Recurrent depressive disorder: epidemiology, etiological theories, clinical features, course, and treatment

01Definition and overview

Recurrent depressive disorder is repeated depressive episodes, at least two, each lasting at least two weeks and separated by several months without significant mood disturbance, with no independent episodes of elevated mood. The illness is the same one DSM-5-TR calls major depressive disorder, recurrent.

The depressive episode is the unit of diagnosis. ICD-10 lists three typical symptoms and seven others, present for at least two weeks:

Mild and moderate episodes are coded with or without the somatic syndrome (melancholic features in DSM-5-TR), at least four of: loss of interest or pleasure in usually enjoyable activities, lack of emotional reactivity, waking two hours or more before the usual time, mood worse in the morning, observable psychomotor retardation or agitation, marked loss of appetite, weight loss of 5 per cent or more of body weight in a month, and marked loss of libido.

Dysthymia is at least two years of persistent low mood, too mild for even a mild recurrent depressive disorder; a depressive episode on top of it is double depression. ICD-11 calls it dysthymic disorder, DSM-5-TR persistent depressive disorder.

02Etiology and pathophysiology

Depression arises from vulnerability and stress acting together. Twin studies put the heritability at about 35 to 40 per cent, higher in recurrent and early-onset depression; first-degree relatives have a two- to threefold risk. Genome-wide studies find hundreds of common variants, each with a tiny effect, and no single gene of large effect; gene-by-stress findings for single variants such as the serotonin transporter promoter have not replicated.

1. 1

   Vulnerability

   Genes, early adversity and abuse, and an anxious, self-critical temperament (high neuroticism) lower the threshold.
2. 2

   Stress

   A loss, humiliation, illness or chronic difficulty, often in the preceding months, sets off a stress response and negative thinking.
3. 3

   Episode

   The stress hormone, monoamine, inflammatory and cognitive changes reinforce one another into a depressive episode.
4. 4

   Recurrence

   Each episode leaves more residual symptoms and a lower threshold, so later episodes need less provocation and come more often.

Other risks are female sex, the months after childbirth, chronic and painful physical illness (myocardial infarction, stroke, Parkinson disease, diabetes, cancer), alcohol and drugs, poverty and loneliness.

03Clinical features

Low mood is often described as flatness, emptiness or irritability rather than sadness, and anhedonia, the loss of pleasure and interest, is as central. The biological symptoms are early morning waking, mood worse in the morning, loss of appetite and weight, loss of libido, constipation and slowing. Patients feel guilty, worthless and hopeless, cannot concentrate or decide, and think of death. Most also meet the criteria for another disorder, most often an anxiety disorder or substance use.

Many present with physical symptoms (fatigue, pain, insomnia, weight loss), especially in primary care. Older patients may present with agitation, hypochondriasis or a cognitive decline that lifts with treatment (depressive pseudodementia). Atypical features are the reverse of the biological ones: reactive mood, oversleeping, overeating, heavy limbs and sensitivity to rejection; a seasonal pattern recurs each autumn and winter.

In psychotic depression, delusions usually match the mood: guilt, deserved punishment, poverty, disease, or nihilism (that the body is rotting or the patient is dead). Hallucinations are mostly second-person accusing or derogatory voices, or smells of rotting. Depressive stupor, or refusal to eat and drink, is life-threatening.

04Diagnosis and management

Screening and assessment

Two questions screen for depression: in the past month, have you often felt down, depressed or hopeless, or had little interest or pleasure in doing things? A yes leads to a full assessment, and the PHQ-9, nine questions scored 0 to 3 each, measures severity:

In the UK, depression is grouped since 2022 as less severe (PHQ-9 below 16) or more severe (16 or more). Its ninth item asks about thoughts of death or self-harm and is always followed up. The HADS suits physical illness, the Edinburgh scale the time after childbirth and the Geriatric Depression Scale older people.

The assessment covers past episodes and past highs: a week or more of elation or irritability with little need for sleep, overspending or overactivity, a family history of bipolar disorder or suicide, alcohol and drugs, medication and physical illness, the social situation, and risk. Blood tests look for treatable causes: full blood count, renal and liver function, thyroid function, glucose or HbA1c, calcium, and B12 and folate where suggested; brain imaging is done when the onset is late with cognitive decline or neurological signs.

Depression with heavy drinking often lifts within weeks of stopping, so alcohol is addressed first where it can be.

Stepped care

The choice is shared with the patient and progress measured, for example with the PHQ-9. Individual CBT is about as effective as an antidepressant in mild to moderate depression and protects better against relapse once treatment ends; in more severe depression the combination beats either alone.

Antidepressants

All antidepressants work better than placebo, with modest differences between them in efficacy and larger ones in side effects, so the choice turns on safety, side effects, previous response and the patient's preference. They are described in antidepressants.

• Benefit starts within one to two weeks and builds over four to six. In UK guidance, people aged 18 to 25 and anyone at raised risk of suicide are reviewed a week after starting, others within two weeks.
• With no improvement at all after about four weeks at an adequate dose, the dose is raised or the drug changed.
• Patients are told about early side effects, that antidepressants are not addictive, and that stopping suddenly causes discontinuation symptoms; small quantities are prescribed when the suicide risk is high.

The psychological therapies are covered in psychotherapy.

Psychotic depression

Psychotic depression is treated with an antidepressant combined with an antipsychotic, which works better than either alone, or with electroconvulsive therapy, which is the treatment of choice when life is at risk from stupor, refusal to eat or drink, or suicidal intent, and helps most such patients. Bipolar disorder is looked for.

Treatment-resistant depression

Depression that has not responded to two adequate trials of antidepressants in the current episode is called treatment-resistant. In a large American trial of outpatients, about a third remitted on the first antidepressant, and fewer with each further step of switching, combining and augmenting.

1. 1

   Review

   The diagnosis (bipolar disorder, organic illness, alcohol, personality), adherence, dose and duration, and what keeps the depression going: debt, a relationship, pain. Psychological therapy is added if not yet tried.
2. 2

   Switch or combine

   A higher dose, a switch to another antidepressant of the same or another class, or mirtazapine added to an SSRI or SNRI.
3. 3

   Augment

   With lithium, with monitoring of its level and of kidney and thyroid function, which also lowers suicide risk; or a second-generation antipsychotic, aripiprazole or quetiapine. Liothyronine is an alternative.
4. 4

   Esketamine

   A nasal spray of esketamine, an NMDA receptor antagonist, given with an SSRI or SNRI under supervision in a clinic, twice weekly at first.
5. 5

   Physical treatments

   ECT for severe or life-threatening depression; repetitive transcranial magnetic stimulation where it is available.

How long to treat

• After a single episode, the antidepressant is continued at the dose that worked for at least six months after remission, then tapered over weeks.
• With a raised risk of relapse (several episodes, above all in recent years, residual symptoms, a severe or psychotic episode, a suicide attempt, a chronic course), it is continued for at least a year, and for at least two years, often longer, at the highest risk, decided with the patient and reviewed at least every six months.
• Stopping early more than doubles the relapse rate: in trials, about four in ten of those switched to placebo relapsed, against under two in ten who continued.
• Mindfulness-based cognitive therapy or CBT protects people in remission who have had several episodes, with or without medication.

Suicide risk

Suicidal thoughts are asked about directly at every contact; asking does not plant the idea. Hopelessness, a plan, access to means, previous attempts, psychotic symptoms, alcohol, male sex, living alone and recent loss raise the risk. The risk is highest early in treatment, when energy returns before mood, and in the weeks after discharge from hospital. A safety plan, a named contact, involvement of the family, limited quantities of medication and, where the risk is high, crisis team care or admission follow. The assessment is covered in suicidal and aggressive behaviour.

05Epidemiology

with depression worldwide in 2023

322 millionpeoplewith depression worldwide in 2023

at any time, 6.2 per cent of women and 4.1 per cent of men

5.2per cent of adultsat any time, 6.2 per cent of women and 4.1 per cent of men

have a depressive episode at some time in life, by most estimates

10 to 20per cent of adultshave a depressive episode at some time in life, by most estimates

Depression is one of the leading causes of disability in the world and in Europe. It can start at any age, most often from the late teens to the forties. It is commoner in the separated and divorced, the unemployed, people with alcohol problems and those with chronic physical illness, where it worsens the outcome of heart disease and diabetes. Around one in ten mothers has depression in the year after childbirth.

06Prognosis

Most episodes resolve: untreated, mild and moderate episodes last from weeks to about six months and severe ones longer; with treatment most patients recover within a year. About one in five develops a chronic course, with symptoms for two years or more. Recurrence is the rule in patients treated by specialists: by the classic estimates, about half have another episode after a first, about seven in ten after a second, and about nine in ten after a third, and the intervals shorten as episodes accumulate. In the community recurrence is lower, about a third within 15 years. Over 12 to 18 years, about one in five of those first diagnosed with depression turn out to have bipolar disorder, most within five years, more often with early onset, psychotic features or a family history of bipolar disorder.

Overall mortality is about one and a half to two times that of the general population, through suicide, accidents, substance misuse and cardiovascular disease. Over a lifetime, about 2 per cent of people treated for a mood disorder in mixed outpatient and inpatient samples die by suicide, about 4 per cent of those once admitted to hospital and about 9 per cent of those admitted for suicidal behaviour, against under 0.5 per cent of others. Follow-up watches for early signs of recurrence, residual symptoms, side effects, adherence, suicide risk and any emerging hypomania.