Can methotrexate (MTX) cause or worsen depression and mania in patients?

Methotrexate and Psychiatric Effects: Depression and Mania

Methotrexate can precipitate or worsen mood disturbances including depression and mania, though this is an uncommon and underreported adverse effect that warrants clinical vigilance, particularly during treatment initiation and dose escalation.

Evidence for Psychiatric Effects

Mania Precipitation

• A documented case report demonstrates methotrexate directly precipitated manic episodes in a patient with bipolar affective disorder, with symptoms reversing upon drug withdrawal 1
• This represents a secondary mood relapse caused by medication, distinct from primary disease progression 1
• To date, this remains the only published case linking methotrexate to mania precipitation in bipolar disorder, suggesting this is a rare but real phenomenon 1

Depression and Mood Changes

• Pediatric patients have experienced significant mood changes with methotrexate treatment for dermatologic conditions (lichen sclerosus, psoriasis), with rapid resolution after methotrexate cessation 2
• The neuropsychiatric effects of low-dose methotrexate for cutaneous disease have been historically underreported in dermatology literature, despite being more commonly described in rheumatology 2
• In patients with rheumatoid arthritis and comorbid depression, methotrexate treatment is associated with higher disease activity scores and worse pain, though causality is complex 3

Paradoxical Improvement in Some Contexts

• In psoriasis patients, methotrexate actually reduced symptoms of depression and anxiety over 24 weeks of treatment, comparable to biologic agents 4
• This improvement appears related to disease control rather than direct psychiatric effects, as systemic inflammation parameters did not correlate with mood symptom changes 4

Clinical Implications and Monitoring

High-Risk Populations Requiring Enhanced Vigilance

• Patients with pre-existing bipolar affective disorder should be monitored closely for manic symptoms when initiating methotrexate 1
• Pediatric patients may be particularly susceptible to mood changes and require careful psychiatric monitoring 2
• Patients with pre-existing depression or anxiety disorders warrant closer follow-up, as these comorbidities are associated with earlier treatment discontinuation 5

Proposed Mechanisms

• Neurotoxicity from methotrexate may involve folate pathway disruption affecting neurotransmitter synthesis 2
• Cognitive effects and mood changes may represent part of a broader spectrum of central nervous system toxicity 2
• The relationship between disease activity improvement and mood improvement suggests indirect effects through inflammation reduction in some conditions 4

Management Algorithm

Before Starting Methotrexate

• Screen for personal or family history of bipolar disorder, mania, or significant mood disorders
• Document baseline mood status in patients with psychiatric history
• Consider psychiatric consultation for patients with active bipolar disorder before initiating therapy 1

During Treatment

• Monitor for new-onset mood symptoms, particularly irritability, decreased need for sleep, racing thoughts, or depressive symptoms at each visit
• Pay particular attention during the first 4-6 weeks of treatment when many methotrexate toxicities emerge 6
• In pediatric patients, specifically inquire about behavioral changes, mood lability, and school performance 2

If Psychiatric Symptoms Emerge

• Immediately discontinue methotrexate if manic symptoms develop, as case evidence demonstrates reversibility with drug withdrawal 1
• For mood changes in children, cessation typically results in rapid symptom resolution 2
• Consider whether symptoms represent primary psychiatric disease progression versus drug-induced effects
• Psychiatric consultation is warranted for diagnostic clarification and management

Critical Caveats

The major clinical guidelines for methotrexate use in dermatologic conditions 7 do not specifically address psychiatric adverse effects, highlighting the underrecognition of this toxicity in dermatology practice. This absence from formal guidelines does not negate the documented cases and should not diminish clinical vigilance.

The evidence base is limited to case reports and small case series for mania 1, 2, making it impossible to quantify true incidence. However, the dramatic reversibility upon drug withdrawal and temporal relationship strongly support causality in reported cases.

Folic acid supplementation (1-5 mg daily or weekly) reduces many methotrexate toxicities 6, 8 and theoretically might mitigate neuropsychiatric effects through folate pathway restoration, though this has not been specifically studied for mood symptoms 2.