Stratifying Psychoses for Personalized REpetitive TMS in Persistent NEgative Symptoms Alleviation (SP-RENESA)

University Hospital, Strasbourg, France

Status: Not yet enrolling

Conditions: Apathy; Schizophrenia; Persistent Negative Symptoms; Progressive Periodic Catatonia; Aviation

Treatments: Procedure: Personalized rTMS

Study type: Interventional

Funder types: Other

Identifiers

NCT06184165

8371

Details and patient eligibility

About

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).

Enrollment: 160 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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160 participants in 4 patient groups

N°1: PMI in PPC

Experimental group

Description:

Progressive periodic catatonia (SSD phenotype) Premotor inhibition using personalized rTMS (40 sec continuous theta-burst on each of the 5 targets corresponding to hyper-perfused regions, i.e. functional biomarker, 120%). N = 40.

Treatment:

Procedure: Personalized rTMS

N°2: PFA in PPC

Active Comparator group

Description:

Progressive periodic catatonia (SSD phenotype) Classical left-prefrontal activation using intermittent theta-burst rTMS (72 trains, 120%). N = 40.

Treatment:

Procedure: Personalized rTMS

N°3: PMI in nPPC

Active Comparator group

Description:

Other phenotype of SSD than PPC (nPPC) Premotor inhibition using personalized rTMS (40 sec continuous theta-burst on each of the 5 targets corresponding to most perfused premotor regions). N = 40.

Treatment:

Procedure: Personalized rTMS

N°4: PFA in nPPC

Experimental group

Description:

Non-progressive periodic catatonia SSD phenotype Classical left-prefrontal activation (PFA) using intermittent theta-burst rTMS (72 trains, 120%). N = 40.

Treatment:

Procedure: Personalized rTMS