Psychiatric adverse effects of zonisamide in patients with epilepsy and mental disorder comorbidities

Over the last few years, zonisamide has been proposed as a potentially useful medication for patients with focal seizures, with or without secondary generalization. Since psychiatric adverse effects, including mania, psychosis, and suicidal ideation, have been associated with its use, it was suggested that the presence of antecedent psychiatric disorders is an important factor associated with the discontinuation of zonisamide therapy in patients with epilepsy. We, therefore, set out to assess the tolerability profile of zonisamide in a retrospective chart review of 23 patients with epilepsy and comorbid mental disorders, recruited from two specialist pediatric (n=11) and adult (n=12) neuropsychiatry clinics. All patients had a clinical diagnosis of treatment-refractory epilepsy after extensive neurophysiological and neuroimaging investigations. The vast majority of patients (n=22/23, 95.7%) had tried previous antiepileptic medications, and most adult patients (n=9/11, 81.8%) were on concomitant medication for epilepsy. In the majority of cases, the psychiatric adverse effects of zonisamide were not severe. Four patients (17.4%) discontinued zonisamide because of lack of efficacy, whereas only one patient (4.3%) discontinued it because of the severity of psychiatric adverse effects (major depressive disorder). The low discontinuation rate of zonisamide in a selected population of patients with epilepsy and neuropsychiatric comorbidity suggests that this medication is safe and reasonably well-tolerated for use in patients with treatment-refractory epilepsy. Given the limitations of the present study, including the relatively small sample size, further research is warranted to confirm this finding. © 2013 Elsevier Inc.

Psychotic symptoms are associated with physical health problems independently of a mental disorder diagnosis:results from the WHO World Health Survey

This study explored whether physical health problems are related to psychotic symptoms independently of a mental disorder diagnosis. A total of 224,254 subjects recruited for the World Health Organization World Health Survey were subdivided into those with both a lifetime diagnosis of psychosis and at least one psychotic symptom in the 12 months prior to the evaluation, those with at least one psychotic symptom in the past 12 months but no lifetime diagnosis of psychosis, and those without psychotic symptoms in the past 12 months and without a lifetime diagnosis of psychosis. The three groups were compared for the presence of medical conditions, health problems, and access to health care. Medical conditions and health problems (angina, asthma, arthritis, tuberculosis, vision or hearing problems, mouth/teeth problems, alcohol consumption, smoking, and accidents), medication consumption, and hospital admissions (but not regular health care visits) were more frequent in individuals with psychotic symptoms but no psychosis diagnosis, compared to those with no symptoms and no diagnosis. The number of medical conditions increased with the number of psychotic symptoms. Given the sample analyzed, this trend seems to be independent from the socio-economic development of the country or the specific health care system.

The continuum of psychotic symptoms in the general population:a cross-national study

OBJECTIVE: To identify the cross-national prevalence of psychotic symptoms in the general population and to analyze their impact on health status. METHOD: The sample was composed of 256,445 subjects (55.9% women), from nationally representative samples of 52 countries worldwide participating in the World Health Organization's World Health Survey. Standardized and weighted prevalence of psychotic symptoms were calculated in addition to the impact on health status as assessed by functioning in multiple domains. RESULTS: Overall prevalences for specific symptoms ranged from 4.80% (SE = 0.14) for delusions of control to 8.37% (SE = 0.20) for delusions of reference and persecution. Prevalence figures varied greatly across countries. All symptoms of psychosis produced a significant decline in health status after controlling for potential confounders. There was a clear change in health impact between subjects not reporting any symptom and those reporting at least one symptom (effect size of 0.55). CONCLUSIONS: The prevalence of the presence of at least one psychotic symptom has a wide range worldwide varying as much as from 0.8% to 31.4%. Psychotic symptoms signal a problem of potential public health concern, independent of the presence of a full diagnosis of psychosis, as they are common and are related to a significant decrement in health status. The presence of at least one psychotic symptom is related to a significant poorer health status, with a regular linear decrement in health depending on the number of symptoms.

Magnetoencephalography in epilepsy

Magnetoencephalographic (MEG) signals, like electroencephalographic (EEG) measures, are the direct extracranial manifestations of neuronal activation. The two techniques can detect time-varying changes in electromagnetic activity with a sub-millisecond time resolution. Extra-cranial electromagnetic measures are the cornerstone of the non-invasive diagnostic armamentarium in patients with epilepsy. Their extremely high temporal resolution – comparable to intracranial recordings – is the basis for a precise definition of onset and propagation of ictal and interictal abnormalities. Given the cost of the infrastructure and equipment, MEG has yet to develop into a routinely applicable diagnostic tool in clinical settings. However, in recent years, an increasing number of patients with epilepsy have been investigated – usually in the context of presurgical evaluation of refractory epilepsies – and initial encouraging results have been reported. We will briefly review the principles and the technology behind MEG and its contribution in the diagnostic work-up of patients with epilepsy.

Sub-cortical sources of the somatosensory pathway are hypoactive in migraine interictally:a Functional Source Separation analysis

Background: Recent morpho-functional evidence pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brainstem remains to be determined. We used a Functional Source Separation algorithm of EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura (MO) patients. Methods: Twenty MO patients and 20 healthy volunteers (HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brainstem and FS16 at thalamic level) and two cortical (FS20 radial and FS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450-750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced sub-cortical brainstem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between the two groups. Conclusions: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergic system may underline the interictal cortical abnormal information processing in migraine. Further studies are needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO. Written informed consent to publication was obtained from the patient(s).

Increased risk of diabetes mellitus among persons with psychotic symptoms:results from the WHO World Health Survey

OBJECTIVE: To analyze with a symptom-based approach the relationship between psychosis and diabetes mellitus in the general population. METHOD: Nationally representative samples from the World Health Organization (WHO) World Health Survey, totaling 224,743 randomly selected adults 18 years and older from 52 countries worldwide, were interviewed to establish the presence of psychotic symptoms and diabetes mellitus. Presence of psychotic symptoms was established using questions pertaining to positive symptoms from the psychosis screening module of the Composite International Diagnostic Interview. Presence of diabetes was established with a response of "yes" to the question, "Have you ever been diagnosed with diabetes (high blood sugar)?" The World Health Survey was conducted between 2002 and 2004. RESULTS: An increasing number of psychotic symptoms was related to increasing likelihood of diabetes mellitus (OR = 1.27; 95% CI, 1.24-1.30). As compared to no symptoms, at least 1 psychotic symptom substantially elevated the risk (OR = 1.71; 95% CI, 1.61-1.81). In people with a lifetime diagnosis of schizophrenia or psychosis, the prevalence of diabetes was higher in those with current psychotic symptoms (7.3% vs 5.2%; OR = 1.65; 95% CI, 1.21-2.26), suggesting that the persistence of symptoms over time could play a central role. After controlling for different potential confounders, there was a clear increase in the probability of having diabetes as the number of psychotic symptoms increased. The relationship between psychotic symptoms and diabetes was tested with multiple mediation models and path analyses for categorical outcomes. Only body mass index appeared as a relevant mediator in a model with a good fit (ie, χ21 = 3.2, P = .0742; comparative fit index = 0.999). CONCLUSIONS: Psychotic symptoms are related to increased rates of diabetes mellitus in nonclinical samples, independent of several potential confounders-including a clinical diagnosis of psychosis or schizophrenia, previous antipsychotic treatment, depression, lifestyle, and individual or country socioeconomic status. The findings highlight the worldwide relevance of the problem and the importance of identifying the specific paths of this association.

Impaired brainstem and thalamic high-frequency oscillatory EEG activity in migraine between attacks

INTRODUCTION: We investigated whether interictal thalamic dysfunction in migraine without aura (MO) patients is a primary determinant or the expression of its functional disconnection from proximal or distal areas along the somatosensory pathway. METHODS: Twenty MO patients and twenty healthy volunteers (HVs) underwent an electroencephalographic (EEG) recording during electrical stimulation of the median nerve at the wrist. We used the functional source separation algorithm to extract four functionally constrained nodes (brainstem, thalamus, primary sensory radial, and primary sensory motor tangential parietal sources) along the somatosensory pathway. Two digital filters (1-400 Hz and 450-750 Hz) were applied in order to extract low- (LFO) and high- frequency (HFO) oscillatory activity from the broadband signal. RESULTS: Compared to HVs, patients presented significantly lower brainstem (BS) and thalamic (Th) HFO activation bilaterally. No difference between the two cortical HFO as well as in LFO peak activations between the two groups was seen. The age of onset of the headache was positively correlated with HFO power in the right brainstem and thalamus. CONCLUSIONS: This study provides evidence for complex dysfunction of brainstem and thalamocortical networks under the control of genetic factors that might act by modulating the severity of migraine phenotype.

Subdural electroencephalogram analysis for extracting discriminating measures in epileptogenic data

This dissertation introduces an integrated algorithm for a new application dedicated at discriminating between electrodes leading to a seizure onset and those that do not, using interictal subdural EEG data. The significance of this study is in determining among all of these channels, all containing interictal spikes, why some electrodes eventually lead to seizure while others do not. A first finding in the development process of the algorithm is that these interictal spikes had to be asynchronous and should be located in different regions of the brain, before any consequential interpretations of EEG behavioral patterns are possible. A singular merit of the proposed approach is that even when the EEG data is randomly selected (independent of the onset of seizure), we are able to classify those channels that lead to seizure from those that do not. It is also revealed that the region of ictal activity does not necessarily evolve from the tissue located at the channels that present interictal activity, as commonly believed.^ The study is also significant in terms of correlating clinical features of EEG with the patient's source of ictal activity, which is coming from a specific subset of channels that present interictal activity. The contributions of this dissertation emanate from (a) the choice made on the discriminating parameters used in the implementation, (b) the unique feature space that was used to optimize the delineation process of these two type of electrodes, (c) the development of back-propagation neural network that automated the decision making process, and (d) the establishment of mathematical functions that elicited the reasons for this delineation process. ^

Design and protocol for the Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial : a randomised controlled trial

Acknowledgements Thank you to all the participants who agreed to take part in the trial. This study was supported NHS Research Scotland (NRS), through Chief Scientist Office (CSO) and the Scottish Mental Health Research Network, and the Clinical Research Network-Mental Health. We are grateful to the Psychosis Research Unit (PRU) Service User Reference Group (SURG) for their consultation regarding the design of the study and contribution to the developments of study related materials. We are grateful to our Independent Trial Steering Committee and Independent Data Monitoring Committee for provided oversight of the trial. Funding This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number10/101/02) and will be published in full in Health Technology Assessment. Visit the HTA programme website for further project information. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Hand somatosensory sub-cortical sources arehypoactive in migraine interictally: a functionalsource separation analysis

Background: Recent morpho-functional evidences pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brain stem remains to be determined.Aim: We used a Functional Source Separation algorithmof EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura(MO) patients. Method: Twenty MO patients and 20 healthy volunteers(HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brain stem andFS16 at thalamic level) and two cortical (FS20 radial andFS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450–750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced subcortical brain stem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between two groups. Conclusion: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergicsystem may underline the interictal cortical abnormal information processing in migraine. Further studiesare needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO.

The Relationship Between Self-Awareness and Psychotic-Like Experiences

The psychosis phenotype is thought to exist on a continuum, such that the same symptoms experienced by individuals diagnosed with psychotic disorders can also manifest in the general population to a less severe degree. The subclinical psychotic-like experiences reported by healthy individuals share a number of risk factors with psychotic disorders and confer greater risk of developing a psychotic disorder. Thus, healthy individuals with psychotic-like experiences comprise a valid population in which to study the underlying mechanisms of clinically significant psychotic symptoms. In this thesis, we aimed to further our understanding of psychotic-like experiences and the individuals who report them. We explored the relationships between tasks measuring different aspects of self-awareness and self-reported psychotic-like experiences using data obtained from 30 university students. We found that greater sensitivity to the difference between one’s own voice and another person’s voice predicted fewer symptoms of persecutory ideation. Additionally, we found that greater tendency to misattribute one’s own voice to an external source predicted greater symptoms of persecutory ideation.

Retour post-isolement en milieu psychiatrique : développement, implantation et évaluation d’une intervention en soins aigus

L’isolement avec ou sans contention (IC) en milieu psychiatrique touche près d’un patient sur quatre au Québec (Dumais, Larue, Drapeau, Ménard, & Giguère-Allard, 2011). Il est pourtant largement documenté que cette pratique porte préjudice aux patients, aux infirmières et à l’organisation (Stewart, Van der Merwe, Bowers, Simpson, & Jones, 2010). Cette mesure posant un problème éthique fait l’objet de politiques visant à la restreindre, voire à l’éliminer. Les études sur l’expérience de l’isolement du patient de même que sur la perception des infirmières identifient le besoin d'un retour sur cet évènement. Plusieurs équipes de chercheurs proposent un retour post-isolement (REPI) intégrant à la fois l’équipe traitante, plus particulièrement les infirmières, et le patient comme intervention afin de diminuer l’incidence de l’IC. Le REPI vise l’échange émotionnel, l’analyse des étapes ayant mené à la prise de décision d’IC et la projection des interventions futures. Le but de cette étude était de développer, implanter et évaluer le REPI auprès des intervenants et des patients d’une unité de soins psychiatriques aigus afin d’améliorer leur expérience de soins. Les questions de recherche étaient : 1) Quel est le contexte d’implantation du REPI? 2) Quels sont les éléments facilitants et les obstacles à l’implantation du REPI selon les patients et les intervenants? 3) Quelle est la perception des patients et des intervenants des modalités et retombées du REPI?; et 4) L’implantation du REPI est-elle associée à une diminution de la prévalence et de la durée des épisodes d’IC? Cette étude de cas instrumentale (Stake, 1995, 2008) était ancrée dans une approche participative. Le cas était celui de l’unité de soins psychiatriques aigus pour premier épisode psychotique où a été implanté le REPI. En premier lieu, le développement du REPI a d’abord fait l’objet d’une documentation du contexte par une immersion dans le milieu (n=56 heures) et des entretiens individuels avec un échantillonnage de convenance (n=3 patients, n=14 intervenants). Un comité d’experts (l’étudiante-chercheuse, six infirmières du milieu et un patient partenaire) a par la suite développé le REPI qui comporte deux volets : avec le patient et en équipe. L’évaluation des retombées a été effectuée par des entretiens individuels (n= 3 patients, n= 12 intervenants) et l’examen de la prévalence et de la durée des IC six mois avant et après l’implantation du REPI. Les données qualitatives ont été examinées selon une analyse thématique (Miles, Huberman, & Saldana, 2014), tandis que les données quantitatives ont fait l’objet de tests descriptifs et non-paramétriques. Les résultats proposent que le contexte d’implantation est défini par des normes implicites et explicites où l’utilisation de l’IC peut générer un cercle vicieux de comportements agressifs nourris par un profond sentiment d’injustice de la part des patients. Ceux-ci ont l’impression qu’ils doivent se conformer aux attentes du personnel et aux règles de l’unité. Les participants ont exprimé le besoin de créer des opportunités pour une communication authentique qui pourrait avoir lieu lors du REPI, bien que sa pratique soit variable d’un intervenant à un autre. Les résultats suggèrent que le principal élément ayant facilité l’implantation du REPI est l’approche participative de l’étude, alors que les obstacles rencontrés relèvent surtout de la complexité de la mise en œuvre du REPI en équipe. Lors du REPI avec le patient, les infirmières ont pu explorer ses sentiments et son point de vue, ce qui a favorisé la reconstruction de la relation thérapeutique. Quant au REPI avec l’équipe de soins, il a été perçu comme une opportunité d’apprentissage, ce qui a permis d’ajuster le plan d’intervention des patients. Suite à l’implantation du REPI, les résultats ont d’ailleurs montré une réduction significative de l’utilisation de l’isolement et du temps passé en isolement. Les résultats de cette thèse soulignent la possibilité d’outrepasser le malaise initial perçu tant par le patient que par l’infirmière en systématisant le REPI. De plus, cette étude met l’accent sur le besoin d’une présence authentique pour atteindre un partage significatif dans la relation thérapeutique, ce qui est la pierre d’assise de la pratique infirmière en santé mentale. Cette étude contribue aux connaissances sur la prévention des comportements agressifs en milieu psychiatrique en documentant le contexte dans lequel se situe l’IC, en proposant un REPI comportant deux volets de REPI et en explorant ses retombées. Nos résultats soutiennent le potentiel du développement d’une prévention tertiaire qui intègre à la fois la perspective des patients et des intervenants.

Núcleo Psicótico numa Psicose em Potencial Complexo de Mãe Morta e Psicose Branca: um estudo de caso

Este estudo teve como objetivo principal explorar dois conceitos importantes na teoria do psicanalista francês André Green: complexo de mãe morta e psicose branca. A decatexia provocada pelo afastamento emocional materno (complexo de mãe morta), induz um vazio interior (angústia branca). Esta sensação de vazio, de paragem, uma depressão sem afetos e a alucinação negativa, são manifestações da psicose branca (estrutura matriz onde se observa o núcleo da psicose sem que esta necessariamente se manifeste). O método utilizado foi o estudo de caso, de um sujeito do sexo masculino em regime de internamento. Os instrumentos de avaliação incluem a técnica projetiva de Rorschach (aplicada no início e no final do internamento) e o Thematic Apperception Test (aplicado no início do internamento). Através do material colhido em contexto de acompanhamento individual e das técnicas projetivas observaram-se pontos de contacto entre o conceito de psicose branca de Green, falso self de Winnicott e as personalidades “as if” de Helene Deutsch. A morte metafórica da mãe, o seu afastamento emocional, poderá estar na origem destas perturbações, onde se observa o núcleo da psicose. Nestas situações clínicas, em que o vazio interno predomina, a prática psicoterapêutica requer um posicionamento particular do clínico, que não deve estar nem muito próximo (sentido como intrusivo) nem muito distante (sentido como abandónico) do seu paciente. / This work had the purpose of exploring two important concepts in the theory of the French psychoanalyst André Green: the dead mother complex and the blank psychosis. The decathexis caused by a maternal emotional withdrawal (dead mother complex) induces an internal void (blank anguish). This feeling of emptiness, stoppage, a depression without affects and the negative hallucination are manifestations of blank psychosis (a matrix structure where one can observe the psychotic kernel, even though without having a manifest psychosis). The applied method was the case study, with a young male institutionalized subject, and to support it we used the Thematic Apperception Test (applied in the early phases of treatment) and the Rorschach projective technique (applied at the beginning and ending of the treatment). Through the data collected in the therapeutic sessions and the projective techniques applied, we observed points of contact between blank psychosis, Winnicott`s False Self and Helene Deutsch “as if” personalities. The mother’s metaphorical death, her emotional withdrawal, could be in the genesis of these disturbances, where we can observe the psychotic kernel. When we are dealing with this kind of patient, where the internal void prevails, the psychotherapeutic technique requires a special positioning from the therapist in relation to the patient, that shouldn’t be too close (experienced as intrusive), nor too distant (experienced with feelings of abandonment).

Mémoire de source, propension à halluciner et psychose : identification de marqueurs cognitifs et cliniques chez une population à haut risque génétique

Les déficits cognitifs sont centraux à la psychose et sont observables plusieurs années avant le premier épisode psychotique. L’atteinte de la mémoire épisodique est fréquemment identifiée comme une des plus sévères, tant chez les patients qu’avant l’apparition de la pathologie chez des populations à risque. Chez les patients psychotiques, l’étude neuropsychologique des processus mnésiques a permis de mieux comprendre l’origine de cette atteinte. Une altération des processus de mémoire de source qui permettent d’associer un souvenir à son origine a ainsi été identifiée et a été associée aux symptômes positifs de psychose, principalement aux hallucinations. La mémoire de source de même que la présence de symptômes sous-cliniques n’ont pourtant jamais été investiguées avant l’apparition de la maladie chez une population à haut risque génétique de psychose (HRG). Or, leur étude permettrait de voir si les déficits en mémoire de source de même que le vécu d’expériences hallucinatoires sont associés à l’apparition de la psychose ou s’ils en précèdent l’émergence, constituant alors des indicateurs précoces de pathologie. Afin d’étudier cette question, trois principaux objectifs ont été poursuivis par la présente thèse : 1) caractériser le fonctionnement de la mémoire de source chez une population HRG afin d’observer si une atteinte de ce processus précède l’apparition de la maladie, 2) évaluer si des manifestations sous-cliniques de symptômes psychotiques, soit les expériences hallucinatoires, sont identifiables chez une population à risque et 3) investiguer si un lien est présent entre le fonctionnement en mémoire de source et la symptomatologie sous-clinique chez une population à risque, à l’instar de ce qui est documenté chez les patients. Les résultats de la thèse ont permis de démontrer que les HRG présentent une atteinte de la mémoire de source ciblée à l’attribution du contexte temporel des souvenirs, ainsi que des distorsions mnésiques qui se manifestent par une fragmentation des souvenirs et par une défaillance de la métacognition en mémoire. Il a également été observé que les expériences hallucinatoires sous-cliniques étaient plus fréquentes chez les HRG. Des associations ont été documentées entre certaines distorsions en mémoire et la propension à halluciner. Ces résultats permettent d’identifier de nouveaux indicateurs cliniques et cognitifs du risque de développer une psychose et permettent de soulever des hypothèses liant l’attribution de la source interne-externe de l’information et le développement de la maladie. Les implications empiriques, théoriques, méthodologiques et cliniques de la thèse sont discutées.

Neurobiology and clinical implications of lucid dreaming

Several lines of evidence converge to the idea that rapid eye movement sleep (REMS) is a good model to foster our understanding of psychosis. Both REMS and psychosis course with internally generated perceptions and lack of rational judgment, which is attributed to a hyperlimbic activity along with hypofrontality. Interestingly, some individuals can become aware of dreaming during REMS, a particular experience known as lucid dreaming (LD), whose neurobiological basis is still controversial. Since the frontal lobe plays a role in self-consciousness, working memory and attention, here we hypothesize that LD is associated with increased frontal activity during REMS. A possible way to test this hypothesis is to check whether transcranial magnetic or electric stimulation of the frontal region during REMS triggers LD. We further suggest that psychosis and LD are opposite phenomena: LD as a physiological awakening while dreaming due to frontal activity, and psychosis as a pathological intrusion of dream features during wake state due to hypofrontality. We further suggest that LD research may have three main clinical implications. First, LD could be important to the study of consciousness, including its pathologies and other altered states. Second, LD could be used as a therapy for recurrent nightmares, a common symptom of depression and post-traumatic stress disorder. Finally, LD may allow for motor imagery during dreaming with possible improvement of physical rehabilitation. In all, we believe that LD research may clarify multiple aspects of brain functioning in its physiological, altered and pathological states.