How to manage psychosis induced by anticancer (anti-cancer) drugs?

Management of Anticancer Drug-Induced Psychosis

Immediately discontinue the offending anticancer agent when psychosis develops, as most episodes are idiosyncratic and reverse after withdrawal of the medication. 1

Immediate Actions

Discontinue the Causative Agent

• Withdraw the anticancer drug immediately as the primary intervention, since delirium and psychosis from chemotherapy and immunotherapies typically resolve when the therapeutic agent is stopped. 1
• Anticancer agents that cross the blood-brain barrier (capecitabine, topotecan, ifosfamide) are most frequently implicated in causing confusion and acute encephalopathy. 1
• Novel cancer immunotherapies can trigger psychosis through acute release of inflammatory cytokines, which usually resolves with drug cessation. 1

Rule Out Other Reversible Causes

Before attributing psychosis solely to the anticancer drug, systematically evaluate and correct:

• Metabolic derangements: Check for hypercalcemia (common with bone metastases), hypomagnesemia (from cisplatin or cetuximab), and SIADH (from platinum-based chemotherapy or vinca alkaloids). 1
• Electrolyte abnormalities: Hypomagnesemia specifically causes confusion, hallucinations, irritability, and seizures—treat with IV magnesium sulfate replacement. 1
• SIADH management: Discontinue implicated medications, implement fluid restriction, and ensure adequate oral salt intake. 1
• Hypercalcemia treatment: Use IV bisphosphonates (zoledronic acid 4 mg) or denosumab for refractory cases to promote calciuresis. 1

Pharmacological Management of Psychotic Symptoms

First-Line Antipsychotic Treatment

Start with low-dose olanzapine 2.5-5 mg orally or subcutaneously as the preferred first-line agent for managing psychotic symptoms in cancer patients. 2, 3

• Olanzapine has demonstrated superior efficacy in improving delirium and agitation in patients with advanced cancer compared to other antipsychotics. 3
• The American Society of Clinical Oncology recommends antipsychotics as the mainstay of pharmacological treatment for delirium with agitation. 2
• Start at the lower end of dosing (2.5 mg) in elderly patients due to age-related changes in drug metabolism. 3

Alternative Antipsychotic Options

If olanzapine is not tolerated or available:

• Quetiapine 25 mg immediate release orally every 12 hours if scheduled dosing is required—has lower risk of extrapyramidal side effects and sedating properties helpful for agitation. 2, 3
• Haloperidol 0.5-1 mg orally or subcutaneously as a second-line option for acute management, with lower doses in older or frail patients. 2
• Risperidone 0.5 mg orally at reduced doses in older patients and those with severe renal or hepatic impairment. 3

Dosing Strategy

• Begin antipsychotics on an as-needed (PRN) basis initially, implementing regular scheduled dosing only for persistent distressing symptoms and for the shortest time possible. 2
• No medication is currently licensed specifically for delirium management worldwide, requiring off-label use. 2

Role of Benzodiazepines

Avoid benzodiazepines as monotherapy except in specific circumstances:

• Use benzodiazepines only for alcohol or benzodiazepine withdrawal delirium, or as crisis medication for severe agitation unresponsive to antipsychotics. 2
• If needed for refractory agitation, use lorazepam 0.25-0.5 mg subcutaneously or intravenously in elderly patients. 2, 3
• Critical warning: Fatalities have been documented when benzodiazepines are combined with high-dose olanzapine, particularly in elderly populations, through oversedation and respiratory depression. 4

Monitoring and Safety Considerations

Antipsychotic Monitoring

Monitor for common side effects:

• Extrapyramidal symptoms
• Sedation and orthostatic hypotension (increases fall risk)
• QTc prolongation
• Paradoxical worsening of delirium 2, 3

Important Caveats

• Antipsychotics themselves can potentially cause or worsen delirium, requiring careful monitoring. 2, 3
• Short-term use at the lowest effective dose is recommended, particularly when the patient poses a risk to themselves or others. 3
• Treatment is aimed at the underlying medical cause (drug withdrawal) and control of psychotic symptoms simultaneously. 1

Non-Pharmacological Interventions

Address contributing factors while managing acute symptoms:

• Ensure effective communication and orientation measures with adequate lighting and familiar objects to reduce confusion. 2
• Treat pain, constipation, or urinary retention as these can worsen delirium. 2
• Consider opioid rotation if delirium worsens despite antipsychotic therapy, as neurotoxicity from the current opioid could be contributing. 3

Prognosis and Follow-Up

• Most anticancer drug-induced psychotic episodes are idiosyncratic and reverse after withdrawal of the offending medication. 1
• Secondary causes of psychosis from drug-related side effects and toxicity require treatment aimed at the underlying medical cause. 1
• Once stabilized, gradually discontinue antipsychotics when the patient is in stable condition. 5