Anticancer Drugs That Cause Psychosis
Ifosfamide is the anticancer drug most notably associated with psychosis and other severe neuropsychiatric toxicities, including confusion, hallucinations, delirium, and coma. 1
Primary Offender: Ifosfamide
The FDA explicitly warns that CNS toxicities such as confusion and coma are associated with ifosfamide use and may require cessation of therapy. 1 This alkylating agent produces dramatic neuropsychiatric effects that can manifest as:
- Visual and paranoid hallucinations (reported in 5 of 7 patients experiencing CNS effects in one series) 2
- Complete confusion and disorientation 2
- Isolated psychotic disorder with delusions 3
- Acute delirium and agitation 4
- Persistent organic brain syndrome lasting up to 10 weeks in some cases 2
Clinical Presentation and Timing
Neurotoxicity typically manifests by the end of the 24-hour infusion period, with symptoms appearing rapidly during or immediately after administration. 5 The incidence is substantial, with 26% of patients experiencing grade 4 neurotoxicity in one gynecologic oncology series. 5
Critical Risk Factor: Hypoalbuminemia
Low serum albumin (<3.5 g/dL) is strongly associated with severe ifosfamide neurotoxicity. When albumin was below this threshold, 6 of 12 cycles resulted in severe neurotoxicity (P < 0.001), compared to no neurotoxicity in 63 cycles when albumin was normal. 5 This represents a critical screening parameter before ifosfamide administration.
Other Chemotherapy Agents Associated with Psychosis/Delirium
According to ESMO guidelines, multiple chemotherapy agents can cause confusion and delirium (which may include psychotic features): 6
- Methotrexate
- Cisplatin (also reported in a case of psychotic disorder with bleomycin and etoposide) 7
- Vincristine
- Procarbazine
- Asparaginase
- Cytarabine (cytosine arabinoside)
- 5-fluorouracil
- Tamoxifen (rare)
- High-dose etoposide
- Nitrosourea compounds
- High-dose or arterial route alkylating agents
Important Distinction
While these agents cause delirium and confusion, ifosfamide stands out for producing frank psychotic symptoms including hallucinations and delusions, not just general cognitive impairment. 3, 2
Management Approach
Immediate cessation of ifosfamide is required when severe neuropsychiatric toxicity occurs. 1 Treatment strategies include:
- Methylene blue administration has been successfully used to treat ifosfamide neurotoxicity 3
- Symptomatic management with antipsychotics: Risperidone at 4 mg/day successfully controlled chemotherapy-induced psychotic symptoms when olanzapine failed 7
- Dexmedetomidine for acute agitation and delirium in the ICU setting 4
Clinical Pitfall to Avoid
Do not assume all chemotherapy-related confusion is simple delirium—ifosfamide can produce isolated psychotic disorders that may persist for weeks and require specific psychiatric intervention. 3, 2 Three of six patients with grade 4 ifosfamide neurotoxicity died within 14 days, underscoring the severity of this complication. 5
Prevention Strategy
Check serum albumin before each ifosfamide cycle—levels below 3.5 g/dL warrant serious reconsideration of ifosfamide use or dose modification, as this dramatically increases neurotoxicity risk. 5