The Hong Kong Practitioner

April 2004, Vol 26, No. 4

Update Article

The diagnosis and management of bipolar affective disorder (manic-depressive disorder) in a primary care setting

K Y Mak 麥基恩

HK Pract 2004;26:187-194

Summary

Many patients presenting with features of a depressive disorder are actually suffering from bipolar affective disorder (also called manic-depressive disorder). If not aware of the condition, physicians who treat the depression vigorously may induce a hypomanic switch in the patient necessitating a complete revamp of treatment regime. Fortunately, there are currently quite a number of safe and effective medications available for treatment at different phases of the disorder. Knowledge about bipolar affective disorder can help early recognition and prompt treatment, thereby minimising the high morbidity and mortality associated with the disorder.

摘要

許多表現為抑鬱症的病人實際上患有雙相性情感障礙（又稱躁狂－抑鬱症）。如果醫生不瞭解這種病，過勇地治療抑鬱症，就可能誘發輕度躁狂，以致不得不完全修改治療方案。可幸的是，目前有不少安全而有效的藥物用於此病的不同階段。掌握雙相性情感障礙的知識，可以幫助做出早期診斷和及時治療，從而將此病的高患病率和高死亡率降至最低。

Introduction

More and more primary care doctors are interested in treating depressive disorders in their clinics, but often they are not aware that some of these patients are actually suffering from a bipolar affective disorder (BAD), also known as manic-depressive disorder. By prescribing high doses of certain antidepressants, they sometimes precipitate the hypomanic (manic) phase in these patients. On the other hand, if diagnosed early enough, these patients can often be well managed in the community setting, especially with the present availability of potent and relatively safe medications.

In fact, BAD is not too infrequently seen, as it can affect up to 1.2% of the general population.¹ It often starts at an early age and runs a chronic and recurrent course, and has a relatively high morbidity and mortality causing much distress and disability to the patients and their family members. There is a higher rate of marital and family breakdown among the patients, with an increased risk of suicide and other physical disorders.²

Definition

BAD is a disturbance of mood that is characterised by inappropriate degree or sustained periods and duration of depression or excitement. It is a serious disorder with a lot of distress to the patients and their carers, in addition to the danger of self-harm or suicide.

According to the American DSM-IV system, BAD have two main types:


1.	Bipolar I Disorder - this term is used when the first episode or the most recent episode has manic symptoms. This disorder is further sub-classified as:

	a.	single manic episode
	b.	most recent episode hypomanic
	c.	most recent episode manic
	d.	most recent episode depressed
	e.	most recent episode mixed
	f.	most recent episode unspecified
	g.	not otherwise specified.

	It should be noted that some patients have "mixed" state (also called dysphoric mania) when they have both mania and depressive symptoms at the same time.


2.	Bipolar II Disorder - this term is used when there are recurrent major depressive episodes with hypomanic episodes in between. This again is further sub-classified into:

	a.	current or most recent episode hypomanic episode,
	b.	current or most recent episode major depressive episode.

	There are also a number of specifiers including: severity, in remission, chronic, seasonal, specific feature (catatonic, melancholic, psychotic), atypical presentation and post-partum onset. The above classification is to separate BAD from unipolar affective disorder (which is a mood disorder without any manic episode). BAD is also subdivided into the rapid cycling pattern (about 15% of bipolar patients, usually transient, sporadic and non-familial)³ and the non-rapid cycling pattern. A diagnosis of rapid cycling is made if there are four or more distinct episodes of mania and depression within a single year. It should be noted that under such diagnostic criteria, it is not possible to be sure whether a depression is unipolar or bipolar without a past history of hypomania or mania.⁴ There is nevertheless some suggestion that bipolar disorder has an earlier onset and runs shorter courses with more frequent accelerating episodes.

Clinical features

The peak age of onset is around 15 to 19 years, but the patients are usually seen at the psychiatric clinics a few years later. Quite a number of them have first been treated by primary care doctors for a depressive episode. Detection of the disorder in children and the elderly is more difficult. Presentation with mild hypomanic features is not common, as the patients often feel well, and when the manic features finally appear they often require hospitalisation. The symptomatology of BAD consists mainly of depressive and/or hypomanic/manic episodes. Such episodes typically begin suddenly, with a rapid escalation of symptoms over a few days. There is no need for all the symptoms to be present before making a diagnosis. However, there should be sufficient symptoms of at least three to qualify, and that such symptoms do cause clinically significant distress or impairment of functioning. Furthermore, the symptoms should not be the direct effects of a substance such as a central stimulant like amphetamine, or a general medical condition such as hypothyroid or hyperthyroidism:

Symptoms of a depressive episode

1.	Preoccupation with failures/inadequacies and loss of self-esteem.
2.	Feelings of uselessness, hopelessness, excessive guilt.
3.	Slow thinking, forgetfulness, difficulty in concentration and making decisions.
4.	Loss of feelings for others and interests in work, hobbies, etc.
5.	Excessive concern about physical complaints e.g. insufficient breath and heart discomfort.
6.	Either agitation or loss of energy, restlessness or tired and weak.
7.	Crying easily (or feel like crying but unable to do so).
8.	Suicidal and occasional homicidal thoughts.
9.	Sleep problems: too much or too little (especially early morning wakefulness).
10.	Changes in appetite and weight, either an increase (comfort eating) or a decrease.
11.	Diurnal variation of mood.
12.	Diminished or loss of libido.

In addition, there is sometimes a loss of touch with reality, even having hallucinations or delusions. There may be constipation and pains of various type, and menstrual irregularities. As a result, the patient may indulge in excessive use of alcohol and non-prescriptive drugs.

Symptoms of a hypomanic or manic episode

1.	Extreme irritability, demanding and becoming angry easily.
2.	Rapid, unpredictable emotional changes.
3.	Racing thoughts, flight of ideas.
4.	Overreaction to stimuli, misinterpretation of events.
5.	Increased interest in activities, overspending, give money away freely, incurring in debts.
6.	Grandiosity, inflated self-esteem.
7.	Excessive energy, go from one activity to another without stopping.
8.	Decreased need for sleep.
9.	Increased libido, sexual indiscretions.
10.	Poor judgement, no insight.
11.	Loss of touch with reality, even having hallucinations and delusions.

A hypomanic episode differs from a manic episode in that there is no psychotic feature or any marked impairment of social or occupational functioning. The psychotic symptoms include incongruous mood, bizarre behaviour and disordered thoughts. It is therefore necessary to exclude schizophrenia, schizoaffective disorder, delusional disorder or other non-specified psychotic disorder. Occasionally, it is difficult to find a full hypomanic/manic episode, and the differences between bipolar disorder and cyclothymia may appear to be a matter of degree in severity and duration.

In fact, euphoria may be the predominant feeling when a patient presents to the doctor. Sometimes the diagnosis comes to mind when an abnormal or bizarre behaviour is noticed such as travelling impulsively, changing dresses, makeup or personal appearance to an out-of-character style, or distributing candy, money or advice to passing strangers. Occasionally, those with psychotic features may become physically assaultive or suicidal.

Aetiologies

Though BAD appears quite biological in nature, psychological and social factors are also of significance in understanding the disorder.

Biological causes

Genetics

Undoubtedly, there is a strong genetic transmission but the exact mode is still not known. Geneticists called it a "complex" to describe partial inheritance characterised by reduced penetrance and/or prominent environmental influence, as evidenced by:

a.	The prevalence rate: it is about 10-15% rate for the patient's first degree relative which is significantly different when compared to a 1-2% for the general population. If both parents have bipolar disorder, the chance of developing the disorder in their children is 75%. There is an observation that the disorder worsens in successive generations, a phenomenon known as "genetic anticipation".

b.	Twins and adoption studies: the concordance rate for affective disorder is 65% for monozygotic twins reared together, 67% if reared apart; and around 15% for dizygotic twins. The rate for bipolar I is even up to 80% and for bipolar II, it is 78%. It should be noted that when one twin has a bipolar diagnosis, 20% of the ill co-twins have unipolar disorder, suggesting that unipolar and bipolar disorders may share some common genetic factors. Adoptive relatives do not show increased risk compared to relatives of probands; and there is a higher rate amongst adopted children with biological parents having the illness.

Physique and personality


a.	Pyknic body build (thick set and rounded) was claimed to be particularly prone, but this finding is not confirmed.

b.	Affective (cyclothymic or depressive) personality appears more vulnerable, but not exclusively inductive to BAD.

Neurochemistry


a.	The amine hypothesis suggests that BAD may be due to a deficiency in, or a dysregulation of, the "receptor sensitivity" towards the monoamine neurotransmitters in the brain. Janowsky et al first described a cholinergic-adrenergic hypothesis and some studies suggest that the dopamine system is important in hypomania, while the serotonin system is involved with depression.⁷

b.	Other neuro-chemicals especially the peptides, corticotropin-releasing factor, vasopressin, opioids, etc. have been studied; but any alternations in their CNS concentrations are more likely the results of secondary events rather than the primary problem.⁸

c.	A number of chronobiological hypotheses have been postulated, including disrupted internal synchronisation of the circadium rhythms,⁹ kindling and stress sensitisation,¹⁰ entrainment of biological rhythms by psychosocial rhythms,⁶ etc., but further confirmatory studies are necessary.

Neuroanatomy


a.	Neuro-imaging techniques have provided converging evidence that the prefrontal and the anterior paralimbic structures are important to the mediation of emotion, and dysfunction in these sites may be important for mood disorders. Nevertheless, there is no definite regional specificity found for primary mood disorders.¹¹

b.	There is evidence of abnormalities in the membrane receptor signal transduction in bipolar patients; and such pathways involve the guanine nucleotide-binding proteins, the cyclic AMP, the polyphosphoinositide generated second messengers and intracellular calcium.¹²

Physical illnesses


a.	Endocrine disturbances: although depression can be caused by changes in the activity of certain endocrine organs, especially the thyroid and the adrenal glands, little attention has been given to the relationship between endocrine disorders and BAD, especially that of mania. Nevertheless, prolactin abnormalities and reduced nocturnal melatonin levels have been implicated for manic spells.¹³

b.	Physical illnesses: a number of illnesses can cause depression e.g. influenza, glandular fever, Parkinson's disease, etc., while others can cause mania e.g. cerebral neoplasms and herpes infection. In fact, some neurological disorders can cause persistent mania e.g. cerebral-vascular accidents (especially in the right hemisphere), and head injuries (especially right caudate or thalamic lesions). About 15-50% of patients with multiple sclerosis will subsequently develop BAD.

Drug effects

Some drugs are notorious for causing depression e.g. methyldopa, reserpine, physiostigmine, etc., while others are prone to induce manic attacks e.g. L-dopa, tricyclics, sympathomimetics, etc. (see Table 1).

Table 1: Classical drugs on mood disorders

Drug	Acute effects onneurotransmitters	Relation to affective disorders
MAOI	NA, DA		can precipitate mania
TCA	NA, 5HT		can precipitate mania
Amphetamine	NA, DA		can precipitate mania
Cocaine	NA, DA		can precipitate mania
Piribedil	DA		can precipitate mania
Bromocriptine	DA		can precipitate mania
L-dopa	DA, ?NA		can precipitate mania
Reserpine	NA, 5HT, NA		can precipitate depression
Physiostigmine	ACh		can precipitate depression

(Adapted from Goodwin & Sack)¹⁵

7.	*Sleep-wake schedule* There is some evidence that changes in the sleep-wake cycle, such as those that occur during time zone changes or sleep deprivation, may precipitate or exacerbate a manic or mixed episode.

Psychological causes


a.	Most psychoanalytic theories are centred around depression. For example, Freud¹⁶ suggested that some depression results from the loss of some kind, similar to mourning resulting from loss by death. Jacobson¹⁷ later modified Freud's theory and suggested that loss of self-esteem is of central importance. On the other hand, mania is a defense against depression, but this is not convincing.

b.	Cognitive theories are also mainly concerned with depression, but the distorted thinking at the other extreme can perhaps be applied to hypomania. Seligman¹⁸ postulated and later modified by Abrahamson et al¹⁹ claimed that depression resulted when "highly desired outcomes are believed improbable or highly aversive outcomes are believed probable and the individual expects that no response (of his) will change their likelihood". Beck²⁰ suggested that "cognitions" are powerful factors in aggravating and perpetuating the disorder. Depressed persons are dominated with negative thoughts, undue expectations and cognitive distortions.

Social causes

An excess of life events especially losses or gains has been shown in the months before the onset of the mood disorder, though this also happens for neurotic and schizophrenic disorders.

Management

General principles

Early clinical diagnosis is important for BAD, and Manning et al²¹ put forward a set of questions to assist the primary care doctor to screen for such disorder (Table 2). Treatment should be targeted at underlying biological causes, if there are any. Attention should be given to co-existing physical conditions. Though prevention of BAD is not yet practical, early intervention is more effective than treating a well-established chronic disorder with multiple episodes. Generally speaking, rapid-cyclers are more difficult to treat than non-rapid ones. In the presence of comorbid substance abuse, personality disorder, psychotic features or genuine suicidal risk, the primary care doctor should consult or refer to a specialist, especially if the response to initial treatment is not satisfactory.

Table 2: Screening questions for BAD

1.	Do you have days of energy or ideas that come and go abruptly?
2.	On those days of energy, are you productive? creative? uncomfortable? convinced of your self-worth, talents, abilities? positive about the future? talkative? distinctly more sociable? irritable?
3.	On those days of energy, do your thoughts feel as if they are racing?
4.	At night during this period of energy, do you need less sleep? continue to be productive? get ideas or make plans for the future?
5.	How many consecutive days does this period of increased energy and change in mood last?
6.	Do others notice the change in your mood or energy level?
7.	During these "up" times, do you do things that you later regret? make plans you find impossible to follow through with? take on tasks that you later suddenly lose interest in or find you are without energy or desire to complete?
8.	Are you particularly more depressed or lethargic immediately before or after the cessation of these periods of energy? Do you feel like you "crash"? Does your body seem as if it is made of lead? Do you need excessive sleep?

(Ref: Manning et al, 1998)

Psycho-pharmacology

Medications form the mainstay for bipolar affective disorders. The choice should be governed by clinical features, especially the mood phase of the disorder. Once the patients have recovered from the acute phase, maintenance therapy is often needed to keep the patient well. The challenge is to prevent breakthrough episodes, relapse of the illness or a rapid cycle.

For non-rapid cyclers, medications include antidepressants for the depressive phase, and anti-manic drugs for the (hypo) manic phase. It should be noted that tricyclic antidepressants especially desipramine can induce manic spells and increase the frequency of the bipolar cycles (see Table 3). The selective serotonin reuptake inhibitors are useful for depression and may be less likely to precipitate mania.

Table 3: Effects of some medications for BAD

Actions		Medications
		TCA*	MAOI*	TyNeuro	AtyNeuro	Lithium*	Anti-conv*
A.	Short-term
	1. Anti-depression	+++	+++	-	-	++	?+
	2. Depressive swtich	-	-	++	?+	-	-
	3. Manic switch	+++	+++	-	-	-	-
	4. Anti-mania	-	-	+++	+++	+++	+++

B.	Long-term
	1. Increase cycles	++	-/+	-	-	-	?-
	2. Decrease cycles	-	-/+	++	++	++	?+

TCA	: tricyclics antidepressants
MAOI	: monoamine oxidase inhibitors
TyNeuro	: typical neuroleptics
AtyNeuro	: atypical neuroleptics
Anti-conv	. : anticonvulsants

(*Modified from Goodwin & Jamison)²⁷

For rapid cyclers, the current mainstay of treatment is the mood stabilisers. Lithium salts have some toxic side-effects and require regular blood monitoring. Anti-convulsants are used increasingly because of their safety profiles. Conventional types include carbamazepine and valproates, while novel types include lamotrigine, gabapentin and topiramate.²²

Antipsychotics (typical, such as haloperidol; and atypical, such as risperidone,²³ quetiapine²⁴ and olanzapine²⁵) are often used when manic or psychotic symptoms occur, especially for those rapid cyclers and those resistant patients.

Long-acting benzodiazepines such as diazepam and clonazepam, are sometimes used for sedative purposes during acute mania, especially when there are signs of agitation.

Other agents including thyroxine and sex hormones have also been used.

N.B.

Combination of the above therapies can be tried e.g. combining a mood stabilizer with an antipsychotic, or adding lithium to carbamazepine.

Electro-convulsive therapy

It is rarely used nowadays except for severe depression and severe mania, especially if there is a high risk of suicide.

Psychotherapies

Such therapies are usually less effective for BAD than for unipolar depression, and are often employed as adjunctive measures. The more practical ones include:

Supportive psychotherapy: the patient is encouraged to talk about his problems while the therapist listens sympathetically. Suggestions and advice are deliberately offered.

Cognitive-behavioural therapy: by asking the patient to record such false ideas and to examine them realistically, one may be able to change the patient's defective cognitions.

Social therapies

One must also attend to the social factors concerned. By helping the close relatives to adapt to the patients maladaptive behaviour, by solving their own conflicts or problems, and by improving the communication between the various family members, the patients are helped. Other social aspects including occupation, housing or financial problems have also to be tackled.

Prognosis

BAD, if untreated, runs a recurrent pattern almost all throughout the lifetime. Over 90% of patients who have a single manic episode go on to have future episodes. Roughly 60-70% of manic episodes occur immediately before or after a major depressive episode. The interval between episodes tends to decrease with age. About 20-30% of the patients have continuous mood lability with functional difficulties. There is an increased risk of suicide (25 to 50%27), marital discord, social dysfunction and even physical morbidity. With treatment, however, there is usually good short-term prognosis, but there is usually a high or persistent morbidity in the long-term. The good prognostic factors include a brief duration, sudden onset, and non-active precipitating factors. The poor prognostic factors, on the other hand, include ill-adjusted premorbid personality, anxiety or depersonalisation, nihilistic delusions, and the presence of other psychotic features.

Conclusion

At present, BAD is a massively neglected problem. It can be a very costly disorder, both to the individual patients and to society. Early detection plus aggressive treatment are important to prevent the gradual progress to more severe and recurrent disorders. Good and safe therapeutic tools are currently available. In this respect, primary care doctors have an important role in delineating patients with such disorder among their patient population presenting with depression. With the support from the specialist sector, family physicians are in a good position to educate, to screen for and to manage BAD in the community.

Key messages

Bipolar affective disorder is significantly underdiagnosed and undertreated, and the primary care physician is in a good position to diagnose it in its early stage.
The disorder has a strong biological element with strong genetic anticipation.
The spectrum of the disorder includes mania, hypomania, major depression, mixed state (dysphoric mania), and rapid (ultradian) cycling.
Treatment at different phases of the disorder requires different medications, including antidepressants, antipsychotics and mood stabilisers.
Newer generations of these medications with a much safety and tolerability profile are now available for use in the primary care setting.

K Y Mak, MBBS(HK), MD(HK), MHA, FRCPsych
Honorary Professor,
Department of Psychiatry, The University of Hong Kong.

Correspondence to : Professor K Y Mak, Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Hong Kong.

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