PSYCHIATRIC DISORDERS

Mood (affective) disorders

Andrea Danese Carmine M Pariante

Whats new?
 Patients suffering from mood disorders have greater risk of developing medical illness (e.g. cardiovascular disease, type II diabetes) and worse outcome of pre-existing conditions2 The risk for medical illness may be concentrated in those patients with a history of childhood abuse or neglect3 Treatment for medical illness like cancers and viral infections with interferon-alpha may induce depressive episodes4

Abstract
Mood disorders are common mental health problems linked to impairment in social and work functioning, and elevated suicide risk. Recent ndings suggest that mood disorders could also be a risk factor for poorer outcome during medical illness. Individual, societal, and healthcare costs of mood disorders can be minimized by adequate assessment and treatment. The assessment of mood disorders should include investigation of mood, thought, and somatic symptoms, precipitating life events, family history, suicide risk, and comorbidities, as well as differential diagnosis with other psychiatric conditions. Treatment strategies for mood disorders should be chosen on the basis of the polarity (depressive or manic episode) and severity of the current episode, and prior history. Residual symptoms are a risk factor for relapses and chronicity, and should be minimized by administering an adequate type, dose, and length of pharmacological treatment. Mood swings could be prevented by administering mood stabilizers and atypical antipsychotics.

Keywords bipolar affective disorder; depression; mania; unipolar

affective disorder

Denition
Mood is a pervasive and sustained emotional state. Unipolar affective disorder (major depression) is a common mood disorder characterized by depressed mood, as well as loss of interest, feelings of guilt and low self-esteem, disturbed sleep and appetite, low energy, and poor concentration. Mood disorders also include bipolar affective disorder, which is characterized by episodes of both depression and mania.

7% and the lifetime prevalence is 16%. Two to three times as many people may have depressive symptoms without meeting the criteria for diagnosis of unipolar disorder. Unipolar affective disorder is more prevalent in women than in men, with a ratio of 2:1. The age of onset is variable, with the mean in early adulthood (3040 years) but possible onset in childhood or old age. Bipolar affective disorder is a less common condition.5 In the general population, the 12-month prevalence of bipolar disorder is 0.6% and the lifetime prevalence is 1%. The prevalence of subthreshold symptoms is, however, higher with 12-month prevalence of 1.4% and lifetime prevalence of 2.4%. Bipolar disorder shows equal prevalence in men and women. The age of onset is most commonly in adolescence or young adulthood (20 years). The prevalence estimates for both conditions are similar worldwide. Because of the correlated functional impairment, mood disorders are among the leading causes of disability and major contributors to the burden of disease worldwide. Most patients with unipolar or bipolar disorders show other comorbid psychiatric conditions, more commonly anxiety disorders, impulse control disorders, and substance use disorders. Comorbidity with medical illness, particularly with cardiovascular disease, is also common.

Pathogenesis
Twin studies suggest that unipolar affective disorder and, to an even greater extent, bipolar disorder have an heritable component. Both conditions are, however, exacerbated by environmental conditions, and the onset of individuals episodes can often be related to stressful life experiences. It has been proposed that genetic and developmental factors (e.g. childhood maltreatment) may alter the physiology of the nervous, endocrine, and immune systems. In turn, the abnormal functioning of these integrated systems may alter the biological response to stressful life events, increasing the risk of developing depression. Neurochemical abnormalities including reduced transmission in the serotonergic, noradrenergic, and dopaminergic systems have been reported in patients with unipolar affective disorder.6 Antidepressant drugs antagonize these decits by increasing neurotransmitters availability. Neurochemical abnormalities in patients with bipolar disorder may include disregulation of second-messenger systems, neuroprotective proteins, and neurotransmitter availability.
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Epidemiology
Unipolar affective disorder is a common condition.1 In the general population, the 12-month prevalence of unipolar disorder is

Andrea Danese MD MSc is a Wellcome Trust Research Fellow at the Institute of Psychiatry, Kings College London, UK, and Specialist in General Psychiatry. Competing interests: none declared. Carmine M Pariante MD MRCPsych PhD is a Reader and MRC Clinician Scientist Fellow at the Institute of Psychiatry, Kings College London, UK, and Honorary Consultant Psychiatrist. Competing interests: Dr Pariante has consulted to, or served on, the Speakers Bureau for AstraZeneca, Bristol-Myers-Squibb, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Lundbeck, Pzer Pharmaceuticals, and Wyeth-Ayerst.

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Clinical features
Mood disorders are characterized by fundamental disturbance of mood and activity, and other associated (secondary) symptoms. Mood disorders include depressive and manic episodes (ICD-10).7 Depressive episode Depression is characterized by persistent lowering of mood (sadness) and decreased energy and activity. Symptom severity is generally greater in the morning and decreases through the day. Patients are tired after minimum effort. They show reduced capacity for enjoyment, interest, and concentration, and reduced self-esteem and self-condence. Depressed patients may show socalled somatic symptoms like insomnia (typically early awakening) or hypersomnia, psychomotor retardation, and loss of appetite, weight, and libido. Depending on the number of symptoms, depressive episodes are classied as mild, moderate, and severe. In mild depression, only two or three of the above symptoms are present, and patients are distressed but usually able to perform most of their daily activities. In moderate depression, four or more of the above symptoms are present, and patients are likely to struggle to perform daily activities. In severe depression, several of the above symptoms are marked and distressing, with ideas of worthlessness and guilt, and patients are not able to perform daily activities. Suicidal thought and acts are more common in moderate and severe depression than in mild. Severe depressive episodes may be associated with psychotic symptoms, such as delusions (e.g. guilt, sin, ruin) or hallucinations (e.g. voices speaking to the patients), and psychomotor retardation or stupor, possibly leading to suicide, dehydration, and starvation. Manic episode Mania is characterized by persistent elevation of mood (excitement) and increased energy and activity. Patients are often overactive, extremely talkative, and easily distracted. They show inated self-esteem with grandiose ideas and overcondence, and loss of social inhibition often leading to inappropriate behaviour. In addition, they have less need for sleep. Manic episodes may be associated with psychotic symptoms, such as delusions (e.g. grandiosity: thinking one is a famous person) or hallucinations (e.g. voices speaking to the patients), uncontrollable excitement and motor activity, and inability to have ordinary communication. Manic episodes may also be characterized by milder symptoms (hypomania), with increased sociability, increased sexual energy, and decreased need for sleep, but without severe disruption of work or social functioning or psychotic symptoms.

commonly induced by antidepressant treatment. The recurrent depressive disorder may include mild, moderate, and severe episodes (with or without psychotic symptoms). Severe forms of recurrent depressive disorder overlap with earlier concepts of melancholia, vital depression, and endogenous depression. The severity of depressive episodes can be assessed through the administration of psychiatric rating scales, such as the Hamilton Depression Rating Scale (HAM-D),8 the Montgomery Asberg Depression Rating Scale (MADRS),9 or the Beck Depression Inventory (BDI).10 The assessment of a depressive episode should be accompanied by an examination of possible precipitating factors, the psychiatric and medical history, and the course of the episode. Physical examination and laboratory investigation may also be important for differential diagnosis (Table 1). Bipolar affective disorder Bipolar affective disorder is characterized by two or more episodes of altered mood and activity levels. Patients with bipo lar affective disorder typically show an alternation of manic and depressive episodes, suffering on some occasion from elevation and in other occasion from lowering in mood and activity. However, repeated manic episodes are also classied in bipolar affective disorder. Bipolar affective disorder may include hypomanic and manic episodes (with or without psychotic symptoms), as well as mild, moderate, and severe depressive episodes (with or without psychotic symptoms).

Treatment
Unipolar affective disorder Major depression is frequently diagnosed in primary care. Currently available antidepressant treatments (drugs alone or in combination with brief, structured psychotherapy) are effective in 6080% of depressed patients. Yet, less than 25% of patients receive adequate treatments. Inadequate treatment may lead to recurrent episodes of depression and suicide. The National Institute for Health and Clinical Excellence (NICE)11 has developed a series of guidelines for the treatment of the major depression according to ICD-10 classication of depressive episode (see Figure 1). Patients with mild depression are generally treated in primary care. They should not be treated with antidepressant drugs because of the poor risk:benet ratio. Rather, they should be advised on exercise and problem-solving strategies. Further assessment should be arranged within 2 weeks. Patients with moderate or severe depression can be treated both in primary or secondary care. The decision to refer to secondary services should be based on the risk of suicide, the degree of functional impairment, and the presence of signicant comorbidities. These patients should be treated with antidepressant drugs and informed about their possible withdrawal effects. Generic selective serotonin reuptake inhibitors (SSRIs) are recommended as rst-choice antidepressant treatment in routine care, because they are effective and usually well tolerated. SSRIs inhibit the action of the serotonin transporter, which captures serotonin from the synapse and promotes serotonin passage into the presynaptic neurons. In this way, SSRIs increase the concentration of serotonin in the synapse. Antidepressant treatment should be titrated to the minimum effective doses (uoxetine 20 mg/day; citalopram 20 mg/day; escitalopram 10 mg/day; uvoxamine
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Diagnosis
Mood disorders may occur only once (depressive or manic episodes) or, more often, can be recurrent.7 Recurrent depressive disorder Recurrent depressive disorder is characterized by repeated episodes of depression, as described above. Depressive episodes must occur in the absence of prior episodes of mood elevation or increased energy (mania). Brief episodes of mild mood elevation can, however, occur after resolution of one depressive episode,

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Differential diagnosis
 Unipolar vs bipolar affective disorder differential diagnosis is often based on longitudinal observation of the patient. Factors supporting a diagnosis of unipolar affective disorder include: no prior manic episodes, gradual onset and resolution  Dysthymia dysthymia is characterized by chronic lowering of mood and decrease in activity, lasting several years, which are not sufciently severe to justify a diagnosis of mild recurrent depressive disorder  Cyclothymia cyclothymia is characterized by persistent instability of mood, with several periods of lowered or elated mood which are not sufciently severe to justify a diagnosis of recurrent depressive disorder or bipolar affective disorder  Schizophrenia-spectrum disorders depressed and manic patients may show delusions and hallucination resembling schizophrenia-spectrum disorders presentation. Factors supporting a diagnosis of mood disorders include: family history of mood disorders, good premorbid work and social functioning, prior depressive or manic episodes, moodcongruent delusions (e.g., delusions of guilt, sin, and ruin), and good response to antidepressant treatment  Dementia above all in old age, patients with unipolar affective disorder may show cognitive impairment resembling dementia presentation. Factors supporting a diagnosis of major depression include: negative EEG, MRI, and Doppler examination, impairment of both short-term and long-term memory, prior depressive episodes, characteristic circadian variation of symptoms (greater impairment in the morning), and good response to antidepressant treatment  Substance intoxication/withdrawal substances (both medications and drug of abuse) may induce agitation resembling manic states. Medications that can cause agitation through idiosyncratic or toxic effects include: corticosteroids, anticholinergic medications, anticonvulsants, antihistamines, antimalarials, antibiotics, lidocaine, psychotropics. Drugs of abuse that can cause agitation include: alcohol (intoxication and withdrawal), stimulants (intoxication and withdrawal), sedatives/anxiolytic/hypnotic medications (withdrawal). Blood or urine toxicology is needed for differential diagnosis  Medical conditions depressive symptoms can be secondary to medical illness like thyroid and adrenal gland disorders. Agitation seen in bipolar patients can also be induced by medical conditions like electrolyte imbalance, diabetes, hypoxia, thyroid and adrenal gland disorders, organ failure, head trauma, stroke, central nervous system infection, central nervous system cancer, and epilepsy. Factors supporting a diagnosis of primary mood disorder include: negative laboratory analysis, family history of major depression, gradual onset of symptoms, adequate spatial/temporal orientation

50mg/day; paroxetine 20 mg/day; sertraline 50 mg/day).12 Careful monitoring of symptoms, side effects (including the possible switch from depressive to manic episode), and suicide risk (particularly in patients aged under 30 and at the beginning of the treatment) is necessary (Table 2). Increased agitation early in treatment could be treated with the concomitant administration of benzodiazepine, followed by clinical evaluation within 2 weeks. If there is no response after a month or inadequate response after 6 weeks from the prescription of a rst antidepressant (taken regularly and at the prescribed dose), switching should be considered. Choices for a second antidepressant include a second SSRI or different classes of antidepressants including noradrenergic and specic serotonergic antidepressants (NaSSA: mirtazapine 30 mg/day, possible sedation and weight gain), but also norepinephrine reuptake inhibitors (NRI: reboxetine 8 mg/day, lack of data on side effect requires careful monitoring), tricyclic antidepressants (TCA) with relatively good tolerance (lofepramine 140 mg/day, possible constipation), or monoamine oxidase inhibitors (MAOI: moclobemide 300 mg/day, requires wash-out of previously prescribed antidepressant, it is mainly used in secondary settings). Other TCA (amitriptyline 75200 mg/ day, with poorer tolerability compared to other equally effective antidepressant, risk of cardiotoxicity, and toxicity in overdose) or serotonin-norepinephrine reuptake inhibitors (SNRI: venlafaxine 75225 mg/day, with poorer tolerability, possible elevation of blood pressure, and cardiac dysfunction risk) may be considered, especially for more severe depression. The switch between antidepressants requires gradual and modest increases of dose, and interactions between antidepressants are possible. Combinations of serotonergic antidepressants may cause serotonin syndrome, characterized by confusion, delirium, shivering, sweating, changes in blood pressure, and myoclonus. Electroconvulsive therapy (ECT) is an effective intervention generally considered for last-line treatment of refractory depression. ECT necessitates general anaesthetics and is performed in specialist settings (see article on Physical treatments in the next issue). The efcacy of the antidepressant treatment should be assessed over 46 weeks (repeated assessment of depressive symptoms with HAM-D or MADRS could assist in measuring treatment response). In the case of poor efcacy, it is possible to either increase the dose of antidepressant or switch to another. Antidepressant treatment should be continued for at least 6 months after remission in order to reduce the risk of relapse. At termination, antidepressant doses should be tapered gradually to avoid risk of withdrawal symptoms. Patients with moderate or severe depression could also be treated with psychological treatments like cognitivebehavioural therapy (CBT) or interpersonal therapy (IPT). A combination of pharmacological and psychological therapies is the most cost-effective strategy for the treatment of patients with moderate to severe depression. Patients with treatment-resistant, recurrent, atypical and psychotic depression should be referred to specialist care. Bipolar affective disorder Discontinuation of antidepressant drugs is the rst step in the management of acute episodes of mania. The timing for antidepressant discontinuation will depend on the clinical need and the risk of discontinuation (withdrawal) for the specic antidepressant medication. It is then necessary to consider antimanic
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Table 1

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The stepped care model

Who is responsible for care? Step 5: Inpatient care, crisis teams What is the focus? Risk to life, severe self-neglect What do they do? Medication, combined treatments, ECT

Step 4: Mental health specialists including crisis teams

Treatment-resistant, recurrent, atypical and psychotic depression, and those at significant risk

Medication, complex psychological interventions, combined treatments

Step 3: Primary care team, primary care mental health worker

Moderate or severe depression

Medication, psychological interventions, social support

Step 2: Primary care team, primary care mental health worker

Mild depression

Watchful waiting, guided self-help, computerized cognitive behavioural therapy, exercise, brief psychological interventions

Step 1: GP, practice nurse

Recognition

Assessment

Source: National Institute for Health and Clinical Excellence. Depression: management of depression in primary and secondary care NICE guidance. London: NICE, 2004.

Figure 1

medications. If the patient is not taking any antimanic medications, NICE14 suggests prescriptions of antipsychotic medications (olanzapine 10 mg/day, quietapine 100 mg/day, or risperidone 23 mg/day) to patients with severe symptoms, and valproate (semisodium 250 mg three times/day; sodium 500 mg/day; not in women with childbearing potential) or lithium (400 mg/day) in patients with milder symptoms. In case antimanic medications are already prescribed, it is important to check compliance, plasma levels, and consider combination antipsychotic/anticonvulsants. For rapid tranquillization, it is possible to use intramuscular olanzapine (10 mg), or lorazepam (2 mg), or haloperidol (210 mg). Long-term treatment for bipolar affective disorder has to be considered after a severe manic episode, or two or more

acute episodes. Lithium, olanzapine, or valproate treatment for 2 5years after an episode is suggested for the long-term treatment of patients with bipolar affective disorder. In addition, psychological therapy (cognitivebehavioural therapy) and psychosocial support may improve the outcome of the treatment.

Prevention
Preventive measures may help to minimize depression relapses (or recurrence) and chronic depression. First, preventive strategies should aim at the optimal resolution of the current depressive episode. Residual depressive symptoms are an important risk factor for relapses and chronicity, and should be avoided by administering an adequate type, dose, and length of antidepressant treatment. Second, preventive interventions should aim at increasing coping skills (e.g. setting realistic goals, seeking social support, participating in pleasurable activities, learning relaxation techniques, engaging in physical exercise) which could help the patients to face stressful life events. Preventive strategies should also target complications of depression like suicide, substance abuse, and self-neglect. Secondary prevention is also important for bipolar affective disorder. Pharmacological treatment with lithium, olanzapine, or valproate can be used to control mood swings and relapses. In addition, non-pharmacological intervention promoting a healthy lifestyle can also help improving patients outcome. Lifestyle measures should include a balanced diet, daily exercise, good sleep, avoidance of drugs of abuse, reduction of stress at work or at home, reduction of night ights and ights across time zones. Patients should be taught how to recognize early symptoms of
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Suicide risk and selective serotonin reuptake inhibitors (SSRIs)

Suicide risk in patients taking SSRIs has recently been at the centre of a heated debate13 It has been proposed that SSRIs may act more quickly on psychomotor retardation than on depressed mood, therefore enabling depressed patients to carry on their suicidal thoughts Current evidence suggests that suicide risk may not be specic to SSRI antidepressants, and could be greater in the rst 2 weeks of treatment and in children and adolescents Table 2

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exacerbation, in order to help them to seek treatment in a timely manner.

RefereNces 1  Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095105. 2 Steptoe A. Depression and physical illness. Cambridge: Cambridge University Press, 2007. 3 Danese A, Moftt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 2008; 65: 40915. 4  Pariante CM, Landev S, Carpiniello B. Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis. N Engl J Med 2002; 347: 14849. 5  Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007; 64: 54352. 6  Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002; 34: 1325. 7  World Health Organization. The ICD-10 classication of mental and behavioural disorders: clinical description and diagnostic guidelines, Geneva: WHO, 1992. 8 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 5662. 9  Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 38289. 10  Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 56171. 11  National Institute for Health and Clinical Excellence. Depression: management of depression in primary and secondary care. London: NICE, 2004 Available at: http://wwwnice org uk/CG023.

12 Taylor D, Paton C, Kerwin R. The Maudsley prescribing guidelines, 9th edn. London: Informa Healthcare, 2007. 13 Hall WD. How have the SSRI antidepressants affected suicide risk? Lancet 2006; 367: 195962. 14  National Institute for Health and Clinical Excellence. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. London: NICE, 2006 Available at: http://wwwnice org uk/CG038

Practice points
 Unipolar affective disorder is a common and signicant mental health problem. Most cases are diagnosed and treated in primary care settings  Bipolar affective disorder is a less common condition, but it is associated with signicant disability The assessment of mood disorders should include consideration of differential diagnosis of schizophreniaspectrum disorders, dementia, substance intoxication/ withdrawal, and medical conditions  Mood disorders must be treated to avoid suicide, substance abuse, and impairment in work and social functioning. Mood disorders are also associated with a greater risk for several chronic diseases (e.g., cardiovascular disease, type II diabetes) Antidepressant medication should be prescribed to patients with moderate-to-severe depression. Residual depressive symptoms are a risk factor for relapses and chronicity, and should be avoided by administering an adequate type, dose, and length of antidepressant treatment Olanzapine, valproate, and lithium should be prescribed to patients with bipolar affective disorder to treat current mood episodes and reduce the risk of relapse

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