Somatic health according to people with severe mental disease.

OBJECTIVES: Patients with schizophrenia have a 15- to 20-year shorter life expectancy compared with the general population. The aim of this study was to explore these patients' perception of their physical health. METHODS: A patient reported outcomes measure (PROM) has been developed by patients with severe mental disease. This survey had to better capture undetected, under-rated and non-prioritized physical domains by traditional routine clinical scales that are important for people who live with mental health disease. These patients have tested the applicability of this PROM with peers with severe mental disease in medical, social and community-based centers from Hauts-de-France. RESULTS: Two and a half years have been required to develop this PROM, to test its applicability to patients with severe mental disease and to analyze the results. The study process has been slowed by the sanitary context induced by the COVID-19 pandemic. Thirty-two questionnaires have been collected by the participants. Despite this low number of data, participants have been satisfied by the results and their experience. The results show that people with severe mental disease consider physical health as a major concern, notably pain and somatic diseases. External factors (such as accessibility to health care and medication) and internal factors (such as self-esteem, cognitive and negative symptoms, sleep, alimentation, and substance use) have been identified as barriers for physical health. CONCLUSIONS: These results support the development of PROMs highlighting personal experience of people with severe mental disease. The data obtained thanks to these measures will allow to build programs to help them to cope with barriers for physical health.

Staging's determinants in early intervention youth: a retrospective study.

OBJECTIVES: Since 2019 our early intervention unit has assessed help-seekers, mainly referred by psychiatric departments, and we have conducted a descriptive retrospective study. Our objective was to identify clinical determinants associated to staging at assessment for our three groups: "no psychosis", "ultra-high risk" and "first episode psychosis". METHODS: One hundred and thirteen participants (mean age 20.05±3.28) were enrolled, mainly referred by adult psychiatry (81.4%). We tested the association of each group with the following determinants: age, gender, family history of psychosis, referral (adolescent or adult psychiatry), cognitive, depressive complaint, cannabis active consumption, and current activity (scholar or employment). RESULTS: Multivariate analyses showed significant association with depressive symptoms (P=0.019) but an absence of family history of psychosis (P=0.002) or current activity (P=0.09) for "no psychosis" group. "Ultra-high risk" was significantly correlated with a family history of psychosis (P=0.001) and adolescent psychiatry referral (P=0.044) but an absence of depressive complaint (P=0.04). As for "first episode psychosis", we found significant cognitive complaint (P=0.026), family history (P=0.024) and current activity (0.026). CONCLUSIONS: As all our participants were seen in tertiary care, adolescent psychiatrists were more efficient in detecting a high-risk state. "No psychosis" help-seekers presented in fact mood issues, which have been confused with attenuated psychotic symptoms by their addressers, who have probably been misled by their absence of activity integration. High-risk and characterized psychotic episodes were logically correlated with family history. Surprisingly, "first episode psychosis" youth were currently integrated in scholarly or professional life despite an active cognitive complaint. Robust studies, especially prospective cohorts, are needed to test these associations.

Does Change over Time in Delusional Beliefs as Measured with PDI Predict Change over Time in Belief Flexibility Measured with MADS?

Delusional beliefs and their behavioral consequences are predominant symptoms in patients with psychosis and play an important role in the treatment. Delusional beliefs are a multidimensional concept which can be divided into three components: distress, preoccupation and conviction of delusions. These can be measured using Peters delusions inventory (PDI-21). We question, whether changes in delusional beliefs over time during treatment measured with the PDI-21 can predict changes in belief flexibility measured with the Maudsley assessment of delusions schedule (MADS). We used a group of patients from a randomized controlled trial for a cognitive intervention for psychosis or psychotic symptoms. Aside standard treatment for psychosis, half of the patients took part in a group treatment "Michael's game". Patients were assessed at baseline (T1), at 3 months (T2), and at 9 months (T3). We measured delusional beliefs using PDI-21 and belief flexibility with the MADS. One hundred seventy-two patients were included in the analysis. We measured a main effect of PDI-21scores on belief flexibility measured with MADS. PDI-21 Conviction scores predicted outcomes for all measured MADS items. Increasing PDI Distress and Preoccupation scores were predictors for being more likely to dismiss beliefs and change conviction. Time itself was a predictor for changing conviction and being able to plan a behavioral experiment. Overall the changes in PDI scores predicted outcomes for belief flexibility measured with MADS items. The PDI-21 could be a simple and effective way to measure progress in treatment on delusional beliefs.

Cognitive complaint inversely associated to UHR transition.

The aim of this study was to identify the impact of staging on a six-months transition in Ultra-High Risk (UHR) youth. Subjects were enrolled at assessment; evolution was monitored for six months. Clinical determinants (unusual thought content, perceptual abnormalities, cognitive complaint, etc.) were collected. 37 non-psychotic and 39 UHR subjects were included. 13 UHR (35.2 %) experienced psychotic transition, while none of non-psychotic subjects did log-rank p < 0.001. Self-reported cognitive complaint was inversely associated to transition OR 0.13 95 % IC [0.03-0.64]. Unusual Thought Content was associated to psychotic transition 0R 8.57 95 % IC [1.17-63]. Self-reported cognitive complaint could be a protective transition marker in UHR.

Prospective Acceptability of Digital Therapy for Major Depressive Disorder in France: Multicentric Real-Life Study.

BACKGROUND: Major depressive disorder is one of the leading causes of disability worldwide. Although most international guidelines recommend psychological and psychosocial interventions as first-line treatment for mild to moderate depression, access remains limited in France due to the limited availability of trained clinicians, high costs for patients in the context of nonreimbursement, and the fear of stigmatization. Therefore, online blended psychological treatment such as Deprexis could improve access to care for people with depression. It has several advantages, such as easy accessibility and scalability, and it is supported by evidence. OBJECTIVE: This study aims to evaluate the real-life acceptability of Deprexis for people with depression in France outside of a reimbursement pathway. METHODS: Deprexis Acceptability Study Measure in Real Life (DARE) was designed as a multicenter cross-sectional study in which Deprexis was offered to any patient meeting the inclusion criteria during the fixed inclusion period (June 2022-March 2023). Inclusion criteria were (1) depression, (2) age between 18 and 65 years, (3) sufficient French language skills, and (4) access to the internet with a device to connect to the Deprexis platform. Exclusion criteria were previous or current diagnoses of bipolar disorder, psychotic symptoms, and suicidal thoughts during the current episode. The primary objective was to measure the prospective acceptability of Deprexis, a new digital therapy. Secondary objectives were to examine differences in acceptability according to patient and clinician characteristics and to identify reasons for refusal. All investigators received video-based training on Deprexis before enrollment to ensure that they all had the same level of information and understanding of the program. RESULTS: A total of 245 patients were eligible (n=159, 64.9% were women and n=138, 56.3% were single). The mean age was 40.7 (SD 14.1) years. A total of 78% (n=191) of the patients had moderate to severe depression (according to the Patient Health Questionnaire-9 [PHQ-9]). More than half of the population had another psychiatric comorbidity (excluding bipolar disorder, psychotic disorders, and suicidal ideation). A total of 33.9% (n=83) of patients accepted the idea of using Deprexis; the main reason for refusal was financial at 83.3% (n=135). Multivariate logistic regression identified factors that might favor the acceptability of Deprexis. Among these, being a couple, being treated with an antidepressant, or having a low severity level favored the acceptance of Deprexis. CONCLUSIONS: DARE is the first French study aiming at evaluating the prospective acceptability of digital therapy in the treatment of depression. The main reason for the refusal of Deprexis was financial. DARE will allow better identification of factors influencing acceptability in a natural setting. This study highlights the importance of investigating factors that may be associated with the acceptability of digital interventions, such as marital status, medication use, and severity of depression.

Understanding the potential of digital therapies in implementing the standard of care for depression in Europe.

Depressive disorders represent the largest proportion of mental illnesses, and by 2030, they are expected to be the first cause of disability-adjusted life years [1]. The COVID-19 pandemic exacerbated prevalence and burden of depression and increased the occurrence of depressive symptoms in general population [2]. The urgency of implementing mental health services to address new barriers to care persuaded clinicians to use telemedicine to follow patients and stay in touch with them, and to explore digital therapeutics (DTx) as potential tools for clinical intervention [2]. The combination of antidepressants and psychotherapy is widely recommended for depression by international guidelines [3] but is less frequently applied in real-world practice. Commonly used treatments are pharmacological, but while being effective, some aspects such as adherence to the drug regimen, residual symptoms, resistance, lack of information, and stigma may hinder successful treatment. In case of less severe depression, standalone psychological therapies should be the first-line treatment option [3], but access to trained psychotherapists remains inequitable. DTx are evidence-based therapies driven by software programs to treat or complement treatment of a specific disease. DTx are classified as Medical Devices, and given their therapeutic purpose, they need to be validated through randomized controlled clinical trials, as for drug-based therapies. In the last 10 years, studies of digital interventions have proliferated; these studies demonstrate that digital interventions increase remission rates and lower the severity of depressive symptoms compared with waitlist, treatment as usual, and attention control conditions [4]. Despite the efficacy demonstrated in clinical trials, many of these tools never reach real-life patients; thus, it might be necessary to implement DTx in the public health system to expand access to valid treatment options. In this framework, DTx represent a good opportunity to help people with depression receive optimal psychotherapeutic care [5].

[Psychosocial Interventions for People with a First-Episode Psychosis: A Narrative and Critical Review]. / Les interventions psychosociales destinées aux personnes composant avec un premier épisode psychotique : une revue narrative et critique.

Objective Treatment guidelines for the treatment of psychotic disorders suggest evidence-based interventions. These interventions target several domains such as self-management of clinical symptoms, social, familial and love relationships as well as cognitive functioning. However, these general guidelines do not provide specific evidence for people with a first-episode psychosis (FEP). The objective of this narrative and critical review is to present evidence supporting the interventions suggested by the treatment guidelines that were validated in people with a FEP, particularly those interventions validated in French. Method Based on the international and national treatment guidelines, a narrative and critical review of the scientific literature conducted in people with FEP and focusing on two recommended interventions for psychotic disorders, cognitive-behavioral therapy for psychosis (CBTp) and cognitive remediation (CR), was performed. Administration modalities adapted to the participant's profile are important to consider in this type of intervention. We thus explored two promising modalities in people with FEP, the group format and the use of digital technologies. Results Several studies support the use of CBTp in people with FEP, including one Quebec study. The effects of CR are less promising in people with FEP compared to those with a chronic evolution of their psychotic illness (e.g. schizophrenia). However, some limitations of the included studies are identified and the specific improvements in people with FEP are presented. Regarding the group format and the digital technologies, most interventions currently available need to be systematically validated, and the results need to be replicated by other groups of researchers to obtain evidence-based results. Conclusion This narrative and critical review of the literature highlights the evidence available for CBTp and CR in people with FEP. The group format used in several interventions with this population reveals encouraging results, while interventions using digital technologies have shown their acceptability and feasibility, but the efficacy remains to be assessed. In addition to contributing to symptomatic recovery, psychosocial interventions also support functional and personal recovery in people with FEP. Nonetheless, some limitations are observed regarding the accessibility of such interventions. While some interventions are currently not available in French, other available evidence-based interventions are not currently systematically used in clinical settings. These limitations call for the importance of developing an implementation science for these interventions to improve the transfer of results from research to clinical settings as well as a service organization model that promote or facilitate access to such interventions.

Sexual dimorphism of spatial working memory profiles in schizophrenia.

INTRODUCTION: The aim of the present study was to compare spatial working memory performance of females and males schizophrenia patients to verify whether the sexual dimorphism of spatial abilities present in the general population is found also in schizophrenia. METHODS: We analysed different types of errors committed by each gender on the spatial working memory test of the Cambridge Neuropsychological Test Automated Battery to determine potential differences between them. RESULTS: Despite the lack of difference in the number of errors between men and women, different profiles of errors were associated with the strategy used according to gender. The men's strategy was better compared to women. Specifically, for women strategy score correlated positively with searches in previously visited boxes, whereas for men it correlated with both previously visited boxes and never visited ones. However, men's strategy is more impaired by the number of revisits in boxes in which tokens have previously been found than female's one. CONCLUSIONS: These results suggested impaired either central executive and/or visuospatial sketchpad of working memory in patients with schizophrenia. We demonstrated also that the worsening of strategy in men is principally due to central executive deficits compared to women with schizophrenia. The study of sex differences in cognitive performances could help in delineating partially different endophenotypes of schizophrenia in men and women.

Does the Beck Cognitive Insight Scale predict change in delusional beliefs?

OBJECTIVES: The Beck Cognitive Insight Scale (BCIS) is composed of two subscales, self-reflectiveness and self-certainty, assessing reflectiveness and openness to feedback, and mental flexibility. Delusions have previously been associated with low cognitive insight. The aim of this study was to determine whether changes in BCIS scores predict changes in delusional beliefs. METHODS: The study is a secondary analysis of a previously published randomized controlled trial. All participants had a psychotic disorder diagnosis and received treatment as usual, with half of them also receiving the cognitive restructuring intervention 'Michael's game'. Participants were assessed at three different times: at baseline (T1), at 3 months (T2), and at 9 months (T3). Cognitive insight was measured with the BCIS, belief flexibility with the Maudsley assessment of delusions schedule (MADS), and psychotic symptoms with the Brief Psychiatric Rating Scale (BPRS). RESULTS: A total of 172 participants took part in the trial. After using generalized estimating equation (GEE) modelling, we observed (1) significant main effects of BCIS self-certainty and Time and (2) significant Time × BCIS self-certainty and Time × treatment group interaction effects on belief flexibility. Improvements in self-certainty (i.e., decrease in scores) were associated with more changes in conviction over time, more accommodation, improved ability in ignoring or rejecting a hypothetical contradiction and increased use of verification of facts. Medication and BPRS total scores were controlled for in the GEE analyses at their baseline values. CONCLUSIONS: Overall improvement in BCIS self-certainty scores over time predicted better treatment outcomes as assessed with MADS items. PRACTITIONER POINTS: Treatments for patients with psychosis should focus on improving cognitive insight as this seems to improve overall treatment outcomes and recovery. The Beck Cognitive Insight Scale can be used to measure changes during treatment and can predict treatment outcomes.

Preserved awareness of their cognitive deficits in patients with schizophrenia: convergent validity of the SSTICS.

This study aimed to examine the convergent validity of the SSTICS. The association between the SSTICS and the five-factor model of the PANSS was also examined. One hundred and seventy-six schizophrenia-spectrum disorder patients were recruited. A correlation analysis was performed. The SSTICS score correlated with the score on the FPSES. The SSTICS score also correlated with the cognition factor of the PANSS. Our results demonstrate that the SSTICS is a good instrument for evaluating the subjective complaints of patients with schizophrenia. They also reveal good concordance between cognitive impairments experienced by patients and cognitive disorders assessed by a clinical rater.

Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments.

Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1-/-) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) - Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.

Functional deficit in the medial prefrontal cortex during a language comprehension task in patients with schizophrenia.

OBJECTIVE: We and others have observed that patients with schizophrenia commonly presented a reduced left recruitment in language semantic brain regions. However, most studies include patients with leftward and rightward lateralizations for language. We investigated whether a cohort comprised purely of patients with typical lateralization (leftward) presented a reduced left recruitment in semantic regions during a language comprehension task. The goal was to reduce the inter-subject variability and thus improve the resolution for studying functional abnormalities in the language network. METHODS: Twenty-three patients with schizophrenia (DSM-IV) were matched with healthy subjects in age, sex, level of education and handedness. All patients exhibited leftward lateralization for language. Functional MRI was performed as subjects listened to a story comprising characters and social interactions. Functional MRI signal variations were analyzed individually and compared among groups. RESULTS: Although no differences were observed in the recruitment of the semantic language network, patients with schizophrenia presented significantly lower signal variations compared to controls in the medial part of the left superior frontal gyrus (MF1) (x=-6, y=58, z=20; Z(score)=5.6; p<0.001 uncorrected). This region corresponded to the Theory of Mind (ToM) network. Only 5 of the 23 patients (21.7%) and 21 of the 23 (91.3%) control subjects demonstrated a positive signal variation in this area. CONCLUSIONS: A left functional deficit was observed in a core region of the ToM network in patients with schizophrenia and typical lateralizations for language. This functional defect could represent a neural basis for impaired social interaction and communication in patients with schizophrenia.

Mobile Intensive Care Unit: A case management team dedicated to early psychosis in France.

AIM: To present the activities of a Mobile Intensive Care Unit in France. METHODS: We summarize participant recruitment as well as the diagnostic procedures and therapeutic interventions offered to individuals with an at-risk mental state or first-episode psychosis (FEP). RESULTS: Since its inception in 2010, 266 individuals from 16 to 30 years old living in an area of 120 000 citizens have been recruited by the Mobile Intensive Care Unit. Patients are evaluated by clinical and neuropsychological assessments, and therapeutic interventions include medication, individual case management and both individual and group cognitive behavioural therapy. Diagnostic assessments are also provided for the patients outside of our geographic area. CONCLUSIONS: The Mobile Intensive Care Unit is a functional unit enabling young adults with a high-risk mental state or FEP to receive high standard of care and mobile management over 2 years, aimed at diminishing the risk of transition to chronic disease and decreasing functional impairment.

Semantic hyperpriming in schizophrenic patients: increased facilitation or impaired inhibition in semantic association processing?

Previous studies analyzing semantic priming in schizophrenic patients have reported conflicting results. In the present study, we explored semantic priming in a sample of schizophrenic patients with mild thought disorders. We wondered if distinct cognitive processes, such as facilitation and/or inhibition, underlie semantic hyperpriming and are variously impaired in schizophrenic patients. Using a lexical decision task, we evaluated semantic priming in 15 schizophrenic patients (DSM-IV) with mild thought disorders and 15 healthy controls matched for sex, age, and education level. The task was designed to divide semantic priming into two additive components, namely facilitation effect and inhibition effect. One-sample t-tests were performed to investigate differences in semantic priming, facilitation, and inhibition within each group. ANOVAs were performed to compare the effects of semantic priming, facilitation, and inhibition between groups. Patients displayed greater semantic priming than controls (i.e., hyperpriming), but this was not due to increased facilitation in processing semantically related pairs. On the contrary, hyperpriming was the result of prolonged response time to process semantically unrelated pairs, corresponding to a requirement to inhibit unrelated information. We demonstrated semantic hyperpriming in stabilized schizophrenic patients with mild severity of symptoms. Thus, semantic hyperpriming may be an intrinsic feature of schizophrenia that is not related to the clinical state of patients. Semantic hyperpriming was due to an inhibition effect involved in processing semantically unrelated information not to increased facilitatory effect for related pairs.

Stability of functional language lateralization over time in schizophrenia patients.

BACKGROUND: Cross-sectional functional imaging studies have shown a reduced leftward language lateralization in schizophrenic patients. An unanswered question is whether this reduced leftward lateralization is stable over time or is modified over the course of the illness. METHODS: Ten right-handed (RH) patients (DSM-IV) and 10 RH controls were matched one-to-one for sex, age, and level of education. The subjects underwent two separate fMRI sessions while engaged in a story listening task, 21 months apart. After each session, story comprehension (task performance) was assessed through a 12-item questionnaire. The stability of the decreased asymmetry indices in the semantic region of interest (LANG) was investigated with an ANOVA to compare groups and sessions. In order to test the evolution of functional asymmetry indices at an individual level, a linear correlation between both fMRI session asymmetry indices was calculated in all subjects. Correlations between asymmetry indices and the severity of psychotic symptoms or task performances were computed. RESULTS: The asymmetry indices of the LANG were significantly reduced in patients as compared to controls and strongly correlated between sessions. Values of asymmetry indices were unrelated to either psychotic symptoms or task performances. CONCLUSIONS: This reduced leftward lateralization for language did not vary over time and was not influenced by the psychosis severity or the task performances. This result reinforces the hypothesis that schizophrenia is characterized by a particular organization of language.

[Quality of life in patients with autosomal dominant polycystic kidney disease]. / Qualité de vie des patients atteints de polykystose rénale autosomique dominante.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disease that usually occurs in adulthood. The majority of affected patients will develop renal complications related to cysts during their life, but may sometimes also develop severe extrarenal complications. The aim of this study is to review quantitative and qualitative results of researches that have investigated quality of life of patients suffering ADPKD. The results obtained with health-relative quality of life scales are contradictory and lack of sensibility according to the special features of ADPKD, for psychological impact for instance. Quality of life is decreased according to the quality of life scales specific to the ADPKD and qualitative studies from the early stages of the kidney failure with respect to physical (pain) and psychological impact of the disease. Untreated anxiety and depression are diagnosed for a significant part of patients. Uncertainty of prognosis, genetic guilt, precariousness of parental future, feelings of powerlessness and hopelessness are responsible at least in part of these disorders. According to the patients, pain remains underestimated by physicians and treatments are considered as insufficiently effective.

[Polycystic kidney disease: An analysis of e-patients exchanges in the public blogosphere]. / Polykystose rénale : analyse des discussions des e-patients sur la blogosphère publique.

The goal this study was to understand the preoccupations of e-patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), through their discussions on social networks, and to compare them with those of members of a specialized association. We collected and analyzed all messages containing an unequivocal expression of the pathology (polycystic kidney disease, PKD, ADPKD, etc.) available on public forums on the French Internet and all french-language messages posted on the forum of the patient group Association Polykystose-France (PKD-France) during 2 years. The automated processing of messages (extraction of themes), using a referential associating each theme with a variety of expressions, allowed classification in different thematic families. 8494themes were extracted from 764 messages sent by 329 different users on 68 public forum websites. The main thematic families were treatments (17%), pathology (16%), signs and symptoms (13%), feelings (11%), healthcare system (7%) and patient life (7%). On the association's forum, 345 messages were sent by 57 different members. The thematic richness was equivalent (number of themes per message: 10.2 versus 11.1 respectively), with 3517 themes, but the thematic families corresponded more to the emotional aspects and daily problems: Feelings (15.5%) came before treatment (14.5%), then anatomy (9%) before the healthcare system (8%) and pathology (7%). Knowing the e-patients' views expressed on the internet will enable physicians to respond to patients real expectations and correct erroneous perceptions. As for the patients, they will know the leading sites of opinion, shared by their peers.

Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis.

Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this meta-analysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used.The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges's g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10(-4)), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position coil showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry.