Affective disorders

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29 Affective disorders

• Diagnosis should be made using standardised criteria, for example, DSM IV, ICD 10.

• Target symptoms should be recorded and response to treatment monitored against these symptoms.

• In patients with depression of mild severity, non-pharmacological strategies should be considered as first-line intervention.

• The evidence base for determining the use of a particular antidepressant in an individual patient does not exist. For most patients, when an antidepressant is indicated, a generic SSRI should be considered as a first-line treatment option.

• Currently, all antidepressants are considered equally effective but differ in their side effect profile, toxicity in overdose, need for dose titration and monitoring.

• In the absence of a previous response or contraindication, antidepressant choice should be guided by evidence-based clinical guidelines and the clinician and the patient’s perception of the risks and benefits of available options. Resource implications should not be ignored.

• Emerging evidence and a greater understanding of the clinical application of pharmacogenomics may increase the ability to individualise treatments in the future.

• Comprehensive assessment, accurate diagnosis, adequate duration of pharmacotherapy and involvement of the patient in the treatment regimen are the cornerstones of effective management of affective disorders.

• Valproate, antipsychotics and benzodiazepines, sometimes in combination, are the treatments of choice in acute mania.

• Either lithium, valproate or specific antipsychotics may be considered to be the first-line prophylactic agent of choice in bipolar I disorder.

This chapter focuses on affective disorders in adults. The issues of affective disorders in children and adolescents are more complex and beyond the scope of this section.

The central feature of an affective disorder is an alteration in mood. The most common presentation is that of a low mood or depression. Less commonly, the mood may become high or elated, as in mania.

Classification

Depression

The term ‘depression’ can in itself be misleading. Everyone in the normal course of daily life will experience alterations in mood. Depressed mood in this context does not represent a disorder or illness; in fact, lowered mood as a response to the ups and downs of living is considered normal and termed sadness or unhappiness. Sometimes clinical depression may present in a mild form, so it is important to differentiate this from normal unhappiness.

Mania

If the mood becomes elated or irritable this may be a symptom of mania. The term ‘mania’ is used to describe severe cases, frequently associated with psychotic symptoms. Hypomania describes a less severe form of the disorder. In clinical practice, this distinction often becomes blurred, with hypomania being seen as patients develop, or recover from, mania.

Bipolar and unipolar disorders

If a patient develops one or more severe episodes of a mood disorder which includes a manic episode, the condition may be termed a bipolar disorder. The existence of repeated manic episodes alone is sufficient to be termed a bipolar disorder. The disorder can be further categorised as bipolar I, where full-blown episodes of mania occur, and bipolar II, where depressive episodes are interspersed with less severe hypomanic episodes. The term ‘manic-depressive’ is now outdated. Rapid cycling describes the existence of four or more episodes within a year. Unipolar mood disorder is used to describe single episodes of depression.

Epidemiology

Differences in diagnosis, particularly of depression, make it difficult to estimate the true incidence of affective disorders. The lifetime risk of developing a bipolar I disorder is said to be about 1% (0.3–1.5%). An accurate estimate for the more broadly defined bipolar II disorder is more difficult and it may be much more common, with studies suggesting a lifetime prevalence of between 0.2% and 10.9%. The incidence of bipolar I is generally reported to be the same for both men and women, whereas some studies suggest that bipolar II may be slightly more common in women. By comparison, the overall incidence of depression is much higher and there does appear to be a significant difference between the sexes. Studies from America and Europe, using standard assessment tools, found a lifetime prevalence of between 16% and 17%, with a 6-month prevalence of about 6%. Higher rates are consistently found in women but social, economic and ethnic factors are also likely to be influential. Although depression may occur at any age, including early childhood, it is estimated that the average age of onset of depression is in the mid-20s. Some earlier studies found the incidence and prevalence of depression in women peaking at the age of 35–45 years. In bipolar disorder, an earlier age of onset is suggested, perhaps in late adolescence, with most people experiencing their first episodes before 30 years of age.

Aetiology

Like most psychiatric disorders, the causes of affective disorders remain unknown. In depression, it is likely that genetic, hormonal, biochemical, environmental and social factors all have some role in determining an individual’s susceptibility to developing the disorder, with major life events sometimes, but not always, acting as a precipitant for a particular episode. Although pharmacological treatments are clearly effective, there is no simple relationship between biochemical abnormalities and affective disorders.

Genetic causes

In depression, one theory suggests that a variant of the gene responsible for encoding the serotonin transporter protein could account for early childhood experiences being translated into an increased risk of depression through stress sensitivity in adulthood. In bipolar disorder, some genetic linkage has been proposed, but a precise marker remains elusive.

The incidence of affective disorder in first-degree relatives of someone with severe depression may be about 20%, which is almost three times the risk for relatives in control groups. Comparisons of the risk of affective disorder in the children of both parents with an affective disorder show a four times greater risk, and the risk is doubled in children with one parent with an affective disorder. Studies looking at twins have found fairly strong evidence for a genetic factor. Evidence of a genetic link has also been found in studies of children from parents with affective disorder who were adopted by healthy parents. A higher incidence of affective disorder was found in the biological parents of adopted children with affective disorder than in the adoptive parents.

Environmental factors

Although environmental stresses can often be identified prior to an episode of mania or depression, a causal relationship between a major event in someone’s life and the development of an affective disorder has not been firmly established. It may be that life events described as ‘threatening’ are more likely to be associated with depression. The lack of prospective studies makes it difficult to interpret data linking early life events, such as loss of a parent, to the development of an affective disorder. The fact that specific environmental stresses have not been identified should not lead to the conclusion that the environment or lifestyle is irrelevant to the course or development of affective disorders. Employment, higher socio-economic status and the existence of a close and confiding relationship have been consistently noted to offer some protection against the development of an episode.

Biochemical factors

In its simplistic form, the biochemical theory of depression postulates a deficiency of neurotransmitter amines in certain areas of the brain. This theory has been developed to suggest that receptor sensitivity changes may be important. Alternative propositions suggest a central role of acetylcholine arising from dysregulation of the cholinergic and noradrenergic neurotransmitter systems. Although many neurotransmitters may be implicated, the theory focuses on an involvement of the neurotransmitters noradrenaline (norepinephrine), serotonin (5-hydroxytryptamine) and dopamine. This theory emerged from the findings that both monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants appeared to increase neurotransmitter amines, particularly noradrenaline (norepinephrine), at important sites in the brain. When it was found that reserpine, previously used as an antihypertensive, caused both a depletion of neurotransmitter and also induced depression, this was taken as an apparent confirmation of the theory.

Although less attention has been paid to dopaminergic activity, some studies have found reduced activity in depressed patients, and an overactivity has been postulated in mania.

The concept of noradrenergic (norepinephrinergic) and serotonergic forms of depression has not gained widespread support, and there is no justification in measuring the activity of neurotransmitters such as noradrenaline (norepinephrine) or serotonin metabolites in routine clinical practice.

Endocrine factors

The endocrine system, particularly the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis, is felt to be implicated in the development of affective disorders. Some endocrine disorders such as hypothyroidism and Cushing’s syndrome have also been associated with changes in mood. People with depression have been found to have increased cortisol levels, which also supported the proposition that mood disorders may be linked to dysfunction within the HPA axis. This led to the development of a dexamethasone suppression test for depression in the 1970s. The relationship between cortisol and symptoms of depression is complex which severely limits the clinical utility of such a test.

Physical illness and side effects of medication

Disorders of mood, particularly depression, have been associated with several types of medication and a number of physical illnesses (Box 29.1). Depression can affect the outcome in people with a range of physical problems. An increase in death rates has been found in those patients with co-morbid depression.

Clinical manifestations

Depression

A low mood is the central feature of depression. This is often accompanied by a loss of interest or pleasure in normally enjoyable activities. Thinking is pessimistic and in some cases suicidal. A depressed person may complain they have little or no energy. In severe cases, psychotic symptoms such as mood congruent hallucination or delusion may be present. Anxiety or agitation frequently accompany the disorder, and the so-called biological features of sleep disturbances, weight loss and loss of appetite are often present. Depressed people typically complain of somatic symptoms, particularly gastric problems, and non-specific aches are common. Sexual drive is often reduced, and some people may lose interest in sex altogether. In some cases, the biological symptoms are reversed and excessive eating and sleeping may occur. In contrast to agitation, psychomotor retardation may be a presenting feature.

Bipolar disorder

Standardised diagnostic criteria vary. For an ICD 10 diagnosis of bipolar disorder, at least two mood episodes must occur, one of which must be manic or hypomanic (Box 29.2). According to DSM IV, at least one episode of mania must have occurred for a diagnosis of bipolar I disorder to be made; depression may also occur, but it is not essential.

Box 29.2 ICD 10 diagnostic criteria for bipolar affective disorder (WHO, 1992)

Characterised by repeated (at least two) episodes in which the patient’s mood and activity levels are significantly disturbed. This disturbance consisting on some occasions of an elevation in mood and increased energy and activity (mania or hypomania), and on others of a lowering of mood and decreased energy and activity (depression).

Manic episodes usually begin abruptly and last for between 2 weeks and 4–6 months (median 4 months). Depression tends to last longer (median about 6 months). Episodes of both kinds often follow stressful life events or other mental trauma, but the presence of such stress is not essential for the diagnosis.

Mania

In mania, the mood is described as elated or irritable and the accompanying overactivity is usually unproductive. Disinhibition may result in excessive spending sprees, inappropriate sexual activity and other high-risk behaviours. Driving may be particularly dangerous. Manic people may describe their thoughts as racing, with ideas rapidly changing from one topic to another. Speech may be very rapid with frequent punning and rhyming. Ideas may become grandiose with patients embarking on fantastic projects which lead nowhere and inevitably are left incomplete and disjointed. Clothing is usually flamboyant, and if make-up is worn it is usually excessive and involves bright colours.

Severity

The severity of the disorder may vary from mild through moderate to severe. In most circumstances, it would be inappropriate for people with mild forms of the disorders to be seen by specialist services and treated with pharmacotherapy. In the absence of a risk of serious self-harm, people with less severe forms of the disorder should be treated by the primary health care team. Guidelines advise that a stepwise approach is taken on the management of depression, with increasing evidence supporting the fact that antidepressant therapy is more likely to be effective in the more severe episodes (NICE, 2009).

If left untreated, it is important to remember that affective disorders carry a risk of mortality. In addition to suicidal attempts by someone who is depressed, the lack of self-care and physical exhaustion resulting from mania may be life-threatening. The social and financial consequences can have a devastating effect on both the patient with mania or hypomania and their family. Depression may also contribute to exacerbation of physical problems such as increased pain and worsening outcomes from cardiac disease (Nicholson et al., 2006).

Investigations

There are no universally accepted biochemical or genetic tests which will confirm the presence of an affective disorder. Various rating scales have been developed that may help to demonstrate the severity of depressive disorder or distinguish a predominantly anxious patient from a depressed patient. Within the limits of our current understanding of the technology, biochemical or genetic tests are unlikely to be helpful in determining the treatment plan or management of affective disorders.

In the UK, mental and behavioural disorders are commonly classified using the International Classification of Diseases, ICD 10 (WHO, 1992).The American Psychiatric Association has developed a precise system of diagnosis, based on the description of symptoms in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV TR), now in its revised, fourth edition (American Psychiatric Association, 2000).

A systematic approach to the diagnosis of affective disorders is important when considering the effectiveness of medication. Most new clinical trials for antidepressants or antipsychotics require a DSM diagnosis as an entry criterion. In the UK, the ICD 10 classification is commonly used, with the severity of depression determined by the presence of the number of symptoms (see Boxes 29.2 and 29.3). More recently, use of the symptom count as a single factor upon which to base treatment decisions has been cautioned against (NICE, 2009). Account should also be taken of the extent of impairment and disability associated with depression.

Box 29.3 ICD 10 diagnostic criteria for a depressive episode (WHO, 1992)

Usual symptoms

Depressed mood, loss of interest and enjoyment, and reduced energy leading to increased fatiguability and diminished activity

Common symptoms

Reduced concentration and attention

Reduced self-esteem and self-confidence

Ideas of guilt and unworthiness (even in a mild type of episode)

Bleak and pessimistic views of the future

Ideas or acts of self-harm or suicide

Disturbed sleep

Diminished appetite

In a depressive episode, the mood varies little from day to day and is often unresponsive to circumstances, yet may show characteristic diurnal variation as the day goes on. The clinical picture shows marked individual variations, and atypical presentations are particularly common in adolescence. In some cases, anxiety, distress and motor agitation may be more prominent at times than the depression.

For depressive episodes of all grades of severity, a duration of 2 weeks is usually required for diagnosis, but shorter periods may be reasonable if symptoms are unusually severe and of rapid onset.

Mild depressive episode: For at least 2 weeks, at least two of the usual symptoms of a depressive episode plus at least two of the common symptoms listed above.

An individual with a mild depressive episode is usually distressed by the symptoms and has some difficulty in continuing with ordinary work and social activities, but will probably not cease to function completely.

Moderate depressive episode: For at least 2 weeks, at least two or three of the usual symptoms of a depressive episode plus at least three (preferably four) of the common symptoms listed above.

An individual with moderately severe depressive episode will have these symptoms to a marked degree, but this is not essential if a particularly wide variety of symptoms is present overall. They will usually have considerable difficulties in continuing with social, work or domestic activities.

Severe depressive episode: For at least 2 weeks, all three of the usual symptoms of a depressive episode plus at least four of the common symptoms listed above, some of which should be of severe intensity.

An individual with severe depressive episode may be unable or unwilling to describe many symptoms in detail, but an overall grading of severe may still be justified. They will usually show considerable distress or agitation, unless retardation is a marked feature. Loss of self-esteem or feelings of uselessness or guilt are likely to be prominent. Suicide is a distinct danger, particularly in severe cases.

National guidelines provide a sound framework for the management of depression (NICE, 2009) and bipolar disorder (NICE, 2006). It is important that people with depression are identified. A simple screening process for the presence of depression could involve asking the patient two questions about their mood and interest. For example, the patient could be asked ‘During the last month, have you often been bothered by feeling down, depressed or hopeless?’ and ‘During the last month, have you often been bothered by having little interest or pleasure in doing things?’. If the answer to either question is ‘no’, it is unlikely the patient will be considered to have a depressive disorder. Patients who answer ‘yes’ warrant further investigation.

Identification of target symptoms may be useful in evaluating the response to treatment. In routine clinical practice, antidepressant medication should not generally be used to treat patients with mild depression. Non-pharmacological strategies are preferable in this group.

Rating scales

Various rating scales can be used to assist with the assessment of the severity of the disorder. Two of the more commonly used rating scales are the Beck Depression Inventory and the Hamilton Depression Rating Scale.

Beck Depression Inventory

This is a self-reporting scale looking at 21 depressive symptoms. The subject is asked to read a series of statements and mark on a scale of 1–4 how severe their symptoms are. The higher the score, the more severely depressed a person may be.

Hamilton Depression Rating Scale

This rating scale is used by a health care professional at the end of an interview to rate the severity of depression.

Treatment

The aim of treatment is to prevent harm and to relieve distress or to be prophylactic. It is important to differentiate symptoms of the disorder from the premorbid personality. In general, the drugs which are used to control the symptoms of mania are not specifically antimanic. These agents are also used to treat other disorders. This means the diagnosis will primarily influence the way in which these drugs are used rather than the choice of drug per se. Clinicians should be aware of the licensed indication of treatments, so that any ‘off label’ use is done knowingly and in line with current best practice.

In the treatment of depression, all the antidepressants currently available in the UK may be considered to be equally effective. There is increasing evidence that patients with more severe episodes of depression are more likely to respond to antidepressant drugs, as opposed to placebo, than those with less severe forms of the disorder (Fournier et al., 2010). There is also some evidence to suggest that sertraline and escitalopram may have a more favourably risk/benefit profile than some other antidepressants (Cipriani et al., 2009). However, it is unclear if the magnitude of the difference between these drugs is sufficient to direct treatment choice for most depressed patients.

There are some generalisations which may help individualise the choice of antidepressant. Females may have a poorer tolerance of migraine than males and tricyclic antidepressants are less well tolerated and more likely to be toxic in overdose than the selective serotonin reuptake inhibitors (SSRIs). Patients may prefer one drug over another based on their past experience of benefit or side effects. Overall, the major difference between antidepressant agents is in their side effect profile and toxicity in overdose. There can also be significant variations in the costs of different agents.

Treatment of depression

In moderate and severe depression, pharmacological intervention is important, but this should never be considered in isolation from the social, cultural and environmental influences on the patient. Non-pharmacological therapies are effective and in mild depression they are considered preferable to drug treatment. Non-drug treatments and antidepressant medication are not mutually exclusive and in some cases it is preferable to use both in combination.

Drug treatment

Despite the availability of many new antidepressants, the therapeutic effectiveness of these agents has changed little since the discovery of the antidepressant properties of drugs used to prevent migraine in the late 1950s. Further research may reveal differences between antidepressants. Advances in the clinical utility of pharmacogenomics may, in time, provide clinicians with a tool to individualise pharmacotherapy. Overall, the SSRI antidepressants appear to be better tolerated than tricyclics and their safety profile in overdose should be an important consideration for use.

A strong response to placebo is found in most of the studies of antidepressants. Tolerability is, therefore, an important factor in the choice of drug; patients who are unable to tolerate the side effects of antidepressants are likely to discontinue these drugs. Antidepressants should be taken in adequate doses for some 4–6 weeks, and up to 12 weeks in older people, to achieve a full response. Following a single episode of depression, treatment should be continued for 6 months, at the same dose at which the patient achieved remission, before attempting withdrawal. In patients experiencing multiple episodes of depression, treatment should be continued for longer periods (2 years).

Withdrawal of antidepressants should normally be undertaken gradually. Following abrupt discontinuation, patients may experience symptoms of withdrawal that include gastro-intestinal symptoms, together with headache, giddiness, sweating, shaking and insomnia. In addition, extrapyramidal reactions may be associated with abrupt withdrawal from some of the SSRI antidepressants. Following successful treatment, antidepressants should be gradually reduced over a period of 4 weeks. This period should be increased if patients experience problems, or where medication has been given for extended periods.

Generally, the long half-life of fluoxetine enables the drug to be stopped without the need for tapering from the standard antidepressant dose of 20 mg. Patients taking MAOIs may experience psychomotor agitation following discontinuation.

As patients do not experience the craving typically associated with drugs of addiction, most health care professionals do not class antidepressants as addictive. Patients should be warned that there is a risk of problems with abrupt discontinuation, but use of emotive words like addiction or dependence is best avoided. In moderate or severe depression, the balance of risks and benefits is usually in favour of using antidepressants. Occasionally, some patients report that they have become dependent on their antidepressants and feel unable to stop taking them. These concerns should not be dismissed lightly, but the focus of discussion with the patient should be on the overall risks and benefits of the treatment in the context of their individual circumstances.

As discussed earlier, there is no strong evidence for the existence of a particular biochemical subtype of depression. However, some patients do respond better to particular antidepressants. This has led to the widely held view that previous response to treatment is a strong indication to use that particular drug in the treatment of a future episode.

In addition to previous response, the other important considerations to take into account when selecting an antidepressant are side effects, contraindications, toxicity in overdose, patient preference and clinician familiarity.

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