The diagnosis and treatment of bipolar affective disorder

Bipolar affective disorder is a common psychiatric illness. The lifetime risk is around 1 per cent and its peak incidence is between the ages of 15 and 30 years, affecting men and women equally. According to World Health Organisation’s International Classification of Diseases (ICD-11), bipolar and related disorders are episodic mood disorders defined by the occurrence of manic, mixed, or hypomanic episodes or symptoms.¹ These episodes typically alternate with depressive episodes or periods of subclinical depressive symptoms.

A depressive episode is characterised by low mood, typically with diurnal variation; markedly diminished interest or pleasure (anhedonia); loss of energy (anergia); psychomotor retardation or agitation; loss of appetite leading to significant weight loss; initial insomnia or early morning wakening; feelings of worthlessness; excessive or inappropriate guilt; and poor concentration. Passive thoughts of death, or more concerted suicidal ideation, planning or behaviour may also occur. The depressive symptoms typically cause clinically significant distress or an impairment in social, occupational, or other important areas of functioning. For a depressive episode to be diagnosed, the symptoms should last for at least two weeks.

Conversely, a hypomanic episode involves a distinct period of at least four days with persistently elevated, expansive, or irritable mood that is not in keeping with the person’s normal demeanour, but that does not impact their work or level of functioning. It is also characterised by persistent, abnormally-increased energy, inflated self-esteem, a reduced need for sleep, and becoming more talkative than usual.

A manic episode has symptoms similar to hypomania, but worse, and lasting for at least one week. Excessive talking typically worsens to pressure of speech, with flight of ideas and distractibility. The person may display persistently-increased energy or activity, impulsive overspending, or engagement in embarrassing or even risky behaviours, while their mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning. Around 20 per cent of patients will experience psychotic features, for example grandiose or religious delusions, hallucinations, or thought disorder. Severe and sustained physical activity and excitement can result in physical neglect or even exhaustion.

The ICD-11 subdivides bipolar affective disorder into type I and type II categories. Type I involves alternating episodes of depression with manic episodes, whereas type II involves alternating episodes of depression with hypomanic episodes. So, what causes it? Certainly, the so-called stress-vulnerability model plays a role. Genetics are thought to be important, with theories on familial contribution supported by twin, family, and adoption studies. Where both parents have bipolar disorder, the risk of their children developing it is around 40 per cent. Certain environmental factors, including stressful life events, pregnancy, illicit substances, and anything causing sleep disturbance, can precipitate episodes of mania or depression.

Treatment follows a biopsychosocial approach. Admission to hospital is needed in more severe cases to facilitate urgent treatment of prevent harm to self or others. In terms of mania, antidepressant medication should usually be discontinued. Antipsychotics licensed for mania by the US Food and Drug Administration (FDA) include aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone.² The Maudsley Prescribing Guidelines in Psychiatry highlight lithium (at a plasma level of 0.8-1.0mmol/l) or valproate as first-line treatments. In 2011, Cipriani and colleagues compared the efficacy of several different anti-manic agents, and found that olanzapine, haloperidol, and risperidone were the best options available to treat acute mania.³ Lithium, valproate, carbamazepine, and other antipsychotics, such as quetiapine, aripiprazole, and ziprasidone were also significantly better than placebo at treating acute mania. In practice, antipsychotics tend to be used first in the treatment of acute mania, because mood stabilisers such as lithium are limited by the fact that they usually take a little longer to achieve a response.

Bipolar depression, compared to its unipolar counterpart, tends to be more rapid, severe, and frequent. According to the NICE guidelines, if a person develops moderate or severe bipolar depression, quetiapine may be used, or alternatively fluoxetine combined with olanzapine.⁴ Lamotrigine is a third mood stabiliser option, while antipsychotics licensed by the FDA include cariprazine and lurasidone. The use of unipolar antidepressants in bipolar depression may precipitate a manic episode so this is usually a last resort and the reserve of specialist care.

In terms of maintenance in bipolar disorder, lithium is the medication with the strongest evidence-base. The earlier lithium is commenced, the better the response. It is excreted through the renal system and has a narrow therapeutic index, meaning lithium blood levels are needed. The optimal range for maintenance is between 0.6-0.8mmol/L, and levels below 0.4mmol/L are considered ineffective (depending on the laboratory). Baseline urea, creatinine, and electrolytes (and calculated eGFR), thyroid function tests, corrected calcium, electrocardiogram, and body mass index are recommended prior to commencement. A 12-hour post-dose serum lithium level should be checked every five-to-seven days until a steady state is reached, and every three-to-six months thereafter. Most side-effects are dose related and typically include dry mouth, a metallic taste, a fine tremor, polyuria, diarrhoea, weight gain, and aggravation of skin conditions. In the longer term, lithium can result in a reduction in renal function and an increased risk of hypothyroidism, therefore warranting the monitoring of renal and thyroid function every six months.

Serum lithium levels of greater than 1.5mmol/L can result in lithium toxicity, which may present with vomiting, coarse tremor, ataxia, nystagmus, confusion, and impaired consciousness. Some drugs, such as ACE inhibitors, non-steroidal anti-inflammatory drugs, and diuretics can interact with lithium to precipitate toxicity. Pregnancy is a relative contraindication to lithium, given the 20-fold increased (or 1:1000) risk of Ebstein’s anomaly – a congenital heart defect – however, the risk of relapse secondary to sudden discontinuation of lithium therapy in pregnancy should also be carefully factored in. A 2019 systematic review by Hui and colleagues highlighted a number of predictors of good response to lithium, including a shorter pre-lithium illness duration, a family history of bipolar disorder, an older age of onset, the absence of rapid cycling, and the absence of psychotic symptoms.⁵ Evidence shows that lithium also offers some protection against both attempted and completed suicide in patients with bipolar illness.

Valproate is another commonly used mood stabiliser, however, the National Institute for Health and Care Excellence guidelines recommend that it should not be used in women of childbearing age due to the high-risk of teratogenicity and neurodevelopmental disorders. Valproate should only be considered in premenopausal women if all other options are ineffective and a pregnancy prevention programme is in place. Common side-effects include nausea, lethargy, weight gain, gastric irritation, sedation, and in some cases hair loss, thrombocytopenia, and hepatic failure. Carbamazepine and lamotrigine are also best avoided in pregnancy because of teratogenic risk.

Structured psychological approaches for bipolar disorder include cognitive behavioural therapy, carer psychoeducation, and the wellness recovery action plan. The emphasis is on relapse prevention. While remission and relapse rates vary in the literature, positive prognostic factors include a shorter duration of illness, fewer psychotic symptoms, fewer comorbid physical problems, a better treatment response, and good adherence to the treatment plan. 

So, what happens to Kevin? He is admitted to his local psychiatric unit and prescribed an antipsychotic medication in combination with lithium therapy, taking into account potential side-effects, his preferences, and also those of his next-of-kin. In due course, he is offered cognitive behavioural therapy and family psychoeducation. Relapse prevention strategies are discussed prior to discharge to outpatient care.

Authors: Dr Alaa Kambal, Registrar in Psychiatry, Saint John of God Hospital, Stillorgan, Co Dublin; and Dr Stephen McWilliams, Associate Clinical Professor, School of Medicine and Medical Sciences, University College Dublin, and Consultant Psychiatrist, Saint John of God Hospital, Stillorgan, Co Dublin