A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids

A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids Hideki Kanemoto, Taisuke Akiyama, Daiki Taomoto, Manabu Ikeda This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6157930/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 May, 2025 Read the published version in BMC Psychiatry → Version 1 posted 8 You are reading this latest preprint version Abstract Background: Hypersensitivity to antipsychotic drugs is one of the supportive features of dementia with Lewy bodies, and side effects to drugs other than antipsychotics are also known to occur frequently. We experienced a case of dementia with Lewy bodies in which hallucinations and delusions repeatedly appeared and disappeared after administration and discontinuation of mirogabalin and pregabalin. Case presentation: The patient, a woman in her late 70s, developed hallucinations and delusional misidentification of places and persons immediately after receiving a prescription of mirogabalin (15 mg daily) for neuropathic pain. After discontinuation of mirogabalin, her hallucinatory delusions improved but remained. Mild dementia and mild parkinsonism were associated, cognitive fluctuations were evident, and dopamine-transporter scintigraphy showed bilateral striatal uptake reduction. Residual psychosis resolved with donepezil. Later, when the pain worsened, pregabalin (25 mg daily) was administered, and the psychosis recurred and resolved with discontinuation. Conclusions: Although pregabalin-induced psychosis has been reported at higher doses (300–450 mg daily), it has not been reported at doses as low as those used in this patient. Gabapentinoids may cause psychosis in patients with dementia with Lewy bodies even at low doses, likely due to hypersensitivity to gabapentinoids in DLB. Dementia with Lewy bodies pregabalin mirogabalin drug-induced psychosis visual hallucinations delusional misidentification irritability Figures Figure 1 1. Background Dementia with Lewy bodies (DLB) is the second most common form of dementia after Alzheimer’s disease and is characterized by various symptoms, including visual hallucinations, cognitive fluctuations, parkinsonism, and rapid eye movement sleep behavioral disorder, from the early stages of the disease [1]. These symptoms can affect the patient’s daily life [2] and increase family care burden [3], making appropriate therapeutic interventions important. Interventions for psychosis and parkinsonism are prime examples. Pharmacological treatment in patients with DLB is challenging owing to their hypersensitivity to drugs. Hypersensitivity to antipsychotics is cited as a supportive clinical feature of DLB [1], and even small doses can cause acute onset or exacerbation of parkinsonism and impaired consciousness [4]. Moreover, patients with DLB can show hypersensitivity to drugs other than antipsychotics. Anti-parkinsonian drugs [5] and zolpidem [6] have been reported to induce psychosis even in small doses, and administration of anticholinergics has been associated with a high risk of delirium [7]. Additionally, studies also suggest that older patients with major depression who subsequently convert to DLB are more likely to experience adverse effects with psychotropic medications, including antidepressants [8]. Therefore, the risk of side effects from a variety of drugs should be considered in patients with DLB. Here, we report a case of DLB with psychosis that appeared after the administration of mirogabalin and pregabalin, which are medications used to treat neuropathic pain. 2. Case presentation The patient was a woman in her late 70s. She had been living with her daughter and son since her husband’s death >10 years prior. Other than leg pain associated with scoliosis, for which she was prescribed mirogabalin (described below), she had no history of any other notable medical conditions, including psychiatric disorders. Her son had also passed away a year before her initial visit to our hospital. Although her activities of daily living were independent, she had begun to show signs of forgetfulness in daily life. Three months earlier, she had visited an orthopedic surgeon for pain in her lower extremities, was diagnosed with scoliosis, and was prescribed mirogabalin (15 mg/day). Thereafter, she had complained frequently of visual hallucinations of her deceased son and husband, misidentified her daughter as her sister, and was irritable. She could not identify her home as the place where she lived, complained that she wanted to go home, and even visited her birthplace >300 km away, alone. Suspecting dementia, her family took her to her general practitioner, who prescribed donepezil, Yokukansan (a Japanese herbal medicine), aripiprazole and olanzapine, which were ineffective. Three months after disease onset, she was referred to our clinic for further evaluation and treatment. Her Mini-Mental State Examination (MMSE) score was 22, with suspected mild impairments in orientation, memory, attention, and visuospatial cognition. According to the family, her cognition fluctuated daily, with a score of 6 on the Mayo Fluctuations Scale [9]. Mild rigidity in the left upper limb and bradykinesia were noted; however, no other indications of parkinsonism were observed. Yokukansan (7.5 g), aripiprazole (2 mg), and mirogabalin (15 mg) were administered daily. Blood tests revealed nothing that could cause cognitive impairment or psychiatric symptoms. The symptoms suggested DLB; however, the patient’s history indicated that these cognitive and psychiatric symptoms were drug-induced. After the discontinuation of mirogabalin, the return-home behavior associated with the misidentification of places and her irritability disappeared. The visual hallucinations and misidentification of people reduced in frequency but persisted. In addition, no pain flare-ups were observed after discontinuing mirogabalin, probably owing to treatment with this drug over a period of 3 months. Magnetic resonance imaging of the brain was unremarkable. However, N-isopropyl-p-iodoamphetamine single-photon emission computed tomography showed reduced perfusion in the bilateral parietal, frontal, precuneus, and occipital lobes (Figure 1a, b). 123 I-meta-iodobenzylguanidine myocardial scintigraphy revealed that the heart-to-mediastinum ratio was maintained at 3.69 and 2.41 in the early and late stages, respectively, but the washout rate was high at 59.5%, suggesting mild abnormality of cardiac sympathetic nerve function (Figure 1c). 123 I-N-omega-fluoropropyl-2-betacarbomethoxy-3-beta (4-iodophenyl) nortropane dopamine-transporter single-photon emission computed tomography showed decreased uptake in the posterior striatum, especially on the left side (Figure 1d). Electroencephalography showed that the basic rhythm was 9–10 Hz occipital predominant, mixed with a generalized 6–7 Hz slow wave. However, no obvious epileptogenic findings were noted. Based on these findings, a diagnosis of probable DLB was made [1], and treatment with donepezil (3 mg) was initiated. When the dose was increased to 5 mg, the patient’s MMSE score increased to 25 points, and the misidentification of people disappeared. Aripiprazole was discontinued soon thereafter, but symptoms did not relapse. Residual insomnia improved with a prescription of quetiapine (12.5 mg). Thereafter, cognitive impairment progressed slowly, and after 1 year, the MMSE score dropped to 20 points. Two years later, her back pain intensified, and she was prescribed 1,200 mg of acetaminophen and 100 mg of tramadol. However, the pain did not improve, and tramadol was discontinued. After being administered 25 mg of pregabalin, she began to exhibit strange behaviors: she became irritable, talked to herself, and prepared meals for four people, despite living with only her daughter. These behaviors disappeared after discontinuation of the pregabalin. Her day care service advised increased exercise therapy, and in subsequent outpatient visits, her complaints of pain had decreased. The scores of the Adverse Drug Reaction Probability Scale [10] were 2 and 3 for mirogabalin and pregabalin, respectively (Table 1). Table 1. The results of Adverse Drug Reaction Probability Scale Scores for Question mirogabalin pregabalin 1. Are there previous conclusive reports on this reaction? 0 0 2. Did the adverse event appear after the suspected drug was administered? 2 2 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 1 1 4. Did the adverse event reappear when the drug was re-administered? 0 0 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? -1 -1 6. Did the reaction reappear when a placebo was given? 0 0 7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic? 0 0 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 0 1 10. Was the adverse event confirmed by any objective evidence? 0 0 Total score 2 3 3. Discussion and Conclusions Here, we report a case of a patient who experienced delusions, hallucinations, and irritability that appeared and disappeared following the initiation and discontinuation of mirogabalin and pregabalin, which have similar mechanisms of action in the treatment of chronic pain. The scores of the Adverse Drug Reaction Probability Scale [10] were 2 and 3 for mirogabalin and pregabalin, respectively, and the likelihood of drug-induced side effects was only “possible.” However, the following reasons suggest that, despite the low scores, these drugs affected the patient's psychiatric symptoms: (1) Although psychosis has been reported with high doses of pregabalin [11, 12], no cases have been reported at low doses, such as in this case; hence, it was appropriate not to assign points to the first item. (2) Some items (4, 6, and 7) on this scale are difficult to implement in general practice from an ethical viewpoint. Moreover, these tests are not yet routinely used in general practice. (3) As discussed below, one point was deducted for the fifth item, because the psychosis could have been a symptom of DLB itself, and the patient met the clinical diagnostic criteria for DLB even with both drugs discontinued. (4) In this case, the reactions appeared following the initial dose of pregabalin. Therefore, evaluation of symptom changes with dose increase or decrease, as required by the eighth item, was not possible. (4) Although the sixth item could not be evaluated because the response to placebo was not assessed, no similar response was observed when acetaminophen or tramadol was added for pain management. Even without these medications, the patient met the clinical diagnostic criteria for DLB [1]: She showed mild generalized cognitive impairment, including two core features of cognitive fluctuation and mild parkinsonism, as well as abnormalities in the indicative biomarker dopamine transporter imaging. In DLB, visual hallucinations are seen early on as a core clinical feature, and delusions of misidentification are supportive clinical features [1]. Therefore, the psychosis observed in this case was characteristic of DLB. Notably, although her psychosis worsened and improved with initiation and discontinuation of medications, some symptoms persisted even after discontinuation of the medications and resolved only with donepezil, which is known to improve psychosis in DLB [13]. This suggests that her psychosis was influenced not only by gabapentinoids but also by DLB itself. Such reactions to drugs in DLB are similar to hypersensitivity to antipsychotics, which is a supportive feature of DLB. Hypersensitivity to antipsychotics in DLB is characterized by an acute onset or exacerbation of parkinsonism [4], a core clinical feature of DLB and a major side effect of antipsychotics. The reaction in this case could be described as hypersensitivity to mirogabalin and pregabalin in DLB. Additionally, DLB induces hypersensitivity reactions to other drugs. Drugs that produce delusions and hallucinations as side effects in DLB include anti-parkinsonian drugs [5] and zolpidem [6]. Owing to the effects of cholinergic neuron damage, the risk of delirium with anticholinergic drugs is also thought to be higher in patients with DLB [7]. Although pregabalin and mirogabalin are generally considered well-tolerated, safe drugs, their reported side effects include somnolence, dizziness, and headaches. Few reports have identified delusions, hallucinations, or other psychiatric symptoms as typical side effects of pregabalin, even in patients receiving low doses [14]. Pregabalin and mirogabalin bind to the α2-δ auxiliary subunit of presynaptic voltage-dependent calcium channels in the central nervous system [15, 16]. Strong binding to this site attenuates depolarization-induced calcium influx at nerve endings and reduces the release of excitatory neurotransmitters such as glutamate, noradrenaline, and substance P. In the rat model of neuropathic pain, chronic pain has been shown to decrease central dopamine function and induce depression-like behavior. However, repeated administration of gabapentin has been reported to modulate dopaminergic system activity and improve depression-like behavior [17]. In light of this, it is conceivable that pregabalin and mirogabalin may modulate the dopaminergic system activity. Although changes in these neurotransmitters may cause psychiatric symptoms such as hallucinations and delusions, the specific reason this patient developed psychotic symptoms while taking pregabalin and mirogabalin remains unclear. Pregabalin-induced psychosis has been reported at higher doses (300–450 mg daily) [11, 12] but not at doses as low as those used for the current patient. This finding may indicate the hypersensitivity of DLB to pregabalin and mirogabalin. These drugs inhibit the release of neurotransmitters by blocking the influx of calcium ions into the presynaptic terminals, thereby producing analgesia [15, 18]. In DLB, the number of Lewy bodies in the cortex is low relative to the total number of neurons and does not correlate with the degree of cognitive impairment, whereas the number of alpha-synuclein aggregates is high in presynaptic terminals [19, 20]. Thus, DLBs may exhibit hypersensitivity to even small doses of pregabalin and mirogabalin, because the presynaptic terminals with alpha-synuclein aggregates are the acting sites of pregabalin and mirogabalin. In a study of patients taking oxycodone for cancer pain, multivariate analysis revealed that the use of pregabalin or mirogabalin was a risk factor for opioid-induced neurotoxicity, including delirium and hallucinations [21]. The use of benzodiazepines or muscarinic antagonists was not a significant risk factor in this study. However, the above findings suggest that pregabalin, mirogabalin, benzodiazepines, and anticholinergics should be considered to have a high risk of inducing delusions and hallucinations in patients with DLB. The temporary exacerbation of cognitive impairment and psychiatric symptoms seen in the current patient was drug-related and may resemble delirium in mechanism. Therefore, although she had presented with mild cognitive impairment that did not affect her daily life for approximately 6 months prior to the current episode, her condition was considered similar to delirium-onset prodromal DLB [22]. Of the five consecutive patients with delirium-onset DLB we described previously, a few were considered to be temporally close to the onset of delirium and cognitive impairment [23]. Thus, in patients with drug-induced psychiatric symptoms, the possibility of conversion to dementia should be considered. In conclusion, this case report suggests that even low doses of pregabalin and mirogabalin may cause psychiatric symptoms, including psychosis and cognitive impairment, in patients with DLB. Furthermore, although psychosis triggered by such drugs may improve after drug discontinuation, some symptoms may remain and trigger the persistent onset of DLB symptoms. As these drugs are widely used for chronic pain, which is a frequent complaint in older people, recognizing that such reactions can occur even at low doses and that Lewy body disease may be present in the background are clinically important. Abbreviations DLB dementia with Lewy bodies MMSE Mini-Mental State Examination Declarations Ethics approval and consent to participate This study was approved by the Research Ethics Committee of Osaka University Hospital (Suita, Japan, No.18470). Consent for publication Written informed consent for the publication of this report was obtained from the patient. Availability of data and materials The data are not publicly available because of privacy or ethical restrictions. Competing interests HK received speaker’s honoraria and consulting fees from Eisai Inc. MI received speaker’s honoraria, consulting fees, and research grants from Eisai Inc. The other authors declare no conflicts of interest. Funding This work was supported by JSPS KAKENHI (grant number T21K157300) awarded to HK. Author’s contributions Hideki Kanemoto: Conceptualization, Data curation, funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft, writing – review, and editing. Taisuke Akiyama: Data curation, and Resources. Daiki Taomoto: Data curation and Resources. Manabu Ikeda: Supervision and Writing – review & editing Acknowledgments We would like to thank the patient, her family, and the staff at the Department of Psychiatry, Osaka University Hospital. We would also like to thank Editage (www.editage.jp) for the English language editing. References McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89:88–100. Hamilton JM, Salmon DP, Raman R, Hansen LA, Masliah E, Peavy GM, et al. Accounting for functional loss in Alzheimer’s disease and dementia with Lewy bodies: beyond cognition. Alzheimers Dement. 2014;10:171–8. Kanemoto H, Sato S, Satake Y, Koizumi F, Taomoto D, Kanda A, et al. Impact of behavioral and psychological symptoms on caregiver burden in patients with dementia with Lewy bodies. Front Psychiatry. 2021;12:753864. Swanberg MM, Cummings JL. Benefit-risk considerations in the treatment of dementia with Lewy bodies. Drug Saf. 2002;25:511–23. Goldman JG, Goetz CG, Brandabur M, Sanfilippo M, Stebbins GT. Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies. Mov Disord. 2008;23:2248–50. Kobayashi R, Morioka D, Suzuki A, Kawakatsu S, Otani K. Low-dose zolpidem-induced visual hallucinations in prodromal dementia with Lewy bodies. Asian J Psychiatr. 2021;66:102908. Kitajima Y, Hori K, Konishi K, Tani M, Tomioka H, Akashi N, et al. A review of the role of anticholinergic activity in Lewy body disease and delirium. Neurodegener Dis. 2015;15:162–7. Takahashi S, Mizukami K, Arai T, Ogawa R, Kikuchi N, Hattori S, et al. Ventilatory response to hypercapnia predicts dementia with Lewy bodies in late-onset major depressive disorder. J Alzheimers Dis. 2016;50:751–8. Ferman TJ, Smith GE, Boeve BF, Ivnik RJ, Petersen RC, Knopman D, et al. DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004;62:181–7. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. Pedroso JL, Nakama GY, Carneiro Filho M, Barsottini OG. Delirium, psychosis, and visual hallucinations induced by pregabalin. Arq Neuro Psiquiatr. 2012;70:960–1. Mousailidis G, Papanna B, Salmon A, Sein A, Al-Hillawi Q. Pregabalin induced visual hallucinations - A rare adverse reaction. BMC Pharmacol Toxicol. 2020;21:16. Stinton C, McKeith I, Taylor J-P, Lafortune L, Mioshi E, Mak E, et al. Pharmacological management of Lewy body dementia: A systematic review and meta-analysis. Am J Psychiatry. 2015;172:731–42. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49:661–9. Domon Y, Arakawa N, Inoue T, Matsuda F, Takahashi M, Yamamura N, et al. Binding characteristics and analgesic effects of mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels. J Pharmacol Exp Ther. 2018;365:573–82. Li Z, Taylor CP, Weber M, Piechan J, Prior F, Bian F, et al. Pregabalin is a potent and selective ligand for α(2)δ-1 and α(2)δ-2 calcium channel subunits. Eur J Pharmacol. 2011;667:80–90. Fu B, Wen S-N, Wang B, Wang K, Zhang J-Y, Weng X-C, et al. Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state. J Pain Res. 2018;11:2247–56. Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006;6:108–13. Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci. 2007;27:1405–10. Colom-Cadena M, Pegueroles J, Herrmann AG, Henstridge CM, Muñoz L, Querol-Vilaseca M, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017;140:3204–14. Omoto T, Asaka J, Nihei S, Kudo K. Identifying risk factors for opioid-induced neurotoxicity in cancer patients receiving oxycodone. Support Care Cancer. 2023;31:208. McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94:743–55. Taomoto D, Nishio Y, Hidaka Y, Kanemoto H, Takahashi S, Ikeda M. Delirium-onset prodromal Lewy body disease: A series of 5 cases. Clin Park Relat Disord. 2024;11:100289. Additional Declarations Competing interest reported. H.K. received speaker’s honoraria and consulting fees from Eisai Inc. M.I. received speaker’s honoraria, consulting fees, and research grants from Eisai Inc. The other authors declare no conflicts of interest. Cite Share Download PDF Status: Published Journal Publication published 15 May, 2025 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 04 Apr, 2025 Reviews received at journal 27 Mar, 2025 Reviews received at journal 24 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviewers invited by journal 24 Mar, 2025 Submission checks completed at journal 24 Mar, 2025 First submitted to journal 24 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6157930","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":433465840,"identity":"2e2c1dc8-ecb5-4838-8a09-909bedd2f2e1","order_by":0,"name":"Hideki Kanemoto","email":"data:image/png;base64,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","orcid":"","institution":"Osaka University","correspondingAuthor":true,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Kanemoto","suffix":""},{"id":433465841,"identity":"2547a8aa-2fb4-41af-88c1-697101aea683","order_by":1,"name":"Taisuke Akiyama","email":"","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Taisuke","middleName":"","lastName":"Akiyama","suffix":""},{"id":433465842,"identity":"90d3110f-b6a5-4352-a23f-c7baef1ca80b","order_by":2,"name":"Daiki Taomoto","email":"","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Daiki","middleName":"","lastName":"Taomoto","suffix":""},{"id":433465843,"identity":"77b0c740-a928-4235-ba19-0206bbcc11da","order_by":3,"name":"Manabu Ikeda","email":"","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Manabu","middleName":"","lastName":"Ikeda","suffix":""}],"badges":[],"createdAt":"2025-03-05 02:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6157930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6157930/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12888-025-06937-7","type":"published","date":"2025-05-15T15:57:55+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79324563,"identity":"e786c411-459f-4d27-9353-1683d5141557","added_by":"auto","created_at":"2025-03-27 05:11:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":552294,"visible":true,"origin":"","legend":"\u003cp\u003eNeuroimaging findings in this patient with dementia with Lewy bodies.\u003c/p\u003e\n\u003cp\u003e(a) Cranial magnetic resonance imaging showed no abnormalities.\u003c/p\u003e\n\u003cp\u003e(b) N-isopropyl-p-iodoamphetamine single-photon emission computed tomography showed reduced perfusion in the bilateral parietal, frontal, precuneus, and occipital lobes.\u003c/p\u003e\n\u003cp\u003e(c) \u003csup\u003e123\u003c/sup\u003eI-meta-iodobenzylguanidine myocardial scintigraphy showed that the heart-to-mediastinum ratio was maintained at 3.69 and 2.41 in the early and late stages, respectively, but the washout rate was high at 59.5%, suggesting mild abnormality of cardiac sympathetic nerve function.\u003c/p\u003e\n\u003cp\u003e(d) \u003csup\u003e123\u003c/sup\u003eI-N-omega-fluoropropyl-2-betacarbomethoxy-3-beta (4-iodophenyl) nortropane dopamine-transporter single-photon emission computed tomography showed decreased uptake in the posterior striatum, especially on the left side.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6157930/v1/203aab112cd3e278bd4e56a3.png"},{"id":83068090,"identity":"e6106b96-f887-4dab-a195-626030c06591","added_by":"auto","created_at":"2025-05-19 16:10:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1041174,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6157930/v1/68918384-67eb-458c-baf5-ad18869f0c19.pdf"}],"financialInterests":"Competing interest reported. H.K. received speaker’s honoraria and consulting fees from Eisai Inc. M.I. received speaker’s honoraria, consulting fees, and research grants from Eisai Inc. The other authors declare no conflicts of interest.","formattedTitle":"A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids","fulltext":[{"header":"1. Background","content":"\u003cp\u003eDementia with Lewy bodies (DLB) is the second most common form of dementia after Alzheimer\u0026rsquo;s disease and is characterized by various symptoms, including visual hallucinations, cognitive fluctuations, parkinsonism, and rapid eye movement sleep behavioral disorder, from the early stages of the disease [1]. These symptoms can affect the patient\u0026rsquo;s daily life [2] and increase family care burden [3], making appropriate therapeutic interventions important. Interventions for psychosis and parkinsonism are prime examples.\u003c/p\u003e \u003cp\u003ePharmacological treatment in patients with DLB is challenging owing to their hypersensitivity to drugs. Hypersensitivity to antipsychotics is cited as a supportive clinical feature of DLB [1], and even small doses can cause acute onset or exacerbation of parkinsonism and impaired consciousness [4]. Moreover, patients with DLB can show hypersensitivity to drugs other than antipsychotics. Anti-parkinsonian drugs [5] and zolpidem [6] have been reported to induce psychosis even in small doses, and administration of anticholinergics has been associated with a high risk of delirium [7]. Additionally, studies also suggest that older patients with major depression who subsequently convert to DLB are more likely to experience adverse effects with psychotropic medications, including antidepressants [8]. Therefore, the risk of side effects from a variety of drugs should be considered in patients with DLB.\u003c/p\u003e \u003cp\u003eHere, we report a case of DLB with psychosis that appeared after the administration of mirogabalin and pregabalin, which are medications used to treat neuropathic pain.\u003c/p\u003e"},{"header":"2. Case presentation","content":"\u003cp\u003eThe patient was a woman in her late 70s. She had been living with her daughter and son since her husband\u0026rsquo;s death \u0026gt;10 years prior.\u0026nbsp;Other than leg pain associated with scoliosis, for which she was prescribed mirogabalin (described below), she had no history of any other notable medical conditions, including psychiatric disorders.\u003c/p\u003e\n\u003cp\u003eHer son had also passed away a year before her initial visit to our hospital. Although her activities of daily living were independent, she had begun to show signs of forgetfulness in daily life. Three months earlier, she had visited an orthopedic surgeon for pain in her lower extremities, was diagnosed with scoliosis, and was prescribed mirogabalin (15 mg/day). Thereafter, she had complained frequently of visual hallucinations of her deceased son and husband, misidentified her daughter as her sister, and was irritable. She could not identify her home as the place where she lived, complained that she wanted to go home, and even visited her birthplace \u0026gt;300 km away, alone. Suspecting dementia, her family took her to her general practitioner, who prescribed donepezil, Yokukansan (a Japanese herbal medicine), aripiprazole and olanzapine, which were ineffective. Three months after disease onset, she was referred to our clinic for further evaluation and treatment.\u003c/p\u003e\n\u003cp\u003eHer Mini-Mental State Examination (MMSE) score was 22, with suspected mild impairments in orientation, memory, attention, and visuospatial cognition. According to the family, her cognition fluctuated daily, with a score of 6 on the Mayo Fluctuations Scale [9]. Mild rigidity in the left upper limb and bradykinesia were noted; however, no other indications of parkinsonism were observed. Yokukansan (7.5 g), aripiprazole (2 mg), and mirogabalin (15 mg) were administered daily. Blood tests revealed nothing that could cause cognitive impairment or psychiatric symptoms. The symptoms suggested DLB; however, the patient\u0026rsquo;s history indicated that these cognitive and psychiatric symptoms were drug-induced. After the discontinuation of mirogabalin, the return-home behavior associated with the misidentification of places and her irritability disappeared. The visual hallucinations and misidentification of people reduced in frequency but persisted.\u0026nbsp;In addition, no pain flare-ups were observed after discontinuing mirogabalin, probably owing to treatment with this drug over a period of 3 months.\u003c/p\u003e\n\u003cp\u003eMagnetic resonance imaging of the brain was unremarkable. However, N-isopropyl-p-iodoamphetamine single-photon emission computed tomography showed reduced perfusion in the bilateral parietal, frontal, precuneus, and occipital lobes (Figure 1a, b). \u003csup\u003e123\u003c/sup\u003eI-meta-iodobenzylguanidine myocardial scintigraphy revealed that the heart-to-mediastinum ratio was maintained at 3.69 and 2.41 in the early and late stages, respectively, but the washout rate was high at 59.5%, suggesting mild abnormality of cardiac sympathetic nerve function (Figure 1c). \u003csup\u003e123\u003c/sup\u003eI-N-omega-fluoropropyl-2-betacarbomethoxy-3-beta (4-iodophenyl) nortropane dopamine-transporter single-photon emission computed tomography showed decreased uptake in the posterior striatum, especially on the left side (Figure 1d).\u003c/p\u003e\n\u003cp\u003eElectroencephalography showed that the basic rhythm was 9\u0026ndash;10 Hz occipital predominant, mixed with a generalized 6\u0026ndash;7 Hz slow wave. However, no obvious epileptogenic findings were noted. Based on these findings, a diagnosis of probable DLB was made [1], and treatment with donepezil (3 mg) was initiated. When the dose was increased to 5 mg, the patient\u0026rsquo;s MMSE score increased to 25 points, and the misidentification of people disappeared.\u0026nbsp;Aripiprazole was discontinued soon thereafter, but symptoms did not relapse.\u0026nbsp;Residual insomnia improved with a prescription of quetiapine (12.5 mg).\u003c/p\u003e\n\u003cp\u003eThereafter, cognitive impairment progressed slowly, and after 1 year, the MMSE score dropped to 20 points. Two years later, her back pain intensified, and she was prescribed 1,200 mg of acetaminophen and 100 mg of tramadol. However, the pain did not improve, and tramadol was discontinued. After being administered 25 mg of pregabalin, she began to exhibit strange behaviors: she became irritable, talked to herself, and prepared meals for four people, despite living with only her daughter. These behaviors disappeared after discontinuation of the pregabalin. Her day care service advised increased exercise therapy, and in subsequent outpatient visits, her complaints of pain had decreased.\u003c/p\u003e\n\u003cp\u003eThe scores of the Adverse Drug Reaction Probability Scale [10] were 2 and 3 for mirogabalin and pregabalin, respectively (Table 1).\u003c/p\u003e\n\u003cp\u003eTable 1. The results of Adverse Drug Reaction Probability Scale\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eScores for\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003eQuestion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003emirogabalin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003epregabalin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e1. Are there previous conclusive reports on this reaction?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e2. Did the adverse event appear after the suspected drug was administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e4. Did the adverse event reappear when the drug was re-administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e-1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e6. Did the reaction reappear when a placebo was given?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003e10. Was the adverse event confirmed by any objective evidence?\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 454px;\"\u003e\n \u003cp\u003eTotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"3. Discussion and Conclusions","content":"\u003cp\u003eHere, we report a case of a patient who experienced delusions, hallucinations, and irritability that appeared and disappeared following the initiation and discontinuation of mirogabalin and pregabalin, which have similar mechanisms of action in the treatment of chronic pain. The scores of the Adverse Drug Reaction Probability Scale [10] were 2 and 3 for mirogabalin and pregabalin, respectively, and the likelihood of drug-induced side effects was only \u0026ldquo;possible.\u0026rdquo; However, the following reasons suggest that, despite the low scores, these drugs affected the patient's psychiatric symptoms: (1) Although psychosis has been reported with high doses of pregabalin [11, 12], no cases have been reported at low doses, such as in this case; hence, it was appropriate not to assign points to the first item. (2) Some items (4, 6, and 7) on this scale are difficult to implement in general practice from an ethical viewpoint. Moreover, these tests are not yet routinely used in general practice. (3) As discussed below, one point was deducted for the fifth item, because the psychosis could have been a symptom of DLB itself, and the patient met the clinical diagnostic criteria for DLB even with both drugs discontinued. (4) In this case, the reactions appeared following the initial dose of pregabalin. Therefore, evaluation of symptom changes with dose increase or decrease, as required by the eighth item, was not possible. (4) Although the sixth item could not be evaluated because the response to placebo was not assessed, no similar response was observed when acetaminophen or tramadol was added for pain management.\u003c/p\u003e \u003cp\u003eEven without these medications, the patient met the clinical diagnostic criteria for DLB [1]: She showed mild generalized cognitive impairment, including two core features of cognitive fluctuation and mild parkinsonism, as well as abnormalities in the indicative biomarker dopamine transporter imaging. In DLB, visual hallucinations are seen early on as a core clinical feature, and delusions of misidentification are supportive clinical features [1]. Therefore, the psychosis observed in this case was characteristic of DLB. Notably, although her psychosis worsened and improved with initiation and discontinuation of medications, some symptoms persisted even after discontinuation of the medications and resolved only with donepezil, which is known to improve psychosis in DLB [13]. This suggests that her psychosis was influenced not only by gabapentinoids but also by DLB itself. Such reactions to drugs in DLB are similar to hypersensitivity to antipsychotics, which is a supportive feature of DLB. Hypersensitivity to antipsychotics in DLB is characterized by an acute onset or exacerbation of parkinsonism [4], a core clinical feature of DLB and a major side effect of antipsychotics. The reaction in this case could be described as hypersensitivity to mirogabalin and pregabalin in DLB. Additionally, DLB induces hypersensitivity reactions to other drugs. Drugs that produce delusions and hallucinations as side effects in DLB include anti-parkinsonian drugs [5] and zolpidem [6]. Owing to the effects of cholinergic neuron damage, the risk of delirium with anticholinergic drugs is also thought to be higher in patients with DLB [7].\u003c/p\u003e \u003cp\u003eAlthough pregabalin and mirogabalin are generally considered well-tolerated, safe drugs, their reported side effects include somnolence, dizziness, and headaches. Few reports have identified delusions, hallucinations, or other psychiatric symptoms as typical side effects of pregabalin, even in patients receiving low doses [14]. Pregabalin and mirogabalin bind to the α2-δ auxiliary subunit of presynaptic voltage-dependent calcium channels in the central nervous system [15, 16]. Strong binding to this site attenuates depolarization-induced calcium influx at nerve endings and reduces the release of excitatory neurotransmitters such as glutamate, noradrenaline, and substance P. In the rat model of neuropathic pain, chronic pain has been shown to decrease central dopamine function and induce depression-like behavior. However, repeated administration of gabapentin has been reported to modulate dopaminergic system activity and improve depression-like behavior [17]. In light of this, it is conceivable that pregabalin and mirogabalin may modulate the dopaminergic system activity. Although changes in these neurotransmitters may cause psychiatric symptoms such as hallucinations and delusions, the specific reason this patient developed psychotic symptoms while taking pregabalin and mirogabalin remains unclear.\u003c/p\u003e \u003cp\u003ePregabalin-induced psychosis has been reported at higher doses (300\u0026ndash;450 mg daily) [11, 12] but not at doses as low as those used for the current patient. This finding may indicate the hypersensitivity of DLB to pregabalin and mirogabalin. These drugs inhibit the release of neurotransmitters by blocking the influx of calcium ions into the presynaptic terminals, thereby producing analgesia [15, 18]. In DLB, the number of Lewy bodies in the cortex is low relative to the total number of neurons and does not correlate with the degree of cognitive impairment, whereas the number of alpha-synuclein aggregates is high in presynaptic terminals [19, 20]. Thus, DLBs may exhibit hypersensitivity to even small doses of pregabalin and mirogabalin, because the presynaptic terminals with alpha-synuclein aggregates are the acting sites of pregabalin and mirogabalin.\u003c/p\u003e \u003cp\u003eIn a study of patients taking oxycodone for cancer pain, multivariate analysis revealed that the use of pregabalin or mirogabalin was a risk factor for opioid-induced neurotoxicity, including delirium and hallucinations [21]. The use of benzodiazepines or muscarinic antagonists was not a significant risk factor in this study. However, the above findings suggest that pregabalin, mirogabalin, benzodiazepines, and anticholinergics should be considered to have a high risk of inducing delusions and hallucinations in patients with DLB.\u003c/p\u003e \u003cp\u003eThe temporary exacerbation of cognitive impairment and psychiatric symptoms seen in the current patient was drug-related and may resemble delirium in mechanism. Therefore, although she had presented with mild cognitive impairment that did not affect her daily life for approximately 6 months prior to the current episode, her condition was considered similar to delirium-onset prodromal DLB [22]. Of the five consecutive patients with delirium-onset DLB we described previously, a few were considered to be temporally close to the onset of delirium and cognitive impairment [23]. Thus, in patients with drug-induced psychiatric symptoms, the possibility of conversion to dementia should be considered.\u003c/p\u003e \u003cp\u003eIn conclusion, this case report suggests that even low doses of pregabalin and mirogabalin may cause psychiatric symptoms, including psychosis and cognitive impairment, in patients with DLB. Furthermore, although psychosis triggered by such drugs may improve after drug discontinuation, some symptoms may remain and trigger the persistent onset of DLB symptoms. As these drugs are widely used for chronic pain, which is a frequent complaint in older people, recognizing that such reactions can occur even at low doses and that Lewy body disease may be present in the background are clinically important.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDLB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edementia with Lewy bodies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMSE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMini-Mental State Examination\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Research Ethics Committee of Osaka University Hospital (Suita, Japan, No.18470).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for the publication of this report was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are not publicly available because of privacy or ethical restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHK received speaker’s honoraria and consulting fees from Eisai Inc. MI received speaker’s honoraria, consulting fees, and research grants from Eisai Inc. The other authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by JSPS KAKENHI (grant number T21K157300) awarded to HK.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHideki Kanemoto: Conceptualization, Data curation, funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft, writing – review, and editing.\u003c/p\u003e\n\u003cp\u003eTaisuke Akiyama: Data curation, and Resources.\u003c/p\u003e\n\u003cp\u003eDaiki Taomoto: Data curation and Resources.\u003c/p\u003e\n\u003cp\u003eManabu Ikeda: Supervision and Writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the patient, her family, and the staff at the Department of Psychiatry, Osaka University Hospital. We would also like to thank Editage (www.editage.jp) for the English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMcKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89:88\u0026ndash;100.\u003c/li\u003e\n \u003cli\u003eHamilton JM, Salmon DP, Raman R, Hansen LA, Masliah E, Peavy GM, et al. Accounting for functional loss in Alzheimer\u0026rsquo;s disease and dementia with Lewy bodies: beyond cognition. Alzheimers Dement. 2014;10:171\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eKanemoto H, Sato S, Satake Y, Koizumi F, Taomoto D, Kanda A, et al. Impact of behavioral and psychological symptoms on caregiver burden in patients with dementia with Lewy bodies. Front Psychiatry. 2021;12:753864.\u003c/li\u003e\n \u003cli\u003eSwanberg MM, Cummings JL. Benefit-risk considerations in the treatment of dementia with Lewy bodies. Drug Saf. 2002;25:511\u0026ndash;23.\u003c/li\u003e\n \u003cli\u003eGoldman JG, Goetz CG, Brandabur M, Sanfilippo M, Stebbins GT. Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies. Mov Disord. 2008;23:2248\u0026ndash;50.\u003c/li\u003e\n \u003cli\u003eKobayashi R, Morioka D, Suzuki A, Kawakatsu S, Otani K. Low-dose zolpidem-induced visual hallucinations in prodromal dementia with Lewy bodies. Asian J Psychiatr. 2021;66:102908.\u003c/li\u003e\n \u003cli\u003eKitajima Y, Hori K, Konishi K, Tani M, Tomioka H, Akashi N, et al. A review of the role of anticholinergic activity in Lewy body disease and delirium. Neurodegener Dis. 2015;15:162\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eTakahashi S, Mizukami K, Arai T, Ogawa R, Kikuchi N, Hattori S, et al. Ventilatory response to hypercapnia predicts dementia with Lewy bodies in late-onset major depressive disorder. J Alzheimers Dis. 2016;50:751\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eFerman TJ, Smith GE, Boeve BF, Ivnik RJ, Petersen RC, Knopman D, et al. DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004;62:181\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eNaranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239\u0026ndash;45.\u003c/li\u003e\n \u003cli\u003ePedroso JL, Nakama GY, Carneiro Filho M, Barsottini OG. Delirium, psychosis, and visual hallucinations induced by pregabalin. Arq Neuro Psiquiatr. 2012;70:960\u0026ndash;1.\u003c/li\u003e\n \u003cli\u003eMousailidis G, Papanna B, Salmon A, Sein A, Al-Hillawi Q. Pregabalin induced visual hallucinations - A rare adverse reaction. BMC Pharmacol Toxicol. 2020;21:16.\u003c/li\u003e\n \u003cli\u003eStinton C, McKeith I, Taylor J-P, Lafortune L, Mioshi E, Mak E, et al. Pharmacological management of Lewy body dementia: A systematic review and meta-analysis. Am J Psychiatry. 2015;172:731\u0026ndash;42.\u003c/li\u003e\n \u003cli\u003eBockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49:661\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eDomon Y, Arakawa N, Inoue T, Matsuda F, Takahashi M, Yamamura N, et al. Binding characteristics and analgesic effects of mirogabalin, a novel ligand for the \u0026alpha;2\u0026delta; subunit of voltage-gated calcium channels. J Pharmacol Exp Ther. 2018;365:573\u0026ndash;82.\u003c/li\u003e\n \u003cli\u003eLi Z, Taylor CP, Weber M, Piechan J, Prior F, Bian F, et al. Pregabalin is a potent and selective ligand for \u0026alpha;(2)\u0026delta;-1 and \u0026alpha;(2)\u0026delta;-2 calcium channel subunits. Eur J Pharmacol. 2011;667:80\u0026ndash;90.\u003c/li\u003e\n \u003cli\u003eFu B, Wen S-N, Wang B, Wang K, Zhang J-Y, Weng X-C, et al. Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state. J Pain Res. 2018;11:2247\u0026ndash;56.\u003c/li\u003e\n \u003cli\u003eSills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006;6:108\u0026ndash;13.\u003c/li\u003e\n \u003cli\u003eKramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci. 2007;27:1405\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003eColom-Cadena M, Pegueroles J, Herrmann AG, Henstridge CM, Mu\u0026ntilde;oz L, Querol-Vilaseca M, et al. Synaptic phosphorylated \u0026alpha;-synuclein in dementia with Lewy bodies. Brain. 2017;140:3204\u0026ndash;14.\u003c/li\u003e\n \u003cli\u003eOmoto T, Asaka J, Nihei S, Kudo K. Identifying risk factors for opioid-induced neurotoxicity in cancer patients receiving oxycodone. Support Care Cancer. 2023;31:208.\u003c/li\u003e\n \u003cli\u003eMcKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94:743\u0026ndash;55.\u003c/li\u003e\n \u003cli\u003eTaomoto D, Nishio Y, Hidaka Y, Kanemoto H, Takahashi S, Ikeda M. Delirium-onset prodromal Lewy body disease: A series of 5 cases. Clin Park Relat Disord. 2024;11:100289.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dementia with Lewy bodies, pregabalin, mirogabalin, drug-induced psychosis, visual hallucinations, delusional misidentification, irritability","lastPublishedDoi":"10.21203/rs.3.rs-6157930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6157930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Hypersensitivity to antipsychotic drugs is one of the supportive features of dementia with Lewy bodies, and side effects to drugs other than antipsychotics are also known to occur frequently. We experienced a case of dementia with Lewy bodies in which hallucinations and delusions repeatedly appeared and disappeared after administration and discontinuation of mirogabalin and pregabalin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eThe patient, a woman in her late 70s, developed hallucinations and delusional misidentification of places and persons immediately after receiving a prescription of mirogabalin (15 mg daily) for neuropathic pain. After discontinuation of mirogabalin, her hallucinatory delusions improved but remained. Mild dementia and mild parkinsonism were associated, cognitive fluctuations were evident, and dopamine-transporter scintigraphy showed bilateral striatal uptake reduction. Residual psychosis resolved with donepezil. Later, when the pain worsened, pregabalin (25 mg daily) was administered, and the psychosis recurred and resolved with discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Although pregabalin-induced psychosis has been reported at higher doses (300–450 mg daily), it has not been reported at doses as low as those used in this patient. Gabapentinoids may cause psychosis in patients with dementia with Lewy bodies even at low doses, likely due to hypersensitivity to gabapentinoids in DLB.\u003c/p\u003e","manuscriptTitle":"A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 05:11:18","doi":"10.21203/rs.3.rs-6157930/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-04T07:38:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-27T07:20:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-25T01:57:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"109831081856346369327019699432806756354","date":"2025-03-25T01:27:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326490262351915322114260249975635592017","date":"2025-03-24T23:51:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-24T15:52:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T12:25:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2025-03-24T12:06:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6e710971-4120-4be4-b99f-59ad38c688a8","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T16:07:00+00:00","versionOfRecord":{"articleIdentity":"rs-6157930","link":"https://doi.org/10.1186/s12888-025-06937-7","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2025-05-15 15:57:55","publishedOnDateReadable":"May 15th, 2025"},"versionCreatedAt":"2025-03-27 05:11:18","video":"","vorDoi":"10.1186/s12888-025-06937-7","vorDoiUrl":"https://doi.org/10.1186/s12888-025-06937-7","workflowStages":[]},"version":"v1","identity":"rs-6157930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6157930","identity":"rs-6157930","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}