1. Department of Psychiatry, Loyola University Medical Center, 2160 S. First Ave, Maywood, IL 60153, USA
2. 3rd year psychiatry resident, Loyola University Medical Center, 2160 S. First Ave, Maywood, IL 60153, USA
3. Department of Psychiatry and Behavioral Neurosciences & Orthopedic Surgery & Rehabilitation, Loyola University Chicago: Stritch School of Medicine, 2160 S. First Ave, Maywood, IL 60153, USA
Academic Editor: Bart Ellenbroek
Special Issue: New Developments in Brain Injury
Received: November 10, 2019 | Accepted: January 09, 2020 | Published: January 10, 2020
OBM Neurobiology 2020, Volume 4, Issue 1, doi:10.21926/obm.neurobiol.2001048
Recommended citation: Meresh E, Daniels D, Owens JH, Thompson D, Mennella S, Levy M, Swartz B. Psychotropics and Neuroprotection: Literature Review and Case Series Report. OBM Neurobiology 2020;4(1):13; doi:10.21926/obm.neurobiol.2001048.
© 2020 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Agitation is a common manifestation of acute brain injury, particularly in the early stages of injury. However, studies on the use of pharmacological agents for the control of agitation in this population remain extremely limited. Most studies available are animal studies or based on subjective observation. There is no current consensus on the most "efficacious and safest strategy" for use of antipsychotics in acute TBI . Williamson et al. note in their 2016 study that a 'safe and effective treatment for agitation, which does not interfere with neurological recovery, remains to be identified". As such, this study aims to provide information that leads to a greater understanding of what pharmacological agents are most advantageous for this population.
Consequences of agitation include harm to self or others, use of chemical and physical restraints, increased length of stay in acute care, and decreased functional independence . Agitation has also been associated with delays in recovery, including delayed admission to acute rehabilitation programs. Antipsychotics are commonly used to control agitation in acute brain injury in the ICU. Interestingly, there are no studies to our knowledge that assess for haloperidol use in TBI patient's specifically . Haloperidal, arguably the commonly used antipsychotic for agitation in ICU setting, does not offer a neuroprotective effect and may have some adverse effects that are particularly harmful. Specifically, the use of haloperidol in acute TBI has been associated with: neuroleptic malignant syndrome (NMS), reduced seizure threshold, impaired long-term cognitive recovery , and neuronal loss . Studies have also shown: a longer length of posttraumatic amnesia, delayed cognitive recovery, and increased incidences of behavioral and cognitive deficits .
PubMed database and reference lists from relevant articles were reviewed. We reviewed articles obtained through the PubMed to identify additional articles pertinent to neuroprotection.
3.1 Neuroprotection versus Neurotoxicity
Severe hypoglycemia causes hippocampal damage [5,6] activation of the N-methyl-d-aspartate, glutamate neurotoxicity, anoxic neuronal death and Amyloid-β neurotoxicity are implicated [7,8]. Animal model shows, Memantine, offering neuroprotective effects in hypoglycemic rats . TBI leads neurochemical alterations  Similar to hypoglycemic injury, glutamatergic system is implicated [11,12] oxidative stress is also implicated  antioxidants has proved to be beneficial [14,15].
3.2 Sedative Agents and Neuroprotection
When these patients are in acute status, it is important to know about medication with neurotoxic effect and neuroprotective effect. Available information are mostly from animal studies.
Propofol is reported to be neurotoxic [16,17]. During acute brain injury and related complications, patients could get intubated and propofol’s neuropsychiatric effect should be taken into consideration. Dexmedetomidine, another medication commonly used for sedation during intubation is considered to have neuroprotective effect [18,19,20].
3.3 Anti-Psychotics and Neuroprotection
During intubation and after extubation, antipsychotics are commonly given for agitation. In neuropsychiatric patients and traumatic brain injury, it is important to be knowledgeable about agents reported to carry neuroprotective effect. Haloperidal, the commonly used antipsychotic for agitation in ICU setting reportedly does not offer neuroprotective effect. In an animal study comparing neuroprotective effect of haloperidol and aripiprazole, haloperidol caused neuronal loss while aripiprazole offered neuroprotection .
Among the mechanism of neuroprotection is the 5-HT1A agonism [21,22,23]. 5-HT1A agonists might be beneficial in brain trauma [21,22]. Atypical antipsychotics agents with 5-HT1A agonist properties may protect against excitotoxic injury and be safely used against TBI-induced agitation. Research suggests that atypical antipsychotics, agents with 5-HT1A agonist properties, may protect against excitotoxic injury and be used safely to reduce TBI-induced agitation [21,23,24]. It has been shown, in mice, that aripiprazole, ziprasidone but not haloperidol can protect against exicitotoxicity in vivo and their neuroprotective activity is antagonized by the selective 5-TH1A antagonist Way 100635 [23,25,26].
Olanzapine, aripiprazole, and ziprasidone have protective properties against oxidative stress, but not haloperidol . This study measured effects of N-methyl-4-phenylpyridinium MPP(+) on cell viability, reactive oxygen species (ROS), superoxide dismutase (SOD). Olanzapine and aripiprazole reversed all the effects of MPP(+) treatment; Ziprasidone changed ROS and SOD but did not influence cell viability while haloperidol did not affect any of these effects . Another study compared the neuroprotective effects of haloperidol, risperidone and paliperidone. In this study, haloperidol decreased cell viability and induced cell death while risperidone and paliperidone offered protection against it. However, strongest neuroprotective effect was seen in paliperidone .
Olanzapine and quetiapine protects cells from oxidative stress  Aripiprazole recovered decreased cell viability . Aripiprazole offers neuroprotection [31,32]. Quetiapine reversed the stress-induced suppression of hippocampal neurogenesis . In a comparative study of anti-oxidant properties, OLA showed the highest antioxidant activity, followed by clozapine and Aripiprazole. In this study, quetiapine, risperidone, ziprasidone, and haloperidol showed minimal or no antioxidant activity .
In a study that evaluated oxidative damage in rat brain, olanzapine and aripiprazole did not induce oxidative damage as observed after haloperidol and clozapine . More studies are needed to see if Olanzapine and aripiprazole offers the best neuroprotection followed by quetiapine, paliperidone, Risperidone and Ziprasidone. Newer agents Asenapine, lurasidone, Brexpiprazole, and cariprazine are also reported to offer neuroprotection [36,37,38]. Lurasidone, Brexpiprazole, and cariprazine are newer agents and their efficacy in agitation management needs more evidence. We identified two studies comparing neuroprotective effect of cariprazine and aripiprazole. In one study, cariprazine and aripiprazole blocked increase in glutamate, but cariprazine was more potent than aripiprazole (5-fold) . In another study, both Cariprazine and aripiprazole decreased PCP-induced attention deficits .
3.4 Cognitive Enhancers and Neuroprotection
Memantine is approved by FDA for treating Alzheimer's dementia. To assess the neuroprotective effect of memantine in TBI, memantine was administered to rats after induced TBI and it prevented the neuronal loss . Memantine offered neuroprotective activity against oxidative stress .
There are reports on the anxiogenic effect of Memantine and this could be a challenge during agitation management . In a study of Memantine for depression, memantine produced an early anxiogenic response, but the effect is limited . Memantine is effective in patients with agitation related to Alzheimer's disease .
Donepezil, another cognitive enhancer, approved by FDA for treating alzheimer’s dementia offers Neuroprotection against glutamate excitotoxicity .
3.5 Anti-Epileptics and Neuroprotection
Valproic acid could be a very good option in agitation management in delirium related to TBI [47,48]. Apart from its anti-epileptic effect in TBI patients, it offers neuroprotection [49,50]. It has anti-oxidant effect. Valproic acid’s antioxidant effect is better when compared to carbamazepine and phenobarbital . In addition to lithium, it offers anti-oxidant and neuroprotective effects [52,53]. Exposure to valproic acid in utero increases the risk of major congenital malformations including neural tube defects, spina bifida, developmental delay, cognitive impairment  and autism . For agitation management in delirium related to TBI in women of child bearing age, atypical antipsychotics should be considered first. Pregnancy test is required.
Similarly, Levetiracetam, lacosamide and zonisamide offers neuroprotection and needs to be considered when seizures are co-morbid or for seizure prevention [56,57,58,59]. Lamotrigine has neuroprotective and anti-oxidant effect [60,61,62]. Levetiracetam, lacosamide and lamotrigine are not good options in acute management. In an animal study on neuroprotective and neurotoxic effects of carbamazepine and oxcarbazepine, toxic effect like apoptosis was identified. In this study, these drugs also did not protect hippocampal neurons from toxicity related to ischaemia. However, it is important to note that this toxic effect was not mediated by N-methyl-D-aspartate (NMDA) . In a study measuring Oxidative Status, Carbamazepine caused oxidation .
3.6 Carbamazepine, Oxcarbazepine, Gabapentin, Pregabalin, Phenobarbital, Phenytoin
Li et al reported that the oxidative stress and impairment of the antioxidant was evident after 2 hours exposure to Carbamazepine [65,66]. In a study comparing the oxidative status of Valproic Acid Carbamazepine, and Phenobarbital, there was better regulation of oxidant and antioxidant status in valproic acid group compared to phenobarbital and carbamazepine . Oxcarbazepine which is related to Carbamazepine also is reported to affect antioxidant systems .
There are varying reports on gabapentin and neuroprotective effect.
Anti-NMDAR encephalitis presents with psychiatric disturbances and cognitive deficits and could lead to rapid progression to catatonia and autonomic instability. Lithium, Gabapentin and Valproic acid could help in mood symptoms [68,69]. In Anti-NMDAR encephalitis, glutamate activation of GABAergic neurons is decreased leading to reduced GABA activity causing significant glutamatergic hyperactivity and neuropsychiatric symptoms of anti-NMDA receptor encephalitis . Gabapentin enhances the release of GABA . Gabapentin offers protection against glutamate-induced neuronal injury . However, a study reports that gabapentin decreases brain antioxidant enzymes . There is one study reporting that gabapentin may be blocking new synapse formation .
3.7 Lithium and Neuroprotection
Lithium has great neuroprotective effect . Lithium's neuroprotective effects on TBI are by stimulating neurogenesis, modulating inflammatory cytokines, inhibiting glycogen synthase kinase and reducing neuronal death . Lithium is neuroprotective and prevent neuronal apoptosis [82,83].
3.7.1 Pramipexole, Amantadine, Benzodiazepines, Trazodone
Pramipexole has neuroprotective effect against glutamate-induced neurotoxicity . Amantadine leads to recovery and decreases dopamine-release deficits in TBI patients [85,86]. Chronic use of benzodiazepines offers no neuroprotection while immediate administration after ischemia is neuroprotective . An animal study identified oxidative damage caused by methylphenidate . Trazodone, commonly used for insomnia has neuroprotective effects on the frontal cortex, hippocampus and dentate gyrus .
3.7.2 Buspirone and Neuroprotection
Buspirone is a5-HT1A partial agonist and provide benefit in TBI. In a study combining environmental enrichment and Buspirone, memory retention and spatial learning were enhanced .
4. Alternatives to Haloperidal in Practice: Case Studies
Patient 1: 49 year-old male, found seizing at home, hypoglycemic to 28, somnolent with Glasgow Coma Scale of 5. MRI: no evidence of acute process. He exhibited waxing and waning mental status with periods of agitation, saying incomprehensible words. On examination, gaze darting around room and he exhibited nonsensical garbled speech. Aripiprazole and Valproic acid were started. Agitation decreased and patient was transferred to neurocognitive rehabilitation.
Patient 2: 55 year-old female with anoxic brain injury after a hypoglycemic episode four weeks prior to admission. The patient was not oriented to person, place, or time, and exhibited unpredictable and violent behavior. She responded to most questions inappropriately, with illogical phrases many neologisms. Aripiprazole and Donepezil were started, agitation and violent behavior decreased and she was discharged to rehabilitation.
Patient 3: 42-year-old male with a past medical history of hypertension was involved in a motor vehicle crash. He was in hospital for 48 day mostly for agitation. After motor vehicle crash, patient had a Glascow Coma Scale of 7T and he was intubated. MRI Brain revealed bilateral occipital subdural hematoma, small right occipital contusion and Left frontal subdural hygroma. Neurosurgery was consulted for ICH coup contra coup type brain injury with left frontal subdural hygroma, bilateral occipital subdural hematoma and a small right occipital intra-parenchymal hemorrhage with suspected diffuse axonal injury. He was transferred back and forth to the ICU for safety and medication management for agitation. For several days, he was continually agitated, hitting head on side rails/light fixtures requiring haloperidol injection every four hours and quetiapine 4 times daily. He was on restraints. Psychiatry was consulted, Haloperidol and quetiapine were discontinued. Aripiprazole 5mg Qam and 7.5mg Qpm was started and Haloperidol prn was replaced by Ziprasidone 5mg Q6hrs PRN. Valproic Acid started and increased to 750mg po or IV bid. Memantine was added Day 43. He was much more calm and rational (able to carry on a conversation). He still exhibited episodic agitation. Aripiprazole changed to Asenapine. Ziprasidone 5mg Q6hrs PRN was changed to Olanzapine5mg IM q4h PRN. Memantine stopped to avoid polypharmacy. Significant progress was made, and patient was off restraints. CT head and EEG were without complication. He slept mostly through the night. He was ambulating with staff, and was using the bathroom on his own. He worked well with therapy and he ate all of his meals. Patient was cooperative and willing to participate throughout session. Patient was able to complete functional mobility to and from his room to the therapy gym with minimal verbal cuing to complete the task suggesting improvements with safety awareness and balance. As his agitation decreased, he was transferred to an outside neuro cognitive rehabilitation center.
Acute agitation in traumatic brain injury is a common occurrence in the ICU. However, there is no consensus regarding the best pharmacological agents for this population. At present, Haloperidol is commonly used to control agitation in this population. However, research shows that the adverse effects of haloperidol may outweigh the benefits. This review provided a number of alternate medications that have not only been shown to reduce agitation, but also offer neuroprotective effects, antioxidant effects, or both. Given that acute agitation in traumatic brain injury has been associated with a longer course of recovery, particularly when Haloperidol is used for an extended period, the hope is to provide alterative agents that will not only improve agitation, but also lead to improved overall outcomes in traumatic brain injury. Studies are needed in this area.
All authors did the literature review, preparation of manuscript, edition.
The authors have declared that no competing interests exist
- Williamson DR, Frenette AJ, Burry L, Perreault MM, Charbonney E, Lamontagne F, et al. Pharmacological interventions for agitation in patients with traumatic brain injury: Protocol for a systematic review and meta-analysis. Syst Rev. 2016; 5: 193. [CrossRef]
- Liu-DeRyke X. Haloperidol use in acute traumatic brain injury: A safety analysis. Arch De Med. 2016; 2: 14.
- Marinescu D, Mogoanta L, Udristoiu T. P03-353 neuroprotective effect of haloperidol vs. Aripiprazole at hippocampal and frontal cortex at rats. Eur Psychiat. 2010; 25: 968. [CrossRef]
- Bellamy CJ, Kane-Gill SL, Falcione BA, Seybert AL. Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol. J Trauma Acute Care Surg. 2009; 66: 954-958. [CrossRef]
- Tasker R, Coyle J, Vornov J. The regional vulnerability to hypoglycemia-induced neurotoxicity in organotypic hippocampal culture: Protection by early tetrodotoxin or delayed mk-801. J Neurosci. 1992; 12: 4298-4308. [CrossRef]
- McDonald JW, Silverstein FS, Johnston MV. Neurotoxicity ofn-methyl-d-aspartate is markedly enhanced in developing rat central nervous system. Brain Res. 1988; 459: 200-203. [CrossRef]
- Facci L, Leon A, Skaper S. Hypoglycemic neurotoxicity in vitro: Involvement of excitatory amino acid receptors and attenuation by monosialoganglioside gm1. Neuroscience. 1990; 37: 709-716. [CrossRef]
- Wang X, Song X, Takata T, Miichi Y, Yokono K, Sakurai T. Amyloid-β neurotoxicity restricts glucose window for neuronal survival in rat hippocampal slice cultures. Exp Gerontol. 2010; 45: 904-908. [CrossRef]
- Willenborg B, Schmoller A, Caspary J, Melchert U, Scholand-Engler H, Jauch-Chara K, et al. Memantine prevents hypoglycemia-induced decrements of the cerebral energy status in healthy subjects. J Clin Endocrinol Metab. 2011; 96: E384-E388. [CrossRef]
- Danilenko UI, Khunteev GA, Bagumyan A, Izykenova GA. Neurotoxicity biomarkers in experimental acute and chronic brain injury. Biomarkers for Traumatic Brain Injury. 2012: 87-105. [CrossRef]
- DeKosky ST, Asken BM. Injury cascades in TBI-related neurodegeneration. Brain Injury. 2017; 31: 1177-1182. [CrossRef]
- Fujisawa H, Landolt H, Bullock R. Glutamate neurotoxicity as a mechanism of ischemic brain damage: A basic study using a new in vivo model. Neurochemical Monitoring in the Intensive Care Unit: Springer; 1995: 26-33. [CrossRef]
- Yu W, Parakramaweera R, Teng S, Gowda M, Sharad Y, Thakker-Varia S, et al. Oxidation of KCNB1 potassium channels causes neurotoxicity and cognitive impairment in a mouse model of traumatic brain injury. J Neurosci. 2016; 36: 11084-11096. [CrossRef]
- Mattson MP, Scheff SW. Endogenous neuroprotection factors and traumatic brain injury: Mechanisms of action and implications for therapy. J Neurotrauma. 1994; 11: 3-33. [CrossRef]
- Turovskaya M, Gaidin S, Mal'tseva V, Zinchenko V, Turovsky E. Taxifolin protects neurons against ischemic injury in vitro via the activation of antioxidant systems and signal transduction pathways of gabaergic neurons. Mol Cell Neurosci. 2019; 96: 10-24. [CrossRef]
- Woldegerima N, Rosenblatt K, Mintz CD. Neurotoxic properties of propofol sedation following traumatic brain injury. Crit Care Med. 2016; 44: 455. [CrossRef]
- Berndt N, Rösner J, ul Haq R, Kann O, Kovács R, Holzhütter HG, et al. Possible neurotoxicity of the anesthetic propofol: Evidence for the inhibition of complex ii of the respiratory chain in area CA3 of rat hippocampal slices. Arch Toxicol. 2018; 92: 3191-3205. [CrossRef]
- Alam A, Suen KC, Hana Z, Sanders RD, Maze M, Ma D. Neuroprotection and neurotoxicity in the developing brain: An update on the effects of dexmedetomidine and xenon. Neurotoxicol Teratol. 2017; 60: 102-116. [CrossRef]
- Perez-Zoghbi J, Zhu W, Grafe M, Brambrink A. Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. BJA: Br J Anaesth. 2017; 119: 506-516. [CrossRef]
- Degos V, Chhor V, Brissaud O, Lebon S, Schwendimann L, Bednareck N, et al. Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. J Am Coll Cardiol. 2013; 118: 1123-1132. [CrossRef]
- Kline A, Yu J, Horvath E, Marion D, Dixon C. The selective 5-ht1a receptor agonist repinotan hcl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats. Neuroscience. 2001; 106: 547-555. [CrossRef]
- Cheng JP, Leary JB, Sembhi A, Edwards CM, Bondi CO, Kline AE. 5-hydroxytryptamine1a (5-HT1A) receptor agonists: A decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. Brain Res. 2016; 1640: 5-14. [CrossRef]
- Cosi C, Waget A, Rollet K, Tesori V, Newman-Tancredi A. Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: Role of 5-HT1A receptor activation. Brain Res. 2005; 1043: 32-41. [CrossRef]
- Okamura N, Hashimoto K, Kanahara N, Shimizu E, Kumakiri C, Komatsu N, et al. Protective effect of the antipsychotic drug zotepine on dizocilpine-induced neuropathological changes in rat retrosplenial cortex. Eur J Pharmacol. 2003; 461: 93-98. [CrossRef]
- Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly Y, et al. A pharmacological profile of the selective silent 5-HT1A receptor antagonist, way-100635. Eur J Pharmacol. 1995; 281: 81-88. [CrossRef]
- Marona-Lewicka D, Nichols DE. Aripiprazole (opc-14597) fully substitutes for the 5-HT1A receptor agonist ly293284 in the drug discrimination assay in rats. Psychopharmacology. 2004; 172: 415-421. [CrossRef]
- Park SW, Lee CH, Lee JG, Kim LW, Shin BS, Lee BJ, et al. Protective effects of atypical antipsychotic drugs against mpp+-induced oxidative stress in PC12 cells. Neurosci Res. 2011; 69: 283-290. [CrossRef]
- Gassó P, Mas S, Molina O, Bernardo M, Lafuente A, Parellada E. Neurotoxic/neuroprotective activity of haloperidol, risperidone and paliperidone in neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry. 2012; 36: 71-77. [CrossRef]
- Wang H, Xu H, Dyck LE, Li XM. Olanzapine and quetiapine protect PC12 cells from β‐amyloid peptide25–35‐induced oxidative stress and the ensuing apoptosis. J Neurosci Res. 2005; 81: 572-580. [CrossRef]
- Park SY, Shin HK, Lee WS, Bae SS, Kim K, Hong KW, et al. Neuroprotection by aripiprazole against β-amyloid-induced toxicity by P-CK2α activation via inhibition of gsk-3β. Oncotarget. 2017; 8: 110380. [CrossRef]
- Gil CH, Kim YR, Lee HJ, Jung DH, Shin HK, Choi BT. Aripiprazole exerts a neuroprotective effect in mouse focal cerebral ischemia. Exp Ther Med. 2018; 15: 745-750. [CrossRef]
- Koprivica V, Regardie K, Wolff C, Fernalld R, Murphy JJ, Kambayashi J, et al. Aripiprazole protects cortical neurons from glutamate toxicity. Eur J Pharmacol. 2011; 651: 73-76. [CrossRef]
- Luo C, Xu H, Li XM. Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress. Brain Res. 2005; 1063: 32-39. [CrossRef]
- Sadowska-Bartosz I, Galiniak S, Bartosz G, Zuberek M, Grzelak A, Dietrich-Muszalska A. Antioxidant properties of atypical antipsychotic drugs used in the treatment of schizophrenia. Schizophrenia Res. 2016; 176: 245-251. [CrossRef]
- Martins MR, Petronilho FC, Gomes KM, Dal-Pizzol F, Streck EL, Quevedo J. Antipsychotic-induced oxidative stress in rat brain. Neurotox Res. 2008; 13: 63-69. [CrossRef]
- Frånberg O, Wiker C, Marcus MM, Konradsson Å, Jardemark K, Schilström B, et al. Asenapine, a novel psychopharmacologic agent: Preclinical evidence for clinical effects in schizophrenia. Psychopharmacology. 2008; 196: 417-429. [CrossRef]
- He B, Yu L, Li S, Xu F, Yang L, Ma S, et al. Neuroprotective effect of lurasidone via antagonist activities on histamine in a rat model of cranial nerve involvement. Mol Med Rep. 2018; 17: 6002-6008. [CrossRef]
- Ishima T, Futamura T, Ohgi Y, Yoshimi N, Kikuchi T, Hashimoto K. Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin–dopamine activity modulator: A role for serotonin 5-HT1A and 5-HT2A receptors. Eur Neuropsychopharmacol. 2015; 25: 505-511. [CrossRef]
- Kehr J, Yoshitake T, Ichinose F, Yoshitake S, Kiss B, Gyertyán I, et al. Effects of cariprazine on extracellular levels of glutamate, gaba, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity. Psychopharmacology. 2018; 235: 1593-1607. [CrossRef]
- Barnes SA, Young JW, Markou A, Adham N, Gyertyán I, Kiss B. The effects of cariprazine and aripiprazole on pcp-induced deficits on attention assessed in the 5-choice serial reaction time task. Psychopharmacology. 2018; 235: 1403-1414. [CrossRef]
- Rao VLR, Dogan A, Todd KG, Bowen KK, Dempsey RJ. Neuroprotection by memantine, a non-competitive nmda receptor antagonist after traumatic brain injury in rats. Brain Res. 2001; 911: 96-100. [CrossRef]
- Fornasari E, Marinelli L, Di Stefano A, Eusepi P, Turkez H, Fulle S, et al. Synthesis and antioxidant properties of novel memantine derivatives. Cent Nerv Syst Agents Med Chem. 2017; 17: 123-128. [CrossRef]
- Monastero R, Camarda C, Pipia C, Camarda R. Visual hallucinations and agitation in Alzheimer’S disease due to memantine: Report of three cases. J Neurol Neurosurg Psychiat. 2007; 78: 546-546. [CrossRef]
- Pringle A, Parsons E, Cowen L, McTavish S, Cowen P, Harmer C. Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine. J Psychopharmacol. 2012; 26: 1417-1423. [CrossRef]
- Wilcock GK, Ballard CG, Cooper JA, Loft H. Memantine for agitation/aggression and psychosis in moderately severe to severe alzheimer's disease: A pooled analysis of 3 studies. J Clin Psychiat. 2008; 69: 341-348. [CrossRef]
- Shen H, Kihara T, Hongo H, Wu X, Kem W, Shimohama S, et al. Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of α7 nicotinic receptors and internalization of nmda receptors. Br J Pharmacol. 2010; 161: 127-139. [CrossRef]
- Gagnon DJ, Fontaine GV, Smith KE, Riker RR, Miller III RR, Lerwick PA, et al. Valproate for agitation in critically ill patients: A retrospective study. J Crit Care. 2017; 37: 119-125. [CrossRef]
- Sher Y, Cramer ACM, Ament A, Lolak S, Maldonado JR. Valproic acid for treatment of hyperactive or mixed delirium: Rationale and literature review. Psychosomatics. 2015; 56: 615-625. [CrossRef]
- Dash PK, Orsi SA, Zhang M, Grill RJ, Pati S, Zhao J, et al. Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PloS One. 2010; 5: e11383. [CrossRef]
- Vajda F. Valproate and neuroprotection. J Clin Neurosci. 2002; 9: 508-514. [CrossRef]
- Aycicek A, Iscan A. The effects of carbamazepine, valproic acid and phenobarbital on the oxidative and antioxidative balance in epileptic children. Eur Neurol. 2007; 57: 65-69. [CrossRef]
- Frey BN, Valvassori SS, Réus GZ, Martins MR, Petronilho FC, Bardini K, et al. Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci. 2006; 31: 326. [CrossRef]
- Chiu C-T, Wang Z, Hunsberger JG, Chuang D-M. Therapeutic potential of mood stabilizers lithium and valproic acid: Beyond bipolar disorder. Pharmacol Rev. 2013; 65: 105-142. [CrossRef]
- Gotlib D, Ramaswamy R, Kurlander JE, DeRiggi A, Riba M. Valproic acid in women and girls of childbearing age. Curr Psychiat Rep. 2017; 19: 58. [CrossRef]
- Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism. Exp Neurol. 2018; 299: 217-227. [CrossRef]
- Oliveira A, Almeida J, Freitas R, Nascimento V, Aguiar L, Júnior H, et al. Effects of levetiracetam in lipid peroxidation level, nitrite–nitrate formation and antioxidant enzymatic activity in mice brain after pilocarpine-induced seizures. Cell Mol Neurobiol. 2007; 27: 395-406. [CrossRef]
- Ahn JY, Yan BC, Park JH, Ahn JH, Lee DH, Kim IH, et al. Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke. Exp Ther Med. 2015; 10: 2007-2014. [CrossRef]
- Kim GH, Byeon JH, Eun B-L. Neuroprotective effect of lacosamide on hypoxic-ischemic brain injury in neonatal rats. J Clin Neurol. 2017; 13: 138-143. [CrossRef]
- Hayakawa T, Higuchi Y, Nigami H, Hattori H. Zonisamide reduces hypoxic-ischemic brain damage in neonatal rats irrespective of its anticonvulsive effect. EurJ Pharmacol. 1994; 257: 131-136. [CrossRef]
- Yi YH, Guo WC, Sun WW, Su T, Lin H, Chen SQ, et al. Neuroprotection of lamotrigine on hypoxic-ischemic brain damage in neonatal rats: Relations to administration time and doses. Biologics. 2008; 2: 339. [CrossRef]
- Agarwal NB, Agarwal NK, Mediratta PK, Sharma KK. Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure. 2011; 20: 257-262. [CrossRef]
- Eren İ, Nazıroğlu M, Demirdaş A. Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain. Neurochem Res. 2007; 32: 1188-1195. [CrossRef]
- Ambrósio AF, Silva AP, Araújo I, Malva JO, Soares-da-Silva Pc, Carvalho AP, et al. Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and two new putative antiepileptic drugs, BIA 2-093 and BIA 2-024. Eur J Pharmacol. 2000; 406: 191-201. [CrossRef]
- Tutanc M, Aras M, Dokuyucu R, Altas M, Zeren C, Arica V, et al. Oxidative status in epileptic children using carbamazepine. Iran J Pediat. 2015; 25. [CrossRef]
- Li Z-H, Li P, Rodina M, Randak T. Effect of human pharmaceutical carbamazepine on the quality parameters and oxidative stress in common carp (cyprinus carpio l.) spermatozoa. Chemosphere. 2010; 80: 530-534. [CrossRef]
- Li Z-H, Zlabek V, Velisek J, Grabic R, Machova J, Randak T. Modulation of antioxidant defence system in brain of rainbow trout (oncorhynchus mykiss) after chronic carbamazepine treatment. Comp Biochem Physiol C: Toxicol Pharmacol. 2010; 151: 137-141. [CrossRef]
- Bolayir E, Celik K, Tas A, Topaktas S, Bakir S. The effects of oxcarbazepine on oxidative stress in epileptic patients. Methods Find Exp Clin Pharmacol. 2004; 26: 345-348. [CrossRef]
- Remy KE, Custer JW, Cappell J, Foster CB, Garber NA, Walker LK, et al. Pediatric anti-N-Methyl-D-aspartate receptor encephalitis: A review with pooled analysis and critical care emphasis. Front Pediat. 2017; 5: 250. [CrossRef]
- Kuppuswamy PS, Takala CR, Sola CL. Management of psychiatric symptoms in anti-nmdar encephalitis: A case series, literature review and future directions. Gen Hosp Psychiatry. 2014; 36: 388-391. [CrossRef]
- Nichols TA. Anti-nmda receptor encephalitis: An emerging differential diagnosis in the psychiatric community. Mental Health Clin. 2016; 6: 297-303. [CrossRef]
- Götz E, Feuerstein T, Lais A, Meyer D. Effects of gabapentin on release of gamma-aminobutyric acid from slices of rat neostriatum. Arzneimittel-Forschung. 1993; 43: 636-638.
- Kim YS, Chang HK, Lee JW, Sung YH, Kim SE, Shin MS, et al. Protective effect of gabapentin on N-Methyl-D-aspartate-induced excitotoxicity in rat hippocampal CA1 neurons. J Pharmacol Sci. 2009; 109: 144-147. [CrossRef]
- Abdel-Salam OM, Khadrawy YA, Mohammed NA, Youness ER. The effect of gabapentin on oxidative stress in a model of toxic demyelination in rat brain. J Basic Clin Physiol Pharmacol. 2012; 23: 61-68. [CrossRef]
- Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Özkan E, et al. Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory cns synaptogenesis. Cell. 2009; 139: 380-392. [CrossRef]
- Sałat K, Librowski T, Nawiesniak B, Gluch-Lutwin M. Evaluation of analgesic, antioxidant, cytotoxic and metabolic effects of pregabalin for the use in neuropathic pain. Neurol Res. 2013; 35: 948-958. [CrossRef]
- Diaz-Ruiz A, Mendez-Armenta M, Galván-Arzate S, Manjarrez J, Nava-Ruiz C, Santander I, et al. Antioxidant, anticonvulsive and neuroprotective effects of dapsone and phenobarbital against kainic acid-induced damage in rats. Neurochem Res. 2013; 38: 1819-1827. [CrossRef]
- Reeta K, Mehla J, Gupta YK. Curcumin is protective against phenytoin-induced cognitive impairment and oxidative stress in rats. Brain Res. 2009; 1301: 52-60. [CrossRef]
- Mamatha M, Priyanka T, Konda S, Madhavi M. Evaluation of nootropic activity of hydroxycitric acid in phenytoin treated rats. Int J Pharm Sci Res. 2014; 5: 2216.
- Bell JD. In vogue: Ketamine for neuroprotection in acute neurologic injury. Anesth Analg. 2017; 124: 1237-1243. [CrossRef]
- Wang CQ, Ye Y, Chen F, Han WC, Sun JM, Lu X, et al. Posttraumatic administration of a sub-anesthetic dose of ketamine exerts neuroprotection via attenuating inflammation and autophagy. Neuroscience. 2017; 343: 30-38. [CrossRef]
- Leeds PR, Yu F, Wang Z, Chiu CT, Zhang Y, Leng Y, et al. A new avenue for lithium: Intervention in traumatic brain injury. ACS Chem Neurosci. 2014; 5: 422-433. [CrossRef]
- Chuang DM. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: Can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol. 2004; 16: 83-90. [CrossRef]
- Young W. Review of lithium effects on brain and blood. Cell Transplant. 2009; 18: 951-975. [CrossRef]
- Kano O, Ikeda K, Kawabe K, Iwamoto K, Iwasaki Y. Pramipexole protects spinal motor neuron death against glutamate-induced neurotoxicity. J Neurol Res. 2011; 1: 127-132. [CrossRef]
- Huang EYK, Tsui PF, Kuo TT, Tsai JJ, Chou YC, Ma HI, et al. Amantadine ameliorates dopamine-releasing deficits and behavioral deficits in rats after fluid percussion injury. PloS One. 2014; 9: e86354. [CrossRef]
- Spritzer SD, Kinney CL, Condie J, Wellik KE, Hoffman-Snyder CR, Wingerchuk DM, et al. Amantadine for patients with severe traumatic brain injury: A critically appraised topic. Neurologist. 2015; 19: 61-64. [CrossRef]
- Iwata M, Inoue S, Kawaguchi M, Furuya H. Effects of diazepam and flumazenil on forebrain ischaemia in a rat model of benzodiazepine tolerance. Br J Anaesth. 2012; 109: 935-942. [CrossRef]
- Martins MR, Reinke A, Petronilho FC, Gomes KM, Dal-Pizzol F, Quevedo J. Methylphenidate treatment induces oxidative stress in young rat brain. Brain Res. 2006; 1078: 189-197. [CrossRef]
- Marinescu IP, Predescu A, Udriştoiu T, Marinescu D. Comparative study of neuroprotective effect of tricyclics vs. Trazodone on animal model of depressive disorder. Rom J Morphol Embryol. 2012; 53: 397-400.
- Kline AE, Olsen AS, Sozda CN, Hoffman AN, Cheng JP. Evaluation of a combined treatment paradigm consisting of environmental enrichment and the 5-HT1A receptor agonist buspirone after experimental traumatic brain injury. J Neurotrauma. 2012; 29: 1960-1969. [CrossRef]