Clozapine-induced cholinergic urticaria: a case report.

Clozapine, renowned for its efficacy in treatment-resistant schizophrenia, is associated with rare yet potentially severe side effects, including hematological disorders, myocarditis, seizures and gastrointestinal obstruction. Dermatological adverse effects, though less serious, can profoundly impact patients' quality of life. We present the first reported case of cholinergic urticaria induced by clozapine, in a 25-year-old male with treatment-resistant schizophrenia. Four months into clozapine therapy, the patient developed intensely pruritic erythematous lesions triggered by sweating, significantly impairing his daily activities. Despite attempts at management, including dose reduction and antihistamine therapy, the urticaria persisted. However, a favorable outcome was achieved upon switching to quetiapine. This case underscores the importance of recognizing and managing treatment-related adverse effects, even when they arise late in treatment, and highlights the need for individualized therapeutic approaches.We discuss potential mechanisms underlying clozapine-induced cholinergic urticaria and emphasize the significance of patient-centered care in optimizing treatment outcomes in schizophrenia.

Itchy rash from sweating with clozapine Despite its undisputed efficacy, clozapine has attracted a great deal of attention for its rare but potentially serious side effects, such as hematological disorders (in particular, low white blood cell counts), seizures and inflammation of the heart muscle. Other effects, notably cutaneous, have also been reported, and although they are not serious, they can have a considerable impact on the patient's quality of life. Such is the case of our patient who became allergic to his own sweat while taking clozapine. To our knowledge, this is the first case described in the literature. The patient was a 25-year-old man suffering from resistant schizophrenia, i.e. who had failed to respond to successive use of two different antipsychotics. Four months after starting treatment with clozapine, he developed a generalized cutaneous eruption characterized by intensely pruritic erythematous punctiform lesions which appeared with each episode of perspiration. The lesions considerably disrupted the patient's daily activities, making it necessary to refrain from physical effort and avoid exposure to heat. Despite attempts to manage symptoms, by treatment with antihistamines and clozapine dose reduction, the urticaria persisted. However, a favorable and durable outcome was observed after switching to quetiapine rather than olanzapine. This case highlights the importance of recognizing and managing treatment-related undesirable side effects, even if they appear late in the course of treatment, and of not neglecting their impact on the patient's daily life. In this report, we have also tried to outline the hypothetical mechanisms that could explain this unusual side effect. This case encourages clinicians to always seek the optimal antipsychotic for their patients, even after several therapeutic failures and/or episodes of intolerance. Trial and error can lead to more effective, personalized treatment.

Effects of the combination of neurostimulation techniques in patients with mental disorders: A systematic review.

BACKGROUND: despite years of development, response to neurostimulation remains partial and variable. Combining techniques could improve clinical efficacy and tolerance. OBJECTIVE: to examine the literature on the effects of combining several neurostimulation techniques in patients with mental disorders. METHODS: this systematic review follows the PRISMA guidelines RESULTS: 23 studies were included. The most studied combination was electroconvulsive therapy (ECT) along with another neurostimulation technique in depression. The RCTs that showed a significant effect targeted the left dorsolateral prefrontal cortex with high-frequency repetitive transcranial magnetic stimulation, before ECT. Combining neurostimulation techniques is a promising field of research.

Real world transcranial magnetic stimulation for major depression: A multisite, naturalistic, retrospective study.

BACKGROUND: In 2008, the U.S. FDA approved rTMS as a treatment against medication-resistant depression. However, real-world rTMS outcomes remain understudied. This study investigates how rTMS for depression is delivered in routine clinical practice in France, and measures its effectiveness as well as its moderators. METHODS: Five centers provided retrospective data on patients who were treated with rTMS for treatment-resistant depression from January 2015 to December 2020. Patients were assessed twice using a hetero-questionnaire, with baseline and immediate post-treatment assessments. We conducted univariate analyses to study which factors were significantly associated with rTMS effectiveness. We then included age, gender, and significant factors in a multivariate model. RESULTS: We collected data from 435 patients with a mean age of 51.27 (14.91): 66 % were female, and 26 % suffered from bipolar depression. Stimulation was delivered using four different stimulation parameters: 1 Hz (7 % of the individuals), 10 Hz (43 %), 20 Hz (12 %), and 50 Hz (intermittent Theta Burst Stimulation, iTBS) (38 %). The mean improvement of depressive symptoms was 33 % (p < 0.001, effect-size: 0.79). Response and remission rates were of 31 % and 22.8 %, respectively. In the multivariate analysis, improvement in depressive symptoms was associated with higher baseline symptoms. CONCLUSION: This is one of the largest studies that investigates, with careful clinician-rated scales by trained psychiatrists, the effect of rTMS in naturalistic settings. Repetitive TMS appears to be effective in routine clinical practice, although its efficacy could be improved by analyzing predictors of response, as well as personalized targeting of specific brain areas.

Moving to accelerated protocols of tDCS in catatonia: a case report.

Catatonia is a severe and potentially life-threatening neuropsychiatric condition. Electroconvulsive therapy (ECT) is the gold standard second-line intervention for catatonia after benzodiazepine failure. However, the access to ECT can be particularly challenging, especially during periods of increased strain on medical facilities, such as the COVID-19 pandemic. Several case reports have suggested the potential efficacy of transcranial direct current stimulation (tDCS) in addressing catatonia. In our case, we present the successful application of intensive tDCS, delivering five sessions per day, each lasting 20 min, with an intensity of 2 mA. The tDCS montage involved placing the anode on the left dorsolateral prefrontal cortex (DLPFC) and the cathode on the left temporoparietal junction (TPJ). This approach was well-tolerated and resulted in a significant improvement in a 70-year-old patient with catatonia, for whom ECT was deemed necessary. While these results are promising, it is crucial to confirm them through a randomized controlled study.

Local Alterations of Left Arcuate Fasciculus and Transcallosal White Matter Microstructure in Schizophrenia Patients with Medication-resistant Auditory Verbal Hallucinations: A Pilot Study.

Auditory verbal hallucinations (AVH) in schizophrenia (SZ) have been associated with abnormalities of the left arcuate fasciculus and transcallosal white matter projections linking homologous language areas of both hemispheres. While most studies have used a whole-tract approach, here we focused on analyzing local alterations of the above-mentioned pathways in SZ patients suffering medication-resistant AVH. Fractional anisotropy (FA) was estimated along the left arcuate fasciculus and interhemispheric projections of the rostral and caudal corpus callosum. Then, potential associations between white matter tracts and SZ symptoms were explored by correlating local site-by-site FA values and AVH severity estimated via the Auditory Hallucinations Rating Scale (AHRS). Compared to a sample of healthy controls, SZ patients displayed lower FA values in the rostral portion of the left arcuate fasciculus, near the frontal operculum, and in the left and right lateral regions of the rostral portion of the transcallosal pathways. In contrast, SZ patients showed higher FA values than healthy controls in the medial portion of the latter transcallosal pathway and in the midsagittal section of the interhemispheric auditory pathway. Finally, significant correlations were found between local FA values in the left arcuate fasciculus and the severity of the AVH's attentional salience. Contributing to the study of associations between local white matter alterations of language networks and SZ symptoms, our findings highlight local alterations of white matter integrity in these pathways linking language areas in SZ patients with AVH. We also hypothesize a link between the left arcuate fasciculus and the attentional capture of AVH.

Inpatient suicide in psychiatric settings: Evaluation of current prevention measures.

The risk of suicide in psychiatric hospitals is 50 times higher than in the general population, despite patient safety being a priority for any hospital. However, to date, due to the complexity of assessing suicide risk, there has been no consensus on the suicide prevention measures that should be in place in hospitals. The aim of this work is: To provide an overview of the progress that has been made in the field of inpatient suicide prevention in recent years; discuss the problems that remain; and suggest potential future developments. As new clinical dimensions (notably anhedonia, psychological pain and hopelessness) develop, they should become new therapeutic targets. Team training (like the Gatekeeper Training Program) and the latest advances in suicide risk assessment (such as the Collaborative Assessment and Management of Suicidality) should be implemented in psychiatric wards. Suicide prevention plans (e.g., ASSIP, SAFE-T, etc.) represent easy-to-administer, low-cost interventions. The Mental Health Environment of Care Checklist has been proven effective to reduce suicide risk at hospitals. Furthermore, the types of psychotherapy recommended to reduce suicide risk are cognitive behavioral therapy (CBT) and dialectical behavioral therapy (DBT). There are several pharmacological treatments for suicide risk, such as lithium and clozapine, which have been shown to be effective in the long term, as well as ketamine and esketamine, which are more effective in the short term. Following some encouraging recent results, buprenorphine may also be proposed to patients with a suicide risk. Triple chronotherapy rapidly improves depressive symptoms over 9 weeks. Regarding brain stimulation techniques, rTMS has proven to be effective in alleviating multiple dimensions of suicidality.

Risperidone-induced priapism: a case report and literature review.

Priapism is a rare pathological condition defined as painful and persistent penile erection that is unrelated to sexual stimulation. It can be classified as ischaemic or non-ischaemic. Many causes have been attributed to ischaemic priapism, including the use of some medications such as antipsychotics. The mechanism of priapism associated with antipsychotics is thought to be related to alpha-adrenergic blockage that is mediated by the alpha receptors in the corpora cavernosa of the penis. In this paper, we describe a case of a patient who suffered from Risperidone-induced priapism, and how this adverse effect was resolved by switching to olanzapine followed by olanzapine pamoate. A literature search on PubMed/Medline up to 2011 was conducted by some doctors from London and found 30 cases of priapism associated with risperidone. Based on this work, we searched PubMed through 2021, using the keywords 'priapism' and 'risperidone' and found a total of 43 cases of priapism involving risperidone. Priapism is not correlated with the dosage of this psychotropic drug, and has also occasionally occurred when risperidone has been used in conjunction with another drug. The question of choosing a replacement antipsychotic after the first one has induced priapism, remains problematic. It would be preferable to switch to a drug with less marked alpha1-blocking properties, but no consensus has been reached as to the best choice of medication. Finally, any prescription of an antipsychotic treatment must be preceded by a careful interrogation in search of risk factors for priapism, and the patient should be made aware of the possible occurrence of this side effect and the need to then seek urgent medical advice.

Prospective survey of psychiatric patients during the first confinement of the COVID 2019 pandemic.

In the early steps of an emerging infectious disease epidemic such as Covid-19, uncertainties about the nature of the disease, its spread and impact can lead to emotional distress. In addition, the studies on confinement during an epidemic have shown a psychological impact of this measure on the feelings of anxiety and depression in the general population. METHOD: We assessed the psychological health of 550 patients followed up in outpatient psychiatry, via a pandemic-related teleconsultation during the first confinement period between March and June 2020. Patients were assessed at the beginning and at the end of the confinement on their personal situation, social relationships, professional activity, anxiety and mood. We also evaluated patients' symptomatology and their quality of life. RESULTS: Patients were well informed about Covid-19 via the media and complied with the confinement and barrier procedures. They appreciated the phone-calls and the teleconsultation follow-up. A small proportion of patients were completely socially isolated mainly at the beginning of the confinement (10%). There was no difference between the beginning and the end of the confinement in terms of depressive and anxiety symptoms or quality of life. The women were more anxious and depressed than men. Only smoking was significantly increased during this period. CONCLUSION: The expected and feared health catastrophe in psychiatry during this first phase of the pandemic in 2020 did not occur. Will the psychiatric wave appear in the "post- pandemic", the future will tell.

Effect of Intermittent Theta Burst Stimulation on the Neural Processing of Emotional Stimuli in Healthy Volunteers.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation that has shown to be effective in treatment-resistant depression. Through studying the effect of iTBS on healthy subjects, we wished to attain a greater understanding of its impact on the brain. Our objective was to assess whether 10 iTBS sessions altered the neural processing of emotional stimuli, mood and brain anatomy in healthy subjects. METHODS: In this double-blind randomized sham-controlled study, 30 subjects received either active iTBS treatment (10 sessions, two sessions a day) or sham treatment over the left dorsolateral prefrontal cortex. Assessments of mood, structural magnetic resonance imaging (MRI) and functional MRI (fMRI) were performed before and after iTBS sessions. During the fMRI, three different categories of stimuli were presented: positive, negative and neutral photographs. RESULTS: This study showed that, during the presentation of negative stimuli (compared with neutral stimuli), 10 sessions of iTBS increased activity in the left anterior insula. However, iTBS did not induce any change in mood, regional gray matter volume or cortical thickness. CONCLUSIONS: iTBS modifies healthy subjects' brain activity in a key region that processes emotional stimuli. (AFSSAPS: ID-RCB 2010A01032-37).

Intermittent Theta-Burst Stimulation Over the DorsoLateral PreFrontal Cortex (DLPFC) in Healthy Subjects Produces No Cumulative Effect on Cortical Excitability.

Background: Intermittent Theta Burst Stimulation (iTBS) is a design of repetitive Transcranial Magnetic Stimulation (rTMS) and could be a candidate to replace rTMS in the treatment of depression, thanks to its efficacy, shorter duration, and ease of use. The antidepressant mechanism of iTBS, and whether this mechanism is mediated by a modulation of cortical excitability, remains unknown. Methods: Using a randomized double-blind, sham-controlled trial, 30 healthy volunteers received either iTBS or a sham treatment targeting the left DorsoLateral PreFrontal Cortex (L-DLPFC), twice a day over 5 consecutive days. Cortical excitability was measured before and after the 5 days of stimulation. Results: No difference in cortical excitability was observed between active or sham iTBS. Conclusion: Our study does not support any effect on cortical excitability of repetitive iTBS targeting the L-DLPFC.

Cognitive Impact of Cerebellar Non-invasive Stimulation in a Patient With Schizophrenia.

Cerebellum plays a role in the regulation of cognitive processes. Cerebellar alterations could explain cognitive impairments in schizophrenia. We describe the case of a 50 years old patient with schizophrenia whom underwent cerebellar transcranial direct current stimulation (tDCS). In order to study the effect of cerebellar stimulation on cognitive functions, the patient underwent a neuropsychological assessment and an eyeblink conditioning (EBC) protocol. Although the effect of brain stimulation cannot be only assessed in a single-case study, our results suggest that cerebellar stimulation may have an effect on a broad range of cognitive functions typically impaired in patients with schizophrenia, including verbal episodic, short term, and working memory. In addition to neuropsychological tests, we evaluated the cerebellar function by performing EBC before and after tDCS. Our data suggest that tDCS can improve EBC. Further clinical trials are required for better understanding of how cerebellar stimulation can modulate cognitive processes in patients with schizophrenia and healthy controls.

[Mood disorders: When should we use repetitive transcranial magnetic stimulation?] / Troubles de l'humeur : quand recourir à la stimulation magnétique transcrânienne ?

Repeated transcranial magnetic stimulation (rTMS) is still a recent treatment in psychiatry. This article aims at updating the clinicians'knowledge about rTMS in the treatment of mood disorders (uni and bipolar depressive disorders, manic/mixed states, suicidal risk, catatonia). It is intended for clinicians who are required to indicate and/or use rTMS in their current practice. rTMShas the highest level of evidence for the treatment of unipolar depression, provided that effective parameters are used, that is to say, for classical high frequency protocols: 20 to 30 sessions, 1000 pulses/session, 5 to 20Hz, and 110 % of the motor threshold. Low frequency protocol are also efficient and well tolerated. The duration of the efficacy varies with relapses rates around 50 % at one year. Pharmacological treatment generally remains associated. With regard to manic states, and mixed states the results are preliminary and limited to a possible reduction in symptoms. In the suicidal risk associated with mood disorders, the interest of rTMS is still to demonstrate, as well as in catatonia. The current place of the rTMS is no longer disputed in the curative treatment of major depressive disorder, preferentially used after one or two lines of antidepressants upstream. Further studies are needed to confirm preliminary positive findings in other aspects of mood disorders.

Gender-Related Brain Activations during an Emotional Task: An fMRI Study.

BACKGROUND: Women have twice the rate of depression and anxiety disorders as men. Some studies suggest that this could be caused by women's greater sensitivity to negative emotions. Few brain imaging studies have compared the brain activity of men to women during a presentation of emotional stimuli. Our objective was to investigate brain activations in men and women during an emotional task. We hypothesized that the pattern of brain activations would differ by gender and valence of the stimuli. METHODS: We conducted a functional magnetic resonance imaging study in 30 healthy participants (15 men and 15 women). Positive, negative and neutral photographs were presented to the subjects. Participants subjectively rated the valence and intensity of the stimuli. RESULTS: No significant gender-by-category interaction effect was observed for the intensity or valence of the stimuli. We found that, during the presentation of negative photographs, there was a higher activity in women's right fusiform gyrus compared to men's. CONCLUSION: Given the involvement of the fusiform gyrus in anxiety disorders, this study yields promising findings in order to better understand women's vulnerability to anxiety disorders.

Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial.

BACKGROUND: The potential of non-invasive repetitive transcranial magnetic stimulation (rTMS) to improve auditory verbal hallucinations (AVH) in schizophrenia patients has been increasingly explored over the past decade. Despite highly promising results, high inter-individual variability of clinical response and ineffective outcomes in a significant number of patients underscored the need to identify factors associated with the clinical response to rTMS. It should help improve the efficacy of rTMS in patients with medication-resistant AVH, and allow a better understanding of its neural impact. Here, we describe an exploratory study protocol which aims to identify structural and functional brain biomarkers associated with clinical response after an rTMS treatment for medication-resistant AVH in schizophrenia. METHODS: Forty-five schizophrenia patients with medication-resistant AVH will be enrolled in a double-blind randomized sham-controlled monocentric clinical trial. Patients will be assigned to a regime of 20 sessions of active or sham 1 Hz rTMS delivered twice a day, 5 days a week for 2 weeks over the left temporo-parietal junction. Response will be assessed after rTMS and patients will be classified in responders or non-responders to treatment. Magnetic resonance imaging (MRI) sessions including diffusion weighted imaging and resting-state functional MRI sequences will be recorded before the onset of the rTMS treatment and 3 days following its discontinuation. The primary outcome measure is difference in fractional anisotropy between responder and non-responder patients at baseline. Differences in resting-state functional MRI data at baseline will be also investigated between responder and non-responder groups. Clinical, neuropsychological, neurophysiological, and blood serum BDNF assessments will be performed at baseline, 3 days, 1 month, and 3 months following rTMS. DISCUSSION: The aim of this research project is to identify and assess the biomarker value of MRI-based structural and functional biomarkers predicting clinical response to rTMS for AVH in schizophrenia patients. The outcome of the trial should improve patient care by offering them a novel suitable therapy and deepen our understanding on how rTMS may impact AVH and develop more effective therapies adapted to individual patient needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02755623 . Registered on 22 April 2016.

Unexpected Improvement of Hand Motor Function with a Left Temporoparietal Low-Frequency Repetitive Transcranial Magnetic Stimulation Regime Suppressing Auditory Hallucinations in a Brainstem Chronic Stroke Patient.

We here report paradoxical hand function recovery in a 61-year-old male tetra-paretic chronic patient following a stroke of the brainstem (with highly degraded right and abolished left-hand finger flexion/extension disabling him to manipulate objects) who experienced insidious auditory hallucinations (AHs) 4 years after such event. Symptomatic treatment for AHs was provided with periodical double sessions of low-frequency repetitive transcranial magnetic stimulation (rTMS) (daily 1 Hz, 2 × 1,200 pulses interleaved by 1 h interval) delivered to the left temporoparietal junction across two periods of 5 and 3 weeks, respectively. At the end of each stimulation period, AHs disappeared completely. Most surprisingly and totally unexpectedly, the patient experienced beneficial improvements of long-lasting impairments in his right-hand function. Detailed examination of onset and offset of rTMS stimulation regimes strongly suggests a temporal relation with the remission and re-appearance of AHs and also with a fragile but clinically meaningful improvements of right (but not left) hand function contingent to the accrual of stimulation sessions. On the basis of post-recovery magnetic resonance imaging structural and functional evidence, mechanistic hypotheses that could subtend such unexpected motor recovery are critically discussed.

A randomized, sham-controlled study of maintenance rTMS for treatment-resistant depression (TRD).

A few open-labeled studies have investigated the use of maintenance rTMS to prevent relapse for treatment-resistant depression (TRD) after rTMS treatment. We aim to assess the benefits of maintenance rTMS treatment for TRD patients who respond to rTMS treatment using a randomized, double-blind controlled design. Fifty eight TRD patients received rTMS over one month in an open-labeled design study (phase I). Responder patients were then randomized into active and sham high-frequency rTMS groups for the subsequent eleven months (phase II). The regularity of sessions was gradually reduced. The antidepressant effect of rTMS was evaluated using the Hamilton Depression Rating Scale (HDRS). Intention-to-treat analysis was performed to assess the effectiveness of maintenance sessions. Of the 58 patients included, 35 patients were responders after one month of active rTMS (phase I), and 17 patients were randomized for the maintenance sessions (phase II). The delta HDRS scores demonstrated a significant improvement between the first month and the fourth month in active group in comparison with sham group (phase II). There was no significant difference between these two groups for other periods of time. Repetitive TMS could represent a novel strategy for preventing relapse in TRD patients who respond to rTMS treatment. These results should be confirmed in a larger sample.

Impact of reward on pain threshold and tolerance to experimental pain (Cold Pressor Task) in healthy subjects and patients with schizophrenia.

Reduced pain sensitivity is considered as a potential endophenotype of schizophrenia. Patient's motivation in pain experimental studies was neither assessed nor controlled. This study aimed to assess the effect of reward on pain in patients with schizophrenia compared to controls. Rewarded subjects showed higher pain threshold and tolerance compared to unrewarded subjects. Pain tolerance was significantly lower in patients than in controls when they were not rewarded. Reward resulted in an increase of pain tolerance with a higher manner in patients. This study suggests that better control of motivational aspects could improve assessment of pain sensitivity in schizophrenia.