Acute and long-term management of bipolar disorder

Bipolar disorder, sometimes called bipolar affective disorder, is a cyclical mood disorder that involves episodes of disruption to mood and behaviour, interspersed with periods of recovery. These disruptive episodes can either be depressive or manic (either mania or hypomania), and can culminate in psychosis and exhaustion if left untreated.

Bipolar disorder has an early age of onset, with the first episode usually occurring before the age of 30 years. The peak rate of onset is between the ages of 15 years and 19 years, and there is often a substantial delay between onset and first contact with mental health services^[1]
.

Different diagnostic criteria are used to categorise bipolar disorder (see ‘Diagnosis’). People with bipolar I disorder experience symptoms of mania, while people with bipolar II disorder experience hypomania, which is similar to mania but less severe.

The lifetime prevalence of bipolar I disorder is around 1%, and bipolar II disorder affects approximately 0.4% of adults^[1]
. The prevalence of bipolar I disorder is similar in both men and women.

Around 17% of patients with bipolar I disorder and 24% of patients with bipolar II disorder attempt suicide. Annually, around 0.4% of patients with bipolar disorder kill themselves, which is substantially higher than the international average suicide rate of 0.017%^[1]
. The risk of suicide is highest during depressive episodes.

Symptoms

Bipolar disorder can involve episodes of mania, hypomania or depression.

Manic episodes are when a patient’s mood is unusually elevated, and may vary from carefree joviality to almost uncontrollable excitement^[2]
. This elation can be accompanied by increased energy, resulting in overactivity; pressured speech; decreased need for sleep; short attention span; and marked distractibility. A patient with mania can have an inflated sense of self-esteem, hold grandiose ideas and feel overconfident. Loss of social inhibitions may result in behaviour that is reckless, inappropriate to the circumstances, and out of character.

Symptoms must last for at least seven days to be diagnosed as mania^[1]
. Sometimes symptoms of mania, such as elation or rapid thoughts, are seen briefly for a few hours at a time in bipolar disorder.

A manic episode can also include psychotic symptoms, such as delusions (usually grandiose); hallucinations (usually of voices speaking directly to the patient); excitement ; excessive motor activity; and rapid thoughts.

Hypomanic episodes are similar to those in mania, but not to the extent that they lead to severe disruption of work or result in social rejection^[2]
. Symptoms can include irritability, conceit, and boorish behaviour rather than sociability. Patients with hypomania do not experience delusions or hallucinations^[2]
.

Symptoms must last for at least four days to be diagnosed as hypomania^[1]
.

Depressive episodes in bipolar disorder are similar to those experienced in unipolar major depression^[2]
. Depressive symptoms are more common than manic symptoms.

Common symptoms include: low mood; low energy and decrease in activity; reduced capacity for enjoyment and interests; poor concentration; marked tiredness after even minimal effort; disturbed sleep (often waking in the morning several hours before the usual time); reduced appetite; reduced self-esteem and self-confidence; ideas of guilt or worthlessness; loss of interest and pleasurable feelings; slowed thought and physical movements; agitation; loss of appetite; weight loss and loss of libido.

Adults presenting with depression should be asked if they have experienced periods of over-activity or disinhibited behaviour, especially if longer than four days, as this may alter the diagnosis^[1]
.

Causes and risk factors

The causes of bipolar disorder are unknown. Recent research has concentrated on genetic components, neurohormonal abnormalities, structural brain differences and psychological factors. The different clinical presentations of bipolar disorder suggest that a number of different mechanisms might be involved^[1]
.

No specific genes have been identified that are associated with bipolar disorder, but several areas of the genome are being investigated. Family studies have shown that first-degree relatives of an individual with bipolar disorder are five to ten times more likely to develop the disorder — and twice as likely to develop unipolar major depression — than the general population. Twin studies have found higher rates of bipolar disorder (40–70%) in monozygotic compared with dizygotic twins^[1]
. There is an increased incidence of bipolar disorder in black and minority ethnic groups, and mania, psychotic symptoms and suicidal behaviour are more common in these patients^[1]
.

The neurobiology of bipolar disorder is poorly understood. The monoamine theory suggests that a lack of monoamine neurotransmitters (serotonin, noradrenaline and dopamine) causes depression while an excess of monoamines may cause a manic episode^[3]
. This may explain why antipsychotics are effective in management of mania.

The hypothalamic-pituitary-adrenal (HPA) axis may also have a role in bipolar disorder. The adrenal system produces cortisol known to be a major regulator of the physiological stress response. Both cortisol and thyroid abnormalities have been observed in all stages of bipolar disorder.

Psychological factors may act as predisposing factors for developing the disorder, and both abuse and neglect during childhood has been shown to alter the HPA axis. Concurrent factors such as social class, social support and self-esteem may act as modifiers or triggers for episodes.

Diagnosis

The Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM-V)^[4]
, published by the American Psychiatric Association, and the International Classification of Disease (ICD-10), published by the World Health Organization^[2]
, both outline diagnostic criteria for bipolar disorder.

The DSM-V recognises a spectrum of bipolar disorders including bipolar I disorder, bipolar II disorder and cyclothymia (a chronic mood disturbance with depression and hypomania symptoms that do not meet a full episode).

A diagnosis of bipolar I disorder requires the experience of at least one manic episode, while bipolar II disorder requires at least one major depressive episode and at least one hypomanic episode. Any manic episode rules out a diagnosis of bipolar II disorder. Episodes of depression or mixed episodes are not required for a diagnosis of bipolar I.

The ICD-10 requires experience of at least two mood episodes, one of which must be mania or hypomania, for a diagnosis of bipolar disorder^[2]
. The ICD-10 does not provide specific criteria for bipolar II disorder as a separate diagnostic entity.

The mania and hypomania stages of bipolar disorder may resemble other conditions, such as cyclothymia, schizophrenia and schizoaffective disorder, substance misuse, personality disorders, organic brain syndromes, metabolic disorders and iatrogenic effects from medicines such as corticosteroids (especially in high doses), levodopa and stimulants (e.g. methylphenidate)^[1]
.

Mania-like symptoms can also be the result of using stimulants such as cocaine, khat, ecstasy or amphetamine. Substance misuse is a common comorbidity in bipolar disorder, and it is important to clarify whether the patient has taken any stimulants.

Several self-rating methods have been developed for the screening and monitoring of bipolar disorder. These scales are designed to assess the severity of symptoms in individuals experiencing bipolar disorder, and not to screen for hypomanic or manic symptoms. There are also some concerns over their validity, because some people with mania do not recognise the presence of mania symptoms that are evident to others.

Management

Psychological factors play an important role in bipolar disorder, and treatment approaches such as psychological treatments (including cognitive behavioural therapy) can improve clinical outcomes. The National Institute for Health and Care Excellence (NICE) recommends psychological interventions form the foundation of therapy for adolescents and children, as medicines used to treat bipolar disorder can have a damaging effect on children’s growth and development (see ‘Main new recommendations from the latest NICE guideline’).

When medicines are needed, the treatment options for adolescents and children are largely the same as for adults (but often unlicensed).

The medicines used to treat bipolar disorder vary depending on the patient’s episodes and whether they are already taking medicines for the condition.

Some of the pharmacological treatments used do not have a product licence for a specified indication as recommended by NICE and the British Association for Psychopharmacology (BAP); however there is strong evidence supporting their use (see ‘Medicines used in managing bipolar disorder’).

Medicines used in managing bipolar disorder

The management of bipolar disorder includes the acute management of manic, hypomanic and depressive episodes together with long-term management to enhance mood stability and prevent further episodes and hospitalisation^[1]
.

A discussion with the patient about continuing current treatment or starting long-term treatment should occur within four weeks of resolution of symptoms following an acute episode. This discussion should emphasise the benefits of long-term treatment while also advising the patient about the risk of side effects^[1]
.

Manic or hypomanic episodes are usually managed with short-term pharmacological treatments. The aim of treatment is to reduce the severity and shorten the duration of the acute episode. Psychological treatments are not used.

Patients should stop taking any substances known to cause mania when an episode begins. This includes medicines such as antidepressants, cold remedies and decongestants, and stimulants such as illegal drugs and caffeine.

The antipsychotics haloperidol, olanzapine, quetiapine and risperidone are used as both first-line and second-line treatments in patients who are currently not taking long-term treatment. Patients are changed to an alternative antipsychotic (of the list above) if the first is not effective. Lithium or valproate^[5]
can be used if antipsychotics are ineffective. The BAP guidelines also recommend aripiprazole as a possible treatment option^[5]
, and aripiprazole is also approved by NICE for treating adolescents during an episode of mania^[6]
.

Patients who experience a manic or hypomanic episode while taking lithium, valproate or another mood stabiliser (mainly the atypical antipsychotics) should have their dose adjusted based on plasma levels (see ‘Monitoring’) or increased to the maximum recommended in the British National Formulary (BNF). If these medicines are still ineffective, then the patient can be prescribed an antipsychotic as add-on therapy^{[1] ,[5]}
. Treatment should be continued for four weeks after symptoms resolve, at which point long-term drug treatment options should be considered^[1]
.

Patients with mania admitted to secondary care should be treated in an environment with reduced noise and stimulation, and with high nursing staff–patient ratios (for example, a psychiatric intensive care unit).

Bipolar depression can be treated with psychological interventions, such as cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy. These can include monitoring for signs of mania or hypomania and deterioration of the depressive symptoms.

Psychological therapy can be used on its own for milder cases of bipolar depression.

Pharmacological treatment for bipolar depression differs from unipolar depression because there is considerable doubt about whether antidepressants have any efficacy, and concerns that antidepressant use can induce mania in some patients^[1]
.

NICE currently recommends that fluoxetine is the only antidepressant that is effective in treating bipolar depression, and should only be used in combination with the atypical antipsychotic olanzapine; previous guidance^[5]
recommended that antidepressant and antimanic agents should be used in combination to reduce the risk of switching into mania, particularly in patients with a history of mania.

Other recommended first-line treatments of bipolar depression include quetiapine, olanzapine (without fluoxetine) or lamotrigine.

Patients with bipolar depression currently taking lithium or valproate should have their levels checked, and the dose increased if necessary^{[1] ,[5]}
. If this treatment is still not effective, quetiapine, olanzapine (with or without fluoxetine) or lamotrigine can be added as concomitant therapy^[1]
.

Long-term therapy is aimed at preventing either manic or depressive episodes, and includes both psychological and pharmacological options.

Structured psychological interventions (individual, group or family) are designed to prevent relapse by improving the patient’s knowledge of bipolar disorder through psychoeducation, encouraging self-monitoring of mood, thoughts and behaviours, and improving self-regulation by establishing action plans and modifying behaviours.

Psychoeducation is an umbrella term that includes illness awareness, treatment adherence, early detection of prodromal symptoms and recurrences, and lifestyle advice. Group psychoeducation appears to be a highly effective adjunct to pharmacotherapy in relapse prevention. There are many tools to aid psychoeducation available through Bipolar UK and the Depression Alliance.

Pharmacological treatment that has been effective during episodes of mania or bipolar depression is often continued as long-term therapy. Lithium^{[1] ,[5] ,[7]}
is the most effective long-term treatment for bipolar disorder and is the treatment of choice for most patients, although it is not recommended for patients with poor adherence as rapid discontinuation may increase the risk of relapse. The mode of action of lithium in bipolar disorder is not fully understood. However, lithium modifies the production and turnover of neurotransmitters, particularly serotonin, and may also block dopamine receptors.

Olanzapine, quetiapine and valproate are recommended as second-line treatments if there is no response or only a partial response to lithium^{[1] ,[5]}
.

Patients primarily affected by mania should be treated with predominantly antimanic medicines (e.g. lithium, valproate, an antipsychotic)^[5]
, while those primarily affected by depressive episodes should be prescribed lamotrigine or quetiapine. In bipolar I disorder, lamotrigine is usually used in combination with an antimanic medicine.

Lamotrigine and quetiapine may be effective monotherapies in patients with bipolar II disorder^[5]
.

Monitoring

All people with bipolar disorder should have an annual health check. This should include:

• Weight or BMI, and assessment of diet, nutritional status and level of physical activity;
• Cardiovascular status, including pulse and blood pressure;
• Metabolic status, including fasting blood glucose, glycated haemoglobin (HbA_1c ) and blood lipid profile;
• Liver function;
• Renal and thyroid function and calcium levels for people taking long-term lithium.

Antipsychotic drugs are associated with a range of side effects, particularly weight gain. Other possible side effects include dry mouth, blurred vision, sedation, sexual dysfunction, extrapyramidal side effects (tremor, stiffness, restlessness and abnormal movements) and dizziness.

Lithium has a narrow therapeutic index and patients should be monitored closely. Plasma levels need to be monitored weekly until the dose is stable with a level of 0.6–1.0 mmol/l^{[1] ,[8]}
. Lithium levels will usually be monitored every three months^{[1] ,[5]}
, which can be reduced to every six months after one year of stable results^[1]
. Monitoring every three months should continue in older people; those taking medicines that interact with lithium; patients who are at risk of impaired renal or thyroid function, raised calcium levels or other complications; patients who have poor symptom control; patients with poor adherence; and patients whose last plasma lithium level was 0.8 mmol per litre or higher^[1]
.

Lithium has adverse effects on the kidneys, thyroid gland and parathyroid gland. Patients should be weighed and tests including urea and electrolytes (including calcium), glomerular filtration rate, thyroid function and full blood count need to be performed prior to starting lithium, and repeated every six months during treatment^{[1] ,[8]}
. Patients with cardiovascular disease or risk factors should also have an electrocardiogram prior to starting lithium treatment.

Other possible side effects of lithium include tremor, stomach upset, polyuria, metallic taste, polydipsia and weight gain. Toxic effects include severe or coarse hand shaking or tremor, blurred vision, muscle weakness, stomach ache with vomiting or severe diarrhoea, ataxia, slurred speech and confusion^[8]
.

If the current blood level is above the target range and the patient has symptoms of toxicity, the patient should be referred to their doctor immediately or, if the patient is unlikely to be seen promptly, to accident and emergency departments (A&E). Pharmacists should consider not dispensing lithium in these circumstances. Patients should always be referred to A&E if they have a blood lithium level of more than 2mmol/L, or more than 1.5mmol/L and symptoms of toxicity.

Lithium is teratogenic and should not be used routinely in pregnancy. Lithium should be avoided when breastfeeding as there have been sporadic reports of toxicity.

Many other medicines interact with lithium (e.g. non-steroidal anti-inflammatory drugs and angiotensin converting enzyme inhibitors), generally by affecting its excretion via the kidneys. Lithium is given a salt, so both dehydration and altered electrolyte balances can affect lithium levels. Other interactions include reports of neurotoxicity when lithium is used with antipsychotics, carbamazepine and selective serotonin reuptake inhibitors. These combinations are generally considered useful, although increased monitoring for adverse effects should occur.

Valproate is available in various forms, including sodium valproate, valproic acid and valproate semi sodium. The most likely mode of action for valproate is potentiation of the inhibitory action of gamma amino butyric acid (GABA) in the brain.

Valproate is associated with a number of side effects including tremor, weight gain and, rarely, liver damage and thrombocytopaenia. It can also interact with a number of commonly prescribed medicines and is known to decrease plasma levels of olanzapine, although it is still recommended for use in combination.

Valproate is teratogenic, and there are significant risks associated with its use during pregnancy. Valproate should be avoided by women of childbearing age^[1]
.

Lamotrigine is associated with causing a rash, which can lead to serious conditions such as Stevens-Johnson syndrome. This adverse effect is most common in the first eight weeks of therapy, and the dose should be increased very slowly when treatment is started to minimise the risk of this occurring.

Lamotrigine can also cause drowsiness, dizziness and blurred vision, and cause bone marrow suppression. It is also teratogenic, although it is considered safer for use in pregnancy than valproate.

Dosage recommendations for lamotrigine are complex, particularly when used with other anticonvulsant drugs, and particularly valproate. Valproate and lamotrigine is not a recommended combination^[1]
, although patients taking valproate may be changed to lamotrigine, and slower titration than usual is recommended in these cases.

Discontinuation

Discontinuation of long-term treatment for bipolar disorder must be done carefully, as relapses can occur even after many years of sustained remission^[1]
. Abrupt discontinuation of treatment is associated with an increased risk of early relapse of mania.

When discontinuing long-term treatment, doses should be gradually tapered over at least two weeks and preferably longer (for lithium, this should be over at least four weeks and preferably over three months, even if the patient has started taking another antimanic drug).

Patients should be monitored for signs of relapse, emerging symptoms, mood and mental state while discontinuing treatment, and for up to two years after treatment has stopped.

Main interactions with lithium

This article was updated on 4 February 2015 to reflect that other valproate preparations other than valproate semi-sodium have the UK marketing authorisation for the treatment of manic episodes.