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Factors affecting the pharmacological treatment of bipolar disorder
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Forskningsenheten Sunderbyn.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: In patients with bipolar disorder, long-term treatment with mood-stabilisers is often required to prevent manic and depressive episodes. At present, our knowledge remains limited regarding factors that influence the outcomes of mood-stabiliser treatment.

Lithium is a first-line treatment of bipolar disorder, thought to be superior regarding the prevention of acute relapse, self-harm and suicide. But despite its therapeutic superiority, patients may find lithium difficult to take long-term. The reasons why patients discontinue lithium treatment remain largely unknown. Neither do we know whether lithium is equally effective in patients with bipolar I and bipolar II disorder. Finally, there is only little evidence on how patients with a dual diagnosis of bipolar disorder and adult attention-deficit hyperactivity disorder (ADHD) should be treated. In this patient group, central stimulant treatment may be of benefit, as long as mood-stabilisers are given simultaneously to prevent manic relapses. However, there are no studies that have explored the impact of central stimulants on suicidal and non-suicidal self-injurious behaviour in patients with such a dual diagnosis.

Aim: The overall aim of this thesis was to study three factors that may modify treatment outcomes in patients with bipolar disorder or schizoaffective disorder; (1) adherence to lithium and reasons for lithium discontinuation, (2) impact of lithium discontinuation on clinical course in different bipolar disorder subtypes, and (3) impact of central stimulants on suicidal and non-suicidal self-injurious behaviour in patients with a dual diagnosis of bipolar disorder and ADHD.

Method shared by all studies: All three studies were part of LiSIE (Lithium – Study into Effects and Side Effects), a retrospective cohort study in the regions of Norrbotten and Västerbotten, exploring effects and side-effects of lithium and other mood-stabilisers.  For our studies, we identified 1566 individuals who had been diagnosed with bipolar disorder or schizoaffective disorder. Study II and III are based on 1564 patients due to consent withdrawal in one patient and diagnosis reassessment in another. For the respective study included in this thesis, we extracted routine clinical data from the medical records.

Study I identified and assessed the reasons for lithium discontinuation in 468 patients with bipolar disorder or schizoaffective disorder in relation to (a) type of underlying disorder, bipolar I or schizoaffective disorder versus bipolar II or other bipolar disorder, (b) gender, and (c) person taking the initiative to discontinue lithium (doctor or patient).

Study II applied a mirror-image design to examine the clinical course and need for hospital admissions in 194 patients with either bipolar I or schizoaffective disorder or bipolar II or other bipolar disorder within two years before and after lithium discontinuation.

Study III assessed occurrence of suicidal or non-suicidal self-injurious behaviour in 206 patients with a dual diagnosis of bipolar disorder or schizoaffective disorder and ADHD. This study also used a mirror-image design, comparing the number of suicide attempts and non-suicidal self-injury events within six months and two years before and after central stimulant initiation.

Results: Study I: More than half of all patients discontinued lithium at some point. Lithium discontinuation mainly occurred because of adverse effects. More patients with bipolar II or other bipolar disorder than patients with bipolar I or schizoaffective disorder discontinued lithium because of a perceived lack of effect. Men were more likely to discontinue lithium when feeling well. They were also less likely to consult with a doctor prior discontinuation.

Study II: The number of hospital admissions and bed-days doubled after lithium discontinuation. This increase was exclusively attributable to patients with bipolar I or schizoaffective disorder. Not having consulted with a doctor prior to lithium discontinuation or no treatment with an alternative mood-stabiliser at the time of lithium discontinuation led to more admissions.

Study III: In patients with a dual diagnosis of bipolar or schizoaffective disorder and ADHD, central stimulant treatment reduced the number of suicide attempts and non-suicidal self-injury events. There was no increase in number of hospital admissions.

Conclusion: Lithium discontinuation in patients with bipolar disorder or schizoaffective disorder is common and mainly occurs because of adverse effects. It is important that patients who may benefit from lithium can continue their treatment. Therefore, clinicians should discuss and manage potential adverse effects of lithium treatment with patients before initiation and continuously during treatment. Particularly men may require proactive follow-up since they may be more likely to discontinue their treatment without consulting a doctor.

Lithium discontinuation in patients with bipolar I or schizoaffective disorder comes at a cost of deteriorated mental health and increased hospital utilisation. In patients with bipolar II or other bipolar disorder, judged on the impact of discontinuation alone, lithium did not appear to prevent more severe depressive episodes requiring hospital admissions. The higher relapse risk in patients with bipolar I or schizoaffective disorder points towards a need to apply a higher threshold for lithium discontinuation in this group.

In patients with both bipolar disorder and ADHD, addition of central stimulant treatment may reduce the risk of suicide attempts and non-suicidal self-injury events. This suggests that central stimulants can be safely given in this patient group, as long mood-stabiliser treatment are given concomitantly.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2020. , p. 113
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2078
Keywords [en]
Lithium, Bipolar Disorder, Schizoaffective Disorder, Physical Health, Compliance, Medication Adherence, Side Effects, Long Term Adverse Effects, Mood Stabiliser, Admission, Hospitalisation, Attention Deficit Disorder with Hyperactivity, Central Nervous System Stimulants, Self-Injurious Behaviour, Non-Suicidal Self Injury, Suicide Attempted, Suicide
National Category
Psychiatry
Research subject
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-170364ISBN: 978-91-7855-251-1 (print)ISBN: 978-91-7855-252-8 (electronic)OAI: oai:DiVA.org:umu-170364DiVA, id: diva2:1428173
Public defence
2020-05-29, Aulan, Konferenscentrum, Sunderby sjukhus, Luleå, 13:00 (English)
Opponent
Supervisors
Available from: 2020-05-08 Created: 2020-05-05 Last updated: 2020-05-07Bibliographically approved
List of papers
1. Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study
Open this publication in new window or tab >>Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study
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2018 (English)In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 18, article id 37Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Lithium, Bipolar disorder, Physical health, Compliance, Side effects
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-145594 (URN)10.1186/s12888-018-1622-1 (DOI)000424707200003 ()29415689 (PubMedID)
Note

Correction: Louise Öhlund, Michael Ott, Sofia Oja, Malin Bergqvist, Robert Lundqvist, Mikael Sandlund, Ellinor Salander Renberg and Ursula Werneke. Correction to: Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study. BMC Psychiatry, 2018;18:322. DOI: 10.1186/s12888-018-1895-4

Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2020-05-05Bibliographically approved
2. Clinical course and need for hospital admission after lithium discontinuation in patients with bipolar disorder type I or II: mirror-image study based on the LiSIE retrospective cohort
Open this publication in new window or tab >>Clinical course and need for hospital admission after lithium discontinuation in patients with bipolar disorder type I or II: mirror-image study based on the LiSIE retrospective cohort
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2019 (English)In: BJPsych Open, E-ISSN 2056-4724, Vol. 5, no 6, article id e101Article in journal (Refereed) Published
Abstract [en]

Background: Currently, the evidence for lithium as a maintenance treatment for bipolar disorder type II (BD-II) remains limited. Guidelines commonly extrapolate recommendations for BD-II from available evidence for bipolar disorder type I (BD-I). Comparing the impact of lithium discontinuation is one way of assessing effectiveness in both groups.

Aims: To compare the impact of lithium discontinuation on hospital admissions and self-harm in patients with BD-I or schizoaffective disorder (SZD) and patients with BD-II or other bipolar disorder.

Method: Mirror-image study, examining hospital admissions within 2 years before and after lithium discontinuation in both patient groups. This study was part of a retrospective cohort study (LiSIE) into effects and side-effects of lithium for maintenance treatment of bipolar disorder as compared with other mood stabilisers.

Results: For the whole sample, the mean number of admissions/patient/review period doubled from 0.44 to 0.95 (P<0.001) after lithium discontinuation. The mean number of bed days/patient/review period doubled from 11 to 22 (P = 0.025). This increase in admissions and bed days was exclusively attributable to patients with BD-I/SZD. Not having consulted with a doctor prior to lithium discontinuation or no treatment with an alternative mood stabiliser at the time of lithium discontinuation led to more admissions.

Conclusions: The higher relapse risk in patients with BD-I/SZD suggests a higher threshold for discontinuing lithium than for patients with BD-II/other bipolar disorder. In patients with BD-II/other bipolar disorder, however, judged on the impact of discontinuation alone, lithium did not appear to prevent more severe depressive episodes requiring hospital admission.

Place, publisher, year, edition, pages
Cambridge University Press, 2019
Keywords
Bipolar disorder, lithium, mood stabiliser, admission, hospitalisation
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-168871 (URN)10.1192/bjo.2019.83 (DOI)000514372200015 ()31753046 (PubMedID)
Funder
Norrbotten County Council
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2020-05-05Bibliographically approved
3. Suicidal and other deliberate self-injurious behaviour in patients with bipolar disorder and comorbid attention deficit hyperactivity disorder after initiation of central stimulant treatment: a mirror-image study based on the LiSIE retrospective cohort
Open this publication in new window or tab >>Suicidal and other deliberate self-injurious behaviour in patients with bipolar disorder and comorbid attention deficit hyperactivity disorder after initiation of central stimulant treatment: a mirror-image study based on the LiSIE retrospective cohort
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-170361 (URN)
Available from: 2020-05-04 Created: 2020-05-04 Last updated: 2020-05-05

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