• Users Online: 92
  • Print this page
  • Email this page

Table of Contents
Year : 2019  |  Volume : 16  |  Issue : 3  |  Page : 171-173

Antiepileptic drug-induced acute psychotic disorder in a nonepileptic patient: A definite prophecy

1 Department of Surgery, Apollo Hospital, Bhat, Ahmedabad, Gujarat, India
2 Department of Pharmacology, Smt- NHL Municipal Medical College, Ahmedabad, Gujarat, India
3 Department of Neurosurgery, Apollo Hospital, Bhat, Ahmedabad, Gujarat, India
4 Department of Orthopaedics, Smt- NHL Municipal Medical College, Ahmedabad, Gujarat, India

Date of Submission02-Aug-2019
Date of Acceptance17-Aug-2019
Date of Web Publication11-Sep-2019

Correspondence Address:
Deepak Malhotra
Apollo Hospitals, Bhat, Ahmedabad, Gujarat
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_47_19

Rights and Permissions

Psychosis induced by antiepileptic drugs (AEDs) is considerably an iatrogenic adverse drug reaction. Various mechanisms operant in the development of iatrogenic psychiatric manifestations are proposed which necessitates analyzing complaints of psychiatric symptoms related to medication. Herein, we present a rare case of short-term use of phenytoin causing toxicity which manifested as acute psychosis with no Vitamin B12 or folic acid deficiency, who had complete recovery following phenytoin withdrawal.

Keywords: Acute psychosis, adverse drug reaction, antiepileptic drug-induced psychotic disorder, antiepileptic drugs, de-challenge, phenytoin

How to cite this article:
Dahiya M, Pandya A, Malhotra D, Patel P. Antiepileptic drug-induced acute psychotic disorder in a nonepileptic patient: A definite prophecy. Apollo Med 2019;16:171-3

How to cite this URL:
Dahiya M, Pandya A, Malhotra D, Patel P. Antiepileptic drug-induced acute psychotic disorder in a nonepileptic patient: A definite prophecy. Apollo Med [serial online] 2019 [cited 2020 Feb 22];16:171-3. Available from: http://www.apollomedicine.org/text.asp?2019/16/3/171/266783

  Introduction Top

Patients with epilepsy are often at an increased risk of psychotic disorders. Particularly, the development of iatrogenic psychiatric manifestations are an account of introduction of high dose AEDs that have negative psychotropic properties or withdrawal of AEDs with positive psychotropic properties in vulnerable patients, pharmacokinetic interaction between enzyme inducing AED and concomitant psychotropic medication and phenomenon of forced normalization.[1] Among various psychotic disorders, antiepileptic drug (AED)-induced psychotic disorder (AIPD) till date has been considered as an iatrogenic adverse drug reaction, with its prevalence being 8.4% as a source of psychotic illness.[2] There is evidence of various AEDs associated with either a positive or a negative effect as pertaining to psychiatric manifestations, including carbamazepine, levetiracetam, ethosuximide, gabapentin, tiagabine, topiramate, valproate, phenytoin, and zonisamide.[3] We report a rare case of phenytoin toxicity manifesting as acute psychosis which completely recovered after phenytoin withdrawal, which suggests that acute psychosis may be the direct result of medication, unrelated to seizures.

  Case Report Top

A 22-year-old male presented with a history of road traffic accident (RTA) with head injury arrived in the emergency department with unstable vitals, GCS–E1VTM4, and bilateral pupil 3 mm and nonreactive. The patient was intubated and started on antibiotics, analgesic, and antiepileptic. Computed tomographic scan brain was done which showed right subdural hematoma with midline shift and cerebral edema. He underwent emergency decompressive craniectomy. The patient's condition gradually improved. He was taken off ventilator. He gained consciousness and no deficit was found, neurologically. He was discharged after 2 weeks of RTA with the following medications – tablet levetiracetam 500 mg BD, tablet phenytoin 100 mg TDS, tablet citicoline 500 mg BD, tablet pantoprazole BD, tablet folic acid OD, multivitamin tablets OD, liquid cremaffin, and liquid aluminum hydroxide + magnesium hydroxide + oxethazaine antacid gel.

On follow-up, levetiracetam 500 mg decreased to 250 mg twice a day. The patient came back for cranioplasty 2½ months later. However, he was found to have on and off aggression in between normal talks with shouting. He was referred to a psychiatrist who confirmed the findings and found that the patient had loose thinking and poor insight. He was started on tablet olanzapine 5 mg BD, and tablet phenytoin 100 mg TDS was continued. Tablet levetiracetam 250 mg was stopped. The patient did not improve, rather his symptoms deteriorated (he became more aggressive, shout violently, and trying to physically assault relatives and stopped eating); hence, the patient was investigated in the form of serum phenytoin level. Phenytoin level was found to be in high toxic range (54 μg/ml). Phenytoin was stopped and started on tablet sodium valproate 500 mg BD. The patient improved symptomatically within 1 week. Tablet olanzapine was gradually reduced and stopped. After 1 week, serum phenytoin level was found to be 15 μg/ml. The patient at 1-month follow-up had no functional complaint. This report depicts that psychosis was certainly due to phenytoin as response to withdrawal was plausible with a confirmed positive de-challenge. This case was reported to the WHO-VigiFlow with I'd-2019–46015.

  Discussion Top

Among all antiepileptics, phenytoin is one of the most commonly prescribed medications in developing countries like India as it is inexpensive and also widely available. With most of the commonly used AEDs, it is well known that it is associated with reduced folate or Vitamin B12 serum levels.[4] Various psychiatric disorders have been diagnosed in patients having folate/Vitamin B12 deficiency, including depression, mood disorder, psychosis, dementia, delirium, panic disorder, and phobia.[4] Phenytoin having very narrow therapeutic window demonstrates nonlinear pharmacokinetics, which requires a balance between its efficacy and dose-related side effects. The enzyme system involved in phenytoin metabolism gradually becomes saturated, resulting in decrease in the rate of elimination of phenytoin, as the dose is increased, leading to drug toxicity.[5] Thus patients presenting with psychosis taking AEDs should lead to detailed evaluation for drug toxicity including Vitamin B12 or folic acid levels. Apart from phenytoin, Vitamin B12 and folate levels were within normal range, ruling this out as a cause of his acute psychosis, making phenytoin toxicity as a definite cause of psychosis in our case.

Previous reports on psychosis are presented by Gatzonis et al.,[6] who reported the case of acute psychosis developing in a case of trigeminal neuralgia, which improved after stopping phenytoin, where serum levels were back to normal. Borasi et al.[7] have reported a chronic epilepsy case with a history of 15 years of phenytoin intake, who presented with acute psychosis and raised serum levels of the same, who improved after stopping phenytoin. Similarly, Agrawal et al.[8] also reported acute psychotic behaviour in a patient who was started on phenytoin and was scheduled for craniotomy for his intracranial space occupying lesion, who postoperatively showed aggressive and delusional behaviour with his serum phenytoin levels >40 μg/ml, who improved on phenytoin withdrawal.

Misdiagnosing AIPD as a primary psychotic disorder can lead to inappropriate management, including continuation of the culprit AED and additional treatment with antipsychotic drugs. Due to persistence of psychotic symptoms of AIPD in a fluctuating manner, identification of reliable factors at presentation which helps to differentiate AIDP from other forms of psychosis in epilepsy is necessary.

The management of AIPD in clinical practice is extremely challenging and not evidence-based. By definition, the definitive diagnosis of AIPD can only be made retrospectively. In theory, the most valid way to determine whether a given AED is responsible in causing a particular adverse event would be to withdraw the culprit drug and observe the remission of symptoms, followed by rechallenging with the medication and observing symptom relapse.[9]

Thus, wider use of phenytoin in developing countries can possibly lead to the development of acute psychotic manifestations even in nonepileptics, which necessitates monitoring serum phenytoin levels after initiating the treatment, especially in elective nonepileptic patients when antiepileptics are used as a prophylactic measure, where the person can completely resolve on treatment discontinuation instead of starting antipsychotics, as all antipsychotics reduce the epileptogenic threshold and may cause epileptic seizures.[10]

  Conclusion Top

The report here does not avert physicians from prescribing phenytoin but implies a message that phenytoin toxicity can present with psychotic syndromes in the absence of or without prominent neurological symptoms, which should be evaluated in detail for the presence of phenytoin toxicity, and that antipsychotics should not be initiated in such patients, instead withdrawal of the drug to bring down the toxic levels to normal can guard improvement.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Mula M. Investigating psychotropic properties of antiepileptic drugs. Expert Rev Neurother 2013;13:639-46.  Back to cited text no. 1
Piedad J, Rickards H, Besag FM, Cavanna AE. Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: A summary of prevalence, underlying mechanisms and data limitations. CNS Drugs 2012;26:319-35.  Back to cited text no. 2
Nadkarni S, Devinsky O. Psychotropic effects of antiepileptic drugs. Epilepsy Curr 2005;5:176-81.  Back to cited text no. 3
Linnebank M, Moskau S, Semmler A, Widman G, Stoffel-Wagner B, Weller M, et al. Antiepileptic drugs interact with folate and Vitamin B12 serum levels. Ann Neurol 2011;69:352-9.  Back to cited text no. 4
Aronson JK, Hardman M, Reynolds DJ. ABC of monitoring drug therapy. Phenytoin. BMJ 1992;305:1215-8.  Back to cited text no. 5
Gatzonis SD, Angelopoulos E, Sarigiannis P, Mantouvalos V, Ploumbidis D, Siafakas A, et al. Acute psychosis due to treatment with phenytoin in a nonepileptic patient. Epilepsy Behav 2003;4:771-2.  Back to cited text no. 6
Borasi M, Verma RP, Gupta SK. Psychosis as harbinger of phenytoin toxicity. Toxicol Int 2015;22:160-1.  Back to cited text no. 7
[PUBMED]  [Full text]  
Agrawal M, Borkar SA, Kale SS. Phenytoin toxicity manifesting as acute psychosis: An uncommon side effect of a common drug. Asian J Neurosurg 2019;14:532-4.  Back to cited text no. 8
[PUBMED]  [Full text]  
Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet 2000;356:1255-9.  Back to cited text no. 9
Ricardo G, Cecílio HJ, Roger W, Rodrigues VT, Veriano AJ, Cristina TB, et al. Pharmacological treatment of psychosis in epilepsy. Braz J Psychiatry 2004;26:57-61.  Back to cited text no. 10


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Case Report

 Article Access Statistics
    PDF Downloaded61    
    Comments [Add]    

Recommend this journal