Stratifying Psychoses for Personalized REpetitive TMS in Persistent NEgative Symptoms Alleviation

Schizophrenia Clinical Trial

— SP-RENESA  

Official title:

Stratifying Psychoses for Personalized REpetitive TMS in Persistent NEgative Symptoms Alleviation

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06184165
• Other study ID #: 8371
• Status: Not yet recruiting
• Phase: N/A
• Start date: March 1, 2024
• Est. completion date: November 1, 2028

Study information

• Verified date: November 2023
• Source: University Hospital, Strasbourg, France
• Contact: Jack Foucher, MD
• Phone: 03.88.11.69.21
• Email: jack.foucher[@]chru-strasbourg.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In its 2012's release guideline on therapy for schizophrenia, the EMA joined the FDA to acknowledge primary and persistent negative symptoms (PNS) as an unmet need in the treatment of schizophrenia. Functional brain imaging studies showed a correlation between NS and reduced perfusion in the left dorsolateral prefrontal cortex (L-DLPFC). Pre-frontal activation (PFA) using repetitive transcranial magnetic stimulation (rTMS) significantly improve PNS (meta-analyses: effect size SMD = 0.55, ΔPANSS-N = -2.5). Yet schizophrenia is likely to gather many different natural entities of distinct pathophysiological mechanisms. Pursuing a one-size-fits-all approach will not adapt to this diversity and might account for inconsistencies in the results. Progressive periodic catatonia (PPC) is a rare psychotic phenotype (0.1 - 0.5 ‰) which has been shown to be longitudinally stable (30-years follow-up) and consistent within families (about 1 third of first-degree relatives are affected). The core of this phenotype is a disintegration of psychomotor processes which progresses with each relapse, resulting in a "deficit state", i.e., PNS, responsible for most social and occupational disabilities. The investigators and others reported PPC to come with hyper-perfusions in premotor cortices compared to controls or non-PPC chronic psychoses (nPPC). These hyper-perfusions discriminate PPC from nPPC or depressive patients (Sensitivity = 82%; Specificity = 95%). Last, in independent proof-of-principle studies the investigators and others have shown that premotor inhibition (PMI) using rTMS significantly improved PNS in PPC and that the most dramatic improvements followed personalized accelerated rTMS protocols (5 days of rTMS; CGI-improvement = 2 which is equivalent to ΔPANSS-N = -10; lasting > 1 month - vs virtually no change for PFA). The efficacy index was very good (no side effects). the investigators hypothesize that: (1) in PPC, add-on personalized premotor inhibition (PMI) is more effective in reducing PNS than L-DLPFC activation (PFA); (2) patient stratification is relevant as personalized PMI will not be as effective in the nPPC group (even expected to be less effective than PFA).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 160
• Est. completion date: November 1, 2028
• Est. primary completion date: November 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• 18-70 years of age; affiliated to health insurance; superior or equal to B2 level of linguistic competency in French.
• Suffering from schizophrenia spectrum disorder (SSD) in residual state with persistent negative symptoms (PNS): (1) SSD: ICD-11 codes beginning with 6A2 + primary catatonia (codes beginning with 6A4) + simple schizophrenia as defined in ICD-10 (F20.6); (2) PNS: persistence (=6 months - based on patient ± informant's interview) of =2 negative symptoms (PANSS-N1, N2, N3, N4, N6 =4) with functional impact.
• Half of subjects having PPC, the other half suffering from another phenotype or nPPC (neuropsychiatric procedure or probabilistic, i.e. Bayes-PPC).
• Under a stable medication regimen for >6 weeks,
• Subjects who have received the protocol information and signed informed consent.

Exclusion Criteria:

• - Contraindications for MRI or rTMS.
• Motor deficit at neurological examination.
• Secondary negative symptoms: (1) withdrawal secondary to severe anxiety (especially due to positive symptoms), (2) depression, (3) maintenance on high dose antipsychotics, (4) extra-pyramidal or (5) sedation side-effects, (6) treatment non-compliance, (7) current substance abuse (except nicotine and caffeine), (8) unsubstituted past opioid addiction, (9) poor health or social condition.
• Under antiepileptic drugs (except lamotrigine and long-term use of benzodiazepines).
• Pregnancy; severe medical condition; care under constraint.

Related Conditions & MeSH terms

• Apathy
• Aviation
• Catatonia
• Schizophrenia

Intervention

Procedure:
• Personalized rTMS
5 "personalized" targets accessible to TMS (at less than 3.5 cm distance from the scalp or the coil's hot spot) are placed in the hyper-perfused premotor regions. The patient is installed on the robotic device. The technician puts a neuro-navigation tracker on the subject's forehead and proceeds to the co-registration. The motor threshold is defined, and stimulator output's intensity is adjusted accordingly (120%) The robotic system ensures that the actual stimulation is performed according to the personalized protocol. This adequacy will be evaluated secondarily based on the recordings of the coil positions during each

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Strasbourg, France

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Decrement in positive and negative syndrome scale - negative sub-score (?PANSS-N).	Positive and negative syndrome scale - negative sub-score ?PANSS-N = ?N1 + ?N2 + ?N3 + ?N4 + ?N6; PMI personalized rTMS superiority claim in PPC: ANOVA within-between 2 factors interaction (two-way comparison): The within factor is "pre-rTMS/end-of-study", i.e., PNS change between the 2 repeated measures: PANSS-N before and at 1.5-months after rTMS.; The between factor is "treatment arm": PMI vs PFA.; Precision medicine claim (phenotype-dependent response): 3-way ANOVA (interaction between the 2 between and 1 within factors): The within factor is "pre/end", i.e., PNS change between the 2 repeated measures: PANSS-N before and at 1.5-months after rTMS.; The first between factor is "treatment arm": PMI vs PFA.; The second between factor is "phenotype": PPC vs nPPC.	Pre-rTMS and end-of-trial (before - week 4, and 6 weeks after rTMS - week12).