Psychotropic Medicines in Liver Disease

Psychotropic prescribing in liver disease is common because depression, anxiety, alcohol use disorder and delirium are frequent in chronic liver disease, and it is risky because most psychotropic drugs are hepatically metabolised, sedating or capable of causing liver injury. The main hazards are precipitation of hepatic encephalopathy, accumulation of parent drug and active metabolites, idiosyncratic hepatotoxicity, hyponatraemia, QT prolongation and bleeding.

Principles. Start at one half to one quarter of the usual dose, increase slowly at intervals of 1 to 2 weeks, use one agent, and treat precipitants of confusion before attributing it to a psychiatric cause.

Bleeding. Serotonergic antidepressants impair platelet function. The risk is highest with non-steroidal anti-inflammatory drugs, anticoagulants, or large unbanded varices.

Hyponatraemia. Serotonergic antidepressants cause hyponatraemia, which adds to the effect of diuretics and worsens encephalopathy.

QT interval. Cirrhosis itself prolongs the QT interval. Check a baseline ECG before citalopram, escitalopram, haloperidol, quetiapine or methadone.

Depression and anxiety.

Antidepressants to avoid. Duloxetine in any chronic liver disease, agomelatine (contraindicated), nefazodone, and tricyclic antidepressants in decompensated disease. If a tricyclic is unavoidable, start amitriptyline or nortriptyline at 10 mg at night.

Antipsychotics and agitation.

• Haloperidol 0.5 to 1 mg orally or intramuscularly, maximum usually 5 mg in 24 hours in frail or older patients.
• Quetiapine 12.5 to 25 mg orally at night, increased by 25 mg daily steps; maximum usually 150 to 300 mg daily in hepatic impairment.
• Risperidone 0.5 mg orally twice daily, increased in steps of 0.5 mg twice daily no more often than weekly above 1.5 mg twice daily.
• Olanzapine 5 mg orally at night in moderate impairment, titrated with care.
• Avoid chlorpromazine (cholestatic injury and sedation) and use clozapine only under specialist care, avoiding it in severe impairment.

Mood stabilisers. - Lithium is renally cleared and not hepatotoxic. Aim for a level of 0.6 to 0.8 mmol/L for maintenance. Diuretics, non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, and hyponatraemia in ascites raise the level and toxicity risk. - Lamotrigine: reduce initial dose, escalation steps and maintenance dose by about 25% in moderate or severe impairment without ascites, and by about 50% in severe impairment with ascites. - Avoid valproate. Use carbamazepine only with specialist input.

Attention deficit disorder. Atomoxetine at 50% of the usual dose in Child-Pugh B and 25% in Child-Pugh C; stop at the first sign of jaundice or ALT rise.

Alcohol use disorder.

• Acamprosate 666 mg orally three times daily (body weight over 60 kg); 333 mg three times daily if creatinine clearance is 30 to 50 mL/min; contraindicated if creatinine clearance is under 30 mL/min or in Child-Pugh C.
• Baclofen 5 mg orally three times daily, increased every 3 to 7 days to a maximum of 10 mg three times daily; renally cleared, so reduce in kidney impairment and watch for sedation and encephalopathy.
• Naltrexone 50 mg orally daily only in compensated disease with stable liver tests; avoid in acute hepatitis and decompensation.
• Disulfiram is contraindicated in cirrhosis.
• Thiamine 100 mg orally three times daily for all patients drinking heavily.

Insomnia and anxiety. Avoid benzodiazepines and hypnotics where possible. Where one is essential, use lorazepam 0.5 mg orally for a few days only.

Pregnancy. Sertraline has the most reassuring data. Valproate is contraindicated. Lithium requires specialist planning and level monitoring.

Breastfeeding. Sertraline is the preferred antidepressant. Avoid doxepin and citalopram at high doses. Observe the infant for sedation when a benzodiazepine is used.

Older adults. Increased risk of falls, hyponatraemia and bleeding. Halve starting doses again.

Kidney impairment. Adjust lithium, baclofen, acamprosate and gabapentinoids. Hepatorenal physiology makes creatinine unreliable, so lower doses.

East Africa. Khat chewing has been linked to liver injury and can precipitate psychosis or mania; ask specifically. Herbal products are frequently taken with antidepressants, and St John’s wort induces enzymes and lowers levels of many drugs.

Interactions. Diuretics with SSRIs (hyponatraemia), SSRIs with anticoagulants or aspirin (bleeding), enzyme inducers such as rifampicin and carbamazepine with sertraline, and fluvoxamine (inhibits CYP1A2 and CYP2C19) with quetiapine, clozapine and many other drugs.

Baseline. Liver tests, INR, sodium, creatinine, ECG and mental state including a sedation and flap check.

Monitoring. Sodium 2 and 4 weeks after starting an SSRI and after any diuretic change. Liver tests at 2 to 4 weeks and again at 3 months. Lithium level 5 to 7 days after any dose or diuretic change, then every 3 months. QTc after dose increases.

Stopping. Stop the drug for ALT over 3 times the upper limit of normal with symptoms, jaundice, new encephalopathy, sodium under 125 mmol/L, or QTc over 500 ms. Taper antidepressants over at least 4 weeks unless stopped for toxicity.

Referral and escalation. Refer to liaison psychiatry for treatment-resistant depression, psychosis, suicidal ideation, delirium tremens, and any use of lithium or clozapine in liver disease.