Factors affecting the pharmacological treatment of bipolar disorder

Sammanfattning: 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.