Psychotic symptoms and disorders secondary to methylphenidate introduction in adults with ADHD: a review of literature

Sommaire

Introduction

Attention deficit and hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder which features inappropriate and impaired inattention, motor hyperactivity and impulsivity [START_REF] Thapar | Attention deficit hyperactivity disorder[END_REF]. Patients with ADHD display higher rates of low academic achievement, adverse socio-economic outcomes, involvement with justice and psychiatric comorbidities such as substance use disorder, antisocial and other personality disorders, anxiety, mood and psychotic disorders [START_REF] Thapar | Attention deficit hyperactivity disorder[END_REF].

In recent years a shift in the understanding of the onset and expression of AHDH has operated. Once believed to wane out in adolescence or early adulthood, it is now common practice to pursue treatment into adulthood or to diagnose ADHD in that age group [START_REF] Zalsman | Adult ADHD: A new disease?[END_REF]. Follow-up studies show that 65% of ADHD patients will continue to meet full criteria for ADHD in adulthood [START_REF] Thapar | Attention deficit hyperactivity disorder[END_REF]. This shift can be seen through updates made in the DSM-IV which introduced the notion of persistence of ADHD into adulthood [START_REF]Diagnostic and statistical manual of mental disorders: DSM-IV-TR[END_REF], and later in the DSM-5 which introduced criteria for the novel diagnosis of ADHD in adults [START_REF]Diagnostic and statistical manual of mental disorders: DSM-5[END_REF]. Reflecting these changes, trends in ADHD diagnosis show a significant increase in outpatient diagnosis in adults in recent years in Europe and America, and a higher increase of the proportion of diagnosed adults compared to that of children [START_REF] Oehrlein | National Trends in ADHD Diagnosis and Treatment: Comparison of Youth and Adult Office-Based Visits[END_REF][START_REF] Bachmann | ADHD in Germany: Trends in Diagnosis and Pharmacotherapy[END_REF].

Worldwide prevalence of ADHD is estimated around 5,2% in children and adolescents [START_REF] Polanczyk | The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis[END_REF], and around 2,5% in adults [START_REF] Song | The prevalence of adult attentiondeficit hyperactivity disorder: A global systematic review and meta-analysis[END_REF]. Expanding the definition of adult ADHD by removing the need for evidence of childhood onset raises this prevalence to 6,7% of the general population [START_REF] Song | The prevalence of adult attentiondeficit hyperactivity disorder: A global systematic review and meta-analysis[END_REF].

Psychostimulants are the treatment of choice for ADHD in children as well as for adults [START_REF] Cortese | Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis[END_REF]. NICE guidelines for instance currently recommend the use of methylphenidate (MPH) in first line for both children and adults [START_REF] Chaplin | Attention deficit hyperactivity disorder: diagnosis and management[END_REF]. MPH was found to be efficacious on core symptoms of ADHD (attentional deficit and motor restlessness) with a moderate to high effect size [START_REF] Cortese | Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis[END_REF], as well as on emotional dysregulation and social functioning which may stem from said core symptoms [START_REF] Zalsman | Adult ADHD: A new disease?[END_REF].

Trends in stimulant prescription suggest similar rates of prescription in adults than in children diagnosed with ADHD, and an overall increase in prevalence of stimulant prescription in adults [START_REF] Oehrlein | National Trends in ADHD Diagnosis and Treatment: Comparison of Youth and Adult Office-Based Visits[END_REF][START_REF] Burcu | Trends in Stimulant Medication Use in Commercially Insured Youths and Adults, 2010-2014[END_REF]. In France where MPH is the only ADHD medication available, adults represented up to 20% of prevalent MPH prescriptions between 2012 and 2014 [12] MPH is considered overall safe to use in children and adults [START_REF] Cortese | Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis[END_REF]. Pre-treatment checks include looking into family and personal medical history for comorbid psychiatric and cardiac disorders, as well as monitoring weight, blood pressure, pulse, and ECG [START_REF] Thapar | Attention deficit hyperactivity disorder[END_REF].

Common psychiatric adverse effects include sleep disturbance, irritability, anxiety, tics and mood changes [START_REF] Thapar | Attention deficit hyperactivity disorder[END_REF]. Psychotic symptoms have been reported with MPH use such as delusions, hallucinations and thought and behavior disorganization [START_REF] Mosholder | Hallucinations and Other Psychotic Symptoms Associated With the Use of Attention-Deficit/Hyperactivity Disorder Drugs in Children[END_REF]. Meta-analysis were run as early as 2006 and 2009 by the US Food and Drug Administration (FDA) to determine risk of psychotic and manic symptoms in children based on data provided by manufacturers and adverse events spontaneous reports [START_REF] Mosholder | Hallucinations and Other Psychotic Symptoms Associated With the Use of Attention-Deficit/Hyperactivity Disorder Drugs in Children[END_REF][START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF]. Most current clinical guidelines are based on this data and suggest caution in patients with a personal of family history of psychosis, and withdrawal if psychotic symptoms occur [START_REF] Chaplin | Attention deficit hyperactivity disorder: diagnosis and management[END_REF][START_REF] Cortese | Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents[END_REF].

Both animal and human studies suggest that punctual high doses of stimulants (dexamphetamine, methylphenidate, but also cocaine and methamphetamine) can induce transient psychotic symptoms and brief psychotic disorders in naïve subjects with or without history of psychotic disorders [START_REF] Curran | Stimulant psychosis: systematic review[END_REF].

MPH is a dopamine agonist and binds to dopamine transporters (DAT) which are responsible for dopamine reuptake in the synapse, thus increasing dopamine synaptic concentration [START_REF] Engert | Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate[END_REF]. MPH may preferentially bind DAT in the mesolimbic pathway, which is suspected to result in acute and transient psychotic symptoms upon initiation, generally in the first weeks of treatment or as soon as a few hours after administration [START_REF] Curran | Stimulant psychosis: systematic review[END_REF][START_REF] Engert | Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate[END_REF][START_REF] Arnsten | Stimulants: Therapeutic Actions in ADHD[END_REF]. So-called theory of sensitization on the other hand postulates that chronic administration of low doses of stimulants could modify mesolimbic dopamine pathways sensitivity and promote psychotic reactions to ulterior stimulant use or high stress with a risk of transition to chronic psychotic disorders [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF][START_REF] Curran | Stimulant psychosis: systematic review[END_REF].

The earliest report of adverse psychotic events with MPH is a case series of "methylphenidate hallucinosis" in 1971 describing 3 children whom experienced transient multimodal hallucinations following MPH initiation [START_REF] Lucas | Methylphenidate Hallucinosis[END_REF]. Further case reports and small observational cohorts suggested correlation with paranoid delusions, coenesthetic, acoustic and visual hallucinations, but also with brief psychotic disorders, higher rates of inpatient care for psychotic events, relapse of psychotic events and antipsychotic prescription [START_REF] Cherland | Psychotic Side Effects of Psychostimulants: A 5-Year Review[END_REF][START_REF] Rashid | Methylphenidate and somatic hallucinations[END_REF][START_REF] Halevy | Methylphenidate Induction of Complex Visual Hallucinations[END_REF][START_REF] Gross-Tsur | Hallucinations during methylphenidate therapy[END_REF][START_REF] Cressman | Prescription Stimulant Use and Hospitalization for Psychosis or Mania: A Population-Based Study[END_REF]. As a whole, transient symptoms could appear in 1 every 400 children treated with MPH [START_REF] Ross | Psychotic and Manic-like Symptoms During Stimulant Treatment of Attention Deficit Hyperactivity Disorder[END_REF].

The 2009 FDA report and a 2019 Cochrane systematic review on psychotic symptoms in children with MPH found that current data is insufficient to conclude on the matter [START_REF] Mosholder | Hallucinations and Other Psychotic Symptoms Associated With the Use of Attention-Deficit/Hyperactivity Disorder Drugs in Children[END_REF][START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF]. A metaanalysis of all RCTs available showed no significant difference but added that most studies were at high risk of bias, reported too few psychotic events to provide sufficient meta-analysis power and might have been too short (the Cochrane review reported studies ranging from 1 day to 16 weeks) to register any psychotic event at all [START_REF] Mosholder | Hallucinations and Other Psychotic Symptoms Associated With the Use of Attention-Deficit/Hyperactivity Disorder Drugs in Children[END_REF][START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF]. When looking upon non randomized trials and observational studies, a significant difference occurred though these studies were also at high risk of bias, heterogenous in terms of design, inclusion and exclusion criteria, and used mostly spontaneous reports or general questioning instead of scales or structured interviews to assess for symptoms [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF].

To our knowledge, no existing review addresses the risk of psychotic symptoms and disorder following introduction of MPH in previously naïve adults with a diagnosis of ADHD, regardless of psychiatric history. This review is of interest as we expect a growing number of adultspecific studies given the current trends in ADHD diagnosis and MPH. As seen in early studies in children and adolescents, we hypothesize that MPH would be in this adult setting statistically associated with a higher risk of psychotic symptoms and disorders.

Method

Protocol

This review was conducted according to PRISMA guidelines and followed a predetermined unpublished protocol.

Search strategy

An electronic literature research was conducted on PubMed and Embase for records indexed up until December 19 th of 2022 using the following terms : ("Psychosis"[All Fields] OR "psychotic disorder"[All Fields] OR "schizophrenia"[All Fields] OR "delusion"[All Fields] OR "hallucination"[All Fields] OR "psychotic symptom"[All Fields]) AND ("methylphenidate"[All Fields] OR "psychostimulant"[All Fields]) AND ("ADHD"[All Fields] OR "ADD"[All Fields] OR "hyperkinetic disorder"[All Fields] OR "attention deficit hyperactivity disorder"[All Fields]).

The search was restricted to peer-reviewed, published studies. Grey literature was consulted on Google Scholar and WHO ICTRP Search Portal.

Inclusion and exclusion criteria

Eligible studies were identified using these inclusion criteria: study must (1) be written in French or English, (2) consist of a case series or report, observational study or clinical trial, [START_REF]Diagnostic and statistical manual of mental disorders: DSM-IV-TR[END_REF] examine incident psychotic symptoms or disorders as a primary outcome, (4) examine MPH initiation in the treatment of ADHD as an intervention, (5) include adults with a diagnosis of ADHD in its population.

Studies were excluded if they met these one or more of these exclusion criteria: (1) animal studies, (2) reviews and meta-analysis, (3) article not written on French nor English, (4) reported MPH misuse or abuse as an intervention, (5) reported on psychostimulant use but not MPH, [START_REF] Bachmann | ADHD in Germany: Trends in Diagnosis and Pharmacotherapy[END_REF] reported MPH use but not for the treatment of ADHD, [START_REF] Polanczyk | The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis[END_REF] reported psychotic symptoms or disorders that preceded MPH intervention.

Outcomes

Primary outcome was risk of incident psychotic symptoms or disorders after MPH initiation. Secondary outcome was results describing potential mechanism of incident psychotic symptoms or disorders.

Data extraction

One author reviewed abstracts for screening and read full articles for eligibility. Data was extracted by the same author.

Quality assessment

Methodological study quality was assessed by the same author using the American National Heart Lung and Blood Institute's (NHLBI) Study Quality Assessment Tools for assessing risk of bias. This tool provides a 14-item questionnaire for observational and cross-sectional studies, and a 9-item questionnaire for case reports and series.

Meta-analysis

No meta-analysis was run because of the scarcity of data and the difference in designs used across studies.

Results

Search results

The literature search yielded 463 articles. 343 records were excluded based on title examination. 87 records were excluded based on abstract examination. 34 records were assessed for eligibility with full-text examination. 6 records were considered eligible and included in this review. Other records were rejected because they did not examine psychotic symptoms or disorders as an outcome [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF], psychotic symptoms preceded MPH intervention (1), they did not examine MPH as an intervention (1), MPH use was not controlled but compared to another psychostimulant (1), they did not study therapeutical use of MPH (i.e. abuse or misuse) (1), they did not include adults in their population (3), MPH was started in childhood (1), the article was not written in French or English [START_REF] Zalsman | Adult ADHD: A new disease?[END_REF], or the article could not be retrieved [START_REF] Zalsman | Adult ADHD: A new disease?[END_REF].

Out of the 6 included records, 2 are observational cohort studies (Stricker B. et al.[26],

Hollis C. et al. [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]), 1 is a case series (Kraemer M. et al. [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF]), and 3 are case reports (Caci H. et al. [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF], Delavenne H. et al. [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF], Grau-Lopez et al. [START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]).

The PRISMA flow-chart is presented in Fig. 1.

Quality assessment

Quality assessment and risk of bias were examined using NHLBI's Study Quality Assessment Tools for observational cohort studies and case-report/series studies.

For both observational cohort studies overall quality was rated as fair. Stricker B. et al. showed lack of comparability between study and control group on BMI and comorbid substance abuse, history of psychiatric disorder and use of psychiatric medication. Hollis C. et al. failed to provide a thorough description of study sample (most notably regarding age groups, despite running analysis stratified on this variable) and did not consider differences in dosage. Both studies did not justify sample size and did not allow for blinding of assessors. Both studies assumed the studied population as patients with ADHD but did not assess this variable in their study groups, Stricker B. et al. had to account for certain off-label uses (i.e. use in palliative care) in a post-hoc analysis.

For all 4 case-report/series, overall quality was rated as poor. Caci H. et al. lacked clear description of case subject. All case reports/series failed to describe outcomes with a standardized diagnosis, did not indicate precise timelapses and did not give a verifiable length of follow-up.

Quality assessment criteria and results applied to the studies are presented in Table 1.

Narrative review of observational studies

Population and intervention

Both observational cohort studies included provided data for 32803 patients, mostly male (58%) across Sweden and the Netherlands, sampled using population-based national health databases. A history of psychotic disorder could be found in 714 subjects (2,2%) [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF].

As cited previously, both studies listed MPH initiation in ADHD patients as a concern in their setting, but none used ADHD diagnosis as an inclusion criterion (or the lack thereof as an exclusion criterion) [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF] A description of population and intervention for both studies is presented in Table 2.

Outcome measures

Outcomes for Hollis C. et al. were psychotic events defined as incident diagnosis with a relevant ICD-10 coding during study period. Incident psychotic events were noticed in 4 different 12-week time frames: one year prior to MPH introduction (period 1), 12 weeks prior to MPH introduction (period 2), 12 weeks after MPH introduction (period 3) and one year after MPH introduction (period 4) [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. Primary analysis aimed to compare incidence of psychotic events in periods 3 and 4 with period 2 [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. Results were presented as incidence rate ratios (IRR) with 95% CI [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. No adjusted analysis was run owing to the within-individual comparison design [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. The study found no significant increase in IRR in either post-MPH-initiation, stratification by age group did not affect results [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. Stratification on history of psychotic events and age suggested a significant reduction of IRR one year after MPH-introduction in adult patients with a history of psychotic events [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. A secondary analysis aimed to compare incidence of psychotic events in periods 2, 3 and 4 with period 1, and found a significant decrease of IRR in period 4 in patients with a history of psychosis, but also a significant increase in all periods (including the 12-week period prior to MPH introduction) in patients without history of psychosis [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. Thus, this study suggests that MPH may not increase the risk of psychotic events in ADHD patients with or without a history of psychotic event, that MPH may decrease risk of psychosis in patients with a history of psychosis, and that ADHD symptoms and need for MPH treatment may be a risk factor for psychosis [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF].

Outcomes for Stricker B. et al. were psychotic events defined as incident diagnosis with a relevant ICPC (International Classification of Primary Care) coding during study period. Incident psychotic events were noticed until loss of follow-up [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF]. Primary analysis aimed to compare incidence of psychotic events between study and control group, results were presented as hazardratios with 95% CI [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF]. Adjusted analysis were run on possible confounding factors which yielded sufficient data, namely history of psychiatric disorder, substance use disorder, past or current use of psychiatric medication (but not BMI nor smoking) [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF]. Unadjusted analysis yielded significant differences in incident psychotic events (except schizophrenic disorder) which are negated by adjustment on ITT, and furthermore by adjustment on the aforementioned cofounders [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF]. Thus, this study suggests that incident psychotic events in ADHD patients may not be mediated by MPH treatment [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF].

Psychopharmacological hypotheses

Both studies contradict the hypothesis that MPH initiation is linked to higher risk of psychotic events, in both patients with and without a history of psychosis.

Hollis C. et al. propose that psychotic symptoms may in fact precede diagnosis of psychotic disorder and MPH initiation [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. They could either sign a comorbid condition to ADHD and accounted for severity of ADHD, or be mistaken altogether with ADHD, leading in both cases to MPH initiation [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. They also provide the hypothesis that several psychotic events could be manic episodes with psychotic features in undiagnosed and/or untreated patients with bipolar disorders [START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF][START_REF] Viktorin | The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder[END_REF]. Stricker B. et al. propose that the incidence of psychotic events in MPH users may be confounded by the baseline risk of psychotic events in ADHD patients [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF].

Narrative review of case-reports/series

Population and intervention

All case-reports/series included provided data for 6 patients (5 men and 1 woman) across 3 countries (France, Spain, Germany) [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. One patient from the case-series by Kraemer M. et al. was excluded from the review because MPH was misused. Ages range from 31 to 45 years old [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF].

One patient had a history of alcohol use disorder [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF], another had a history of cocaine use disorder [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF], another had a history of both substances use disorder [START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. Both patients with alcohol use disorder were medicated with disulfiram prior to MPH initiation [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. The patient with cocaine use disorder had a history of psychotic symptoms occurring during acute cocaine-crack intoxication, all others are unremarkable for history of psychosis (personal of familywise) [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF].

All patients were diagnosed with ADHD according to DSM-IV or V criteria in their adulthood [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. Three cases provide detail on the scales used (namely ASRS, WURS and CAADID) [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF].

MPH was OROS (osmotic-release oral system) in 3 cases with dosage ranging from 30 to 54mg/day [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF], IR (immediate release) in 1 case with a dosage a 15mg/day [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF], and a mix of OROS and IR and one case with a dosage 54mg/day and 20mg/day respectively [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF].

A description of population and interventions for all 4 studies is presented in Table 3.

Outcome measures

Outcomes for all case-reports/series were incident psychotic events, defined in all cases by a clinical vignette describing various psychotic symptoms but without providing scales or standardized diagnosis. Caci H. et al. described "psychotic like symptoms" without further description [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF]. Kraemer M.et al. described one patient having paranoid delusions and olfactory hallucinations, and another having insomnia, anxiety, paranoid delusions and illusions of reference [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF]. Delavenne H. et al. described paranoid delusions, auditory and visual hallucinations [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF]. Grau Lopez L. et al. described blockage of though, paranoid delusions, auditory hallucinations and illusions of reference [START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF].

Onset delay varied between "immediately" for Caci H. [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. Duration of treatment was not mentioned barring one case where Olanzapine was interrupted after one month [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF].

Follow-up data was available for only two cases ranging between one and three months, no recurrence of psychotic symptoms was described by either case [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF].

Differential diagnosis consisted mainly of drug screenings, which retrieved negative results barring for one case in which cocaine was consumed two days prior [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF].

Reintroduction trial was only proposed by Caci H. et al. three months after discontinuation of disulfiram, with absence of recurrence during a three-month follow-up [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF].

Psychopharmacological hypotheses

Case reports by Caci H. et al. and Grau-Lopez L. et al. argue the possibility of drug-drug interaction in the emergence of MPH-induced psychotic events. In both cases disulfiram was suspected to raise the risk of psychosis through dopamine-ß-hydroxylase blockade which in turn would increase dopamine levels and raise stimulant-induced psychosis proneness [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF].

Case report by Delavenne H. et al. argues that cocaine use disorder could facilitate MPHinduced psychosis, either via direct dopamine surge, or via sensitization of dopaminergic mesocorticolimbic pathways imbued by prolonged use of stimulants which could promote basal dopaminergic hyperactivity and raise proneness to stimulant-induced psychosis [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF]. They also argue that history of psychotic symptoms during acute cocaine intoxication could sign psychosis proneness and thus be a risk factor for stimulant-induced psychosis including MPH [START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF].

Case series by Kraemer et al. also argues in favor of interaction with other factors, such as use of alcohol or illegal stimulants (though both cases included have no past of current substance use disorder) [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF]. They also propose that MPH-induced psychotic events could be related to an underlying vulnerability that could be shared with other substances, they cite for instance dopamine-ß-hydroxylase gene polymorphisms that are known to be associated with cocaineinduced psychotic events [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF].

Grey literature

The grey literature manual search did not yield relevant data. The search for unpublished studies yielded one retrospective cohort study completed in October 2019, aiming to estimate the incidence of various psychiatric health outcomes including psychotic disorders in adult and children first users of MPH with a diagnosis of ADHD. As of March 18 th of 2023, no results were published.

Discussion

This review is the first to our knowledge to provide an overview of psychotic symptoms secondary to MPH initiation in adults with ADHD. We conducted a systematic search which yielded 6 articles, of which 2 observational studies and 4 case-series/reports. We deemed the data too scarce to undergo a meta-analysis and operated a narrative review of the evidence. Both observational studies suggested that MPH initiation may be statistically associated with psychosis but may not be a risk factor and that other cofounders should be considered [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. All casereports/series suggested that MPH could induce psychosis in conjunction with other factors, such as concomitant medication that might affect dopamine metabolism in the brain, comorbid SUD (substance use disorder) and/or acute intoxication especially with other stimulants [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF].

However, several factors impact the significance of these conclusions and do not allow to make clear guidelines based on the evidence.

Limitations in eligible studies and in overall body of proof

The low number of eligible studies came as a surprise. Preliminary research for this review found several articles focusing on psychotic symptoms following MPH initiation in children and adolescents with ADHD, including the previously cited Cochrane review by Ramstad et al. which found 45 eligible papers, of which 10 randomized controlled trials (RCT) and 17 non-randomized studies [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF].

No RCT met the inclusion criteria of our study. One RCT by Medori R. et al. reported delusions in one patient even though psychotic events were not specifically assessed in the protocol and no analysis were run [START_REF] Medori | A Randomized, Placebo-Controlled Trial of Three Fixed Dosages of Prolonged-Release OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder[END_REF]. Other RCTs cited psychotic events as a tolerability outcome but none comprised a systematic evaluation and rather relied on spontaneous reports or unspecific evaluation during outpatient attendance, as such no psychotic events were reported [START_REF] Buitelaar | Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder[END_REF][START_REF] Asherson | OROS-methylphenidate to reduce ADHD symptoms in male prisoners aged 16-25 years: a RCT[END_REF]. These studies were designed with a focus on common and/or short-term side effects such as anxiety, irritability and somatic disturbances, with sample sizes ranged from 200 to 400 and duration ranged from 5 to 8 weeks, which were probably unfit to elicit psychotic events [START_REF] Medori | A Randomized, Placebo-Controlled Trial of Three Fixed Dosages of Prolonged-Release OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder[END_REF][START_REF] Buitelaar | Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder[END_REF][START_REF] Asherson | OROS-methylphenidate to reduce ADHD symptoms in male prisoners aged 16-25 years: a RCT[END_REF]. The same caveat was encountered by Ramstad and al. in their Cochrane review, in which they decided nevertheless to include safety MPH RCTs [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF]. Only 6 out of 10 RCTs elicited psychotic events, which led the authors to conclude that test power of such studies was insufficient to explore psychotic events [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF].

In a review of safety and tolerability RCTs of MPH initiation in adults up to 2009, Godfrey J. identified 13 trials for ADHD with sample sizes ranging from 19 to 146 and durations ranging from 1 to 6 weeks [START_REF] Godfrey | Safety of therapeutic methylphenidate in adults: A systematic review of the evidence[END_REF]. One study reported hallucinations but in a population of patients with attention-deficit symptoms secondary to brain injury [START_REF] Godfrey | Safety of therapeutic methylphenidate in adults: A systematic review of the evidence[END_REF]. This further demonstrates the inadequacy of standard all-encompassing tolerability studies to investigate the matter and the need for RCTs specifically targeting psychotic events. Two observational studies were found to be eligible [START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. We did not expect this low number given the proportion of adults in prevalent MPH prescriptions, especially compared to Ramstad's sample. However in contrast, we found more registry-based studies (two versus one), which resulted in comparable total sample sizes between our study and Ramstad's, as well as higher overall quality, owing to both studies being controlled and one of them having a within individual design which allows for better control of confounders [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF][START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF]. Combined with our preliminary research we identified a total of 4 registry-based studies across adults and children, with the oldest being published in 2015, suggesting that the evidence gap affects both populations, and that interest in further exploring MPH-related psychotic events is recent [START_REF] Ramstad | Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with metaanalysis and trial sequential analysis #[END_REF][START_REF] Stricker | General practice database on mortality in adults on methylphenidate: cohort study[END_REF][START_REF] Hollis | Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study[END_REF][START_REF] Man | Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system[END_REF].

Four case-reports/series were found to be eligible, with an overall low quality [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. They contribute poorly to the body of evidence and were too heterogenous and unrepresentative to elicit a trend. Comorbid SUD was over-represented, with co-occurrent acute cocaine intoxication featured in one case, as well as co-prescription with Disulfiram in two cases [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. The range of intervals between exposition and outcome was wide (from a few hours to 3 years) and interval was undocumented in one case, follow-up data was either unavailable or inferior to a year [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF].

MPH cessation was accompanied by antipsychotic medication in four out of five cases, without information on timelapse between MPH cessation and antipsychotic introduction [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF][START_REF] Grau-López | Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent[END_REF]. Only one case documented reintroduction trial of MPH, and one case documented antipsychotic cessation [START_REF] Caci | A case of disulfiram-methylphenidate interaction: implications for treatment[END_REF][START_REF] Delavenne | Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate[END_REF].

Changes in the understanding of dopaminergic properties of MPH

The causality model between MPH usage and psychotic events relies on MPH's dopamine agonist activity in the mesolimbic pathways paired with its high affinity for DAT in these structures [START_REF] Curran | Stimulant psychosis: systematic review[END_REF][START_REF] Engert | Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate[END_REF]. This is especially true for high doses of MPH such as those used in older trials with single oral or intravenous administrations inducing transient psychotic symptoms in the following hours [START_REF] Curran | Stimulant psychosis: systematic review[END_REF][START_REF] Arnsten | Stimulants: Therapeutic Actions in ADHD[END_REF]. However, animal studies suggest that low doses such as those used in ADHD medication produce little to no effect on dopaminergic activity in mesolimbic pathways [START_REF] Engert | Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate[END_REF][START_REF] Arnsten | Stimulants: Therapeutic Actions in ADHD[END_REF]. Therapeutic effects may come instead from improvement of prefrontal cortical functioning by facilitation of endogenous catecholamine stimulation, especially of D1 (dopamine) and α2A (norepinephrine) receptors, similar to how Atomoxetine, a non-stimulant ADHD medication, works [START_REF] Engert | Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate[END_REF][START_REF] Arnsten | Stimulants: Therapeutic Actions in ADHD[END_REF]. A complementary model of MPH action in the brain suggests that low doses of MPH may induce a moderate increase in extra-synaptic dopamine levels, which in turn reduces post-synaptic response of D1 and D2 receptor activation, resulting in overall lower dopaminergic activity, which may explain action on locomotor hyperactivity [START_REF] Seeman | Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis[END_REF]. This prompted us to exclude studies exploring MPH misuse, including one case in Kraemer's case-series. Consistent with results of single high dose administration studies, symptoms were reported in the few hours following misuse [START_REF] Curran | Stimulant psychosis: systematic review[END_REF][START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Ghadrdan | Methylphenidate-Induced Psychotic Symptoms in 65-Year-Old Female with ADHD[END_REF]. However they showcase misuse intricated with other factors such as hypothyroidism or comorbid psychiatric conditions, which limits their relevance [START_REF] Kraemer | Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder: Report of 3 New Cases and Review of the Literature[END_REF][START_REF] Ghadrdan | Methylphenidate-Induced Psychotic Symptoms in 65-Year-Old Female with ADHD[END_REF].

The preferential activation of prefrontal dopaminergic pathways in low-dose MPH raises the question whether patients with schizophrenic disorder could benefit from MPH in order to reduce negative symptoms of schizophrenia (NSS). The dopamine dysregulation hypothesis of schizophrenia proposes that NSS could stem from lowered dopaminergic activity in mesocortical pathways and in the prefrontal cortex [START_REF] Toda | Dopamine hypothesis of schizophrenia: Making sense of it all[END_REF]. Other complementary models support that noradrenergic activity may also be lowered in these regions and contribute to NSS [START_REF] Toda | Dopamine hypothesis of schizophrenia: Making sense of it all[END_REF]. A 2013 systematic review by Lindenmayer J-P. et al. investigated use of prescription stimulants in treatment of NSS and suggests that stimulants may improve NSS in select patients with stable clinical features and adequate antipsychotic coverage [START_REF] Lindenmayer | A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: Challenges and therapeutic opportunities[END_REF]. A 2017 observational study by Rohde C. et al. aimed to examine the effect of stimulant prescription on naturalistic outcomes for patients with schizophrenia and suggests that stimulant prescription may reduce rehospitalization rate and duration of hospitalizations [START_REF] Rohde | Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia: A Nation-Wide Register Study[END_REF]. Whether stimulants prescription is safe for patients with schizophrenia remains unclear, as historic stimulant challenge trials suggest worsening of positive symptoms, while a 2018 systematic review by Solmi M. et al. of the efficacy and safety of stimulants in patients with schizophrenia did not find a significative increase in positive symptoms [START_REF] Toda | Dopamine hypothesis of schizophrenia: Making sense of it all[END_REF][START_REF] Solmi | Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder[END_REF].

ADHD and attention-deficit symptoms as risk factors for psychotic disorders

Current data suggests that MPH usage in children and adolescents with ADHD and subsequent psychotic disorders in late adolescence or adulthood are statistically associated [START_REF] Shyu | Attentiondeficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan[END_REF][START_REF] Nourredine | Association of Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence With the Risk of Subsequent Psychotic Disorder: A Systematic Review and Meta-analysis[END_REF][START_REF] Gering | TDAH dans l'enfance et trouble psychotique à l'âge adulte : quel lien ?[END_REF]. In a 2015 population-based observational study by Shyu Y-C. et al. MPH users with ADHD had a significant risk for subsequent schizophrenic disorder compared to controls without ADHD, but not compared to untreated controls with ADHD, which suggests that causality may be mediated by other factors linked to ADHD diagnosis [START_REF] Shyu | Attentiondeficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan[END_REF]. A 2021 systematic review by Nourredine M. et al. suggests solid evidence for a strong association between childhood or adolescent ADHD diagnosis and subsequent psychotic disorder diagnosis, with a pooled relative effect with 95%CI of 4.74 (4.11-5.46) for any psychotic disorder [START_REF] Nourredine | Association of Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence With the Risk of Subsequent Psychotic Disorder: A Systematic Review and Meta-analysis[END_REF]. The role of MPH usage cannot be ruled out, as most studies did not account for stimulant use in their adjusted analyses, but other hypotheses may be considered [START_REF] Nourredine | Association of Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence With the Risk of Subsequent Psychotic Disorder: A Systematic Review and Meta-analysis[END_REF].

Schizophrenic disorder is a late-onset neurodevelopmental disorder and may share common risk factors with ADHD [START_REF] Gering | TDAH dans l'enfance et trouble psychotique à l'âge adulte : quel lien ?[END_REF][START_REF] Nivard | Genetic Overlap Between Schizophrenia and Developmental Psychopathology: Longitudinal and Multivariate Polygenic Risk Prediction of Common Psychiatric Traits During Development[END_REF]. A genetic overlap exists between ADHD (and childhood-onset neurodevelopmental disorders in general) and schizophrenic disorder [START_REF] Nivard | Genetic Overlap Between Schizophrenia and Developmental Psychopathology: Longitudinal and Multivariate Polygenic Risk Prediction of Common Psychiatric Traits During Development[END_REF]. Select monogenic variations in gene copy number have been found to be at risk for both disorders, though polygenic polymorphisms of genes implicated in monoaminergic transmission in the brain are a more common feature [START_REF] Gering | TDAH dans l'enfance et trouble psychotique à l'âge adulte : quel lien ?[END_REF]. Early risk factors also include perinatal factors (prematurity, obstructed labor, substance use during pregnancy) and immunologic factors (auto-antibodies targeting monoamine synthesis enzymes) [START_REF] Gering | TDAH dans l'enfance et trouble psychotique à l'âge adulte : quel lien ?[END_REF].

Patients with schizophrenic disorder commonly exhibit an array of attention-deficit symptoms also shared with ADHD, such as impairments in sustained attention, vigilance and working memory [START_REF] Egeland | Differentiating attention deficit in adult ADHD and schizophrenia[END_REF]. Despite these common features misdiagnosis is exceptional in the symptomatic phase of schizophrenic disorder [START_REF] Egeland | Differentiating attention deficit in adult ADHD and schizophrenia[END_REF]. In the prodromal phase however, attentiondeficit symptoms may be in the forefront of the clinical presentation. Prodromal symptoms may appear as early as childhood and lead to a diagnosis of ADHD and MPH prescription [START_REF] Egeland | Differentiating attention deficit in adult ADHD and schizophrenia[END_REF]. A 2019 systematic review by Arican I. et al. suggests that attention-deficit symptoms in childhood are significantly more prevalent in patients with schizophrenic disorder compared to the general population, with up to 34% of patients rating positive for retrospective scales routinely used in ADHD diagnosis [START_REF] Arican | Prevalence of attention deficit hyperactivity disorder symptoms in patients with schizophrenia[END_REF]. In this perspective, a child or adolescent may display attention-deficit symptoms in relation to a complex neurodevelopmental process which may lead to subsequent 29 psychotic disorders, symptom severity and late onset may attest of higher vulnerability, and MPH initiation may be more common in this subset of patients [START_REF] Man | Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system[END_REF][START_REF] Nourredine | Association of Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence With the Risk of Subsequent Psychotic Disorder: A Systematic Review and Meta-analysis[END_REF][START_REF] Gering | TDAH dans l'enfance et trouble psychotique à l'âge adulte : quel lien ?[END_REF].

Conclusion

This study provides a new overview of the risk for psychotic symptoms and disorders with MPH introduction in adults with ADHD. Our results suggest that MPH introduction may be associated with psychotic symptoms or disorders, but that causality between both factors remains unclear. The extent of our findings is severely hindered by the quality of current body of proof currently surrounding the matter. Future research should aim to produce good-quality populationbased studies and RCTs designed with psychotic disorders as an outcome in mind. Moving forward studies should consider competing hypotheses which may also explain statistic associations between MPH usage and psychotic symptoms and disorders. CD CD Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants?

Yes Yes

Was a sample size justification, power description, or variance and effect estimates provided?

No No

For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured?

Yes Yes

Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?

Yes Yes Psychotic side effects may occur within weeks following initiation For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)?

No No

Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

Yes Yes

Was the exposure(s) assessed more than once over time? Yes Yes Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

Yes Yes

Were the outcome assessors blinded to the exposure status of participants? No No Was loss to follow-up after baseline 20% or less? CD CD Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Résumé / Abstract

Troubles et symptômes psychotiques secondaires à l'introduction du méthylphénidate chez l'adulte présentant un TDAH : une revue de la littérature

Le trouble déficitaire de l'attention hyperactivité (TDAH) est un trouble neurodéveloppemental débutant dans l'enfance pouvant persister à l'âge adulte où la prévalence mondiale atteint 2,5%. Le primo-diagnostic chez l'adulte est désormais fréquent, ainsi que l'initiation d'un traitement comme par méthylphénidate (MPH). Le MPH serait associé à un risque de psychose d'après les études chez l'enfant réalisées après mise sur le marché américain. Cette revue de la littérature vise à explorer le risque de troubles ou symptômes psychotiques secondaires à l'introduction du MPH chez des adultes présentant un TDAH.

Nous avons mené une revue systématique de toutes les études évaluant l'initiation du MPH chez l'adulte TDAH avec pour critère de jugement le risque de troubles ou symptômes psychotiques. Nous avons réalisé une revue narrative et une évaluation de la qualité de l'échantillon. Le manque de données n'a pas permis la réalisation d'une méta-analyse.

Notre revue systématique a retrouvé 6 articles, dont 2 études observationnelles basées sur des registres nationaux et 4 études de cas. La revue narrative est en défaveur d'une augmentation du risque de psychose secondaire à l'initiation du MPH et suggère une susceptibilité plutôt liée au diagnostic de TDAH, surtout en cas de TLUS associé.

La portée de notre revue est limitée par la faible qualité de l'échantillon. Les recherches futures devront comporter des essais cliniques conçus pour détecter ces évènements rares et prendre en compte l'intérêt grandissant du MPH dans les symptômes négatifs des troubles schizophréniques, ainsi que l'exploration du lien direct entre TDAH et troubles psychotiques.

Psychotic symptoms and disorders secondary to methylphenidate introduction in adults with ADHD: a review of literature

Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder which may persist into adulthood with a worldwide prevalence of 2,5%. First diagnosis and treatment in adults is a growing trend, methylphenidate (MPH) being one of the most prevalent choices of medication. MPH may be associated with psychotic events according to safety studies in children. This review aims to explore the risk of incident psychotic symptoms and disorders after MPH introduction in adults.

We conducted a systematic review of studies of all designs which examine MPH initiation in ADHD adults as intervention and incident risk of psychotic events as outcome. We ran a narrative review and quality assessment of the sample. No meta-analysis was run owing to the scarcity of data.

Our systematic search yielded 6 articles, of which 2 nation-wide registry-based observational studies and 4 case-reports/series. The narrative review does not suggest a higher risk of psychotic events secondary to MPH initiation and highlights a possible higher baseline risk in ADHD patients and more so if there is a comorbid SUD.

These conclusions are hindered by the lack of good quality studies. Future research should aim to produce RCTs designed to elicit such rare events and should consider the growing interest in MPH to treat negative symptoms of schizophrenic disorder, as well as the body evidence suggesting a direct link between ADHD and psychotic disorders.

Mots-clés :

Trouble du Déficitaire de l'Attention avec Hyperactivité ; Adulte ; Méthylphénidate ; Troubles Psychotiques ; Effets Secondaires Indésirables des Médicaments Spécialité : Psychiatrie

  Psychotic symptoms and disorders secondary to methylphenidate introduction in adults with ADHD: a review of literature ................................................................................. Introduction .............................................................................................................................. Method ...................................................................................................................................... Protocol ................................................................................................................................................. Search strategy ...................................................................................................................................... Inclusion and exclusion criteria ............................................................................................................ Outcomes .............................................................................................................................................. Data extraction ...................................................................................................................................... Quality assessment................................................................................................................................ Meta-analysis ........................................................................................................................................ Results ....................................................................................................................................... Search results ........................................................................................................................................ Quality assessment................................................................................................................................ Narrative review of observational studies ............................................................................................ Narrative review of case-reports/series ................................................................................................ Grey literature ....................................................................................................................................... Discussion ................................................................................................................................. Limitations in eligible studies and in overall body of proof ................................................................. Changes in the understanding of dopaminergic properties of MPH ..................................................... ADHD and attention-deficit symptoms as risk factors for psychotic disorders ................................... Conclusion ................................................................................................................................ Annexes .............................................................................................................................

Figure 1 :Table 1 :Table 2 :Table 3 :

 1123 Figure 1: PRISMA Flow Chart ..............................................................................................

  Hollis C. et al. included patients between 12 and 30 years, without providing justification for this age range[27]. Stricker B. et al. used a control group of 88293 (with 10 non-MPH-user for one MPH-user) sampled in the same database as the study subjects and matched on sex, age and GP-practice[26]. Hollis C. et al. used a within-individual control design, each participant being its own control preintervention[27]. Stricker B. et al.'s study population was found to be significantly different to the control group, owing to a higher proportion of patients BMI > 25 and with a history of alcohol use disorder, tobacco use disorder, medicine misuse, substance use disorder, organic psychosis, affective psychosis and non-specified psychotic disorders (but not schizophrenic disorder), anxiety disorders, depression disorder, suicide attempts, personality disorders, or previous or current use of antipsychotics, antidepressants, anxiolytics and sedatives[26]. Both studies use MPH initiation as an intervention, relying on prescription registries for Stricker B. et al. or dispensation registries for Hollis C et al[26,27]. Stricker B. et al. traced galenic and dosage of MPH for secondary analysis but did not provide a description of the study population regarding this data[26]. Mean follow-up was 277 weeks for Stricker B. et al. and 64 weeks for Hollis C. et al.

  et al. and 3 years for Kraemer M et al. Resolution of symptoms ranged between one day for Caci H. et al. and one month for Delavenne H. et al. Resolution was obtained via cessation of MPH in all cases, plus additional antipsychotic medication in four cases (Olanzapine raging from 2,5mg/day to 10mg/day or Risperidone 9mg/day)

Table 1 :

 1 Quality assessment criteria and results

NHLBI Study Quality Assessment Tools for Observational Studies

	CRITERIA	Hollis C. et	Stricker B.
		al.[27]	et al.[26]
	Was the research question or objective in this paper clearly stated?	Yes	Yes
	Was the study population clearly specified and defined?	Yes	Yes
	Was the participation rate of eligible persons at least 50%?

Table 2 :

 2 Population and intervention of observational studies

	REF. AUTHOR YEAR COUNTRY DESIGN		SOURCE POPULATION	INCLUSION CRIT.	EXCL. CRIT.	DURATION
	[27] Hollis C.	2019	Sweden	Population based within-	Swedish in and outpatients	MPH starter or last	Prescription of	64 weeks
	et al.			individual comparison	registered in the Swedish	prescription > 1,5y	other ADHD
				prospective cohort study	National Patient Registry	Age 12-30yo at	medication
								initiation
	[26] Stricker	2022	Netherlands Population based	Deutsch outpatients with >1y	MPH starter	MPH started	Mean follow-
	B. et al.			matched prospective	of medical history registered	>18yo	before ICPI	up of 1943
				cohort study	on the Deutsch ICPI database		registering	days
	MPH: Methylphenidate ; ICPI: Integrated Primary Care Information
	(continued)
	REF. INTERVENTION N (INT.) N (CON.) OUTCOMES		RESULTS		COMMENTS
	[27] MPH any		23898 (within	Incidence of psychotic	IRR(95%CI) in patients with	IRR(95%CI) in secondary analysis in patients with
	formulation		individual		events as defined by	history of psychosis for		history of psychosis for period 2 0.8(0.59-1.7), period 3
	Mean dosage not	comparison)	inpatient admission or	period 3 0.95(0.69-1.3),		0.76(0.56-1.02), period 4 0.51(0.36-0.72) ; in patients
	specified				outpatient attendance	period 4 0.64(0.45-0.91) ; in	without history of psychosis for period 2 2.11(1.53,2.92),
					(in or outpatient) with	patients without history of		period 3 2.19(1.58-3.02), period 4 1.72(1.23-2.41)
					a matching diagnosis	psychosis for period 3
					(ICD-10 coding)		1.04(0.8-1.34), period 4
							0.82(0.62-1.07)
	[26] MPH any		8905	88293	Incidence of		Adjusted HR(95%CI) for		Difference (95%CI) between intervention and control
	formulation				psychiatric adverse	organic psychosis 1.7(0.9-3),	group for proportion of AUD 4.1(3.6-4.7), medication
	Mean dosage			event as defined by	schizophrenia 0.9(0.2-4.3),	use disorder 3.8(3-4.8), any SUD 6.4(5.7-7.1), history of
	30mg at start,			coding of a matching	affective psychosis 1.2(0.4-	organic psychosis 2.6(1.6-3.3), affective psychosis
	35mg on last				diagnosis after index	3.6), other non-specified		3.3(2.6-4.3), other non-specified psychotic disorder
	prescription				date (ICPC coding)	psychotic disorder 1.4(0.9-	2.2(1.7-2.8), any psychiatric disorder 4.5(4.3-4.7),
							1.8), any psychosis 1.3(0.9-2)	previous or current use of antipsychotics 4.8(4.4-5.2)

Table 3 :

 3 Population and intervention of case-series/reports : Alcohol use disorder ; OROS : Osmotic Release Oral System ; MDD : Major depressive disorder ; CUD : Cocaine use disorder ; SUD: Substance use disorder 40

	REF. AUTHOR YEAR COUNTRY CASE DESCRIPTION	INTERVENTION OUTCOME RESULTS	RESOLUTION FOLLOW-UP
	[29] Caci H. et	2007	France	33yo male. ADHD diagnosed at 33yo.	OROS-MPH	"Psychotic-like	Immediate cessation of
	al.			History of AUD since age 15, convulsive	36mg/day	experience" during a few	symptoms after Disulfiram and
				episode before MPH initiation (timelapse		hours after first intake,	MPH withdrawal. MPH
				unknown). Disulfiram 400mg/day		no evidence of	reintroduction (w/o Disulfiram)
				prescribed before MPH initiation		concomitant intoxication	trial at 3 months. 8 months
				(timelapse unknown)			total follow-up without relapse
	[28] Kraemer	2010	Germany	38yo female. ADHD diagnosed at 38yo.	Ritaline (IR)	Paranoid delusions,	Cessation of symptoms "a few
	M. et al.			History of MDD and panic disorder	15mg/day	olfactory hallucinations	days" after MPH withdrawal
						for 3 weeks, after "a few	and introduction of Olanzapine
						months" of treatment	2,5mg/day. No follow-up data
							available
				45yo male. ADHD diagnosed at 42yo.	Concerta (OROS)	Anxiety, insomnia,	Cessation 3 weeks after MPH
				History of birth trauma with right	54mg/day +	paranoid delusions and	withdrawal and Paliperidone
				cervical plexus paresis.	Ritaline (IR) 10-	illusions of reference 3	9mg/day. 5 weeks total follow-
					20mg/day	years after MPH	up without relapse
						initiation
	[30] Delavenne	2013	France	43yo male. ADHD diagnosed at 43yo.	Ritaline (OROS)	Paranoid delusions,	"Gradual" cessation of
	H. et al.			History of CUD since age 19, multiple	30mg/day	auditory and visual	symptoms after MPH
				instances of psychotic symptoms during		hallucinations 10 days	withdrawal and Olanzapine
				acute cocaine intoxication		after MPH introduction	20mg/day for 1 month. 1
						and concomitant cocaine	month total follow-up without
						intoxication	relapse.
	[31] Grau-	2012	Spain	31yo male. ADHD diagnosed at 31yo.	OROS-MPH	Paranoid delusions,	Cessation 2 weeks after MPH
	Lopez L.			History of borderline personality	36mg/day for 2	auditory hallucinations,	withdrawal (but not
	et al.			disorder, AUD since age 25, CUD since	weeks, then	thought blockades after	Disulfiram) and introduction of
				age 21, ceased cannabis use disorder.	54mg/day	54mg/day stage	Olanzapine 10mg/day. No
				Family history of SUD and pathological		(timelapse unknown), no	follow-up data available
				gambling in identical-twin. Disulfiram		evidence of concomitant
				250mg/day prescription concomitant to		intoxication
				MPH initiation

AUD

INT.: Intervention ; CON.: Control ; ICD: International Classification of Diseases ; IRR: Incidence Rate Ratios ; ICPC: International Classification of Primary Care

Annexes


Emeline Lhoumaud

Yann Gunzburger

Marianne Conin

Jannes Kinscher

Origin of seismic repeaters in a deep mine: what do we learn from in-situ investigation coupling geology, geomechanics and geophysics?

Keywords: Induced seismicity, seismic repeaters, deep mining, in-situ investigation

Seismic repeaters (i.e. seismic events with highly similar waveforms) have been observed in the deep mine of Garpenberg, Sweden. In natural seismology, repeaters are commonly associated with the presence of aseismic slip (i.e. creep) on fault planes, loading seismogenic asperities. This raises questions regarding what these asperities and creeping zone consist of and how they behave from a mechanical point of view. A local monitoring network has been installed in situ, close to the source area of one family of repeaters at 1km depth, with the objective of identifying the origin of these repeaters. The network comprises boreholes, geophones and strain cells. We show that the presence of a fault plane with creeping portions and an asperity is compatible with field data. We also discuss the difficulty of clearly identifying the origin of the repeaters, as we couldn't reach the seismic asperity itself, even with such a local network.

INTRODUCTION

Type area and previous analyses

The Garpenberg mine is located in central Sweden and is exploited by Boliden mining company. It is composed by several vertical massive sulphides lenses, hosted by altered and metamorphosed felsic volcanic rocks and limestone [START_REF] Tiu | Ore mineralogy and trace element (re)distribution at the metamorphosed Lappberget Zn-Pb-Ag-(Cu-Au) deposit, Garpenberg, Sweden[END_REF]. The orebody of Lappberget is the largest in the mine [START_REF] De Santis | Impact of Geological Heterogeneities on Induced-Seismicity in a Deep Sublevel Stoping Mine[END_REF]. It is cut by several shear zones, parallel to the orebody and associated with talc and chlorite. The area of our study is located within a sill-pillar at 1km depth, just above the panel of excavation block 1250 (see Figure 1). The mainly-used mining method is sublevel stoping. [START_REF] Kinscher | Seismic repeaters linked to weak rock-mass creep in deep excavation mining[END_REF] highlighted the presence of 17 families of repeaters within the block 1250 and the sill-pillar (-2.5 < Mw < 1, on moment magnitude scale). Repeaters are well-known in natural seismology. They have been for example intensively studied on the San-Andreas fault [START_REF] Nadeau | Clustering and periodic recurrence of microearthquakes on the San Andreas fault at Parkfield, California[END_REF] and on the North Anatolian fault [START_REF] Uchida | Detection of repeating earthquakes and their application in characterizing slow fault slip[END_REF]. They are commonly associated with the presence of the seismogenic breaking of asperities loaded by aseismic slip within weak material filled fault planes [START_REF] Carpenter | Weakness of the San Andreas Fault revealed by samples from the active fault zone[END_REF][START_REF] Chen | Scaling of small repeating earthquakes explained by interaction of seismic and aseismic slip in a rate and state fault model[END_REF][START_REF] Dieterich | Earthquake nucleation on faults with rate-and state-dependent strength[END_REF].

Source mechanisms of the repeaters show a strike-slip movement with a reverse component. Their sources align along horizontal directions parallel to the stopes (Y axis) and are reactivated over long periods of time (from several days up to several years). Magnitudes range between -2 and 1, at the moment scale magnitude. [START_REF] Kinscher | Seismic repeaters linked to weak rock-mass creep in deep excavation mining[END_REF] suggest repeaters are triggered by fractures filled with weak-material like talc, loading asperities of a few meters size. To identify the origin of these repeaters more precisely, we focused on one specific family (Table 1) located within the sill-pillar, accessible from mine drifts. We aim at reaching the structure at the origin of the repeaters and study its characteristics.

Local installation

Several boreholes with different orientations and inclinations were drilled to reach the source of the repeaters family and compare field data with what is usually observed in presence of repeaters in seismology (see Figure 2). Four CSIRO Hi12 strain cells were installed in the boreholes. Each of them comprises 12 gauges and records strains every minute. The installation is located between the orebody (siliceous rocks with different types of micas) and the hosting rocks (sedimentary and marble rocks), which are lithologies commonly observed elsewhere in the mine.

DATA ANALYSES

Drill cores analysis

The orientations of the fractures in the cores have been measured using the method of Holcombe (2013). Only one family of fractures has an orientation compatible with the orientation of the target fault plane given by the seismic analyses (Figure 3). X-ray diffraction (XRD) shows that these fractures contain muscovite and chlorite infilling. Chlorite has a low coefficient of friction [START_REF] Ikari | Frictional and hydrologic properties of clay-rich fault gouge[END_REF], which suggests it may slip aseismically. Therefore, similarly to what is known from natural seismology, we can assume the boreholes have intersected the aseismic part of the fault plane at the origin of the repeaters. The locked part of the fault with higher coefficient of friction (i.e. seismic asperity), loaded by this aseismic slip and breaking repetitively, is unknown. with the seismic nodal plane given by previous seismic analyses.

Strain monitoring

An instantaneous co-seismic shift of deformation of around 6 microstrains (µɛ) was monitored by the strain cell BH4 during a seismic event of magnitude M=-1. This event is an order of magnitude higher than the other events monitored during the eight months of observation, which explains why it has been detected. The immediate response is visible on the cell recordings and we have calculated the strain tensor associated with this event [START_REF] Amadei | Rock stress and its measurement[END_REF][START_REF] Worotnicki | Csiro Triaxial Stress Measurement Cell[END_REF]. The three principal strains are shown in Figure 4.

EVALUATION OF THE PRESENCE OF AN ASEISMIC/SEISMIC COUPLED FAULT PLANE

Location of the seismogenic asperity

Strain data were used, along with Okada's model [START_REF] Okada | Internal deformation due to shear and tensile faults in a half-space[END_REF] to locate the seismic asperity, using an inverse-problem approach. With Okada's model, the strain tensors induced by a rectangular dislocation within an elastic and isotropic medium can be calculated analytically. We computed the induced strains for different possible locations of the asperity, within a radius of 10 meters around the location of the seismic event of the 18th of January given by seismic analyses (based on location error). The size of the asperity in the model ranges between 1 and 10 meters. For each location of the dislocation, strain tensors are computed at the location of the strain cells and compared with strain measurements. Computed and measured strains are considered as compatible if the signs are the same, if strain mainly occurs along the extensive component (ɛ3) and if the orientations of principal strains are within the uncertainty range of the strain cells. Modeled and BH3/BH1 cells are compatible if their values are considered sufficiently small not to be detected by the cells. Doing so, we identified two clusters of possible locations for the seismic asperity (Figure 5). Both are outside the area reached by the drillings. The area located to west is generally closer to the seismic event location and we show a possible location for the asperity within the cluster. The chosen asperity has a size of 3m x 3m and is at 6 m from the location given by seismic analysis, which is consistent with the location error.

Aseismic/seismic fault plane

We consider that the asperity is part of a fault plane slipping aseismically, as commonly described in seismology. Dimensions of the plane are unknown but we consider the plane large enough to be reached by the drillings. The orientation is assumed to be the same as that given by seismic analyses.

One drilling intersects the plane where most of F3 fractures (oriented similarly to the seismic nodal plane and with chlorite infilling) have been observed in the drill cores. This shows an excellent agreement between geophysical, geological and geomechanical data. Blue spheres represent two clusters C1 and C2 of possible localizations of the asperity, determined from both seismic and strain data. One asperity has been chosen and is showed in dark blue. The asperity is located at 6meters from the seismic event (purple sphere). The asperity is assumed to be located on an aseismically slipping fault (light blue) with similar orientation. This fault plane crosses the drillings where F3 fractures have been observed in the drill cores. Slip on the asperity simulated with Okada model gives strain values compatible with BH4 cell.

CONCLUSION

The studied area represents an incredible opportunity to investigate the origin of seismic repeaters in a deep mine. We show seismic repeaters in the monitored area can be triggered by the presence of a fault plane entailing aseismic portions and at least one asperity, as commonly observed in natural seismology. Drillings crossed a family of fractures with a weak-material infilling and with an orientation similar to the seismic nodal plane, which might correspond to the aseismic portion of the fault plane. The seismic asperity was not observed in the drillings but strain cells allowed us to locate it outside the area reached by the drillings but not far away. Our model also shows that a size of the asperity between 1-10 m, as given by as seismic analysis, give strain measurements consistent with what is monitored. Further investigations are needed to actually conclude on the origin of these repeaters. One option would be to drill in the clusters of new constrained locations of the asperity to try to reach it. If successful, we would have access to both seismic and aseismic portions of the plane, which will represent an incredible opportunity to study the behavior of such a fault plane.

Figure 1 .

 1 Figure 1. (a) Vertical view of the orebody of Lappberget and (b) a zoom of the area of monitoring of Ineris since 2015. Spheres of different colors represent the 17th families of repeaters detected by the previous network. Upper right image (c) is a plane view of the monitored area and shows the alignment of the families along Y-axis direction. Red square indicates the family of repeaters described in table 1, which is the target family of our study, located in the sill-pillar of the area.

Figure 2 .

 2 Figure 2. Local installation within the sill-pillar. Events of the target family are showed in blue spheres. Colored stars and green lines represent the strain cells and their associated drillings. Red lines show two additional drillings for lithological and fracturation information. Upper and below drifts of excavation of the sill-pillar are represented in grey.

Figure 3 .

 3 Figure 3. Orientation of the fractures in the drill cores. Main families are F1 and F2 families, highly represented in the drill cores. Blue circle represents the only secondary family with orientation compatible with the seismic nodal plane given by previous seismic analyses.

Figure 4 .

 4 Figure 4. Principal strains during the co-seismic shift of deformation. Dots represent incertitude on the orientations. Values are ɛ3=-6,6µɛ (extension), ɛ2 = +0,96µɛ (shortening), ɛ1 = +1,7µɛ (shortening). The deformation occurs mainly as an extension (ɛ3) in the drilling direction (BH4).

Figure 5 .

 5 Figure 5. Localization of one possible fault plane responsible of the monitored seismicity with one asperity.Blue spheres represent two clusters C1 and C2 of possible localizations of the asperity, determined from both seismic and strain data. One asperity has been chosen and is showed in dark blue. The asperity is located at 6meters from the seismic event (purple sphere). The asperity is assumed to be located on an aseismically slipping fault (light blue) with similar orientation. This fault plane crosses the drillings where F3 fractures have been observed in the drill cores. Slip on the asperity simulated with Okada model gives strain values compatible with BH4 cell.

Table 1 .

 1 Characteristics of the nodal plane of target family of repeaters given by seismic analyses. The nodal plane is deduced from the seismic source mechanism and events location.

	Strike	Dip	Rake Source mechanism	Mw average	Slip average
	190°	75°	130° strike-slip with reverse component	-0,3	1mm