Clinical Review: Bipolar affective disorder

How to diagnose and manage patients in the long term. By psychiatrist Dr Muffazal Rawala and Dr Sanober Saleem

Section 1: Epidemiology and aetiology

About one in 100 adults will experience cyclical extreme mood fluctuations between mania and depression not caused by drugs or another medical condition.

This results in significant distress and impaired social functioning, but is interspersed with periods of almost full recovery.

In comparison to depression, the Epidemiological Catchment Area study identified a lower prevalence of 0.8% for bipolar disorder I and 0.5% for bipolar disorder II.

This may have involved misdiagnosed bipolar disorder, because 21% of patients might have presented in the depressive phase.

Most patients present at 15-24 years, although some present later in life after having been diagnosed with depression. Patients presenting with first-onset mania after the age of 50 years should prompt investigations to rule out secondary mania.

The risk of bipolar disorder is increased in first-degree relatives; 40-70% for monozygotic twins and 5-10% for other relatives. The heritability estimate of 85% suggests the variance is due to genetic factors.1,2 Bipolar disorder is seen with equal prevalence in both sexes.

The strong genetic aetiological component is shown by twin and family studies with the involvement of ANK3, CACNA1C, and CLOCK genes. Gene expression studies have shown a decreased expression of oligodendrocyte-myelin related genes and abnormalities of white matter in various brain regions.3,4

The role of serotonin, norepinephrine and dopamine has been postulated on the basis that drugs increasing their levels, for example, antidepressants, can trigger mania.

The role of glutamate has been suggested on the basis of a postmortem study, which showed increased levels in bipolar patients' frontal lobes.5

Some studies have shown problems with emotional regulation, as evidenced by decreased activation of grey matter and reduced activation of ventric limbic circuits.6

A genetic predisposition may be triggered by stress, for example, pregnancy; the risk of puerperal psychosis is increased in patients with a family history of bipolar affective disorder.

Psychodynamically, the features of mania are explained as a defence against the ego-destroying negative thought patterns of depression, suggesting that manic patients, especially in remission, have a negative self-concept, variable self-esteem and increased drive.7,8

Section 2: Making the diagnosis

The DSM-IV criteria for mania are a period of persistently abnormally elevated, expansive or irritable mood, lasting at least a week and causing occupational or social malfunctioning, or with psychotic features and not secondary to a psychoactive substance or general medical condition.

During this period, three of the following symptoms (four if the mood is only irritable) have persisted:

  • Inflated self-esteem or grandiosity.
  • Decreased need for sleep.
  • More talkative than usual or pressure to keep talking.
  • Flight of ideas or subjective expression of thoughts racing.
  • Increase in goal-directed anxiety (social, work or sexual), or psychomotor agitation.
  • Distractibility.
  • Excessive involvement in activity with potential for painful consequences, such as overspending or sexual indiscretions.

DSM-IV states the core symptoms of hypomania as similar to mania, but with a shorter duration of four days and an observable but not impaired change of functioning.

Rapid cycling

Patients with four or more episodes of depression, mania, mixed state or hypomania over a 12-month period are described as having rapid cycling. The lifetime risk in a clinic population is 16% and it is loosely associated with female gender, bipolar type II and hypothyroidism.9

DSM-IV criteria for bipolar affective disorder

Bipolar I disorder

One or more manic episodes. A depressive or hypomanic episode is not required for diagnosis, but frequently occurs.

Bipolar II disorder

No manic episodes. One or more hypomanic episodes and one or more major depressive episodes.


A history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes. There is a low-grade cycling of mood which appears to the observer as a personality trait and interferes with functioning.

Bipolar disorder NOS (not otherwise specified)

This is a catch-all category, diagnosed when the disorder does not fall within a specific subtype.

    Differential diagnoses

    • Schizophrenia and schizoaffective disorder
    • Substance misuse - psychoactive substances such as cocaine can cause mania-like symptoms
    • Organic disorder - in patients with manic symptoms after age 40, this needs to be ruled out first
    • Metabolic disorder
    • Prescribed medications - corticosteroids, L-dopa and methylphenidate can result in mania-like symptoms

    Section 3: Managing the condition

    Acute manic phase

    Most patients would benefit from admission or assertive community management by a psychiatric team.

    Lithium, valproate semisodium, olanzapine, risperidone, aripiprazole and quetiapine are licensed for use in acute mania.

    If the patient is on antipsychotics, consider checking compliance and increase dose if needed; add lithium or valproate. If the patient is on lithium or valproate, check plasma level and increase the dose to maintain at the top of the therapeutic range. An antipsychotic could be considered with lithium and valproate.

    If the patient does not take any antimanic medication, consider starting an antipsychotic or valproate, due to faster onset of action, especially if behaviourally disturbed.

    Depressive phase

    In contrast to unipolar depression, depressive episodes in bipolar disorder tend to be more acute, more frequent and shorter. NICE recommends an SSRI with an antimanic or quetiapine if an antipsychotic is not already prescribed. Antidepressants can cause a switch to manic state and could cause mood destabilisation.

    For mild depressive episodes, a 'wait and watch' approach over two weeks might be appropriate. For moderate to severe episodes, consider starting an SSRI, owing to the lower risk of causing a switch to mania when compared with tricyclic antidepressants.

    Antidepressants should not be prescribed if the patient has a history of rapid cycling or a recent hypomanic episode. In these cases, consider optimising the antimanic or adding quetiapine or lamotrigine.

    In contrast to the NICE guidelines, recent evidence suggests antidepressants should not be considered first-line in bipolar depression, owing to the risk of switching to mania.10,11

    Based on the evidence, quetiapine should be considered the agent of choice in bipolar depression, owing to its antimanic and prophylactic effect, followed by lithium and valproate. Antidepressants could still be used with an antimanic agent in patients who have shown a favourable past response.

    Long-term prophylaxis

    NICE recommends prophylaxis:

    • In cases of bipolar I, after two or more acute episodes.
    • After a single manic episode if associated with significant risks and adverse consequences.
    • In bipolar II, if significant functional impairment or suicide risk, or frequent episodes.

    Lithium, valproate, quetiapine and olanzapine are most commonly prescribed long-term. The choice depends on response to previous treatment, physical risk factors (renal and thyroid disorders in case of lithium; diabetes and obesity in case of olanzapine) and gender (valproate should not routinely be prescribed for females of childbearing age).

    Prophylaxis should continue for at least two years after one episode, or for five years if there is a history of frequent relapses, psychotic symptoms and comorbid substance misuse.

    Psychological treatment
    Consider CBT, interpersonal therapy or family-focused therapy. There is evidence for the role of psychoeducation and structured regular activities for maintaining stability.

    Important considerations

    • Contraception should be discussed in all females of childbearing age owing to the teratogenic potential of many antimanic agents.
    • The postnatal period is a time of high risk of relapse in females.
    • In patients on long-term lithium, levels should be checked every three months, and renal and thyroid function every six months.

    Section 4: Prognosis

    Bipolar disorder is a chronic recurring illness. Patients have an average of 10 episodes in their lifetime.12

    The risk of recurrence after an episode of mood disorder is in the region of 50% after the first year, 75% at four years and thereafter, 10% annually.

    Patients with bipolar disorder frequently have significant physical comorbidities, such as diabetes and cardiovascular problems.

    The standardised mortality ratio (SMR) for premature death due to natural causes is 1.9 in males and 2.1 in females.13

    Suicide risk
    The SMR for suicide is higher (15 for males, 22.4 for females), corresponding to 0.4% of bipolar patients dying by suicide annually, compared with 0.017% of the general population.14

    The European Mania in Bipolar Longitudinal Evaluation of Medication study suggests these characteristics are found in patients with bipolar disorder who are suicidal:15

    • Female gender
    • A history of alcohol abuse
    • A history of substance abuse
    • Young age at first treatment for a mood episode
    • Longer disease duration
    • Greater severity of depressive symptoms
    • Poor compliance

    Prognostic factors
    Patients with bipolar I fare worse than patients with a major depression. Within the first two years after the initial episode, 40-50% of patients experience another manic attack. Often, the cycling between depression and mania accelerates with increasing age.

    Factors suggesting a worse prognosis include:

    • Impairment of occupational functioning
    • Alcohol abuse
    • Psychotic features
    • Depressive features between periods of mania and depression
    • Male sex

    Factors suggesting a better prognosis include:

    • Shorter duration of manic phases
    • Later age of onset
    • No psychotic symptoms
    • Few medical problems

    Section 5: Case study

    A 23-year-old female presents with low mood, anhedonia, and sleep and appetite problems for the past four weeks. She is diagnosed with depression and offered fluoxetine 20mg once daily and CBT.

    The patient saw her GP regularly to monitor her mental state

    After nine weeks, you receive a call from the patient's mother, who says she has been behaving out of character, seemed to have excess energy, broke up a long-term relationship and has been irritable. You offer to see the patient the same day. The patient refuses to attend.

    Two days later you are informed that the patient has been sectioned after behaving in a sexually disinhibited manner. She is stabilised on olanzapine and discharged after three weeks. She sees her GP regularly to monitor her mental state. She engages well and psychoeducation is provided to her mother and herself.

    You decide to continue her olanzapine for at least another two years. After a period of eight months she is brought in by her mother, showing possible signs of relapse - spending large sums on her credit cards, not sleeping and unexpectedly changing her college course.

    The patient agrees to be referred to the psychiatric team. She is started on lithium and olanzapine.

    Section 6: Evidence base

    Clinical trials

    • Liu HY, Potter MP, Woodworth KY et al. Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis. J Amer Acad Child Adolesc Psychiatry 2011; 50(8): 749-62.

    A meta-analysis of 46 RCTs for the use of antimanics in children.

    • Kilbourne AM, Goodrich DE, O'Donnell AN et al. Integrating bipolar disorder management in primary care. Curr Psychiatry Rep 2012; 14(6): 687-95.

    This interesting paper discusses the burden of bipolar disorder in primary care and the use of collaborative chronic care models for the management of bipolar patients, and the challenges of such an approach.

    • Kyaga S, Landen M, Boman M et al. Mental illness, suicide and creativity: 40-year prospective total population study. J Psychiatr Res 2013; 47(1): 83-90.

    This study from Sweden tracked about 1.2m patients and their relatives, and showed that bipolar disorder is prevalent among the entire group of artistic or scientific professions, such as dancers, researchers and authors.

    Authors specifically presented more commonly with most of the other psychiatric diseases (including schizophrenia, depression, anxiety syndrome and substance abuse) and were almost 50% more likely to commit suicide than the general population.



    • Contributed by Dr Muffazal Rawala, specialty registrar in general adult psychiatry, South London and Maudsley NHS Foundation Trust, London, and Dr Sanober Saleem, specialty trainee in general practice, Kent, Surrey and Sussex deanery.

    Reflect on this article and add notes to your CPD Organiser on MIMS Learning


    These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

    • Ensure you are up-to-date with local mental health protocols.
    • Consider the benefits and risks of prescribing antidepressants to patients with bipolar disorder.
    • Revise which drugs are contraindicated in women of childbearing potential and what alternatives may be offered.


    1. McGuffin P et al. Arch Gen Psychiatry 2003; 60: 497-502.

    2. Craddock N, Jones I. J Med Genet 1999; 36: 585-94.

    3. Baum AE et al. Mol Psychiatry 2008; 13: 197-207.

    4. Wellcome Trust Case Control Consortium. Nature 2007; 447: 661-78.

    5. Hashimoto K, Sawa A, Iyo M. Biol Psychiatry 2007; 62: 1310-16.

    6. Houenou J et al. J Affect Disord 2011; 132: 344-55.

    7. Winters KC, Neale JM. J Abn Behavior 1995; 94: 282-90.

    8. Lyon HM, Startup M, Bentall RP. J Abn Psychol 1999; 108: 273-82.

    9. Calabrese JR et al. J Clin Psychiatry 1999; 60: 79-88.

    10. Calabrese JR et al. Am J Psychiatry 2005; 1351-60.

    11. Suppes T et al. J Affect Disord 2010; 121: 106-15.

    12. MacQueen GM et al. Acta Psychiatr Scand 2001; 103: 163-70.

    13. Osby U et al. Arch Gen Psychiatry 2001; 58: 844-50.

    14. Baldessarini RJ et al. J Clin Psychiatry 1999; 60 Suppl 2: 77-84.

    15. Bellivier F et al. Bipolar Disord 2011; 13: 377-86.

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