What other medications can cause iatrogenic personality changes?

From the Guidelines

Medications such as corticosteroids, benzodiazepines, antipsychotics, antidepressants, anti-epileptic drugs, and dopamine agonists can cause iatrogenic personality changes, with the most recent evidence suggesting that SSRIs, in particular, can lead to emotional blunting or apathy in some individuals 1.

Medications Associated with Iatrogenic Personality Changes

• Corticosteroids like prednisone can cause mood swings, irritability, and even psychosis, especially at higher doses (>40mg daily)
• Benzodiazepines such as diazepam and alprazolam may lead to disinhibition, irritability, and emotional blunting with prolonged use
• Antipsychotics, particularly first-generation drugs like haloperidol, can cause emotional flattening and reduced motivation, as noted in guidelines for managing Alzheimer's disease 1
• SSRIs and other antidepressants sometimes produce emotional blunting or apathy, with a boxed warning for suicidal thinking and behavior through age 24 years 1
• Anti-epileptic medications like levetiracetam may trigger irritability and aggression
• Dopamine agonists used for Parkinson's disease (pramipexole, ropinirole) can lead to impulse control disorders including gambling, hypersexuality, and compulsive shopping

Key Considerations

• The risk of iatrogenic personality changes varies based on individual factors, dosage, and duration of treatment
• Most changes are reversible upon medication adjustment or discontinuation
• Close monitoring for suicidality is recommended, especially in the first months of treatment and following dosage adjustments 1
• A strong recommendation is made to assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy 1

From the FDA Drug Label

Adverse events were usually mild to moderate in intensity (%) (Adverse Events Occurred In At Least 1% Of Levetiracetam- Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) ... Personality Disorder 87

Table 11 lists treatment-emergent adverse events that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo... Psychiatric disorders Irritability 62 Mood swings 51

Medications that can cause iatrogenic personality changes include:

• Levetiracetam, which has been associated with personality disorder and other psychiatric adverse events such as irritability and mood swings 2
• Valproate, which has been linked to suicidal behavior and ideation, and may also contribute to changes in mood or behavior, although it does not explicitly mention personality changes 3

From the Research

Medications Causing Iatrogenic Personality Changes

• Several medications have been reported to cause iatrogenic personality changes, including:
  • Levetiracetam: a broad-spectrum antiepileptic drug that has been associated with behavioral side effects, such as hostility and aggressive behavior 4
  • Phenytoin: an antiepileptic medication that has been linked to cognitive and behavioral adverse effects, including personality changes 5, 6, 7
• The evidence suggests that levetiracetam may be more likely to cause behavioral side effects, including personality changes, compared to other antiepileptic medications 8
• However, it is essential to note that the relationship between these medications and personality changes is complex and may depend on various factors, including the individual patient's condition, dosage, and duration of treatment

Comparison of Levetiracetam and Phenytoin

• Studies have compared the efficacy and safety of levetiracetam and phenytoin in the treatment of status epilepticus and convulsive seizures:
  • A systematic review and meta-analysis found that levetiracetam was not significantly superior to phenytoin in seizure cessation in patients with established status epilepticus 7
  • Another study found that levetiracetam was associated with a lower risk of seizure recurrence and intubation compared to phenytoin in pediatric patients with convulsive status epilepticus 6
• These findings suggest that both levetiracetam and phenytoin can be effective in the treatment of seizures, but may have different side effect profiles and risks of iatrogenic personality changes

Mechanisms and Risk Factors

• The mechanisms underlying iatrogenic personality changes associated with these medications are not fully understood, but may involve alterations in neurotransmitter release and synaptic plasticity:
  • Levetiracetam's mechanism of action involves the modulation of neurotransmitter release through binding to the synaptic vesicle glycoprotein 2A 8
  • Phenytoin's mechanism of action is less well understood, but may involve the inhibition of sodium channels and the modulation of neurotransmitter release 5
• Risk factors for iatrogenic personality changes associated with these medications may include:
  • High doses or prolonged treatment duration
  • Individual patient characteristics, such as age, sex, and underlying medical conditions
  • Concomitant use of other medications that may interact with levetiracetam or phenytoin 4, 8