1. Definition of bipolar disorders

1.1.

Bipolar disorder (or bipolar affective disorder, or manic depressive illness) is a mental disorder characterized by episodes or both mania and major depression (bipolar depression).

1.2.

A manic episode is a clinical condition characterized by a persistent elevation of mood, increased energy and activity, and usually marked feelings of well-being and both physical and mental efficiency. Mood is elevated out of keeping with the patient's circumstances and may vary from carefree joviality to almost uncontrollable excitement. Increased sociability, talkativeness, over-familiarity, increased sexual energy, and a decreased need for sleep are often present. Irritability, conceit, and boorish behaviour may take the place of the more usual euphoric sociability. In severe manic episodes, attention cannot be sustained, and there is often marked distractibility. Self-esteem is often inflated with grandiose ideas and overconfidence. Loss of normal social inhibitions may result in behaviour that is reckless, foolhardy, or inappropriate to the circumstances, and out of character. In very severe cases, delusions (usually grandiose) or hallucinations (usually of voices speaking directly to the patient) are present, or the excitement, excessive motor activity, and flight of ideas are so extreme that the subject is incomprehensible or inaccessible to ordinary communication. The onset of manic symptoms may be gradual with weeks or months before the disorder becomes full-blown.

1.3.

Manic episodes may be associated with significant personal distress and social dysfunction.

1.4.

Manic symptoms may be the consequence of a general medical condition or substance abuse.

1.5.

Age at first onset ranges between 19 and 29 years. Epidemiological data suggest that it may affect up to 1% of the adult population, with men and women at similar risk. There seems not to be significant differences in prevalence among racial or ethnic groups.

1.6.

Almost 40% of people with bipolar disorder have a recurrent manic or depressive episode within 2 years after recovering from the first episode. In people with bipolar disorder the lifetime prevalence of suicide is about 2%.

1.7.

Alcohol and medicine abuse frequently complicate the treatment and the clinical course of the disease: the extent of substance abuse varies greatly according to culture, country of residence, and socioeconomic status.

2. Preliminary assessment and initial management strategies

2.1.

Health care providers should initially exclude the possibility that an organic illness or a substance abuse disorder is the underlying cause of manic symptoms. A detailed medical and psychiatric history, physical and neurologic examination, and mental status assessment should be carried out.

2.2.

If manic symptoms are caused by medical conditions the underlying condition should be managed, with adjunctive psychiatric management for the behavioural problems. If manic symptoms are caused by substance abuse detoxification may be required.

2.3.

If feasible, manic patients should be evaluated without delay, considering that agitation and uncooperativeness may be present. Health care providers should be ready to manage the patient's agitation.

2.4.

Health care providers may obtain relevant clinical details from individuals who know the patient well. Precipitants of mood change which might be predicted or controlled (life events) should be taken into consideration.

2.5.

If physician suspects a manic episode, it is critical to evaluate whether the patient is contemplating self injury.

2.6.

Patients with acute manic symptoms contemplating self injury should be intensively monitored; monitoring may include admission to an inpatient facility, close supervision by family members or by other individuals who know the patient well.

3. Short-term treatment with antimanic medicines

3.1.

In patients with severe manic episodes or marked behavioural disturbances as part of the syndrome of mania, health care providers should consider a prescription of an antipsychotic, as these medicines are rapidly effective in mania and are therefore considered antimanic agents. The antimanic medicine valproate has in addition been shown to be rapidly effective in the acute treatment of mania. In less severe manic episodes, lithium may be considered, as this agent has slower onset of action than antipsychotics or valproate.

3.2.

In agitated overactive patients, health care providers may consider adjunctive short-term treatment with a benzodiazepine, such as diazepam.

3.3.

Before starting antipsychotic therapy, it is generally recommended to check weight and blood pressure. Other suggested monitoring includes electrocardiogram (mandatory in some countries for specific antipsychotics, for example haloperidol), full blood count, urea and electrolytes, renal function tests, liver function tests, blood glucose, lipid pattern and prolactin. If these laboratory examinations are not feasible, health care providers should ask the patient and/or family member about the existence of cardiovascular, renal or hepatic abnormalities, and whether drug therapies for these medical conditions have been prescribed and taken.

3.4.

Before starting lithium therapy, suggested monitoring includes: renal function tests, thyroid function tests, electrocardiogram, full blood count, pregnancy test. If these laboratory examinations are not feasible, and if health care providers consider that monitoring lithium blood levels is not feasible, lithium should not be prescribed. Health care providers may chose to prescribe an antipsychotic.

3.5.

Before starting valproate therapy, suggested monitoring includes: renal and hepatic function tests, full blood count, pregnancy test. If these laboratory examinations are not feasible, health care providers should ask the patient and/or family member about the existence of cardiovascular, renal or hepatic abnormalities, and whether drug therapies for these medical conditions have been prescribed and taken.

3.6.

If benzodiazepines are used for symptomatic effect, they should be gradually discontinued as soon as symptoms improve.

3.7.

Treatment should be regularly monitored, and its effect should be assessed after 3 and 6 weeks. If no improvement is seen after 6 weeks, health care providers may discuss with the patient and/or family member the possibility to augment treatment in combination strategies: antipsychotic plus lithium or antipsychotic plus valproate. If adverse reactions are a major problem, health care providers may discuss with the patient and/or family member the possibility to decrease the dose. If adverse reactions persist despite a dose reduction, a switch to another antimanic agent may be considered.

3.8.

For prompt control of acute manic episodes with psychotic symptoms health care providers should consider intramuscular treatment only if oral treatment is not feasible. According to the WHO EML, essential medicines are chlorpromazine injection (e.g. 25 mg intramuscular) or haloperidol injection (e.g. 5 mg intramuscular). After intramuscular antipsychotic administration, health care providers should monitor blood pressure, pulse, body temperature and respiratory rate.

3.9.

Bipolar depression generally responds to antidepressants. However, health care providers should consider that antidepressants, especially tricyclics, may induce a switch from depression to mania. Antidepressants appear less likely to induce mania when added to lithium, valproate or to antipsychotic therapy. If health care providers prescribe an antidepressant, an antimanic agent should concurrently be prescribed.

3.10.

Health care providers should offer information to patients and family members, empathetic listening, reassurance and psychological support. This may help develop a good relationship and a therapeutic alliance that may positively influence the patient subjective well-being and the long-term outcome of the disorder.

4. Long-term treatment with antimanic medicines

4.1.

Lithium is considered the medicine of choice in the long-term maintenance phase of bipolar disorder. Health care providers may consider lithium as initial monotherapy. Lithium monotherapy is probably effective against both manic and depressive relapse, although it is more effective in preventing mania. Health care providers should consider that lithium has a narrow therapeutic index, and blood levels must be monitored. Severe toxic effects can occur when renal excretion is impaired. During lithium treatment, check thyroid function every six months. If monitoring lithium blood levels is not feasible, lithium should not be prescribed.

4.2.

In situations where lithium supply may be frequently interrupted, lithium should not be prescribed.

4.3.

If lithium is ineffective or poorly tolerated, or if lithium therapy is not feasible, consider valproate. During valproate treatment suggested monitoring includes hepatic function, full blood count and pregnancy test. If these laboratory tests are not feasible, health care providers should remember to regularly take a medical examination, including a recent medical history that may help recognize symptoms suggesting the development of blood or hepatic abnormalities.

4.4.

If lithium and valproate are ineffective or poorly tolerated, or if therapy with one of these agents is not feasible, consider carbamazepine. Before and during carbamazepine therapy, suggested monitoring includes: full blood count, liver and renal function tests, pregnancy test. If these laboratory tests are not feasible, health care providers should remember to regularly take a medical examination, including a recent medical history that may help recognize symptoms suggesting the development of blood or renal or hepatic abnormalities.

4.5.

Long-term treatment should generally continue for at least two years after an episode of bipolar disorder. However, in patients with risk-factors for relapse, such as history of frequent relapses or severe manic episodes with psychotic symptoms, treatment may be prolonged for up to five years.

4.6.

Treatment should normally be tapered over at least 2 weeks and preferably longer. Abrupt lithium discontinuation is associated with early manic relapse.

4.7.

According to the WHO Model EML, essential medicines for bipolar disorders are carbamazepine, lithium and valproic acid.

5. Administration of antimanic medicines

5.1.

Lithium. Health care providers should start with a low-dose (300 mg/day at bedtime), and then increase gradually and monitor blood concentrations every 7 days until level is between 0.6-1.0 milliequivalents (mEq)/litre. Thereafter, blood levels may be checked every 2-3 months (all samples must be taken 12 hours post dose). Renal and thyroid function should be checked every 12 months.

5.2.

If treatment adherence is a major problem, lithium treatment may not be feasible.

5.3.

Valproate. Start on low-dose (500 mg/day), then increase gradually according to tolerability.

5.4.

Carbamazepine. Start with a low-dose (200 mg/day at bedtime), slowly increase until dose 600-1000 mg/day is achieved. Health care providers should consider that the dose may need to be adjusted after two weeks due to hepatic enzyme induction.

6. Adverse reactions of antimanic medicines

6.1.

Lithium causes a wide range of adverse reactions including tremor, muscular weakness, polyuria, polydypsia, diabetes insipidus, cardiac arrhythmias, weight gain, cognitive problems, sedation or lethargy, impaired coordination, gastrointestinal distress, hair loss, benign leukocytosis, hypothyroidism, acne and oedema.

6.2.

Carbamazepine causes a wide range of adverse reactions including drowsiness, ataxia, diplopia, nausea. Less frequent side-effects include rash, mild leucopenia, mild liver enzyme elevations, mild thrombocytopenia, hyponatraemia and hypoosmolality. Rare, idiosyncratic, serious and potentially fatal side-effects include agranulocytosis, aplastic anaemia, thrombocytopenia, hepatic failure, Stevens–Johnson syndrome, toxic epidermolysis and pancreatitis.

6.3.

Diplopia, ataxia and sedation may suggest carbamazepine intoxication.

6.4.

Valproate causes a wide range of adverse reactions including gastrointestinal pain, benign hepatic transaminase elevations, tremor and sedation. Patients with hepatic disease may be at increased risk for hepatotoxicity. Mild, asymptomatic leucopenia and thrombocytopenia less frequently occur and are reversible after medicine discontinuation. Rare, idiosyncratic, potentially fatal adverse events include irreversible hepatic failure, haemorrhagic pancreatitis and agranulocytosis.

7. Overdosage of antimanic medicines

7.1.

If intoxication is suspected, referral to acute medical facility is recommended.

7.2.

The severity of chronic lithium intoxication correlates directly with the serum lithium concentration and may be categorised as mild (1.5 to 2.0 mEq/litre), moderate (2.0 to 2.5 mEq/litre) or severe (>2.5 mEq/litre). Symptoms associated with mild poisoning include lethargy, drowsiness, coarse tremor, muscle weakness, nausea, vomiting, and diarrhoea. Moderate toxicity is associated with confusion, dysarthria, nystagmus, ataxia, myoclonic twitches, and electrocardiogram changes. Severe toxicity, which can be life-threatening, is associated with grossly impaired consciousness, increased deep tendon reflexes, seizures, syncope, renal insufficiency, coma and death.

7.3.

The symptoms of carbamazepine overdose include somnolence, tachycardia, atrioventricular conduction defects, seizures, coma, nystagmus, hyporeflexia or hyperreflexia, rigidity, orofacial dyskinesia, and mild respiratory depression.

7.4.

The symptoms of valproic acid overdose include hypotension, somnolence, convulsions, coma, respiratory depression, blood dyscrasia.

8. Special patient populations

8.1.

In the elderly health care providers should prescribe lower doses.

8.2.

If possible, health care providers should not prescribe lithium during pregnancy. Lithium in the first trimester of pregnancy increases the incidence of birth defects, specifically Ebstein's anomaly. Administration during the final months of pregnancy can result in babies who are lithium-toxic at birth.

8.3.

Although the teratogenicity of carbamazepine and valproic acid is not entirely clear, their use in pregnancy should be avoided. Both agents are associated with an increased risk of foetal abnormalities, specifically spina bifida. Valproic acid may be more dangerous than carbamazepine.

8.4.

If absolutely indicated, the use of low doses of haloperidol may be consider after discussion with the patient and/or family member. Haloperidol is excreted into breast milk.

8.5.

Lithium, carbamazepine and valproic acid are excreted in breast milk.

8.6.

Lithium is contraindicated in severe renal impairment, as the risk of toxicity is enhanced. Carbamazepine and valproic acid do not generally require dose adjustment in renal impairment.

8.7.

Carbamazepine and valproic acid are contraindicated in acute liver disease. In chronic liver disease, health care providers should prescribed lower doses. Lithium does not generally require dose adjustment in liver impairment.

9. Potentially relevant interactions

Angiotensin-converting enzyme inhibitors and lithium. Lithium toxicity may be increased.

Thiazide diuretics and lithium. Renal clearance of lithium is reduced, and levels increased within a few days.

Non-steroidal anti-inflammatory medicines and lithium. Lithium levels should be frequently monitored.

Methyldopa and lithium. Lithium levels may be icnreased.

Increased carbamazepine levels and toxicity produced by: danazol, diltiazem, erythromycin, influenza vaccine, isoniazid, nafimidone, verapamil, viloxazine.

Decreased carbamazepine levels produced by: phenobarbital, phenytoin, primidone, theophylline, tricyclic antidepressants.

Carbamazepine decreases levels or effects of: clonazepam, cyclosporine, dexamethasone, dicoumarol, doxycycline, ethosuximide, haloperidol, pregnancy tests, theophylline, valproic acid, warfarin.

10. Essential medicines for bipolar disorders

Carbamazepine

• Starting dose: 200 mg/day orally.
• Therapeutic dose: 400-600 mg/day orally.
• Common adverse effects: dizziness, drowsiness, ataxia, visual disturbances, confusion, agitation, nausea, vomiting, constipation, leukopenia and other blood disorders, erythematous rash, cholestatic jaundice, hepatitis.
• Serious adverse effects: Stevens-Johnson syndrome, toxic epidermal necrolysis, hyponatraemia, agranulocytosis, cardiac conduction disturbances, renal failure.
• WHO Model List: tablet 100 mg; tablet 200 mg.

Lithium carbonate

• Starting dose: 300 mg/day orally, increasing every 5-7 days according to plasma levels.
• Therapeutic dose: 600-1200 mg/day orally, according to plasma levels.
• Common adverse effects: gastrointestinal disturbances, fine hand tremor, thirst, polyuria, acne, psoriasis, hypothyroidism, leucocytosis, weight gain, hyperparathyroidism and hypercalcaemia.
• Serious adverse effects: nausea, diarrhoea, muscle weakness, drowsiness, ataxia, coarse tremor, muscle twitching, disorientation, renal failure, cardiovascular failure, convulsions, coma.
• WHO Model List: capsule or tablet 300 mg.

Valproic acid

• Starting dose: 500 mg/day orally in divided doses.
• Therapeutic dose: 1000-2000 mg/day orally.
• Common adverse effects: nausea, gastric irritation, diarrhoea, weight gain, hyperammonaemia, leucopenia, thrombocytopenia, hair loss, drowsiness, confusion, jaundice, oedema.
• Serious adverse effects: ataxia, tremor, vasculitis, hepatic abnormalities, lethargy, anaemia, pancytopenia, pancreatitis.
• WHO Model List: tablet 200 mg; tablet 500 mg.