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Background:
Systematic Review

Perampanel-Induced Psychosis and Psychosis-like Symptoms: A Systematic Review

by
Petar Z. Taslaković
1,
Miloš N. Milosavljević
1,*,
Vladimir Janjić
2,* and
Srđan Stefanović
3
1
Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
2
Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
3
Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
*
Authors to whom correspondence should be addressed.
Future Pharmacol. 2026, 6(1), 10; https://doi.org/10.3390/futurepharmacol6010010
Submission received: 19 December 2025 / Revised: 21 January 2026 / Accepted: 30 January 2026 / Published: 3 February 2026
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Abstract

Background/Objectives: This study aimed to investigate whether therapy with perampanel is associated with the development of psychosis or psychosis-like symptoms in patients with epilepsy. Methods: We conducted systematic electronic searches in PubMed, Google Scholar, ScienceDirect, and Scindex databases. We included articles published as case reports/case series, as well as conference abstracts and letters from the editor, if they contained enough data for analysis and quality assessment. The main inclusion criteria relate to patients who experienced psychosis or psychosis-like symptoms described by the authors during perampanel therapy or during its recent use. Results: Publications (n = 17) describing a total of 33 patients who met the inclusion criteria were included. Patient ages ranged from 11 to 70 years, and the majority of them were female (66.67%). A confirmed personal psychiatric history was identified in 60.61% of patients. The time interval between the initiation of perampanel and the onset of adverse events varied significantly across cases. The most frequently reported symptom was aggression (75.75%), followed by irritability (30.30%), while delusions or hallucinations were observed in 8 patients (24.24%). Conclusions: Clinicians should be aware that psychosis or psychosis-like symptoms may represent dose-dependent adverse effects of perampanel with a satisfactory prognosis. Identified risk factors for these developments were positive personal psychiatric history, antiseizure polytherapy at high doses, women’s gender, and focal epilepsies with secondary generalization, mainly manifested as tonic–clonic seizures. Early recognition of symptoms, followed by drug discontinuation, dose reduction, symptomatic treatment, or a combination of the mentioned strategies, is crucial for achieving better outcomes.

1. Introduction

Perampanel is a third-generation antiseizure medication indicated for the treatment of both focal and generalized epilepsies. It is approved for use as monotherapy as well as in combination with other antiseizure drugs. Compared with older generations of antiseizure medications, perampanel offers several advantages, including improved treatment adherence due to its once-daily dosing regimen, a lower potential for clinically significant drug–drug interactions, and reduced overall treatment costs [1]. Perampanel exerts its pharmacological effects through selective, non-competitive antagonism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which play a central role in glutamatergic neurotransmission within the central nervous system. By inhibiting AMPA receptor–mediated signaling, perampanel attenuates excitatory glutamate transmission [2]. In addition to its antiepileptic efficacy, recent post-marketing data suggest potential ancillary benefits, including improvements in sleep quality, with occasional off-label use reported in the management of insomnia [3]. According to the International League Against Epilepsy (ILAE), epilepsy encompasses a broad spectrum of clinical seizure types and syndromes, with a continuously expanding number of etiology-defined entities [4].
Psychotic disorders represent a significant public health concern, and individuals with epilepsy constitute a particularly vulnerable population. This vulnerability is especially pronounced among patients with focal epilepsies and pharmacoresistant forms of the disease. The prevalence of psychosis in patients with epilepsy is estimated to be approximately 5.6%, reaching up to 7% in those with focal epilepsies [5]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), a psychotic disorder is characterized by the presence of symptoms such as hallucinations, delusions, and disorganized thinking, persisting for at least one day. These core features are frequently accompanied by social dysfunction, irritability, aggression, and other behavioral disturbances that substantially impair quality of life [6].
Perampanel is generally well tolerated, with the most commonly reported adverse effects including somnolence, headache, dizziness, nausea, and vomiting. Clinical experience and post-marketing data indicate that many adverse effects are dose-dependent and, to some extent, predictable. Notably, preregistration clinical trials demonstrated a higher prevalence of psychiatric adverse events in patients receiving perampanel compared with those receiving placebo [7]. In recent years, an increasing incidence of psychiatric adverse effects has been reported for several antiseizure drugs, including the occurrence of psychosis. Initially, the highest risk for this rare but serious adverse effect was associated with levetiracetam and other newer-generation antiseizure medications, including perampanel.
The interpretation of psychiatric manifestations in patients with epilepsy is particularly challenging, as psychosis may arise as a consequence of poor seizure control, underlying neuropathological mechanisms, or as an adverse effect of antiseizure therapy. Therefore, distinguishing drug-induced psychosis from epilepsy-related psychotic disorders is of critical clinical importance [1]. Chen et al. reported a prevalence of antiseizure drug–induced psychosis of approximately 0.5% in a cohort of 2630 patients with epilepsy [6]. During the past decade, the first case reports suggesting an association between perampanel and psychotic symptoms described confusional states and delirium [8,9]. Subsequent studies indicated that individual susceptibility, including genetic factors and immune-mediated mechanisms, may contribute to the risk of developing perampanel-associated psychosis [10].
The primary objective of this systematic review is to investigate whether treatment with perampanel is associated with the development of psychosis or psychosis-like symptoms in patients with epilepsy. Secondary objectives include summarizing the available evidence on the frequency and severity of these manifestations, assessing the causality of reported adverse drug reactions, identifying potential risk factors, evaluating dose-dependency, and analyzing clinical outcomes and management strategies for perampanel-induced psychotic or psychosis-like symptoms.

2. Materials and Methods

2.1. Information Sources and Search Strategy

This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251101594, available at https://www.crd.york.ac.uk/PROSPERO/view/CRD420251101594 (accessed on 16 October 2025). The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (2020 update). The completed PRISMA checklist is provided as Supplementary Table S1.
Two authors (P.Z.T. and M.N.M.) independently searched the following electronic databases from their inception to 30 September 2025, without language or date restrictions: PubMed, Google Scholar, ScienceDirect, and the Serbian Citation Index (SCIndeks). The detailed search strategies for each database are presented in Supplementary Table S2. Eligible publications included full-text case reports and case series, as well as conference abstracts and letters to the editor, provided they contained sufficient data for qualitative analysis and quality assessment. In addition, the reference lists of all retrieved articles were manually screened to identify further relevant publications.
For inclusion, each reported case was required to provide, at a minimum, the following information: patient age and sex; identification of perampanel as the suspected drug prior to the onset of psychosis or psychosis-like symptoms; details regarding perampanel use, including dosage and temporal relationship to adverse event onset; a clear clinical description of psychotic or psychosis-like manifestations; therapeutic interventions undertaken; and reported clinical outcomes.

2.2. Eligibility Criteria

2.2.1. Inclusion Criteria

Studies were included if they reported patients who developed psychosis or psychosis-like symptoms during treatment with perampanel or shortly after its discontinuation. Eligible clinical manifestations included delusions (any type), hallucinations (any type), and psychosis-like symptoms such as aggression (verbal or physical), irritability, suicidality (suicidal ideation or attempts), and self-harm (documented self-injurious behavior). Only patients receiving therapeutic doses of perampanel in accordance with the Summary of Product Characteristics were included [11]. No restrictions were applied with regard to age, sex, race, ethnicity, seizure type, treatment setting, or comorbidities, except as specified in the exclusion criteria.

2.2.2. Exclusion Criteria

Studies were excluded if they provided incomplete clinical or demographic data; involved animal experiments; described patients with a current or prior diagnosis of schizophrenia or bipolar disorder; failed to report outcomes or provided insufficient information regarding perampanel exposure or management of the adverse event; or reported depression or other psychiatric adverse effects without concomitant psychotic or psychosis-like symptoms (e.g., aggression, irritability, or suicidality). Additionally, studies were excluded if they described perampanel poisoning, psychosis attributable to alternative etiologies, psychosis induced by other antiseizure medications, off-label perampanel use without a confirmed epilepsy diagnosis, or non-drug-related psychotic episodes.

2.3. Selection Process and Data Extraction

Two authors (P.Z.T. and M.N.M.) independently screened titles and abstracts of all retrieved records for eligibility. When relevance could not be determined from the title and abstract alone, the full text was obtained and assessed. Publications were included only after both reviewers confirmed that all eligibility criteria were met. Any disagreements during the selection process were resolved through arbitration by a third author (S.M.S.).
Data extraction was performed independently by two authors (P.Z.T. and M.N.M.), with discrepancies resolved through consensus among all authors. A third investigator (V.S.J.) compiled the final extraction table by merging the individual datasets. Extracted variables included first author and year of publication; number of patients; country of origin; demographic characteristics (age and sex); personal history of neuropsychiatric disorders; seizure type; clinical features of the adverse drug event; concomitant antiseizure medications and dosages (when reported); perampanel dosage at the time of symptom onset, including initial dose; time interval from initiation or dose escalation of perampanel to the onset of psychosis; management strategies, including symptomatic treatment; evidence of dechallenge and rechallenge; and clinical outcomes.
Causality between perampanel exposure and psychotic manifestations was assessed for each individual case using the Naranjo Adverse Drug Reaction Probability Scale, in order to estimate the likelihood that perampanel was responsible for the observed adverse event [12].

2.4. Quality Assessment and Statistical Analysis

The quality of included reports was assessed using the “Guidelines for Submitting Adverse Event Reports for Publication” jointly developed by the International Society for Pharmacoepidemiology and the International Society of Pharmacovigilance [13]. The following domains were evaluated: consistency between title and content; patient information (demographics, medical history, clinical status, and disposition); suspected drug information (identification, dosage, temporal relationship, and concomitant therapies); description of the adverse event; and discussion. Each domain was rated as present, partially present, or absent.
Overall quality was classified as high if more than 75% of domains were rated as present, moderate if 50–75% were present, and poor if fewer than 50% were present. Methodological quality was independently assessed by two authors (P.Z.T. and M.N.M.), with disagreements resolved by a third reviewer (S.M.S.).
In this systematic review, the primary unit of analysis was the individual patient. Data were synthesized using descriptive statistics (median, range, and proportions), complemented by narrative synthesis and tabular presentation of extracted findings.

3. Results

3.1. Study Selection and Results of Quality Assessment

The study selection process is summarized in Figure 1. A total of 17 publications were included in this systematic review [8,9,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]. These comprised nine case reports, eight published as full-text articles [8,15,17,18,21,22,24,28] and one as a conference abstract [9]. Additionally, five letters to the editor were included, four of which reported single cases [14,16,20,23] and one reported two cases [27]. Furthermore, three case series were included [19,25,26], contributing a total of eighteen cases: five cases from a series of fifteen reported by Datta et al. [19], one case from a series of three [25], and twelve cases from the series reported by Juhl et al. [26].
The results of the methodological quality assessment are presented in Figure 2. Most studies adequately reported the majority of required information. Complete reporting was observed for the following domains: title consistency (n = 17; 100%), physical examination (n = 17; 100%), patient disposition (n = 17; 100%), and adverse event description (n = 17; 100%). High rates of completeness were also noted for patient demographics (n = 16; 94.12%), current health status (n = 16; 94.12%), drug identification (n = 16; 94.12%), dosage information (n = 16; 94.12%), medical history (n = 13; 76.47%), and drug–reaction interface (n = 14; 82.35%). Section 4 was fully reported in 10 studies (58.82%).
Incomplete reporting was most frequently observed in the assessment of concomitant therapies, which were insufficiently described in nine studies (52.94%). Six publications did not provide any information regarding concomitant medication assessment [9,14,16,22,25,28]. Missing demographic data were identified in one study (5.88%) [8], while incomplete medical histories were noted in two studies (11.76%) [8,9], including three cases (17.65%) lacking a comprehensive psychiatric history [8,9,24]. In several studies, the discussion was rated as partial because the authors did not explain the absence of rechallenge or failed to compare their findings with previously reported cases.
No study was classified as having poor methodological quality (0%). Three studies (17.65%) were rated as moderate quality [9,19,23], while the remaining fourteen (82.35%) were assessed as high quality [8,14,15,16,17,18,20,21,22,24,25,26,27,28].

3.2. Excluded Publications

As shown in Figure 1, a total of 62 publications [5,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89] were excluded for reasons related to study design, insufficient data, or alternative etiologies. One case was excluded due to the development of a non-psychotic psychiatric adverse effect attributed to perampanel [29]. Additional cases were excluded due to forced normalization associated with depressive symptoms [29] or insufficient clinical data [30].
A total of 37 publications were excluded because of inappropriate study design, including 21 observational studies [5,31,32,33,34,35,36,37,38,39,40,41,42,46,47,48,49,50,51,52,53],3 retrospective post hoc analyses of randomized controlled trials [43,44,45],4 randomized controlled trials [54,55,56,57],6 narrative reviews [58,59,60,61,62,63], and 3 systematic reviews [64,65,66].
Six case reports were excluded because psychosis was attributed to alternative etiologies: four were related to epilepsy-related complications [67,68,69,70], while two described encephalitis, potentially autoimmune in origin [71,72]. Two case reports were excluded due to unavailable full texts [73,74].
Although the case reported by Rodríguez et al. initially appeared eligible based on the title and abstract, insufficient data precluded inclusion [73]. Additional information published later by Sulais et al. revealed that the patient—a 29-year-old woman—had intentionally tripled the recommended perampanel dose (12 mg/day) following missed doses, leading to acute neuropsychiatric symptoms [15]. A subsequent rechallenge at 8 mg/day resulted in severe psychosis, necessitating permanent discontinuation of perampanel [15,73]. Due to overdose and confounding factors, this case was excluded.
Similarly, the report by Jesus et al. lacked sufficient information to establish causality, as psychosis could not be clearly attributed to perampanel exposure or distinguished from epilepsy-related complications [74].
Two cases involving off-label use of perampanel for insomnia were excluded [75,76]. Additional reports were excluded due to missing data required for causality assessment [30,77,78], incomplete reporting of treatment and outcomes [79,80,81], documented perampanel poisoning [82,83], or psychosis attributed to other antiseizure medications, particularly levetiracetam [84,85,86,87,88,89].

3.3. Characteristics of Included Patients

In Table 1, we show the basic characteristics of included cases (n = 33), whereas Table 2 provides an overview of each included case. Patient ages ranged from 11 to 70 years, with a mean of 34.22 years. The majority of patients were women (n = 22, [66.67%]) with missing demographic data in one case [8]. Most cases occurred in Denmark (n = 12 [36.36%]), which were all identified from one study [26]. Prevalence of the history of any neuropsychiatric disorder or psychological reactions was in n = 20 (60.61%) cases in our population [15,16,17,18,19,21,23,26,27,28], where six patients are from a case series [26], five from another [19], and two from a letter to the editor [27]. The main identified reason was a history of psychiatric adverse events identified in (n = 5, [15.15%]) patients caused by antiseizure medications: levetiracetam occurred three times in the whole study sample, valproic acid occurred twice, and brivaracetam, topiramate, etosuximide, zonisamide, and oxcarbazepine each occurred once. Clinical signs and symptoms of these adverse events, if reported by the authors, are shown in Table 2. The most common reason for positive psychiatric personal history was detected intellectual disability in seven cases (21.21%): in the case with ring 20 chromosome mosaicism [18], disability combined with challenging behavior in the case with Tourette syndrome [21], in one case not precisely defined [15] and in four cases from Juhl’s case series also with not precisely defined etiology [26]. Also, the main reason was detected cognitive impairment of various severity in 4 patients (n = 4, [12.12%]) [21,27,28], 2 of whom were from a case series [27]. That we noticed by reading the general characteristics of the whole study population [19]. In most cases (n = 26, [78.79%]), we could not estimate the family history of neuropsychiatric diseases due to missing data. For other included cases (n = 7, [21.21%]), we found clearly confirmed absent psychiatric family history [14,15,17,18,22,23,28]. More information about the personal history of psychiatric diseases is provided in Table 2.
In 2 cases (n = 2, [6.06%]), authors confirmed the absence of any other medical history [14,18], while in 15 cases (n = 15, [45.45%]), it was not reported. Other medical history was identified and described in (n = 16, [48.49%]) cases such as acute lymphocytic leukemia [15], hyponatremia due to carbamazepine [8], loss of vision due to traumatic injury [21], pancreatitis due to sodium valproate [22], polycystic ovary syndrome [23], brain contusion [24], nonepileptic seizures [25], abdominal cramps with constipation due to ethosuximide [16], drowsiness due to clobazam [16], meningitis, which caused secondary epilepsy [17], HIV infection [28], mesial temporal sclerosis, cortical dysplasia, brain tumor glioma, cavernous angioma, cytomegalovirus infection, and stroke—all one case each in the case series [26].
Patients had various types of seizures, focal with secondary generalization dominating in terms of presentation in our study population (n = 10, [30.30%]), as presented in Table 2. Most of the generalized seizures had a presentation as tonic–clonic seizures in 16 (48.48%) patients from partial seizures. Also, we noticed a lower proportion of myoclonic seizures in (n = 3, [9.09%]) cases [9,16,23], atonic seizures in (n = 1, [3.03%]) case [15], and absence seizures in (n = 1, [3.03%]) case [18]. Myoclonic epilepsy was manifested as eyelid myoclonia (n = 1, [7.69%]), named Jeavons syndrome, which was successfully treated with acetazolamide one year after the adverse event occurred [16], and the juvenile form in (n = 2, [6.06%]) cases [9,23]. We show more information about the types of seizures for each case in Table 2. We could not estimate it for the five included patients from N. Datta et al.’s case series by reading information about particular cases where perampanel was discontinued [19]. The last case with missing data was described by Kakunje et al., where it was not specified if partial seizures were with or without secondary generalization, but it was known that he had refractory right hemispheric seizures [22]. Unfortunately, due to missing data, we could not confirm the localization of the development of partial seizures if this type of epilepsy was confirmed in 16 (n = 16, [72,73%]) from 22 cases, either with mixed forms or focal epilepsies only. For these estimations, we excluded six patients with confirmed generalized attacks only and five cases where the types of seizures were not reported. On the other hand, focal seizures, either with or without secondary generalization, in the majority of known cases had a localization of confirmed development in the temporal lobe in (n = 3, [13,64%]) cases [17,20,26] and in the right hemisphere in three cases [17,20,22] and in the left hemisphere in two patients [14,24], while hemisphere origin was unknown in (n = 17, [77,27%]) patients with confirmed history of focal seizures attacks.
Perampanel showed satisfactory efficacy in 13 (39.39%) patients, where seizure frequency was reduced by 50% or more. For seven patients, two of whom are from N. N.Datta’s case series and three from Juhl’s series, the reduction in seizure frequency was over 50% [16,18,19,26]. Also (n = 6, [18.18%]) patients were seizure-free [8,14,15,23,24,26]. We detected a lack of efficacy in 13 cases (39.39%), of which 11 had no change in frequency: 1 case [17], 2 cases [19], 2 cases [27], and 6 cases [26] were detected, respectively. The rest of the two patients reduced seizure frequency by less than 50% from baseline [26]. For 4 cases (n = 4, [12.12%]), we could not estimate efficacy due to missing data [9,19,20,22], while in 2 cases, efficacy was probably achieved [21,28], and for 1 case, it was probably not achieved [25], so we could not confirm efficacy precisely.
The majority of patients (n = 31, [93.94%]) developed adverse events during outpatient treatment, while others (n = 2, [6.06%]) developed them during hospitalization, where perampanel was introduced due to poor seizure control [8,28]. In all reported cases, perampanel was administered in the form of film-coated tablets. Most of them (n = 26, [78.79%]) received an initial dose of 2 mg daily at bedtime. On the other hand, we could not estimate it for 6 cases (n = 6, [18.18%]) [9,14,15,18,21,23], while 1 patient received a different initial dose of 1.5 mg [16]. Table 1 shows the prevalence of adverse events due to perampanel, comparing different doses, with the highest during receiving a daily dose of 4 mg in 11 (33.33%) cases.
Titration was performed to achieve satisfactory efficacy in 27 cases (81.82%), whereas in 3 cases (9.09%), titration was not undertaken because patients remained on the initial dose throughout treatment [16,19,26]. For the remaining three cases (9.09%), data on the initial dose were missing, precluding confirmation of whether titration had been performed [15,18,23]. Dose titration of perampanel most commonly followed a regimen of 2 mg increments every 2 or 3 weeks in 16 cases (48.48%), including 4 patients from one study [19], 11 patients from another [26], and 1 patient from a separate report [20]. In eight cases (24.24%), the exact titration schedule could not be determined, although the authors stated that dosing was titrated and individualized [14,17,21,22,24,25,27,28].
The mean number of concomitant antiseizure medications used during adverse events was 2.59 per patient (n = 27), with a range of one to four medications per case. The largest proportion of patients (n = 10; 30.30%) received three concomitant antiseizure medications, and none were treated with perampanel monotherapy at the time of the adverse event. The most frequently co-administered antiseizure drugs were valproic acid and levetiracetam, each reported in 11 cases (33.33%). Additional details regarding initial and suspected doses of perampanel, as well as concomitant antiseizure medications and their doses (when reported), are provided in Table 2.
The prevalence of clinical signs and symptoms of adverse drug events is summarized in Table 3 and categorized according to neuropsychiatric manifestations. Aggression was the most frequently reported symptom, occurring in 25 patients (75.76%), followed by irritability in 10 patients (30.30%). Psychotic symptoms, including delusions and/or hallucinations, were identified in eight patients (24.24%), whereas the remaining cases exhibited other psychosis-like symptoms defined in the inclusion criteria. Detailed descriptions of clinical manifestations and the precise timing of symptom onset for individual cases are presented in Table 2.
The interval between initiation of the suspected perampanel dose and the onset of adverse events varied considerably across cases. In four reports, the timing was not specified precisely but was described as occurring shortly after dose escalation. Dolton reported symptom onset following an increase to 8 mg/day [21], Coyle used the term “once increased” [25], and Arimany described onset as occurring “after increasing the dosage of perampanel” [9]. Kakunje et al. reported that symptoms developed a few weeks after treatment initiation; however, these data could not be incorporated into the calculation of average onset time expressed in weeks [22].
In most cases (n = 15; 45.45%), the time to onset was reported in months, with a mean duration of 13.8 months. Takeshima et al. reported onset only in terms of days following perampanel initiation [8]. Seven studies [14,16,18,19,20,24,27] reported time to onset in weeks, encompassing a total of 11 patients (33.33%). For seven of these cases, onset was measured from the initiation of perampanel therapy, with a mean of 15.9 weeks, whereas in the remaining four cases, symptoms emerged after dose escalation, with a mean onset time of 3.2 weeks. Finally, two cases were classified as delayed reactions, with onset occurring one year after treatment initiation (seven months after dose escalation to 6 mg/day) [17] and two years after initiation [23], yielding a mean delay of 1.5 years.
In all cases (n = 33, [100%]), authors reported ways of treating adverse drug events. Perampanel was withdrawn only after detecting adverse events in n = 23 (69.70%) cases without symptomatic treatment, while in additional cases, it was discontinued gradually with symptomatic treatment [17]. Therapy was continued in 7 cases (n = 7, [21.21%]), where 5 of them received symptomatic treatment. In three cases, therapy was continued at the same dose. In all cases (n = 33, [100%]), rechallenge was not completed. Most patients (n = 31, [93.94%]) had full recovery without any consequences, while the rest of them had partial recovery, which implies the need for further follow-up for other clinical examinations. All cases (n = 33, [100.0%]) survived adverse events during the whole monitoring period; in some cases, an adverse event was detected [15,18,23], and for others, the dosage was reduced per case [14,21], in 2 cases [26]. Symptomatic treatment was administered in 8 (n = 8, [24.24%]) patients. More details about treatment strategies for adverse events are shown in Table 2.
Causality assessment was investigated by calculating the Naranjo score for estimating the cause–effect relationship [12] for all cases. Only one patient had a score that caused cause-and-effect to be in the category “possible” with a score of four [21], while all other cases (n = 32, [96.97%]) were in the category of probable causality. The majority of them (n = 24, [72.73%]) had a score of seven, while two others had a score of five, and finally, six cases had the biggest estimated score of eight in our population. The mean value of the estimated Naranjo score for the whole study population was 6.97. As presented in Table 2, most cases had positive dechallenge (n = 26, [78.79%]) without any case of negative dechallenge (n = 0, [0%]) if it was implemented.

4. Discussion

The described adverse events are more frequent in other population groups with risk factors. Our population was young but with a wide range of reported ages, so we did not conclude that patient age had a significant impact on the development of adverse events. Approximately two-thirds of all cases had a previous history of psychiatric conditions or reactions. Family history of psychiatric conditions may have an impact on the development of adverse events, but we could not confirm that because we had mainly patients with missing data. Also, medical history varies between patients, so we could not confirm that particular medical comorbidity had a high impact. The dominant seizure type in our population was focal seizures with secondary generalization, but its prevalence was not significantly higher in comparison to other focal or generalized seizures. We conclude that focal seizures, especially with secondary generalization, contribute to a slight increase in risk but without significant differences in comparison with other seizure types. We suggest that temporal lobe epilepsy may have an influence on increasing the ability for the development of psychosis in patients, but we could not confirm that in our study population due to limited data about epileptogenic focus location. Perampanel efficacy was variable between cases, so we could not confirm that it is in correlation with the development of adverse events. On the other hand, diagnosis of forced normalization had a significant impact on complete seizure disappearance without any electroencephalography signs during the whole period of psychotic symptoms [17,18,23]. Also, Leite et al. noticed that forced normalization was a possible cause for the psychiatric presentation without a confirmed diagnosis [15]. On the other hand, Sulais et al. confirmed that forced normalization was excluded, although the patient was seizure-free during the whole period [14].
Compared to observational studies where authors described the prevalence of psychosis or psychosis-like symptoms due to perampanel, analyzing the FAERS database delivered by the Food and Drug Administration [31,32,33,34], we noticed certain similar findings and minor differences in relation to our results. Pengcheng et al. noticed mainly reported signals by psychosis development, among which suicide behavior or aggression commonly occurred with unknown prevalence. Special caution for the development of homicide threats and aggression is described for males [31]. Gui J. et al. reported that perampanel, with eight other antiseizure drugs, may increase the risk for self-injurious behavior, homicide threats, and suicide in children. The highest prevalence of psychosis was described for topiramate, levetiracetam, and lorazepam, with an unknown prevalence of psychosis [32]. In contrast to the previous study, Porwal et al. reported that perampanel did not statistically significantly improve the risk of self-injury and suicide by analyzing patients without age restrictions. The highest risk was estimated for diazepam without analyzing other psychotic-like symptoms [33]. Chang et al. suggest a confirmed risk for the development of psychosis due to perampanel use in comparison with lacosamide and special caution for the development of suicidal behavior [34], which is in accordance with included cases [24,25,27] and with mainly other mentioned studies [32,33]. Also, he reported a high prevalence of aggression, suicide attempts or thoughts, irritability, and psychosis in the seventh place by representation, calculating from the study sample of 2073 patients who received perampanel [34]. Our results, which analyzed the prevalence of all followed symptoms, differ from other studies due to significant variations in the study sample, suggesting the possible risk for the development of all followed symptoms, with possible variations between ages and sex.
During perampanel titration, in all cases, adverse events started or worsened while receiving the maximum reported dose, so we could confirm that perampanel-induced psychosis or psychosis-like symptoms are dose-dependent side effects. The results are mainly consistent with the statements of observational studies [35,36,37,38,39,40], while two have contradictory statements about dose dependence [41,42]. Yamamoto et al. reported a high relation between the development of intellectual disability and concentration dependence for any psychiatric side effects [35]. Maurousset and Nuthalapati concluded that there was a significant need for attention during its introduction and titration, especially at the start of treatment [36,37]. Dose dependence of aggression development was confirmed by Goji et al., where perampanel increased the BAQ index of aggression (Buss Perry Aggression Questionnaire) without impacting the development of depression symptoms [38], and by Lee, where perampanel dosage higher than 8 mg daily with depression as a comorbidity increased the risk for severe aggression measured by the Korean version of the Aggression Questionnaire [40]. Hasegawa et al. reported significantly increased risk for dose-dependent irritability in comparison with levetiracetam treatment [39]. On the other hand, Kim et al. showed that approximately three-quarters of all patients developed aggression, irritability, acute psychosis, and affective disorder in low daily doses of perampanel (6 mg or lower) without statistically significant associations between using higher daily doses and development of the following conditions [41]. Matsunuma et al. reported a short time to onset for developing any psychiatric adverse events, lower than 1 month, without dose-dependence and with higher prevalence, when perampanel was combined with levetiracetam, in comparison with perampanel–lacosamide treatment, which had a more favorable safety profile [42]. Retrospective analysis of phase 3 clinical trials suggests a high relationship between receiving doses of 8 and 12 mg and the development of the following psychiatric side effects: both psychosis and psychosis-like symptoms are more prevalent in comparison with the placebo group [43,44,45].
Based on all of the above, it can be concluded that perampanel causes a wide range of psychiatric side effects. Due to the possible development of depression, we had to exclude one case with developed forced normalization, with a mainly present depressed mood combined with daytime somnolence, loss of appetite, and insomnia [29]. Also, we excluded three patients from N. Datta et al.’s case series due to similar symptoms such as low mood or unmotivated behavior. One patient described that he “could not think straight,” so we could not be sure if this condition was a form of disorganized thinking as part of psychosis pathology or if it was a cognitive disorder independent from psychosis [19]. The third case of increased risk of suicidality from Huber’s case series was excluded due to confirmed depression without aggression, irritability, or any symptoms possibly related to psychosis [27]. That is the same reason for the exclusion of the other two cases from Coyle’s case series [25].
Psychiatric side effects of perampanel could be explained according to its unique neurobiological mechanisms of these developments. This was confirmed by preclinical studies on animals, where the role of the modification of glutamate neurotransmission was implicated in causing aggression in animals. Vekovischeva et al. examined the application of 3 different competitive antagonists of AMPA receptors. It was mentioned that there was a significant difference between these compounds in the development of aggression in TNA (Turku Non-Aggressive) mice, with the maintenance of aggressive behavior more than 1 week [90]. Shimizu K. et al. noticed a significant level of aggression in the population of chronic social isolation (SI)-reared mice. We observed up-regulation of AMPA receptors with increased levels of GluR1 and GluR2 subunits in the amygdala, and at the same time, down-regulation of 5-HT3 receptor levels in the hypothalamus. After social isolation of mice, an antagonist was administered (NBQX) (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione), which did not reduce the level of aggression, but it had an impact on a slight decrease in depressive symptoms in mice [91]. X. Peng et al. suggested a possible role of two rare missense variants, G630R and E787G, in the X-linked GRIA3 gene in human males who showed intensive aggressive behavior. These mutations are located in the AMPA receptor GluA3 subunit and result in lost functions of their ion channels. In order to confirm these findings, researchers did experiments in GluA3 knockout mice, where it was observed that significant damage occurred in the medial prefrontal cortex, where excitatory neurotransmission and neuronal activity were impaired, which caused aggressive behavior [92]. Administration of perampanel in a period of two months, with a more precise explanation of the molecular mechanism for the development of aggression, was confirmed by W. Yang et al. in a population of C57BL/6J mice. Authors reported a significantly increased level of 93 various proteins in the hippocampus in the perampanel-treated group after proteomic analysis (p < 0.050). Also, validation results confirmed by the western blot technique demonstrated that glutamate receptor 1 (GluA1) and phosphorylation of mitogen-activated protein kinase (ERK1/2) were significantly up-regulated, while at the same time, synaptophysin (Syn) and postsynaptic density 95 (PSD95) were down-regulated [93]. Unfortunately, there was a limit of evidence about possible molecular mechanisms for the development of psychosis symptoms like delusions and hallucinations after perampanel administration, but we suggest a possible role of glutamate neurotransmission and correlation with the dopaminergic neurotransmission system, which is known for its pathophysiological role in the development of psychosis in humans. We suggest the need for future studies that will further clarify possible mechanisms for the development of psychosis.
This study has several limitations: (1) We analyzed a relatively small number of reported cases, particularly about perampanel-induced psychotic disorder with confirmed diagnosis and presence of delusions or hallucinations. (2) The majority of studies had significant variations in completeness of published data. These problems led to the possibility of completely missed, partially missed, or not precisely important information for the causality assessment, specifically related to possible associations with concomitant therapies or the whole medical history. (3) We could not estimate the causality assessment precisely and establish final conclusions, even though the reported case contained all significant data. Also, due to the descriptive character of this systematic review, there is a risk of information bias due to the possibility that authors who did the extraction from individual studies did not include all significant data accidentally. (4) There was a possibility of estimating psychosis for some other described patients with missing data of verified diagnosis, so we could not be sure if psychosis definitely occurred. The use of medical charts or other documentation of patients, prospective follow-up of cases, or individual patient data design may give us the opportunity for better clinical estimation of every included case. Despite the mentioned limitations, the results of our systematic review could help all healthcare professionals to recognize, manage, and prevent perampanel-induced psychosis or psychosis-like symptoms in the future.

5. Conclusions

Clinicians, particularly neurologists, should be aware that psychosis or psychosis-like symptoms may be dose-dependent adverse effects of perampanel, with their sudden onset and rapid development of symptoms, which can be serious, with significant differences in the time period from the start of using the suspected dose of perampanel to the onset of the adverse event. Significant risk factors identified were positive personal psychiatric history (as detected by adverse reactions to other antiseizure drugs), intellectual disability or cognitive impairment, drug-resistant epilepsy (which requires antiseizure polytherapy combined with high doses, especially levetiracetam and valproic acid), women’s gender, and focal epilepsies with secondary generalization, mainly manifested as tonic–clonic seizures. Adequate recognition of adverse drug effects by using treatment strategies such as drug withdrawal, dosage decrease, symptomatic treatment, or combining the mentioned strategies is crucial for achieving full recovery with its high satisfactory prognosis. Future research may provide us with information about the possible assessment of the other factors, particularly in a large study sample. A slower and individualized dose escalation during perampanel titration is recommended. Particular caution is warranted when perampanel is used concomitantly with antiepileptic drugs such as levetiracetam and valproic acid, given the potential for additive or synergistic neuropsychiatric adverse effects, especially in patients with a history of psychiatric disorders. Careful clinical monitoring is advised in these patients. Furthermore, patients with pharmacoresistant epilepsy require special consideration due to their increased baseline risk of psychiatric comorbidities associated with epilepsy itself, which should be carefully differentiated from psychiatric adverse reactions related to antiseizure medication exposure.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/futurepharmacol6010010/s1, Table S1: PRISMA checklist; Table S2: Detailed search strategy for the each database.

Author Contributions

Conceptualization, P.Z.T. and M.N.M.; methodology, P.Z.T. and M.N.M.; software, P.Z.T.; validation, P.Z.T., M.N.M., V.J. and S.S.; formal analysis, P.Z.T. and M.N.M.; investigation, P.Z.T. and M.N.M.; resources, V.J. and S.S.; data curation, P.Z.T. and M.N.M.; writing—original draft preparation, P.Z.T.; writing—review and editing, M.N.M., V.J. and S.S.; visualization, M.N.M. and S.S.; supervision, V.J. and S.S.; project administration, M.N.M.; funding acquisition, M.N.M., V.J. and S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Ministry of Science, Technological Development, and Innovations of the Republic of Serbia (Grant number 451-03-137/2025-03/200111). The main author (P.Z.T.) is a scholarship holder of the Ministry of Science, Technological Development, and Innovations of the Republic of Serbia for students of Doctoral Academic studies.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were generated or analyzed in this study. All data originate from previously published sources.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
TNATurku Non-Aggressive mice
AMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
ILAEInternational League Against Epilepsy (ILAE)
DSM-5Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
PROSPEROInternational Prospective Register of Systematic Reviews
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses

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Futurepharmacol 06 00010 g001
Figure 1. Selection of the publications.
Figure 1. Selection of the publications.
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Figure 2. Quality assessment of the included studies.
Figure 2. Quality assessment of the included studies.
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Table 1. Summary of the basic characteristics of included cases (n = 33).
Table 1. Summary of the basic characteristics of included cases (n = 33).
CharacteristicValue
Age, mean (range), (n = 32)34.22; (11–70)
Sex, No., (%)Males10; (30.30%)
Females22; (66.67%)
Not reported1; (3.03%)
Country, No., (%)Denmark12; (36.36%)
Canada5; (15.15%)
United Kingdom3; (9.09%)
Japan3; (9.09%)
Spain2; (6.06%)
Germany2; (6.06%)
India1; (3.03%)
France1; (3.03%)
Saudi Arabia1; (3.03%)
Portugal1; (3.03%)
USA1; (3.03%)
Montenegro1; (3.03%)
Perampanel daily dosage during adverse event, No., (%)1.5 mg1; (3.03%)
2 mg2; (6.06%)
4 mg11; (33.33%)
6 mg7; (21.21%)
8 mg9; (27.27%)
10 mg1; (3.03%)
12 mg2; (6.06%)
Number of concomitant antiseizure medications used during adverse event except perampanel, No., (%)one4; (12.12%)
two8; (24.24%)
three10; (30.30%)
four5; (15.15%)
Not reported6; (18.18%)
Personal history of neuropsychiatric disorders or psychological reactions, No., (%)Yes20; (60.61%)
No10; (30.30%)
Not reported3; (9.09%)
Family history of neuropsychiatric disorders or psychological reactions, No., (%)Yes0; (0%)
No7; (21.21%)
Not reported26; (78.79%)
Types of seizures, No., (%)Focal; simple partial only2; (6.06%)
Focal (both simple or complex) with secondary generalization10; (30.30%)
Focal; complex partial only4; (12.12%)
Generalized only6; (18.18%)
Mixed forms5; (15.15%)
Not precise6; (18.18%)
Outcome, No., (%)Full recovery31; (93.94%)
Partial recovery2; (6.06%)
Died0; (0%)
Table 2. Overview of the included cases.
Table 2. Overview of the included cases.
No.StudyNo. of Patients and CountryAge; SexType of SeizuresPersonal Psychiatric HistoryPER Dosage (Starting Dose; Dose on Which Adverse Event OccurredConcomitant
Antiseizure
Medications with Daily Doses		Clinical Signs and Symptoms of Adverse
Event with Time of Onset		Dechallenge/
Rechallenge		ST with
Daily Doses		Outcome
1Sulais et al. 2024 [15]1; SA15; FGS; tonic–clonic and atonic seizuresModerate intellectual disability—NSNS; 4 mg dailyLEV 1600 mg and VAL 1300 mgAbout 2 months after PER introduction: irritability, aggression, (physically and verbal), homicide threats, insomnia, psychomotor agitation, disorganized speech, persecutory delusions and hallucinations (auditory and visual) with hallucinatory gestures.Not completed/not completed; PER continued at the same doseRIS increased to 1.5 mgFull recovery after a few days
2Takeshima et al. 2018 [8]1; JPNNRSPS; focal motorseizuresNR2 mg daily; 4 mg daily-worsening at 8 mg dailyLEV 3000 mgA day after increasing PER to 4 mg: drowsiness and irritability; symptoms worsened at the same day after increasing PER to 8 mg (63 days of treatment): cognitive, memory and attentional impairment, worsening irritability, disorientation, confusion during conversation and abnormal movements.Positive/not completedNoneFull recovery after 17 days
3S. Arimany et al. 2017 [9]1; ESP32; FGS; juvenile myoclonus seizuresNRNS; 12 mg dailyNRShortly after increasing PER dosage from 6 to 12 mg: insomnia, irritability, aggression, behavioral disturbances, confusion with fluctuations of mental state and level of consciousness (acute confusonal syndrome was diagnosed)Positive/not completedRIS (dose NR)Full recovery after 4 weeks
4Leite et al. 2021 [14]1; POR57; FPWSG: temporal and left front opercular epilepsyNoneNS; 12 mg dailyTPM 200 mg; CLZ 4 mg and LCM 200 mg2 weeks after increasing PER dose to 12 mg: hostility, extreme irritability, disorganized thoughts, persecutory and self-referential delusions combined with multiple delusional interpretations and perplexity and hallucinations (auditory-verbal, olfactory and somatic)Not completed/not completed; PER was reduced to 6 mg dailyRIS 2 mg and LOR 2.5 mgFull recovery after 1 week
5Rogac et al. 2025 [16]1; MON11; MGS; eyelid myoclonia-Jeavons syndrome with tonic–clonic seizuresaggression (LEV, BRV), suicidal ideations with social impairment (TPM), symptoms similar to ADHD (BRV)1.5 mg daily; 1.5 mg dailyVAL 40 mg/kg, LTG 5 mg/kg and CLZ 0.3 mg/kg2 weeks after PER introduction: severe visual hallucinationsPositive/not completedNoneFull recovery after 1 month
6Fujiwara et al. 2025 [17]1; JPN30; FMixed: SPS and PWSG; right temporal lobe epilepsyParanoid delusions with auditory hallucinations 5 months after neurosurgery intervention (3 years before adverse event)2 mg daily; 6 mg dailyLCM 300 mg; LEV 3000 mg; VAL 800 mg and ACZ 500 mg7 months after increasing PER to 6 mg, exacerbating of de novo psychosis: delusions, irritability, aggression, psychomotor agitation, apart attention, disorientation with rigid demeanor (suggested PER induced encephalopathy) presumably responsible for development these symptomsPositive/not completedFLN 2 mg—IV injectionFull Recovery after 29 days
7Shelton et al. 2017 [18]1; UK21; FMixed: CPS with SG and GS (absence, attacks similar to absence and tonic–clonic seizures)Intellectual disability due to ring 20 chromosome mosaicism; similar psychosis symptoms (ZNS, ETX), aggression (VAL) and letargia (unknown ASM)NS; 4 mg dailyLTG 525 mg; ZNS 300 mg and MDZ 10 mg as “rescue medication”3 weeks after PER introduction: tactile hallucinations, delusions, self-harm, restlessness, agitation, increase in challenging behavior, significant distress without being confused or disorientatedNot completed/not completed; PER continued at the same doseRIS 0.75 mgPartial recovery; patient was on further follow-up
8Kheloufi et al. 2017 [20]1; FRA35; MPWSG: right temporal epilepsyNone2 mg daily; 4 mg dailyOXC 1800 mg2 weeks after PER dose increased to 4 mg: compulsive self-mutilation ideation; self-harm ideation without suicidal intentionPositive/not completedNoneFull recovery within a week
9Dolton et al. 2014 [21]1; UK37; FGS: tonic–clonic seizuresModerate cognitive disability with history of challenging behavior causing hospital admission—NS symptomsNS; 8 mg dailyGBP, ZNS and VAL (doses NR)Since PER was increased to 8 mg: psychomotor agitation, aggression (verbal and especially physical), self-injurious behaviors with worsening symptoms over the weeksNot completed/ not completed; PER was reduced to 6 and shortly to 4 mg dailyQUT 350 mg; RIS 2 mg; AML 200 mg; ZCP-later excluded due to EXP side effects and replaced with ARP-dose NRPartial recovery; patient was on further follow-up
10Kakunje et al. 2024 [22]1; IND24; MPS—NS refractory right hemisfere seizuresNone2 mg daily; 8 mg dailyCBZ 20 mg; BRV 200 mg and LCM 200 mgPatient experienced drowsiness initially. After a few weeks of PER introduction: anger, less talking, irritability, aggression (physical and verbal), tremors of hand with exclusion of mood disorder (PER-associated psychiatric adverse event diagnosis)Positive/not completedNoneFull recovery after few days
11A.V. Jose et al. 2023 [23]1; ESP19; FGS; juvenile myoclonus seizuresADHD syndromeNS; 4 mg dailyVAL 1000 mg and CLZ 3 mgAbout 2 years of PER introduction: aggression with significant behavioral changes and fluctuating bizarre behavior, irritability, unmotivated laughter, disorganized speech and thought, delusions and auditory hallucinations. Symptoms improved during 1st admission without any treatment (brief psychotic disorder). A week after discharge patient readmitted with reoccurrence of psychotic episode: bewilderment and slowness of thought when forced normalization was diagnosed.Not completed/not completed; PER continued at the same doseCRP 1.5 mg; replaced with ARP due to EXP side effects (dose NR)Full recovery after 3 weeks
12Yamada et al. 2020 [24]1; JPN70; FSPS; right hand focal convulsionNR2 mg daily; 4 mg dailyLEV 2000 mg2 weeks after PER dosage increased to 4 mg: patient could not walk, aggression, especially verbal, hostility, extremely talkative and suicidal ideation. She was aware herself of the strangeness of her psychological status.Positive/not completedNoneFull recovery (time NS)
13Coyle et al. 2014 [25]1; UK51; MMixed: CPS with SG and GS (tonic–clonic seizures)None2 mg daily; 8 mg dailyCBZ (dose NR) and LEV 4000 mgShortly after PER dosage increased to 8 mg: intermittent confusion, aggression and suicidal ideationPositive/not completedBNZ drug—NSFull recovery (time NS)
14Kenaan et al. 2020 [28]1; USA32; MGS: tonic–clonic seizuresDepression, Anxiety, hospitalization due to mood lability with cognitive and social impairment2 mg daily; 10 mg dailyLEV 1000 mg and CAR 400 mgInitially patient experienced symptoms of cataplexy, which was completely resolved at the 4th day of hospitalization. Due to poor seizure control, PER was reintroduced at the same dose when it was withdrawn at admission (10 mg daily). After several hours patient developed: confusion, visual hallucinations, severe agitation requiring physical restraints with reoccurrence of cataplexy.Positive/not completedNoneFull recovery after 2 days
15Huber et al. 2013 [27]2; GER21; FMixed: SPS, CPS and GS (tonic–clonic seizures)Cognitive impairment—NS2 mg daily; 8 mg dailyLTG and VAL (doses NR)1 month after PER increased to 8 mg, she complained due to weight increase, dizziness, and blurred vision. Later, she was unusually sensitive, irritable, would become upset over any minor adversity and suicidal ideasPositive/not completedNoneFull recovery after few days
22; FMixed: SPS, CPS and GS (tonic–clonic seizuresCognitive impairment—NS; history of suicide attempt by using toxic doses of LEV, 7 years ago2 mg daily; 4 mg dailyOXC and RTG (doses NR)Shortly after PER was increased, patient initially felt dizzy and unwell. About 8 weeks later at the same dose, symptoms worsened, and she felt thin-skinned, abnormally sensitive, irritable, aggressive with suicidal ideasPositive/not completedNoneFull recovery after few days
16Datta et al. 2017 [19]5; CAN20; FNSConfirmed for other psychiatric comorbidities; NS2 mg daily; 2 mg dailyNR1 week after PER introduction: verbal and physical aggressionPositive/not completedNoneFull recovery (time NS)
18; MNSBehavioral adverse events-not specified symptoms (LEV, OXC); Confirmed for other psychiatric comorbidities—NS2 mg daily; 4 mg dailyNR9 weeks after PER introduction: mood swings, irritability, auditory hallucinations, dizziness, and poor appetitePositive/not completedNoneFull recovery (time NS)
14; FNSBehavioral adverse events-NS symptoms (LEV); Confirmed for other psychiatric comorbidities—NS2 mg daily; 6 mg dailyNR9 weeks after PER introduction: verbal and physical aggression, homicidal thoughtsPositive/not completedNoneFull recovery (time NS)
17; FNSBehavioral adverse events-NS symptoms (VAL); None history for other psychiatric comorbidities.2 mg daily; 6 mg dailyNR72 weeks after PER introduction: verbal and physical aggression, hair lossPositive/not completedNoneFull recovery (time NS)
21; FNSConfirmed for other psychiatric comorbidities—NS2 mg daily; 6 mg dailyNR15 weeks after PER introduction: verbal and physical aggression, actual self-harmPositive/not completedNoneFull recovery (time NS)
17Juhl et al. 2017 [26]12; DEN50; FCPSdepression2 mg daily; 6 mg dailyLEV, LTG, PGB and CBZ (doses NR)28 months after PER introduction: aggression, bad mood, tiredness, dizziness, and concentration difficultiesNot completed/not completed; only PER was reduced to 4 mg daily.None.Full recovery (time NS)
32; FCPS with SG tonic–clonic seizuresIntellectual disability—NS2 mg daily; 2 mg dailyTPM, SLT and VAL (doses NR)2 months after PER introduction: aggression, tiredness, and mood swingsPositive/not completedNoneFull recovery (time NS)
32; MCPS with SG (tonic–clonic seizuresIntellectual disability—NS2 mg daily; 8 mg dailyTPM, SLT, VAL and CBZ (doses NR)12 months after PER introduction: aggression and tirednessPositive/not completedNoneFull recovery (time NS)
59; FCPSObsessive-compulsive anxiety disorder2 mg daily; 4 mg dailyLEV, CLZ and CAR (doses NR)7 months after PER introduction: aggression, bad mood, and difficulty in finding wordsPositive/not completedNoneFull recovery (time NS)
49; FCPSNone2 mg daily; 8 mg dailyLTG, LCM, CBZ and RTG (doses NR)26 months after PER introduction: aggression and mood swingsNot completed/not completed; only PER was reduced to 4 mg dailyNone.Full recovery (time NS)
43; FCPSNone2 mg daily; 8 mg dailyLTG, CBZ and RTG (doses NR)6 months after PER introduction: aggression and bad moodPositive/not completedNoneFull recovery (time NS)
67; MCPS with SG tonic–clonic seizuresNone2 mg daily; 4 mg dailyLCM, CBZ and VAL (doses NR)5 months after PER introduction: aggression onlyPositive/not completedNoneFull recovery (time NS)
51; FSPS with SG tonic–clonic seizuresNone2 mg daily; 4 mg dailyLEV and ZNS (doses NR)24 months after PER introduction: aggression, bad mood, concentration difficulties, and tirednessPositive/not completedNoneFull recovery (time NS)
48; FSPS with SG tonic–clonic seizuresNone2 mg daily; 8 mg dailyLTG (dose NR)18 months after PER introduction: aggression, bad mood and concentration difficultiesPositive/not completedNoneFull recovery (time NS)
25; MSG tonic clonic seizuresIntellectual disability—NS2 mg daily; 8 mg dailyLEV and VAL (doses NR)32 months after PER introduction: aggression onlyPositive/not completedNoneFull recovery (time NS)
30; FSPS with SG tonic–clonic seizuresIntellectual disability—NS2 mg daily; 6 mg dailyLEV, VAL, TPM and LCM (doses NR)10 months after PER introduction: aggression, tiredness and irascibilityPositive/not completedNoneFull recovery (time NS)
42; MCPS with SG tonic–clonic seizuresNone2 mg daily; 6 mg dailyCBZ, CAR and LCM (doses NR)7 months after PER introduction: aggression, tiredness, headache, and double visionPositive/not completedNoneFull recovery (time NS)
List of abbreviations: No.—Number; NR—Not reported; NS—Not specified; MON—Montenegro; POR—Portugal; UK—United Kingdom; USA—United States of America; SA—Saudi Arabia; CAN—Canada; FRA—France; GER—Germany; ESP-Spain; JPN—Japan; IND—India; DEN—Denmark; F—Female; M—Male; GS—Generalized seizures; SPS—Simple partial seizures; CPS—Complex partial seizures; PS—Partial seizures; PWSG—Partial seizures with secondary generalization; SG—Secondary generalization; ADHD—Attention deficit hyperactivity disorder; ASM—Antiseizure medication; LEV—Levetiracetam; VAL—Valproic acid; TPM—Topiramate; CLZ—Clonazepam; LCM—Lacosamide; LTG—Lamotrigine; ACZ—Acetazolamide; ZNS—Zonisamide; MDZ—Midazolam; ETX—Ethosuximide; BRV—Brivaracetam; OXC—Oxcarbazepine; GBP—Gabapentine; CBZ—Clobazam; CAR—Carbamazepine; RTG—Retigabine; PGB—Pregabaline; SLT—Sulthiam; PER—Perampanel; ST—Symptomatic treatment; RIS—Risperidone; LOR—Lorazepam; FLN—Flunitrazepam; IV—Intravenous; QUT—Quetiapine; AML—Amisulpride; ZCP—Zuclopenthixol; ARP—Aripiprazole; CRP—Cariprazine; BNZ—Benzodiazepine; EXP—Extrapyramidal.
Table 3. Number of various cases, which were expressed following neuropsychiatric symptoms and signs of adverse event due to perampanel (n = 33).
Table 3. Number of various cases, which were expressed following neuropsychiatric symptoms and signs of adverse event due to perampanel (n = 33).
Neuropsychiatric Symptoms or SignsValue
Aggression (verbal or physical)25; (75.76%)
Irritability10; (30.30%)
Hallucinations (both auditory, tactile, visual, verbal, olfactory, or somatic)7; (21.21%)
“Bad” or unwell mood6; (18.18%)
Tiredness6; (18.18%)
Psychomotor agitation5, (15.15%)
Delusions (self-referential or persecutory)5, (15.15%)
Suicide threats or thoughts4, (12.12%)
Self-harm thoughts or injuries4, (12.12%)
Dizziness4, (12.12%)
Challenging or bizarre behavior or behavioral disturbances-unspecified3, (9.09%)
Disorganized speech or confusion during conversation3, (9.09%)
Tremors or abnormal or impair movements3, (9.09%)
Restlessness or anxiety or significant distress3, (9.09%)
Mood swings3, (9.09%)
Concentration difficulties3, (9.09%)
Confusion3, (9.09%)
Disorientation2, (6.06%)
Disorganized thought or slowness of thought2, (6.06%)
Cognitive or memory impairment2, (6.06%)
Perplexity or bewilderment2, (6.06%)
Insomnia2, (6.06%)
Drowsiness2, (6.06%)
Attention impairment2, (6.06%)
Vision problems (blurred or double vision)2, (6.06%)
Homicide threats or thoughts2, (6.06%)
Abnormal sensitivity2, (6.06%)
Loss of consciousness1, (3.03%)
Social impairment1, (3.03%)
Cataplexy1, (3.03%)
Feel thin-skinned1, (3.03%)
Headache1, (3.03%)
Angry or anger1, (3.03%)
Irascibility1, (3.03%)
Poor appetite1, (3.03%)
Rigid demeanor1, (3.03%)
Hostility1, (3.03%)
Extreme talking1, (3.03%)
Less talking1, (3.03%)
Unmotivated laughter1, (3.03%)
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Taslaković, P.Z.; Milosavljević, M.N.; Janjić, V.; Stefanović, S. Perampanel-Induced Psychosis and Psychosis-like Symptoms: A Systematic Review. Future Pharmacol. 2026, 6, 10. https://doi.org/10.3390/futurepharmacol6010010

AMA Style

Taslaković PZ, Milosavljević MN, Janjić V, Stefanović S. Perampanel-Induced Psychosis and Psychosis-like Symptoms: A Systematic Review. Future Pharmacology. 2026; 6(1):10. https://doi.org/10.3390/futurepharmacol6010010

Chicago/Turabian Style

Taslaković, Petar Z., Miloš N. Milosavljević, Vladimir Janjić, and Srđan Stefanović. 2026. "Perampanel-Induced Psychosis and Psychosis-like Symptoms: A Systematic Review" Future Pharmacology 6, no. 1: 10. https://doi.org/10.3390/futurepharmacol6010010

APA Style

Taslaković, P. Z., Milosavljević, M. N., Janjić, V., & Stefanović, S. (2026). Perampanel-Induced Psychosis and Psychosis-like Symptoms: A Systematic Review. Future Pharmacology, 6(1), 10. https://doi.org/10.3390/futurepharmacol6010010

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