The medicolegal challenges of diagnosing and treating bipolar disorder

Bipolar disorder (BD) refers to a group of affective disorders in which patients experience episodes of depression and either mania or hypomania, where symptoms are less severe or less protracted than in mania. Symptoms during depressive episodes include loss of pleasure and reduced energy, while those for mania episodes include increased energy and a decreased need for sleep. BD can be divided into four main sub-groups: bipolar disorder type I (episodes of depression and at least one episode of full-blown mania), bipolar disorder type II (several protracted episodes of depression and at least one hypomanic, but no manic, episodes), cyclothymic disorder (periods of hypomania and depressive symptoms that do not meet the criteria for depressive episodes) and bipolar disorder not otherwise specified (depressive and hypomanic-like symptoms and episodes that do not meet the full criteria for any of the three other subgroups) (1).

The diagnosis of psychiatric disorders is based exclusively on clinical criteria and there are no relevant genetic, biochemical or neurophysiological markers (2, 3). BD is particularly difficult to diagnose accurately, particularly types I and II. Only 20% of patients with BD who are experiencing a depressive episode will be correctly diagnosed within the first year of seeking treatment, and around 60% of these patients will receive an incorrect diagnosis of recurrent unipolar depression (1). The average length of time between onset of illness and diagnosis is 5-10 years (1-4), which can have significant ramifications, as length to first treatment is associated with treatment resistance (3).

A major challenge is the difficulty in differentiating BD types I and II from unipolar depression, which is itself characterised by recurrent depressive episodes. This is particularly the case with patients who present during a depressive episode or who have no clear history of mania symptoms (1, 2). Not surprisingly, unipolar depression is the commonest misdiagnosis in patients with BD, especially those in the type II subgroup, who, by definition, do not experience mania episodes (1).

The higher prevalence of depressive symptoms compared to manic or hypomanic symptoms, and the fact that most disorders begin with a depressive episode also make distinguishing between BD and unipolar depression more difficult. For example, patients with BD type II spend much of their lives in a depressed state and are much more likely to seek treatment for depressive symptoms than for manic or hypomanic symptoms. Often, they do not recognise the consequences of the latter symptoms and fail to report them, which adds to the diagnostic challenge (1).

The traditional view of BD is of a group of illnesses characterised by discrete episodes of depression, mania or hypomania (1). However, mixed mood episodes, where both depressive and manic symptoms are present, are being increasingly recognised. Identification of manic or hypomanic symptoms is even more difficult in patients with mixed mood episodes (1, 5). However, it is now known that patients whose symptoms do not meet the thresholds for BD diagnosis will experience relapse into full-blown illness episodes more quickly than patients without subthreshold symptoms (1). Furthermore, those with mixed states tend to have more severe symptoms and more lifetime episodes of illness (5).

These factors suggest that the boundary between BD and unipolar depression is not clear cut. Unfortunately, misdiagnosis of BD can have serious consequences. These include the prescription of inappropriate drugs, such as an antidepressant where a mood-stabilising drug is indicated, which may lead to a manic episode. Many misdiagnosed patients also have poor clinical and functional outcomes, which are associated with high healthcare costs (1).

Diagnosis of BD in children and adolescents can be particularly challenging. Due partly to the stigma associated with psychiatric conditions, accurate diagnosis can be even more elusive than in adults. Further difficulties are caused by the developmentally different symptoms of mania presentation in young patients, high rates of mixed states and complex cycling, and the frequent presence of comorbidities, including depression. Some doctors do not even believe that BD can occur in paediatric populations and that the severe mood dysregulation seen in this age group does not represent the true condition (3). Delayed recognition and treatment are associated with an increased risk of relapses, social and educational dysfunction. There is also a higher risk of cognitive dysfunction if further episodes occur within the first year of an initial mania episode (6).

Recent measures to improve the diagnosis of BD include self- and clinician-administered rating scales (1, 4). These aim to detect clinical features indicative of BD in patients with a history of depressive episodes who might otherwise receive a diagnosis of unipolar depression. However, while these clinical approaches are useful, they lack objective biomarkers which would not only aid diagnosis but also provide targets for the development of new interventions, including personalised treatment. Neuroimaging techniques are showing some promise in this respect. By analysing the neural circuitry underlying cognitive and emotional processes, functional abnormalities that distinguish BD and unipolar depression might be identified. For example, more substantial abnormalities in white matter connecting the neural regions involved in emotion processing and regulation, and differential patterns of amygdala activity and connectivity, have been reported in depressed patients with BD compared to those with unipolar depression (1).

Another major issue in the management of BD is the occurrence of comorbidities. Many patients also suffer from conditions such as anxiety disorders, borderline personality disorder (BPD) and other personality disorders. There is a significant overlap in the symptoms of BPD and the depressive and hypomanic mixed states of BD type II. This, combined with the often-unstable disease course of BPD, can add to the difficulty of obtaining a correct diagnosis (4, 5). However, differences in the regulation of emotional processes may provide a basis for distinguishing the two conditions (5).

In younger patients, there is considerable overlap of symptoms between BD and attention-deficit hyperactivity disorder (ADHD). Abnormally high energy, distractibility and talkative speech are common to both. However, while ADHD frequently occurs without comorbid BD, the onset of BD before puberty is usually accompanied by ADHD. Co-occurrence of the two conditions is associated with worse functioning than ADHD alone. There is also some evidence that early-onset BD with ADHD is caused by a genetic mechanism that is different from adult-onset BD. Additionally, around 30% of young patients referred for treatment of autism spectrum disorder have comorbid BD, although a genetic mechanism for this has not yet been identified (3).

Patients with mixed states have a particularly high incidence of substance abuse. There is also evidence that this relationship may be bidirectional, with data suggesting that individuals with substance abuse disorders experience a higher prevalence of BD. The reasons for this are not completely clear, but it has been suggested that a history of substance abuse leads to greater mood instability in patients experiencing depressive episodes, thus increasing the risk of mixed state episodes (5).

Current treatments for BD aim to improve symptoms of pure mania or depression and prevent relapse. Mixed states are more difficult to treat, as the response to monotherapies is generally poor, and are associated with worse outcomes and a higher suicide rate (5). Antidepressants are usually deemed unsuitable, due to the risks of exacerbation of manic symptoms and an increased suicide risk (3, 5).

Lithium is the gold standard treatment for mania (5, 6) and has also been shown to improve cognitive deterioration in patients with mild impairment. It is most effective in patients with a family history of mood disorders, particularly if this was successfully treated with lithium and in those without anxiety or substance abuse comorbidities (6). However, it appears to be less effective when mania and depression occur together. Instead, valproate, which has a more rapid onset of action, may be more effective in the treatment of acute mixed states, with lithium being used as a long-term preventive medication (5).

Second-generation neuroleptics, such as aripiprazole, olanzapine and risperidone, are more effective against manic symptoms than depressive ones (3, 5, 6). Patients with a family history of non-response to lithium are sometimes successfully treated with this class of medication (6).  Electroconvulsive treatment is an effective treatment for mixed manic episodes, particularly where medication has failed or cannot be used (5). However, it is rarely used in paediatric patients due to potential side effects. Whichever medication is chosen, poor adherence is common due to annoying and serious side effects coupled with diminishing insight during relapse episodes. As inadequate treatment with relapses of manic and/or depressive episodes can contribute to treatment resistance, it is vital that medication is continued (3).

Although medication is the first-line treatment for BD, adjuvant psychotherapy can augment pharmacological treatment adherence and is particularly beneficial for patients with greater functional impairment and comorbid anxiety (3). Family and similar group therapies have shown good results in young patients and can help to reduce behavioural symptoms and achieve and maintain mood stability (3, 6).

Many of the comorbid conditions that occur in conjunction with BD are severely impairing in their own right and require treatment to ensure a good patient outcome. Often, a combined pharmacotherapy approach is required. For example, ADHD can be treated with stimulants, but only once the patient’s BD symptoms have been stabilised. Anxiety should not be treated with antidepressants; instead, mood stabilising anticonvulsants and second-generation antipsychotics can be used. In general, comorbid conditions remain difficult to treat and the need for combined pharmacotherapy increases the risk of side effects, which may themselves require additional medication (3).

Early diagnosis and intervention are vital to improve the prognosis of BD. However, diagnosis remains challenging. The use of unified structured interviews, and the development of new measures, such as biomarkers or functional imaging, may help to identify manic symptoms in patients with depressive episodes, which when combined with information from carers, should improve the diagnostic accuracy of BD. Identifying a family history of mood disorders may indicate the likelihood of a positive response to treatment and should guide the choice of medication. It is also important that patients with mixed state disease are identified as treatment differs from that for non-mixed BD. Taken together, these factors could contribute towards better outcomes for BD patients.