What psychiatric side effects can levodopa/carbidopa (Syndopa) cause in a 65‑year‑old patient with progressive supranuclear palsy, and how should they be monitored and managed?

Psychiatric Effects of Levodopa/Carbidopa (Syndopa) in Progressive Supranuclear Palsy

Limited Therapeutic Benefit and Poor Response Profile

Levodopa/carbidopa provides minimal to no benefit in progressive supranuclear palsy (PSP), and "poor response to levodopa" is actually part of the diagnostic criteria for PSP. 1, 2 Even when modest improvement occurs, it is typically negligible, short-lived, and limited to bradykinesia and rigidity rather than the core features of PSP such as postural instability, falls, or supranuclear gaze palsy. 1

Psychiatric Side Effects: Psychosis and Behavioral Changes

Acute Psychotic Reactions

• Levodopa/carbidopa can precipitate acute psychotic episodes even in patients with no prior psychiatric history, particularly when treatment is initiated or doses are adjusted. 3 Two documented cases showed patients developing psychosis specifically after switching from levodopa alone to levodopa-carbidopa combination therapy, with symptoms resolving upon discontinuation. 3

Cognitive and Behavioral Deterioration

• PSP patients already experience significant cognitive impairment dominated by executive dysfunction, memory difficulties, and visuospatial deficits. 4 Adding levodopa/carbidopa does not improve these cognitive symptoms and may potentially worsen behavioral disturbances. 1, 4

• Antidepressants may be more appropriate than levodopa for managing behavioral symptoms and depression in PSP, though they are often poorly tolerated due to adverse effects. 1

Frontotemporal Dementia-Like Presentations

• Some PSP patients develop prominent frontotemporal dementia (FTD) features including apathy, emotional blunting, disinhibition, and executive dysfunction. 5 In these cases, levodopa/carbidopa provides no cognitive benefit and the psychiatric symptoms require alternative management strategies. 5

Monitoring Requirements

Baseline Psychiatric Assessment

• Document any pre-existing psychiatric symptoms, cognitive impairment severity, and behavioral changes before initiating levodopa/carbidopa. 1, 4
• Use standardized cognitive assessments to establish baseline executive function, memory, and behavioral status. 4

Ongoing Surveillance

• Monitor for emergence of hallucinations, delusions, paranoia, or acute confusion within the first weeks of treatment initiation or dose changes. 3
• Assess for worsening apathy, disinhibition, or behavioral dyscontrol that may indicate progression of underlying frontotemporal pathology rather than medication effect. 5
• Watch for respiratory complications including stridor or vocal cord dysfunction, as PSP patients can develop bilateral vocal cord abductor paralysis requiring emergency intervention. 2

Management of Psychiatric Complications

Immediate Discontinuation Protocol

• If acute psychosis develops after initiating levodopa/carbidopa, discontinue the medication immediately, as symptoms typically resolve with cessation. 3
• Do not attempt to manage levodopa-induced psychosis with antipsychotics in PSP patients, as most antipsychotics worsen parkinsonism and carry increased mortality risk in elderly patients with neurodegenerative conditions. 1

Alternative Symptom Management

• For behavioral symptoms and depression, consider antidepressants despite tolerability concerns, as they are more appropriate than continuing ineffective levodopa therapy. 1
• For dystonia or blepharospasm, use botulinum toxin injections rather than increasing dopaminergic medications. 1
• For myoclonus, use levetiracetam or benzodiazepines rather than levodopa adjustments. 1

Critical Pitfalls to Avoid

• Do not persist with levodopa/carbidopa trials in PSP patients hoping for delayed response—poor levodopa response is a diagnostic feature, not a temporary phenomenon. 1, 2
• Do not add antipsychotics to manage levodopa-induced psychiatric symptoms in PSP—this worsens motor function and increases mortality risk. 1
• Do not use acetylcholinesterase inhibitors or memantine for cognitive symptoms in PSP—limited evidence of benefit and risk of adverse effects outweighs potential gains. 1
• Do not overlook respiratory complications—PSP patients can develop life-threatening vocal cord paralysis requiring emergency tracheostomy. 2

Multidisciplinary Management Priority

Given the minimal motor benefit and psychiatric risks of levodopa/carbidopa in PSP, focus management on multidisciplinary supportive care including physiotherapy, occupational therapy, speech therapy, and palliative care rather than escalating dopaminergic medications. 1 Quality of life optimization through symptom relief and assistance with activities of daily living should take precedence over pharmacological trials with poor risk-benefit profiles. 1