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Safety aspects of lithium treatment for affective disorders
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.ORCID iD: 0000-0002-8303-1210
2025 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Säkerhetsaspekter vid litiumbehandlingen hos affektiva sjukdomar (Swedish)
Abstract [en]

Bipolar disorder (BD) and schizoaffective disorder (SZD) are two serious mental disorders mostly requiring life-long treatment with mood stabilisers. Lithium is a first-line treatment for BD, generally considered superior to other mood stabilisers in terms of affective relapse and suicide prevention. However, lithium is not without problems, and adherence rates vary. One concern with lithium is its narrow therapeutic index, which carries a risk of intoxications. Several other types of adverse effects are also recognised. Of these, renal impairment may be the most well-known and feared. It is mandatory to be able to understand and recognise early signs of potentially severe or even catastrophic adverse effects. Although lithium is well established, many safety aspects remain unclear and underexplored. The overall aim of this thesis was therefore to examine some of these safety aspects of lithium treatment that are clinically relevant but insufficiently explored.

In four different studies, this thesis has examined (a) the impact on toxic lithium concentrations on the cardiac conduction system, (b) the incidence, nature, and aetiology of serious adverse drug events (ADE) arising from lithium treatment compared to other psychotropic medications, (c) the reasons for multiple lithium discontinuations in patients with BD or SZD, and (d) the effect of lithium dosing regimen on glomerular and tubular kidney function, namely whether lithium given as single daily lithium dosing (SDD) causes less renal impairment than lithium given as multiple daily lithium dosing (MDD).

The first two studies were based on the LiSIE (Lithium- Study into Effects and Side Effects), a retrospective medical recordbased cohort study from Northern Sweden. LiSIE explores both effects and side effects of lithium treatment as compared to other mood stabilisers. In the first study we found that in summary statistics, on the electrocardiogram, lithium intoxication led to changes in heart rate (p=0.046), but not in QT interval (p=0.104, p=0.070). However, few patients had clinically relevant QT changes. In the second study, we found an incidence of 1.9/1000 person years (PY) for serious ADE in patients with BD and SZD. Patients on lithium treatment and older individuals were more affected (p=0.0094, p= 0.0007).

The third study was based on the South London and Maudsley Biomedical Research Centre Case Register (SLaM-BRC case register) in the United Kingdom. Anonymised medical records were reviewed with the Clinical Record Interactive Search (CRIS) application. We found that during the 11-year observation time frame, 123 patients with BD and SZD had discontinued lithium on at least three occasions. Psychiatric reasons, such as suspected lack of insight or feeling subjectively well, were the most common reasons for lithium discontinuations in this particular group. They accounted for over 70% of all lithium discontinuations.

Finally, in the fourth study, we conducted systematic review. Of 709 studies screened, a total of 20 studies were included, measuring various tubular and glomerular outcomes. No study was assessed to be of good quality for investigating the research question. Only one study met the criteria of fair quality regarding tubular outcome. Confounding factors such as the daily total lithium dose were rarely considered.

Our results indicate that cardiac adverse effects during lithium intoxication seem mostly discrete, but can occur. The same applies to serious ADE related to the treatment of BD or SZD; the overall incidence was classified as uncommon but not rare. However, older individuals and lithium treatment seem to carry a higher risk of developing serious ADE. In multiple lithium discontinuers, lithium seems mainly discontinued for psychiatric reasons rather than adverse effects, leading to a subsequent restart due to affective relapse. A better understanding is needed of how to best promote adherence in this group of patients, to prevent a perpetual cycle of remitting when on lithium and relapsing when off lithium. Lastly, based on the low quality of the available studies, the question of whether the lithium dosing regimen is relevant for the protection of kidney function cannot be decided. Hence, there is no current evidence supporting the assumption that lithium given as SDD would be to be superior to MDD for the prevention or containment of renal impairment.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2025. , p. 125
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2371
Keywords [en]
Bipolar disorder, schizoaffective disorders, mood disorders, lithium, mood stabilisers, drug-related side effects and adverse reactions, poisoning, drug interaction, medication adherence, toxicity, long QT syndrome, electrocardiography, systematic review, kidney, diabetes insipidus, renal insufficiency, psychotropic drugs, incidence
National Category
Psychiatry
Research subject
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-243055ISBN: 9789180707367 (print)ISBN: 9789180707374 (electronic)OAI: oai:DiVA.org:umu-243055DiVA, id: diva2:1989002
Public defence
2025-09-05, Konferenscentrum, Sunderby Hospital, Luleå, 09:00 (Swedish)
Opponent
Supervisors
Note

Public defence available via Zoom.

Available from: 2025-08-15 Created: 2025-08-14 Last updated: 2025-09-16Bibliographically approved
List of papers
1. Effects of toxic lithium levels on ECG: findings from the LiSIE retrospective cohort study
Open this publication in new window or tab >>Effects of toxic lithium levels on ECG: findings from the LiSIE retrospective cohort study
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2022 (English)In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, no 19, article id 5941Article in journal (Refereed) Published
Abstract [en]

(1) Background: Few studies have explored the impact of lithium intoxication on the heart.

(2) Methods: We examined electrocardiogram (ECG) changes associated with lithium intoxication in the framework of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. We analysed ECGs before, during, and after intoxication.

(3) Results: Of the 1136 patients included, 92 patients had experienced 112 episodes of lithium intoxication. For 55 episodes, there was an ECG available at the time; for 48 episodes, there was a reference ECG available before and/or after the lithium intoxication. Lithium intoxication led to a statistically significant decrease in heart rate from a mean 76 beats/min (SD 16.6) before intoxication to 73 beats/min (SD 17.1) during intoxication (p = 0.046). QTc correlated only weakly with lithium concentration (ρ = 0.329, p = 0.014). However, in 24% of lithium intoxication episodes, there were QT prolongations. In 54% of these, QTc exceeded 500 ms; patients with chronic intoxications being more affected.

(4) Conclusions: Based on summary statistics, effects of lithium intoxication on HR and QTc seem mostly discrete and not clinically relevant. However, QT prolongation can carry a risk of becoming severe. Therefore, an ECG should always be taken in patients presenting with lithium intoxication.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
lithium, drug-related side effects and adverse reactions, toxicity, long QT syndrome, electrocardiography
National Category
Psychiatry Cardiology and Cardiovascular Disease
Research subject
Medicine; Cardiology; Psychiatry
Identifiers
urn:nbn:se:umu:diva-201264 (URN)10.3390/jcm11195941 (DOI)000866822000001 ()36233807 (PubMedID)2-s2.0-85139754027 (Scopus ID)
Funder
Norrbotten County Council, NLL-931604Norrbotten County Council, NLL-941888Norrbotten County Council, NLL-969413
Available from: 2022-11-24 Created: 2022-11-24 Last updated: 2025-08-14Bibliographically approved
2. Serious adverse drug events associated with psychotropic treatment of bipolar or schizoaffective disorder: a 17-year follow-up on the LiSIE retrospective cohort study
Open this publication in new window or tab >>Serious adverse drug events associated with psychotropic treatment of bipolar or schizoaffective disorder: a 17-year follow-up on the LiSIE retrospective cohort study
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2024 (English)In: Frontiers in Psychiatry, E-ISSN 1664-0640, Vol. 15, article id 1358461Article in journal (Refereed) Published
Abstract [en]

Introduction: Mood stabilisers and other psychotropic drugs can lead to serious adverse drug events (ADEs). However, the incidence remains unknown. We aimed to (a) determine the incidence of serious ADEs in patients with bipolar or schizoaffective disorders, (b) explore the role of lithium exposure, and (c) describe the aetiology.

Methods: This study is part of the LiSIE (Lithium—Study into Effects and Side Effects) retrospective cohort study. Between 2001 and 2017, patients in the Swedish region of Norrbotten, with a diagnosis of bipolar or schizoaffective disorder, were screened for serious ADEs to psychotropic drugs, having resulted in critical, post-anaesthesia, or intensive care. We determined the incidence rate of serious ADEs/1,000 person-years (PY).

Results: In 1,521 patients, we identified 41 serious ADEs, yielding an incidence rate of 1.9 events per 1,000 PY. The incidence rate ratio (IRR) between ADEs with lithium present and causally implicated and ADEs without lithium exposure was significant at 2.59 (95% CI 1.20–5.51; p = 0.0094). The IRR of ADEs in patients <65 and ≥65 years was significant at 3.36 (95% CI 1.63–6.63; p = 0.0007). The most common ADEs were chronic lithium intoxication, oversedation, and cardiac/blood pressure-related events.

Discussion: Serious ADEs related to treatment of bipolar (BD) or schizoaffective disorder (SZD) were uncommon but not rare. Older individuals were particularly at risk. The risk was higher in individuals exposed to lithium. Serum lithium concentration should always be checked when patients present with new or unclear somatic symptoms. However, severe ADEs also occurred with other mood stabilisers and other psychotropic drugs.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
adverse drug events, bipolar disorder, incidence, intoxication, lithium, neuroleptic malignant syndrome, psychotropic drugs, serotonin syndrome
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-223627 (URN)10.3389/fpsyt.2024.1358461 (DOI)001203542400001 ()2-s2.0-85190497315 (Scopus ID)
Funder
Norrbotten County CouncilRegion Västerbotten, RV-939217Umeå University
Available from: 2024-04-29 Created: 2024-04-29 Last updated: 2025-08-14Bibliographically approved
3. Reasons for discontinuing and restarting lithium multiple times: a case-register study based on the South London and Maudsley NHS Foundation Trust Clinical Record Interactive Search system
Open this publication in new window or tab >>Reasons for discontinuing and restarting lithium multiple times: a case-register study based on the South London and Maudsley NHS Foundation Trust Clinical Record Interactive Search system
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2025 (English)In: Therapeutic Advances in Psychopharmacology, ISSN 2045-1253, E-ISSN 2045-1261, Vol. 15, p. 1-16Article in journal (Refereed) Published
Abstract [en]

Background: Despite the therapeutic benefits, non-adherence to lithium is common. One recent study showed that most patients discontinue lithium due to adverse effects. Little is known about individuals starting and discontinuing lithium repeatedly.

Objectives: We aimed to determine reasons for discontinuing and restarting lithium multiple times in patients with bipolar or schizoaffective disorder.

Design: Retrospective cohort study based on psychiatric case records of the SLaM Biomedical Research Centre Case Register (SLaM BRC case register).

Method: Anonymised clinical data were extracted via the Clinical Record Interactive Search (CRIS) application. Patients with at least three events of lithium discontinuation between 2012 and 2022 were included.

Results: Of 2888 eligible patients, 123 patients had discontinued lithium on at least three occasions. Psychiatric reasons, such as suspected lack of insight, feeling subjectively well or disagreeing with diagnosis, were the most common reasons for lithium discontinuations. They accounted for 77.2% of cases in the first event of discontinuation, 73.2% in the second and 72.3% in the third event. Adverse physical effects accounted for 19.5% of cases in the first event of discontinuation, 25.2% in the second and 26.0% in the third event. Relapse into the underlying affective disorder accounted for 83.7% each of reinstatements in the first and second events and 82.1% in the third event.

Discussion: In our sample, lithium was discontinued due to adverse effects in only a minority of patients. In most cases, the reasons for lithium discontinuation were considered psychiatric. Lithium was mainly restarted due to relapse. This warrants a better understanding of the reasons for repeatedly discontinuing lithium and the best way to promote lithium adherence to prevent a perpetual cycle of remitting when on lithium and relapsing when off lithium.

Place, publisher, year, edition, pages
Sage Publications, 2025
Keywords
bipolar disorder, drug-related side effects and adverse reactions, lithium, medication adherence, schizoaffective disorder
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-238720 (URN)10.1177/20451253251332275 (DOI)001475942400001 ()40296869 (PubMedID)2-s2.0-105003963759 (Scopus ID)
Funder
Norrbotten County Council
Available from: 2025-05-16 Created: 2025-05-16 Last updated: 2025-08-14Bibliographically approved
4. Lithium dosing regimen (one or multiple doses) and its impact on kidney function – a systematic review
Open this publication in new window or tab >>Lithium dosing regimen (one or multiple doses) and its impact on kidney function – a systematic review
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(English)Manuscript (preprint) (Other academic)
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-243051 (URN)
Available from: 2025-08-14 Created: 2025-08-14 Last updated: 2025-08-14Bibliographically approved

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