Therapies — 14 September 2012

Over the last decade there has been growing professional and public interest in bipolar disorder. Once regarded as an uncommon and somewhat “Cinderella” condition, it now receives considerable media interest, with increasingly frequent accounts of high-profile figures such as actors and sportsmen who purportedly have this illness.

Although bipolar disorder has undoubtedly been historically ignored and underdiagnosed, there is growing evidence that the condition may be becoming overdiagnosed.1

Irrespective of these shifts in diagnostic practice, bipolar disorder undoubtedly presents a major challenge to the general practitioner. The chaos of mania, the disruption of repeated episodes of illness, and the common reluctance to comply with medications each present major difficulties for the clinician.

The positive news is that there is an increasing range of effective treatments – both pharmacological and psychological. The vast majority of patients with bipolar disorder benefit substantially from treatment.

General practitioners play a central and critical role in the management of this condition, in conjunction with psychiatrists, psychologists and community mental health teams.

EPIDEMIOLOGY
Between 1% and 1.5% of Australians have bipolar disorder. In the 2007 Australian Survey of Mental Health and Well-being which included almost 9000 Australians from urban and rural regions we found that 0.9% of the population had experienced an episode of bipolar disorder in the previous 12 months, while 1.3% had experienced this condition at some stage of their life.2

This Australian survey confirmed the severe impact of bipolar disorder. Those with this condition were more likely to be: single (due to either broken relationships or never having been in a long term relationship), living alone, unemployed, or in receipt of a government pension. The effect on day-to-day functioning was highlighted by the high number of days each month individuals were less able or unable to carry out their usual roles (23 days per month). In particular, there was major interference with their ability to manage daily household responsibilities.

Those with bipolar disorder were also more likely to have a comorbid psychiatric disorder, with 63% having an anxiety disorder and 25% an alcohol or substance use disorder.

Another measure of the severity of bipolar disorder demonstrated in that Australian survey was that those with the illness were more likely to have made suicide attempts in the prior year (9%) – even when compared to those who had recurrent depressive episodes (2%).

Other studies have highlighted the increased mortality rate due to this illness. Patients with bipolar disorder die, on average, about 10–15 years earlier than their peers. This is mainly due to death from physical causes, predominantly related to cardiovascular and cerebrovascular disease.

Rates of completed suicide are also a major contributant, with 10–20% of those with bipolar disorder ending their own life.

PATHOPHYSIOLOGY
Bipolar disorder is strongly genetic, with inherited factors accounting for about 80–85% of the cause of this condition. A recent study3 reported first-degree relatives of those with bipolar disorder were 10–14 times more likely to have this condition than those without such a family history.

Family studies have shown rates of bipolar disorder of 4–15% in the offspring of parents with this condition, compared to 0–2% in the offspring of controls.

Twin studies confirm these high family rates are mainly genetic rather than merely due to shared environmental factors, with rates of concordance for severe mood disorders (bipolar disorder or severe depression) being 67% for monozygotic (identical) twins compared to 19% for dizygotic (non-identical) twins. Interestingly, it is also now apparent that there is considerable genetic sharing with schizophrenia.4 In addition to higher rates of bipolar disorder among first-degree relatives, there are also greater than expected rates of schizophrenia.

In many ways it is not surprising that there is some sharing of genetic factors, as there are many clinical overlaps between these conditions; for example, both share similar delusions and hallucinations.

In addition to increased rates of bipolar disorder and schizophrenia in these families, there are also more relatives with recurrent depression (major depressive disorder), schizo-affective disorder and cyclothymia – consistent with a broad clinical spectrum of inheritance.

In recent years, new technology has identified the specific genes responsible for bipolar disorder. The mode of transmission is that of complex genetics, i.e. multiple genes (each of small effect) interacting with environmental factors. Ultimately, such gene discoveries5 will make clearer the molecular and biochemical abnormalities causing bipolar disorder, which will lead to the future development of targeted and more effective pharmacological treatments.

‘Secondary mania’
Manic episodes may be caused by underlying physical disorders or medications, though these are rarely responsible for the typical ongoing episodic form of the condition. Such episodes are termed ‘secondary mania’. The most common causes of such presentations are iatrogenic, with medications such as steroids, dopaminergic agents for Parkinson’s disease or antidepressants being the most frequently reported.

Other causes are neurological conditions such as multiple sclerosis, space occupying lesions (often in frontal regions) or cerebrovascular accidents.

Red flag
A first presentation of mania in mid-life or old age should arouse suspicion of organic factors.

Not surprisingly, secondary mania is associated with increased mortality rates, particularly those related to underlying CNS disorders.

DIAGNOSIS
The hallmark characteristic of bipolar disorder is the episodic nature of the illness, with periods of normal mood between the episodes of hypo/mania and depression.

This distinguishes bipolar disorder from schizophrenia, in which most patients have some ongoing symptoms and/or functional deficit.

Furthermore, unlike schizophrenia, in bipolar disorder any psychotic features arise from the underlying mood disturbance – mania or depression.

Mania and Hypomania
The features of mania and hypomania are detailed in Table 1.

The essential differences between these two presentations are severity and duration.

In mania, there is significant functional impairment and/or psychotic features and/or hospitalisation, whereas in hypomania, none of these pertain, despite there being differences in behaviour distinct from the person’s normal self.

Furthermore, hypomanic episodes are shorter than those in mania, with most diagnostic systems requiring a minimum duration of at least 2–4 days, whereas manic episodes require a duration of at least a week.

It should be emphasised that here we are talking about the most severe lifetime episodes.

In practice, many patients also have shorter periods of elevated mood, that may last for only days or even hours.

Furthermore, manic episodes usually persist for at least several weeks, and often several months.

Table 1. Features of manic and hypomanic episodes

  • Duration – at least seven days for mania; at least 2–4 days for hypomania
  • Elevated or euphoric mood and/or irritability
  • Other symptoms
    • Inflated sense of own abilities or capabilities (grandiosity)
    • Disinhibition – increased libido, excessive spending, overly frank comments about others
    • Over-talkative, increased subjective speed of thoughts
    • Increased activity levels
    • More distractible, difficulty focusing on task completion
    • Decreased need for sleep
    • Aggressiveness
  • Significant impairment of function and/or psychotic features (delusions – most commonly paranoid, sometimes grandiose; hallucinations – usually auditory or visual) and/or need for hospitalisation (mania only)
  • Distinct change in functioning noticeable by others, but not significantly impaired (hypomania only).


DEPRESSION

There is growing evidence that the depressive episodes in bipolar disorder (bipolar depression) show different characteristics to those in major depressive disorder (unipolar depression).6 These are detailed in Table 2.

In general, bipolar depressive episodes are of longer duration than the periods of hypo/mania, with episodes of 2–6 months being not uncommon.

It should also be emphasised that patients are often significantly cognitively impaired during periods of bipolar depression, with profound impairments in concentration, short term memory and overall thinking capacity.

Table 2. Features more common in depressive episodes in bipolar disorder (bipolar depression) than in major depressive disorder (unipolar depression)

  • Physical slowing (psychomotor retardation)
  • Increased sleep
  • Increased appetite
  • Mixed features (some features of elevated mood intermingled with depressive symptoms)
  • Psychotic features (delusions, hallucinations)
  • Early morning wakening and diurnal variation with mood worse in morning
  • Early onset of first depressive episode (< 25 years)
  • Multiple episodes of depression
  • Family history of bipolar disorder

Mixed episodes
Some patients present with a mixture of hypo/manic and depressive symptoms. Such presentations have been termed ‘mixed episodes’.

In practice, the most common form of these is episodes that are primarily hypo/manic with some interspersed depressive symptoms.

‘Unipolar Mania’:A bipolar variant
A small number of patients (about 10%) only experience episodes of mania. This presentation was originally described as ‘unipolar mania’ and thereby distinguished from bipolar disorder.

However, over time it became apparent from treatment and genetic studies that the unipolar manic presentation was in fact a variant of bipolar disorder rather than a distinct condition, so this term is no longer employed.

My own clinical experience is that closer questioning of such patients often reveals phases following the manic episodes during which patients are demotivated, lacking in energy and physically slowed (though not necessarily reporting sadness or unhappiness); such episodes probably represent a more physical presentation of depression.

Bipolar I and Bipolar II disorder
Readers would be increasingly familiar with the terms bipolar I disorder and bipolar II disorder.

‘Bipolar I disorder’ is used to describe patients who have had at least one episode of clear mania during their lifetime, whereas ‘bipolar II disorder’ is used to describe patients who have only ever experience periods of hypomania and depression.

Overdiagnosis of bipolar disorder
In the US, there have been a number of reports of high rates of bipolar disorder diagnosed in clinical practice which could not be confirmed by formal structured diagnostic interviews.1

Many of these patients were diagnosed as having bipolar disorder by their clinicians merely on the basis of “mood instability”, with the diagnosis on structured interview being rather borderline personality disorder, substance use disorders or an anxiety disorder.

The major concern about such over-diagnosis is the potential for over-use of medications such as antipsychotics (with their risk of serious complications) and the associated under-utilisation of relevant psychological treatments.

It is the author’s impression that the major overdiagnosis is for those with presumed bipolar II disorder, rather than the more definitive bipolar I disorder.

PRESENTATION
Bipolar disorder first presents most commonly in late adolescence or during the 20s. Some individuals do present for the first time in their 30s or 40s, but later presentations – particularly during the 50s or later – should raise suspicion about an underlying physical illness. The most common first presentation of bipolar disorder is that of depression, so for such patients the true nature of their condition will not be apparent until their first period of hypo/mania.

Bipolar disorder is recurrent for the vast majority of patients, with the average patient experiencing an episode of hypo/mania or depression each 1–2 years. However, the number and frequency of episodes is highly variable. Some only have a handful of episodes over their entire life, whereas others have periods of continual cycling between hypo/mania and depression. The term ‘rapid cycling’ is used to describe those who experience a total of four or more episodes of either pole of mood over a 12-month period.

MANAGEMENT
According to the Australian survey, only half of those with active symptoms of bipolar disorder in the last year had received psychiatric medications, reflecting possible low rates of diagnosis, poor service provision, or low rates of treatment compliance, a major concern in view of the major impacts of this illness in terms of disability and high risk of suicide.

Acute treatment of mania
The major characteristic of mania that impacts on management is the almost invariable loss of insight (unlike during periods of depression when insight is usually exquisitely maintained).

The manic patient cannot comprehend why family and friends do not share their insights, enthusiasms, plans and concerns. They remain firmly adamant in their beliefs – even in the face of contrary evidence.

On the other hand, family and friends are acutely aware of the damage that is occurring, or is about to happen – in terms of irritability or aggressiveness, hurtful comments, extramarital affairs, excessive spending (perhaps accumulating large credit card debts) and disrupted chaotic behaviour, all with the high likelihood of profound implications for maintaining current relationships and employment.

The dilemma for the family is when to engage medical assistance (perhaps involving hospitalisation), as they may have been severely admonished by the patient for doing so during past episodes. For the GP, the dilemma is when to initiate involuntary referral for treatment using state mental health provisions. Most practitioners prefer to initially engage and manage the situation with the patient’s consent and voluntary compliance. However, the reality is that often legal controls become imperative because of the major potential of harm to the patient’s reputation or financial well-being, or even risk of physical harm to family members or others.

In terms of pharmacological management, the most effective options in the acute situation in general practice, according to a recent meta-analysis,7 are the antipsychotics – both the newer second-generation antipsychotics (in particular olanzapine and risperidone) and also the older first-generation antipsychotics (in particular, haloperidol).

The traditional mood stabilisers such as lithium and valproate are also effective in mania, though less so than the antipsychotics. In practice, lithium and valproate should be introduced later once the symptoms of mania have begun to resolve, with an eye to preventing relapse. All of the second-generation antipsychotics have been shown to be effective anti-manic agents.

Acute treatment of bipolar depression
There is much controversy about the preferred means for managing bipolar depression. If antidepressants are to be used, they should only be used in conjunction with a mood stabiliser, as they have the potential of inducing either mania or rapid-cycling if used as monotherapy.

In recent years there has also been growing evidence for the efficacy of some of the second-generation antipsychotics in the acute treatment of bipolar depression – in particular quetiapine and olanzapine. Some authorities recommend these as first-line treatment in such situations.

Maintenance treatment: Prevention of recurrence in bipolar disorder
There is now strong evidence for the prophylactic efficacy of lithium, second-generation antipsychotics and lamotrigine. While valproate is widely used clinically, the only large randomised controlled trial showed no benefit compared to lithium. This result may have been due to some of the limitations in trial design. Lithium has very strong preventive capacity against mania, but the evidence for prevention of depressive episodes is more equivocal.

A recent meta-analysis,8 clarified the prevalence of adverse effects such as weight gain and hypothyroidism. This study also confirmed the association with hyperparathyroidism and suggested a low risk of renal impairment. A recent clinical review in the BMJ 9 is a helpful resource for managing renal impairment.

All of the second-generation antipsychotics have been shown to possess prophylactic efficacy for bipolar disorder, though with the exception of olanzapine and quetiapine, this effect is on manic episodes only, not depressive. Lamotrigine, while effective in preventing depressive episodes more so than manic, has limited use in Australia in that it is only approved, but not subsidised, for this indication.

The prophylactic management of bipolar disorder is much more than just medications. There is now a large body of evidence for the role of psychological managements adjunctive to pharmacology.10

Those treatments shown to be most effective, particularly in preventing depressive relapse, are cognitive behavioural therapy, structured psycho-education, and interpersonal and social rhythms therapy (IPSRT). These treatments are most usefully commenced when the patient is no longer symptomatic. There is an increasing number of clinical psychologists in Australia skilled in such interventions.

Social and legal interventions that should be considered when the patient is recovered include initiation of strategies such as a power-of-attorney if the patient commonly over-spends or is overly generous during periods of mania. This is also the time to discuss with the patient their preferences on how they should be managed when unwell.

CONCLUSION

Bipolar disorder is a common and impairing condition that provides a major challenge for the GP. There is now a broad range of effective treatment strategies – pharmacological, psychological and social/legal – with which the GP should become familiar.

KEY POINTS

  • The chaos of mania, the disruption of repeated episodes of illness, and the common reluctance to comply with medications each present major difficulties for the clinician.
  • The vast majority of patients with bipolar disorder benefit substantially from treatment.
  • Those with this condition are more likely to be: single, living alone, unemployed, or in receipt of a government pension.
  • Those with bipolar disorder are more likely to have a comorbid psychiatric disorder, with 63% having an anxiety disorder and 25% an alcohol or substance use disorder.
  • Bipolar disorder is a strongly genetic condition, with inherited factors accounting for about 80–85% of the cause of this condition

REFERENCES
1. Mitchell, P.B. (2012) Bipolar disorder: The shift to over-diagnosis. Canadian Journal of Psychiatry (In Press)
2. Mitchell, P., Johnston, A.K., Frankland, A., Slade, T., Green, M.J., Roberts, G., Wright, A., Corry, J., Hadzi-Pavlovic, D. (2012) Bipolar disorder in a national survey using the WMH-CIDI: The impact of differing diagnostic algorithms. Acta Psychiatrica Scandinavica. Aug 20 1-13. doi: 10.111/acps.12005 [Epub ahead of print]
3. Mortensen PB, Pedersen CB, Melbye M, Mors O, Ewald H. Individual and familial risk factors for bipolar affective disorders in Denmark. Arch Gen Psychiatry. 2003 Dec;60(12):1209-15.
4. Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009 Jan 17;373(9659):234-9.
5. Sklar P, et al. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011 Sep 18;43(10):977-83.
6. Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RM. Diagnostic guidelines for bipolar depression: a probabilistic approach. Bipolar Disord. 2008 Feb;10(1 Pt 2):144-52.
7. Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011 Oct 8;378(9799):1306-15.
8. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012 Feb 25;379(9817):721-8.
9. Kripalani M, Shawcross J, Reilly J, Main J. Lithium and chronic kidney disease. BMJ. 2009 Jul 3;339:b2452.
10. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry. 2008 Nov;165(11):1408-19.

Professor Philip Mitchell, AM, MB BS, MD, FRANZCP, FRCPsych
Scientia Professor and Head, School of Psychiatry, University of New South Wales; Director, Bipolar Disorders Clinic, Black Dog Institute, Sydney.

As first appeared in Medical Observer

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