Combination Therapy of Deferiprone and N-Acetylcysteine for Treating Negative Symptoms in Schizophrenia

NCT07759895 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: 0239-24-HMOIsrael Innovation Authority
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 2

Brief Summary

In following guidelines for studying negative symptoms in schizophrenia, 60 patients aged 18-40, diagnosed with schizophrenia or schizoaffective disorder during the last ten years, will receive a combination of the iron chelator DFP plus NAC or a matching placebo plus NAC combination, as add-on to their maintenance antipsychotic drug (APD) treatment, for a duration of 36 weeks. Prior to initiation of treatment, all participants will undergo baseline MRI scan. A follow-up MRI will be conducted at the end of the 36-week study period, or upon early withdrawal if applicable, to evaluate the effect of the add-on treatment on iron dyshomeostasis and morphology.

Conditions

Schizoaffecitve Disorder; Schizophrenia and Schizoaffective Disorder; Schizophrenia and Predominant Negative Symptoms

Keywords

Deferiprone; N-acetylcysteine; Schizophrenia; Clinical Trial; negative symptoms

Outcome Measures

Primary Outcomes (1)

• Change in Total PANSS Score

  Change from Baseline to Week 36 in the PANSS (Positive and Negative Syndrome Scale) total score. PANSS total score range: 30 to 210 (30 items, each rated 1-7, so minimum 30 and maximum 210). Higher scores indicate more severe symptoms.

  36 Weeks (LOCF)

Secondary Outcomes (37)

• PANSS Marder Negative Symptom Factor Score

  12, 24 and 36 weeks

• PANSS Positive Subscale Score

  12, 24 and 36 weeks

• PANSS Negative Subscale Score

  12, 24 and 36 weeks

• PANSS General Psychopathological Subscale Score

  12, 24 and 36 weeks

• BNSS (Brief Negative Symptom Scale) Score

  12, 24 and 36 weeks

Other Outcomes (7)

• Proportion of patients showing a PANSS response of ≥30% reduction

  12, 24 and 36 weeks

• CDSS (Calgary Depression Scale for Schizophrenia) Scale

  12, 24 and 36 weeks

• CGI-Schizophrenia (CGI-SCH) : Negative Symptoms Severity of Illness sub-scale

  12, 24 and 36 weeks

Study Arms (2)

Placebo + N-Acetylcysteine

PLACEBO COMPARATOR

Drug: N-Acetyl Cysteine (NAC)

Deferiprone + N-Acetylcysteine

ACTIVE COMPARATOR

Drug: Deferiprone (DFP); Drug: N-Acetyl Cysteine (NAC)

Interventions

Deferiprone (DFP) DRUG

This intervention has not been used before on Schizophrenia or Schizoaffective patients with predominant negative symptoms.

Deferiprone + N-Acetylcysteine

N-Acetyl Cysteine (NAC) DRUG

This drug is given to both groups.

Deferiprone + N-Acetylcysteine; Placebo + N-Acetylcysteine

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Aged 18-55 years.
• Diagnosis of schizophrenia/schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders- Fifth Edition (DSM-5) criteria. The diagnostic assessment will be conducted using the Structured Clinical Interview for DSM-5 Clinical Trials Version (SCID-5-CT).
• Adequate antipsychotic treatment for ≥ 4 months prior to screening (excluding clozapine use).
• Stable dose of antipsychotic medication for ≥ 8 weeks prior to screening (excluding clozapine use).
• When relevant, stable dose of antidepressants, mood stabilizers and benzodiazepines/Z-drugs for ≥ 8 weeks prior to screening.
• Screening and baseline PANSS total score ranging from 60 to 120.
• Sum ≥ 20 for the 7 items in the Negative Symptoms subscale of the PANSS.
• At least two items in the PANSS Negative Symptoms subscale scored ≥ 4.
• Sum \< 20 for the 7 items in the Positive Symptoms subscale of the PANSS.
• Score ≤ 5 for each item in the Positive Symptoms subscale of the PANSS.
• Calgary Depression Schizophrenia Scale (CDSS) score of ≤ 6.
• Persistent and predominant negative symptoms for ≥ 6 months, in the opinion of the investigator
• The subject exhibits clinical stability in both positive and negative symptoms of schizophrenia over the past 6 months, as assessed by the treating psychiatrist and supported by documentation in the medical record.
• No incarceration in prison or acute crisis intervention due to symptom exacerbation within 6 months of screening. The subject must be considered psychiatrically stable in the opinion of the investigator.
• For males or postmenopausal women, either of the following:

You may not qualify if:

• Primary DSM-5 diagnosis other than schizophrenia or schizoaffective disorder in the 12 months prior to screening, according to SCID-5-CT.
• Subjects diagnosed with Autistic Spectrum Disorder (ASD).
• Subjects diagnosed with Intellectual Developmental Disorder.
• Patients who received clozapine within the 6 months preceding the screening.
• Patients with a history of relapsing neutropenia (Absolute Neutrophile Count (ANC) \< 1,500 cells/µL)
• Screening ANC ≤ 2,000 cells/µL.
• Non-compliance during run-in period (percent adherence ≤ 80%, as examined by pill count).
• Improvement \> 20% in PANSS total score or PANSS negative subscale during the run-in period.
• Suicide attempt or serious suicidal behavior within the past 12 months.
• Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS).
• The subject has a history of substance use disorder or any illicit drug use (other than nicotine) within the past 3 years.
• Positive urine drug screen for drugs of abuse (cocaine, methadone, amphetamines, cannabinoids, opiates, and barbiturates).
• Risk of violent behavior in the opinion of the Investigator.
• Known hypersensitivity to deferiprone or N-Acetylcysteine.
• Pregnancy or intention to become pregnant during the study duration.

Sponsors & Collaborators

• Amit Lotan: lead
• Hadassah Medical Organization: collaborator
• Jerusalem Mental Health Center: collaborator
• Hebrew University of Jerusalem: collaborator

Study Sites (2)

Hadassah Medical Organization

Jerusalem, Israel

Location

Jerusalem Mental Health Center

Jerusalem, Israel

Location

Related Publications (78)

• Beebe LH, Smith K. Informed consent to research in persons with schizophrenia spectrum disorders. Nurs Ethics. 2010 Jul;17(4):425-34. doi: 10.1177/0969733010364581.

  PMID: 20610576 BACKGROUND

• Janno S, Holi MM, Tuisku K, Wahlbeck K. Validity of Simpson-Angus Scale (SAS) in a naturalistic schizophrenia population. BMC Neurol. 2005 Mar 17;5(1):5. doi: 10.1186/1471-2377-5-5.

  PMID: 15774006 BACKGROUND

• Blanchet PJ, Rompre PH. Clinimetric evaluation of the Simpson-Angus Scale in older adults with schizophrenia. J Clin Psychopharmacol. 2014 Feb;34(1):36-9. doi: 10.1097/JCP.0b013e3182a6a2e3.

  PMID: 24145218 BACKGROUND

• Keefe RS, Harvey PD, Goldberg TE, Gold JM, Walker TM, Kennel C, Hawkins K. Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophr Res. 2008 Jul;102(1-3):108-15. doi: 10.1016/j.schres.2008.03.024. Epub 2008 May 20.

  PMID: 18495435 BACKGROUND

• Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004 Jun 1;68(2-3):283-97. doi: 10.1016/j.schres.2003.09.011.

  PMID: 15099610 BACKGROUND

• Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res. 2005 Nov 15;79(2-3):231-8. doi: 10.1016/j.schres.2005.04.008. Epub 2005 Jun 27.

  PMID: 15982856 BACKGROUND

• Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E, Zhang Y, Francis MM. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 2018 Sep;199:395-402. doi: 10.1016/j.schres.2018.03.012. Epub 2018 Mar 24.

  PMID: 29588126 BACKGROUND

• Betts MJ, Kirilina E, Otaduy MCG, Ivanov D, Acosta-Cabronero J, Callaghan MF, Lambert C, Cardenas-Blanco A, Pine K, Passamonti L, Loane C, Keuken MC, Trujillo P, Lusebrink F, Mattern H, Liu KY, Priovoulos N, Fliessbach K, Dahl MJ, Maass A, Madelung CF, Meder D, Ehrenberg AJ, Speck O, Weiskopf N, Dolan R, Inglis B, Tosun D, Morawski M, Zucca FA, Siebner HR, Mather M, Uludag K, Heinsen H, Poser BA, Howard R, Zecca L, Rowe JB, Grinberg LT, Jacobs HIL, Duzel E, Hammerer D. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain. 2019 Sep 1;142(9):2558-2571. doi: 10.1093/brain/awz193.

  PMID: 31327002 BACKGROUND

• Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006 Jul 1;31(3):968-80. doi: 10.1016/j.neuroimage.2006.01.021. Epub 2006 Mar 10.

  PMID: 16530430 BACKGROUND

• Klein A, Andersson J, Ardekani BA, Ashburner J, Avants B, Chiang MC, Christensen GE, Collins DL, Gee J, Hellier P, Song JH, Jenkinson M, Lepage C, Rueckert D, Thompson P, Vercauteren T, Woods RP, Mann JJ, Parsey RV. Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. Neuroimage. 2009 Jul 1;46(3):786-802. doi: 10.1016/j.neuroimage.2008.12.037. Epub 2009 Jan 13.

  PMID: 19195496 BACKGROUND

• Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, Takahashi S, Ehara S, Terayama Y, Sakai A. Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease. Neuroreport. 2006 Jul 31;17(11):1215-8. doi: 10.1097/01.wnr.0000227984.84927.a7.

  PMID: 16837857 BACKGROUND

• Shibata E, Sasaki M, Tohyama K, Kanbara Y, Otsuka K, Ehara S, Sakai A. Age-related changes in locus ceruleus on neuromelanin magnetic resonance imaging at 3 Tesla. Magn Reson Med Sci. 2006 Dec;5(4):197-200. doi: 10.2463/mrms.5.197.

  PMID: 17332710 BACKGROUND

• Mullins PG, McGonigle DJ, O'Gorman RL, Puts NA, Vidyasagar R, Evans CJ; Cardiff Symposium on MRS of GABA; Edden RA. Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage. 2014 Feb 1;86:43-52. doi: 10.1016/j.neuroimage.2012.12.004. Epub 2012 Dec 13.

  PMID: 23246994 BACKGROUND

• Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002 Jan 31;33(3):341-55. doi: 10.1016/s0896-6273(02)00569-x.

  PMID: 11832223 BACKGROUND

• Stikov N, Campbell JS, Stroh T, Lavelee M, Frey S, Novek J, Nuara S, Ho MK, Bedell BJ, Dougherty RF, Leppert IR, Boudreau M, Narayanan S, Duval T, Cohen-Adad J, Picard PA, Gasecka A, Cote D, Pike GB. In vivo histology of the myelin g-ratio with magnetic resonance imaging. Neuroimage. 2015 Sep;118:397-405. doi: 10.1016/j.neuroimage.2015.05.023. Epub 2015 May 21.

  PMID: 26004502 BACKGROUND

• Berman S, Filo S, Mezer AA. Modeling conduction delays in the corpus callosum using MRI-measured g-ratio. Neuroimage. 2019 Jul 15;195:128-139. doi: 10.1016/j.neuroimage.2019.03.025. Epub 2019 Mar 22.

  PMID: 30910729 BACKGROUND

• Zhang H, Zhang GF, He ZY, Li ZY, Zhu M, Zhang GX. Evaluation of primary adnexal masses by 3T MRI: categorization with conventional MR imaging and diffusion-weighted imaging. J Ovarian Res. 2012 Nov 14;5(1):33. doi: 10.1186/1757-2215-5-33.

  PMID: 23148860 BACKGROUND

• Basser PJ, Mattiello J, LeBihan D. MR diffusion tensor spectroscopy and imaging. Biophys J. 1994 Jan;66(1):259-67. doi: 10.1016/S0006-3495(94)80775-1.

  PMID: 8130344 BACKGROUND

• Pasternak O, Sochen N, Gur Y, Intrator N, Assaf Y. Free water elimination and mapping from diffusion MRI. Magn Reson Med. 2009 Sep;62(3):717-30. doi: 10.1002/mrm.22055.

  PMID: 19623619 BACKGROUND

• Filo S, Shtangel O, Salamon N, Kol A, Weisinger B, Shifman S, Mezer AA. Disentangling molecular alterations from water-content changes in the aging human brain using quantitative MRI. Nat Commun. 2019 Jul 30;10(1):3403. doi: 10.1038/s41467-019-11319-1.

  PMID: 31363094 BACKGROUND

• Lee H, Wiggermann V, Rauscher A, Kames C, Beg MF, Popuri K, Tam R, Lam K, Jacova C, Shahinfard E, Sossi V, Pettersen JA, Hsiung GR. Brain Imaging Abnormalities in Mixed Alzheimer's and Subcortical Vascular Dementia. Can J Neurol Sci. 2023 Jul;50(4):515-528. doi: 10.1017/cjn.2022.65. Epub 2022 May 26.

  PMID: 35614521 BACKGROUND

• Shin HG, Lee J, Yun YH, Yoo SH, Jang J, Oh SH, Nam Y, Jung S, Kim S, Fukunaga M, Kim W, Choi HJ, Lee J. chi-separation: Magnetic susceptibility source separation toward iron and myelin mapping in the brain. Neuroimage. 2021 Oct 15;240:118371. doi: 10.1016/j.neuroimage.2021.118371. Epub 2021 Jul 6.

  PMID: 34242783 BACKGROUND

• Ben-Eliezer N, Sodickson DK, Block KT. Rapid and accurate T2 mapping from multi-spin-echo data using Bloch-simulation-based reconstruction. Magn Reson Med. 2015 Feb;73(2):809-17. doi: 10.1002/mrm.25156. Epub 2014 Mar 19.

  PMID: 24648387 BACKGROUND

• Wang Y, Liu T. Quantitative susceptibility mapping (QSM): Decoding MRI data for a tissue magnetic biomarker. Magn Reson Med. 2015 Jan;73(1):82-101. doi: 10.1002/mrm.25358. Epub 2014 Jul 17.

  PMID: 25044035 BACKGROUND

• Yao B, Li TQ, Gelderen Pv, Shmueli K, de Zwart JA, Duyn JH. Susceptibility contrast in high field MRI of human brain as a function of tissue iron content. Neuroimage. 2009 Feb 15;44(4):1259-66. doi: 10.1016/j.neuroimage.2008.10.029. Epub 2008 Nov 5.

  PMID: 19027861 BACKGROUND

• Weiskopf N, Suckling J, Williams G, Correia MM, Inkster B, Tait R, Ooi C, Bullmore ET, Lutti A. Quantitative multi-parameter mapping of R1, PD(*), MT, and R2(*) at 3T: a multi-center validation. Front Neurosci. 2013 Jun 10;7:95. doi: 10.3389/fnins.2013.00095. eCollection 2013.

  PMID: 23772204 BACKGROUND

• Lutti A, Dick F, Sereno MI, Weiskopf N. Using high-resolution quantitative mapping of R1 as an index of cortical myelination. Neuroimage. 2014 Jun;93 Pt 2:176-88. doi: 10.1016/j.neuroimage.2013.06.005. Epub 2013 Jun 10.

  PMID: 23756203 BACKGROUND

• Mezer A, Yeatman JD, Stikov N, Kay KN, Cho NJ, Dougherty RF, Perry ML, Parvizi J, Hua le H, Butts-Pauly K, Wandell BA. Quantifying the local tissue volume and composition in individual brains with magnetic resonance imaging. Nat Med. 2013 Dec;19(12):1667-72. doi: 10.1038/nm.3390. Epub 2013 Nov 3.

  PMID: 24185694 BACKGROUND

• Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 May;154:672-6. doi: 10.1192/bjp.154.5.672.

  PMID: 2574607 BACKGROUND

• Barnes TR. The Barnes Akathisia Rating Scale--revisited. J Psychopharmacol. 2003 Dec;17(4):365-70. doi: 10.1177/0269881103174013.

  PMID: 14870947 BACKGROUND

• Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-9. doi: 10.1111/j.1600-0447.1970.tb02066.x. No abstract available.

  PMID: 4917967 BACKGROUND

• Hawley C, Fineberg N, Roberts A, Baldwin D, Sahadevan A, Sharman V. The use of the Simpson Angus Scale for the assessment of movement disorder: A training guide. Int J Psychiatry Clin Pract. 2003;7(4):349-2257. doi: 10.1080/13651500310002986.

  PMID: 24930422 BACKGROUND

• Dollfus S, Mach C, Morello R. Self-Evaluation of Negative Symptoms: A Novel Tool to Assess Negative Symptoms. Schizophr Bull. 2016 May;42(3):571-8. doi: 10.1093/schbul/sbv161. Epub 2015 Nov 12.

  PMID: 26564898 BACKGROUND

• Nasrallah H, Morosini P, Gagnon DD. Reliability, validity and ability to detect change of the Personal and Social Performance scale in patients with stable schizophrenia. Psychiatry Res. 2008 Nov 30;161(2):213-24. doi: 10.1016/j.psychres.2007.11.012. Epub 2008 Oct 11.

  PMID: 18848731 BACKGROUND

• Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A, Rodriguez MJ, Rele R, Orta J, Kharbeng A, Araya S, Gervin M, Alonso J, Mavreas V, Lavrentzou E, Liontos N, Gregor K, Jones PB; SOHO Study Group. The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl. 2003;(416):16-23. doi: 10.1034/j.1600-0447.107.s416.5.x.

  PMID: 12755850 BACKGROUND

• Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl. 1993 Dec;(22):39-44.

  PMID: 8110442 BACKGROUND

• Wongjaikam S, Kumfu S, Khamseekaew J, Chattipakorn SC, Chattipakorn N. Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine. Sci Rep. 2017 Mar 13;7:44460. doi: 10.1038/srep44460.

  PMID: 28287621 BACKGROUND

• Sumneang N, Kumfu S, Khamseekaew J, Siri-Angkul N, Fucharoen S, Chattipakorn SC, Chattipakorn N. Combined iron chelator with N-acetylcysteine exerts the greatest effect on improving cardiac calcium homeostasis in iron-overloaded thalassemic mice. Toxicology. 2019 Nov 1;427:152289. doi: 10.1016/j.tox.2019.152289. Epub 2019 Sep 19.

  PMID: 31542421 BACKGROUND

• Neill E, Rossell SL, Yolland C, Meyer D, Galletly C, Harris A, Siskind D, Berk M, Bozaoglu K, Dark F, Dean OM, Francis PS, Liu D, Phillipou A, Sarris J, Castle DJ. N-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms. Schizophr Bull. 2022 Nov 18;48(6):1263-1272. doi: 10.1093/schbul/sbac065.

  PMID: 35857752 BACKGROUND

• Dean OM, Mancuso SG, Bush AI, Copolov D, Do KQ, Cuenod M, Conus P, Rossell SL, Castle DJ, Berk M. Benefits of adjunctive N-acetylcysteine in a sub-group of clozapine-treated individuals diagnosed with schizophrenia. Psychiatry Res. 2015 Dec 30;230(3):982-3. doi: 10.1016/j.psychres.2015.10.037. Epub 2015 Nov 2. No abstract available.

  PMID: 26626948 BACKGROUND

• Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep 1;64(5):361-8. doi: 10.1016/j.biopsych.2008.03.004. Epub 2008 Apr 23.

  PMID: 18436195 BACKGROUND

• Yolland CO, Hanratty D, Neill E, Rossell SL, Berk M, Dean OM, Castle DJ, Tan EJ, Phillipou A, Harris AW, Barreiros AR, Hansen A, Siskind D. Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia. Aust N Z J Psychiatry. 2020 May;54(5):453-466. doi: 10.1177/0004867419893439. Epub 2019 Dec 11.

  PMID: 31826654 BACKGROUND

• Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, Poewe W, Compta Y, Pavese N, Ruzicka E, Dusek P, Post B, Bloem BR, Berg D, Maetzler W, Otto M, Habert MO, Lehericy S, Ferreira J, Dodel R, Tranchant C, Eusebio A, Thobois S, Marques AR, Meissner WG, Ory-Magne F, Walter U, de Bie RMA, Gago M, Vilas D, Kulisevsky J, Januario C, Coelho MVS, Behnke S, Worth P, Seppi K, Ouk T, Potey C, Leclercq C, Viard R, Kuchcinski G, Lopes R, Pruvo JP, Pigny P, Garcon G, Simonin O, Carpentier J, Rolland AS, Nyholm D, Scherfler C, Mangin JF, Chupin M, Bordet R, Dexter DT, Fradette C, Spino M, Tricta F, Ayton S, Bush AI, Devedjian JC, Duce JA, Cabantchik I, Defebvre L, Deplanque D, Moreau C; FAIRPARK-II Study Group. Trial of Deferiprone in Parkinson's Disease. N Engl J Med. 2022 Dec 1;387(22):2045-2055. doi: 10.1056/NEJMoa2209254.

  PMID: 36449420 BACKGROUND

• Filo S, Shaharabani R, Bar Hanin D, Adam M, Ben-David E, Schoffman H, Margalit N, Habib N, Shahar T, Mezer AA. Non-invasive assessment of normal and impaired iron homeostasis in the brain. Nat Commun. 2023 Sep 12;14(1):5467. doi: 10.1038/s41467-023-40999-z.

  PMID: 37699931 BACKGROUND

• Moreau C, Danel V, Devedjian JC, Grolez G, Timmerman K, Laloux C, Petrault M, Gouel F, Jonneaux A, Dutheil M, Lachaud C, Lopes R, Kuchcinski G, Auger F, Kyheng M, Duhamel A, Perez T, Pradat PF, Blasco H, Veyrat-Durebex C, Corcia P, Oeckl P, Otto M, Dupuis L, Garcon G, Defebvre L, Cabantchik ZI, Duce J, Bordet R, Devos D. Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis? Antioxid Redox Signal. 2018 Sep 10;29(8):742-748. doi: 10.1089/ars.2017.7493. Epub 2018 Feb 8.

  PMID: 29287521 BACKGROUND

• Catts VS, Weickert CS. Gene expression analysis implicates a death receptor pathway in schizophrenia pathology. PLoS One. 2012;7(4):e35511. doi: 10.1371/journal.pone.0035511. Epub 2012 Apr 24.

  PMID: 22545112 BACKGROUND

• Morris G, Berk M, Carvalho AF, Maes M, Walker AJ, Puri BK. Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases. Behav Brain Res. 2018 Apr 2;341:154-175. doi: 10.1016/j.bbr.2017.12.036. Epub 2017 Dec 28.

  PMID: 29289598 BACKGROUND

• Zhang Y, Catts VS, Shannon Weickert C. Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia. Aust N Z J Psychiatry. 2018 Jul;52(7):690-698. doi: 10.1177/0004867417728805. Epub 2017 Sep 9.

  PMID: 28891319 BACKGROUND

• Kumar J, Liddle EB, Fernandes CC, Palaniyappan L, Hall EL, Robson SE, Simmonite M, Fiesal J, Katshu MZ, Qureshi A, Skelton M, Christodoulou NG, Brookes MJ, Morris PG, Liddle PF. Glutathione and glutamate in schizophrenia: a 7T MRS study. Mol Psychiatry. 2020 Apr;25(4):873-882. doi: 10.1038/s41380-018-0104-7. Epub 2018 Jun 22.

  PMID: 29934548 BACKGROUND

• Coughlin JM, Yang K, Marsman A, Pradhan S, Wang M, Ward RE, Bonekamp S, Ambinder EB, Higgs CP, Kim PK, Edwards JA, Varvaris M, Wang H, Posporelis S, Ma S, Tsujimura T, Edden RAE, Pomper MG, Sedlak TW, Fournier M, Schretlen DJ, Cascella NG, Barker PB, Sawa A. A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia. Mol Psychiatry. 2021 Jul;26(7):3502-3511. doi: 10.1038/s41380-020-00901-5. Epub 2020 Oct 19.

  PMID: 33077854 BACKGROUND

• Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, Deppen P, Preisig M, Ruiz V, Steullet P, Tosic M, Werge T, Cuenod M, Do KQ. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16621-6. doi: 10.1073/pnas.0706778104. Epub 2007 Oct 5.

  PMID: 17921251 BACKGROUND

• Romano A, Serviddio G, Calcagnini S, Villani R, Giudetti AM, Cassano T, Gaetani S. Linking lipid peroxidation and neuropsychiatric disorders: focus on 4-hydroxy-2-nonenal. Free Radic Biol Med. 2017 Oct;111:281-293. doi: 10.1016/j.freeradbiomed.2016.12.046. Epub 2017 Jan 4.

  PMID: 28063940 BACKGROUND

• Zhang N, Yu X, Song L, Xiao Z, Xie J, Xu H. Ferritin confers protection against iron-mediated neurotoxicity and ferroptosis through iron chelating mechanisms in MPP+-induced MES23.5 dopaminergic cells. Free Radic Biol Med. 2022 Nov 20;193(Pt 2):751-763. doi: 10.1016/j.freeradbiomed.2022.11.018. Epub 2022 Nov 15.

  PMID: 36395957 BACKGROUND

• Ravanfar P, Syeda WT, Jayaram M, Rushmore RJ, Moffat B, Lin AP, Lyall AE, Merritt AH, Yaghmaie N, Laskaris L, Luza S, Opazo CM, Liberg B, Chakravarty MM, Devenyi GA, Desmond P, Cropley VL, Makris N, Shenton ME, Bush AI, Velakoulis D, Pantelis C. In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia. Schizophrenia (Heidelb). 2022 Oct 26;8(1):86. doi: 10.1038/s41537-022-00293-1.

  PMID: 36289238 BACKGROUND

• Lotan A, Luza S, Opazo CM, Ayton S, Lane DJR, Mancuso S, Pereira A, Sundram S, Weickert CS, Bousman C, Pantelis C, Everall IP, Bush AI. Perturbed iron biology in the prefrontal cortex of people with schizophrenia. Mol Psychiatry. 2023 May;28(5):2058-2070. doi: 10.1038/s41380-023-01979-3. Epub 2023 Feb 7.

  PMID: 36750734 BACKGROUND

• Kidane TZ, Sauble E, Linder MC. Release of iron from ferritin requires lysosomal activity. Am J Physiol Cell Physiol. 2006 Sep;291(3):C445-55. doi: 10.1152/ajpcell.00505.2005. Epub 2006 Apr 12.

  PMID: 16611735 BACKGROUND

• Carlson GC, Lin RE, Chen Y, Brookshire BR, White RS, Lucki I, Siegel SJ, Kim SF. Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. Neuroscience. 2016 May 13;322:408-15. doi: 10.1016/j.neuroscience.2016.02.063. Epub 2016 Mar 3.

  PMID: 26946266 BACKGROUND

• White RS, Bhattacharya AK, Chen Y, Byrd M, McMullen MF, Siegel SJ, Carlson GC, Kim SF. Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1. Mol Brain. 2016 Apr 14;9:38. doi: 10.1186/s13041-016-0220-8.

  PMID: 27080392 BACKGROUND

• Xu H, Liu X, Xia J, Yu T, Qu Y, Jiang H, Xie J. Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease. FASEB J. 2018 Jun 13:fj201800060RR. doi: 10.1096/fj.201800060RR. Online ahead of print.

  PMID: 29897813 BACKGROUND

• Cheah JH, Kim SF, Hester LD, Clancy KW, Patterson SE 3rd, Papadopoulos V, Snyder SH. NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron. 2006 Aug 17;51(4):431-40. doi: 10.1016/j.neuron.2006.07.011.

  PMID: 16908409 BACKGROUND

• Xu H, Jiang H, Xie J. New Insights into the Crosstalk between NMDARs and Iron: Implications for Understanding Pathology of Neurological Diseases. Front Mol Neurosci. 2017 Mar 16;10:71. doi: 10.3389/fnmol.2017.00071. eCollection 2017.

  PMID: 28360837 BACKGROUND

• Murphy CE, Walker AK, Weickert CS. Neuroinflammation in schizophrenia: the role of nuclear factor kappa B. Transl Psychiatry. 2021 Oct 14;11(1):528. doi: 10.1038/s41398-021-01607-0.

  PMID: 34650030 BACKGROUND

• Parellada E, Gasso P. Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia. Transl Psychiatry. 2021 May 6;11(1):271. doi: 10.1038/s41398-021-01385-9.

  PMID: 33958577 BACKGROUND

• Ermakov EA, Dmitrieva EM, Parshukova DA, Kazantseva DV, Vasilieva AR, Smirnova LP. Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives. Oxid Med Cell Longev. 2021 Jan 23;2021:8881770. doi: 10.1155/2021/8881770. eCollection 2021.

  PMID: 33552387 BACKGROUND

• Kahn RS, Sommer IE. The neurobiology and treatment of first-episode schizophrenia. Mol Psychiatry. 2015 Feb;20(1):84-97. doi: 10.1038/mp.2014.66. Epub 2014 Jul 22.

  PMID: 25048005 BACKGROUND

• Reddy-Thootkur M, Kraguljac NV, Lahti AC. The role of glutamate and GABA in cognitive dysfunction in schizophrenia and mood disorders - A systematic review of magnetic resonance spectroscopy studies. Schizophr Res. 2022 Nov;249:74-84. doi: 10.1016/j.schres.2020.02.001. Epub 2020 Feb 24.

  PMID: 32107102 BACKGROUND

• Nicoletti F, Orlando R, Di Menna L, Cannella M, Notartomaso S, Mascio G, Iacovelli L, Matrisciano F, Fazio F, Caraci F, Copani A, Battaglia G, Bruno V. Targeting mGlu Receptors for Optimization of Antipsychotic Activity and Disease-Modifying Effect in Schizophrenia. Front Psychiatry. 2019 Feb 14;10:49. doi: 10.3389/fpsyt.2019.00049. eCollection 2019.

  PMID: 30890967 BACKGROUND

• Best MW, Grossman M, Oyewumi LK, Bowie CR. Examination of the Positive and Negative Syndrome Scale factor structure and longitudinal relationships with functioning in early psychosis. Early Interv Psychiatry. 2016 Apr;10(2):165-70. doi: 10.1111/eip.12190. Epub 2014 Oct 2.

  PMID: 25277757 BACKGROUND

• Ventura J, Subotnik KL, Gitlin MJ, Gretchen-Doorly D, Ered A, Villa KF, Hellemann GS, Nuechterlein KH. Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later. Schizophr Res. 2015 Feb;161(2-3):407-13. doi: 10.1016/j.schres.2014.10.043. Epub 2014 Dec 8.

  PMID: 25499044 BACKGROUND

• Diaz-Caneja CM, Pina-Camacho L, Rodriguez-Quiroga A, Fraguas D, Parellada M, Arango C. Predictors of outcome in early-onset psychosis: a systematic review. NPJ Schizophr. 2015 Mar 4;1:14005. doi: 10.1038/npjschz.2014.5. eCollection 2015.

  PMID: 27336027 BACKGROUND

• Austin SF, Mors O, Budtz-Jorgensen E, Secher RG, Hjorthoj CR, Bertelsen M, Jeppesen P, Petersen L, Thorup A, Nordentoft M. Long-term trajectories of positive and negative symptoms in first episode psychosis: A 10year follow-up study in the OPUS cohort. Schizophr Res. 2015 Oct;168(1-2):84-91. doi: 10.1016/j.schres.2015.07.021. Epub 2015 Aug 8.

  PMID: 26265299 BACKGROUND

• Milev P, Ho BC, Arndt S, Andreasen NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005 Mar;162(3):495-506. doi: 10.1176/appi.ajp.162.3.495.

  PMID: 15741466 BACKGROUND

• Hanson E, Healey K, Wolf D, Kohler C. Assessment of pharmacotherapy for negative symptoms of schizophrenia. Curr Psychiatry Rep. 2010 Dec;12(6):563-71. doi: 10.1007/s11920-010-0148-0.

  PMID: 20821286 BACKGROUND

• Vita A, Gaebel W, Mucci A, Sachs G, Erfurth A, Barlati S, Zanca F, Giordano GM, Birkedal Glenthoj L, Nordentoft M, Galderisi S. European Psychiatric Association guidance on assessment of cognitive impairment in schizophrenia. Eur Psychiatry. 2022 Sep 5;65(1):e58. doi: 10.1192/j.eurpsy.2022.2316.

  PMID: 36059109 BACKGROUND

• Kirkpatrick B, Strauss GP, Nguyen L, Fischer BA, Daniel DG, Cienfuegos A, Marder SR. The brief negative symptom scale: psychometric properties. Schizophr Bull. 2011 Mar;37(2):300-5. doi: 10.1093/schbul/sbq059. Epub 2010 Jun 17.

  PMID: 20558531 BACKGROUND

• Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D. Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia. Schizophr Res. 2012 May;137(1-3):246-50. doi: 10.1016/j.schres.2012.01.031. Epub 2012 Feb 21.

  PMID: 22356801 BACKGROUND

• Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. doi: 10.1093/schbul/13.2.261.

  PMID: 3616518 BACKGROUND

• Galderisi S, Mucci A, Dollfus S, Nordentoft M, Falkai P, Kaiser S, Giordano GM, Vandevelde A, Nielsen MO, Glenthoj LB, Sabe M, Pezzella P, Bitter I, Gaebel W. EPA guidance on assessment of negative symptoms in schizophrenia. Eur Psychiatry. 2021 Feb 18;64(1):e23. doi: 10.1192/j.eurpsy.2021.11.

  PMID: 33597064 BACKGROUND

Related Links

• Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus
• ECDEU ASSESSMENT MANUAL FOR PSYCHOPHARMACOLOGY Revised, 1976
• Quantitative magnetic resonance imaging of brain anatomy and in vivo histology.
• Bayesian Non-Linear Modeling for the Prediction Competition
• A qMRI approach for mapping microscopic water populations and tissue relaxivity in the in vivo human brain

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Interventions

Deferiprone; Acetylcysteine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pyridones; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Central Study Contacts

Amit Lotan

CONTACT

+972-2-6777184; amitlo@hadassah.org.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, Department of Adult Psychiatry and the Biological Psychiatry Lab, Hadassah University Medical Center; Chair, Department of Psychiatry, Hebrew University Medical School

Study Record Dates

• First Submitted: November 20, 2025
• First Posted: August 12, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029
• Last Updated: August 12, 2026

Record last verified: 2026-08

Locations

IL (2)