PSİKİYATRİK BOZUKLUKLAR VE BİLİŞSEL İŞLEVLER

Psikiyatrik_Bozukluklar_ve_Bilissel_Islevler

ŞİZOFRENİDE BİLİŞSEL İŞLEV BOZUKLUKLARINA YAKLAŞIM

Talat Sarıkavak

İstanbul Atlas Üniversitesi, Tıp Fakültesi, Ruh Sağlığı ve Hastalıkları AD, İstanbul, Türkiye

Sarıkavak T. Şizofrenide Bilişsel İşlev Bozukluklarına Yaklaşım. Aydemir Ö, Esen Danacı A, editörler. Psikiyatrik Bozukluklar ve Bilişsel İşlevler. 1. Baskı. Ankara: Türkiye Klinikleri; 2025. p.49-61.

ÖZET

Şizofreni, pozitif (sanrılar, varsanılar), negatif (duygulanımda küntlük, sosyal çekilme) ve bilişsel belirtiler olmak üzere üç temel belirti kümesiyle tanımlanan karmaşık bir nöropsikiyatrik bozukluktur. Hastalığın tarihçesi incelendiğinde, bilişsel belirtilerin başlangıçta net olarak tanımlanmadığı, ancak günümüzde temel belirti kümelerinden biri olarak kabul edildiği görülmektedir. Bilişsel bozulmalar, şizofreni tanısı almış bireylerin yaşam kalitesini ve işlevselliklerini ciddi biçimde etkileyen önemli bir sorundur ve mevcut antipsikotik tedavilere genellikle dirençlidir.

Şizofrenide bilişsel bozulmalar genel olarak tüm bilişsel alanları kapsamakla birlikte; özellikle dikkat, çalışma belleği, yürütücü işlevler, işlem hızı ve sosyal biliş alanlarında belirginleşmektedir. Dikkat süreçlerindeki bozulma, özellikle dikkati sürdürme ve yöneltme zorlukları şeklinde kendini gösterirken, çalışma belleğindeki ve sözel bellekteki performans düşüklükleri hastalığın en kalıcı özellikleri arasındadır. Ayrıca, yürütücü işlevlerde gözlenen esnek düşünme yetisindeki azalmanın yanı sıra, perseverasyonların artması da sıklıkla rapor edilmektedir. İşlem hızının yavaşlaması, diğer bilişsel işlevlerdeki performansı dolaylı olarak olumsuz yönde etkilemektedir.

Sosyal biliş alanındaki bozukluklar da dikkat çekicidir. Özellikle duygu tanıma ve mentalizasyon süreçlerinde sorunlar yaşayan hastalar, bu bozukluk nedeniyle sosyal etkileşimlerde belirgin zorluklar yaşarlar. Sosyal biliş bozuklukları, pozitif ve negatif belirtilerle de doğrudan ilişkili olup hastalığın genel seyri ve prognozu açısından kritik öneme sahiptir.

Bilişsel bozuklukların altında yatan etiyolojide genetik faktörlerin rolü büyüktür. Özellikle DISC-1, DTNBP ve COMT Val158Met polimorfizmi gibi genetik varyantların bilişsel süreçlerdeki duyarlılığı artırdığı bilinmektedir. Bu genetik yatkınlık, epigenetik faktörlerle etkileşime girerek nörogelişimsel süreçlerde aksamalara neden olur. Göç, kentleşme, çocukluk çağı travmaları ve madde kullanımı gibi çevresel stres faktörleri, bu genetik yatkınlıkla etkileşime girerek bilişsel bozuklukların ortaya çıkışını hızlandırır ve derinleştirir.

Bilişsel bozuklukların nöroanatomik temellerinde frontopariyetal ağ, özellikle dorsolateral prefrontal korteks (DLPFK) ön plana çıkar. Şizofreni hastalarında DLPFK aktivasyonunda ve yapısal bağlantılarında bozulmalar görülmektedir. Bilişsel bozuklukların nörotransmitter sistemleri açısından incelendiğinde dopamin, glutamat ve asetilkolin sistemlerindeki dengesizlikler dikkat çekmektedir. Özellikle dopaminerjik sistemdeki aksamaların, prefrontal kortikal devrelerdeki bilişsel işlev bozuklukları ile ilişkisi vurgulanmaktadır.

Bilişsel bozuklukların tespiti ve değerlendirilmesi amacıyla MATRICS Consensus Cognitive Battery (MCCB), Brief Assessment of Cognition in Schizophrenia (BACS) gibi standardize edilmiş bataryalar sıklıkla kullanılmaktadır. Tedavi seçenekleri arasında farmakolojik ajan olarak klozapin önemli bir yer tutar, ancak son dönemde TAAR1 agonistleri gibi yeni ajanlar da umut vaat etmektedir. Farmakolojik olmayan yöntemler arasında aerobik egzersiz, diyet düzenlemeleri ve bilişsel rehabilitasyon programlarının etkinliği kanıtlanmıştır. Ayrıca, seçilmiş hastalarda dorsolateral prefrontal kortekse uygulanan transkranial manyetik stimülasyonun (TMS) olumlu etkileri gözlenmiştir. Bilişsel bozulmaların yönetiminde kişiye özel yaklaşımlar ve erken müdahale kritik önem taşır.

Anahtar Kelimeler: Şizofreni; Bilişsel bozukluklar; Sosyal biliş; MATRICS; Frontoparietal network; DLPFC

Referanslar

  1. Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. The Lancet. 2014;383(9929):1677-1687. [Crossref]  [PubMed]  [PMC]
  2. McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Molecular Psychiatry 2023 28:5. 2023;28(5):1902-1918. [Crossref]  [PubMed]  [PMC]
  3. Whitson S, O’Donoghue B, Hester R, et al. Cognitive ability and metabolic physical health in first-episode psychosis. Schizophr Res Cogn. 2021;24. [Crossref]  [PubMed]  [PMC]
  4. Javitt DC. Cognitive Impairment Associated with Schizophrenia: From Pathophysiology to Treatment. Annual Review of Pharmacology and Toxicology Annu Rev Pharmacol Toxicol 2023. 2025;18:33. [Crossref]  [PubMed]
  5. Mamah D, Mutiso VN, Ndetei DM. Neurocognition in Kenyan youth at clinical high risk for psychosis. Schizophr Res Cogn. 2021;25. [Crossref]  [PubMed]  [PMC]
  6. Tang W, Fan K li, Zhao S zhen, et al. Correlations between age, biomedical variables, and cognition in patients with schizophrenia. Schizophr Res Cogn. 2020;22:100182. [Crossref]  [PubMed]  [PMC]
  7. Zoupa E, Bogiatzidou O, Siokas V, et al. Cognitive Rehabilitation in Schizophrenia-Associated Cognitive Impairment: A Review. Neurol Int. 2023;15(1):12-23. [Crossref]  [PubMed]  [PMC]
  8. Seccomandi B, Tsapekos D, Newbery K, Wykes T, Cella M. A systematic review of moderators of cognitive remediation response for people with schizophrenia. Schizophr Res Cogn. 2020;19:100160. [Crossref]  [PubMed]  [PMC]
  9. Zhang T, Cui H, Wei Y, et al. Neurocognitive Assessments Are More Important Among Adolescents Than Adults for Predicting Psychosis in Clinical High Risk. Biol Psychiatry Cogn Neurosci Neuroimaging. 2022;7(1):56-65. [Crossref]  [PubMed]
  10. Martínez AL, Brea J, Rico S, de los Frailes MT, Loza MI. Cognitive deficit in schizophrenia: From etiology to novel treatments. Int J Mol Sci. 2021;22(18). [Crossref]  [PubMed]  [PMC]
  11. Hahn B, Robinson BM, Kiat JE, et al. Impaired Filtering and Hyperfocusing: Neural Evidence for Distinct Selective Attention Abnormalities in People with Schizophrenia. Cerebral Cortex. 2022;32(9):1950-1964. [Crossref]  [PubMed]  [PMC]
  12. Zhou J, Li J, Zhao Q, Ou P, Zhao W. Working memory deficits in children with schizophrenia and its mechanism, susceptibility genes, and improvement: A literature review. Front Psychiatry. 2022;13. [Crossref]  [PubMed]  [PMC]
  13. Khalil M, Hollander P, Raucher-Chéné D, Lepage M, Lavigne KM. Structural brain correlates of cognitive function in schizophrenia: A meta-analysis. Neurosci Biobehav Rev. 2022;132:37-49. [Crossref]  [PubMed]
  14. Granato G, Costanzo R, Borghi A, et al. An experimental and computational investigation of executive functions and inner speech in schizophrenia spectrum disorders. Sci Rep. 2025;15(1):5185. [Crossref]  [PubMed]  [PMC]
  15. Chu RST, Chu IWL, Yip EWC, et al. Cognitive functioning in people with psychotic experiences: a systematic review and meta-analysis study. Mol Psychiatry. 2025;30(3):11841194. [Crossref]  [PubMed]
  16. Cao Y, Han C, Peng X, et al. Correlation Between Resting Theta Power and Cognitive Performance in Patients With Schizophrenia. Front Hum Neurosci. 2022;16. [Crossref]  [PubMed]  [PMC]
  17. Abel DB, Minor KS. Social functioning in schizophrenia: Comparing laboratory-based assessment with real-world measures. J Psychiatr Res. 2021;138:500-506. [Crossref]  [PubMed]  [PMC]
  18. Vaskinn A, Sundet K, Melle I, Andreassen OA, Friis S. The factor structure of social cognition in schizophrenia: Weak evidence for separable domains. Schizophr Res Cogn. 2021;26. [Crossref]  [PubMed]  [PMC]
  19. Trubetskoy V, Pardiñas AF, Qi T, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604(7906):502-508. [Crossref]  [PubMed]
  20. Jaaro-Peled H, Sawa A. Neurodevelopmental Factors in Schizophrenia. Psychiatric Clinics of North America. 2020;43(2):263-274. [Crossref]  [PubMed]
  21. Davies C, Segre G, Estradé A, et al. Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2020;7(5):399-410. [Crossref]  [PubMed]
  22. Walker EF, Savoie T, Davis D. Neuromotor Precursors of Schizophrenia. Schizophr Bull. 1994;20(3):441-451. [Crossref]  [PubMed]
  23. Bora E. Neurodevelopmental origin of cognitive impairment in schizophrenia. Psychol Med. 2015;45(1):1-9. [Crossref]  [PubMed]
  24. Gamo NJ, Duque A, Paspalas CD, et al. Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction. Transl Psychiatry. 2013;3(12):e328-e328. [Crossref]  [PubMed]  [PMC]
  25. Bora E. Peripheral inflammatory and neurotrophic biomarkers of cognitive impairment in schizophrenia: a meta-analysis. Psychol Med. 2019;49(12):1971-1979. [Crossref]  [PubMed]
  26. North HF, Bruggemann J, Cropley V, et al. Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions. Eur Arch Psychiatry Clin Neurosci. 2021;271(4):595607. [Crossref]  [PubMed]
  27. Li Z. 40.2 DYSBINDIN-1 REGULATES DENDRITIC SPINE DEVELOPMENT DURING ADOLESCENCE. Schizophr Bull. 2019;45(Supplement_2):S153-S154. [Crossref]  [PMC]
  28. Xiu MH, Lang X, Chen DC, et al. Cognitive Deficits and Clinical Symptoms with Hippocampal Subfields in First-Episode and Never-Treated Patients with Schizophrenia. Cerebral Cortex. 2021;31(1):89-96. [Crossref]  [PubMed]
  29. Kruse AO, Bustillo JR. Glutamatergic dysfunction in Schizophrenia. Transl Psychiatry. 2022;12(1):500. [Crossref]  [PubMed]  [PMC]
  30. Bauminger H, Gaisler-Salomon I. Beyond NMDA Receptors: Homeostasis at the Glutamate Tripartite Synapse and Its Contributions to Cognitive Dysfunction in Schizophrenia. Int J Mol Sci. 2022;23(15):8617. [Crossref]  [PubMed]  [PMC]
  31. Arnsten AFT, Girgis RR, Gray DL, Mailman RB. Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry. 2017;81(1):67-77. [Crossref]  [PubMed]  [PMC]
  32. Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC. Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. American Journal of Psychiatry. 2022;179(9):611-627. [Crossref]  [PubMed]
  33. Recio-Barbero M, Segarra R, Zabala A, González-Fraile E, González-Pinto A, Ballesteros J. Cognitive Enhancers in Schizophrenia: A Systematic Review and Meta-Analysis of Alpha-7 Nicotinic Acetylcholine Receptor Agonists for Cognitive Deficits and Negative Symptoms. Front Psychiatry. 2021;12. [Crossref]  [PubMed]  [PMC]
  34. Georgiou R, Lamnisos D, Giannakou K. Anticholinergic Burden and Cognitive Performance in Patients With Schizophrenia: A Systematic Literature Review. Front Psychiatry. 2021;12. [Crossref]  [PubMed]  [PMC]
  35. King S, Mothersill D, Holleran L, et al. Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia. Transl Psychiatry. 2023;13(1):213. [Crossref]  [PubMed]  [PMC]
  36. Menon V, Palaniyappan L, Supekar K. Integrative Brain Network and Salience Models of Psychopathology and Cognitive Dysfunction in Schizophrenia. Biol Psychiatry. 2023;94(2):108-120. [Crossref]  [PubMed]
  37. Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-o-Methyltransferase, Cognition, and Psychosis: Val158Met and Beyond. Biol Psychiatry. 2006;60(2):141-151. [Crossref]  [PubMed]
  38. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences. 2001;98(12):6917-6922. [Crossref]  [PubMed]  [PMC]
  39. Krabbendam L. Schizophrenia and Urbanicity: A Major Environmental Influence--Conditional on Genetic Risk. Schizophr Bull. 2005;31(4):795-799. [Crossref]  [PubMed]
  40. Selten JP, van der Ven E, Termorshuizen F. Migration and psychosis: a meta-analysis of incidence studies. Psychol Med. 2020;50(2):303-313. [Crossref]  [PubMed]  [PMC]
  41. Hogerzeil SJ, van Hemert AM, Veling W, Hoek HW. Incidence of schizophrenia among migrants in the Netherlands: a direct comparison of first contact longitudinal register approaches. Soc Psychiatry Psychiatr Epidemiol. 2017;52(2):147-154. [Crossref]  [PubMed]  [PMC]
  42. Teicher MH, Anderson CM, Polcari A. Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proceedings of the National Academy of Sciences. 2012;109(9). [Crossref]  [PubMed]  [PMC]
  43. Aas M, Dazzan P, Mondelli V, Melle I, Murray RM, Pariante CM. A Systematic Review of Cognitive Function in First-Episode Psychosis, Including a Discussion on Childhood Trauma, Stress, and Inflammation. Front Psychiatry. 2014;4. [Crossref]  [PubMed]  [PMC]
  44. Georgiou R, Lamnisos D, Giannakou K. Anticholinergic Burden and Cognitive Performance in Patients With Schizophrenia: A Systematic Literature Review. Front Psychiatry. 2021;12. [Crossref]  [PubMed]  [PMC]
  45. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction. Biol Psychiatry. 2005;57(10):1117-1127. [Crossref]  [PubMed]
  46. Hagi K, Nosaka T, Dickinson D, et al. Association Between Cardiovascular Risk Factors and Cognitive Impairment in People With Schizophrenia. JAMA Psychiatry. 2021;78(5):510. [Crossref]  [PubMed]  [PMC]
  47. Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive Battery, Part 1: Test Selection, Reliability, and Validity. American Journal of Psychiatry. 2008;165(2):203-213. [Crossref]  [PubMed]
  48. Özak N, Hoşgelen EI, Akdede BB, Alptekin K. Reliability and validity study of the Turkish version of the Schizophrenia Cognition Rating Scale (SCoRS-TR). Asian J Psychiatr. 2024;102:104301. [Crossref]  [PubMed]
  49. Fikas K, Chwaliszewski K, Waz D, et al. Exploring the Therapeutic Role of Physical Activity in Psychotic Disorders: Cognitive, Somatic, and Mental Health Impacts. Quality in Sport. 2025;37:57744. [Crossref]
  50. Soldevila-Matías P, Sánchez-Ortí JV, Correa-Ghisays P, et al. Clinical outcomes and anti-inflammatory mechanisms predict maximum heart rate improvement after physical activity training in individuals with psychiatric disorders and comorbid obesity. PLoS One. 2025;20(1):e0313759. [Crossref]  [PubMed]  [PMC]
  51. Poul MK, Raji P, Gharib M, Faghihzadeh E. The Effectiveness of Volleyball Exercises on Cognitive Function and Daily Living Skills in Patients with Schizophrenia: A Randomized Clinical Trial. Journal of Iranian Medical Council. Published online January 30, 2025. [Crossref]  [PubMed]
  52. Adamowicz K, Mazur A, Mak M, Samochowiec J, Kucharska-Mazur J. Metabolic Syndrome and Cognitive Functions in Schizophrenia—Implementation of Dietary Intervention. Front Psychiatry. 2020;11. [Crossref]  [PubMed]  [PMC]
  53. Aucoin M, LaChance L, Clouthier SN, Cooley K. Dietary modification in the treatment of schizophrenia spectrum disorders: A systematic review. World J Psychiatry. 2020;10(8):187-201. [Crossref]  [PubMed]  [PMC]
  54. Goff DC, Hill M, Barch D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011;99(2):245-253. [Crossref]  [PubMed]  [PMC]
  55. Feber L, Peter NL, Chiocchia V, et al. Antipsychotic Drugs and Cognitive Function. JAMA Psychiatry. 2025;82(1):47. [Crossref]  [PubMed]  [PMC]
  56. Cheuk NKW, Tse W, Tsui HKH, et al. A systematic review and meta-analysis of the effect of clozapine on cognitive functions in patients with treatment-resistant schizophrenia. Schizophr Res. 2024;268:205-222. [Crossref]  [PubMed]
  57. Mantas I, Flais I, Branzell N, et al. A molecular mechanism mediating clozapine-enhanced sensorimotor gating. Neuropsychopharmacology. 2025;50(5):721-730. [Crossref]  [PubMed]  [PMC]
  58. Kawai *Shunya, Yoshimi A, Kato A, et al. EFFECT OF CLOZAPINE ON NEUROCOGNITIVE AND SOCIAL COGNITIVE FUNCTIONS IN A SCHIZOPHRENIA-LIKE MOUSE MODEL. International Journal of Neuropsychopharmacology. 2025;28(Supplement_1):i174-i175. [Crossref]  [PMC]
  59. Arsenault-Mehta K, Hochman-Bérard M, Johnson A, et al. Pharmacological management of neurocognitive impairment in schizophrenia: A narrative review. Neuropsychopharmacol Rep. 2024;44(1):2-16. [Crossref]  [PubMed]  [PMC]
  60. Neill E, Rossell SL, Yolland C, et al. N -Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms. Schizophr Bull. 2022;48(6):12631272. [Crossref]  [PubMed]  [PMC]
  61. Buonocore M, Spangaro M, Bechi M, et al. Integrated cognitive remediation and standard rehabilitation therapy in patients of schizophrenia: persistence after 5 years. Schizophr Res. 2018;192:335-339.
  62. García-Fernández L, Cabot-Ivorra N, Rodríguez-García V, et al. Computerized cognitive remediation therapy, REHACOM, in first episode of schizophrenia: A randomized controlled trial. Psychiatry Res. 2019;281. [Crossref]  [PubMed]
  63. Golas AC, Elgallab BM, Abdool PS, Bowie CR, Rajji TK. Cognitive remediation for patients with late-life schizophrenia: A follow-up pilot study. Int Psychogeriatr. 2025;37(2):100006.
  64. Primavera D, Migliaccio GM, Garau V, et al. Improving Quality of Life in Bipolar Disorders with an Immersive Virtual Reality Remediation Training Randomized Controlled Trial (RCT). J Clin Med. 2024;13(13):3886. [Crossref]  [PubMed]  [PMC]
  65. Güleken MD, Akbaş T, Erden SÇ, Akansel V, Al ZC, Özer ÖA. The effect of bilateral high frequency repetitive transcranial magnetic stimulation on cognitive functions in schizophrenia. Schizophr Res Cogn. 2020;22. [Crossref]  [PubMed]  [PMC]
  66. Li X, Dai J, Liu Q, Zhao Z, Zhang X. Efficacy and safety of non-invasive brain stimulation on cognitive function for cognitive impairment associated with schizophrenia: A systemat ic review and meta-analysis. J Psychiatr Res. 2024;170:174-186. [Crossref]  [PubMed]
  67. Han C. Editorial: Mechanism of neural oscillations and their relationship with multiple cognitive functions and mental disorders. Front Neurosci. 2025;18. [Crossref]  [PubMed]  [PMC]
  68. Hartmann JA, McGorry PD, Destree L, et al. Pluripotential Risk and Clinical Staging: Theoretical Considerations and Preliminary Data From a Transdiagnostic Risk Identification Approach. Front Psychiatry. 2021;11. [Crossref]  [PubMed]  [PMC]
  69. van der Gaag M, Nieman DH, Rietdijk J, et al. Cognitive Behavioral Therapy for Subjects at Ultrahigh Risk for Developing Psychosis: A Randomized Controlled Clinical Trial. Schizophr Bull. 2012;38(6):1180-1188. [Crossref]  [PubMed]  [PMC]
  70. Devoe DJ, Farris MS, Townes P, Addington J. Interventions and social functioning in youth at risk of psychosis: A systematic review and meta-analysis. Early Interv Psychiatry. 2019;13(2):169-180. [Crossref]  [PubMed]
  71. Frearson G, de Otazu Olivares J, Catalan A, Aymerich C, Salazar de Pablo G. Review: Efficacy of preventative interventions for children and adolescents at clinical high risk of psychosis – a systematic review and meta-analysis of intervention studies. Child Adolesc Ment Health. 2025;30(1):66-82. [Crossref]  [PubMed]  [PMC]
  72. Suvisaari J, Mantere O, Keinänen J, et al. Is It Possible to Predict the Future in First-Episode Psychosis? Front Psychiatry. 2018;9. [Crossref]  [PubMed]  [PMC]