PSİKİYATRİK BOZUKLUKLAR VE BİLİŞSEL İŞLEVLER

Psikiyatrik_Bozukluklar_ve_Bilissel_Islevler

BİLİŞSEL İŞLEV BOZUKLUKLARINA PSİKOFARMAKOLOJİK YAKLAŞIM

Ekin Atay

Kars Harakani Devlet Hastanesi, Psikiyatri Kliniği, Kars, Türkiye

Atay E. Bilişsel İşlev Bozukluklarına Psikofarmakolojik Yaklaşım. Aydemir Ö, Esen Danacı A, editörler. Psikiyatrik Bozukluklar ve Bilişsel İşlevler. 1. Baskı. Ankara: Türkiye Klinikleri; 2025. p.205-219.

ÖZET

Biliş, bilgiyi işleme, organize etme ve kullanma süreçlerini içerir. Dikkat, algı, anlama ve bellek gibi süreçleri kapsar ve motor becerilerle dışa vurulur. Bilişsel işlevlerdeki bozukluklar nörogelişimsel, nörodejeneratif, nöroenflamatuvar süreçlere bağlı görülebildiği gibi yorgunluk, uyku eksikliği gibi geçici fizyolojik durumlarda da görülebilir.

Dopaminerjik sistem, özellikle yürütücü işlevler ve motivasyon üzerinde önemli bir rol oynar. Dopamin reseptör agonistleri ve dopamin geri alım inhibitörleri, bilişsel işlevleri desteklemek amacıyla araştırılan ilaç grupları arasındadır. Stimulan ilaçlar (amfetamin, metilfenidat, modafinil) dikkat eksikliği ve hiperaktivite bozukluğu (DEHB) tedavisinde kullanılır. Sağlıklı bireylerde dikkat, bellek ve karar verme süreçlerini iyileştirdiği rapor edilmiştir. Şizofrenide psikostimülanlar önerilmezken, bipolar bozukluk ve travmatik beyin hasarında belirli durumlarda kullanılabilir. Dopaminerjik agonistler (pramipeksol gibi), Parkinson hastalığında motor semptomları iyileştirmek için kullanılır ve bazı çalışmalarda bilişsel işlevleri desteklediği görülmüştür. Ancak şizofreni ve bipolar bozuklukta çelişkili sonuçlar elde edilmiştir. Monoamin oksidaz B (MAO-B) inhibitörleri (selejilin gibi), Parkinson hastalığında kullanılan dopamin artırıcı ilaçlardır. Olası nöroprotektif etkilerine dair veriler bulunsa da bilişsel iyileştirme konusunda kesin kanıtlar yoktur.

Kolinerjik sistem de bilişsel süreçlerde önemlidir. Asetilkolin esteraz inhibitörleri (AChEI’ler), Alzheimer ve demans hastalarında bilişsel işlevleri desteklemek için kullanılır. Sağlıklı bireylerde bilişsel iyileştirme açısından etkileri sınırlıdır. Şizofreni, bipolar bozukluk ve travmatik beyin hasarında etkileri belirsizdir. Galantamin gibi a7 nikotinik reseptör agonistleri belirli durumlarda fayda sağlayabilir ancak genel olarak bu ilaçların sağlıklı bireylerde kullanımı henüz kesin bir bilimsel temele dayanmamaktadır. Muskarinik reseptör agonistleri ise şizofrenide bilişsel işlevlere faydasının yanında pozitif ve negatif belirtilere de etkili ajanlar olarak tekli antipsikotik tedavi alternatifleri olması hedefiyle araştırılmaktadır ancak demans, bipolar bozukluk gibi hasta gruplarında ve sağlıklı popülasyonda bilişsel iyileştirme amacıyla kullanımına dair çalışmalar henüz yetersizdir.

Glutamat, öğrenme ve hafıza süreçlerinde kritik rol oynayan bir nörotransmitterdir. Aşırı glutamat salınımı ise hücre ölümüne sebep olmaktadır. Bu bağlamda, glutamaterjik sistemi hedefleyen ilaçlar bilişsel işlevlerin desteklenmesi açısından önem taşır. Memantin yarışmasız bir N-metil D-aspartat (NMDA) reseptör antagonistidir ve glutamat tarafından aşırı uyarımı kontrol eder. Memantinin nörodejeneratif süreçte etkili olabileceği ve bilişsel işlevlerde iyileşme sağlayabileceği düşünülmektedir. Şizofrenide antipsikotik tedaviye memantin eklenmesiyle negatif belirtilerde gerileme ve bilişsel işlevler üzerine olumlu etkiler saptanmıştır. NMDA reseptör modülatörleri de şizofreni ve demans gruplarında bilişsel işlevler üzerine olumlu etkiler gösterebilmektedir.

Antipsikotikler ve antidepresanlar da bilişsel işlevler üzerine daha az olumsuz etki gösterenler ve küçük de olsa olumlu etki gösterenler şeklinde bilişsel iyileştirim önerileri olarak kılavuzlarda kendilerine yer bulmaktadır. Özellikle seçici serotonin geri alım inhibitörleri (SSRI), serotonin-norepinefrin geri alım inhibitörleri (SNRI) gibi antidepresanlar ve lurasidon, kariprazin, brexpiprazol, lumateperon gibi yakın zamanda geliştirilen antipsikotikler lehine henüz yeterli düzeye ulaşmamış kanıtlar mevcuttur.

Eritropoetin, intranazal insülin, sosyal biliş üzerine etkileri açısından intranazal oksitosin, Hint ginsengi ve pregnonolon ise bilişsel işlevler üzerine olumlu etkiler bildirilen ancak henüz yeterli kanıt düzeyine ulaşılamayan diğer moleküllerdir.

Anahtar Kelimeler: Bilişsel disfonksiyon; Nörobilişsel bozukluklar; Kognitif geliştiriciler; Dopamin agonistleri; Kolinerjik ajanlar; NMDA reseptörleri; Nöroinflamasyon; Nöron dejenerasyonu

Referanslar

  1. Floresco SB, Magyar O. Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology (Berl). 2006;188(4):567-85. [Crossref]  [PubMed]
  2. Berridge KC. The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology (Berl). 2007;191(3):391-431. [Crossref]  [PubMed]
  3. Schultz W. Multiple dopamine functions at different time courses. Annu Rev Neurosci. 2007;30:259-88. [Crossref]  [PubMed]
  4. Wickens JR, Horvitz JC, Costa RM, Killcross S. Dopaminergic mechanisms in actions and habits. J Neurosci. 2007;27(31):8181-3. [Crossref]  [PubMed]  [PMC]
  5. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68(5):815-34. [Crossref]  [PubMed]  [PMC]
  6. Berke JD. What does dopamine mean? Nat Neurosci. 2018;21(6):787-93. [Crossref]  [PubMed]  [PMC]
  7. Morales M, Margolis EB. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci. 2017;18(2):73-85. [Crossref]  [PubMed]
  8. Ren J, Xu H, Choi JK, Jenkins BG, Chen YI. Dopaminergic response to graded dopamine concentration elicited by four amphetamine doses. Synapse. 2009;63(9):764-72. [Crossref]  [PubMed]  [PMC]
  9. Avelar AJ, Juliano SA, Garris PA. Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem. 2013;125(3):373-85. [Crossref]  [PubMed]  [PMC]
  10. Floor E, Meng L. Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett. 1996;215(1):53-6. [Crossref]  [PubMed]
  11. Kuczenski R, Segal DS. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem. 1997;68(5):2032-7. [Crossref]  [PubMed]
  12. Coghill D, Banaschewski T, Cortese S, Asherson P, Brandeis D, Buitelaar J, et al. The management of ADHD in children and adolescents: bringing evidence to the clinic: perspective from the European ADHD Guidelines Group (EAGG). Eur Child Adolesc Psychiatry. 2023;32(8):1337-61. [Crossref]  [PubMed]  [PMC]
  13. Wolraich ML, Hagan JF, Allan C, Chan E, Davison D, Earls M, et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019;144(4). [Crossref]  [PubMed]
  14. Faraone S V, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. Eur Child Adolesc Psychiatry. 2010;19(4):353-64. [Crossref]  [PubMed]
  15. Faraone S V. The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018;87:255-70,. [Crossref]  [PubMed]  [PMC]
  16. Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-38. [Crossref]  [PubMed]  [PMC]
  17. Coghill DR, Banaschewski T, Soutullo C, Cottingham MG, Zuddas A. Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry. 2017;26(11):1283-307. [Crossref]  [PubMed]  [PMC]
  18. Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015;2015(11).
  19. Hennissen L, Bakker MJ, Banaschewski T, Carucci S, Coghill D, Danckaerts M, et al. Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine. CNS Drugs. 2017;31(3):199-215. [Crossref]  [PubMed]  [PMC]
  20. Shin JY, Roughead EE, Park BJ, Pratt NL. Cardiovascular safety of methylphenidate among children and young people with attention-deficit/hyperactivity disorder (ADHD): nationwide self controlled case series study. BMJ. 2016;353. [Crossref]  [PubMed]  [PMC]
  21. Storebø OJ, Pedersen N, Ramstad E, Kielsholm ML, Nielsen SS, Krogh HB, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents assessment of adverse events in non-randomised studies. Cochrane Database Syst Rev. 2018;5(5). [Crossref]  [PubMed]  [PMC]
  22. Shyu YC, Yuan SS, Lee SY, Yang CJ, Yang KC, Lee TL, et al. Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan. Schizophr Res. 2015;168(1-2):161-7. [Crossref]  [PubMed]
  23. Carucci S, Balia C, Gagliano A, Lampis A, Buitelaar JK, Danckaerts M, et al. Long term methylphenidate exposure and growth in children and adolescents with ADHD. A sys tematic review and meta-analysis. Neurosci Biobehav Rev. 2021;120:509-25. [Crossref]  [PubMed]
  24. Sahakian B, Morein-Zamir S. Professor’s little helper. Nature. 2007;450(7173):1157-9. [Crossref]  [PubMed]
  25. Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, et al. Towards responsible use of cognitive-enhancing drugs by the healthy. Nature. 2008;456(7223):702-5. [Crossref]  [PubMed]
  26. Avelar AJ, Cao J, Newman AH, Beckstead MJ. Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons. Neuropharmacology. 2017;123:410-9. [Crossref]  [PubMed]  [PMC]
  27. Cao J, Slack RD, Bakare OM, Burzynski C, Rais R, Slusher BS, et al. Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors. J Med Chem. 2016;59(23):10676-91. [Crossref]  [PubMed]  [PMC]
  28. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol. 2000;14(1):53-60. [Crossref]  [PubMed]
  29. Battleday RM, Brem AK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review. Eur Neuropsychopharmacol. 2015;25(11):1865-81. [Crossref]  [PubMed]
  30. Roberts CA, Jones A, Sumnall H, Gage SH, Montgomery C. How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine. Eur Neuropsychopharmacol. 2020;38:40-62. [Crossref]  [PubMed]
  31. Maier LJ, Liechti ME, Herzig F, Schaub MP. To dope or not to dope: neuroenhancement with prescription drugs and drugs of abuse among Swiss university students. PLoS One. 2013;8(11). [Crossref]  [PubMed]  [PMC]
  32. Micoulaud Franchi J-A, MacGregor A, Fond G. A preliminary study on cognitive enhancer consumption behaviors and motives of French Medicine and Pharmacology students. Eur Rev Med Pharmacol Sci. 2014;18:1875-8.
  33. Agay N, Yechiam E, Carmel Z, Levkovitz Y. Methylphenidate enhances cognitive performance in adults with poor baseline capacities regardless of attention-deficit/hyperactivity disorder diagnosis. J Clin Psychopharmacol. 2014;34(2):261-5. [Crossref]
  34. Ilieva IP, Hook CJ, Farah MJ. Prescription Stimulants’ Effects on Healthy Inhibitory Control, Working Mem ory, and Episodic Memory: A Meta-analysis. J Cogn Neurosci. 2015;27(6):1069-89. [Crossref]  [PubMed]
  35. Marraccini ME, Weyandt LL, Rossi JS, Gudmundsdottir BG. Neurocognitive enhancement or impairment? A systematic meta-analysis of prescription stimulant effects on processing speed, decision-making, planning, and cognitive perseveration. Exp Clin Psychopharmacol. 2016;24(4):269-84. [Crossref]  [PubMed]  [PMC]
  36. Vita A, Gaebel W, Mucci A, Sachs G, Barlati S, Giordano GM, et al. European Psychiatric Association guidance on treatment of cognitive impairment in schizophrenia. Eur Psychiatry. 2022;65(1). [Crossref]  [PubMed]  [PMC]
  37. Solmi M, Fornaro M, Toyoshima K, Carvalho AF, Köhler CA, Veronese N, et al. Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder. CNS Spectr. 2019;24(5):479-95. [Crossref]  [PubMed]
  38. Yatham LN, Kennedy SH, Parikh S V, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170, [Crossref]
  39. Miskowiak KW, Obel ZK, Guglielmo R, Bonnin C del M, Bowie CR, Balanzá-Martínez V, et al. Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force. Bipolar Disord. 2024;26(3):216-39. [Crossref]  [PubMed]
  40. van der Veen R, Königs M, Bakker S, van Iperen A, Peerdeman S, Bet PM, et al. Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression. Clin Pharmacol Ther. 2024;115(5):971-87. [Crossref]  [PubMed]
  41. Varga LI, Ako-Agugua N, Colasante J, Hertweck L, Houser T, Smith J, et al. Critical review of ropinirole and pramipexole putative dopamine D(3)-receptor selective agonists for the treatment of RLS. J Clin Pharm Ther. 2009;34(5):493-505. [Crossref]  [PubMed]
  42. Burdick KE, Braga RJ, Nnadi CU, Shaya Y, Stearns WH, Malhotra AK. Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting cognitive dysfunction. J Clin Psychiatry. 2012;73(1):103-12. [Crossref]  [PubMed]  [PMC]
  43. Van Meter AR, Perez-Rodriguez MM, Braga RJ, Shanahan M, Hanna L, Malhotra AK, et al. Pramipexole to Improve Cognition in Bipolar Disorder: A Randomized Controlled Trial. J Clin Psychopharmacol. 2021;41(4):421-7. [Crossref]  [PubMed]  [PMC]
  44. Kelleher JP, Centorrino F, Huxley NA, Bates JA, Drake JK, Egli S, et al. Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment. Eur Neuropsychopharmacol. 2012;22(6):415-8. [Crossref]  [PubMed]
  45. Girgis RR, Van Snellenberg JX, Glass A, Kegeles LS, Thompson JL, Wall M, et al. A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. J Psychopharmacol. 2016;30(5):428-35. [Crossref]  [PubMed]
  46. Hsu WY, Lane HY, Lin CH. Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer’s Disease, and Parkinson’s Disease. Front Psychiatry. 2018;9(APR). [Crossref]  [PubMed]  [PMC]
  47. Heinonen EH, Lammintausta R. A review of the pharmacology of selegiline. Acta Neurol Scand Suppl. 1991;136(136 S):44-59. [Crossref]  [PubMed]
  48. Alborghetti M, Bianchini E, De Carolis L, Galli S, Pontieri FE, Rinaldi D. Type-B monoamine oxidase inhibitors in neurological diseases: clinical applications based on preclinical findings. Neural Regen Res. 2023;19(1):16. [Crossref]  [PubMed]  [PMC]
  49. Rossano F, Caiazza C, Sobrino A, Solini N, Vellucci A, Zotti N, et al. Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations. Eur Neuropsychopharmacol. 2023;72:60-78. [Crossref]  [PubMed]
  50. Hasselmo ME. The role of acetylcholine in learning and memory. Curr Opin Neurobiol. 2006;16(6):710-5. [Crossref]  [PubMed]  [PMC]
  51. Newman EL, Gupta K, Climer JR, Monaghan CK, Hasselmo ME. Cholinergic modulation of cognitive processing: insights drawn from computational models. Front Behav Neurosci. 2012;6(JUNE), FNBEH.2012.00024 [Crossref]
  52. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;2006(1). [Crossref]  [PubMed]
  53. Repantis D, Laisney O, Heuser I. Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010;61(6):473-81. [Crossref]  [PubMed]
  54. Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, et al. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ. 2013;185(16):1393-401. [Crossref]  [PubMed]  [PMC]
  55. Sinkeviciute I, Begemann M, Prikken M, Oranje B, Johnsen E, Lei WU, et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis. NPJ Schizophr. 2018;4(1). [Crossref]  [PubMed]  [PMC]
  56. Singh J, Kour K, Jayaram MB. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst Rev. 2012;1(1). [Crossref]  [PubMed]  [PMC]
  57. Koola MM, Looney SW, Hong H, Pillai A, Hou W. Meta-analysis of randomized controlled trials of galantamine in schizophrenia: significant cognitive enhancement. Psychiatry Res. 2020;291. [Crossref]  [PubMed]
  58. Lewis AS, van Schalkwyk GI, Bloch MH. Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies. Prog Neuropsychopharmacol Biol Psychiatry. 2017;75:45-53. [Crossref]  [PubMed]  [PMC]
  59. 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]
  60. Veronese N, Solmi M, Luchini C, Lu RB, Stubbs B, Zaninotto L, et al. Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions. J Affect Disord. 2016;197:268-80. [Crossref]  [PubMed]
  61. Ghaemi SN, Gilmer WS, Dunn RT, Hanlon RE, Kemp DE, Bauer AD, et al. A double-blind, placebo-controlled pilot study of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder. J Clin Psychopharmacol. 2009;29(3):291-5. [Crossref]  [PubMed]
  62. Iosifescu D V, Moore CM, Deckersbach T, Tilley CA, Ostacher MJ, Sachs GS, et al. Galantamine-ER for cognitive dysfunction in bipolar disorder and correlation with hippocampal neuronal viability: a proof-of-concept study. CNS Neurosci Ther. 2009;15(4):309-19. [Crossref]  [PubMed]  [PMC]
  63. Matthews JD, Siefert CJ, Blais MA, Park LT, Siefert CJ, Welch CA, et al. A double-blind, placebo-controlled study of the impact of galantamine on anterograde memory impairment during electroconvulsive therapy. J ECT. 2013;29(3):170-8. [Crossref]  [PubMed]
  64. Dean B, Bakker G, Ueda HR, Tobin AB, Brown A, Kanaan RAA. A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia. Front Cell Neurosci. 2023;17. [Crossref]  [PubMed]  [PMC]
  65. Bakker G, Vingerhoets C, Boucherie D, Caan M, Bloemen O, Eersels J, et al. Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis. Neuroimage Clin. 2018;18:713-9. [Crossref]  [PubMed]  [PMC]
  66. Kaul I, Sawchak S, Correll CU, Kakar R, Breier A, Zhu H, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-70. [Crossref]  [PubMed]
  67. Sauder C, Allen LA, Baker E, Miller AC, Paul SM, Brannan SK. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Transl Psychiatry. 2022;12(1). [Crossref]  [PubMed]  [PMC]
  68. U.S. Food and Drug Administration Namenda (Memantine HCI) approval letter. (2003).
  69. Kishi T, Matsunaga S, Iwata N. The effects of memantine on behavioral disturbances in patients with Alzheimer’s disease: a meta-analysis. Neuropsychiatr Dis Treat. 2017;13:1909-28. [Crossref]  [PubMed]  [PMC]
  70. Zheng W, Li XH, Yang XH, Cai DB, Ungvari GS, Ng CH, et al. Adjunctive memantine for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Psychol Med. 2018;48(1):72-81. [Crossref]  [PubMed]
  71. Zheng W, Zhu XM, Zhang QE, Cai D Bin, Yang XH, Zhou YL, et al. Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials. Schizophr Res. 2019;209:12-21. [Crossref]  [PubMed]
  72. Murthy V, Hanson E, DeMartinis N, Asgharnejad M, Dong C, Evans R, et al. INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia. Schizophr Res. 2024;270:249-57. [Crossref]  [PubMed]
  73. Chengappa KNR, Turkin SR, DeSanti S, Bowie CR, Brar JS, Schlicht PJ, et al. A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia. Schizophr Res. 2012;142(1–3):145-52, [Crossref]
  74. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70(12):1267-75. [Crossref]  [PubMed]
  75. Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF, et al. High dose D-serine in the treatment of schizophrenia. Schizophr Res. 2010;121(1–3):125-30. [Crossref]  [PubMed]  [PMC]
  76. Chang CH, Lane HY, Tseng PT, Chen SJ, Liu CY, Lin CH. Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials. J Psychopharmacol. 2019;33(4):436-48. [Crossref]  [PubMed]
  77. Chang CH, Liu CY, Chen SJ, Tsai HC. Effect of N-meth yl-D-aspartate receptor enhancing agents on cognition in dementia: an exploratory systematic review and meta-analysis of randomized controlled trials. Sci Rep. 2021;11(1). [Crossref]  [PubMed]  [PMC]
  78. Keefe RSE, McClintock SM, Roth RM, Murali Doraiswamy P, Tiger S, Madhoo M. Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(8):864-76. [Crossref]  [PubMed]
  79. Baldessarini RJ, Vázquez GH, Tondo L. Bipolar depression: a major unsolved challenge. Int J Bipolar Disord. 2020;8(1), [Crossref]
  80. Wang GHM, Li P, Wang Y, Guo J, Wilson DL, Lo-Ciganic WH. Association between Antidepressants and Dementia Risk in Older Adults with Depression: A Systematic Review and Meta-Analysis. J Clin Med. 2023;12(19). [Crossref]  [PubMed]  [PMC]
  81. Niitsu T, Fujisaki M, Shiina A, Yoshida T, Hasegawa T, Kanahara N, et al. A randomized, double-blind, placebo-controlled trial of fluvoxamine in patients with schizophrenia: a preliminary study. J Clin Psychopharmacol. 2012;32(5):593-601. [Crossref]  [PubMed]
  82. Haji Seyed Javadi A, Shafikhani AA, Zamir SM, Khanshir ZF. Evaluation of the Effect of Fluvoxamine in Patients With Schizophrenia Under Risperidone Treatment: A Clinical Trial. J Clin Psychopharmacol. 2018;38(2):119-24. [Crossref]  [PubMed]
  83. Perry LA, Ramson D, Stricklin S. Mirtazapine adjunct for people with schizophrenia. Cochrane Database Syst Rev. 2018;5(5). [Crossref]  [PubMed]  [PMC]
  84. Vernon JA, Grudnikoff E, Seidman AJ, Frazier TW, Vemulapalli MS, Pareek P, et al. Antidepressants for cognitive impairment in schizophrenia--a systematic review and meta-analysis. Schizophr Res. 2014;159(2-3):385-94. [Crossref]  [PubMed]  [PMC]
  85. Baldez DP, Biazus TB, Rabelo-da-Ponte FD, Nogaro GP, Martins DS, Kunz M, et al. The effect of antipsychotics on the cognitive performance of individuals with psychotic disorders: Network meta-analyses of randomized controlled trials. Neurosci Biobehav Rev. 2021;126:265-75. [Crossref]  [PubMed]
  86. Désaméricq G, Schurhoff F, Meary A, Szöke A, Macquin-Mavier I, Bachoud-Lévi AC, et al. Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis. Eur J Clin Pharmacol. 2014;70(2):127-34. [Crossref]  [PubMed]
  87. Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SOW, Østergaard Christensen T, Leucht S. Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials. Acta Psychiatr Scand. 2015;131(3):185-96. [Crossref]  [PubMed]
  88. Clissold M, Crowe SF. Comparing the effect of the subcat egories of atypical antipsychotic medications on cognition in schizophrenia using a meta-analytic approach. J Clin Exp Neuropsychol. 2019;41(1):26-42.3803395.2018.1488952 [Crossref]  [PubMed]
  89. Ohi K, Muto Y, Sugiyama S, Shioiri T. Safety and Efficacy in Randomized Controlled Trials of Second-Generation Antipsychotics Versus Placebo for Cognitive Impairments in Schizophrenia: A Meta-Analysis. J Clin Psychopharmacol. 2022;42(2):227-9. [Crossref]  [PubMed]
  90. Corponi F, Fabbri C, Bitter I, Montgomery S, Vieta E, Kasper S, et al. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur Neuropsychopharmacol. 2019;29(9):971-85. [Crossref]  [PubMed]
  91. Olivola M, Bassetti N, Parente S, Arienti V, Civardi SC, Topa PA, et al. Cognitive Effects of Lurasidone and Cariprazine: A Mini Systematic Review. Curr Neuropharmacol. 2023;21(12):2431-46. [Crossref]  [PubMed]  [PMC]
  92. Solé B, Jiménez E, Torrent C, Reinares M, Del Mar Bonnin C, Torres I, et al. Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies. Int J Neuropsychopharmacol. 2017;20(8):670-80. [Crossref]  [PubMed]  [PMC]
  93. Yatham LN, Mackala S, Basivireddy J, Ahn S, Walji N, Hu C, et al. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. Lancet Psychiatry. 2017;4(3):208-17. [Crossref]  [PubMed]
  94. Sirén AL, Ehrenreich H. Erythropoietin--a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci. 2001;251(4):179-84. [Crossref]  [PubMed]
  95. Sirén AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001;98(7):4044-9. [Crossref]  [PubMed]  [PMC]
  96. Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A. 1998;95(8):4635-40. [Crossref]  [PubMed]  [PMC]
  97. Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S, et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry. 2007;12(2):206-20. [Crossref]  [PubMed]
  98. Pedroso I, Bringas Vega ML, Aguiar A, Morales L, Álvarez M, Valdés PA, et al. Use of Cuban recombinant human erythropoietin in Parkinson’s disease treatment. MEDICC Rev. 2012;14(1):11-7. [Crossref]  [PubMed]
  99. Jang W, Park J, Shin KJ, Kim JS, Kim JS, Youn J, et al. Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson’s disease. J Neurol Sci. 2014;337(1-2):47-54. [Crossref]  [PubMed]
  100. Sosa S, Bringas G, Urrutia N, Peñalver AI, López D, González E, et al. NeuroEPO plus (NeuralCIM®) in mild-to-moderate Alzheimer’s clinical syndrome: the ATHENEA randomized clinical trial. Alzheimers Res Ther. 2023;15(1). [Crossref]  [PubMed]
  101. Miskowiak KW, Ehrenreich H, Christensen EM, Kessing L V, Vinberg M. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. J Clin Psychiatry. 2014;75(12):1347-55. [Crossref]  [PubMed]
  102. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2013;47(1):145-71. [Crossref]  [PubMed]
  103. Lewis GF, Carpentier AC, Pereira S, Hahn M, Giacca A. Direct and indirect control of hepatic glucose production by insulin. Cell Metab. 2021;33(4):709-20. [Crossref]  [PubMed]
  104. Ferrario CR, Reagan LP. Insulin-mediated synaptic plasticity in the CNS: Anatomical, functional and temporal contexts. Neuropharmacology. 2018;136(Pt B):182-91. [Crossref]  [PubMed]  [PMC]
  105. Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16(11):660-71. [Crossref]  [PubMed]
  106. Feldman DE. Synaptic mechanisms for plasticity in neocortex. Annu Rev Neurosci. 2009;32:33-55. [Crossref]  [PubMed]  [PMC]
  107. Wozniak M, Rydzewski B, Baker SP, Raizada MK. The cellular and physiological actions of insulin in the central nervous system. Neurochem Int. 1993;22(1):1-10. [Crossref]  [PubMed]
  108. Mcintyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, Macqueen G, et al. A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord. 2012;14(7):697-706. [Crossref]  [PubMed]
  109. Fan X, Liu E, Freudenreich O, Copeland P, Hayden D, Ghebremichael M, et al. No effect of adjunctive, repeated-dose intranasal insulin treatment on psychopathology and cognition in patients with schizophrenia. J Clin Psychopharmacol. 2013;33(2):226-30. [Crossref]  [PubMed]  [PMC]
  110. Cha DS, Best MW, Bowie CR, Gallaugher LA, Woldeyohannes HO, Soczynska JK, et al. A randomized, double-blind, placebo-controlled, crossover trial evaluating the effect of intranasal insulin on cognition and mood in individuals with treatment-resistant major depressive disorder. J Affect Disord. 2017;210:57-65. [Crossref]  [PubMed]
  111. Wu S, Stogios N, Hahn M, Navagnanavel J, Emami Z, Chintoh A, et al. Outcomes and clinical implications of intranasal insulin on cognition in humans: A systematic review and meta-analysis. PLoS One. 2023;18(6). [Crossref]  [PubMed]  [PMC]
  112. Sue Carter C. Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology. 1998;23(8):779818.
  113. Young LJ, Barrett CE. Neuroscience. Can oxytocin treat autism? Science. 2015;347(6224):825-56. [Crossref]  [PubMed]  [PMC]
  114. Hammock EAD. Developmental perspectives on oxytocin and vasopressin. Neuropsychopharmacology. 2015;40(1):24-42.
  115. Keech B, Crowe S, Hocking DR. Intranasal oxytocin, social cognition and neurodevelopmental disorders: A meta-analysis. Psychoneuroendocrinology. 2018;87:9-19. [Crossref]  [PubMed]
  116. Pedersen CA, Gibson CM, Rau SW, Salimi K, Smedley KL, Casey RL, et al. Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia. Schizophr Res. 2011;132(1):50-3. [Crossref]  [PubMed]
  117. Gibson CM, Penn DL, Smedley KL, Leserman J, Elliott T, Pedersen CA. A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia. Schizophr Res. 2014;156(2-3):261-5. [Crossref]  [PubMed]
  118. Davis MC, Lee J, Horan WP, Clarke AD, McGee MR, Green MF, et al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res. 2013;147(23):393-7. [Crossref]  [PubMed]
  119. Lee MR, Wehring HJ, McMahon RP, Liu F, Linthicum J, Buchanan RW, et al. The Effect of Intranasal Oxytocin on Measures of Social Cognition in Schizophrenia: A Negative Report. J Psychiatr Brain Sci. 2019;4(1). [Crossref]  [PubMed]  [PMC]
  120. Jarskog LF, Pedersen CA, Johnson JL, Hamer RM, Rau SW, Elliott T, et al. A 12-week randomized controlled trial of twice-daily intranasal oxytocin for social cognitive deficits in people with schizophrenia. Schizophr Res. 2017;185:8895, [Crossref]
  121. Young AH, Gallagher P, Watson S, Del-Estal D, Owen BM, Ferrier IN. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychophar macology. 2004;29(8):1538-45.
  122. Watson S, Gallagher P, Porter RJ, Smith MS, Herron LJ, Bulmer S, et al. A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression. Biol Psychiatry. 2012;72(11):943-9. [Crossref]  [PubMed]
  123. Gallagher P, Watson S, Smith MS, Ferrier IN, Young AH. Effects of adjunctive mifepristone (RU-486) administration on neurocognitive function and symptoms in schizophrenia. Biol Psychiatry. 2005;57(2):155-61. [Crossref]  [PubMed]
  124. Çakici N, Van Beveren NJM, Judge-Hundal G, Koola MM, Sommer IEC. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med. 2019;49(14):2307-19. [Crossref]  [PubMed]  [PMC]
  125. Cho M, Lee TY, Kwak Y Bin, Yoon YB, Kim M, Kwon JS. Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials. Aust N Z J Psychiatry. 2019;53(8):742-59.
  126. Weiser M, Levi L, Burshtein S, Chiriță R, Cirjaliu D, Gonen I, et al. The effect of minocycline on symptoms in schizophrenia: Results from a randomized controlled trial. Schizophr Res. 2019;206:325-32. [Crossref]  [PubMed]
  127. Chengappa KNR, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013;74(11):1076-83. [Crossref]  [PubMed]
  128. Chengappa KNR, Brar JS, Gannon JM, Schlicht PJ. Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. 2018;79(5). [Crossref]  [PubMed]
  129. Pingali U, Pilli R, Fatima N. Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy Res. 2014;6(1):12-8.
  130. Choudhary D, Bhattacharyya S, Bose S. Efficacy and Safety of Ashwagandha (Withania somnifera (L.) Dunal) Root Extract in Improving Memory and Cognitive Functions. J Diet Suppl. 2017;14(6):599-612.11.2017.1284970 [Crossref]  [PubMed]