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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 firstline 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 http://www.ic.nhs.uk/statistics-and-datacollections/mental-health/mental-health-surveys/adult-psychiatric-morbidity-in-england2007-results-of-a-household-survey
(5) National Institute for Health and Clinical Excellence. Clinical Guideline 91. Depression in
adults with a chronic health problem: full guideline. 2009
http://guidance.nice.org.uk/CG91/Guidance .
(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 http://guidance.nice.org.uk/CG90/Guidance
(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 [824-2011] 2011 http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm.
(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):799808.
(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.
3.
loss of interest or pleasure in almost all activities
significant appetite/weight loss or gain
4.
5.
6.
7.
insomnia or hypersomnia
psychomotor agitation or retardation (observable by others)
fatigue or loss of energy
feelings of worthlessness or excessive guilt
8.
9.
diminished concentration or indecisiveness
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)
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.