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2000
Volume 31, Issue 22
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Schizophrenia is a heterogeneous neuropsychological disorder characterized by three distinct sets of symptoms: positive, negative, and cognitive. It carries significant public health implications and is estimated to affect up to 1% of the population. Despite extensive research, the underlying mechanisms of schizophrenia are not entirely understood, and existing antipsychotic treatments have notable limitations. Firstly, these treatments are effective for only approximately half of the patients. Secondly, they primarily alleviate positive symptoms such as misperceptions and thought disorders, which are core to the illness, while neglecting the negative symptoms like flat affect and social withdrawal, as well as cognitive symptoms such as learning and attention difficulties. Thirdly, these treatments come with significant neurofunctional and metabolic side effects, and in some cases, they can lead to issues like sexual dysfunction or agranulocytosis (in the case of Clozapine (CLZ). In this review, we delve into currently available treatments for schizophrenia, with the utilization of Deep brain stimulation techniques to overcome the limitations of antipsychotics. We also discuss the major clinical trials for schizophrenia along with deep brain stimulation intervention.

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2025-10-03
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References

  1. KahnR.S. SommerI.E. MurrayR.M. Meyer-LindenbergA. WeinbergerD.R. CannonT.D. O'DonovanM. CorrellC.U. KaneJ.M. van OsJ. InselT.R. Schizophrenia.Nat. Rev. Dis. Primers.201516910.1038/nrdp.2015.6727189524
    [Google Scholar]
  2. RopperA.H. MarderS.R. CannonT.D. Schizophrenia.N. Engl. J. Med.2019381181753176110.1056/NEJMra1808803
    [Google Scholar]
  3. AvramopoulosD. Recent advances in the genetics of schizophrenia.Mol. Neuropsychiatry201841355110.1159/00048867929998117
    [Google Scholar]
  4. DeanB. Understanding the pathology of schizophrenia: recent advances from the study of the molecular architecture of postmortem CNS tissue.Postgrad. Med. J.200278917142810.1136/pmj.78.917.14211884695
    [Google Scholar]
  5. DeepikaD. DewanganH.K. MauryaL. SinghS. Intranasal drug delivery of frovatriptan succinate loaded polymeric nanoparticles for brain targeting.J. Pharm. Sci.2019108285185910.1016/j.xphs.2018.07.01330053555
    [Google Scholar]
  6. BenesF.M. The GABA system in schizophrenia: cells, molecules and microcircuitry.Schizophr. Res.20151671-31310.1016/j.schres.2015.07.01726255083
    [Google Scholar]
  7. HaleemD.J. 5-HT1A receptor-dependent control of nigrostriatal dopamine neurotransmission in the pharmacotherapy of Parkinson’s disease and schizophrenia.Behav. Pharmacol.2015261-2455810.1097/FBP.000000000000012325503261
    [Google Scholar]
  8. MuzioM.R. LeeJ. Neuroanatomy, extrapyramidal system.StatPearlsStatPearls PublishingTreasure Island (FL)202432119429
    [Google Scholar]
  9. HerreroM.T. BarciaC. NavarroJ. Functional anatomy of thalamus and basal ganglia.Childs Nerv. Syst.200218838640410.1007/s00381‑002‑0604‑112192499
    [Google Scholar]
  10. RenardJ. NorrisC. RushlowW. LavioletteS.R. Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments.Neurosci. Biobehav. Rev.20177515716510.1016/j.neubiorev.2017.02.00628185872
    [Google Scholar]
  11. CsernanskyJ.G. MurphyG.M. FaustmanW.O. Limbic/mesolimbic connections and the pathogenesis of schizophrenia.Biol. Psychiatry199130438340010.1016/0006‑3223(91)90295‑W1912130
    [Google Scholar]
  12. AdellA. Brain NMDA receptors in schizophrenia and depression.Biomolecules202010694710.3390/biom1006094732585886
    [Google Scholar]
  13. JavittD.C. Glutamate and schizophrenia: Phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions.Int. Rev. Neurobiol.2007786910810.1016/S0074‑7742(06)78003‑517349858
    [Google Scholar]
  14. BennettM. Positive and negative symptoms in schizophrenia: The NMDA receptor hypofunction hypothesis, neuregulin/ErbB4 and synapse regression.Aust. N. Z. J. Psychiatry200943871172110.1080/0004867090300194319629792
    [Google Scholar]
  15. MeltzerH. The role of serotonin in antipsychotic drug action.Neuropsychopharmacology1999212 Suppl106S115S10.1016/S0893‑133X(99)00046‑910432496
    [Google Scholar]
  16. PerreaultM.L. O’DowdB.F. GeorgeS.R. Dopamine receptor homooligomers and heterooligomers in schizophrenia.CNS Neurosci. Ther.2011171525710.1111/j.1755‑5949.2010.00228.x21199449
    [Google Scholar]
  17. NordM. FardeL. Antipsychotic occupancy of dopamine receptors in schizophrenia.CNS Neurosci. Ther.20111729710310.1111/j.1755‑5949.2010.00222.x21143431
    [Google Scholar]
  18. Diagnostic and Statistical Manual of Mental Disorders.5th Ed.American Physicatric Association20138912210.1176/appi.books.9780890425596
    [Google Scholar]
  19. ToolkitW. EllisR.J. BilimoriaK.Y. GoldmanM.L. PincusH.A. Mistreatment and burnout in surgical residency training.N. Engl. J. Med.2020382658158310.1056/NEJMc1915992
    [Google Scholar]
  20. RangH.P. DaleM.M. RitterJ.M. FlowerR.J. HendersonG. Rang and Dale’s pharmacology.7th ed.EnglandElsevier2012
    [Google Scholar]
  21. PrasadA.B. British national formulary.Psychiatr. Bull.199418530430410.1192/pb.18.5.304
    [Google Scholar]
  22. UrsN.M. PetersonS.M. CaronM.G. New concepts in dopamine D2 receptor biased signaling and implications for schizophrenia therapy.Biol Psychiatry2017811788510.1016/j.biopsych.2016.10.01127832841
    [Google Scholar]
  23. PisaniA. BernardiG. DingJ. SurmeierD.J. Re-emergence of striatal cholinergic interneurons in movement disorders.Trends Neurosci.2007301054555310.1016/j.tins.2007.07.00817904652
    [Google Scholar]
  24. López-MuñozF. AlamoC. cuencaE. ShenW. ClervoyP. RubioG. History of the discovery and clinical introduction of chlorpromazine.Ann. Clin. Psychiat.200517311313510.1080/1040123059100200216433053
    [Google Scholar]
  25. CrillyJ. The history of clozapine and its emergence in the US market.Hist. Psychiat.2007181396010.1177/0957154X0707033517580753
    [Google Scholar]
  26. RemingtonG. Encyclopedia of PsychopharmacologyLondon, UKSpringer201019
    [Google Scholar]
  27. BurrisK.D. MolskiT.F. XuC. RyanE. TottoriK. KikuchiT. YoccaF.D. MolinoffP.B. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors.J. Pharmacol. Exp. Ther.2002302138138910.1124/jpet.102.03317512065741
    [Google Scholar]
  28. SelvarajS. ArnoneD. CappaiA. HowesO. Alterations in the serotonin system in schizophrenia: A systematic review and meta-analysis of postmortem and molecular imaging studies.Neurosci. Biobehav. Rev.20144523324510.1016/j.neubiorev.2014.06.00524971825
    [Google Scholar]
  29. De DeurwaerdèreP. Di GiovanniG. Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications.Prog. Neurobiol.201715117523610.1016/j.pneurobio.2016.03.00427013075
    [Google Scholar]
  30. StępnickiP. KondejM. KaczorA.A. Current concepts and treatments of schizophrenia.Molecules2018238208710.3390/molecules2308208730127324
    [Google Scholar]
  31. BridlerR. Aripiprazol (Abilify®) in der Schizophreniebehandlung.Praxis2005942397597710.1024/0369‑8394.94.23.975
    [Google Scholar]
  32. MarderS.R. HakalaM.J. JosiassenM.K. ZhangP. OuyangJ. WeillerE. WeissC. HobartM. Brexpiprazole in patients with schizophrenia: Overview of short- and long-term phase 3 controlled studies.Acta Neuropsychiatr.201729527829010.1017/neu.2016.5727846922
    [Google Scholar]
  33. KikuchiT. MaedaK. SuzukiM. HiroseT. FutamuraT. McQuadeR.D. Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole.Neuropsychopharmacol. Rep.202141213414310.1002/npr2.1218033960741
    [Google Scholar]
  34. HsuW.Y. LaneH.Y. LinC.H. Brexpiprazole for the treatment of schizophrenia.Expert Opin. Pharmacother.201718221722310.1080/14656566.2016.127497227997809
    [Google Scholar]
  35. FramptonJ.E. Brexpiprazole: A review in schizophrenia.Drugs201979218920010.1007/s40265‑019‑1052‑530671869
    [Google Scholar]
  36. PahwaM. SleemA. ElsayedO.H. GoodM.E. El-MallakhR.S. New antipsychotic medications in the last decade.Curr. Psychiatry Rep.202123128710.1007/s11920‑021‑01298‑w34843030
    [Google Scholar]
  37. HopeJ. KeksN.A. Cariprazine: A new partial dopamine agonist with a familiar profile.Australas. Psychiatry202230338238510.1177/1039856221106425435156402
    [Google Scholar]
  38. SuzukiK. CastelliM. KomaroffM. StarlingB. TeraharaT. CitromeL. Pharmacokinetic profile of the asenapine transdermal system (HP-3070).J. Clin. Psychopharmacol.202141328629410.1097/JCP.000000000000138333734167
    [Google Scholar]
  39. CeskovaE. Pharmacological strategies for the management of comorbid depression and schizophrenia.Expert Opin. Pharmacother.202021445946510.1080/14656566.2020.171746631983254
    [Google Scholar]
  40. Safety and Efficacy of Brilaroxazine (RP5063) in Schizophrenia.2023Available from: https://classic.clinicaltrials.gov/ct2/show/record/NCT05184335?view=record (Accessed on: 20 Sep 2023).
  41. KoblanK.S. KentJ. HopkinsS.C. KrystalJ.H. ChengH. GoldmanR. LoebelA. A non–D2-receptor-binding drug for the treatment of schizophrenia.N. Engl. J. Med.2020382161497150610.1056/NEJMoa191177232294346
    [Google Scholar]
  42. BrannanS.K. SawchakS. MillerA.C. LiebermanJ.A. PaulS.M. BreierA. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia.N. Engl. J. Med.2021384871710.1056/NEJMoa201701533626254
    [Google Scholar]
  43. ThornC.A. MoonJ. BourbonaisC.A. HarmsJ. EdgertonJ.R. StarkE. SteynS.J. ButlerC.R. LazzaroJ.T. O’ConnorR.E. PopiolekM. Striatal, hippocampal, and cortical networks are differentially responsive to the M4- and M1-muscarinic acetylcholine receptor mediated effects of xanomeline.ACS Chem. Neurosci.2019108391010.1021/acschemneuro.9b0033531286767
    [Google Scholar]
  44. ShannonH.E. BymasterF.P. CalligaroD.O. GreenwoodB. MitchC.H. SawyerB.D. WardJ.S. WongD.T. OlesenP.H. SheardownM.J. SwedbergM.D. SuzdakP.D. SauerbergP. Xanomeline: A novel muscarinic receptor agonist with functional selectivity for M1 receptors.J. Pharmacol. Exp. Ther.19942691271817909557
    [Google Scholar]
  45. Orzelska-GórkaJ. MikulskaJ. WiszniewskaA. BiałaG. New atypical antipsychotics in the treatment of schizophrenia and depression.Int. J. Mol. Sci.202223181062410.3390/ijms23181062436142523
    [Google Scholar]
  46. DarwishM. Bugarski-KirolaD. PassarellJ. OwenJ. JaworowiczD. DeKarskeD. StankovicS. Pimavanserin exposure-response analyses in patients with schizophrenia.J. Clin. Psychopharmacol.202242654455110.1097/JCP.000000000000161136190440
    [Google Scholar]
  47. Clinical Trials Register.2023Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-006062-36/DE (Accessed on: 20 Sep 2023).
  48. BioqueM. RumiàJ. RoldánP. Hidalgo-MazzeiD. MontejoL. BenabarreA. Gil-BadenesJ. TerceroJ. ParelladaE. VietaE. Deep brain stimulation and digital monitoring for patients with treatment-resistant schizophrenia and bipolar disorder: A case series.Rev. Psiquiatr. Salud. Ment.2023S1888-989123000130001710.1016/j.rpsm.2023.05.00137798202
    [Google Scholar]
  49. SoltaniE. AhmadN. SulemanU. ShadM. Pros and cons of using transcranial magnetic stimulation to address schizophrenic patients.Brain Stimul.2021146168010.1016/j.brs.2021.10.291
    [Google Scholar]
  50. TaiC.H. TsengS.H. Cerebellar deep brain stimulation for movement disorders.Neurobiol. Dis.202217510589910.1016/j.nbd.2022.10589936265768
    [Google Scholar]
  51. LiM.C.H. CookM.J. Deep brain stimulation for drug-resistant epilepsy.Epilepsia201859227329010.1111/epi.1396429218702
    [Google Scholar]
  52. ShethS.A. BijankiK.R. MetzgerB. AllawalaA. PirtleV. AdkinsonJ.A. MyersJ. MathuraR.K. OswaltD. TsolakiE. XiaoJ. NoeckerA. StruttA.M. CohnJ.F. McIntyreC.C. MathewS.J. BortonD. GoodmanW. PouratianN. Deep brain stimulation for depression informed by intracranial recordings.Biol. Psychiatry202292324625110.1016/j.biopsych.2021.11.00735063186
    [Google Scholar]
  53. WarwickK. LegatoM.J. Cyborgs: Understanding and Mutual Treatment.Principles of Gender-Specific Medicine3rd Ed.Academic Press201770571510.1016/B978‑0‑12‑803506‑1.00010‑3
    [Google Scholar]
  54. BellE. RacineE. Ethics guidance for neurological and psychiatric deep brain stimulation.Handb. Clin. Neurol.201311631332510.1016/B978‑0‑444‑53497‑2.00026‑724112905
    [Google Scholar]
  55. WongJ.K. LopesJ.M.L.J. HuW. WangA. AuK.L.K. StiepT. FreyJ. ToledoJ.B. RaikeR.S. OkunM.S. AlmeidaL. Double blind, nonrandomized crossover study of active recharge biphasic deep brain stimulation for primary dystonia.Parkinsonism Relat. Disord.202310910532810.1016/j.parkreldis.2023.10532836827951
    [Google Scholar]
  56. GaméX. RuffionA. CornuJ.N. PhéV. PeyronnetB. Perrouin-VerbeM.A. AublantC. AdéA. Chartier-KastlerE. Sacral neuromodulation: Rechargeable versus non-rechargeable device. What would the patient preferences be in France?Prog. Urol.2022321067268010.1016/j.purol.2022.04.01135752523
    [Google Scholar]
  57. JakobsM. HajiabadiM.M. Aguirre-PadillaD.H. GiaccobeP. UnterbergA.W. LozanoA.M. Recharge PSYCH: A study on rechargeable implantable pulse generators in deep brain stimulation for psychiatric disorders.World Neurosurg.2023170e331e33910.1016/j.wneu.2022.11.01736368453
    [Google Scholar]
  58. CoenenV.A. SajonzB. ReisertM. BostroemJ. BewernickB. UrbachH. JenknerC. ReinacherP.C. SchlaepferT.E. MädlerB. Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.Neuroimage Clin.20182058059310.1016/j.nicl.2018.08.02030186762
    [Google Scholar]
  59. MantioneM. NiemanD. FigeeM. van den MunckhofP. SchuurmanR. DenysD. Cognitive effects of deep brain stimulation in patients with obsessive–compulsive disorder.J. Psychiatry Neurosci.201540637838610.1503/jpn.14021026107159
    [Google Scholar]
  60. SmithE.E. SchüllerT. HuysD. BaldermannJ.C. AndradeP. AllenJ.J.B. Visser-VandewalleV. UllspergerM. GruendlerT.O.J. KuhnJ. A brief demonstration of frontostriatal connectivity in OCD patients with intracranial electrodes.Neuroimage202022011713810.1016/j.neuroimage.2020.11713832634597
    [Google Scholar]
  61. CorripioI. RoldánA. McKennaP. SarróS. Alonso-SolísA. SalgadoL. ÁlvarezE. MoletJ. Pomarol-ClotetE. PortellaM. Target selection for deep brain stimulation in treatment resistant schizophrenia.Prog. Neuropsychopharmacol. Biol. Psychiatry202211211043610.1016/j.pnpbp.2021.11043634517055
    [Google Scholar]
  62. FigeeM. Riva-PosseP. ChoiK.S. BedersonL. MaybergH.S. KopellB.H. Deep brain stimulation for depression.Neurotherapeutics20221941229124510.1007/s13311‑022‑01270‑335817944
    [Google Scholar]
  63. CascellaN. ButalaA.A. MillsK. KimM.J. SalimpourY. WojtasieviczT. HwangB. CullenB. FigeeM. MoranL. LenzF. SawaA. SchretlenD.J. AndersonW. Deep brain stimulation of the substantia nigra pars reticulata for treatment-resistant schizophrenia: A case report.Biol. Psychiatry20219010e57e5910.1016/j.biopsych.2021.03.00733906736
    [Google Scholar]
  64. FerreiraJ.J. MestreT.A. LyonsK.E. Benito-LeónJ. TanE.K. AbbruzzeseG. HallettM. HaubenbergerD. ElbleR. DeuschlG. MDS evidence-based review of treatments for essential tremor.Mov. Disord.201934795095810.1002/mds.2770031046186
    [Google Scholar]
  65. AndreeA. LiN. ButenkoK. KoberM. ChenJ.Z. HiguchiT. FauserM. StorchA. IpC.W. KühnA.A. HornA. van RienenU. Deep brain stimulation electrode modeling in rats.Exp. Neurol.202235011397810.1016/j.expneurol.2022.11397835026227
    [Google Scholar]
  66. SinghV. GargA. DewanganH.K. Recent advances in drug design and delivery across biological barriers using computational models.Lett. Drug Des. Discovery2022191086587610.2174/1570180819999220204110306
    [Google Scholar]
  67. YadavR.K. ShahK. DewanganH.K. Intranasal drug delivery of sumatriptan succinate-loaded polymeric solid lipid nanoparticles for brain targeting.Drug Dev. Ind. Pharm.2022481212810.1080/03639045.2022.209057535703403
    [Google Scholar]
  68. VanshitaS. GargA. SharmaR. DewanganH.K. Review: Recent advances of nanotechnology in brain targeting.Curr. Nanosci.202219335036110.2174/1573413718666220820113550
    [Google Scholar]
  69. SharmaR. KourA. DewanganH.K. Enhancements in parkinson’s disease management: Leveraging levodopa optimization and surgical breakthroughs.Curr. Drug Targets2024261173210.2174/011389450131981724091910380239350551
    [Google Scholar]
  70. TomarS. YadavR.K. ShahK. DewanganH.K. A comprehensive review on carrier mediated nose to brain targeting: Emphasis on molecular targets, current trends, future prospects, and challenges.Int. J. Polym. Mater.20227329110310.1080/00914037.2022.2124255
    [Google Scholar]
  71. NehaS.L. MishraA.K. RaniL. ParohaS. DewanganH.K. SahooP.K. Design and evaluations of a nanostructured lipid carrier loaded with dopamine hydrochloride for intranasal bypass drug delivery in Parkinson’s disease.J. Microencapsul.202340859961210.1080/02652048.2023.226438637787159
    [Google Scholar]
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