Affective disorders

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29 Affective disorders

J.P. Pratt

Key points

• 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.

Box 29.1 Drugs and physical illnesses implicated in disorders of mood

Drugs

Analgesics
Antidepressants
Antihypertensives
Anticonvulsants
Opiate withdrawal
Amfetamine withdrawal
Benzodiazepine withdrawal
Antipsychotics
Benzodiazepines
Antiparkinsonism agents
Steroids
Oral contraceptives

Physical illness

Viral illness
Carcinoma
Neurological disorders
Diabetes
Multiple sclerosis
Thyroid disease
Addison’s disease
Systemic lupus erythematosus
Pernicious anaemia

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.

Generally speaking, the older drugs have a poorer side effect (Barbui et al., 2001; Geddes et al., 2002) and toxicity profile than the more recently introduced agents. Traditionally, the antidepressant drugs are categorised by their chemical structure, for example, tricyclic, or their predominant pharmacological action, for example, MAOI, SSRI.

Tricyclic antidepressants

A greater understanding of the pharmacology of antidepressants has given much support to the so-called biochemical theory of depression. Although substantial data on the pharmacological effects of the tricyclic antidepressants exist, it is still not clear how the drugs relieve the symptoms of depression. This is an important point often overlooked when discussing the issue with patients. The notion that depression is a simple lack of, or imbalance of, chemicals has little basis in fact. It merely provides a useful framework from which to discuss the benefits and harms of antidepressants.

It was thought originally that the primary effect of these drugs was related to their ability to block the reuptake of noradrenaline (norepinephrine) and/or 5HT following their release and action as neurotransmitters. As this effect occurs some weeks before the antidepressant response, clearly this is not the whole story. Following chronic administration, further biochemical changes take place, particularly with pre- and postsynaptic receptor sensitivity. Reduction of presynaptic α2-inhibitory receptor sensitivity occurs, and this increases the production of noradrenaline (norepinephrine). Other effects which may be relevant include an increase in α1 and β1 receptor sensitivity. It is now felt that these receptor changes in the cerebral cortex and hippocampus may be more relevant to the antidepressant response than simple reuptake inhibition.

There are a number of tricyclic antidepressants in current clinical use. The basic chemical structures of these compounds are similar but there are differences between them. All the tricyclic antidepressants block the reuptake of noradrenaline (norepinephrine) and 5HT to a greater or lesser degree. In view of the risks associated with cardiac abnormalities, an ECG is advised prior to initiating treatment with this group of drugs.

Imipramine

The antidepressant effect of imipramine was demonstrated around 50 years ago and it has been widely prescribed in subsequent years. Although imipramine is less sedating than other tricyclic drugs, some patients may still experience problems. As well as cardiovascular problems, significant antimuscarinic effects such as dry mouth, blurred vision and constipation occur. Females tend to tolerate imipramine less well than males. At one time it was felt to be important that the drug should be prescribed at the full therapeutic dose. Recent analysis of clinical trials suggests this is not the case. If patients respond to lower doses, there is no rationale for increasing the dose further. Tolerance may develop to some of the unpleasant side effects, and this may be facilitated by starting with a lower dose of the drug and gradually increasing the dose over a week.

In addition to the unpleasant side effect profile, imipramine is toxic following overdose. Considering that the drug is used to treat a disorder which involves suicide, this relative lack of safety is an important disadvantage. As with all tricyclics, imipramine should only be used in circumstances where cardiac tolerability can be assured and intentional overdose can be prevented. Imipramine is metabolised by demethylation to an active metabolite, desipramine. Both the parent drug and its metabolite have long half-lives, of 9–20 and 10–35 h, respectively, that permit single daily dosing.

Amitriptyline

Also developed in the late 1950s, amitriptyline has a similar poor side effect and toxicity profile to imipramine but is more sedative. Additional sedative properties are sometimes considered an advantage in selected patients. The widespread use of low doses of amitriptyline commonly relate to its use in the management of pain, rather than depressive disorders. Like imipramine, the drug and its active metabolite (nortriptyline) have long half-lives, of 9–46 and 18–56 h, respectively. The dose range is similar to imipramine.

Clomipramine

This was one of the first antidepressants found to be a potent 5HT reuptake inhibitor. Some clinicians believed that the drug was more effective than other antidepressants, but little evidence exists to support this anecdotal view. However, the effects on 5HT may explain the benefit of this drug in the management of obsessive-compulsive disorder.

Data from a fatal toxicity index (Buckley and McManus, 2002) show clomipramine to have a lower than expected toxicity index. It is unlikely that clomipramine is inherently less toxic than other antidepressants, so this finding could be accounted for by other factors, such as the relatively high rate of prescribing in non-depressive states.

Dosulepin

Guidelines for the management of depression (NICE, 2009) advise that dosulepin should not be prescribed because of the risks associated with cardiac problems and toxicity in overdose compared to other available treatments.

Doxepin

Doxepin has similar effects and side effects to the traditional tricyclics. Limited evidence suggests that it may have fewer cardiac effects in patients with pre-existing cardiac disease than other traditional tricyclics. However, direct comparisons do not exist and a newer, alternative agent should be considered in preference to doxepin in patients with cardiac disease.

Lofepramine

Although desipramine is a metabolite of lofepramine, the latter should not be considered purely as a pro-drug. Important differences exist between lofepramine and the other traditional tricyclics. Antimuscarinic effects do occur with lofepramine, but these are less severe than with other tricyclics. In addition, despite being metabolised to desipramine, lofepramine is significantly safer in overdose than the traditional agents. This may be due to lofepramine antagonising the cardiac effects of desipramine. Lofepramine does not have a significant sedative effect, which may be an advantage in some patients, but in others the lack of sedation may be seen as a disadvantage. Some patients may complain of an alerting effect from lofepramine, particularly if the majority of the dose is given at bedtime. Despite a few reports of hepatic problems, given the favourable side effect profile and low toxicity in overdose, lofepramine may be considered as a reasonable option if an SSRI is ineffective or not tolerated.

Nortriptyline

Nortriptyline is the major metabolite of amitriptyline, but appears to have little effect on blood pressure. Nortriptyline shares many of the properties of the traditional tricyclic antidepressants.

Trimipramine

This is a particularly sedative tricyclic antidepressant with few differences from the rest of the traditional tricyclics.

Monoamine oxidase inhibitors

Two types of MAOI are available: the traditional MAOIs, which are both non-selective and irreversible, and moclobemide, which is a selective reversible inhibitor of monoamine oxidase type A (RIMA). In clinical practice, the traditional MAOIs are not widely prescribed. If patients are able to tolerate adequate doses, they are effective antidepressants, particularly in patients with atypical symptoms of depression. Due to the potential for drug and food interactions, MAOIs should be reserved for use in situations where a first-line SSRI antidepressant has failed. The potential for MAOIs to interact with other drugs and tyramine-containing foods has been well known since the 1960s. It is important that patients are made aware of the dietary restrictions and potential for serious drug interactions. These can be found in standard texts such as the British National Formulary.

Although the inhibitory effect of these drugs on monoamine oxidase is well understood, as with other antidepressants it is still not clear exactly how the MAOIs exert their antidepressant effect. MAOIs inhibit the enzymes responsible for the oxidation of noradrenaline (norepinephrine), 5HT and other biogenic amines. Two forms of monoamine oxidase have been found to exist, MAO-A and MAO-B. The traditional MAOIs are all non-selective and inhibit both forms of the enzyme.

Inhibition of MAO-A is thought to be responsible for the antidepressant effects. It is also responsible for metabolising tyramine and producing the cheese interaction. Moclobemide is an antidepressant that acts as a reversible inhibitor of MAO-A. As tyramine is metabolised by both forms of the enzyme, if tyramine-containing foods are consumed, tyramine is metabolised by MAO-B enzymes as well as being able to reverse the inhibition of MAO-A. Unless very large quantities of tyramine are ingested, this appears to prevent the typical hypertensive reaction seen with conventional MAOIs and tyramine-containing foods.

Traditional MAOIs

The traditional MAOIs and moclobemide have little anticholinergic effect. Nevertheless, some patients do experience dry mouth, constipation and urinary retention. In contrast to the hypertension which follows the interaction of tyramine-rich foods with the traditional MAOIs, these drugs are liable to cause postural hypotension as a side effect. This side effect may be particularly problematic with phenelzine and may prevent adequate dosages being achieved.

Tranylcypromine

Tranylcypromine has a structure that closely resembles amfetamine. It has a significant stimulant effect, and because of this could be more likely to give rise to problems around dependence. Unlike the other MAOIs, it does not irreversibly inhibit monoamine oxidase, which is said to recover some 5 days after withdrawal of the drug. Even so, the precautions associated with the MAOIs must still be continued for 2 weeks after discontinuing the drug. Due to the amfetamine-like alerting effect of tranylcypromine, the last dose should not be given after about 3 p.m. The risk of severe interaction is also said to be greater with tranylcypromine than with other MAOIs.

Phenelzine

Phenelzine has a hydrazine structure and because hydrazines have been associated with hepatocellular jaundice, it is recommended that phenelzine should be avoided in patients with hepatic impairment or abnormal liver function tests.

Reversible inhibitors of monoamine oxidase

Although moclobemide is an effective antidepressant, with less propensity for interactions with tyramine-rich foods, caution should still be exercised as other drug interactions do occur. It could be considered, after a suitable wash-out period, as an option if a first- or second-line SSRI is ineffective.

Selective serotonin reuptake inhibitors

These agents were developed in an attempt to reduce some of the problems associated with the tricyclic antidepressants. Overall, the SSRIs are better tolerated by most patients and coupled with the fact that they are considerably less toxic in overdose; this means that they should be the first-line choice for the pharmacological management of moderate or severe depression (NICE, 2009). As generic versions of the drugs are available, the financial impact of using SSRIs first line has reduced in recent years. The SSRIs have a broadly similar range of side effects, but there are variations in the intensity or duration. The degree of specificity for serotonin reuptake differs between the SSRIs, but this does not correlate with clinical efficacy. If given in adequate doses for an adequate period of time, all the drugs in this class appear to be equally effective.

They do not appear to be significantly more or less effective than traditional tricyclics. They are, however, better tolerated than tricyclics and importantly much less toxic if taken in overdose. There are differences between SSRI’s effect on the cytochrome P450 isoenzyme system. This may also be an important factor to consider when individualising treatment.

Fluvoxamine

Although patients experience few antimuscarinic side effects, other problems related to serotonergic enhancement such as nausea, headache and nervousness have been reported.

Fluoxetine

The main difference between fluoxetine and the other SSRIs is the long half-lives of both the parent drug and its primary active metabolite, desmethylfluoxetine. In the initial stages of treatment, some patients may experience a greater feeling of nervousness with fluoxetine than with the other SSRIs, but in most cases tolerance to this develops. The long half-life of fluoxetine and its major metabolite is a problem if severe side effects develop. In other situations, the long half-life means that the risks of discontinuation syndrome is reduced. Formulations of fluoxetine that can be taken on a weekly basis are available in some parts of the world.

Paroxetine

Although all the SSRIs have been reported to cause extrapyramidal-type movements, paroxetine appears to be more commonly implicated. The problem may be particularly severe following abrupt discontinuation of high doses.

Sertraline

Like the other SSRIs, sertraline is an effective antidepressant. Although doses of up to 200 mg have been used, doses of 150 mg and above should not be given for longer than 8 weeks.

Citalopram

The efficacy and side effect profile of citalopram appear similar to the other agents but, like sertraline, the reduced propensity for interactions with drugs metabolised by the cyctochrome P450 2D6 isoenzyme may be an advantage in some cases.

Escitalopram

Escitalopram is thought to be the active S enantiomer of citalopram, which is a racemic mixture of R– and S-citalopram. The use of escitalopram has been advocated on the basis that the R enantiomer has no antidepressant effect, and may even counteract some of the antidepressant effects of the S enantiomer of escitalopram.

Lithium

Lithium does have antidepressant properties but will be discussed in more detail in the antimanic section.

Other drugs

Trazodone

In vitro, trazodone appears to operate as a mixed serotonin agonist/antagonist, but clinically it is thought to operate as a serotonin agonist. Trazodone is much safer than the tricyclics following overdose but causes pronounced sedative and hypotensive effects in some patients. Priapism has also been noted as a rare but distressing side effect. This is probably due to its potent α-receptor blocking properties.

Mianserin

Mianserin was one of the first antidepressants to demonstrate an improved toxicity profile following overdose. Like many of the newer drugs, it has fewer antimuscarinic side effects than the traditional tricyclics. One drawback in using mianserin is the need for monthly blood counts during the first 3 months of treatment, due to a high reported incidence of blood dyscrasias, particularly in the elderly. Mianserin is no longer widely prescribed in the UK.

Venlafaxine

Venlafaxine was reported to be the first in a new class of antidepressants, the serotonin-noradrenaline reuptake inhibitors (SNRIs). These antidepressants were developed in an attempt to improve efficacy over the standard agents. As the name suggests, they prevent the reuptake of both serotonin and noradrenaline (norepinephrine), a mechanism they have in common with the tricyclic antidepressants. It was hoped this would result in a drug with similar efficacy to the tricyclics in more severe cases but without the antimuscarinic, cardiac or toxic effects of the older drugs. Guidelines for depression (NICE, 2009) highlight the relative poor tolerability and increased risks of toxicity compared to the SSRIs. In view of this, venlafaxine is not recommended as a first-line treatment for patients with moderate or severe depression.

Duloxetine

Like venlafaxine, duloxetine is an SNRI. It weakly inhibits dopamine reuptake and may be less well tolerated than SSRIs. Given the relative benefit/tolerability profile, the drug is considered to be a second-line treatment option.

Reboxetine

Reboxetine is a specific noradrenergic (norepinephrinergic) reuptake inhibitor (NARI). Response rates appear similar to other antidepressants. This casts further doubt on the existence of particular subtypes of depression likely to respond to particular antidepressants. Patients experiencing problems with serotonergic-related side effects may benefit from a switch to reboxetine.

Mirtazapine

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). It enhances both noradrenergic (norepinephrinergic) and 5HT1 serotonergic transmission. Specific 5HT1 neurotransmission is achieved as the drug also acts as a 5HT2 and 5HT3 antagonist. The receptor-specific effects of mirtazapine may explain some reduction in sexual dysfunction and nausea compared to other SSRIs. Despite this novel pharmacology, mirtazapine appears little different from other antidepressants in terms of efficacy.

Agomelatine

Agomelatine is structurally related to melatonin, it gained regulatory approval for use as an antidepressant in Europe in 2009. It is thought to act as an agonist at melatonin MT1 and MT2 and antagonist at 5HT2c (Kasper and Hamon, 2009). In contrast to other antidepressants, it has no effect on monoamine uptake systems. Liver function tests are required prior to commencement and at intervals during treatment as rare cases of hepatic dysfunction have been reported. As yet there is insufficient evidence to comment on the place of this drug in the management of depression, but its relatively high cost may limit its use within the UK.

Choice of antidepressant

Whilst it has been suggested (Cipriani et al., 2009) that sertraline and escitalopram should be considered first-choice antidepressants for the majority of patients, it is unclear whether this will be translated into routine practice. The severity of the disorder, patient preference and previous experience should also play a part as they are also likely to affect outcome. In some areas, cost has become a critical factor in choice. For most people with moderate-to-severe depression, unless otherwise contraindicated, the use of a generic SSRI as the first-line choice is appropriate. Previous response, tolerance and the likelihood of drug interactions should also be considered.

In clinical practice, the identification of patients at high risk of suicide is difficult, and all patients with severe depression should be considered at risk of self-harm. The quantities of medication supplied to these patients should be carefully monitored.

Other treatments

Non-drug treatments

In addition to drug treatment, it is important to consider the patient’s wider social, cultural and environmental circumstances. Although most patients with moderate to severe symptoms of depression will be offered pharmacological treatment, all patients and their close family should be offered help and support to cope with depression. Specific non-pharmacological interventions such as cognitive behaviour therapy (CBT) can be as effective as drug treatments. For people with more severe symptoms of depression, a combination of antidepressants and CBT is recommended. For mild-to-moderate forms of depression or persistent sub-threshold symptoms, then non-drug strategies based on the principals of CBT should be considered as the first-line treatment (NICE, 2009).

The basis of CBT was developed over 50 years ago and subsequently refined into a specific therapy in the 1970s. This type of treatment helps patients to address their unhelpful thoughts and actions associated with depression. Over a series of up to 20 sessions the CBT therapist works with the patient either alone or in groups, to replace negative or self-critical thoughts and actions with more positive and helpful ones. CBT is not a ‘quick fix’ solution to depression, patients are often given ‘homework’ between sessions to try and put their positive actions into place. Interpersonal psychotherapy (IPT) is another form of psychotherapy which may help patients overcome symptoms of depression. This type of therapy aims to improve the patient’s social functioning by linking their mood with interpersonal contacts so that their depressive mood and relationships can simultaneously improve.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) would only be considered after referral to a psychiatrist. Although it is said to have a faster onset of action, its effects are fairly short-lived and antidepressants are normally required to prevent relapse. Although the treatment itself is considered safe, there are risks from the anaesthetic agent, and some patients suffer short-term memory loss following treatment.

St John’s wort (Hypericum perforatum)

Extracts of hypericum have been shown to be as effective as standard antidepressants in the management of major depression (Linde et al., 2008). In England and Wales, prescribers are advised against prescribing hypericum because of uncertainty about appropriate doses and persistence of effect. Problems can also be caused due to the variation in the nature of preparations available and the potential for serious interactions with other drugs.

Treatment of mania

Valproate semisodium (divalproate) is licensed in the UK as a specific treatment for mania associated with bipolar disorder. Other antipsychotics, including lithium and benzodiazepines, may also have a role in the management of mania. There appears to be insufficient evidence to differentiate between the various antipsychotics licensed for use in the acute management of mania and as a consequence the side effect profile, tolerability, previous experience and patient preference should all be considered when selecting the agent to use. Short-term adjunctive treatment with a benzodiazepine may be also be required.

Lithium may be used as an antimanic agent but it takes longer than other agents to produce its full effect and few would consider lithium as their agent of choice for acute antimanic treatment. However, it remains a drug of choice for long-term use to prevent recurrence or relapse. Valproate, certain antipsychotics, carbamazepine and lamotrigine (off-label use) may also be considered for this indication. In the future, further evidence or new technologies may emerge that permit better individualisation of treatment.

When used prophylactically the antimanic agents are commonly referred to as mood stabilisers.

If an episode of mania occurs in patients taking antidepressants, the antidepressant should be withdrawn. If mania occurs in patients already taking an antimanic agent for prophylaxis, attention should be given to maximising the dose and, if necessary, adding a second agent.

Valproate semisodium

This is a 1:1 molar combination of sodium valproate and valproic acid. Following administration, valproate ion is released and subsequently absorbed. The therapeutic differences between sodium valproate and valproate semisodium have not been established. However, the latter is the only form of valproate licensed for the acute treatment of mania. The mechanism of action in mania is unclear but may be related to increased levels of GABA. The antimanic effects of valproate are seen within 3 days, but the full benefit of treatment may not be apparent for up to 3 weeks. Dose should be rapidly titrated to between 1000 and 2000 mg per day. Routine valproate serum levels are not necessary, but levels between 50 and 100 mg/L have been reported to be associated with optimal response in some patients. Although the risks of liver damage are greater in young children, liver function tests should be performed prior to initiation of therapy and periodically thereafter in all patients. In addition, the patient must be instructed to report any problems, such as unexplained bruising, that may indicate abnormalities in coagulation. Although valproate is well established as a prophylactic treatment to prevent relapse, this is an off-label use and should not be used in patients likely to become pregnant because of its teratogenic potential.

Antipsychotics

All the antipsychotics share a common effect of blocking dopamine D2 postsynaptic receptors to some degree. Most of the newer antipsychotics, for example olanzapine, risperidone, quetiapine and aripiprazole, are licensed for use in the management of acute mania and prevention of new manic episodes.

Concerns about the side effect profiles of antipsychotic drugs often limit use, but in reality individual patients vary in their concern for and susceptibility to different side effects. Therefore, it is important that treatment choices are individualised and patients monitored regularly for side effects. Haloperidol, in an appropriate dose, is still commonly prescribed as part of the acute management of mania. It is less sedating than other antipsychotics which means it may occasionally be necessary to control severe behaviour disturbances with additional sedatives such as lorazepam, either orally or by injection. When a single agent is not considered to be effective, consideration should be given to augmenting the antipsychotic with valproate. Dose and duration of treatment are important considerations when treating acute mania. The dose of antipsychotic should be reviewed as the patient improves and where necessary consideration given to switching to an alternative prophylactic agent or continuing treatment to prevent relapse.

Lithium

Although lithium is effective in the acute management of mania, other treatments are generally preferred. This is due to the delay in response and variability of physical exertion and fluid intake which may compromise the safe use of lithium. In the acute situation, lithium may take up to 10–14 days to exert an effect. Dose is adjusted to achieve a target serum lithium concentration of 0.8–1 mmol/L for the management of acute episodes of mania, and for patients who have previously or have subsyndromal symptoms.

Antipsychotics or valproate semisodium, either alone or in combination, along with benzodiazepines should be considered the first-line treatment in the acute phase of mania.

Following an acute episode, lithium is a well-established treatment that may be considered as a first-line option for prophylaxis (Baldessarini and Tondo, 2000). Continuation therapy with a prophylactic mood stabiliser should be considered in all bipolar patients who have had two or more acute episodes within 2–4 years. It may also be reasonable to consider prophylaxis in any patient following a severe manic episode. As treatment is long term, the cooperation of the patient is essential and so a thorough explanation of the risks and benefits of the treatment is vital.

Before lithium treatment is initiated, an assessment of the patient’s physical state is essential. Thyroid, renal and cardiac function should all be within normal limits. It is, however, still possible to use lithium, with caution, in patients with mild-to-moderate renal failure or cardiovascular impairment. Any thyroid deficiency should be corrected before lithium treatment is commenced. Patients should be informed of the need for monitoring and cautioned about the consequences of dehydration and risks of drug interactions.

Serum levels

There is a narrow therapeutic window for lithium serum levels and variation in the reference ranges reported. Some of this variation can be accounted for by variation in dose schedules. In the main, 12-h (post-dose) levels above 1.2 mmol/L are considered to be toxic and levels below 0.4 mmol/L are not considered to be effective. In adults, if lithium serum levels are kept in the range 0.4–0.8 mmol/L, then lithium is usually well tolerated with minimal side effects. Levels at or above 0.7 mmol/L are reported as being more effective than lower doses.

For most patients the range of 0.4–0.8 mmol/L is appropriate for prophylaxis, but if lithium is used to control the acute phase, levels may need to be around 1.0 mmol/L. To accurately interpret lithium levels, it is important that the correct schedule is followed and to establish consistent results, the 12-h standard serum lithium protocol has been devised. This means that lithium levels should be taken in the morning as near as possible to 12 h after the last dose of lithium.

As the absorption and bioavailability of lithium may vary from brand to brand, it is important that patients do not inadvertently change brands or dosage forms without levels being checked. Lithium not only has a narrow therapeutic range but is particularly toxic in overdose. Common side effects reported by patients are gastro-intestinal disturbances, tremor, thirst, polyuria, weight gain and lethargy. In addition to complaints of side effects, some patients prefer to remain untreated as they feel lithium ‘damps down’ their creativity and they miss the slight ‘highs’ that occur as part of their illness.

Patients taking a prophylactic mood stabiliser may occasionally stop taking their medication when they feel they no longer need it, or want to see if they can overcome the disorder without the need for drugs. Patients commonly have several trials on a mood stabiliser before they accept that the balance of risks and benefits is usually in favour of longer term treatment. There is a significant risk of relapse if lithium is discontinued abruptly.

Other anticonvulsants

Carbamazepine is generally considered as a second-line prophylactic treatment, when first-line therapy is either not tolerated or is ineffective. Emerging evidence continues to support the use of lamotrigine as an alternative in patients with bipolar depression (Geddes et al., 2009).

Treatment combinations

In patients who cannot be controlled on a single mood stabiliser, consideration should be given to combining treatments. Although not entirely without risks, all the above drugs have been used in various combinations in resistant cases.

Patient care

In the acute phase of an affective disorder, a patient will have little or no insight into his or her condition. This often makes it difficult to prescribe medication following an informed discussion on the risks and benefits of treatment. Depressed patients may say they are not worth treating; most manic patients will find it impossible to engage in meaningful dialogue, or they may insist they do not need medication and consistently refuse treatment. Thus, in the initial stages of treatment, some patients are treated against their will. As patients respond to treatment, it is crucial that the benefits and risks of treatment are explained. This may need to be repeated and backed up by written information. Engaging the patient and including them in the choice of treatment not only supports their basic human rights but is also likely to lead to a better therapeutic outcome. The discussion should also allow the patient to record their preference for future treatment. This may include drug regimens they would prefer to receive should they relapse as well as medication they would find objectionable.

During the acute phase of their illness, patients may often forget what they have been told about their medication. It is, therefore, important to regularly offer information or reassurance about medication, even if the patient is reported to have fully discussed the actions and effects with a health care professional.

Many patients are frightened by the notion of taking medication that will affect their mind. Taking an antidepressant is often felt to be a sign of failure or weakness by the patient as well as their family and friends. This often leads people to try and deal with their depression without medication. This is fine for the milder forms of the disorder and is sometimes referred to as ‘watchful waiting’. In more severe cases, such an approach could have life-threatening consequences for the patient.

Patients should always be offered the opportunity of discussing their medication. The use of patient information leaflets and the involvement of the family or close friends may help patients understand the risks and benefits of their treatment. Many of the drugs used in the treatment of affective disorders have the potential to interact with other drugs that have been prescribed or purchased. Some of these are summarised in Table 29.1.

Table 29.1 Examples of important drug interactions with drugs used in the management of affective disorders

Antidepressant Interacting drug Effect
Tricyclics Adrenaline (epinephrine) and other directly acting sympathomimetics Greatly enhances effect. Dangerous acting sympathomimetics
Alcohol Enhanced sedation
Antiarrhythmics Risk of ventricular arrhythmias
Anticonvulsants Lowered seizure threshold and possible lowered tricyclic levels
MAOIs Severe hypertension
Fluoxetine Increased tricyclic serum levels
SSRIs Anticoagulants Enhanced effects
MAOIs Dangerous
Lithium Possible serotonin syndrome
MAOIs Alcohol, fermented beverages, tyramine-rich foods Hypertensive crisis
Antihypertensives Increased effect
Anticonvulsants Lowered seizure threshold
Levodopa Hypertensive crisis
Sympathomimetics Hypertensive crisis
Antipsychotics Anaesthetic agents Hypotension
Anticonvulsants Lowered seizure threshold
Antiarrhythmics Risk of ventricular arrhythmias
Astemizole and terfenadine Risk of ventricular arrhythmias
Lithium Non-steroidal anti-inflammatory drugs (NSAIDs) Possible serotonin syndrome
SSRIs Possible serotonin syndrome
Diuretics Enhanced lithium serum levels particularly with thiazides
Angiotensin-converting enzyme (ACE) inhibitors Enhanced lithium serum levels
Sumatriptan Possible central nervous system toxicity
St John’s wort Induces cytochrome P450 enzymes, particularly  
1A2, 2C9 and 3A4  
Indinavir Reduced serum concentration (avoid)
Warfarin Reduced anticoagulant effect (avoid)
SSRIs Increased serotonergic effect (avoid)
Carbamazepine (and other anticonvulsants) Reduced serum concentrations (avoid)
Digoxin Reduced serum concentration (avoid)
Oestrogens and progestogens Reduced contraceptive effect (avoid)
Theophylline Reduced serum concentration (avoid)
Ciclosporin Reduced serum concentration (avoid)

Common therapeutic problems in the management of affective disorder are outlined in Table 29.2.

Table 29.2 Common therapeutic problems in the management of affective disorder

Problem Possible solution
Antidepressants
Treatment failure (30–40% of patients will not respond to first antidepressant) Ensure adequate dose and duration of treatment
Check adherence, engage the patient, develop therapeutic alliance
Reassess response against target symptoms
Risk of self-harm Reconfirm diagnosis and identify compounding factors, for example, high levels of alcohol consumption in unsupervised situations
Withdrawal reactions Ensure gradual withdrawal
Relapse on discontinuation Consider long-term treatment
Intolerance Consider changing to a different class
Antimanic agents
Treatment failure Ensure adequate dose, check serum levels and adherence; consider drug combinations
Toxicity adverse effects Determine dose by clinical response, guided by serum levels
  Ensure patient is well informed and able to recognise impending toxicity and adverse effects of treatment
Weight gain Dietary advice; consider alternative pharmacotherapy
Lithium levels Ensure serum levels are 12 h post-dose, taken in the morning. Regular monitoring is important

Case studies

Case 29.1

Ms PS is a 17-year-old woman who presented to her primary care doctor with a 2-month history of difficulty in getting to sleep. She described herself as feeling generally unhappy. She had lost interest in socialising but was able to perform most of her usual daily routines. She sometimes felt as though she had little energy and was spending more time just watching the television.

Question

What diagnosis is likely to be given to Ms PS and what are the important factors to take into account when advising on treatment?

Answer

On further questioning by her primary care doctor, Ms PS does not reveal any ideas of self-harm. She is in a supportive relationship and, although she has some financial concerns, these are not excessive. It is likely that her depression is sub-threshold or of mild severity. Referral to specialist services is not appropriate. The patient should be given advice on sleep hygiene, including the removal of the television from her bedroom. A watching brief should be maintained and the patient asked to attend for a follow-up appointment within 2 weeks.

Antidepressants should not be prescribed. The risk/benefit balance is generally against prescribing antidepressants in people under 18 years of age. There is also little evidence to support the use of antidepressants in this case. More appropriate treatment options to consider would be a structured group exercise programme, guided self-help based on the principles of cognitive behavioural therapy or computerised cognitive behavioural therapy. The specific intervention should be guided by Ms PS’s preferences.

Case 29.2

Mr DD is a 50-year-old unemployed man with a long-standing history of bipolar I disorder. He was admitted, as a voluntary patient, to an acute psychiatric ward by his community psychiatric nurse (CPN). The admission followed a short period of increasingly disturbed behaviour. Mr DD’s daughter had contacted the CPN when she discovered that her father had just spent over £5000 on scientific instruments from an Internet auction site. Over the same period she had noticed that her father had lost interest in his self-care and become elated at the prospect of being on the verge of developing a special formula to solve the fuel crisis. On the ward Mr DD said he felt ‘fine, fine all the time’. He told staff on the ward that he didn’t need to be in hospital and it was keeping him away from his top secret mission. He also told ward staff that they could not keep him on the ward and insisted he was within his rights to go home. Mr DD’s speech was sometimes very rapid, and it was sometimes difficult to understand what he was saying. His records showed that on his last admission he had been treated with haloperidol.

Question

What treatment is appropriate for Mr DD?

Answer

Before initiating treatment it is important to rule out any organic or physical causes for Mr DD’s presentation. Following a thorough physical and psychiatric examination, it was established that Mr DD had been relatively well since commencing treatment with lithium almost 4 years previously.

It is important that symptoms of mania are brought under control. Haloperidol would be a suitable choice, in view of his previous response. However, a review of Mr DD’s medication history revealed that he had experienced several acute dystonic reactions to haloperidol during previous admissions. His daughter also reported that her father had commented on how awful it felt being given haloperidol during his last admission. Mr DD was, therefore, given the option to discuss alternative antipsychotic treatment. He agreed to take olanzapine which was prescribed at a dose of 15 mg daily.

When Mr DD’s manic symptoms are controlled, prophylactic treatment should be discussed with him. This should include a discussion about why he had discontinued lithium several months earlier. The opportunity should be taken to provide written information with the offer of a further discussion that should include his daughter.

Mr DD had stopped lithium as he felt he no longer needed it but after discussion was prepared to restart treatment. Renal, thyroid and cardiac function should be assessed, and if within normal limits, lithium carbonate 400 mg at night may be prescribed.

One week later a 12-h standard serum lithium level should be performed and the dose of lithium adjusted to achieve the same lithium levels as before (0.6 mmol/L).

The side effects and signs of impending toxicity from lithium should be explained to Mr DD and if possible his daughter. They should be given written information about the side effects, potential interactions, signs of toxicity and provided with a booklet to enable them to record the results of regular investigation. The arrangements for future prescribing and monitoring of lithium should be clarified so that Mr DD’s care is not compromised by moving across organisational boundaries.

Case 29.3

Mrs FA is a 40-year-old designer. She was admitted to an acute psychiatric unit from the emergency department of the local hospital. She had taken an overdose of 32 co-codamol tablets when her husband told her he was going to leave her. On the ward she told staff she hated her life, and that everything was going wrong. She was angry that she had not been successful in killing herself as there was no point in living. She could see no hope for the future and had no interest in anything, not even eating.

Question

What course of action would you advise?

Answer

Mrs FA has a severe episode of depression. Antidepressant drug treatment should be initiated immediately. In line with guidelines for the management of depression, one of the SSRIs, for example, citalopram, should be considered as a suitable choice. Although Mrs FA may be reluctant to take medication, it should be explained that the drug does relieve the symptoms of depression. As soon as practical, the explanation should be followed up by discussing the importance of taking treatment for 4–6 weeks before the full benefit is realised and the likely time course of antidepressant treatment being in the region of 6 months. Mrs FA should also be given the opportunity to discuss any concerns she may have about becoming dependent on the antidepressant as well as a general explanation about possible side effects.

Case 29.4

Mr MA is a 49-year-old unemployed man. He was admitted to a psychiatric unit at the request of the crisis intervention team. Mr MA had been prescribed fluoxetine 20 mg 2 months ago, and after no apparent response the prescriber in the crisis team had changed this to citalopram 4 weeks earlier. On admission he was noted to be withdrawn, lacking motivation and just gave ‘yes’ or ‘no’ in response to questioning. He reported no interests in his life, and it was noted that he had attempted to harm himself in the past. Two weeks after admission there was no significant improvement in his symptoms.

Question

What treatment options are appropriate for Mr MA?

Answer

Before considering a change in treatment, it should be confirmed that Mr MA has regularly taken his antidepressant medication. Serum levels are not generally available, or particularly helpful. Scrutiny of the medicine charts, discussion with nursing staff, relatives, key workers and the patient will enable a reasonable judgement to be reached. A dose increase could be considered if the patient had shown a limited response. In this case, the patient had received no apparent benefit and a change in treatment was warranted.

An in-depth review of his physical condition and previous medication should be undertaken. This should include discussion with the patient about any previous antidepressant treatment he had found to be particularly effective, or troublesome.

This review revealed that Mr MA had received several different antidepressants over the past 20 years. Three years ago he was treated with venlafaxine S/R 75 mg twice daily. The medical records confirmed Mr MA’s view that this medication had helped him in the past, but on further questioning he stated that he had not taken medication for long after discharge from hospital as he did not want to get ‘hooked’ on it.

The importance of long-term treatment and the proposed treatment plan should be discussed with Mr MA. Particular issues to be addressed include an assessment of physical functioning including base line blood pressure and the need for ongoing periodic monitoring. In view of Mr MA’s concerns about dependence, particular attention should be given to discussion around this issue. Based on Mr MA’s agreement to the treatment plan, his previous response, the lack of any physical contraindication and the ability to organise ongoing, periodic blood pressure monitoring would be a reasonable treatment option.

Case 29.5

Ms YS is a 28-year-old student with a history of bipolar I disorder. She had recently moved to the area in the hope of continuing her studies. She was admitted to an acute psychiatric unit at the request of her key worker who reported that Ms YS had recently become increasingly elated and her partner was very concerned about the increased credit card bills she was incurring.

Whilst on the ward she attempted to develop sexual relationships with several young male patients.

Question

Describe the treatment options available for Ms YS.

Answer

There is insufficient information to determine whether or not Ms YS was being treated adequately with a prophylactic mood stabiliser. It is important to determine if the current episode was related to inadequate prophylactic treatment.

The current episode of hypomania must be treated. She is currently at risk through her promiscuity and the excessive use of her credit card. Both behaviours are likely to affect her ability to maintain a relationship with her partner.

As Ms YS was taking adequate contraceptive precautions and was adamant that she had no intention or desire to become pregnant, initially treatment with valproate semisodium should be considered. Olanzapine or another antipsychotic could also be considered, but Ms YS did not want to be treated with an antipsychotic. An assessment of liver function, prothrombin rate and full blood count should be performed prior to initiating therapy.

The patient should be informed of the important adverse effects of therapy. In particular, she should be advised to report any unexplained bruising and to avoid the use of salicylates. Treatment should be commenced at 250 mg three times daily and increased in accordance with response and tolerability. Benzodiazepines may also be considered as a short-term adjunct if additional sedation is required.

Following resolution of the acute episode, long-term prophylaxis must be considered. In this case, Ms YS had previously been treated with lithium, but had refused to continue as this had caused significant weight gain.

In view of the patient’s refusal to consider lithium, prophylactic options include carbamazepine or valproate semisodium (valproate semisodium is not licensed for prophylactic use in the UK). Little hard evidence currently exists to guide the choice. It is important to take the patient’s view into account. Even though valproate does not have a UK marketing authorisation for prophylaxis in bipolar disorder, on the basis of informed choice, prophylactic treatment with valproate was agreed with Ms YS.

Case 29.6

Ms AB is a 55-year-old unemployed lady with a long-standing history of depression. She has been treated with several antidepressants over the years and is currently under the care of the community mental health team.

The only treatment that appears to have had any effect on her depressive episodes has been dosulepin. She has taken several overdoses in the past and her psychiatrist is reluctant to prescribe this drug.

Question

What measures could be taken to enable Ms AB to be treated effectively?

Answer

Ms AB does not have treatment-resistant depression. She has been successfully treated with dosulepin in the past, but impulsively takes an overdose as a way of dealing with difficult circumstances even when she is not depressed.

Non-drug strategies by the mental health team should be directed at enabling Ms AB to find alternative ways of dealing with these difficulties.

In view of the obvious risk of fatality, alternative antidepressant treatment should be considered. Dosulepin could remain as an option for Ms AB due to her previous response to this drug and the lack of response to other antidepressants, but this would fall outside current guidance for the management of depression (NICE, 2009). Practical measures of controlling the quantities of medication should be introduced such as ensuring she only receives sufficient medication for 2 or 3 days treatment.

Communication between all those involved in the care of Ms AB is crucial. When individualizing the supply of medication in this way, all those involved must be alert to the possibility that the system of supply may break down. In this case, an apparently routine prescription for 1 month’s supply of medication may have fatal consequences.

References

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Baldessarini R.J., Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch. Gen. Psychiatry. 2000;57:187-908.

Barbui C., Hotopf M., Freemantle N., et al. Selective serotonin re-uptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug adherence. Cochrane Review. 2001. Cochrane Library, Issue 2. Update Software, Oxford

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Cipriani A., Furukawa T.A., Salanti G., et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.

Fournier J., DeRubeis R.J., Hollon S., et al. Antidepressant drug effects and depression severity A patient-level meta-analysis. J. Am. Med. Assoc.. 2010;303:47-53.

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Geddes J.R., Calabrese J.R., Goodwin G.M. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br. J. Psychiatry. 2009;194:4-9.

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Linde K., Berner M.M., Kriston L. St John’s wort for major depression. Cochrane Database of Systematic Reviews.. 2008. Issue 4, Art No. CD000448. doi:10.1002/14651858.CD000448.pub3

National Institute for Clinical Excellence. Bipolar Disorder. The Management of Bipolar Disorder in Adults, Children and Adolescents in Primary and Secondary Care, Clinical Guideline 38. London: NICE. 2006. Available at: http://www.nice.org.uk/nicemedia/live/10990/30193/30193.pdf Accessed 13 April. 2011

National Institute for Clinical Excellence. Depression. The Treatment and Management of Depression in Adults (Partial Update of NICE Clinical Guideline 23 on in Primary and secondary Care), Clinical Guideline 90.. London: NICE. 2009. Available at: http://www.nice.org.uk/nicemedia/live/12329/45888/45888.pdf Accessed 13 April. 2011

Nicholson A., Kuper H., Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur. Heart J.. 2006;27:2763-2774.

World Health Organization. International Classification of Diseases and Related Health Problems, 10th Revision. Geneva: World Health Organisation; 1992. (ICD 10)

Further reading

Cipriani A., Santilli C., Furukawa T.A., et al. Escitalopram versus other antidepressive agents for depression. Cochrane Database of Systematic Reviews.. (Issue 2):2009. Art. No.: CD006532. doi:10.1002/14651858.CD006532.pub2

Geddes J.R., Burgess S., Hawton K., et al. Long term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am. J. Psychiatry. 2004;161:217-222.

Gelder M., Andreasen N., Lopez-Ibor J., et al. Oxford Textbook of Psychiatry, second ed. Oxford: Oxford University Press; 2009.

Goodwin G. Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J. Psychopharmacol.. 2009;23:346-388.

Mann J.J. The medical management of depression. N. Engl. J. Med.. 2005;353:1819-1834.

Scottish Intercollegiate Guidelines Network. Bipolar Affective Disorder. Edinburgh: SIGN; 2005. Available at www.sign.ac.uk/pdf/sign82.pdf Accessed 13 April. 2011

Shiloh R., Stryjer R., Weizman A., et al. Atlas of Psychiatric Pharmacotherapy, second ed. Abingdon: Informa Healthcare; 2006.

Walden J., Heinz G., editors. Bipolar Affective Disorders: Etiology and Treatment. Stuttgart: Thieme Publishing Group, 2004.

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