14th February 2025

Bipolar affective disorder

Overview of bipolar disorder

Bipolar disorder is a common but variable illness in which episodes of mania and depression typically alternate, with periods of remission. Depressive episodes usually predominate. However, it often does not present as described in textbooks; hypomania, mixed episodes, an absence of depressive episodes, and prolonged residual symptoms of mania or depression are also common.

Epidemiology and aetiology of bipolar disorder

Risk factors for bipolar disorder

It is more common in those with a family history of bipolar disorder or a personal history of depressive illness (especially in childhood or adolescence). As with many mental illnesses, adverse life events and concurrent alcohol or substance misuse increase the risk.

Medication-induced mania

Medications can cause or increase the risk of mania or hypomania, both in patients with established bipolar disorder and those who are yet to experience their first mood episode. Antidepressants are the most typical cause; TCAs and SNRIs, e.g. venlafaxine, are particularly culpable. SSRIs and bupropion are less likely to cause mania but it is still seen.

Other psychotropic medication causes include benzodiazepines (a paradoxical reaction), lithium, and stimulants, e.g. dexamfetamine (used in attention deficit hyperactivity disorder, ADHD).

Medications used in other health conditions can also induce mania, such as Parkinson’s treatment, steroids, propranolol, salbutamol and TB treatment.

Presentation and diagnosis of bipolar disorder

Bipolar disorder requires two mood episodes, at least one of which is manic, hypomanic or mixed (see below), with full recovery between them.

Mania

A manic episode is an elevated mood state lasting at least one week (unless treated). It presents with elation, irritability or expansive mood, with features such as increased energy, increased self-esteem and grandiose ideas, reduced sleep, and impulsivity. There may be pressured or rapid speech and flight of ideas.

As with any mental disorder, there is disruption of occupational, social and/or interpersonal functioning. This may lead to poor self-care, such as poor oral intake and maintenance of living conditions.

When more severe, mania can present with psychotic symptoms, which are usually consistent with the person’s mood. Grandiose ideas may become delusions, for example involving special powers or abilities. Similarly, paranoid ideas may develop into persecutory delusions.

Psychiatric differential diagnoses include anxiety disorders, ADHD, personality disorder and alcohol or substance misuse. Organic illness can also cause manic features, such as hyperthyroidism, Cushing’s, encephalopathies and epilepsy. These must be considered and investigated with blood tests, brain imaging and EEG as appropriate.

Hypomania

This is a milder version of mania, whereby symptoms are less severe and do not cause occupational and social dysfunction. The minimum length of an episode is four days. By definition, hypomania does not lead to hospital admission or involve psychotic features.

Depressive episodes

Depressive episodes in bipolar affective disorder present in a similar fashion to a unipolar depressive disorder. This often leads to misdiagnosis.

Mixed episodes

In mixed bipolar episodes there are both manic and depressive features for at least two weeks. Mixed episodes typically present as depression with overactivity, mania with reduced energy, dysphoria with manic symptoms, and rapid cycling between manic and depressive symptoms.

Management of bipolar disorder

Management of acute mania or hypomania

NICE recommends an antipsychotic as first-line treatment of acute mania or hypomania: haloperidol, olanzapine, quetiapine or risperidone. Another of these can be trialled if the first is not effective or tolerated.

Second and third-line options are lithium and valproate respectively. If the patient already takes lithium, plasma levels should be taken to ensure they are within range.

For severe, treatment-resistant mania, electroconvulsive therapy (ECT) may be considered.

Management of bipolar depressive episodes

In bipolar depression, psychological interventions such as CBT should be offered. If the depressive episode is moderate or severe and the patient is not taking any medications, NICE recommends fluoxetine with olanzapine (as a mood stabiliser) or quetiapine (has antidepressant and mood-stabilising qualities).

Antidepressants should not be given alone in bipolar; a mood stabiliser is needed to reduce the risk of manic relapse.

Maintenance therapy for bipolar disorder

NICE advises that drugs effective in the acute phases of bipolar should be considered for long-term treatment. Antidepressants must not be given without a mood stabiliser.

Lithium is the most effective long-term treatment, and switching to it should be considered for all patients if not contraindicated. Valproate and olanzapine are second-line long-term mood stabilisers.

Structured psychological treatment such as individual, group or family therapy is also recommended.

Lithium

Lithium is the gold standard for long-term management of bipolar disorder. However, it has a narrow therapeutic window and is associated with several significant adverse effects.

It can also be used to augment the effects of antidepressants in treatment-resistant depression.

Lithium monitoring and target levels

Prior to starting lithium, BMI, FBC, U&Es, calcium, and TFTs are required in all patients. An ECG is required for patients with cardiovascular disease or those at high risk. Whilst on treatment, BMI, U&Es, calcium, and TFTs need to be monitored every 6 months (more frequently if abnormal).

Lithium levels must be checked 5 days after starting or changing the dose (12 hours post-dose). Once established, levels should be checked every 3 months for the first year, and 6 monthly thereafter, or 3 monthly for patients over 65, those taking interacting medications, with impaired renal or thyroid function, or with poor adherence.

Adverse effects of lithium

Short-term adverse effects include polyuria and polydipsia (due to ADH antagonism leading to nephrogenic diabetes insipidus), weight gain, cognitive impairment, fine tremor, GI upset and benign leucocytosis. Benign ECG changes or exacerbation of existing arrhythmias may occur.

Long-term adverse effects include renal impairment, hyperparathyroidism (and thus hypercalcaemia) and hypothyroidism.

Lithium is teratogenic; it is classically associated with Ebstein’s anomaly of the tricuspid valve.

Drug interactions with lithium

Drug interactions can rapidly lead to toxicity or reduced efficacy (and relapse).

ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, and diuretics are important and common causes of increased plasma concentration, due to lithium being excreted wholly renally in an unchanged form. Antacids and theophylline can decrease the plasma concentration.

When given with amiodarone, it increases the risk of hypothyroidism.

Lithium toxicity

Early clinical features include coarse tremor, anorexia, nausea and vomiting, diarrhoea and fatigue. As the level increases, severe complications develop such as myoclonus, hypertonia, drowsiness, confusion, cardiovascular collapse, seizures and coma. Neurological damage may be permanent.

Lithium toxicity requires urgent IV isotonic saline and possibly haemodialysis.

Sodium valproate

Valproate is licensed for acute mania and is also commonly used (unlicensed) for long-term prophylaxis.

It should not be offered to females of childbearing age unless other options are inappropriate, ineffective or not tolerated and a pregnancy prevention programme is in place.

Adverse effects of valproate

Dose-related adverse effects include GI upset, deranged LFTs, tremor and sedation. Leucopaenia, thrombocytopaenia, alopecia, weight gain, and pancreatitis are non dose-related adverse effects.

Like lithium, it has a narrow therapeutic window and thus toxicity can occur with high plasma levels; hypersomnolence, atrioventricular block, coma and death are seen.

Valproate monitoring

FBC, LFTs and BMI should be checked prior to starting then 6 monthly. An ECG should be done at initiation.

References

• Semple D, Smyth R. Oxford handbook of psychiatry. Oxford; New York: Oxford University Press; 2019
• World Health Organization. ICD-11 for Mortality and Morbidity Statistics [Internet]. World Health Organization; 2019 [cited 2022 Mar 3]. Available from: https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1707067746
• Selvaraj S. Bipolar disorder in adults [Internet]. BMJ Best Practice; 2020 [cited 2022 Mar 7]. Available from: https://bestpractice.bmj.com/topics/en-gb/488
• National Institute for Health and Care Excellence. Bipolar disorder [Internet]. NICE; 2020 [cited 2022 Mar 7]. Available from: https://www.nice.org.uk/guidance/cg185
• Joint Formulary Committee. British National Formulary. Lithium Carbonate [Internet]. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2020 [cited 2022 Mar 9]. Available from: https://bnf.nice.org.uk/drug/lithium-carbonate.html
• Joint Formulary Committee. British National Formulary. Sodium Valproate [Internet]. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2019 [cited 2022 Mar 10]. Available from: https://bnf.nice.org.uk/drug/sodium-valproate.html