Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study

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Abstract

Background

Lithium remains first choice as maintenance treatment for bipolar affective disorder. Yet, about half of all individuals may stop their treatment at some point, despite lithium’s proven benefits concerning the prevention of severe affective episodes and suicide.

Methods

Retrospective cohort study in the Swedish region of Norrbotten into the causes of lithium discontinuation. The study was set up to (1) test whether patients with bipolar affective disorder or schizoaffective disorder, treated with lithium maintenance therapy, were more likely to discontinue lithium because of adverse effects than lack of therapeutic effectiveness, (2) explore gender differences, (3) understand the role of diagnosis and (4) identify who, patient or doctor, took the initiative to stop lithium. Review of medical records for all episodes of lithium discontinuation that had occurred between 1997 and 2013 with the intent to stop lithium for good.

Results

Of 873 patients treated with lithium, 54% discontinued lithium, corresponding to 561 episodes of lithium discontinuation. In 62% of episodes, lithium was discontinued due to adverse effects, in 44% due to psychiatric reasons, and in 12% due to physical reasons interfering with lithium treatment. The five single most common adverse effects leading to lithium discontinuation were diarrhoea (13%), tremor (11%), polyuria/polydipsia/diabetes insipidus (9%), creatinine increase (9%) and weight gain (7%). Women were as likely as men to take the initiative to stop lithium, but twice as likely to consult a doctor before taking action ( p < 0.01). Patients with type 1 BPAD or SZD were more likely to discontinue lithium than patients with type 2 or unspecified BPAD ( p < 0.01). Patients with type 1 BPAD or SZD were more likely to refuse medication ( p < 0.01). Conversely, patients with type 2 or unspecified BPAD were three times as likely to discontinue lithium for lack or perceived lack of effectiveness ( p < 0.001).

Conclusions

Stopping lithium treatment is common and occurs mostly due to adverse effects . It is important to discuss potential adverse effects with patients before initiation and continuously during lithium treatment, to reduce the frequency of potentially unnecessary discontinuations.

Related collections

Most cited references 23

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Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000–2014†

Joseph Hayes, Louise Marston, Kate Walters … (2017)

Background Bipolar disorder and schizophrenia are associated with increased mortality relative to the general population. There is an international emphasis on decreasing this excess mortality. Aims To determine whether the mortality gap between individuals with bipolar disorder and schizophrenia and the general population has decreased. Method A nationally representative cohort study using primary care electronic health records from 2000 to 2014, comparing all patients diagnosed with bipolar disorder or schizophrenia and the general population. The primary outcome was all-cause mortality. Results Individuals with bipolar disorder and schizophrenia had elevated mortality (adjusted hazard ratio (HR) = 1.79, 95% CI 1.67–1.88 and 2.08, 95% CI 1.98–2.19 respectively). Adjusted HRs for bipolar disorder increased by 0.14/year (95% CI 0.10–0.19) from 2006 to 2014. The adjusted HRs for schizophrenia increased gradually from 2004 to 2010 (0.11/year, 95% CI 0.04–0.17) and rapidly after 2010 (0.34/year, 95% CI 0.18–0.49). Conclusions The mortality gap between individuals with bipolar disorder and schizophrenia, and the general population is widening.

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Lithium side effects and toxicity: prevalence and management strategies

Michael Gitlin (2016)

Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon.

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Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.

Andrea Cipriani, Seena Fazel, Shon Lewis (2010)

Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder. 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332. 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death). For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy. Stanley Medical Research Institute; Sanofi-Aventis. Copyright 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Louise Öhlund: louise.olund@norrbotten.se

Michael Ott: author@ott.eu

Sofia Oja: sofia.oja@norrbotten.se

Malin Bergqvist: malin.bergqvist@norrbotten.se

Robert Lundqvist: robert.lundqvist@norrbotten.se

Mikael Sandlund: mikael.sandlund@umu.se

Ellinor Salander Renberg: ellinor.salander.renberg@umu.se

Ursula Werneke:

ORCID: http://orcid.org/0000-0002-5023-3254

+46 702 067151 , uwerneke@gmail.com

Journal

Journal ID (nlm-ta): BMC Psychiatry

Journal ID (iso-abbrev): BMC Psychiatry

Title: BMC Psychiatry

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-244X

Publication date (Electronic): 7 February 2018

Publication date PMC-release: 7 February 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 37

Affiliations

[1 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Sunderby Research Unit, Department of Clinical Sciences, Division of Psychiatry, , Umeå University, ; Umeå, Sweden

[2 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Public Health and Clinical Medicine, Division of Medicine, , Umeå University, ; Umeå, Sweden

[3 ]ISNI 0000 0004 0626 5317, GRID grid.416723.5, Department of Psychiatry, , Sunderby Hospital, ; Luleå, Sweden

[4 ]Department of Psychiatry, Piteå Älvdals Hospital, Piteå, Sweden

[5 ]Research and Innovation Unit, Luleå, Norrbotten Region Sweden

[6 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Clinical Science, Division of Psychiatry, , Umeå University, ; Umeå, Sweden

[7 ]ISNI 0000 0004 0626 5317, GRID grid.416723.5, Sunderby Hospital – Psychiatry, ; 97180 Luleå, Sweden

Author information

Ursula Werneke http://orcid.org/0000-0002-5023-3254

Article

Publisher ID: 1622

DOI: 10.1186/s12888-018-1622-1

PMC ID: 5804058

PubMed ID: 29415689

SO-VID: 53805151-b95c-4e7a-b48f-95afbad8413d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.