Low mood and persistent sadness

Low mood and persistent sadness is a sustained depressed mood, loss of interest or pleasure (anhedonia), or both, with associated cognitive, somatic and behavioural change.

Definition of major depressive episode. Five or more of the following for at least 2 weeks, including depressed mood or anhedonia: depressed mood, anhedonia, change in appetite or weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, worthlessness or guilt, poor concentration or indecision, and recurrent thoughts of death or suicidal ideation.

Symptoms cause distress or impairment and are not caused by a substance or medical condition.

Classification. Major depressive disorder (single or recurrent), persistent depressive disorder (2 years or more of depressed mood), bipolar depression, adjustment disorder, perinatal depression, seasonal pattern, premenstrual dysphoric disorder.

Also: depression with psychotic features, melancholic features, atypical features, catatonia, and depressive disorder due to a medical condition or substance.

Severity. The Patient Health Questionnaire (PHQ-9) scores 0 to 27: 0 to 4 minimal, 5 to 9 mild, 10 to 14 moderate, 15 to 19 moderately severe, 20 to 27 severe. A cut off of 10 or more indicates probable major depression (high sensitivity and specificity).

Item 9 asks about thoughts of death or self harm and needs direct follow up whatever the total.

Neurobiology. Altered monoamine signalling, stress axis activation with raised cortisol, reduced hippocampal volume, inflammation and altered neuroplasticity, with genetic and environmental vulnerability.

Key distinctions. Anhedonia and loss of energy over weeks suggest major depression. Grief is typically waves of sadness centred on loss with preserved self worth, though a major depressive episode can coexist. Elevated, irritable or expansive episodes in the past mean bipolar disorder until proven otherwise.

History

• Mood symptoms, onset, duration, severity and course, anhedonia, hopelessness, guilt, worthlessness, slowing, agitation, sleep, appetite and weight, libido, concentration and energy.
• Suicide risk: ideation (passive or active), plan, intent, access to means, previous attempts and self harm, recent loss or stress, impulsivity, hopelessness, alcohol, firearms, medicines at home, and protective factors (family, children, faith, future plans).
• Screening for mania or hypomania: periods of elevated or irritable mood, reduced need for sleep, racing thoughts, increased activity or spending, with family history of bipolar disorder.
• Psychosis: hallucinations, delusions of guilt, poverty or nihilism.
• Anxiety, panic, obsessions, trauma, eating disorder symptoms and attention problems.
• Alcohol, drugs and tobacco (use, withdrawal), screened with AUDIT-C.
• Past psychiatric history, treatments and response, adverse effects, family history of depression, suicide and bipolar disorder.
• Medical history: thyroid disease, diabetes, cardiovascular disease, stroke, Parkinson disease, epilepsy, cancer, chronic pain, HIV, sleep apnoea, chronic kidney disease, anaemia, pregnancy and postpartum status, menopause and hormonal symptoms.
• Drugs: corticosteroids, interferon, isotretinoin, levetiracetam, other antiepileptics, efavirenz, mefloquine, beta blockers (evidence weak), antihypertensives such as methyldopa and reserpine, hormonal contraceptives (evidence limited), benzodiazepines, opioids, finasteride, montelukast and checkpoint inhibitors.
• Psychosocial: bereavement, relationship, work, financial stress, housing, abuse, isolation and caring duties.
• Functioning, occupation, driving and responsibilities for dependants.

Examination

• General appearance, grooming, weight, vital signs, psychomotor change, speech rate and volume, eye contact, affect, thought content, perception, orientation and cognition (cognitive screen in older adults), insight and judgement.
• Physical: thyroid, cardiovascular, neurological examination (tremor, rigidity, focal signs), signs of anaemia, signs of Cushing and Addison disease, signs of alcohol use, injection marks and self harm scars.
• Bedside tests: PHQ-9, glucose, pregnancy test, and cognitive tests (clock drawing, orientation) in older adults.

Red flags

• Active suicidal ideation with plan or intent, recent attempt, access to means, or command hallucinations.
• Psychotic features, catatonia (mutism, posturing, refusal of food and fluids), or stupor.
• Past or current mania or hypomania.
• Severe self neglect, refusal of food or fluids, or dehydration.
• Thoughts of harming others, including children (infanticide risk in postpartum psychosis).
• Postpartum onset with confusion, rapid mood swings or delusions.
• Delirium or new cognitive decline, particularly in older adults.
• First episode after age 50 years, abrupt onset, or focal neurological signs.
• Severe alcohol or drug dependence, or recent serious physical illness.
• Rapid weight loss.
• Adolescent or young adult with new antidepressant start (higher risk of emergent suicidality).

Special groups

• Pregnancy and postpartum: screen for perinatal depression and bipolar disorder, assess infant safety and bonding.
• Children and adolescents: irritability may replace sadness, with school refusal and somatic complaints.
• Older adults: apathy, cognitive complaints, somatic symptoms and polypharmacy, and differentiate from dementia.
• Chronic illness: depression worsens outcomes and adherence.
• Region specific: stigma, somatic presentation, traditional healers, HIV related depression, and violence or conflict related trauma.

Primary mood and related disorders

• Major depressive disorder (single or recurrent).
• Persistent depressive disorder.
• Bipolar I and II disorder (depressive episode).
• Cyclothymic disorder.
• Adjustment disorder with depressed mood.
• Normal grief and prolonged grief disorder.
• Perinatal depression and postpartum psychosis.
• Seasonal affective disorder.
• Premenstrual dysphoric disorder.
• Depression with psychotic features and psychotic depression.
• Catatonia.
• Dysthymia with double depression.
• Disruptive mood dysregulation disorder (children).

Other psychiatric conditions

• Generalised anxiety disorder, panic disorder, social anxiety and obsessive compulsive disorder.
• Posttraumatic stress disorder.
• Schizophrenia and schizoaffective disorder (negative symptoms).
• Eating disorders.
• Personality disorders (borderline).
• Attention deficit hyperactivity disorder.
• Substance use disorders and withdrawal (alcohol, benzodiazepines, stimulants, cannabis, opioids).
• Insomnia disorder and sleep apnoea.
• Somatic symptom and illness anxiety disorders.

Medical causes

• Hypothyroidism and hyperthyroidism.
• Anaemia and iron deficiency.
• Vitamin B12, folate and vitamin D deficiency.
• Diabetes mellitus.
• Cushing syndrome and Addison disease.
• Hyperparathyroidism and hypercalcaemia.
• Hypogonadism and menopause.
• Chronic kidney and liver disease.
• Sleep apnoea.
• Heart failure and chronic obstructive pulmonary disease.
• HIV infection and neurosyphilis.
• Stroke, Parkinson disease, multiple sclerosis, epilepsy, traumatic brain injury and brain tumour.
• Dementia and delirium (hypoactive).
• Systemic lupus erythematosus.
• Cancer (pancreatic cancer) and paraneoplastic syndromes.
• Chronic pain, fibromyalgia and chronic fatigue syndrome.
• Post viral illness including post COVID.
• Infectious mononucleosis.

Drug induced

• Corticosteroids, interferon alpha, isotretinoin, levetiracetam, efavirenz, mefloquine, hormonal agents, beta blockers (weak evidence), benzodiazepines, opioids, alcohol, stimulant withdrawal, and finasteride.

Step 1. Risk assessment first. Assess suicide and self harm risk, risk to others, capacity and safety in every patient. Document ideation, plan, intent, means, protective factors and level of risk (low, moderate, high). Use a structured tool (for example the Columbia Suicide Severity Rating Scale) as an adjunct. Risk scales do not predict suicide and are not a substitute for clinical judgement.

Step 2. Make the psychiatric diagnosis. Use diagnostic criteria for a major depressive episode. Measure severity with the PHQ-9 and repeat at each visit (a 5 point fall is a clinically meaningful change, and a 50% fall is a treatment response). Screen for bipolar disorder with direct questions or the Mood Disorder Questionnaire, and for anxiety (GAD-7), alcohol (AUDIT-C), trauma and psychosis. Ask about grief and recent loss.

In older adults use the Geriatric Depression Scale and a cognitive test. In the perinatal period use the Edinburgh Postnatal Depression Scale (score of 13 or over suggests depression). Step 3. First line tests to exclude medical causes

• Full blood count, urea, creatinine, electrolytes (sodium), liver tests, calcium, glucose or HbA1c, thyroid stimulating hormone, vitamin B12 and folate, and ferritin.
• HIV test and syphilis serology when risk exists.
• Urine or serum drug screen when substance use is suspected.
• Pregnancy test in women of reproductive age.
• ECG before starting citalopram, escitalopram, tricyclic antidepressants or when there is cardiac disease or QT risk.
• Vitamin D, morning cortisol, testosterone, calcium and parathyroid hormone, and sleep studies directed by symptoms and signs (evidence for routine testing is limited).
• Cognitive assessment and neuroimaging (CT or MRI) for first episode after age 50 years, focal signs, cognitive decline, abrupt change, or atypical features.
• Electroencephalogram when seizures or delirium are suspected.

Step 4. Interpretation. Abnormal thyroid function should be corrected before attributing symptoms to primary depression, though depression often persists and still needs treatment. Mild anaemia and subclinical thyroid disease seldom explain moderate to severe depression. Test results do not replace psychiatric diagnosis.

Limits. Screening questionnaires do not make the diagnosis. Overlap with grief, medical illness, demoralisation and dementia is common, and bipolar disorder can be missed on first presentation. Collateral history improves accuracy.

Immediate safety. For active suicidal ideation with plan or intent, do not leave the patient alone, remove access to means, and arrange same day specialist mental health assessment, with emergency department or inpatient admission when risk is high. Use statutory powers when a patient with capacity limitation refuses necessary care.

For catatonia, give lorazepam 1 to 2 mg intravenously or intramuscularly (challenge test with response in 5 to 10 minutes, repeat up to every 3 to 8 hours as needed) with urgent specialist care. For psychotic depression, severe depression with food refusal or high suicide risk, electroconvulsive therapy is an effective option.

Safety plan. Write a safety plan with warning signs, coping strategies, contacts, emergency numbers, and removal or restriction of means (medicines, firearms, pesticides). Limit quantities of medicines supplied. Arrange follow up within 1 week of a crisis.

Psychological treatment. All patients benefit from psychoeducation, sleep hygiene, physical activity, and regular structured activity.

Cognitive behavioural therapy, behavioural activation, interpersonal therapy and problem solving therapy are effective in mild to moderate disease (equal efficacy to antidepressants in mild to moderate depression). Combine them with antidepressants in moderate to severe disease.

Pharmacological treatment (moderate to severe depression, or mild with history, persistent symptoms or patient preference).

• Sertraline 50 mg orally once daily (25 mg for the first week if anxious or older), increased in steps of 25 to 50 mg every 1 to 2 weeks to a usual 50 to 200 mg daily, maximum 200 mg daily. Adjust in severe hepatic impairment (lower dose, less frequent).
• Sertraline is first line, with fewer interactions, and preferred in cardiac disease, pregnancy and breastfeeding.
• Escitalopram 10 mg orally once daily (5 mg for 1 week if anxious), maximum 20 mg daily (maximum 10 mg daily in people over 65 years and in hepatic impairment). Monitor QT interval.
• Citalopram 20 mg orally once daily, maximum 40 mg daily (20 mg daily over 65 years, in hepatic impairment and with CYP2C19 inhibitors) with QT monitoring.
• Fluoxetine 20 mg orally once daily in the morning, maximum 60 mg daily (80 mg in some settings). Long half life reduces discontinuation symptoms. It is a strong CYP2D6 inhibitor (interacts with tamoxifen, codeine, metoprolol and tricyclics).
• Mirtazapine 15 mg orally at night, increased after 1 to 2 weeks to 30 mg, maximum 45 mg daily. Helpful when insomnia, anorexia or weight loss predominate, with weight gain and sedation as risks. Monitor blood count for agranulocytosis symptoms (sore throat, fever).
• Venlafaxine modified release 75 mg orally once daily with food, increased after 2 to 4 weeks to 150 mg and up to 225 mg daily (375 mg immediate release in severe depression under specialist care). Monitor blood pressure, reduce the dose in kidney and hepatic impairment, and taper slowly.
• Duloxetine 30 mg once daily for 1 week then 60 mg once daily, maximum 120 mg daily (avoid at creatinine clearance under 30 mL/min and in hepatic impairment). Helpful in painful physical symptoms.
• Bupropion extended release 150 mg once daily, increased after 1 to 2 weeks to 300 mg daily, maximum 450 mg daily. Contraindicated in seizure disorders, eating disorders and alcohol or benzodiazepine withdrawal. Reduce the dose in hepatic and kidney impairment.
• Vortioxetine 10 mg orally once daily (5 mg for some), maximum 20 mg daily.
• Avoid tricyclic antidepressants (dangerous in overdose, with cardiac conduction effects and anticholinergic effects) as first line.
• Monoamine oxidase inhibitors: specialist use only, with strict washout of 2 weeks (5 weeks after fluoxetine).

Cautions with antidepressants

• Serotonin syndrome with combinations of serotonergic drugs (linezolid, tramadol, triptans, methylene blue, lithium, St John wort, other antidepressants, monoamine oxidase inhibitors).
• Bleeding risk with SSRIs and NSAIDs, aspirin or anticoagulants (give a proton pump inhibitor).
• Hyponatraemia, especially older adults (check sodium at 2 weeks).
• QT prolongation (citalopram, escitalopram).
• Sexual dysfunction and weight changes.
• Early activation, anxiety, and increased suicidality in people under 25 years in the first month, requiring weekly review.
• Switch to mania in bipolar disorder, so avoid antidepressant monotherapy when bipolar disorder is suspected.
• Discontinuation symptoms (dizziness, paraesthesia, irritability, flu-like symptoms) after missed doses or abrupt stop. Taper over at least 4 weeks.
• Overdose: citalopram (QT), venlafaxine (seizures, arrhythmia) and tricyclics are particularly dangerous, so limit supply.

Response and duration. Review at 1 to 2 weeks for tolerability and risk, and at 4 to 6 weeks for response. When improvement is under 20% at 2 to 4 weeks at an adequate dose, increase the dose or switch.

If no response after 4 to 6 weeks at the maximum tolerated dose, switch to another class or augment. Continue treatment for at least 6 months after remission (12 months or longer is common), and for 2 years or longer after 2 or more episodes with functional impairment. Taper over 4 or more weeks, and monitor for relapse.

Treatment resistant or severe depression (specialist)

• Augmentation with lithium (400 mg at night, titrated to a serum level of 0.4 to 0.8 mmol/L at 12 hours after dose, with kidney and thyroid monitoring), quetiapine extended release 150 to 300 mg at night, aripiprazole 2 to 5 mg daily, or add mirtazapine.
• Esketamine nasal spray for treatment resistant depression in specialist units, intravenous ketamine, repetitive transcranial magnetic stimulation and electroconvulsive therapy.
• Psychotic depression: antidepressant plus antipsychotic (for example sertraline with olanzapine 5 to 10 mg at night, or quetiapine) or electroconvulsive therapy.

Bipolar depression. Avoid antidepressant monotherapy.

Quetiapine 50 mg at night on day 1, 100 mg day 2, 200 mg day 3, and 300 mg from day 4 (maximum 600 mg daily; monitor weight, glucose, lipids and QT). Alternatively use lurasidone 20 to 60 mg daily with food (maximum 120 mg).

Another option is lamotrigine titrated slowly (25 mg daily for 2 weeks, 50 mg daily for 2 weeks, 100 mg daily for 1 week, then 200 mg daily). Halve the schedule with valproate and double with carbamazepine. Stop and review for any rash because of Stevens-Johnson syndrome risk.

Special populations

• Pregnancy and breastfeeding: sertraline is the first choice (compatible with breastfeeding), and fluoxetine and citalopram are alternatives. Avoid paroxetine in pregnancy (cardiac malformation risk, with evidence being mixed). Do not stop treatment abruptly. For postpartum psychosis or severe depression, urgent specialist admission, ideally to a mother and baby unit.
• Adolescents (12 to 17 years): psychological therapy first. Fluoxetine 10 mg daily for 1 week then 20 mg daily (maximum 60 mg) as the first drug when needed (from age 8 years in some settings), with weekly review for the first 4 weeks.
• Older adults: sertraline 25 mg daily increasing to 50 to 100 mg, or mirtazapine 7.5 to 15 mg at night. Avoid tricyclic antidepressants and monitor sodium and falls risk. Treat reversible causes.
• Medical illness: treat coexisting conditions and consider collaborative care.
• Kidney and liver impairment: start low and titrate slowly.

Monitoring. Measure PHQ-9 at each visit, review suicidality, adherence, adverse effects, sleep, weight, blood pressure (venlafaxine), sodium (older adults), QT (citalopram and escitalopram), and lithium levels, kidney and thyroid function.

Referral and escalation. Psychiatry the same day for active suicidal ideation, psychosis, catatonia, mania and postpartum psychosis. Routine psychiatry referral for diagnostic uncertainty, bipolar disorder, treatment resistance, severe or recurrent disease, perinatal disease, and complex comorbidity.

Psychological therapy services, social work, substance misuse services and primary care follow up.

Admission criteria. Imminent risk of suicide or harm to others, psychosis, catatonia, severe self neglect, refusal of food or fluids, and failure of community support.

Discharge and follow up. Review within 1 to 2 weeks after starting treatment, then every 2 to 4 weeks until improved, then at intervals. Safety net advice: return or call urgently for worsening mood, agitation, thoughts of self harm or suicide, new elevated mood, severe side effects, or inability to function.