthyroid status and the need to elucidate the nature of conditions affecting both the thyroid and the brain, like encephalopathy associated with autoimmune thyroid disease, probably represent the current hottest points in the huge and only partially revealed area of research focusing on thyroid and neurological or psychiatric disorders.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.