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Affective disorders and their treatments: implications for thyroid function
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. (LiSIE)ORCID-id: 0000-0002-3536-6227
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background

The relationship between affective disorders, mood-stabilisers and thyroid dysfunction is complex and poorly understood. Symptoms of thyroid dysfunction can overlap with symptoms of affective disorder, destabilise mood, and impact physical health. Subjective symptoms and biochemical abnormalities may not always match, especially when changes in thyroid function are only mild. Therefore, diagnosis and treatment of both hypothyroidism and hyperthyroidism in individuals with affective disorders remain complex. For lithium, a first-line treatment for bipolar disorder, an impact on thyroid function was first described in 1968. Since that time, it has become evident that lithium is much more frequently associated with hypothyroidism than hyperthyroidism. But even for lithium, many aspects of how associated thyroid dysfunction should be handled remain unclear. 

Aims 

The overall aim of this thesis was, in five studies, to examine aspects of the diagnosis and treatment of thyroid dysfunction in individuals with affective disorders, with a particular focus on lithium. The individual aims of the five studies were to

  • determine if lithium-associated hypothyroidism was reversible in individuals who had discontinued lithium.
  • identify patterns and trends in thyroid hormone replacement therapy prescribed for individuals with bipolar or schizoaffective disorder.
  • assess whether elevated thyroxine concentrations (hyperthyroxinaemia) were a risk factor for lithium intoxication caused by a change in tubular renal function.
  • examine the incidence rate and aetiology of lithium-associated hyperthyroidism in individuals with bipolar or schizoaffective disorder.
  • explore the attitudes of practising clinicians towards the diagnosis and treatment of subclinical hypothyroidism in individuals with or without affective disorder or anxiety.

Methods

Studies 1–4 were part of the LiSIE (Lithium - Study into Effects and Side Effects) retrospective cohort study. LiSIE compares the effects and adverse effects of lithium treatment and other mood stabilisers in the Norrbotten Region and the Region of Västerbotten over a time period of up to 21 years between 1997–2017. For our studies, we used data from the Norrbotten Region only. Study 5 used a three-round modified Delphi consensus-building process. Study 5 was conducted with clinicians from three specialties, general practice, endocrinology and psychiatry, from two countries with similar health care systems, Sweden and the UK. 

Results

Study 1: Of 1340 potentially eligible individuals with lithium treatment, 90 individuals (who had developed hypothyroidism while treated with lithium and later discontinued lithium), were included. Of these, 27% had overt hypothyroidism at the start of thyroid hormone replacement therapy. Of the 85 individuals available for follow-up, 41% stopped thyroid hormone replacement therapy after lithium discontinuation. Only six individuals reinstated thyroid hormone replacement therapy subsequently. Only one had overt hypothyroidism.

Study 2: Of 1564 potentially eligible individuals with bipolar or schizoaffective disorder, 291 (27%) had received thyroid hormone replacement therapy at some point during the 21-year review period. In 41% of cases, thyroid hormone replacement therapy was started for subclinical hypothyroidism. At the start of thyroid hormone replacement therapy, the median thyroid stimulating hormone (TSH) concentration was 6.0 (IQR 4.0) mIU/L. The median free serum thyroxine (fT4) was 11.8 (IQR 3.9) pmol/L. The median TSH concentration at the start of thyroid hormone replacement therapy decreased annually by 0.10 mIU/L, being significantly higher in individuals treated with lithium than in individuals treated with other mood stabilisers.

Study 3: Of 1562 potentially eligible individuals with bipolar or schizoaffective disorder, 53 individuals had experienced a total of 65 episodes of unintentional lithium intoxication during the review period. In nine episodes, there was elevated fT4 at the time of lithium intoxication, corresponding to an incidence of 1.3 episodes/1000 person-years. For all nine episodes of unintentional lithium intoxication, we could identify alternative explanations that were more plausible than hyperthyroxinaemia. 

Study 4: In 1562 individuals with bipolar disorder or schizoaffective disorder, we identified 16 episodes of hyperthyroidism, corresponding to an incidence rate of 0.9 episodes/1000 person-years. Individuals who had concurrently been exposed to lithium, had an incidence rate of 1.3 episodes/1000 person-years. Individuals who had been previously exposed to lithium had an incidence rate of 0.8/1000 person-years. Individuals who had never been exposed to lithium (lithium naïve) had a 0.5/1000 person-years incidence rate. There were no significant differences in the risk ratios for individuals with concurrent or previous exposure compared to lithium-naïve individuals, neither for hyperthyroidism overall, nor for thyrotoxicosis or thyroiditis. 

Study 5: For the expert panel, 60 clinicians; 20 general practitioners, 20 endocrinologists and 20 psychiatrists were recruited. Fifty-three (88%) participants completed all three rounds. The participants reached a consensus on five of the 26 practice statements. The participants agreed that (a) repeated testing was required for the diagnosis of subclinical hypothyroidism, (b) antibody screening should usually occur, and (c and d) antibody screening would strengthen the indication for thyroid hormone replacement therapy in both individuals with and without affective disorder or anxiety. The participants disagreed with (e) requiring a TSH threshold of ≥ 20 mIU/L before starting thyroid hormone replacement therapy.

Conclusions

Study 1: In most cases, lithium-associated hypothyroidism appears reversible. Therefore, thyroid hormone replacement therapy could be discontinued more often once lithium is stopped. 

Study 2: In most cases, thyroid hormone replacement therapy was started with mild or absent thyroid function changes. The TSH level at which thyroid hormone replacement therapy was initiated decreased over time. When starting thyroid hormone replacement therapy for subclinical hypothyroidism in people with bipolar or schizoaffective disorder, clinicians must carefully weigh the benefits and risks.

Study 3: Lithium intoxication with simultaneously elevated fT4 is uncommon. A direct causal link between elevated fT4 and altered tubular renal function remains elusive. An increased frequency of routine thyroid function tests is unlikely to decrease the risk of lithium intoxication. 

Study 4: Lithium-associated hyperthyroidism is uncommon. The risk of hyperthyroidism does not differ significantly between lithium-exposed and lithium-naïve individuals.

Study 5: Attitudes toward diagnosing and treating subclinical hypothyroidism remain diverse. A threshold of an TSH of at least 20 mIU/L for thyroid hormone replacement therapy start, suggested in a previously published guideline, was deemed too high. As the evidence regarding diagnosis and treatment of subclinical hypothyroidism remains limited, future guidelines should consider the views of a broad range of practising clinicians to increase their clinical acceptability and usefulness. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet , 2023. , s. 108
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2220
Nyckelord [en]
Bipolar disorder, affective disorder, lithium, thyroid dysfunction, hyperthyroidism, hypothyroidism, Delphi-consensus
Nationell ämneskategori
Psykiatri
Forskningsämne
psykiatri
Identifikatorer
URN: urn:nbn:se:umu:diva-204335ISBN: 978-91-7855-967-1 (digital)ISBN: 978-91-7855-966-4 (tryckt)OAI: oai:DiVA.org:umu-204335DiVA, id: diva2:1733277
Disputation
2023-03-03, Aulan, Sunderby sjukhus, Luleå, 13:00 (Engelska)
Opponent
Handledare
Anmärkning

List of studies in the full text does not include the paper Incidence of hyperthyroidism in patients with bipolar disorder with or without lithium – 21-year follow-up from the LiSIE retrospective cohort study.

Tillgänglig från: 2023-02-10 Skapad: 2023-02-01 Senast uppdaterad: 2024-03-03Bibliografiskt granskad
Delarbeten
1. Lithium-associated hypothyroidism and potential for reversibility after lithium discontinuation: findings from the LiSIE retrospective cohort study
Öppna denna publikation i ny flik eller fönster >>Lithium-associated hypothyroidism and potential for reversibility after lithium discontinuation: findings from the LiSIE retrospective cohort study
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2020 (Engelska)Ingår i: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 34, nr 3, s. 293-303Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: The association between lithium and thyroid dysfunction has long been known. However, it remains unknown if lithium-associated hypothyroidism is reversible once lithium treatment has been stopped.

Aims: To determine whether lithium-associated hypothyroidism was reversible in patients who subsequently discontinued lithium.

Methods: A retrospective cohort study in the Swedish region of Norrbotten into the effects and side- effects of lithium treatment and other drugs for relapse prevention (Lithium – Study into Effects and Side Effects). For this particular study, we reviewed medical records between 1997 and 2015 of patients with lithium-associated hypothyroidism who had discontinued lithium.

Results: Of 1340 patients screened, 90 were included. Of these, 27% had overt hypothyroidism at the start of thyroid replacement therapy. The mean delay from starting lithium to starting thyroid replacement therapy was 2.3 years (SD 4.7). In total, 50% of patients received thyroid replacement therapy within 10 months of starting lithium. Of 85 patients available for follow-up, 41% stopped thyroid replacement therapy after lithium discontinuation. Only six patients reinstated thyroid replacement therapy subsequently. Of these, only one had overt hypothyroidism.

Conclusions: Lithium-associated hypothyroidism seems reversible in most patients once lithium has been discontinued. In such cases, thyroid replacement therapy discontinuation could be attempted much more often than currently done. Based on the limited evidence of our study, we can expect hypothyroidism to recur early after thyroid replacement therapy discontinuation, if at all.

Ort, förlag, år, upplaga, sidor
Sage Publications, 2020
Nyckelord
Bipolar disorder, lithium, hypothyroidism, thyroxine, adverse effect
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:umu:diva-165328 (URN)10.1177/0269881119882858 (DOI)000495170900001 ()31670617 (PubMedID)2-s2.0-85074812491 (Scopus ID)
Forskningsfinansiär
Region NorrbottenAstraZeneca
Tillgänglig från: 2019-12-02 Skapad: 2019-12-02 Senast uppdaterad: 2023-02-02Bibliografiskt granskad
2. Patterns of thyroid hormone prescription in patients with bipolar or schizoaffective disorder: Findings from the lisie retrospective cohort study
Öppna denna publikation i ny flik eller fönster >>Patterns of thyroid hormone prescription in patients with bipolar or schizoaffective disorder: Findings from the lisie retrospective cohort study
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2021 (Engelska)Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 10, nr 21, artikel-id 5062Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The prescription of thyroid hormone replacement therapy (THRT) has increased in the general population; the thyroid stimulating hormone (TSH) threshold to initiate THRT has decreased. It remains unclear whether a similar trend has occurred in patients with bipolar disorder (BD). In this work we explore patterns and trends of prescribing THRT in patients with BD or schizoaffective disorder (SZD) with an observational study and time‐trend analysis in the framework of the LiSIE (Lithium—Study into Effects and Side Effects) retrospective cohort study. In most patients, THRT was initiated for subclinical hypothyroidism. The median TSH at which THRT was started was 6.0 (IQR 4.0) mIU/L and the median free serum thyroxine (fT4) at which THRT was started was 11.8 (IQR 3.9) pmol/L. The median TSH concentration at the start of THRT decreased annually with 0.10 mIU/L (p = 0.047) and was higher in patients treated with lithium than in patients treated with other mood stabilisers (p = 0.02). In conclusion, THRT was typically initiated in the context of mild or absent alterations of thyroid function tests with a decreasing TSH threshold. As THRT is rarely reversed once initiated, clinicians need to weigh up potential benefits and risks when prescribing THRT for subclinical hypothyroidism in patients with BD or SZD.

Ort, förlag, år, upplaga, sidor
MDPI, 2021
Nyckelord
Bipolar disorder, Hypothyroidism, Lithium, Mood stabilizer, Schizoaffective disorder, Thyroid dysfunction, TSH
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-189214 (URN)10.3390/jcm10215062 (DOI)000718656200001 ()2-s2.0-85118180676 (Scopus ID)
Tillgänglig från: 2021-11-12 Skapad: 2021-11-12 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
3. Elevated Thyroxine Concentration and Lithium Intoxication - An Analysis Based on the LiSIE Retrospective Cohort Study
Öppna denna publikation i ny flik eller fönster >>Elevated Thyroxine Concentration and Lithium Intoxication - An Analysis Based on the LiSIE Retrospective Cohort Study
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2022 (Engelska)Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, nr 11, artikel-id 3041Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

(1) Background: It has been suggested that hyperthyroxinaemia is a risk factor for lithium intoxication by altering tubular renal function. (2) Methods: We determined the relevance of hyperthyroxinaemia as a risk factor for lithium intoxication in patients with bipolar or schizoaffective disorder in the framework of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. Of 1562 patients included in the study, 897 patients had been exposed to lithium at any time between 1997 and 2017 with 6684 person-years of observation. (3) Results: There were 65 episodes of unintentional lithium intoxication in 53 patients. There were nine episodes with hyperthyroxinaemia at the time of lithium intoxication, yielding an incidence of 1.3 episodes/1000 person-years. For all nine episodes, we could identify alternative, more plausible, explanations for the observed lithium intoxications. (4) Conclusions: We conclude that hyperthyroxinaemia-associated unintentional lithium intoxication is an uncommon event. A direct causal link between hyperthyroxinaemia and altered tubular renal function remains elusive. Increasing the frequency of routine thyroid function tests seems unlikely to decrease the risk of lithium intoxication.

Ort, förlag, år, upplaga, sidor
MDPI, 2022
Nyckelord
hyperthyroxinaemia, hyperthyroidism, thyroxine, lithium, intoxication, bipolar disorder, schizoaffective disorder, thyroid disorder
Nationell ämneskategori
Psykiatri Endokrinologi och diabetes Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:umu:diva-199132 (URN)10.3390/jcm11113041 (DOI)000809003400001 ()35683429 (PubMedID)2-s2.0-85130738317 (Scopus ID)
Forskningsfinansiär
Region NorrbottenVisare Norr, 847881Visare Norr, 939391
Tillgänglig från: 2022-09-05 Skapad: 2022-09-05 Senast uppdaterad: 2023-05-23Bibliografiskt granskad
4. Incidence of hyperthyroidism in patients with bipolar or schizoaffective disorder with or without lithium: 21-year follow-up from the LiSIE retrospective cohort study
Öppna denna publikation i ny flik eller fönster >>Incidence of hyperthyroidism in patients with bipolar or schizoaffective disorder with or without lithium: 21-year follow-up from the LiSIE retrospective cohort study
Visa övriga...
2023 (Engelska)Ingår i: Therapeutic Advances in Psychopharmacology, ISSN 2045-1253, E-ISSN 2045-1261, Vol. 13, artikel-id 20451253231151514Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Lithium-associated hyperthyroidism is much rarer than lithium-associated hypothyroidism. Yet, it may be of substantial clinical significance for affected individuals. For instance, lithium-associated hyperthyroidism could destabilise mood, mimic manic episodes and impact physical health. Only few studies have explored incidence rates of lithium-associated hyperthyroidism. Even fewer studies have compared incidence rates according to lithium exposure history.

Objectives: To determine the impact of lithium treatment on the incidence rate of hyperthyroidism in patients with bipolar or schizoaffective disorder and assess its aetiology.

Design: This study is part of the LiSIE (Lithium - Study into Effects and Side Effects) retrospective cohort study.

Methods: Between 1997 and 2017, patients in the Swedish region of Norrbotten with a diagnosis of bipolar or schizoaffective disorder were screened for all episodes of overt hyperthyroidism in form of thyrotoxicosis or thyroiditis. Incidence rates of episodes of hyperthyroidism per 1000 person-years (PY) were compared in relation to lithium exposure; concurrent, previous, or no exposure ever (lithium-naïve patients).

Results: In 1562 patients, we identified 16 episodes of hyperthyroidism corresponding to an incidence rate of 0.88 episodes per 1000 PY. Ninety-four percent of episodes had occurred in women. Patients who had concurrently been exposed to lithium, had an incidence rate of 1.35 episodes per 1000 PY. Patients who had previously been exposed to lithium had an incidence rate of 0.79 per 1000 PY. Patients who had never been exposed to lithium had an incidence rate of 0.47 per 1000 PY. There were no significant differences in the risk ratios for patients with concurrent or previous exposure compared with lithium-naïve patients, neither for hyperthyroidism overall, thyrotoxicosis, or thyroiditis.

Conclusion: Lithium-associated hyperthyroidism seems uncommon. The risk of hyperthyroidism does not seem significantly higher in patients with current or previous lithium exposure than in lithium-naïve patients.

Ort, förlag, år, upplaga, sidor
Sage Publications, 2023
Nyckelord
bipolar disorder, hyperthyroidism, incidence rate, lithium, schizoaffective disorder, thyroiditis, thyrotoxicosis
Nationell ämneskategori
Psykiatri Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-203909 (URN)10.1177/20451253231151514 (DOI)000928749700001 ()36776622 (PubMedID)2-s2.0-85174272670 (Scopus ID)
Forskningsfinansiär
Visare Norr, 847881Visare Norr, 939391
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2023-01-23 Skapad: 2023-01-23 Senast uppdaterad: 2023-10-27Bibliografiskt granskad
5. Treating subclinical hypothyroidism in individuals with or without mental health problems – a Delphi based expert consensus study in two countries
Öppna denna publikation i ny flik eller fönster >>Treating subclinical hypothyroidism in individuals with or without mental health problems – a Delphi based expert consensus study in two countries
Visa övriga...
2023 (Engelska)Ingår i: Frontiers in Endocrinology, E-ISSN 1664-2392, artikel-id 1204842Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Subclinical hypothyroidism (SCH) is a common endocrine problem with prevalence estimates between 4% and 20%. Symptoms are often non-specific but can substantially affect well-being leading to repeated medical consultations. The effect of thyroid hormone replacement therapy (THRT) in patients with SCH remains uncertain. Current guidelines, limited by the lack of high-quality evidence, have been controversial with limited adherence in clinical practice.

Methods: Three-round modified Delphi method to establish consensus regarding diagnosis and treatment of individuals with SCH with and without affective disorder or anxiety, conducted with clinicians from three specialties, general practice, endocrinology and psychiatry, and two countries, Sweden and the United Kingdom.

Results: Sixty clinicians, 20 per specialty, were recruited. Fifty-three (88%) participants completed all three rounds. The participants reached consensus on five of the 26 practice statements that (a) repeated testing was required for the diagnosis of subclinical hypothyroidism, (b) antibody screening should usually occur, and (c and d) antibody screening would strengthen the indication for thyroid hormone replacement therapy in both individuals with or without affective disorder or anxiety. The participants disagreed with (e) a requirement of a TSH threshold ≥ 20 mIU/L for thyroid hormone replacement therapy start. Psychiatrists and GPs but not endocrinologists, agreed that there was a frequent discrepancy between laboratory results and clinical symptoms, and disagreed that testing for thyroid dysfunction was overused in patients presenting with depression or anxiety, or fatigue.

Conclusions: In many aspects, attitudes toward diagnosing and treating SCH remain diverse. The inability of our Delphi panel to achieve consensus on most items and the disagreement with a TSH ≥ 20 mIU/L threshold for treatment suggest that the concept of SCH may need rethinking with a better understanding of the hypothalamic-pituitary-thyroid physiology. Given that the scientific evidence is currently not conclusive, guidelines in this area should not be taken as definitive.

Ort, förlag, år, upplaga, sidor
Frontiers Media S.A., 2023
Nyckelord
subclinical hypothyroidism, TSH, affective disorder, Delphi method, consensus, practice guideline, thyroxine, diagnosis
Nationell ämneskategori
Psykiatri
Identifikatorer
urn:nbn:se:umu:diva-203908 (URN)10.3389/fendo.2023.1204842 (DOI)001035764500001 ()37501790 (PubMedID)2-s2.0-85165991855 (Scopus ID)
Forskningsfinansiär
Visare Norr, VISARENORR968201Region Norrbotten, NLL-969485
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2023-01-23 Skapad: 2023-01-23 Senast uppdaterad: 2024-01-17Bibliografiskt granskad

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