Manic-Depressive Disorder

The central feature of this disorder is an abnormality of mood, either depression or elation or both. Mood is best considered in terms of a continuum ranging from severe depression at one extreme to severe mania at the other, with normal, stable mood at the centre. Manic-depressive disorders are divided into bipolar manic-depression, in which patients suffer attacks of both depression and mania, and unipolar disorders, in which there is either mania alone or, more commonly, depression alone. First-degree relatives of patients suffering from bipolar illness have an increased risk of manic-depressive illness but not those of patients with unipolar illness.

Depression is classically divided into endogenous depression and reactive depression, although the validity of this distinction is doubtful.

The criteria of endogenous depression include:

• Pervasive and unresponsive depression
• Early morning waking
• Diurnal variation of mood (worse in the morning)
• Profoundly depressive ideas (e.g. guilt, suicidal feelings)
• The lack of an obvious precipitating cause
• A stable premorbid personality

The criteria of reactive depression include:

• A fluctuating depression responsive to environmental change
• Self-pity rather than self-blame
• A clear precipitating cause
• A vulnerable or predisposed personality
• Absence of the criteria of endogenous depression

A mixture of both types is a commoner presentation than a pure form of either.


The clinical features of mania reflect a marked elevation of mood . The term hypomania refers to a mild form of mania characterized by euphoria, overactivity and disinhibition. It can be difficult to distinguish this from simple exuberance, enthusiasm and good humour.

Clinical features of mania
Clinical features of mania

At the opposite pole of the affective continuum, major depressive illness is also characterized by disturbances of mood, talk, energy and ideation. The mood may be described by the patient in physical terms, e.g. lilee a weight in the head, a tightness of the chest, or a feeling of almost physical pain. Depressed patients  describe the world as grey, themselves as lacking a zest for living, and their bodies as devoid of pleasure and feeling.

Anxiety is common, obsessional symptoms may emerge and, in the severer forms, delusions of guilt, persecution and of bodily disease are not uncommon. In severe depression apparent organic impairment, detectable on cognitive testing, can result in disorientation.

Depression is a common experience. It occurs in the setting of physical disease, social stress, personal problems and life crises. It is important to distinguish the more severe and potentially life-threatening major form, requiring energetic treatment, from the less severe minor  form, which, with simple support, sympathy and reassurance, usually lifts.

The aetiological factors in manic-depressive disorders are listed .

Features that help distinguish major from minor depression .
Features that help distinguish major from minor depression .

10-15% of first-degree relatives have an affective disorder (risk in community is 1-2%)
68% of monozygotic twins reared together or apart are concordant for manic-depressive disorder
23% of dizygotic twins are concordant
Possible links with genetic markers

Imbalance in neurotransmitters (e.g. monoamine neurotransmitters are depleted in depression, but increased in mania)
Lossof diurnal rhythm of plasma cortisol in depression
Hormonal factors (e.g. depression is more common after childbirth, in premenstrual phase, with use of oral contraceptives, the menopause and post-hysterectomy)
Electrolytes-intracellular sodium is high in affective disorders

Maternal deprivation
Psychoanalysisinitially suggested that loss of maternal affection in early life and any significant loss in early childhood
predisposes individuals to affective disorder in later life

Learned helplessness
Experimental animals put in a position where they cannot escape or control punishing stimuli develop a behavioural syndrome that resembles depression in humans. It has led to the suggestion that a similar mechanism is at work in humans

Stressful events
An excessof life events is found in the months before the onset of depression. Life events include bereavement, loss of a job, moving house, marriage and going on vacation

Vulnerability factors
In women, it has been claimed that certain factors render them vulnerable to become depressed. These include lack of a job outside the home, the presence of three or more young children in the family, and lack of a confiding, intimate relationship

Possible aetiological factors involved in manic-depressive disorders.

The premenstrual syndrome

Symptoms consist of irritability, depression and tension during the 7-10 day premenstrual period. These symptoms are often accompanied by breast tenderness, a subjective feeling of weight gain and bloatedness, and headache, and are usually dramatically relieved with the onset of the period. Women who suffer from affective disorders may be more prone to experience premenstrual symptoms and to have exacerbations of their psychiatric disorder during the premenstrual phase.

The cause or causes of the premenstrual syndrome remain unclear and the various treatments proposed, which include the use of vitamin B6, diuretics, progesterone, oral contraceptives, oil of evening primrose and oestrogen implants, remain empirical.

Puerperal affective disorders

In postpartum women, affective disorders also occur. Such disturbances are divided into maternity blues, postpartum (puerperal) psychosis and chronic depression. Maternity blues is used to describe the brief episodes of emotional lability, irritability and tearfulness that occur in 65-90% of women 2-3 days postpartum and that resolve spontaneously in a few days. Postpartum psychosis occurs  once in every 500-1000 births. Over 80% of cases are affective in type and the onset is usually within the first 2 weeks following delivery. In addition to the classical features of an affective psychosis, disorientation and confusion are often noted. Severely depressed patients may have delusional ideas that the child is deformed, evil or otherwise affected in some way, and such false ideas may lead to attempts to kill the child and to suicide. The response to speedy treatment is generally good. The recurrence rate for a depressive illness in a subsequent puerperium is 15-20%.

Less severe depressive disorders occur during the first postpartum year in 10-20% of mothers. Most patients recover after a few months. Social and psychological factors are important but the underlying aetiological factor is unknown.


The treatment of affective disorders involves physical, psychological and social therapies. Hospitalization is usually required in the case of severely depressed, potentially suicidal patients and in mania. In general, neither severe depression nor mania respond to psychotherapy, and both require energetic physical treatment. Simple support, reassurance, sympathy and the opportunity to express distress and negative feelings are often sufficient to bring about relief of minor depressive episodes.

Differential diagnosis of manic-depressive disorders
Differential diagnosis of manic-depressive disorders

Physical treatment of depression

TRICYCLIC AND RELATED ANTIDEPRESSANTS. These are the most frequently used drugs. Imipramine and amitriptyline are the two most commonly used but many related compounds have been introduced, some having fewer autonomic and cardiotoxic effects. Imipramine and amitriptyline are given by mouth in initial doses of 25- 75 mg daily, building up over a week to 150-200 mg daily. The full therapeutic impact can take up to 2 or 3 weeks to occur. These drugs potentiate the action of monoamines, noradrenaline and serotonin by inhibiting their reuptake into nerve terminals. Other tricyclics in common use include nortriptyline, doxepin, mianserin, clomipramine, lofepramine and trazodone. Tricyclic antidepressants have a number of side-effects; in patients with established cardiac disease mianserin, dothiepin or trazodone are preferred over the more cardiotoxic compounds.

Bereavement reaction versus depressive illness following bereavement (morbid grief reaction).
Bereavement reaction versus depressive illness following bereavement (morbid grief reaction).

SEROTONIN UPTAKE INHIBITORS. Fluvoxamine, fluoxetine, paroxetine and sertraline appear to produce less troublesome side-effects and a speedier onset of therapeutic effect. These drugs appear to act by way of selective inhibition of serotonin reuptake within the synaptic cleft and are thus termed selective serotonin reuptake inhibitors or SSRIs. While there is still argument as to their superiority as antidepressants over the more established tricyclics, they are becoming popular (fluoxetine is now one of the most commonly prescribed antidepressants in the USA) because of their lower rate of serious side-effects.

MONOAMINE OXIDASE INHIBITORS (MAOIs). These act by inhibiting the intracellular enzymes monoamine oxidase A and B, leading to an increase of noradrenaline, dopamine and 5-hydroxytryptamine in the brain. There are two types:

1 Hydrazine derivatives, e.g. isocarboxazid, phenelzine (potentially hepatotoxic)
2 Amphetamine-related, e.g. tranylcypromine (potentially addictive)

The most widely used is phenelzine, which is given in doses of 30-60 mg daily. The onset of action of MAOIs is within 24-48 hours. Unwanted effects include increased appetite and weight gain and difficulty in sleeping. MAOIs also produce hypertensive reactions with foods containing tyramine or dopamine and therefore a restricted diet is prescribed. These amines are normally broken down in the gut mucosa and the liver. Tyramine is present in cheese, pickled herrings, yeast extract, certain red wines and any food, such as game, that has undergone partial decomposition. Dopa is present in broad beans. This tyramine reaction is treated with intravenous phentolamine.

MAOIs interact with drugs such as pethidine and can also occasionally cause liver damage. Particular caution should be taken when changing from an MAOI to a tricyclic or vice versa; it is safest to allow a 2 week drug-free interval between the two ty pes of drug. Newer forms of MAOIs have recently been produced which only inhibit monoamine oxidase A. Their effects appear more readily reversible-hence their description as reversible inhibitors of monoamine oxidase A (RIMA).

An example is moclobemide 300 mg daily. These drugs appear to have fewer side-effects, work rapidly and constitute a low risk in overdose. At present, patients prescribed such antidepressants are advised that they can eat a broad diet but they should be careful to avoid excessive amounts of food rich in tyramine. MAOIs are used in depressions that present with marked anxiety and obsessional or hypochondriacal features,  and that lack marked biological symptoms characteristic of severe depression.

ELECTROCONVULSIVE THERAPY (ECT). This is the most rapidly acting of the available physical treatments of depression. It can be the treatment of first choice in those cases where:

• The patient is dangerously suicidal
• A delay in treatment represents a serious risk to health
• The patient is refusing food and drink
• The patient is in a depressive stupor

The treatment involves the passage of an electric current, usually 80 V for a duration of 0.1-0.3 s, across two electrodes applied to the anterior temporal areas of the scalp. Before the treatment is given, the patient is anaesthetized (usually by means of thiopental 125-150 mg) and receives a muscle relaxant (usually suxamethonium 30-50 mg). A modified convulsion is produced. A course of six to eight treatments over 3 weeks has been shown to be superior to placebo treatment in severe depression characterized by retardation and delusions.

EeT is sometimes used in the management of acute schizophrenia, but the evidence of its effectiveness in this condition is less clear.

EeT is a controversial treatment, yet it is remarkably safe and free of serious side-effects. Serious complications are rare. However, post-ictal, short-term retrograde amnesia and a temporary defect in new learning can occur but these are short-lived effects. The mode of action of EeT in depressive illness is unclear.

Physical treatment of mania
ACUTE ATTACKS. The main physical treatment in mania is the use of neuroleptic drugs such as chlorpromazine, haloperidol and pimozide. Doses similar to those used in schizophrenia are used. Excitement and overactivity are usually reduced within days, but elation, grandiosity and associated delusions often take longer to respond. If improvement does not occur rapidly, larger doses of haloperidol (up to 120 mg daily) may be required. First attacks of mania usually require treatment for up to 3 months. Subsequent attacks, especially if they occur rapidly on cessation of treatment, may need drugs for at least a year after hypomanic features have disappeared.

PROPHYLAXIS. Lithium carbonate or citrate is used for prophylaxis in patients with repeated episodes of mania and/or depression. It is rapidly absorbed into the gastrointestinal tract and more than 95% is excreted by the kidneys; small amounts are found in the saliva, sweat and breast mille Renal clearance of lithium correlates with renal creatinine clearance. In the body it substitutes for sodium and potassium ions and thus can exercise profound effects on a number of metabolic processes. Its  mode of action is unknown.

Patients should be screened for thyroid and renal disease before starting on lithium. The therapeutic range for prophylaxis is between 0.4 and 1 mmol litre””. Regular serum estimations are required 12 hours after the last dose. Lithium levels should be checked every 3 or 4 months, along with regular thyroid and renal function tests.

Lithium takes 10 days to take effect. Unwanted effects include:

Gastrointestinal symptoms (6%)
• A fine tremor (15%)
• Polyuria and polydipsia (due to inhibition of the antidiuretic hormone (ADH)-sensitive adenylate cyclase in the distal tubule of the nephron and hence a rise in plasma ADH)
• Weight gain (mainly increased appetite)

Toxic symptoms begin to occur when the serum concentration exceeds 1.5 mmollitre-I. These include drowsiness, blurred vision, a coarse tremor, ataxia and dysarthria. Such symptoms progress to delirium and convulsions, and coma and death can occur. Long-term effects include non-toxic goitre, hypothyroidism and nephrogenic diabetes insipidus.

Carbamazepine is used in prophylaxis, but is also effective in the treatment of manic states. Some patients who do not respond to lithium may respond to carbamazepine. For antimanic treatment, dosage in the initial stage of treatment will be 200 mg once a day for 2 days, followed by 200 mg twice daily for 2 days, then 200 mg three times daily. Rarely dosage may have to be increased to a maximum of 1200 mg daily. The usual prophylactic dosage is 600 mg daily. The combination of lithium and carbamazepine is occasionally more effective than either drug alone.

Social treatment

Many patients with depression, particularly of the milder form, have associated social problems. Assistance with such social problems can make a significant contribution to clinical recovery. Other social interventions include the provision of group support, social clubs, occupational therapy and training to cope with particularly stressful situations

Psychological treatment

The psychological treatments in affective disorders can be divided into:

SUPPORTIVE. Sympathy, reassurance and information should be part of every patient’s treatment.
DYNAMIC PSYCHOTHERAPY . This form of psychotherapy has a limited value in the treatment of
affective disorders. In general, its use is restricted to the less severe cases.

COGNITIVE THERAPY. This is a behavioural form of therapy that combines behavioural tasks with questioning and arguments designed to alter some of the ideas that are common among depressed patients and that appear to prolong their depression. Among these are negative interpretations of events and maladaptive assumptions (e.g. assuming that because friends do not telephone means they no longer care about the patient). In treatment, the patient is required to record such ideas and examine the evidence for and against them. Patients are also encouraged to undertake some of the pleasurable activities they gave up when they became depressed. There is some evidence that the effects of cognitive therapy are about the same as those of antidepressant drugs in the treatment of mild to moderate depression.


Between two-thirds and three-quarters of patients admitted with a major depressive illness will suffer at least one relapse requiring hospital admission. The number of less severe relapses is even higher. It has been estimated that between 15 and 20% of depressives never fully recover. It may take those who do recover between 4 and 18 months before they can expect to regain full social functioning.

Virtually all manic patients recover and the main problem is the prevention of relapse. Estimates of the proportion of patients who have only a single episode of mania vary widely between 1 and 50%! Subsequent depressive disorder is common in manic patients who relapse. Between 5 and 10% of manic-depressive sufferers develop a chronic disability that may follow the first episode. Between 5 and 10% become long-term hospital inpatients and an additional 25% have persistent affective symptoms that are disabling to some degree. The continuation of antidepressant therapy for up to 6 months after recovery from a depressive episode does reduce the probability of recurrence, while the use of lithium carbonate and carbamazepine as prophylactic therapy to prevent recurrence of bipolar manic-depressive swings is  widely recommended.

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