Unipolar Depression and Dysthymia



Unipolar Depression and Dysthymia

Catherine Symonds and Ian M Anderson

Catherine Symonds MRCP (UK) is an Academic Clinical Fellow in Psychiatry and Manchester Biomedical Research Centre Clinical Fellow at the Neuroscience and Psychiatry Unit, Manchester University, Manchester, UK. Competing interests: none declared.

Ian Anderson MD, MRCP (UK), FRCPsych is Professor of Psychiatry at the University of Manchester, Neuroscience and Psychiatry Unit, Manchester University, and Honorary Consultant Psychiatrist at Manchester Mental Health and Social Care Trust, Manchester, UK. Competing interests: Prof Anderson has been a consultant to, received grants, honoraria for speaking and/or support for conference attendance from, Servier, Lilly, AstraZeneca, Wyeth, Pfizer and Lundbeck.

Abstract

Depression is common relapsing disorder which causes significant distress and impairment in social and occupational functioning. It is associated with an increased risk of death, not only through suicide but also from physical illnesses such as cardiovascular disease. It is under-recognised and undertreated and it should be screened for in those at high-risk for depression such as those suffering from chronic physical health problems. Its aetiology is multifactorial and comorbidity with other psychiatric disorders is common. Assessment of depression requires determining the duration, symptom severity, suicide risk and functional impairment in the current episode, comorbid diagnoses, past mood and treatment history as well as a developmental, social and family history. Treatment is guided by illness severity, presentation and prior history and includes psychosocial interventions, medication and their combination, with antidepressant medication reserved for persistent and moderate to severe depression. Prevention of relapse is a priority and risk factors for this should be assessed and used to guide prophylactic drug and psychological treatment.

Definition

Unipolar depression is defined by persistent low mood and/or lack of enjoyment (anhedonia) together with other emotional, cognitive and physical symptoms and significant functional impairment in the absence of a history of mood elevation (see Bipolar Affective Disorder). Dysthymia refers to chronic depressive symptoms not meeting criteria for major depression.

Epidemiology

Depression is the 4th most common cause of disability worldwide(1) with a 12-month prevalence of major depression about 6%(2), milder degrees of depression about 2-3 times this and dysthymia about 2%(3); twice as many women are affected as men. Lower rates are seen in married people and higher income households(4). Depression is commonly association with other psychiatric disorders, especially anxiety and substance misuse disorders%(3) and chronic physical illness, for example 2-3 times the rate in diabetes, coronary artery disease, end-stage renal failure and chronic obstructive pulmonary disease)(5).

Aetiology

In the ‘biopsychosocial’ model of depression developmental biological and psychological vulnerability interact with environmental precipitating and maintaining factors. ‘Secondary’ depression (symptomatically arising directly from a physical illness or treatment) can be difficult to tease out from depression precipitated by the physical cause.

Vulnerability to depression is hereditable involving multiple genes interacting with developmental and environmental factors(6). The monoamine theory postulates a functional decrease in serotonin (5-hydroxytryptamine) and/or noradrenaline neurotransmission leading to depression, reversed by antidepressant drug treatment, but many other neurochemical and neuroendocrine systems are implicated as well as neurogenesis and synaptic plasticity. Neuroanatomically there is altered activity and connectivity of mood-related brain areas such as amygdala and anterior cingulate cortex. Vulnerability is strongly associated with childhood neglect/sexual abuse, personality factors (neuroticism), chronic social difficulties and isolation. Adverse life events commonly trigger depression and frequently exacerbate ongoing social adversity. Psychological factors include low self-esteem, a bias to appraise things negatively and ruminate, reinforced by withdrawal from pleasurable activities.

Clinical features

DSM-IV(7) criteria for the syndrome of major depression (Box 1) are preferred over those of ICD-10 in current clinical guidelines from the National Institute for Health and Clinical Excellence (NICE)(8). Depressive symptoms occur on a continuum of severity and duration making threshold cases common. Three main symptom patterns are 1) Melancholic depression, often seen in the elderly and more severely ill patients. Low mood is experienced as distinct from sadness, is worse in the morning and unreactive to positive events, there is appetite and weight loss, reduced sleep with early morning waking and inability to get back to sleep and marked physical slowness (or agitation). 2) Atypical pattern depression with temporary mood improvement to positive events, lack of melancholic features with increased appetite (often for carbohydrates), weight gain and hypersomnia. 3) Depression with psychotic symptoms (commonly mood-congruent such as derogatory auditory hallucinations and/or delusions of poverty) usually associated with severe and melancholic depression. Depression can also be classified by whether it is seasonal (usually winter) or occurs after childbirth (postnatal depression).

Milder symptoms, ‘subthreshold’ for major depression are common, are associated with significant morbidity, and warrant monitoring followed by treatment if persistent (dysthymia)(8).

Natural history and prognosis

Onset is usually in the mid-20s but can occur at any time. Outcome varies by setting and severity, the median episode duration ranges from 4-12 months with 10% having an unremitting course and many others experiencing fluctuating degrees of symptoms. At least 50% of people will experience a subsequent relapse increasing to 90% after the third episode with a median of 4 lifetime episodes(3;8). Poorer outcome is associated with earlier age of onset, episode number, duration, severity and treatment resistance, psychosis, cognitive impairment, physical and psychiatric comorbidity and ongoing social adversity(4). About 10% of patients, especially after early onset, are subsequently diagnosed with bipolar disorder (NICE). Eventual death through suicide is increased fourfold to 2% in community samples rising to 9% in the most severely ill(3). Depression increases the morbidity and mortality in a range of physical illnesses(5) .

Assessment

Systematic enquiry should be made about the severity and duration of depressive symptoms, those of potential psychiatric and physical comorbidities (Box 2), suicide risk and medication. History of past episodes should include mania/hypomania, precipitants, severity including psychosis, suicidality, treatment and response. In the patient’s background, review family psychiatric history, personal development, social history especially of trauma, social adjustment and relationships, precipitating life events and ongoing social difficulties. In mental state examination, note apparent mood and reactivity, speech rate and motor activity, agitation, hopelessness and psychotic signs/symptoms. Differential or comorbid diagnoses should be explored by relevant cognitive and physical examination, guided by history and presentation.

Management

Most cases of depression can be managed in primary and general medical care. Criteria for referral are given in Box 3. NICE (8) recommend a ’Stepped Care’ approach to match presentation with appropriate treatment (Figure 1). Patients with mild, recent onset, depression may improve after discussion of their concerns, provision of information and scheduled follow-up (active monitoring). Lifestyle (e.g. alcohol, physical exercise) and sleep hygiene advice should be given. Psychosocial treatment, antidepressant medication, and their combination, are the mainstay of treatment. The use of medication should be based on the balance of risks (higher in physically ill) and benefits (lower efficacy in milder severity).

Poor or incomplete response to initial treatment occurs in 30-50% of patients approaching 90% after 3-4 trials(9). Next-step treatment approaches are to increase the dose, switch therapy, combine medication/ medication with psychological treatment, and electroconvulsive therapy (ECT) (3;8). Moderate and severe depression with chronic physical illness not responding to treatment warrants collaborative care with coordination of multidisciplinary input and long term follow up.

All patients treated with antidepressants require 6-9 months continuation treatment following symptom resolution. Longer, sometimes indefinite, treatment is required if there is a high risk of relapse (e.g. persisting symptoms, severe or recurrent depression, comorbidity, family history of depression, persistence of social adversity).

Psychosocial and psychological treatments: Box 4 lists evidence-based treatments(8). These are first-line treatments for mild and moderately severe depression (Figure 1) and should be combined with antidepressants if there is poor response. Commonly used non-directive counselling lacks evidence of efficacy.

Medication: Selective serotonin reuptake inhibitors (SSRIs) are first line based on efficacy and tolerability of which sertaline and escitalopram have a slight efficacy advantage(10) and are least likely, along with citalopram, to cause drug-drug interactions. However citalopram and escitalopram increase the QTc interval(11) leading to cautions/contraindications (see Chapter 30). Next-step drug treatment after insufficient response includes, dose increase, switching to another SSRI or newer antidepressant (see Box 5). Tricyclic antidepressants are third line due to lower tolerability and toxicity in overdose, the exception is lofepramine which is safer in overdose. Irreversible inhibitors of monoamine oxidase are specialist drugs but moclobemide, a reversible inhibitor of monoamine oxidase A is well tolerated and safer.

Lithium, the longest established augmenter of antidepressants, requires regular monitoring of serum level due a narrow therapeutic window. Augmentation of SSRIs with atypical antipsychotics, especially quetiapine (see Chapter 30), has good evidence for efficacy at the cost of sedation and weight gain. Combination antidepressants (especially mirtazapine with an SSRI) may also be effective.

Other treatments: ECT, an extremely effective antidepressant(12) but with concerns about its cognitive adverse effects, is used for severe depression that has not responded to other treatments and takes place in specialist centres under general anaesthetic. Other experimental brain stimulation techniques are not available clinically. Drugs in development include those with antiglucocorticoid and glutamatergic effects.

References

(1) Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997 349(9063):1436-42.

(2) Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011 21:655-79.

(3) Anderson IM, Ferrier IN, Baldwin RC, Cowen PJ, Howard L, Lewis G et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008 22:343-96.

(4) McManus S, Meltzer H, Brugha T, Bebbington P, Jenkins R. Adult psychiatric morbidity in England, 2007. Results of a household survey. The Health and Social Care Information Centre, Social Care Statistics. 2009

(5) National Institute for Health and Clinical Excellence. Clinical Guideline 91. Depression in adults with a chronic health problem: full guideline. 2009 .

(6) Charney DS, Manji HK. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE 2004 2004(225):re5.

(7) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). 2000 Arlington, VA: American Psychiatric Association;

(8) National Institute for Health and Clinical Excellence. Clinical Guideline 90. Depression in adults (update): full guideline. 2009

(9) Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006 163:1905-17.

(10) Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009 373(9665):746-58.

(11) Food and Drug Administration. FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). Safety Announcement [8-24-2011] 2011 .

(12) UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis.[comment]. Lancet 2003 361(9360):799-808.

(13) Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001 16:606-13.

(14) Zigmond AS, Snaith RD. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scandinav 1983 67:361-70.

Box 1: Abridged DSM-IV criteria for depression and dysthymia

Major depression

Over the last 2 weeks, 5 or more of the following are present most of the time (must include 1 or 2):

1. depressed mood

2. loss of interest or pleasure in almost all activities

3. significant appetite/weight loss or gain

4. insomnia or hypersomnia

5. psychomotor agitation or retardation (observable by others)

6. fatigue or loss of energy

7. feelings of worthlessness or excessive guilt

8. diminished concentration or indecisiveness

9. recurrent thoughts of death, or suicidal thoughts, plans or attempts

The symptoms cause clinically significant distress or impairment in functioning, are not due to a medical/organic factor or illness or better explained by bereavement.

Severity: mild (few symptoms beyond minimum, mild functional impairment), moderate (symptoms and functional impairment between mild and severe), severe (most symptoms present, marked or greater functional impairment).

Dysthymia

1. Depressed mood for the majority of the last 2 years

2. 2 or more of: decreased or increased appetite, decreased or increased sleep, fatigue or low energy, low self-esteem, decreased concentration, feeling hopeless or pessimistic

3. The criteria for major depression are not met and symptoms don’t follow on from a prior major depression

4. Significant functional problems or distress

5. Not part of bipolar disorder or a psychotic illness or caused by a physical illness

Box 2: Differential diagnosis

Bipolar disorder - bipolar and unipolar depression cannot be distinguished clinically and the diagnosis is made on a history of hypomania or mania

Other psychiatric disorders such as anxiety and eating disorders may share features of depression such as decreased enjoyment, appetite disturbance and social withdrawal but are also commonly comorbid and may predate depression onset

Substance abuse including alcohol misuse and dependence can cause persistant dysphoria, however comorbidity with depression is also common

Schizophrenia - prodromal symptoms can resemble depression and negative symptoms including apathy can mimic depression. The course of illness, presence of mood incongruent psychotic symptoms and thought disorder strongly suggest non-affective cause of the symptoms

Dementia - loss of interest and affect and be mistaken for depression. But note that depression is common in the early stages of dementia and conversely depression in the elderly can present with cognitive impairment (‘pseudodementia’)

Medical cause of depression such as hypothyroidism, Cushing’s or Addison’s disease or iatrogenic depression caused by medication such as beta blockers or gamma-interferon.

Box 3: Referral to specialist services

Refer to specialist care if:

• there is significant risk of harm to self or others,

• there has been failure to respond to treatment, usually at least two antidepressants and psychological treatment in primary care,

• there is the possibility or suspicion of bipolar disorder,

• there are complex problems or significant comorbidity (such as psychosis, psychiatric comorbidity or severe psychosocial difficulties)

Figure 1: NICE stepped care model(9)

[pic]

a Complex refers to inadequate response to multiple treatments/with psychosis/significant comorbidity or psychosocial factors

b For depression complicating a chronic physical illness (see text)

Box 4: Psychological treatments

Low-intensity (subthreshold and mild depression)

• guided self-help based on CBT principles

• computerised CBT

• structured group physical exercise.

High intensity (persistent milder depression, moderate to severe depression)

Individual therapy

• CBT (addressing negative thoughts and associated behavioural patterns)

• behavioural activation (addressing unrewarding behavioural patterns and withdrawal)

• interpersonal psychotherapy (addressing relationship and role difficulties)

Group therapy

• individual therapies delivered in a group settings

• couples therapy (focussing on partner interactions and conflicts)

• mindfulness-based cognitive therapy for relapse prevention (includes meditation techniques, bodily awareness and self-acceptance)

CBT: cognitive behaviour therapy

Box 5: Drug treatments

Antidepressants

• Selective serotonin reuptake inhibitors (SSRIs)

- citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

• Other newer antidepressants

- venlafaxine, duloxetine (serotonin and noradrenaline reuptake inhibitors)

- reboxetine (noradrenaline reuptake inhibitor) but efficacy questioned

- mirtazapine (serotonin and noradrenaline receptor antagonist)

- agomelatine (melatonin agonist and serotonin receptor antagonist)

• Older receptor antagonists

- mianserin, trazodone (serotonin and noradrenaline receptor antagonists)

• Tricyclic antidepressants (nonselective noradrenaline +/- serotonin reuptake inhibitors)

- amitriptyline, clomipramine, imipramine, lofepramine

• Monoamine oxidase inhibitors

- phenelzine, tranylcypromine (irreversible)

- moclobemide (irreversible inhibitor of monoamine oxidase A

Drugs used to augment antidepressants

• Lithium

• Atypical (second generation) antipsychotics

- quetiapine, olanzapine, risperidone

• Tri-iodothyronine

What’s new?

It is now recognised that antidepressants start to work immediately even although clinically significant improvement may only become apparent over a few weeks.

Citalopram and escitalopram prolong the QTc interval and should be used with caution in polypharmacy and in those with existing cardiac morbidity

Agomelatine is a new well tolerated antidepressant with agonism at melatonin receptors. Effects on the circadian rhythm may contribute to efficacy

Augmentation of SSRIs with the atypical antipsychotic quetiapine is now licensed for insufficient response to SSRIs alone

Mindfulness-based cognitive therapy is effective in preventing the relapse of depression

Practice points

Depression is frequently undiagnosed and undertreated; screen for depression in high risk groups including those with a chronic physical illness

Assessment must include determination of suicide risk, any history of elevated mood and current alcohol or substance misuse

Over-the-counter complementary and herbal treatments (e.g. St John’s wort) are commonly used and may interact with prescribed medication

Use a symptom rating scale such as the Patient Health Questionnaire, PHQ-9(13) or Hospital Anxiety and Depression Scale(14) to aid assessment of severity and monitor treatment progress

Psychosocial approaches should be used first in patients with mild depression

Treated patients should be assessed regularly for symptom severity, suicidality and adverse effects; at least every 2 weeks initially but more frequently in those with higher suicide risk

Drug treatment trials should usually be 6-8 weeks although a dose increase or change of treatment is indicated if there is no improvement after 4 weeks.

Combined drug and psychosocial treatment should be used in patients not responding to either alone

Combination drug treatments are useful when there has been partial response to the first drug or a failure to respond to a number of trials.

Relapse prevention is a priority following successful treatment.

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