Case-based learning: understanding and managing levetiracetam-induced psychiatric symptoms

Introduction

Levetiracetam is an anticonvulsant that is indicated as monotherapy for partial onset seizures in adults and adolescents aged 16 years and older with newly diagnosed epilepsy^​1,2​. The medicine can also be used as adjunctive therapy for partial onset seizures in patients aged one month and older with epilepsy, in the treatment of myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy and in the treatment of primary generalised tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalised epilepsy^​1​ .

In 2019, more than 2.4 million levetiracetam prescriptions were dispensed in the community in England^​3​. A retrospective cohort study, published in December 2019, assessed the evolution of antiepileptic drug treatment patterns and seizure outcomes in England over a 13-year period from 2003 until 2016 and discovered that levetiracetam use in adults as an antiepileptic increased significantly — from 2.6% of patients to 26.2%^​4​. This growing usage underscores the need for increased research and practitioner awareness of its side effect profile to ensure patient safety and effective care.

Among levetiracetam’s adverse effects, behavioural adverse effects are notably common. A systematic review by Halma et al., published in 2004, suggested that 89 out of 524 patients (17%) reported behavioural adverse effects associated with the use of levetiracetam^​5​. Behavioural adverse effects, including depression, hostility, aggression, anxiety, insomnia and nervousness/irritability, are also reported as common (≥1/100 to <1/10) in the summary of product characteristics submitted by the manufacturer ^​1,2​. In addition, a cohort analysis, published in 2023, identified behavioural adverse effects in 46% of patients, with more than 60% of those patients having documentation of agitation/restlessness, delirium or anxiety^​6​. Also prevalent are suicide attempts, suicidal ideation, psychotic disorders, abnormal behaviours, hallucination, anger, confusional state, panic attack, affect lability/mood swings and agitation (≥1/1,000 to <1/100)^​1​. Completed suicide, personality disorders, abnormal thinking and delirium have also been reported as rare adverse effects (≥1/10,000 to <1/1,000)^​1​.

The clinical implications of these adverse effects are significant and can lead to severe behavioural and psychological disturbances, exacerbation of pre-existing psychiatric and neurobehavioural conditions, potential discontinuation, worsening quality of life, and diagnostic challenges for clinicians distinguishing between a patient’s underlying mental illness and behavioural changes caused by medication, particularly when symptoms are similar^​7–9​. If levetiracetam-induced behavioural adverse effects (BAEs) are not considered, these symptoms can be attributed to alternative causes, such as pre-existing or newly presenting psychiatric disorders. 

For example, a 2015 case report describes a 23-year-old woman who developed seething rage and made several suicide attempts following levetiracetam initiation. She was initially managed for depression, before withdrawal led to symptom cessation^​8​. A further case report, published in 2022, describes the diagnostic challenge of a 28-year-old woman with a past medical history of seizure disorder and past psychiatric diagnosis of schizoaffective disorder, bipolar type. Following an increase in levetiracetam dose, she presented as physically and verbally aggressive, disruptive, angry and irritable, had paranoid ideation, required frequent redirection and was admitted for observation in a psychiatric unit. However, owing to the timing of symptoms and levetiracetam initiation, a causality assessment and neurological exam, her clinicians were able to distinguish a diagnosis of levetiracetam-induced behavioural abnormalities^​7​. 

However, practice experience has shown that the potential psychiatric impact of levetiracetam is often overlooked, with new psychiatric diagnoses and medications added when switching off antiepileptic therapy or the withdrawal of levetiracetam may be an appropriate clinical option to resolve or significantly mitigate symptoms^​10​. Multiple studies have also demonstrated a negative effect on quality of life associated with levetiracetam use. One study, published in 2011, found that 16.9% of patients had to discontinue levetiracetam owing to serious adverse effects, while a further study, published in 2022, found that levetiracetam use correlated with poorer psychosocial quality of life, suggesting that psychiatric side effects can significantly impact daily functioning and overall wellbeing^​11,12​.

Pharmacists possess the necessary skills to identify such adverse effects. By monitoring for and identifying these symptoms, pharmacists can collaborate with physicians to adjust treatment regimens and provide patient education. By proactively addressing these issues and suggesting dose reduction or treatment cessation, pharmacists can help mitigate the impact of psychiatric symptoms on patients’ quality of life and ensure more effective management of epilepsy.

This article presents three case studies of patients admitted to an older adult’s inpatient mental health unit owing to the increased severity of psychiatric symptoms.

Case example one

Patient A, a 68-year-old woman, has a diagnosis of lifelong petit mal epilepsy, which is well controlled. She was diagnosed with dementia in 2023 and has further comorbidities, including syndrome of inappropriate antidiuretic hormone secretion (SIADH), thought to be linked to long-term medication use, anxiety, panic attacks, hypertension, high cholesterol and spondylosis.

In 2016, she was started on levetiracetam by a neurologist to help manage her epilepsy. In August 2024, she was admitted to general hospital with aggressive behaviour, mostly targeted at her husband, after she was found by police wandering outside and her husband became unable to cope with her behaviour at home. Her family described her as getting more aggressive, which was extreme and unpredictable, including multiple physical attacks on her husband. Her anxiety worsened, and she was emotionally volatile. Her family reported that the aggression was occurring roughly two to three times per week.

Her medication on admission was carbamazepine, levetiracetam, phenytoin, simvastatin, lercanidipine and macrogols. Her aggression and emotional lability were initially thought to be Behavioural and Psychological Symptoms of Dementia (BPSD) on her background of Alzheimer’s dementia, and no medication changes were made at this stage. Delirium and provoking factors of infection, urine retention and constipation were excluded. However, a psychiatric consultant was brought in to consult on the case and disagreed with this impression. Patient A could describe with good understanding the episodes of aggression she was having and reported subsequent feelings of guilt and remorse. This differs from patients with BPSD who do not typically have insight into their behaviour. In addition, her aggressive behaviour went back several years and was not a new development in line with decreasing cognitive function. Her GP record shows regular aggressive behaviour since at least 2019, which pre-dates her 2023 diagnosis of dementia in Alzheimer’s disease.

Subsequently, patient A was admitted to an inpatient psychiatric unit for older adults. No psychotropic treatment was started and a decision was made to slowly withdraw levetiracetam, decreasing the dose from 750mg twice daily in decrements of 250mg every two weeks. This was cross titrated with lamotrigine, as neurology were concerned about the risk of seizure breakthrough in stopping an anti-epileptic.

Patient A remained on the ward for monitoring for adverse effects or loss of seizure control while the levetiracetam was withdrawn, which continued for a few weeks afterwards. She was sent home on multiple short-term leaves from the ward to see how she coped at home. Levetiracetam was titrated down on admission and the effects were noted immediately, with no aggressive behaviour observed by staff during her inpatient stay on the ward or by patient A and her family during the short-term leaves from the ward. Two weeks after withdrawal was complete, patient A told the multidisciplinary team present at her ward round that she had noticed a difference in herself and cannot stop smiling. Subsequently, she was discharged to home, with no evidence of agitation, anxiety or aggression. Follow-up appointments after discharge noted no evidence of mood disturbances, disordered thoughts or abnormal behaviour.

Discussion

This case highlights several important clinical considerations. Levetiracetam, although effective for seizure control, has potential for behavioural and psychological side effects, which may emerge even years after initiation. Levetiracetam-induced BAEs can be misdiagnosed — for example, as BPSD or a separate psychiatric comorbidity. Additionally, these adverse effects can resolve completely upon gradual cessation of levetiracetam, without the need for additional psychotropic drugs. Recognition of levetiracetam-induced BAEs and subsequent cessation can improve overall quality of life and prevent unnecessary polypharmacy. Finally, this case underscores the importance of identifying medication-related causes of symptoms. Pharmacists play an important role in considering iatrogenic factors in complex patients, particularly in older adults with multiple comorbidities and long-term medication use.

Case example two

Patient B is an 88-year-old man with a diagnosis of vascular dementia. His comorbidities are type 2 diabetes, chronic kidney disease, heart failure with reduced ejection fraction and essential hypertension.

When diagnosed with vascular dementia, he had a mini-Addenbrooke’s cognitive examination score of 9/30 and no notable behavioural disturbances. One year later, he had a hypoglycaemic-induced seizure and was started on levetiracetam. Shortly after this, he was moved to a care home. Staff reported challenging behaviour, including being verbally aggressive, throwing items and physically attacking staff. At this stage, his behaviour was thought to be sundowning, which is a presentation observed in dementia, characterised by increased agitation, confusion and distress occurring in the late afternoon or evening hours^​13​. He was eventually admitted to general hospital, owing to increasingly erratic and aggressive behaviours, falls and confusion. He was treated for a non-specific infection, and his symptoms did improve but did not resolve. His presentation was decided to be that of BPSD. He was subsequently transferred to a mental health unit.

A review of his GP record, care home reports, Dementia Intensive Support Service and Psychiatric Liaison Service entries and family input made it apparent that the start of his behavioural disturbances coincided with the introduction of levetiracetam. He had no significant past psychiatric history, apart from his recent dementia diagnosis. His psychiatric consultant, therefore, decided to withdraw levetiracetam rather than introducing more psychotropic medication.

As his epilepsy history was related to hypoglycaemic-induced seizures only, his diabetes was well managed in a monitored environment. Patient B’s levetiracetam was discontinued with no other antiepileptic started in replacement. After levetiracetam was withdrawn, he had one episode of agitation but was easily redirected and calmed. Aside from this, Patient B was not observed to exhibit any challenging or aggressive behaviour on the ward over his seven-week admission. He was trialled on home leave for one week, and his family reported no episodes of behavioural issues. Patient B was able to be discharged back to his own home — not a care home as before — and still presented as calm and free of aggression when he was reviewed six months on from discontinuation.

Discussion

This case illustrates the potential for levetiracetam to induce aggression and other behavioural and psychological side effects. Patient B’s challenging behaviour began shortly after the initiation of levetiracetam, highlighting the importance of considering medication side effects as a cause of new psychiatric symptoms in people with dementia. Importantly, his symptoms were completely resolved after cessation, which avoided the need for additional psychotropic medications. This approach had a significant positive impact on quality of life, enabling him to return home and avoid long-term care placement. This case also evidences the role of family and multidisciplinary input in recognising adverse drug reactions and supporting clinical decision-making.

Case example three

Patient C is a 76-year-old woman with a diagnosis of Alzheimer’s dementia. Her only comorbidity is paroxysmal atrial fibrillation. Patient C was started on levetiracetam in 2017, after she experienced a seizure following the excavation of an intracranial subdural haematoma. She was diagnosed with dementia in 2020 and prescribed donepezil and risperidone 250 micrograms once daily to manage this. In 2023, she was admitted to hospital after expressing increasingly delusional and paranoid behaviour. This behaviour included paranoid delusions focusing on family and those around her, violence and destruction of property and threats of physical harm to others. In response, risperidone was increased to 250 micrograms twice daily. Recognising the psychiatric adverse effects associated with levetiracetam, her psychiatric consultant chose to reduce her dose from 500mg twice daily to 250mg twice daily for four weeks, 250mg once daily for two weeks and then withdrawn completely. Neurology was consulted to approve the withdrawal titration. Donepezil was also stopped, owing to worsening disease severity and its potential to cause agitation and abnormal behaviour^​14​. No new psychotropic medication was started during this admission. Patient C was discharged after a 12-week admission. Significant cognitive improvement and engagement in ward activities had been noted by doctors, ward staff, family and the patient herself.

Discussion

This case differs from patients A and B, as her presentation did not immediately change on discontinuation of levetiracetam. However, the case serves to demonstrate how deprescribing medication, including levetiracetam, that is known to cause psychiatric adverse effects should still be conducted when psychiatric conditions arise independently from the medication. Levetiracetam has the potential to exacerbate pre-existing psychiatric conditions and dementia. In addition, these exacerbations may be resolved through the controlled withdrawal of the drug. 

This case highlights how withdrawal of levetiracetam can help to reduce exacerbations of pre-existing psychiatric conditions and behavioural disturbances in individuals with dementia. Unlike Patient B, where behavioural symptoms appeared soon after initiation, Patient C’s symptoms developed years later. The essential learning point here is that adverse psychiatric effects may emerge or intensify over time, particularly in those with underling cognitive impairment. Once again, this case reinforces the importance of considering medication withdrawal as a therapeutic intervention, even when psychiatric symptoms are not immediately linked to the timing of drug initiation. It also evidences that levetiracetam has the potential to not only cause but worsen psychiatric symptoms, and clinical improvement can follow its cessation, which reduces polypharmacy and enhances patient quality of life.

Conclusion

It is well evidenced that psychiatric reactions are a common side effect of levetiracetam.  

This case-based learning article aims to show two main points. Firstly, for any behavioural or psychiatric changes in patients prescribed levetiracetam, the initial hypothesis should be that it is the medication that is responsible. In these instances, symptoms are reversible on cessation, and replacement of levetiracetam with an alternative anti-epileptic should be considered. 

Secondly, patients with pre-existing psychiatric diagnoses can have their conditions triggered or exacerbated by levetiracetam, whether newly started or not. Withdrawing levetiracetam in these patients also improves their presentations, despite not being considered an independent cause. Levetiracetam should be cautioned in patients with psychiatric conditions, behavioural disturbances and dementia. 

Pharmacists have a responsibility to highlight this to prescribers and encourage patients to report any psychological or behavioural changes experienced once starting the medication. 

The case examples presented in this article demonstrate the likelihood for behavioural disturbances to be attributed to an independent psychiatric cause, whether a new diagnosis is given or a pre-existing condition is assumed responsible. Prescribers and pharmacists alike should be able to identify the potential for levetiracetam to trigger psychiatric symptoms and consider safe cessation.