EFFECTIVE LONG-TERM TREATMENT OF BIPOLAR DISORDER

Journal of Psychiatry Reform vol 12 #8, May 13, 2025

Authors

Alan Eppel, MB, FRCPC, Professor, Department of Psychiatry and Behavioural Neurosciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. iD: https://orcid.org/0000-0002-4880-4097.

Ana Hategan, MD, FRCPC, Clinical Professor, Division of Geriatric Psychiatry, Department of Psychiatry and Behavioural Neurosciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. iD: https://orcid.org/0000-0003-0221-1154.

The authors have no conflicts of interest

Bipolar disorder is one of the most complex disorders to manage well in psychiatry. The illness is accompanied by significant disability over many years. There continues to remain differences of opinion regarding the appropriate management and long-term care of patients with bipolar disorder. Central to this is the question of the role of lithium, antipsychotic medications and antidepressants. Many patients experience recurrent episodes of depression, hypomania and mania, even when superficially well patients frequently may experience persistent subthreshold depression, mood instability, chronic irritability, mixed states, and accelerated mood cycling [1, 2, 3].

Controlled trials have failed to resolve the controversy as to whether antidepressants have any role to play in bipolar disorder. Trials are frequently much too short to determine recurrence or relapse.  Moreover, there are concerns regarding the worldwide decline of the use of lithium therapy despite many previous studies indicating that lithium is the most effective  medication in bipolar disorder [2, 3, 4].

CASE HISTORY

Margaret was a 51-year-old married mother of 2 when she presented to our clinic. She first experienced depressive symptoms as a teen following the death of a family member. The depressive symptoms continued into adolescence and early adulthood.

Over many years she was treated principally with antidepressants and quetiapine. This led to constant mood cycling. She required acute and maintenance courses of electroconvulsive therapy (ECT). She had approximately 11 hospitalizations during this timeframe.

At age 41 she was admitted to hospital after an overdose of antidepressant medication. She was diagnosed with bipolar disorder and started on lithium.

She developed marked hypothyroidism and lithium was discontinued. One year later she was readmitted to hospital. Valproate was prescribed as an alternative to lithium.

Approximately eight months later she was readmitted to hospital for the third time following a second medication overdose. Bupropion and citalopram were initiated along with quetiapine risperidone and clonazepam.  One month later she was admitted for a fourth time and diagnosed with major depressive disorder. Six months later she was admitted to the ICU due to another medication overdose. She was diagnosed with dysthymia and borderline personality disorder. She received a first course of ECT and her depressive symptoms improved.

Five months later she was readmitted with the diagnosis of major depressive disorder with psychotic features and borderline personality traits. She received her second course of ECT. She was later diagnosed by a different physician with bipolar disorder type 2, currently depressed. Medications included clomipramine, quetiapine and lorazepam.

Nine months later she was admitted again and diagnosed with bipolar disorder type 1 currently depressed. She was treated with clomipramine and quetiapine. She received her third course of ECT while an inpatient, with good response.

She was readmitted one year later with depression and diagnosed with  bipolar disorder, type 2. Clomipramine was discontinued and she was started on fluoxetine 40 mg daily, lamotrigine 300 mg qhs, quetiapine 200 mg at noon and 300 mg qhs.

She had a further admission five months later and another admission one year after that. She had her 4th course of ECT, with subsequent remission.

For the next three years the patient was reported to have been stable on fluoxetine 40 mg daily, perphenazine 8 mg daily and quetiapine 50 mg bid and 300 mg qhs. At the end of the three years she relapsed and received a fifth course of ECT.

After she came under the care of one of the authors (AE), the antidepressants were discontinued and lithium was resumed. Quetiapine was subsequently discontinued and a second mood stabilizer valproate was added. Over the subsequent six years, she did not have any hospital admissions and she did not require ECT. For most of the time, her mood was satisfactory although she did have some low mood periods which lasted one to two weeks. Her thyroid hormone levels did drop after she was restarted on lithium but this was managed with thyroid hormone replacement.

NEW EVIDENCE

Ermis et al. [4], using the Swedish Nationwide Registers, undertook a recent study of the effectiveness of pharmacological maintenance treatment in reducing hospitalization of patients with bipolar disorder. The study cohort included over 105,000 individuals; mean age was 44.2 years and

62.2% were women. The primary outcome was hospitalisation due to a bipolar depressive episode. The mean follow-up time was 9.1 years (SD 5.1). Of these, 16,190 (15.3%) individuals were hospitalised with a depressive episode at least once during the follow-up period. As Ermis et al. acknowledged, medications are typically started when depressive symptoms re-emerge, and thus all treatments may appear less effective than they actually are when the reference is non-use of medication (antidepressants, antipsychotic, and mood stabilisers) [4]. Nevertheless, in this study, mood stabilisers were associated with a reduced risk of hospitalisation for depression (adjusted hazard ratios  (aHR) 0.89, 95% CI 0.81–0.98) and antidepressant-mood stabiliser combinations were associated with marginally reduced risk (0.92, 0.85–1.00). Use of antidepressants only (1.25, 1.16–1.34), antipsychotics only (1.39, 1.24–1.55), and antidepressant–antipsychotic combinations (1.28, 1.18–1.39) was associated with an increased risk of depression-related hospitalisation. In this analysis, lithium was the only specific monotherapy associated with decreased risk of depression-related hospitalisation (aHR 0.75, 95% CI 0.67–0.85) [4].

CONCLUSION

There remains a robust evidence to support the use of lithium as the mainstay of treatment in bipolar disorder. As recent literature has shown [4], and also illustrated by the case study, the clinical implications are that lithium is the only monotherapy associated with a decreased risk of depression-related hospitalisations. Because lithium remains the only beneficial monotherapy for both polarity types of bipolar disorder, it still should be considered the foundational long-term treatment for bipolar disorder.

REFERENCES

1. Eppel AB. Antidepressants in the treatment of bipolar disorder: decoding contradictory evidence and opinion. Harv Rev Psychiatry. 2008;16(3):205-9. doi:10.1080/10673220802160381
2. Eppel AB. Lithium is superior to second-generation antipsychotic medications in bipolar disorder. J Psychiatry Reform.  Vol 10, #4 March, 2021
3. Eppel AB. Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines for Mood disorders: A Review. J Psychiatry Reform. Vol 2, #9 July 30, 2017
4. Ermis C, Taipale H, Tanskanen A, et al. Real-world effectiveness of pharmacological maintenance treatment of bipolar depression: a within-subject analysis in a Swedish nationwide cohort. Lancet Psychiatry. 2025;12(3):198-207. doi:10.1016/S2215-0366(24)00411-5

ADDITIONAL READINGS

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