Differential diagnosis and physical-health screening

01Purpose and principlesWhat the assessment is for and the core concepts behind it.

Unipolar depression is a longitudinal diagnosis. Ask about every previous episode and recovery, not only the current low mood. A period of elevated or irritable mood with reduced need for sleep, increased activity, talkativeness, grandiosity or risky behaviour raises bipolarity. Clarify duration, impairment, substance relationship and whether antidepressants preceded activation. Family history supports probability but cannot decide the diagnosis. Refer when bipolar disorder remains plausible rather than escalating antidepressant monotherapy automatically.

Psychiatric differentials overlap. Grief may bring waves tied to reminders and preserved positive emotion, although depression can coexist. Adjustment disorder remains related to an identifiable stressor without the full depressive pattern. Generalised anxiety, panic and PTSD can produce insomnia, fatigue and concentration difficulty but have distinct worry, panic, intrusion, avoidance or hyperarousal mechanisms. Negative symptoms, early psychosis, eating disorders, ADHD, autism and personality-related crises require developmental and longitudinal evidence rather than labels based on one presentation.

Physical causes are selected from phenotype. Hypothyroidism, anaemia, B12 or folate deficiency, hypercalcaemia, renal or liver disease, infection, neurological disease, sleep apnoea, chronic pain and malignancy may cause or compound symptoms. Examine thyroid, cardiovascular, respiratory, neurological and nutritional systems as indicated. New cognitive change requires delirium and dementia assessment. Pregnancy and postpartum timing changes risk, differential and prescribing. Reproductive testing requires explanation and consent.

Medicines and substances matter. Corticosteroids can alter mood; sedating, anticholinergic or dopamine-active medicines can affect energy and cognition. Alcohol may temporarily reduce distress while worsening sleep, mood and suicide risk; stimulant withdrawal can cause marked dysphoria. Ask dose, pattern, last use and withdrawal rather than recording recreational drugs yes or no. Do not infer causation from one positive urine screen, and avoid abrupt cessation of dependence-forming medicines without a safe plan.

Investigations should answer questions. FBC, U&E, eGFR, liver tests, calcium, glucose or HbA1c, TSH, B12 and folate are common choices when history supports them or before particular treatment. Add pregnancy testing, infection tests, inflammatory markers, ECG, sleep study or neuroimaging for relevant clues. A universal panel can generate incidental findings without excluding major differentials. Document the question, limitation and who will review each result.

Key points

Build a dated timeline of mood, biological change, function, prior episodes, activation, medical illness, reproductive events, medicines and substances.
Screen lifetime mania and hypomania before antidepressant treatment; ask about reduced sleep need, increased activity, pressured speech, confidence, irritability and risky behaviour.
Differentiate grief, adjustment disorder, anxiety, PTSD, psychotic disorders, eating disorders, neurodevelopmental conditions and personality-related difficulties by dominant pattern and course.
Review alcohol, cannabis, stimulants, opioids, sedatives and withdrawal, plus corticosteroids, interferons, hormonal treatments and other relevant medicines.
Perform physical and neurological examination when symptoms, age, onset or treatment require it, including observations, weight and targeted endocrine or movement signs.
Choose FBC, renal and liver profiles, glucose, calcium, thyroid, B12, folate, pregnancy, infection or other tests from a stated clinical question.
Assess sleep apnoea, restless legs, chronic pain, inflammatory disease and social deprivation when fatigue and sleep disturbance dominate.
Use ECG when cardiac symptoms, overdose, electrolyte risk or a QT-prolonging medicine such as citalopram makes the result relevant.
Explain what normal tests do and do not exclude and reopen the differential when course or treatment response is discordant.

02Indications, selection and cautionsWhen it is useful, when urgency changes and important limitations.

Bipolar course

Distinct activation with reduced sleep need and increased energy, activity or risk-taking separates possible bipolar illness from ordinary mood reactivity.

Grief pattern

Distress may fluctuate around reminders and retain connection or positive emotion, while pervasive anhedonia and worthlessness suggest coexisting depression.

Endocrine or metabolic clue

Systemic symptoms, physical signs, medicine exposure or atypical onset support targeted thyroid, calcium, glucose, organ-function or nutritional testing.

Sleep disorder

Snoring, witnessed apnoeas, morning headache, restless legs or profound daytime sleepiness may explain fatigue and cognitive symptoms beyond depression.

Neurological syndrome

Focal signs, seizure, parkinsonism, altered arousal or rapid cognitive change requires neurological assessment rather than a purely affective formulation.

Red flags requiring action

A history of mania or hypomania, antidepressant activation or episodic reduced sleep need suggests bipolar depression and changes treatment risk.
Abrupt late onset, cognitive fluctuation, new seizure, focal deficit, movement disorder or rapidly progressive personality change requires neurological investigation.
Weight change, tremor, temperature intolerance, menstrual disturbance, constipation, anaemia symptoms or steroid exposure can signal endocrine, metabolic or medicine contributors.
Postpartum psychosis, severe perinatal depression or thoughts of harming the baby requires urgent specialist perinatal assessment and safeguarding support.
Routine normal blood tests do not exclude sleep apnoea, epilepsy, Parkinson disease, substance effects, trauma or bipolar disorder.

03Method and interpretationA systematic approach to the test and its findings.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Longitudinal mood and activation historyFirst step
Why
Distinguish unipolar, bipolar, substance-related and adjustment courses before treatment selection.
Interpretation and limitations
Use collateral evidence where possible. One energetic day is not hypomania, while sustained reduced sleep need with change in function is important.
02
Physical and neurological examination
Why
Identify endocrine, cardiovascular, neurological, nutritional, infection and medicine-related signs.
Interpretation and limitations
Target examination to symptoms and onset and repeat after intoxication or distress when the first assessment is limited.
03
History-led blood tests
Why
Assess anaemia, renal, liver, thyroid, calcium, glucose and nutritional contributors and prescribing safety.
Interpretation and limitations
Select and interpret tests in context. Normal results cannot exclude bipolar disorder, sleep apnoea, epilepsy or psychosocial causes.
04
Pregnancy and reproductive assessment
Why
Identify perinatal risk and information that materially alters investigation and treatment choices.
Interpretation and limitations
Seek consent, discuss results sensitively and use urgent specialist pathways for postpartum psychosis or severe perinatal danger.
05
ECG and targeted advanced testing
Why
Assess cardiac risk, overdose, sleep-disordered breathing or structural and neurological disease when indicated.
Interpretation and limitations
Use ECG, sleep study, imaging or specialist tests for a defined question; a normal initial result may not end an evolving neurological work-up.

04Clinical next stepsHow the result changes management or prompts escalation.

01Initial differentialUse course before testsFirst stepA depressive syndrome is suspected or treatment has not yet begun.

1Establish chronology, previous activation, grief or trauma context, substances, medicines, physical symptoms and reproductive timing.
2Perform mental-state, suicide, functional and indicated physical or neurological assessment and obtain collateral baseline evidence.
3Rank unipolar, bipolar, psychiatric, medical and substance explanations and choose tests that could change management.

02Targeted work-upAsk a question with every investigationHistory or examination suggests a physical contributor or treatment requires baseline information.

1Specify the suspected condition and select proportionate blood, ECG, pregnancy, sleep, imaging or specialist investigations.
2Explain purpose and limitation, obtain consent and assign responsibility for acting on every result.
3Integrate findings with chronology and function and avoid declaring symptoms psychological solely because common tests are normal.

03Discordant courseReopen the diagnosisSymptoms progress atypically, new signs emerge or adequate treatment produces an unexpected response.

1Repeat activation, substance, medicine and medical history and review adherence, dose, duration and psychosocial delivery barriers.
2Re-examine neurological, cognitive, endocrine, sleep and reproductive clues and obtain specialist advice where needed.
3Explain revised uncertainty, amend treatment safely and document what evidence will confirm or refute the new hypotheses.

05Risks, monitoring and follow-upComplications, safety checks and further assessment.

Review all requested results with an assigned clinician and communicate abnormalities and limitations rather than treating completion as interpretation.
Reassess bipolar features after activation, reduced sleep need, unusual early treatment agitation or recurrent episodic course.
Track alcohol, substances, sleep, pain, physical illness and medicine changes alongside mood to identify temporal relationships without assuming causation.
Repeat physical or neurological assessment after new focal signs, cognitive fluctuation, seizure or rapid progression.
Update the formulation when a physical contributor is treated; improvement can be partial because medical and depressive disorders often coexist.

06Special situationsVariants, exceptions and circumstances that change the usual approach.

Bipolar history is prospective safety

Identifying previous activation changes antidepressant decisions and can prevent treatment-emergent mood destabilisation or delayed mood-stabilising care.

One cause rarely owns fatigue

Sleep apnoea, pain, anaemia, inactivity, poverty and depression can coexist, making treatment of one factor an incomplete diagnostic experiment.

Normal screening has boundaries

Routine bloods do not test grief, bipolarity, PTSD, sleep apnoea, epilepsy or structural disease without the appropriate clinical method.

Medication timing informs

Symptoms beginning after initiation, dose escalation or withdrawal increase suspicion but still require assessment of alternative and interacting causes.

Postpartum urgency differs

Confusion, insomnia, activation or psychosis after childbirth can progress rapidly and demands specialist assessment beyond routine depression follow-up.

07Common pitfallsFrequent interpretation and management errors.

01
Starting antidepressant treatment without asking about previous mania or hypomania.
02
Ordering a universal blood panel and calling depression excluded when results are normal.
03
Attributing fatigue to mood without assessing sleep, pain, medicines and physical disease.
04
Diagnosing substance-induced symptoms from a urine result without timing or clinical correlation.
05
Pathologising ordinary grief while missing a coexisting pervasive depressive syndrome.
06
Ignoring postpartum timing, safeguarding and risk to the baby.
07
Leaving incidental or abnormal results without a named reviewer and communication plan.