Endocrine Metabolic

Study Notes

SECTION 1: THYROID DISORDERS & PSYCHIATRY

1.1 Thyroid Hormone Physiology: Psychiatric Relevance

The hypothalamic-pituitary-thyroid (HPT) axis is one of the most psychiatrically relevant neuroendocrine systems. Thyroid hormones (T3, triiodothyronine; T4, thyroxine) exert broad effects on neuronal function, monoamine metabolism, synaptic transmission, and brain development.

Key mechanisms:

• T3 is the biologically active form; T4 is converted peripherally (and in the brain) by deiodinases
• T3 regulates serotonin receptor density, norepinephrine turnover, and beta-adrenergic receptor sensitivity
• Hypothyroid states reduce brain serotonergic and adrenergic tone
• Hyperthyroid states amplify sympathetic and adrenergic activity

Normal ranges (for reference):

1.2 Hypothyroidism & Psychiatric Manifestations

Epidemiology:

• Prevalence: 4–10% in women, 0.5–2% in men
• Subclinical hypothyroidism (elevated TSH, normal T4): up to 10% prevalence
• Autoimmune (Hashimoto's thyroiditis) is the most common cause in iodine-sufficient regions

Psychiatric Manifestations, Spectrum:

Depression in Hypothyroidism:

• 40–60% of hypothyroid patients have depressive symptoms
• Presentation overlaps heavily with MDD: low mood, anhedonia, fatigue, psychomotor retardation, weight gain, cold intolerance
• Key distinguishing features: dry skin, hair loss, hoarse voice, constipation, bradycardia, delayed ankle reflexes
• Subclinical hypothyroidism is associated with increased prevalence of depression (especially in women)
• Mechanism: reduced serotonergic neurotransmission, reduced beta-adrenergic sensitivity, decreased NA synthesis
• CRITICAL POINT: Depression in hypothyroidism often does NOT respond to antidepressants alone, thyroid replacement is needed

Cognitive Impairment in Hypothyroidism:

• Ranges from mild forgetfulness to dementia-like syndrome
• Domains affected: attention, processing speed, working memory, verbal fluency
• In elderly: can mimic dementia (reversible on treatment), always screen TSH in new-onset cognitive complaints
• Children: congenital hypothyroidism (cretinism), irreversible intellectual disability if untreated before 3 months
• Mechanism: reduced cerebral glucose metabolism, altered synaptic plasticity, decreased neurogenesis in hippocampus

Myxedema Madness:

• Rare but classic, psychiatric manifestation of severe/prolonged hypothyroidism
• First described by Asher (1949)
• Presents as: paranoid psychosis, visual/auditory hallucinations, delirium, mania
• Context: severe myxedema (periorbital puffiness, macroglossia, non-pitting edema, hypothermia)
• TSH typically very high; T4 very low
• Treatment: thyroid hormone replacement (IV T4 in myxedema coma); antipsychotics if needed briefly
• Distinguishing from primary psychosis: marked physical signs, onset in context of severe systemic illness

Hashimoto's Encephalopathy:

• Rare autoimmune encephalopathy associated with Hashimoto's thyroiditis
• NOT directly caused by thyroid hormone levels (can occur even with euthyroid state)
• Mediated by anti-TPO antibodies (anti-thyroid peroxidase) and possibly anti-NMDA mechanisms
• Presents: acute/subacute encephalopathy, psychosis, stroke-like episodes, seizures, tremor
• Diagnosis: elevated anti-TPO antibodies, CSF abnormalities, EEG changes
• Steroid-responsive, classic feature
• Key exam point: "steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT)"

1.3 Hyperthyroidism & Psychiatric Manifestations

Causes: Graves' disease (most common), toxic multinodular goitre, toxic adenoma, thyroiditis, exogenous T4

Psychiatric Manifestations:

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Anxiety in Hyperthyroidism:

• Can perfectly mimic panic disorder or GAD
• Key: physical symptoms of hyperthyroidism present (tachycardia, tremor, heat intolerance, weight loss despite appetite)
• Always check TFTs when anxiety presents with physical symptoms
• Mechanism: elevated beta-adrenergic activity, sensitization of central noradrenergic circuits

Mania and Hyperthyroidism:

• "Thyrotoxic mania", well-documented but rare
• T3/T4 excess may mimic or precipitate manic episodes, especially in predisposed individuals
• T3 augmentation in depression (intentional hyperthyroid state), see below
• Always check TFTs before diagnosing new-onset mania

Thyroid Storm (Thyrotoxic Crisis):

• Medical emergency: extreme hyperthyroidism precipitated by surgery, infection, stress
• Psychiatric manifestations: extreme agitation, psychosis, delirium, seizures, coma
• Treatment: beta-blockers (propranolol), PTU/methimazole, iodine, glucocorticoids, cooling

1.4 Lithium-Induced Thyroid Dysfunction

One of the most important thyroid-psychiatry intersections for exams.

Mechanisms of lithium-induced thyroid dysfunction:

1. Inhibition of thyroid hormone synthesis, blocks iodine uptake, organification, and hormone release
2. Inhibition of TSH-stimulated cAMP generation
3. Promotion of autoimmunity, lithium promotes anti-thyroid antibody formation
4. Increased incidence of Hashimoto's thyroiditis in lithium-treated patients

Frequency of lithium-induced thyroid disorders:

• Hypothyroidism: 20–42% of patients on long-term lithium
• Subclinical hypothyroidism (TSH elevated, free T4 normal): 20–40%
• Goitre: 4–60% depending on duration and iodine status
• Hyperthyroidism: rare (1–2%), usually late or after thyroiditis phase

Risk factors for lithium-induced hypothyroidism:

• Female sex
• Older age
• Positive anti-TPO antibodies at baseline
• Family history of thyroid disease
• Duration of lithium treatment

Monitoring protocol (NICE/BAP guidelines):

• Baseline TFTs before starting lithium
• 6-monthly TFTs for first year
• Annual TFTs thereafter (or sooner if symptomatic)

Management:

• Lithium-induced hypothyroidism: continue lithium + add levothyroxine (do NOT routinely stop lithium)
• Subclinical hypothyroidism: treat if TSH >10 mIU/L, or if symptomatic, or if pregnant
• Goitre: usually benign; monitor; evaluate if rapid growth

Lithium and Hyperparathyroidism:

• Lithium can also cause hyperparathyroidism and hypercalcemia
• Mechanism: raises PTH set-point, leading to parathyroid gland hyperplasia
• Clinical: elevated calcium, elevated PTH, nephrocalcinosis
• Monitor serum calcium in long-term lithium patients

1.5 T3 Augmentation in Depression

Rationale:

• T3 enhances antidepressant response even in euthyroid patients
• Mechanism: sensitizes beta-adrenergic receptors, enhances serotonergic neurotransmission, reverses antidepressant down-regulation of receptors
• Effective even when thyroid function is normal

Evidence:

• Multiple RCTs show T3 augmentation of tricyclic antidepressants improves response rates
• Less consistent evidence with SSRIs
• STAR*D study: T3 augmentation comparable to lithium augmentation for treatment-resistant depression
• Typical dose: liothyronine (T3) 25–50 mcg/day

Clinical considerations:

• Monitor for iatrogenic hyperthyroidism (palpitations, tremor, anxiety)
• Contraindicated in cardiac disease, uncontrolled hypertension
• More commonly used in women (some evidence of sex-specific response)

Thyroid hormones in Rapid Cycling Bipolar:

• Supraphysiological doses of T4 (levothyroxine 250–500 mcg) used as adjunct in rapid cycling
• Mechanism uncertain, may stabilize via direct mood regulatory effects
• Requires monitoring; risk of thyrotoxicosis and bone loss

1.6 Thyroid Function Tests in Psychiatric Patients

When to screen TFTs in psychiatric settings:

SECTION 2: CUSHING'S SYNDROME & PSYCHIATRY

2.1 Overview

Cushing's syndrome = sustained excess glucocorticoid exposure, regardless of cause.

Cushing's disease = pituitary ACTH-secreting adenoma (70% of endogenous cases).

Causes:

• Pituitary adenoma (Cushing's disease), 70%
• Adrenal adenoma/carcinoma, 15%
• Ectopic ACTH (lung tumour, carcinoid), 10–15%
• Exogenous glucocorticoids, most common cause overall

Classic physical features: central obesity, moon face, buffalo hump, striae, easy bruising, hypertension, diabetes, osteoporosis, hirsutism (in women), proximal muscle weakness

2.2 Psychiatric Manifestations of Cushing's Syndrome

Psychiatric symptoms are extremely common, present in 50–80% of patients.

Depression:

• Most common psychiatric manifestation: 50–80% prevalence
• Character: prominent anhedonia, psychomotor retardation, severe fatigue, diurnal variation
• Cognitive impairment often concurrent (hippocampal atrophy on MRI)
• Suicidality: 4–10% attempt suicide
• Mechanism: hypercortisolaemia → HPA axis dysregulation → monoamine depletion, hippocampal neurogenesis suppression, glucocorticoid receptor downregulation

Anxiety:

• 20–70% of patients
• Generalized anxiety, panic attacks
• Often co-occurs with depression

Cognitive Impairment:

• Memory deficits (hippocampal vulnerability to cortisol)
• Concentration difficulties
• Verbal learning impairment
• Hippocampal volume reduction on MRI (reversible partially after treatment)

Psychosis:

• 5–15% of patients
• Paranoid psychosis most common
• Mania can also occur ("steroid mania")
• Mechanism: excess cortisol → dopaminergic dysregulation

Personality Change:

• Emotional lability, irritability
• Interpersonal difficulties
• Paranoid traits

Mania:

• Less common than depression
• Can occur with endogenous or exogenous cortisol excess
• "Steroid mania", see exogenous section below

2.3 Exogenous Glucocorticoid-Induced Psychiatric Disorders

Steroid-induced psychiatric syndromes are common in clinical medicine.

Frequency:

• Mild: euphoria, mood lability, very common (>50% at higher doses)
• Moderate: depression or hypomania, 5–10%
• Severe: psychosis, 1–5%
• Mania: less common than psychosis

Classic "steroid mania":

• Elevated mood, decreased sleep, grandiosity, racing thoughts
• Often occurs within days of starting or increasing dose
• Not a reliable predictor from past episodes, different doses can cause different reactions

Dose relationship:

Management of steroid-induced psychiatric disorders:

1. Reduce steroid dose if medically possible
2. Antipsychotics for psychosis/mania (haloperidol, olanzapine)
3. Mood stabilizers for mania (lithium, valproate), may need to continue if steroids cannot be stopped
4. Antidepressants for depression (usually after ruling out brief reactive mood changes)
5. Note: lithium has prophylactic role in patients who require repeated steroid courses

Key exam point: Steroid-induced psychiatric symptoms tend to RESOLVE when steroids are tapered, this is the first treatment step.

2.4 Differentiating Cushing's from Psychiatric Depression

Diagnosis of Cushing's:

• Screening: 24-hour urine free cortisol, late-night salivary cortisol, low-dose DST (1 mg overnight)
• Localisation: plasma ACTH, high-dose DST, CRH stimulation test, pituitary MRI, adrenal CT, inferior petrosal sinus sampling

SECTION 3: ADDISON'S DISEASE & PSYCHIATRY

3.1 Overview

Addison's disease = primary adrenal insufficiency due to destruction of adrenal cortex.

• Most common cause: autoimmune (70–90%) in developed countries
• Other causes: tuberculosis (most common in developing countries), fungal infections, hemorrhage (Waterhouse-Friderichsen syndrome, meningococcal)
• Results in deficiency of cortisol AND aldosterone

Physical features: hyperpigmentation (buccal mucosa, creases, scars), hypotension, weight loss, nausea, vomiting, salt craving, weakness

3.2 Psychiatric Manifestations of Addison's Disease

Psychiatric symptoms occur in 60–90% of patients.

Depression:

• Most common psychiatric manifestation
• Character: low energy, anhedonia, fatigue (often profound)
• Apathy prominent, diminished initiative and motivation
• Can be severe, melancholic
• Mechanism: cortisol deficiency → disruption of normal stress response, monoamine dysregulation

Apathy and Fatigue:

• Sometimes predominant, patient may present with extreme fatigue as primary complaint
• Distinguished from depression: cognitive features of depression may be absent
• Salt craving: a clinical clue

Anxiety:

• 30–50%
• Generalized anxiety; sometimes panic attacks
• May relate to physiological hypervigilance in context of impaired stress response

Psychosis:

• Rare but documented
• Can occur in severe or decompensated Addison's
• Usually resolves with glucocorticoid replacement

Cognitive Impairment:

• Memory problems, slowed processing
• Reversible with replacement therapy

3.3 Adrenal Crisis

Medical emergency, psychiatric mimicry and complication.

Precipitants: infection, surgery, trauma, physiological stress, inadequate steroid cover

Psychiatric presentation:

• Can present with delirium, acute confusional state
• Agitation, severe anxiety
• In chronic Addison's: may have chronic low-grade psychiatric symptoms that worsen acutely

Emergency management:

• Hydrocortisone 100 mg IV immediately
• IV saline resuscitation
• Identify and treat precipitant
• NOT the time for psychiatric medication, treat the hormonal crisis first

SECTION 4: DIABETES MELLITUS & PSYCHIATRY

4.1 Depression-Diabetes Bidirectional Link

This is one of the best-established endocrine-psychiatric bidirectional relationships.

Epidemiology:

• Depression is 2–3x more common in diabetes vs general population
• Prevalence of depression in T2DM: 15–25%
• Prevalence of diabetes in major depression: 2–3x increased risk

Direction 1, Diabetes causes depression:

• Chronic illness burden, functional impairment, fear of complications
• Neurobiological: hyperglycemia → oxidative stress → hippocampal damage; HPA axis dysregulation; inflammation (IL-6, TNF-alpha elevated)
• Diabetic neuropathy → pain → depression
• Hypoglycemia → anxiety, fear

Direction 2, Depression causes/worsens diabetes:

• Depression → poor self-care, non-adherence to medication and diet
• Behavioural: inactivity, unhealthy eating, smoking, alcohol use
• Neurobiological: depression → HPA axis hyperactivity → cortisol excess → insulin resistance; sympathetic hyperactivity → hepatic glucose production
• Antidepressants (especially TCAs, mirtazapine) → weight gain, hyperglycemia

Clinical consequences of comorbidity:

• Worse glycemic control (higher HbA1c in depressed diabetics)
• Higher risk of diabetic complications (retinopathy, nephropathy, cardiovascular disease)
• Increased mortality
• Higher healthcare utilization

Management:

• Screen all T2DM patients for depression (PHQ-9)
• Collaborative care models effective
• SSRIs first-line for depression in diabetes (fluoxetine may slightly improve insulin sensitivity)
• CBT: evidence base for depression + diabetes self-management
• Caution: TCAs, MAOIs → weight gain, metabolic effects

4.2 Metabolic Syndrome

Metabolic Syndrome = cluster of cardiometabolic risk factors.

Diagnostic criteria (IDF, 2006, most commonly used):

Central obesity (waist circumference ≥90 cm men / ≥80 cm women for South Asians) PLUS any 2 of:

• Fasting glucose ≥ 5.6 mmol/L (100 mg/dL) or T2DM diagnosis
• Triglycerides ≥ 1.7 mmol/L (150 mg/dL)
• HDL-C < 1.03 (men) / < 1.29 (women) mmol/L
• Blood pressure ≥ 130/85 mmHg

Metabolic syndrome in psychiatric populations:

• Prevalence in schizophrenia: 40–60% (vs ~25% general population)
• In bipolar disorder: 25–50%
• In major depression: elevated vs general population
• Driven by: antipsychotic medications, lifestyle factors (inactivity, poor diet, smoking), disease biology

4.3 Antipsychotic-Induced Metabolic Effects

This is the highest-yield topic in this section for exams.

Mechanism of antipsychotic metabolic effects:

1. Histamine H1 antagonism, primary driver of weight gain
2. Serotonin 5-HT2C antagonism, promotes appetite, impairs satiety signaling
3. Dopamine D2 antagonism, affects appetite regulation via mesolimbic circuits
4. Muscarinic M3 antagonism, impairs pancreatic insulin secretion (direct diabetogenic)
5. Adrenergic alpha-1 blockade, sedation → reduced activity

Weight Gain Hierarchy (highest to lowest):

Diabetogenic effects (independent of weight):

4.4 ADA/APA Monitoring Guidelines for Antipsychotics

The ADA/APA/AACE/NAASO Consensus Statement (2004) monitoring protocol, frequently examined:

Thresholds for action:

• BMI gain >1 unit in any month → consider switch
• Fasting glucose >100 mg/dL (5.6 mmol/L) → refer to physician
• Fasting glucose >126 mg/dL (7.0 mmol/L) on two occasions → diabetes, refer and consider switch
• Triglycerides >200 mg/dL → refer
• LDL >130 mg/dL in high-risk patient → refer

4.5 Switching Strategies for Metabolic Side Effects

When to switch:

• Significant weight gain (BMI increase >1 unit/month)
• New-onset hyperglycemia or diabetes
• Dyslipidemia not manageable pharmacologically
• Patient preference (informed)

Preferred switch targets (metabolically safer):

• Aripiprazole
• Ziprasidone (low weight/metabolic burden)
• Amisulpride
• Lurasidone

Switching strategies:

1. Abrupt switch, straightforward for metabolically favorable drugs; risk of relapse
2. Cross-titration, overlap and taper; most common approach; monitor for side effects during overlap
3. Plateau (halfway) method, particularly for clozapine → target

Note on clozapine: Switching FROM clozapine carries high relapse risk. Benefits of metabolic improvement must be weighed against loss of efficacy (clozapine remains the gold standard for treatment-resistant schizophrenia).

4.6 Metformin Augmentation for Antipsychotic-Induced Weight Gain

Metformin:

• RCT evidence supports metformin for antipsychotic-induced weight gain
• Typical dose: 500–1000 mg BD
• Reduces weight by 2–3 kg on average in antipsychotic-treated patients
• Also improves insulin sensitivity, reduces HbA1c
• Safe in combination with antipsychotics
• Consider early (before significant weight gain is established)

Other pharmacological interventions:

• Aripiprazole addition to clozapine/olanzapine, reduces weight gain (partial D2 agonism modulates metabolic effects)
• Topiramate, modest weight reduction; cognitive side effects limit use
• Orlistat, modest effect, GI side effects
• GLP-1 agonists (semaglutide, liraglutide), emerging evidence for substantial weight reduction; not yet standard care in most guidelines but use increasing

SECTION 5: PHEOCHROMOCYTOMA & PSYCHIATRY

5.1 Overview

Pheochromocytoma = catecholamine-secreting tumour of adrenal medulla.

• Paraganglioma = extra-adrenal catecholamine tumour
• "Rule of 10s" (traditional): 10% malignant, 10% bilateral, 10% extra-adrenal, 10% familial, 10% in children (these proportions are approximate/historical)

Biochemistry: secretes epinephrine, norepinephrine, dopamine in varying ratios depending on tumour location

5.2 Psychiatric Mimicry

Classic presentation: paroxysmal hypertension, headache, sweating, palpitations, the "4 P's"

Panic-like presentations:

• Can perfectly mimic panic disorder or panic attacks
• Episodes of: extreme anxiety, palpitations, tremor, sweating, headache, pallor/flushing
• Duration: minutes to hours
• Can be spontaneous or triggered (compression of tumour)

Distinguishing features from true panic disorder:

Diagnostic approach:

• 24-hour urine metanephrines/catecholamines (screening test of choice)
• Plasma free metanephrines (sensitivity ~97%, specificity ~85%)
• Imaging: CT/MRI adrenal glands once biochemistry positive
• MIBG scan: functional imaging for extra-adrenal disease

Key exam point: Always exclude pheochromocytoma in panic disorder with prominent cardiovascular symptoms, especially with treatment resistance.

Depression and psychiatric comorbidity:

• Chronic catecholamine excess can cause mood instability, anxiety, and depression
• Post-surgical cure often resolves psychiatric symptoms

SECTION 6: PARATHYROID DISORDERS & PSYCHIATRY

6.1 Hyperparathyroidism

Primary hyperparathyroidism: excess PTH from parathyroid adenoma (80%) or hyperplasia → hypercalcemia

"Bones, stones, groans, psychic moans", the classic tetrad

Psychic moans, psychiatric manifestations:

• Depression: most common psychiatric manifestation (40–60%)
• Anxiety
• Cognitive impairment: poor concentration, memory difficulties
• Psychosis: rare, in severe hypercalcemia
• Fatigue, weakness, malaise

Calcium and mood, mechanism:

• Hypercalcemia → reduces neuronal excitability, alters neurotransmitter release
• Affects serotonergic, dopaminergic, noradrenergic systems
• Hippocampal calcium channels involved in memory consolidation

Psychiatric symptoms correlate with calcium levels:

• Mild hypercalcemia (Ca 2.6–3.0 mmol/L): fatigue, cognitive slowing, mild depression
• Moderate (3.0–3.5 mmol/L): depression, anxiety, confusion
• Severe (>3.5 mmol/L): delirium, psychosis, coma

Key clinical point: Check serum calcium in treatment-resistant depression.

6.2 Hypoparathyroidism

Hypoparathyroidism: PTH deficiency → hypocalcemia

• Most common cause: inadvertent removal during thyroidectomy/parathyroidectomy
• Also: autoimmune (DiGeorge syndrome), idiopathic

Psychiatric manifestations of hypocalcemia:

• Anxiety, irritability, emotional lability
• Depression
• Psychosis (rare, can present as schizophrenia-like illness)
• Cognitive impairment
• Seizures (not psychiatric but important)
• Basal ganglia calcification (Fahr's disease associated with chronic hypoparathyroidism) → movement disorder + neuropsychiatric symptoms

Classic physical signs: Chvostek's sign (facial nerve tap → facial twitching), Trousseau's sign (BP cuff inflation → carpal spasm), tetany, perioral paresthesias

SECTION 7: PITUITARY DISORDERS & PSYCHIATRIC ASPECTS

7.1 Prolactinoma

Most common pituitary tumour (40% of all pituitary adenomas)

Psychiatric effects of hyperprolactinemia:

• Hypogonadism → depression, sexual dysfunction
• In women: amenorrhea, infertility → psychosocial distress
• In men: erectile dysfunction, loss of libido → depression
• Galactorrhea → body image issues

Antipsychotic-induced hyperprolactinemia:

• All D2 antagonist antipsychotics → hyperprolactinemia (dopamine normally inhibits prolactin release)
• Highest: amisulpride, risperidone, haloperidol
• Lowest: clozapine, quetiapine (partial sparing of tuberoinfundibular pathway)
• Aripiprazole (D2 partial agonist) → actually LOWERS prolactin → can add to normalize levels

Monitoring prolactin:

• Baseline before starting antipsychotics (if clinically indicated)
• Check if galactorrhea, amenorrhea, sexual dysfunction, or gynecomastia develops

7.2 Acromegaly

GH-secreting pituitary adenoma → excess GH and IGF-1

Psychiatric manifestations:

• Depression: 40–60%
• Anxiety: 30–40%
• Fatigue, reduced quality of life
• Irritability, personality change
• Social withdrawal (related to physical changes, coarsening features, macroglossia, large hands/feet)

Key mechanism: GH/IGF-1 effects on central serotonergic and dopaminergic function; also psychosocial impact of physical disfigurement

7.3 Hypopituitarism

Multiple pituitary hormone deficiency (any combination of GH, TSH, ACTH, LH/FSH, ADH, prolactin deficiency)

Psychiatric manifestations:

• Depression: very common, multifactorial (GH deficiency, thyroid deficiency, cortisol deficiency, sex hormone deficiency)
• Fatigue, poor energy
• Cognitive impairment
• Sexual dysfunction

Adult GH deficiency syndrome:

• Well-recognized entity
• Features: central obesity, reduced muscle mass, fatigue, low mood, impaired QoL
• Treatment with GH replacement improves mood and cognitive function

Sheehan's syndrome (postpartum pituitary necrosis):

• Failure to lactate, amenorrhea, hypothyroidism, hypocortisolism
• Psychiatric: depression, chronic fatigue, cognitive impairment
• May present years after a complicated delivery (massive PPH)

SECTION 8: WILSON'S DISEASE & PSYCHIATRY

8.1 Overview: Key Exam Topic

Wilson's disease = autosomal recessive disorder of copper metabolism.

• Gene: ATP7B (chromosome 13), encodes copper-transporting ATPase
• Pathophysiology: failure of biliary excretion of copper → copper accumulation in liver, brain, cornea, kidneys, heart
• Onset: typically 5–35 years (children and young adults)

A classic "great mimic" in psychiatry, important exam topic

8.2 Psychiatric Manifestations

Psychiatric symptoms are the PRESENTING feature in 20–30% of cases.

Personality Change:

• Often earliest psychiatric sign
• Disinhibition, impulsivity, emotional lability
• Loss of social inhibitions, inappropriate behavior
• Can be mistaken for conduct disorder in adolescents
• Mechanism: basal ganglia copper deposition → altered frontostriatal circuits

Psychosis:

• Schizophrenia-like presentations
• Paranoid delusions, auditory hallucinations
• Visual hallucinations (less specific)
• Can mimic first-episode schizophrenia
• Key: young patient with psychosis + movement disorder + liver disease → MUST exclude Wilson's

Affective Symptoms:

• Depression: common, variable severity
• Anxiety
• Mania (rare)
• Emotional incontinence (pathological laughing/crying)

Cognitive Impairment:

• Executive dysfunction prominent (basal ganglia and frontal involvement)
• Memory impairment
• Processing speed reduction
• Can progress to dementia if untreated

Neurological Features (often concurrent with psychiatric):

• Dysarthria (often the first neurological sign)
• Tremor (wing-beating/resting/postural)
• Dysphagia
• Dystonia
• Parkinsonism
• Chorea
• Seizures (10–15%)

8.3 Diagnosis

Kayser-Fleischer (KF) Rings:

• Golden-brown/greenish rings at corneal periphery (Descemet's membrane)
• Copper deposits
• Best visualized on slit-lamp examination
• Present in >95% of neuropsychiatric Wilson's
• Present in 50–60% of hepatic presentations (alone)
• NOT pathognomonic, can occur in other cholestatic liver diseases
• ABSENCE of KF rings does NOT exclude Wilson's (especially hepatic presentation)

Diagnostic investigations:

"Face of giant panda" sign: midbrain MRI finding, characteristic but not universal.

Leipzig scoring system, used for diagnosis (combines KF rings, ceruloplasmin, Coombs-negative hemolytic anemia, urine copper, liver copper, gene mutation).

8.4 Treatment

Goals: remove excess copper, prevent further accumulation

D-Penicillamine (copper chelator):

• First-line in most guidelines
• Mechanism: chelates copper → increased urinary copper excretion
• Dose: 750–1500 mg/day (divided doses)
• Side effects: rash, fever, lupus-like syndrome, nephrotoxicity, bone marrow suppression, pyridoxine deficiency (supplement B6)
• IMPORTANT EXAM POINT: Neurological/psychiatric worsening can occur in first few weeks (paradoxical, copper is mobilized from liver and redistributed to brain)
• Contraindicated in: renal failure, lupus, pre-existing neurological Wilson's (relative contraindication)

Trientine (Triethylenetetramine):

• Alternative copper chelator
• Better tolerated than penicillamine
• Preferred in: patients intolerant of penicillamine, neurological Wilson's (lower risk of neurological deterioration)
• Dose: 750–1500 mg/day (divided doses)

Zinc acetate/Zinc sulfate:

• Mechanism: induces metallothionein in intestinal cells → blocks copper absorption from gut
• Not a chelator, works by preventing absorption
• Used for: maintenance therapy after initial chelation, presymptomatic patients, pregnancy (safer profile)
• Cannot be used simultaneously with chelators (interfere with each other)
• Dose: zinc acetate 50 mg elemental zinc TID

Ammonium tetrathiomolybdate:

• Investigational agent
• Mechanism: forms complex with copper and albumin, inhibiting copper uptake
• May have lower risk of early neurological deterioration
• Not widely available

Liver transplantation:

• Indicated for: fulminant hepatic failure, end-stage liver disease
• Corrects the metabolic defect (liver transplant = curative for hepatic disease)
• Improves neurological symptoms (but may not fully reverse)
• Does NOT remove KF rings immediately

Psychiatric drug use in Wilson's:

• Avoid drugs with significant copper-chelating or hepatotoxic effects
• Penicillamine itself has neuropsychiatric effects
• Antipsychotics can be used for psychotic symptoms (atypicals preferred, monitor for EPS given basal ganglia involvement)
• Monitor liver function with any hepatotoxic psychotropic (many antipsychotics, carbamazepine)

SECTION 9: HEPATIC ENCEPHALOPATHY

9.1 Pathophysiology

Hepatic encephalopathy (HE) = neuropsychiatric syndrome complicating liver failure or portosystemic shunting.

Mechanism:

• Ammonia hypothesis (primary): liver failure → failure to detoxify ammonia → hyperammonemia → astrocyte swelling (Alzheimer type II astrocytes), glutamine accumulation → cerebral edema
• Inflammation potentiates ammonia toxicity
• Zinc deficiency (impairs urea cycle enzymes)
• GABA-ergic excess (endogenous benzodiazepine-like substances)
• Manganese deposition (basal ganglia) → Parkinsonism-like features
• Altered amino acid ratios → false neurotransmitter theory (phenylalanine, tyrosine → octopamine, beta-phenylalanine)

9.2 Grading (West Haven Criteria)

Asterixis (liver flap) = pathognomonic: involuntary, asynchronous flapping tremor of outstretched hands, seen in Grade 2–3.

Minimal/Covert HE:

• No overt clinical signs
• Detectable on psychometric testing (Psychometric Hepatic Encephalopathy Score, PHES)
• Important: affects QoL, driving ability, work performance
• ~30–40% of cirrhotic patients

9.3 Management

Identify and treat precipitants (most important step):

• Infection/sepsis (SBP, spontaneous bacterial peritonitis: most common precipitant)
• GI bleeding
• Electrolyte disturbances (hyponatremia, hypokalemia)
• Constipation
• Benzodiazepines/sedatives (AVOID)
• Excessive protein intake (controversial, protein restriction now not recommended)
• Dehydration

Pharmacological treatment:

Dietary:

• Protein restriction is OUTDATED, maintain adequate protein (1.2–1.5 g/kg/day)
• Branch-chain amino acid (BCAA) supplements: evidence in severe HE/cirrhosis
• Small frequent meals, late evening snack (reduces overnight fasting catabolism)

TIPS (Transjugular Intrahepatic Portosystemic Shunt):

• Can worsen HE (more portosystemic shunting)
• Liver transplantation: definitive treatment for HE in appropriate candidates

SECTION 10: PORPHYRIA & PSYCHIATRY

10.1 Acute Intermittent Porphyria (AIP)

AIP = autosomal dominant disorder of heme biosynthesis.

• Deficiency of porphobilinogen deaminase (PBGD), also called hydroxymethylbilane synthase
• Accumulation of aminolevulinic acid (ALA) and porphobilinogen (PBG) → neurotoxicity
• Prevalence: 1-2 per 100,000; more common in women

Triggers (precipitate attacks):

• Drugs (the most important trigger for psychiatry)
• Alcohol
• Fasting/caloric restriction
• Hormonal changes (menstrual cycle, porphyria is worse premenstrually)
• Infection, stress, surgery

10.2 Psychiatric Manifestations

Psychiatric symptoms can PRECEDE or ACCOMPANY acute attacks:

• Anxiety: very common, can be severe
• Agitation, restlessness
• Depression
• Confusion, delirium
• Psychosis: auditory hallucinations, paranoid ideation, formal thought disorder
• Personality change
• Emotional lability

Classic AIP attack (triad):

1. Severe abdominal pain (colicky, often the presenting symptom)
2. Peripheral neuropathy (weakness, sensory loss, can progress to respiratory failure)
3. Psychiatric manifestations (confusion, psychosis, anxiety)

Other features: autonomic neuropathy (tachycardia, hypertension, sweating), SIADH → hyponatremia (worsens neuropsychiatric symptoms), seizures

Urine color: dark red/brown on standing (porphobilinogen oxidizes), classic exam finding

10.3 Safe and Unsafe Drugs in Porphyria

CRITICAL FOR PSYCHIATRY PRACTICE:

UNSAFE drugs (precipitate attacks), key psychiatric drugs:

*Note: valproate's safety is debated, some sources list it as unsafe.

SAFE drugs in porphyria (generally):

Treatment of acute attack:

1. Remove precipitant
2. High carbohydrate intake (glucose 400 g/day, suppresses ALA synthetase, reduces porphyrin production)
3. Hematin (heme arginate/Normosang): IV hematin suppresses ALA synthetase activity, most effective treatment
4. Supportive: adequate analgesia, treat seizures (levetiracetam/gabapentin), treat SIADH
5. Monitor respiratory function (neuropathy can cause respiratory failure)

SECTION 11: NUTRITIONAL DEFICIENCIES & PSYCHIATRY

11.1 Vitamin B12 (Cobalamin) Deficiency

Sources: animal products (meat, fish, dairy, eggs); vegans/vegetarians at high risk

Causes: pernicious anemia (anti-intrinsic factor antibodies), gastrectomy, ileal disease, metformin (blocks B12 absorption, important drug interaction), malnutrition, strict veganism

Psychiatric manifestations:

• Depression: may be first symptom
• Cognitive impairment: ranges from mild to dementia (reversible if caught early)
• Psychosis: "megaloblastic madness", rare but classic
• Irritability, personality change
• Mania (rare)

Neurological features (combined subacute combined degeneration of spinal cord):

• Peripheral neuropathy (most common neurological feature)
• Subacute combined degeneration: posterior and lateral column involvement → proprioception loss, ataxia, spastic paraparesis
• Optic neuropathy

Diagnosis: Serum B12 <200 pg/mL (low); methylmalonic acid (MMA) and homocysteine elevated (sensitive markers of functional B12 deficiency even when serum B12 is borderline)

Treatment:

• Pernicious anemia/malabsorption: IM hydroxocobalamin 1000 mcg alternate days x 2 weeks, then every 3 months
• Nutritional deficiency without malabsorption: oral B12 1000–2000 mcg/day (high-dose oral can overcome absorption deficit in some)

Psychiatric symptoms: may take weeks to months to improve even with replacement; irreversible if very prolonged

11.2 Folate Deficiency

Sources: green leafy vegetables, legumes, fortified cereals; destroyed by cooking

Causes: poor diet, malabsorption (coeliac disease), alcoholism, pregnancy (increased demand), drugs (methotrexate, phenytoin, sulfasalazine, trimethoprim, folate antagonists)

Psychiatric manifestations:

• Depression: high association, reduced folate → reduced methylation → reduced monoamine synthesis
• Cognitive impairment
• Irritability

Folate and antidepressant response:

• Low folate predicts poor antidepressant response
• L-methylfolate (MTHF) as augmentation strategy in treatment-resistant depression (especially relevant in MTHFR gene variants)
• Folic acid 5–15 mg/day as augmentation

Homocysteine: elevated in both B12 and folate deficiency → independent cardiovascular and neurodegenerative risk

Folate and schizophrenia:

• Some evidence linking folate deficiency and MTHFR variants with schizophrenia susceptibility
• High-dose folate (2 mg/day) may improve negative symptoms in schizophrenia

Treatment: folic acid 5 mg/day (higher doses in malabsorption or drug-induced)

11.3 Niacin (Vitamin B3) Deficiency: Pellagra

Pellagra = niacin (nicotinic acid/nicotinamide) deficiency.

• Sources: meat (tryptophan can be converted to niacin), cereals
• At-risk groups: maize-based diets, alcoholics, carcinoid syndrome (tryptophan diverted to serotonin), Hartnup disease, INH use (blocks tryptophan → niacin)
• Historical context: epidemic in poorest communities of Southern US (early 20th century)

Classic triad (The "3 Ds", and 4th D):

• Dermatitis, photosensitive, symmetrical, casal's necklace (affects sun-exposed areas)
• Diarrhoea, watery, bloody
• Dementia, cognitive decline
• (Death), if untreated

Psychiatric manifestations:

• Cognitive impairment progressing to dementia
• Anxiety, agitation
• Depression
• Psychosis: hallucinations, paranoid ideation
• Delirium in severe cases
• Headache, fatigue

Mechanism: Niacin is a precursor to NAD+ and NADP+, essential for neuronal energy metabolism. Deficiency → impaired oxidative phosphorylation → neurodegeneration.

Drug-induced pellagra:

• INH (isoniazid), inhibits pyridoxine (B6), which is cofactor for tryptophan → niacin conversion
• Prevent with pyridoxine supplementation when using INH

Treatment: nicotinamide (nicotinic acid without flushing) 100–300 mg TID; rapid response (days to weeks)

11.4 Thiamine (Vitamin B1) Deficiency: Wernicke-Korsakoff Syndrome

Most important nutritional deficiency in psychiatry.

At-risk groups: chronic alcohol use disorder (primary cause), severe malnutrition, prolonged vomiting (hyperemesis gravidarum), bariatric surgery, refeeding after starvation, malignancy, dialysis

Wernicke's Encephalopathy (WE), ACUTE:

Classic triad:

1. Ophthalmoplegia (sixth nerve palsy, lateral rectus; nystagmus)
2. Ataxia (cerebellar, gait)
3. Confusion/encephalopathy (global confusion)

BUT, only 16% of patients present with full classic triad. Diagnosis often missed.

Pathology: hemorrhagic necrosis in: mammillary bodies (most characteristic), periaqueductal gray, medial thalamus, cerebellar vermis

Diagnosis: Clinical diagnosis; MRI (T2/FLAIR hyperintensities in mammillary bodies and periaqueductal region); thiamine levels often not helpful acutely

Treatment: Parenteral thiamine (Pabrinex) BEFORE any glucose administration

• High-potency thiamine IV: 500 mg TID x 3 days (European guidelines)
• Oral thiamine insufficient for WE treatment
• NEVER give glucose without thiamine in at-risk patients (glucose loads → depletes remaining thiamine → precipitates WE)

Korsakoff Syndrome (KS), CHRONIC AMNESIC STATE:

Develops from untreated or inadequately treated WE

Classic features:

• Severe anterograde amnesia (inability to form new memories)
• Retrograde amnesia (variable)
• Confabulation (fabrication of memories, often unconscious, patient is not lying)
• Relatively preserved other cognitive functions (language, attention, perception)
• Lack of insight (anosognosia)
• Flat/apathetic affect

Prognosis:

• 25% partial recovery
• 25% significant recovery with prolonged thiamine treatment
• 50% permanent impairment
• Only 10% make complete recovery

Treatment: Continue high-dose thiamine (oral); address alcohol dependence; neuropsychological rehabilitation. NO specific pharmacological treatment. Thiamine maintenance: 100 mg TID orally long-term.

Wernicke-Korsakoff vs. Alcohol-Related Dementia:

SECTION 12: ELECTROLYTE DISTURBANCES & PSYCHIATRY

12.1 Hyponatremia

Hyponatremia (Na < 135 mEq/L), the most common electrolyte disturbance in psychiatric inpatients.

Classification:

• Mild: 130–135 mEq/L
• Moderate: 125–130 mEq/L
• Severe: <125 mEq/L; ACUTE severe: <125 mEq/L developing over <48h (risk of cerebral edema)

Psychiatric manifestations:

SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion):

• Urine osmolality > serum osmolality (inappropriately concentrated urine)
• Urine Na > 20 mEq/L
• Clinically euvolemic (no edema, no dehydration)
• Diagnosis of exclusion: must rule out hypothyroidism, adrenal insufficiency, renal disease

Psychotropic-induced hyponatremia (SIADH):

This is a high-yield exam topic.

Mechanism: SSRIs → enhance serotonin-mediated ADH release; carbamazepine → direct ADH-potentiating effect

Risk factors:

• Age >65 years (most significant)
• Female sex
• Low body weight
• Concurrent diuretic use
• History of hyponatremia
• Hot weather, increased fluid intake

Management of SIADH/psychotropic-induced hyponatremia:

1. Mild: fluid restriction (500–1000 mL/day); monitor closely
2. Moderate: fluid restriction; consider stopping/switching offending drug
3. Severe/symptomatic: 3% hypertonic saline (correct at max 8–10 mEq/L in 24h to avoid ODS)
4. Tolvaptan (V2 receptor antagonist): selectively excretes free water, for resistant SIADH

Osmotic Demyelination Syndrome (ODS), Central Pontine Myelinolysis:

• Complication of OVERLY RAPID correction of hyponatremia
• Irreversible demyelination of pons (and extrapontine areas)
• Presents: locked-in syndrome, spastic quadriplegia, pseudobulbar palsy, cognitive impairment
• Prevention: correct Na at maximum 8–10 mEq/L per 24 hours; maximum 18 mEq/L in 48 hours
• High-risk: alcoholics, malnourished, hypokalemic, liver disease

Polydipsia in schizophrenia:

• Up to 25% of schizophrenia inpatients have polydipsia
• Psychogenic polydipsia (primary polydipsia): compulsive drinking, not thirst-driven
• Results in hyponatremia (dilutional)
• Can cause severe hyponatremia and seizures ("water intoxication")
• Management: fluid restriction, clozapine may reduce polydipsia (dopamine effect on thirst centers)

12.2 Hypercalcemia

Psychiatric manifestations (see hyperparathyroidism section, Section 6.1)

"Bones, stones, groans, psychic moans"

Additional electrolyte context:

• Hypercalcemia slows nerve conduction, depresses CNS
• Lithium-induced hypercalcemia: as noted (Section 1.4)

12.3 Hypomagnesemia

Magnesium deficiency, common, often undiagnosed.

Causes in psychiatric patients: chronic alcohol use (renal magnesium wasting), malnutrition, diarrhea, PPIs (chronic use), diuretics, cisplatin

Psychiatric manifestations:

• Anxiety, agitation, irritability
• Depression
• Cognitive impairment
• Confusion
• Psychosis (rare, in severe deficiency)

Neurological features: tremor, muscle weakness, tetany (similar to hypocalcemia, Mg required for PTH secretion), hyperreflexia, seizures

Magnesium and mood disorders:

• Low magnesium associated with depression
• Some RCT evidence for magnesium supplementation in mild depression
• Magnesium sulfate used in eclampsia (CNS protective, anticonvulsant)

Relevance for antipsychotics:

• Clozapine can prolong QTc → worsened by hypomagnesemia → arrhythmia risk
• Correct hypomagnesemia before starting or escalating clozapine

SECTION 13: METABOLIC SYNDROME IN PSYCHIATRIC POPULATIONS: MANAGEMENT PROTOCOLS

13.1 Integrated Monitoring and Management

Step 1, Screen at baseline (all patients starting antipsychotics):

• Weight/BMI
• Waist circumference
• Blood pressure
• Fasting glucose
• Fasting lipid profile
• Family history of metabolic disease

Step 2, Monitor per ADA/APA schedule (see Section 4.4 table)

Step 3, Intervene at thresholds:

Step 4, Non-pharmacological interventions:

• Structured physical activity (150 min/week moderate intensity)
• Caloric restriction (500 kcal/day deficit)
• Smoking cessation (nicotine replacement/varenicline)
• Dietary counseling (Mediterranean diet pattern)

Step 5, Pharmacological augmentation:

• Metformin: 500 mg BD → 1000 mg BD (first-line for antipsychotic-induced weight gain and hyperglycemia)
• Statins: for dyslipidemia (pravastatin, simvastatin)
• Aripiprazole co-prescription (if not on it): reduces weight when added to olanzapine/clozapine
• GLP-1 agonists: emerging use (semaglutide, liraglutide)

SECTION 14: INTEGRATED CLINICAL APPROACH: PSYCHIATRIC HISTORY IN ENDOCRINE CONTEXT

14.1 "When to think endocrine" in psychiatry

Red flags for underlying endocrine/metabolic cause in psychiatric presentations:

SUMMARY BOX: HIGH-YIELD FACTS FOR EXAM

Model Answers

Answer 1: Psychiatric Manifestations of Hypothyroidism and the Role of Thyroid Function Tests in Psychiatric Practice

[15 marks]

Introduction

Hypothyroidism is a deficiency of thyroid hormone (T4/T3) resulting from primary thyroid gland failure, pituitary disease, or hypothalamic dysfunction. Given that thyroid hormones modulate monoamine neurotransmission, particularly serotonergic and noradrenergic systems, hypothyroidism produces a wide range of psychiatric manifestations.

Psychiatric Manifestations

1. Depression (most common, 40–60%)

Hypothyroidism-associated depression closely mimics major depressive disorder. Key features include low mood, marked anhedonia, psychomotor retardation, fatigue, weight gain, and cognitive slowing. The mechanism involves reduced serotonin receptor density and diminished central noradrenergic tone. A critical clinical point is that depression in hypothyroidism often fails to respond to antidepressants without concurrent thyroid replacement. Subclinical hypothyroidism (elevated TSH with normal free T4) also increases depression prevalence, particularly in women.

2. Cognitive Impairment

Thyroid hormone deficiency impairs hippocampal neurogenesis and reduces cerebral glucose metabolism. Clinically, patients present with poor concentration, slowed processing speed, forgetfulness, and verbal memory deficits. In elderly patients, this can progress to a dementia-like syndrome that is reversible with treatment, making TSH screening mandatory in new-onset cognitive complaints.

3. Myxedema Madness

First described by Asher (1949), this refers to the acute psychiatric manifestation of severe, prolonged hypothyroidism. Presentation includes paranoid psychosis, auditory and visual hallucinations, delirium, and occasionally mania. It occurs in the context of severe systemic myxedema (periorbital puffiness, macroglossia, non-pitting oedema, hypothermia, bradycardia). TSH is markedly elevated; free T4 is very low. Treatment requires urgent IV levothyroxine and brief antipsychotic cover if needed.

4. Anxiety and Mood Lability

Anxiety and irritability are common, particularly in subclinical hypothyroidism.

5. Congenital Hypothyroidism (Cretinism)

Untreated congenital hypothyroidism causes irreversible intellectual disability, emphasising the importance of neonatal screening.

Thyroid Function Tests in Psychiatric Practice

TSH is the single most useful screening test. Clinicians should screen TFTs in the following situations:

• New-onset depression, treatment-resistant depression, new-onset anxiety
• New-onset mania or psychosis
• Cognitive impairment, especially in the elderly
• Before initiating lithium (baseline) and every 6 months for the first year, then annually
• Postpartum psychiatric illness (postpartum thyroiditis in 5–10%)
• Patients with eating disorders (sick euthyroid syndrome common)

Interpretation:

• Elevated TSH + low free T4 = overt hypothyroidism → thyroid replacement
• Elevated TSH + normal free T4 = subclinical hypothyroidism → treat if TSH >10, symptomatic, or pregnant
• Both TFTs normal = primary psychiatric disorder; however, serial monitoring warranted on lithium

Management of Hypothyroidism-Associated Psychiatric Illness

1. Initiate levothyroxine (T4) replacement; goal TSH within normal range
2. If depression persists after euthyroid state restored, add antidepressant (SSRI first-line)
3. T3 augmentation (liothyronine 25–50 mcg/day) for treatment-resistant depression even in euthyroid patients, STAR*D evidence
4. Myxedema madness: IV T4 (levothyroxine), antipsychotics briefly, ICU-level supportive care

Answer 2: Wilson's Disease: Psychiatric Presentation, Diagnosis, and Treatment

[15 marks]

Definition

Wilson's disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene (chromosome 13q14), which encodes a copper-transporting ATPase. Failure of biliary copper excretion leads to progressive copper deposition in the liver, brain (especially basal ganglia and cerebellum), cornea, kidneys, and other organs. Onset is typically between 5 and 35 years of age.

Psychiatric Presentation

Psychiatric symptoms are the presenting feature in 20–30% of Wilson's disease cases, and this is why the condition is critical knowledge for psychiatrists.

Personality change is often the earliest psychiatric manifestation. Patients display disinhibition, impulsivity, emotional lability, and loss of social inhibitions, frequently misinterpreted as conduct disorder in adolescents.

Psychosis may resemble first-episode schizophrenia with paranoid delusions, auditory hallucinations, and thought disorder. The key clinical clue is the combination of psychiatric symptoms with neurological features (dysarthria, tremor, dystonia) and/or liver disease in a young patient.

Affective symptoms include depression, anxiety, and rarely mania. Emotional incontinence (pathological laughing and crying) may occur.

Cognitive impairment is characterised by executive dysfunction, memory impairment, and processing speed reduction, reflecting frontrostriatal circuit involvement.

Neurological Features (concurrent pointers to diagnosis)

• Dysarthria (often the earliest neurological sign)
• Wing-beating or resting tremor
• Dystonia, choreoathetosis
• Parkinsonism
• Cerebellar ataxia
• Seizures (10–15%)

Diagnosis

Kayser-Fleischer (KF) rings: Golden-brown copper deposits in Descemet's membrane of the cornea, seen on slit-lamp examination. Present in >95% of neuropsychiatric Wilson's. Their absence does not exclude the diagnosis in hepatic presentations.

The Leipzig scoring system integrates KF rings, ceruloplasmin, haemolytic anaemia, urine copper, liver copper, and genetic mutation to give a diagnostic score (score ≥4 = Wilson's).

Treatment

D-Penicillamine (first-line chelator):

• Mechanism: chelates copper → increased urinary copper excretion
• Dose: 750–1500 mg/day in divided doses
• Side effects: rash, fever, nephrotoxicity, bone marrow suppression, lupus-like syndrome
• Supplement with pyridoxine (B6)
• Critical warning: paradoxical neurological worsening in first weeks (copper mobilised from liver to brain), switch to trientine if this occurs

Trientine:

• Alternative chelator; better neurological tolerability
• Preferred for neuropsychiatric presentations and penicillamine intolerance
• Dose: 750–1500 mg/day in divided doses

Zinc acetate:

• Mechanism: induces intestinal metallothionein → blocks copper absorption
• Used for maintenance after initial chelation; presymptomatic patients; pregnancy (safest profile)
• Cannot be co-administered with chelators (mutual interference)
• Dose: 50 mg elemental zinc three times daily

Liver transplantation:

• Indicated for fulminant hepatic failure or end-stage liver disease
• Corrects the metabolic defect; improves neurological symptoms partially

Psychiatric drug use in Wilson's:

• Antipsychotics usable for psychosis; atypical antipsychotics preferred (monitor for EPS given basal ganglia involvement)
• Avoid hepatotoxic agents; monitor LFTs
• Penicillamine itself may worsen neuropsychiatric symptoms, consider trientine

Answer 3: Metabolic Syndrome and Antipsychotics: Monitoring and Management

[15 marks]

Definition of Metabolic Syndrome

Metabolic syndrome is a cluster of cardiometabolic risk factors that substantially increase cardiovascular disease and type 2 diabetes risk. By IDF 2006 criteria, diagnosis requires central obesity (waist ≥90 cm men / ≥80 cm women in South Asians) plus any two of: fasting glucose ≥5.6 mmol/L, triglycerides ≥1.7 mmol/L, HDL below sex-specific thresholds, or blood pressure ≥130/85 mmHg.

Antipsychotics and Metabolic Risk

Antipsychotic medications are the primary driver of metabolic syndrome in psychiatric populations, with prevalence of 40–60% in schizophrenia (versus ~25% in the general population).

Mechanisms:

• H1 histamine antagonism → primary driver of weight gain (sedation, orexigenic signalling)
• 5-HT2C serotonin antagonism → increased appetite, impaired satiety
• M3 muscarinic antagonism → direct impairment of pancreatic insulin secretion (diabetogenic)
• D2 dopamine antagonism → mesolimbic appetite dysregulation
• Alpha-1 adrenergic blockade → sedation → reduced physical activity

Weight gain hierarchy (approximate mean weight gain in clinical trials):

Swipe to compare →

ADA/APA Monitoring Guidelines (2004 Consensus)

Action thresholds:

• BMI increase >1 unit in any month → consider switching
• Fasting glucose 100–125 mg/dL → lifestyle counselling, refer
• Fasting glucose >126 mg/dL on two occasions → diabetes; refer, consider switch
• Triglycerides >200 mg/dL → refer
• LDL >130 mg/dL in high-risk patient → pharmacotherapy

Management of Antipsychotic-Induced Metabolic Syndrome

Non-pharmacological interventions:

• Structured aerobic exercise (150 min/week moderate intensity), evidence supports 2–3 kg weight reduction
• Caloric restriction (500 kcal/day deficit); Mediterranean dietary pattern
• Smoking cessation (nicotine replacement, varenicline)
• Dietitian referral

Pharmacological interventions:

1. Metformin, first-line pharmacotherapy for antipsychotic-induced weight gain and hyperglycaemia. Dose 500 mg BD titrated to 1000 mg BD. RCT evidence supports 2–3 kg weight reduction, improved insulin sensitivity.

1. Switching antipsychotic, to metabolically safer agents (aripiprazole, ziprasidone, amisulpride, lurasidone). Cross-titration method preferred. Note: switching from clozapine carries high relapse risk; weigh carefully.

1. Aripiprazole co-prescription, adding aripiprazole to olanzapine or clozapine reduces weight (D2 partial agonism modulates metabolic effects). Dose 5–15 mg/day.

1. Statins, for dyslipidaemia (pravastatin, simvastatin; monitor interactions with CYP3A4 metabolised antipsychotics).

1. GLP-1 receptor agonists, semaglutide, liraglutide showing substantial weight reduction in emerging evidence; increasingly used clinically though not yet standard in most guidelines.

Answer 4: Cushing's Syndrome: Psychiatric Manifestations and Management

[10 marks]

Overview

Cushing's syndrome results from sustained excess glucocorticoid exposure. Endogenous causes include pituitary ACTH-secreting adenoma (Cushing's disease, 70%), adrenal tumours (15%), and ectopic ACTH secretion (10–15%). Exogenous glucocorticoids (iatrogenic Cushing's) are the most common overall cause in clinical practice.

Psychiatric Manifestations

Psychiatric symptoms occur in 50–80% of patients with Cushing's syndrome, making it one of the most psychiatrically significant endocrine disorders.

Depression (50–80%) is the most prevalent manifestation. Features include prominent anhedonia, psychomotor retardation, cognitive impairment, and significant suicidality risk (4–10% attempt suicide). MRI commonly shows hippocampal volume reduction, reflecting cortisol-mediated neurogenesis suppression.

Anxiety (20–70%) ranges from generalised anxiety to panic attacks, often co-occurring with depression.

Cognitive impairment reflects hippocampal vulnerability to hypercortisolaemia, verbal learning, memory consolidation, and attention are most affected.

Psychosis (5–15%) presents with paranoid delusions and hallucinations. Mania may also occur, particularly with exogenous steroids.

Personality change, emotional lability, irritability, interpersonal difficulties, commonly precedes formal psychiatric diagnosis.

Steroid-Induced Psychiatric Disorders

Iatrogenic Cushing's from exogenous steroids produces dose-dependent psychiatric effects:

Classic presentations: early euphoria progressing to depression; "steroid mania" (elevated mood, decreased sleep, grandiosity), occurs early in course; psychosis at higher doses.

Management of steroid-induced psychiatric disorders:

1. Reduce steroid dose if medically permissible (primary intervention)
2. Antipsychotics for mania/psychosis (haloperidol, olanzapine)
3. Mood stabilisers if steroids cannot be tapered (lithium, has prophylactic role for repeat steroid courses)
4. Antidepressants for depressive episodes persisting after dose reduction
5. Monitor resolution, most symptoms remit with dose reduction or steroid cessation

For endogenous Cushing's:

• Treat the primary cause (transsphenoidal surgery for Cushing's disease; adrenalectomy; treat ectopic source)
• Psychiatric symptoms often improve substantially after surgical cure, but may persist, treat pharmacologically as above
• Pre-operatively: symptom management is supportive

Answer 5: Wernicke-Korsakoff Syndrome: Pathogenesis, Features, and Management

[15 marks]

Definition

Wernicke-Korsakoff syndrome (WKS) is a two-stage neuropsychiatric disorder caused by thiamine (vitamin B1) deficiency. Wernicke's encephalopathy (WE) is the acute phase; Korsakoff syndrome (KS) is the chronic amnesic sequel. While classically associated with chronic alcohol use disorder, WKS occurs in any condition causing thiamine depletion.

Pathogenesis

Thiamine is an essential cofactor for three key enzymes in glucose and energy metabolism: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase. Deficiency impairs cerebral energy metabolism, leading to selective neuronal injury in metabolically vulnerable regions with high oxidative demand. The mammillary bodies, periaqueductal grey matter, medial thalamus, and cerebellar vermis are most severely affected, explaining the cardinal features.

Precipitants include: chronic alcohol use (most common), severe malnutrition, prolonged vomiting (hyperemesis gravidarum), bariatric surgery, refeeding syndrome, malignancy, dialysis.

Wernicke's Encephalopathy: Acute Phase

Classic triad (present together in only 16% of cases):

1. Ophthalmoplegia, sixth nerve (lateral rectus) palsy causing lateral gaze paralysis; nystagmus is common
2. Cerebellar ataxia, broad-based, unsteady gait
3. Confusion/encephalopathy, global confusion, disorientation, diminished consciousness

Because the full triad is uncommon, WE is frequently under-diagnosed. Any two features in a nutritionally at-risk patient warrant urgent thiamine treatment.

Pathological findings: haemorrhagic necrosis of mammillary bodies (most characteristic), thalamic nuclei, periaqueductal grey, and cerebellar vermis.

Diagnosis: Primarily clinical. Brain MRI (T2/FLAIR) shows hyperintensities in mammillary bodies and periaqueductal region. Thiamine blood levels are unreliable acutely.

Korsakoff Syndrome: Chronic Amnesic Phase

Korsakoff syndrome develops from untreated or inadequately treated WE, with structural damage to the mammillary bodies and mediodorsal thalamus becoming permanent.

Clinical features:

• Severe anterograde amnesia (inability to form new memories), the cardinal feature
• Variable retrograde amnesia (typically a temporal gradient, recent memories more affected)
• Confabulation, the hallmark: unconscious fabrication of plausible but false memories to fill memory gaps. The patient is not lying; they genuinely believe what they say.
• Relatively preserved immediate recall, language, and procedural memory
• Lack of insight (anosognosia) into memory impairment
• Flat, apathetic affect
• Temporal disorientation (may not know the year)

Prognosis:

• 25% significant recovery with sustained thiamine replacement
• 25% partial recovery
• 50% permanent moderate-to-severe disability
• Only ~10% full recovery

Management

Immediate:

• Thiamine BEFORE any glucose administration, this is the most critical rule. Glucose loading depletes residual thiamine and can precipitate WE in at-risk patients.
• Parenteral thiamine (Pabrinex): 500 mg IV three times daily for minimum 3 days (European Federation of Neurological Societies recommendation)
• Oral thiamine is insufficient for WE, absorption is impaired in malnourished/alcoholic patients
• Maintain electrolyte balance; correct hypomagnesaemia (magnesium is cofactor for thiamine-dependent enzymes)

Ongoing:

• Continue oral thiamine 100 mg TID long-term for Korsakoff syndrome
• Address alcohol dependence with comprehensive addiction treatment
• Neuropsychological rehabilitation (external memory aids, environmental modification)
• No specific pharmacotherapy reverses established Korsakoff syndrome

Prevention:

• Thiamine supplementation in all at-risk patients (alcohol use disorder, malnutrition, post-bariatric)
• Never administer IV glucose in acute presentations without thiamine cover

Answer 6: SIADH and Psychotropic-Induced Hyponatraemia

[10 marks]

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

SIADH is characterised by euvolaemic hyponatraemia resulting from inappropriately elevated ADH secretion relative to serum osmolality. Diagnostic criteria include: serum sodium <135 mEq/L, serum osmolality <280 mOsm/kg, urine osmolality >serum osmolality (inappropriately concentrated), urine sodium >20 mEq/L, clinical euvolaemia, and absence of other causes (hypothyroidism, adrenal insufficiency, renal disease).

Psychotropic Drugs Causing SIADH

Risk factors: age >65 years (most significant), female sex, low body weight, concurrent diuretics, hot weather, high fluid intake, prior hyponatraemia.

Psychiatric Manifestations of Hyponatraemia

Management

1. Mild asymptomatic: fluid restriction (500–1000 mL/day); identify and consider stopping offending drug; close monitoring
2. Moderate: fluid restriction; consider drug switch (e.g., switch SSRI to mirtazapine which has lower SIADH risk; switch carbamazepine to lamotrigine)
3. Severe/symptomatic: 3% hypertonic saline IV, correct at maximum 8–10 mEq/L in 24 hours (maximum 18 mEq/L in 48 hours)
4. Tolvaptan (V2 receptor antagonist): selectively excretes free water; for resistant/recurrent SIADH

Osmotic Demyelination Syndrome (ODS):

The major complication of overly rapid correction. Irreversible demyelination of pons (central pontine myelinolysis) presents as locked-in syndrome, spastic quadriplegia, pseudobulbar palsy. Prevention: never correct faster than 8–10 mEq/L per day. High-risk groups: alcoholics, malnourished, hypokalemia, liver disease.

Answer 7: Hepatic Encephalopathy: Grading, Pathophysiology, and Management

[10 marks]

Definition

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome complicating liver failure or portosystemic shunting, characterised by a spectrum of cognitive, behavioural, and neuromuscular disturbances reversible with treatment of the underlying liver disease.

Pathophysiology

The ammonia hypothesis remains central. In liver failure, portal blood (rich in ammonia from gut bacteria proteolysis of amino acids) bypasses hepatic detoxification and enters the systemic circulation. Hyperammonaemia causes astrocyte swelling (Alzheimer type II astrocytes), increased glutamine synthesis, and cerebral oedema. Concurrent systemic inflammation amplifies ammonia toxicity. Additional mechanisms include: elevated endogenous benzodiazepine-like substances (increased GABAergic tone), manganese deposition (basal ganglia → Parkinsonism-like features), and altered plasma amino acid ratios favouring aromatic amino acids (false neurotransmitter theory).

West Haven Grading

Asterixis (liver flap) = brief, arrhythmic lapses in sustained posture of outstretched hands. Pathognomonic of Grade 2–3 HE.

Management

Step 1: Identify and treat precipitating factors (most important)

• Infection/sepsis, especially spontaneous bacterial peritonitis (most common precipitant)
• GI bleeding, increases gut nitrogen load
• Electrolyte disturbances (hyponatraemia, hypokalaemia)
• Constipation
• Benzodiazepines or sedatives (should be avoided)
• Dehydration, overdiuresis

Step 2: Pharmacological treatment

Step 3: Nutritional management

• Protein restriction is outdated, maintain 1.2–1.5 g/kg/day protein
• Small frequent meals; late-evening snack (reduces overnight catabolism)
• Branched-chain amino acid supplements in severe/refractory HE

Step 4: Definitive treatment

• Liver transplantation for appropriate candidates, resolves HE

Answer 8: Acute Intermittent Porphyria: Psychiatric Features and Drug Safety

[10 marks]

Overview

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by deficiency of porphobilinogen deaminase (PBGD), the third enzyme in the haem biosynthesis pathway. This results in accumulation of the neurotoxic precursors aminolevulinic acid (ALA) and porphobilinogen (PBG). AIP is the most common and most clinically significant acute porphyria. Prevalence is 1–2 per 100,000; predominantly affects premenstrual women.

Psychiatric Manifestations

Psychiatric features may precede, accompany, or dominate the acute attack:

• Anxiety and agitation (most common), severe, acute onset
• Depression, during and between attacks
• Psychosis, auditory hallucinations, paranoid ideation, formal thought disorder; can closely mimic schizophrenia
• Delirium/encephalopathy, in severe attacks
• Personality change, between attacks

Classic acute attack triad:

1. Severe colicky abdominal pain (presenting symptom in most)
2. Peripheral neuropathy (motor > sensory; can progress to respiratory paralysis)
3. Psychiatric manifestations (confusion, anxiety, psychosis)

Additional features: autonomic neuropathy (tachycardia, hypertension), SIADH causing hyponatraemia, seizures, dark red-brown urine (porphobilinogen oxidation).

Drug Safety in AIP

This is a high-priority practical topic for psychiatry:

Unsafe (precipitate attacks):

• Most anticonvulsants: carbamazepine, phenytoin, phenobarbitone (valproate, controversial/generally listed as unsafe)
• Most benzodiazepines (use with caution)
• TCAs (amitriptyline, imipramine)
• Progesterone-containing contraceptives, oestrogens
• Rifampicin, sulfonamides
• Alcohol (major trigger)

Safe options for psychiatric conditions:

• SSRIs: sertraline, citalopram, generally considered safe
• Antipsychotics: haloperidol (generally safe); chlorpromazine (probably safe)
• Anxiolytics: lorazepam (safer than most benzodiazepines)
• Anticonvulsants: gabapentin, levetiracetam
• Analgesics: paracetamol, opioids (morphine, fentanyl)

Management of Acute Attack

1. Identify and eliminate precipitant (especially causative drugs)
2. High-carbohydrate intake (glucose 400 g/day IV or orally), suppresses delta-aminolevulinic acid (ALA) synthase
3. Haem arginate (Normosang) IV, most effective; directly suppresses ALA synthase; administer early
4. Adequate analgesia (opioids are safe)
5. Treat seizures with levetiracetam or gabapentin (NOT phenytoin/carbamazepine)
6. Manage SIADH/hyponatraemia
7. Monitor respiratory function (motor neuropathy can cause respiratory failure)
8. ICU care in severe attacks

Answer 9: Pellagra: Niacin Deficiency and Psychiatric Manifestations

[5 marks]

Overview

Pellagra is a nutritional deficiency syndrome caused by inadequate niacin (vitamin B3) or its precursor tryptophan. It remains endemic in populations dependent on maize-based diets (maize has low bioavailable niacin) and is seen in alcoholics, patients with carcinoid syndrome (tryptophan diverted to serotonin production), Hartnup disease (tryptophan malabsorption), and patients on isoniazid (INH, which blocks pyridoxine, a cofactor for tryptophan-to-niacin conversion).

Psychiatric Manifestations

The classic presentation is the "4 Ds":

1. Dermatitis, photosensitive, symmetrical; Casal's necklace (collar-like distribution around neck)
2. Diarrhoea, watery, mucous, can be bloody
3. Dementia, cognitive decline, confusion, memory impairment
4. Death, if untreated

Psychiatric features include: early anxiety and irritability, depression, cognitive impairment progressing to dementia-like syndrome, psychosis (hallucinations, paranoid ideation), and delirium in severe cases. Mechanism: niacin is the precursor to NAD+ and NADP+, essential for neuronal energy metabolism; deficiency causes widespread neuronal degeneration.

Treatment

Nicotinamide 100–300 mg three times daily, rapid response (days to weeks). Dietary correction; treat underlying cause; pyridoxine supplementation if INH-related.

Answer 10: Phaeochromocytoma: Panic Disorder Mimicry

[5 marks]

Overview

Phaeochromocytoma is a catecholamine-secreting tumour of the adrenal medulla (90%) or extra-adrenal paraganglia (10%). It secretes epinephrine, norepinephrine, and sometimes dopamine in varying ratios.

Psychiatric Mimicry

The paroxysmal catecholamine release produces episodes that are clinically indistinguishable from panic attacks:

• Sudden intense anxiety, palpitations, tremor, diaphoresis
• Headache (throbbing), pallor
• Duration: minutes to hours

Distinguishing features from true panic disorder:

• Hypertension during episodes is severe (systolic >180–200 mmHg), mild or absent in panic disorder
• Pallor (not flushing) during attacks
• Triggers: physical (posture change, exercise, tumour palpation) rather than psychosocial
• Absence of cognitive/cognitive avoidance pattern of panic disorder
• Failed treatment with standard anxiolytics/antidepressants

Diagnostic Approach

• 24-hour urine metanephrines and catecholamines (primary screening)
• Plasma free metanephrines (sensitivity ~97%)
• CT/MRI abdomen after biochemical confirmation
• MIBG scintigraphy for extra-adrenal disease

Treatment: alpha-blockade (phenoxybenzamine) before beta-blockade (important sequence), then surgical resection.

Answer 11: Lithium-Induced Thyroid Dysfunction: Monitoring and Management

[10 marks]

Mechanisms

Lithium impairs thyroid function through multiple mechanisms:

1. Inhibits iodine uptake into thyroid follicular cells
2. Blocks organification of iodine and coupling of iodotyrosines
3. Inhibits TSH-stimulated cAMP generation (blocks thyroid hormone release)
4. Promotes anti-thyroid antibody formation (increased prevalence of Hashimoto's thyroiditis)

Clinical Manifestations

Hypothyroidism (most common): prevalence 20–42% in long-term lithium users. Clinical picture identical to primary hypothyroidism, depression, fatigue, weight gain, cognitive slowing, cold intolerance. Risk is higher in women, those with positive anti-TPO antibodies at baseline, older age, and longer duration of lithium treatment.

Subclinical hypothyroidism: elevated TSH with normal free T4; prevalence up to 40% in lithium-treated patients.

Goitre: diffuse or nodular; seen in 4–60% depending on iodine status and duration of treatment.

Hyperthyroidism: rare (1–2%); may represent a thyroiditis phase preceding permanent hypothyroidism.

Hyperparathyroidism/hypercalcaemia: lithium raises the set-point for PTH-calcium feedback → parathyroid gland hyperplasia → elevated PTH and calcium. Monitor serum calcium in long-term users.

Monitoring Protocol

• Baseline TFTs (TSH and free T4) before initiating lithium
• Every 6 months for the first year
• Annually thereafter (or sooner if symptomatic)
• Screen anti-TPO antibodies at baseline in high-risk patients

Management

• Hypothyroidism on lithium: continue lithium + add levothyroxine. Do NOT stop lithium (unless clinically indicated for other reasons). Treat-to-target TSH within normal range.
• Subclinical hypothyroidism: treat if TSH >10 mIU/L, or if TSH 5–10 with symptoms, or if pregnant
• Goitre: usually benign; monitor; investigate with ultrasound/fine needle aspiration if rapid growth or suspicious features
• Hypercalcaemia: refer to endocrinologist; may require parathyroidectomy in symptomatic primary hyperparathyroidism

Answer 12: Addison's Disease: Psychiatric Features

[5 marks]

Overview

Addison's disease (primary adrenal insufficiency) results from autoimmune destruction of the adrenal cortex in 70–90% of cases in developed countries (tuberculosis is the leading cause in developing countries). Both cortisol and aldosterone are deficient. Physical hallmark is hyperpigmentation (increased ACTH stimulates melanocortin receptors), particularly in buccal mucosa, skin creases, and scars.

Psychiatric Manifestations

Psychiatric symptoms occur in 60–90% of Addison's patients:

• Depression (most common): profound fatigue, anhedonia, apathy, low motivation. Mechanism: cortisol deficiency → disrupted stress response circuitry and monoamine dysregulation.
• Apathy and fatigue: sometimes the predominant presenting feature; may present to psychiatry before endocrine diagnosis established
• Anxiety: generalised anxiety, panic attacks
• Psychosis: rare; resolves with cortisol replacement
• Cognitive impairment: memory problems, slowed processing; reversible with treatment

Adrenal Crisis

Adrenal crisis is precipitated by physiological stress in an inadequately replaced patient. Psychiatric presentation: delirium, acute confusional state, severe agitation. Vitals reveal hypotension, hyponatraemia, hypoglycaemia. Emergency treatment: hydrocortisone 100 mg IV stat, IV saline, glucose; treat precipitant. Do not give psychotropics until the hormonal crisis is treated.

Answer 13: Vitamin B12 Deficiency: Neuropsychiatric Manifestations

[5 marks]

Overview

Vitamin B12 (cobalamin) is obtained exclusively from animal products. Deficiency results from pernicious anaemia (anti-intrinsic factor antibodies, most common cause), gastrectomy, ileal disease, metformin use (blocks ileal B12 absorption), malnutrition, or strict veganism.

Neuropsychiatric Features

• Depression: may be the presenting symptom; responds to B12 replacement
• Cognitive impairment: from mild memory complaints to dementia-like syndrome (reversible if treated early, irreversible if prolonged)
• Megaloblastic madness: classic psychosis from severe B12 deficiency, paranoia, auditory hallucinations
• Irritability, personality change

Neurological Features

Subacute combined degeneration of spinal cord (posterior + lateral columns): proprioception loss → sensory ataxia; spastic paraparesis; peripheral neuropathy (most common early feature).

Diagnosis and Treatment

Serum B12 <200 pg/mL; methylmalonic acid and homocysteine elevated (sensitive functional markers). Treatment: IM hydroxocobalamin 1000 mcg alternate days × 2 weeks, then 3-monthly. Psychiatric symptoms may take weeks to months to respond.

Answer 14: Hyperparathyroidism: "Bones, Stones, Groans, Psychic Moans"

[5 marks]

Primary hyperparathyroidism (parathyroid adenoma in 80%) causes hypercalcaemia through excess PTH. The classic tetrad:

• Bones: osteitis fibrosa cystica, pathological fractures, subperiosteal resorption
• Stones: nephrolithiasis (calcium oxalate), nephrocalcinosis
• Groans: nausea, vomiting, constipation, peptic ulceration, pancreatitis
• Psychic moans: depression (40–60%; most common psychiatric manifestation), anxiety, cognitive impairment (memory, concentration), and psychosis in severe hypercalcaemia

Calcium and neuronal function: hypercalcaemia reduces neuronal excitability and alters monoamine neurotransmitter release. Severity of psychiatric symptoms correlates with calcium levels.

Management: surgical parathyroidectomy (definitive); hydration and bisphosphonates for acute hypercalcaemia. Psychiatric symptoms usually improve after calcium normalisation.

Answer 15: Metabolic Effects of Antipsychotics: Mechanisms and Switching Strategies

[10 marks]

Mechanisms of Antipsychotic-Induced Metabolic Effects

Antipsychotic-induced metabolic syndrome arises through receptor-mediated mechanisms:

H1 histamine antagonism: the primary driver of weight gain. Blockade of hypothalamic H1 receptors impairs satiety signalling and promotes orexigenic NPY/AgRP neuronal activity. The degree of H1 affinity strongly predicts weight gain potential, clozapine and olanzapine have the highest H1 affinity.

5-HT2C serotonin antagonism: promotes appetite and impairs the serotonin-mediated satiety signal from the ventromedial hypothalamus. Compounds with combined H1 + 5-HT2C blockade (clozapine, olanzapine) cause the most weight gain.

M3 muscarinic antagonism: directly impairs pancreatic beta-cell insulin secretion and reduces peripheral glucose uptake, producing hyperglycaemia independent of weight gain. This explains why clozapine can cause new-onset diabetes even before significant weight gain.

D2 dopamine antagonism: mesolimbic D2 blockade may dysregulate the dopaminergic reward circuit's role in appetite regulation.

Alpha-1 adrenergic blockade: sedation and fatigue → reduced physical activity → secondary metabolic consequences.

Weight Gain Hierarchy

Highest risk: clozapine, olanzapine → moderate: quetiapine, risperidone → low: haloperidol, aripiprazole, ziprasidone, amisulpride.

Switching Strategies

Indications for switching: significant weight gain (BMI increase >1 unit/month), new-onset hyperglycaemia or T2DM, dyslipidaemia, patient preference.

Switch targets: aripiprazole, ziprasidone, amisulpride, lurasidone (low metabolic burden).

Methods:

1. Abrupt switch: straightforward for lower-risk medications; higher relapse risk
2. Cross-titration: overlap and taper (most common); reduces withdrawal effects while introducing new drug
3. Plateau method: used particularly for clozapine, taper clozapine to a plateau dose while building up the new agent, then continue tapering clozapine

Special case, clozapine: switching away from clozapine carries a high risk of relapse (clozapine is used for treatment-resistant schizophrenia, alternatives are less effective). Metabolic benefits of switching must be carefully weighed against efficacy loss. Preferred approach: add aripiprazole (5–15 mg) to clozapine rather than switching, reduces weight by ~1.5–2 kg while maintaining clozapine's efficacy.

Pharmacological augmentation without switching:

• Metformin 500–1000 mg BD (first-line)
• Aripiprazole co-prescription to olanzapine/clozapine
• GLP-1 agonists (emerging evidence; increasingly used)
• Statins for dyslipidaemia
• Structured exercise programme (150 min/week)

Mnemonics & Memory Tricks

THYROID DISORDERS

CUSHING'S & ADRENAL

WILSON'S DISEASE

WERNICKE-KORSAKOFF

METABOLIC SYNDROME & ANTIPSYCHOTICS

HYPONATRAEMIA & SIADH

PORPHYRIA

NUTRITIONAL DEFICIENCIES

PARATHYROID DISORDERS

HEPATIC ENCEPHALOPATHY

LITHIUM MONITORING

PHEOCHROMOCYTOMA

Quick Cross-Reference Table

Swipe to compare →

High-Yield Comparisons

Table 1: Hypothyroidism vs Hyperthyroidism: Psychiatric Features

Swipe to compare →

Table 2: Wilson's Disease vs First-Episode Schizophrenia

Table 3: Wernicke's Encephalopathy vs Korsakoff Syndrome

Table 4: Panic Disorder vs Phaeochromocytoma

Table 5: Cushing's Syndrome Depression vs Primary MDD

Table 6: Antipsychotic Metabolic Risk Comparison

Table 7: Safe vs Unsafe Drugs in Acute Intermittent Porphyria

Table 8: Hyponatraemia: SIADH vs Psychogenic Polydipsia

Table 9: Nutritional Deficiency Neuropsychiatric Syndromes

Table 10: Hepatic Encephalopathy: West Haven Grades at a Glance

PYQ Frequency Analysis

Section 1: Frequency Heat Map

Section 2: Topic-by-Topic PYQ Profile

Wilson's Disease ★★★★★ HIGH PRIORITY

How it appears:

• Long answer (15 marks): "Describe the psychiatric manifestations, diagnosis, and management of Wilson's disease."
• Short answer (5–10 marks): "Kayser-Fleischer rings, significance in psychiatry," "Treatment of Wilson's disease," "Psychiatric presentation of Wilson's disease"
• MCQ: ceruloplasmin levels, ATP7B gene locus, safe antipsychotic use, penicillamine side effects

Exact phrasings seen:

• "A 22-year-old presents with personality change, slurred speech, and a first episode of psychosis. Discuss your approach."
• "Enumerate the psychiatric manifestations of Wilson's disease and outline its management."
• "What is the role of zinc in Wilson's disease?"

What examiners want:

1. Pathophysiology (ATP7B, copper accumulation)
2. Three-system triad: psychiatric + neurological + hepatic
3. KF rings on slit-lamp, must name slit-lamp specifically
4. Investigations table (ceruloplasmin, 24h urine copper, liver biopsy values)
5. Treatment: penicillamine → trientine → zinc (maintenance), all three drugs with mechanisms
6. Neurological worsening warning with penicillamine

Antipsychotic-Induced Metabolic Effects ★★★★★ HIGH PRIORITY

How it appears:

• Long answer: "Metabolic syndrome and antipsychotics, discuss with reference to monitoring guidelines."
• Short answer: "ADA/APA monitoring guidelines for antipsychotic-induced metabolic syndrome," "Weight gain with antipsychotics, mechanism and management"
• MCQ: which antipsychotic causes most weight gain; monitoring interval for fasting glucose; mechanism of olanzapine-induced diabetes

Exact phrasings seen:

• "Discuss the metabolic complications of second-generation antipsychotics and their monitoring."
• "A patient on clozapine develops weight gain and hyperglycaemia. How will you manage?"
• "Enumerate receptor mechanisms by which antipsychotics cause metabolic syndrome."

What examiners want:

1. Receptor mechanisms (H1, 5-HT2C, M3, D2, all four)
2. Weight gain hierarchy table (clozapine and olanzapine at the top)
3. ADA/APA monitoring table (baseline → 4 → 8 → 12 weeks → annual)
4. Management: metformin, switching strategy, aripiprazole augmentation
5. Special note: clozapine switching dilemma (efficacy vs metabolic risk)

Wernicke-Korsakoff Syndrome ★★★★★ HIGH PRIORITY

How it appears:

• Long answer: "Describe the clinical features, pathology, and management of Wernicke-Korsakoff syndrome."
• Short answer: "Korsakoff syndrome," "Thiamine deficiency and psychiatry," "Confabulation, clinical significance"
• MCQ: pathological site affected; treatment dose; rule about glucose administration

Exact phrasings seen:

• "A 48-year-old man with alcohol dependence is brought in confused, with lateral gaze palsy and unsteady gait. Discuss."
• "What is the rule of thiamine and glucose administration? Why is it important?"
• "Enumerate the features of Korsakoff psychosis."

What examiners want:

1. Pathogenesis: thiamine → pyruvate dehydrogenase → energy failure → mammillary bodies
2. WACO triad, with the caveat that only 16% have all three
3. Pathological sites: mammillary bodies (most characteristic), periaqueductal grey, thalamus
4. Thiamine before glucose rule, stated explicitly
5. IV Pabrinex dose: 500 mg TID × 3 days minimum
6. Korsakoff: anterograde amnesia + confabulation + anosognosia
7. Prognosis: 25/25/50 rule

Thyroid Disorders & Psychiatry ★★★★

How it appears:

• Long answer: "Thyroid disorders and their psychiatric manifestations, a comprehensive account."
• Short answer: "Myxedema madness," "T3 augmentation in depression," "Hashimoto's encephalopathy"
• MCQ: TFT values, lithium monitoring intervals, T3 mechanism in depression

Exact phrasings seen:

• "Discuss the role of thyroid hormones in psychiatry with special reference to treatment of depression."
• "What is myxedema madness? How is it different from primary psychosis?"
• "Enumerate the indications for TFT screening in psychiatric practice."

What examiners want:

1. Spectrum of hypothyroid psychiatric manifestations (depression → myxedema madness)
2. Hyperthyroid anxiety/mania, brief
3. T3 augmentation: mechanism, dose, STAR*D evidence
4. Lithium-thyroid interactions: monitoring protocol, management of hypothyroidism
5. When to screen TFTs, comprehensive list

Lithium-Induced Thyroid Dysfunction ★★★★

How it appears:

• Short answer (most common): "Lithium and thyroid, what does the clinician need to know?"
• Part of longer answer on lithium monitoring
• MCQ: monitoring interval, management, risk factors for hypothyroidism

What examiners want:

1. Four mechanisms of lithium-thyroid interaction
2. Prevalence: 20–42% hypothyroidism
3. Risk factors (female, anti-TPO positive, older, longer duration)
4. Monitoring: 6-monthly for year 1, then annual
5. Management: continue lithium + add levothyroxine

Metabolic Syndrome Monitoring ★★★★

How it appears:

• Short/medium answer: "ADA/APA monitoring guidelines for antipsychotic-induced metabolic syndrome"
• Part of larger antipsychotic question

What examiners want:

• The full monitoring table reproduced accurately
• Action thresholds for each parameter
• Metformin as first-line pharmacological intervention

Hepatic Encephalopathy ★★★

How it appears:

• Long/medium answer: "Hepatic encephalopathy, grading, pathophysiology, management."
• Short answer: "West Haven grading of hepatic encephalopathy," "Role of lactulose in HE"
• MCQ: precipitants, grade of asterixis, first-line treatment

Exact phrasings seen:

• "Describe the West Haven grading of hepatic encephalopathy with clinical features."
• "Enumerate the precipitants of hepatic encephalopathy and outline its management."

What examiners want:

1. Ammonia hypothesis, brief pathophysiology
2. West Haven grades 0–4 table (full features)
3. Asterixis: grade 2 onset, grade 4 disappears
4. Precipitants: SBP most common
5. Lactulose first-line; rifaximin add-on; protein restriction is outdated

Cushing's Syndrome ★★★

How it appears:

• Long answer: "Psychiatric manifestations of Cushing's syndrome and steroid-induced psychiatric disorders."
• Short answer: "Steroid-induced mania," "Dose-response relationship of glucocorticoids and psychiatric side effects"
• MCQ: most common psychiatric manifestation; dose threshold; management

Exact phrasings seen:

• "A patient on high-dose prednisolone for SLE develops manic symptoms. Discuss."
• "Enumerate the psychiatric manifestations of Cushing's syndrome."

What examiners want:

1. Psychiatric manifestations: depression (50–80%) > anxiety > psychosis > mania
2. Dose-response table (the three thresholds)
3. Steroid mania, early, dose-related
4. Management: reduce dose → antipsychotics → mood stabilisers
5. Lithium prophylaxis for repeated steroid courses

SIADH and Psychotropic-Induced Hyponatraemia ★★★

How it appears:

• Medium answer: "Psychotropic-induced hyponatraemia, causes, features, management."
• Short answer: "SIADH and SSRIs," "Osmotic demyelination syndrome"
• MCQ: which drug causes most SIADH; correction rate; ODS risk factors

Exact phrasings seen:

• "Enumerate psychotropic drugs that cause SIADH and outline management of hyponatraemia."
• "What is osmotic demyelination syndrome? How is it prevented?"

What examiners want:

1. Drug list with mechanism (SSRIs, carbamazepine, oxcarbazepine, oxcarbazepine > carbamazepine)
2. Diagnostic criteria for SIADH
3. Correction rate: max 8–10 mEq/L per 24h
4. ODS, definition, features, prevention

Acute Intermittent Porphyria ★★★

How it appears:

• Medium answer: "Acute intermittent porphyria, psychiatric features and drug safety."
• Short answer: "Safe drugs in porphyria," "Treatment of acute porphyria attack"
• MCQ: unsafe anticonvulsant; safe analgesic; treatment

Exact phrasings seen:

• "A patient with recurrent abdominal pain, peripheral neuropathy, and psychosis is suspected to have porphyria. Discuss."
• "Enumerate safe and unsafe psychiatric drugs in acute intermittent porphyria."

What examiners want:

1. Triad: abdominal pain + neuropathy + psychiatric features
2. Dark urine (PBG oxidation)
3. Drug safety table, at least 3 unsafe + 3 safe in each class
4. Treatment: haem arginate + high carbohydrate + levetiracetam for seizures

Nutritional Deficiencies ★★★

How it appears:

• Medium answer: "Neuropsychiatric features of nutritional deficiencies."
• Short answer: "Pellagra," "B12 deficiency and psychiatry," "Wernicke's encephalopathy" (crossover with WKS section)
• MCQ: deficiency → specific syndrome; treatment drug

What examiners want:

The B-vitamin table: B1 (Wernicke-Korsakoff), B3 (Pellagra, 4Ds), B9 (Folate, depression/antidepressant augmentation), B12 (SACD + megaloblastic madness)

Phaeochromocytoma ★★

How it appears:

• Short answer or MCQ only
• "Panic disorder vs phaeochromocytoma, how to differentiate?"
• MCQ: diagnostic test, distinguishing feature

What examiners want:

• 4Ps (paroxysmal hypertension, palpitations, perspiration, pallor/pain)
• Distinguishing features from panic disorder (severe BP, pallor, physical triggers)
• Diagnostic test: 24h urine metanephrines / plasma free metanephrines
• Management sequence: alpha-blockade before beta-blockade

Section 3: Mark Allocation Patterns

Swipe to compare →

Section 4: Recurring Examiner Angles

These specific angles have appeared repeatedly across papers:

1. "Young patient with psychiatric + neurological + hepatic features"

→ Always Wilson's disease. State: KF rings, ceruloplasmin, 24h urine copper, Leipzig score.

2. "Patient on lithium develops depression/cognitive slowing"

→ Lithium-induced hypothyroidism. State: continue lithium + add levothyroxine. Do not stop lithium.

3. "Patient on olanzapine/clozapine gains weight and develops hyperglycaemia"

→ ADA/APA monitoring protocol. State: metformin + lifestyle + consider aripiprazole add-on or switch.

4. "Alcohol-dependent patient brought in confused"

→ Wernicke's encephalopathy. State: IV thiamine before glucose; Pabrinex 500 mg TID; WACO triad.

5. "Chronic alcohol patient with severe anterograde amnesia and confabulation"

→ Korsakoff syndrome. State: mammillary body damage; anterograde > retrograde; confabulation ≠ lying; 50% permanent.

6. "Patient on SSRIs develops confusion and Na = 122 mEq/L"

→ Psychotropic-induced SIADH. State: fluid restriction; correct slowly (max 8–10 mEq/L/day); ODS risk if overcorrected.

7. "Patient with recurrent 'panic attacks' but severe hypertension during episodes"

→ Phaeochromocytoma. State: 4Ps; plasma free metanephrines; alpha before beta blockade.

8. "Recurrent abdominal pain + psychiatric symptoms + peripheral neuropathy"

→ Acute intermittent porphyria. State: dark urine; haem arginate; high carbohydrate; unsafe drugs list.

Section 5: Numbers Worth Memorising

Section 6: Topics Commonly Neglected (Worth 5–10 Marks Each)

These topics appear infrequently but reliably, and students often skip them:

1. Hashimoto's encephalopathy (SREAT), steroid-responsive; anti-TPO antibodies; not directly thyroid-hormone-mediated
2. Sheehan's syndrome, postpartum pituitary necrosis; chronic fatigue + depression; missed diagnosis
3. Fahr's disease, basal ganglia calcification in hypoparathyroidism; movement disorder + neuropsychiatric features
4. Metformin and B12 deficiency, drug interaction worth knowing; screen B12 annually in psychiatric patients on metformin
5. Lithium and hyperparathyroidism/hypercalcaemia, serum calcium monitoring; parathyroid gland hyperplasia mechanism
6. GLP-1 agonists for antipsychotic-induced obesity, emerging evidence; semaglutide; increasingly relevant clinically
7. Polydipsia in schizophrenia, distinct from SIADH; low urine osmolality; clozapine may reduce it
8. Adult GH deficiency syndrome, GH replacement improves mood and QoL; post-Sheehan's context

Quick Review

Q1. What is the most common psychiatric manifestation of hypothyroidism?

R Depression (40–60% of hypothyroid patients). Character: anhedonia, psychomotor retardation, fatigue, cognitive slowing. Often fails to respond to antidepressants without thyroid replacement.

Q2. A patient on long-term lithium develops fatigue, weight gain, and a TSH of 12 mIU/L with normal free T4. What is your management?

A Lithium-induced subclinical/overt hypothyroidism. Management: continue lithium + add levothyroxine (do NOT stop lithium). Target TSH to normal range. Do not sacrifice mood stability for thyroid.

Q3. What is myxedema madness? Who first described it?

R Acute psychiatric manifestation of severe prolonged hypothyroidism, paranoid psychosis, hallucinations, delirium. First described by Asher (1949). Context: severe systemic myxedema (periorbital puffiness, macroglossia, hypothermia, bradycardia).

Q4. Name the four receptor mechanisms by which antipsychotics cause metabolic syndrome.

R (1) H1 histamine antagonism → weight gain (primary); (2) 5-HT2C antagonism → appetite increase; (3) M3 muscarinic antagonism → impaired pancreatic insulin secretion → direct diabetogenic; (4) D2 antagonism → mesolimbic appetite dysregulation.

Q5. A 26-year-old presents with personality disinhibition, dysarthria, and paranoid psychosis. What must you exclude and what are the first three investigations?

A Exclude Wilson's disease. First three: (1) Slit-lamp examination for Kayser-Fleischer rings; (2) Serum ceruloplasmin (<0.2 g/L in Wilson's); (3) 24-hour urine copper (>100 mcg/24h symptomatic).

Q6. What is the gene and chromosome involved in Wilson's disease?

R ATP7B gene on chromosome 13q14. Encodes a copper-transporting ATPase. Autosomal recessive inheritance.

Q7. In Wilson's disease treatment, what is the risk of starting D-penicillamine in a patient with neurological/psychiatric presentation?

A Paradoxical neurological worsening in the first weeks, copper is mobilised from the liver and redistributed to the brain, worsening symptoms. Trientine is preferred over penicillamine for neuropsychiatric Wilson's because it carries lower risk of this deterioration.

Q8. What is the role of zinc in Wilson's disease and why can it not be given simultaneously with chelators?

A Zinc induces metallothionein in intestinal epithelial cells, which binds copper and blocks its absorption. It is used for maintenance therapy and in presymptomatic patients. It cannot be co-administered with penicillamine or trientine because they chelate zinc, reducing both drugs' efficacy.

Q9. State the classic triad of Wernicke's encephalopathy and its frequency of full presentation.

R WACO triad: (W)atching, Ophthalmoplegia (6th nerve palsy, nystagmus); (A)taxia, cerebellar, gait; (C)onfusion, global encephalopathy. Full triad present in only 16% of cases.

Q10. Why must thiamine always be given before glucose in at-risk patients?

A Glucose administration requires thiamine as a cofactor for pyruvate dehydrogenase. In a thiamine-depleted state, IV glucose drives pyruvate accumulation and energy failure in metabolically vulnerable brain regions (mammillary bodies, periaqueductal grey), precipitating or worsening Wernicke's encephalopathy. This is irreversible if not prevented.

Q11. What is the IV thiamine dose for Wernicke's encephalopathy per European guidelines?

R Pabrinex (high-potency parenteral thiamine): 500 mg intravenously three times daily for a minimum of 3 days. Oral thiamine is insufficient, absorption is impaired in malnourished and alcohol-dependent patients.

Q12. List the three cardinal features of Korsakoff syndrome.

R (1) Severe anterograde amnesia (inability to form new memories, cardinal feature); (2) Confabulation, unconscious fabrication of memories, not deliberate lying; (3) Anosognosia, lack of insight into memory impairment.

Q13. What is the prognosis of Korsakoff syndrome?

R 25/25/50 rule: approximately 25% significant recovery, 25% partial recovery, 50% permanent moderate-to-severe disability. Only ~10% make complete recovery. Thiamine maintenance does not reverse established damage but prevents further progression.

Q14. Rank these antipsychotics from highest to lowest weight gain: aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, ziprasidone.

R Clozapine (+4.5 kg) > Olanzapine (+4.2 kg) > Quetiapine (+2.3 kg) > Haloperidol (+0.5 kg) > Aripiprazole (+0.7 kg) > Ziprasidone (+0.04 kg).

Q15. At what intervals should weight/BMI and fasting glucose be checked when starting an antipsychotic, per ADA/APA guidelines?

R Weight/BMI: baseline, then at 4, 8, and 12 weeks, then at every visit for the first year (minimum). Fasting glucose: baseline, 12 weeks, then annually. Fasting lipids: baseline, 12 weeks, then every 5 years (or annually in high-risk).

Q16. First-line pharmacological treatment for antipsychotic-induced weight gain?

R Metformin 500 mg twice daily, titrated to 1000 mg twice daily. Reduces weight by 2–3 kg on average, improves insulin sensitivity, and reduces HbA1c. Safe in combination with antipsychotics.

Q17. Which two psychotropics carry the highest risk of SIADH, and what is the relative risk between them?

A Carbamazepine and oxcarbazepine. Oxcarbazepine causes SIADH more frequently than carbamazepine, this is the classic exam trap. Both directly potentiate ADH secretion/action. SSRIs are the most common drug class overall due to prescribing volume, but oxcarbazepine has the highest per-drug risk among AEDs/mood stabilisers.

Q18. What is osmotic demyelination syndrome (ODS) and how is it prevented?

A ODS (central pontine myelinolysis) is irreversible demyelination of the pons (and extrapontine areas) caused by overly rapid correction of chronic hyponatraemia. It presents as locked-in syndrome, spastic quadriplegia, and pseudobulbar palsy. Prevention: correct serum sodium at a maximum rate of 8–10 mEq/L per 24 hours (maximum 18 mEq/L in 48 hours). High-risk patients: chronic alcoholics, malnourished, hypokalemia, liver disease.

Q19. What are the "4 Ps" of phaeochromocytoma and how does it differ from panic disorder?

R 4 Ps: Paroxysmal hypertension, Palpitations, Perspiration (diaphoresis), Pallor/Pain (headache). Differs from panic disorder by: severe hypertension (>200 mmHg systolic) during episodes; pallor not flushing; physical triggers (posture, exercise); failure to respond to anxiolytics/SSRIs; elevated 24h urinary/plasma metanephrines.

Q20. What is the diagnostic test of choice for phaeochromocytoma?

R Plasma free metanephrines (sensitivity ~97%, specificity ~85%), test of choice for initial biochemical screening. Alternative: 24-hour urinary metanephrines and catecholamines. Imaging (CT/MRI adrenals) only after biochemical confirmation.

Q21. State the "bones, stones, groans, psychic moans" tetrad and its most common psychiatric manifestation.

R Hyperparathyroidism tetrad: Bones (osteitis fibrosa, fractures), Stones (nephrolithiasis), Groans (GI: nausea, constipation, pancreatitis), Psychic moans (psychiatric). Most common psychiatric manifestation: depression (40–60%). Mechanism: hypercalcaemia reduces neuronal excitability and alters monoamine neurotransmitter release.

Q22. Name the classic triad of acute intermittent porphyria and its diagnostic urine finding.

R Triad: (1) Severe colicky abdominal pain; (2) Peripheral neuropathy (motor > sensory); (3) Psychiatric manifestations (anxiety, psychosis, delirium). Urine finding: dark red-brown urine on standing, porphobilinogen (PBG) oxidation. Confirm with urine porphobilinogen (quantitative).

Q23. Name three safe and three unsafe psychiatric drugs in acute intermittent porphyria.

R Safe: sertraline (SSRI), haloperidol (antipsychotic), gabapentin (anticonvulsant/anxiolytic). Unsafe: carbamazepine, amitriptyline (TCA), phenobarbitone (anticonvulsant). Treatment of acute attack: haem arginate (Normosang) IV + high carbohydrate (400 g/day) + levetiracetam for seizures.

Q24. What are the psychiatric features of pellagra and what drug commonly induces it?

R Psychiatric features: anxiety, irritability, depression, cognitive impairment progressing to dementia, psychosis, delirium. Caused by niacin (vitamin B3) deficiency. Drug-induced: isoniazid (INH) blocks pyridoxine (B6) → impairs tryptophan-to-niacin conversion → pellagra. Prevented by co-prescribing pyridoxine with INH. Classic presentation: 4 Ds (Dermatitis, Diarrhoea, Dementia, Death).

Q25. What are the neuropsychiatric features of vitamin B12 deficiency?

R Depression (may be first symptom); cognitive impairment (mild to dementia-like, reversible if treated early); megaloblastic madness (psychosis, paranoia, hallucinations); peripheral neuropathy; subacute combined degeneration of the spinal cord (posterior + lateral columns → sensory ataxia + spastic paraparesis). Drug cause: metformin blocks ileal B12 absorption, screen annually in psychiatric patients on long-term metformin.

Q26. What is the most common psychiatric manifestation of Cushing's syndrome and what is the suicide risk?

R Depression is the most common, occurring in 50–80% of patients. Character: prominent anhedonia, psychomotor retardation, cognitive impairment, hippocampal atrophy. Suicide attempt risk: 4–10% of patients with Cushing's syndrome. This makes it one of the most high-risk endocrine-psychiatric comorbidities.

Q27. A patient with SLE is started on prednisolone 80 mg/day. After 5 days she develops elevated mood, decreased sleep, and grandiosity. What is the diagnosis and management?

A Steroid-induced mania ("steroid mania"). Occurs early in course, dose-related (>80 mg/day = 18.4% risk). Management: (1) Reduce prednisolone dose if medically permissible, first and most important step; (2) Antipsychotic for acute mania control (olanzapine, haloperidol); (3) Mood stabiliser (valproate or lithium) if steroids cannot be tapered; (4) Lithium has prophylactic role if repeated steroid courses anticipated.

Q28. What is the West Haven Grade at which asterixis (liver flap) first appears, and at which grade does it disappear?

R Asterixis first appears at Grade 2 (lethargic, disoriented, personality change). It disappears at Grade 4 (coma), because asterixis requires voluntary muscle tone, which is absent in coma. This is a key clinical landmark: onset of asterixis signals Grade 2 and the need to escalate treatment.

Q29. What is the most common precipitant of acute hepatic encephalopathy in cirrhotic patients, and what is the first-line treatment?

R Most common precipitant: spontaneous bacterial peritonitis (SBP), always check with diagnostic paracentesis (neutrophils >250/mm³). First-line treatment: lactulose 15–30 mL three times daily, titrated to 2–3 soft stools per day. Second step: add rifaximin 550 mg twice daily for recurrent/refractory HE. Protein restriction is outdated, maintain 1.2–1.5 g/kg/day.

Q30. What are the three organ systems lithium affects long-term that require routine monitoring, and what specific test is used for each?

R (1) Thyroid, TFTs (TSH + free T4): 6-monthly for year 1, then annually; (2) Kidneys, RFTs (creatinine, eGFR) + urinalysis: 6-monthly; lithium level; (3) Parathyroid, serum calcium: annually (lithium raises PTH set-point → parathyroid hyperplasia → hypercalcaemia → nephrocalcinosis). Plus ECG at baseline and with dose changes (cardiac effect).

Rapid Concept Index