[Epigenetics of early interactions, depression and schizophrenia]. / Epigénetique des interactions précoces, de la dépression et de la schizophrénie.

Epigenetics is the study of the variations of genetic expression that occur not because of differences in DNA structure, but because of chromatin alternations that modulate DNA transcription. The mechanisms of epigenetics are thus the link between genome and phenotype. This article will explore the best known epigenetic mechanisms, namely DNA methylation and histone modifications and how they may lead to the emergence of depression and schizophrenia. The practical interest of this research is an understanding of the role of early interactions in the development of mental illness. Hopefully this understanding will lead to therapeutic pathways aimed at neutralizing these unfavourable epigenetic influences, with the ultimate goal of prevention of mental illness.

[Medicamental treatment of schizophrenia]. / Traitement médicamenteux de la schizophrénie.

Antipsychotics play a key role in biologic therapy of schizophrenia. Following the first-generation neuroleptics, associated with many extrapyramidal side effects (severe dystonias, parkinsonian syndrome, akatisia and late dyskinesia) altering patients' compliance to the treatment, one can now find a new generation of molecules considered as atypical antipsychotics because they rarely cause neurological complications. This propriety provides a better compliance, along with a clear decrease of late dyskinesia risk but the effectiveness compared to ordinary molecules is still questioned. However, some of them can cause an increased risk of metabolic syndrome. Some molecules such as benzodiazepines and some antidepressants can also be prescribed to cure schizophrenic patients.

[An unusual hospitalization under constraint]. / Une mise en observation peu ordinaire.

The case report describes a 45-year old man presenting of the behavioral problems and an aphasia of Wernicke, hospitalized under constraint. The urinary screening in the search of psychotropic substances is positive for the cannabis and the amphetamines. The neurological localization is confirmed by cerebral CT-scan. The discussion relates on the differential diagnosis between a schizophasia and an aphasia of Wernicke, on the difficulty of a somatic diagnosis among patients agitated under the effect of a drug and to the tendency to hospitalize those too quickly under constraint, on the noxious effect of drugs on the brain.

[Psychoanalysis and neuroscience: the end of a schism ?]. / Psychanalyse et neuroscience: la fin d'un schisme ?

For some neurobiologists, present biological descriptions of the brain may integrate the theoretical frame initiated by Freud. The recent acquisitions of neurobiology prove a plasticity of the neural network anabling the inscription of the experiment. The neuroplasticity constitutes the cornerstone of the reconciliation between the psychoanalysis and neurosciences. The brain must not be considered as a rigid organ, determined and determining but well as a dynamic structure, in constant rebuilding. Contrary to the genetic determinism, the plasticity involves diversity and singularity. The variations of the feasible offered by the plasticity are seducing but to what extent towards the constraint of genetics and the epigenetic ? Both concepts, plasticity and epigenesis are well distinct. An epigenetic phenomenon associated to a maternal behaviour seems to have been proved recently in the rat. Attachment and depression require reflection in the sight of epigenesis and plasticity. The Freud concepts are not always applied to biological patterns without any clumsiness. Demonstrating psychoanalysis from neurosciences or the contrary does not seem very realistic. On the other hand there should a good reason to give rise to exchange, to make a clear distinction between psychoanalytical unconsciousness and neurological unconsciousness, and put an end to the groundless opposition between mental and cerebral.

[Biological models of schizophrenia: an update]. / Les modèles biologiques de la schizophrénie: mise à jour.

This paper is a review of the principal, currently proposed, biological models of schizophrenia. The convergence of recent neurobiological studies indicates that schizophrenia may be a neurodevelopmental and progressive disorder with multiple biochemical abnormalities involving dopamine, serotonin, glutamate and gamma-aminobutyric acidergic systems. In post-mortem tissue, structural abnormalities and alterations in synaptic connectivity have been observed in the intracortical circuitry of the prefrontal dorsal cortex. These morphological modifications could be sequelae of earlier environmental insults and genetic processes. There are probably multiple susceptibility genes, each of small effect, which act in conjunction with environmental factors: obstetric abnormalities, intra-uterine infection and abnormal nutrition. Candidate identified genes could influence neurodevelopment, synaptic plasticity and neurotransmission. If schizophrenia is clearly related to an abnormality of early brain development, the clinical expression of the illness itself is delayed typically for about two decades after birth. A similar delayed onset is also observed in the secondary psychosis associated with metachromatic leukodystrophy, a genetic disease affecting myelin. Schizophrenia is a term reserved for idiopathic cases of chronic psychosis. Strictly speaking, schizophrenia is a syndrome. There are no established laboratory tests, neuro-imaging studies, electrophysiological paradigms or neuropsychological testing batteries that can explicitly confirm this behavioural disorder to the exclusion of symptomatology: what physicians diagnose as schizophrenia today may prove to be a cluster of different illnesses, with similar and overlapping symptoms. The diagnosis criteria of the various DSM reflect the American psychiatrists' concern for establishing a consensus classification preserving a wider definition of schizophrenia or more precisely of the schizophrenic disorder. One can presume that research work established from too numerous and insufficiently specific variables doesn't permit the definition of one or several aetiologies. We hope that one day all schizophrenia will be correlated to one precise causal factor permitting the optimal targeting of interesting therapeutic approaches. The multiplicity of concepts and models reflects our questioning.

[Frontal dementia or dementia praecox? A case report of a psychotic disorder with a severe decline]. / Démence frontale ou "démence précoce"? A propos de l'observation d'un trouble psychotique associé a une détérioration sévère.

INTRODUCTION: Many authors have described these last years the difficulty to establish a differential diagnosis between schizophrenia and frontotemporal dementia. However treatment and prognosis of these two separate diseases are not the same. Schizophrenia is a chronic syndrome with an early onset during teenage or young adulthood period and the major features consist of delirious ideas, hallucinations and psychic dissociation. However a large variety of different symptoms describes the disease and creates a heterogeneous entity. The diagnosis, exclusively defined by clinical signs, is then difficult and has led to the research of specific symptoms. These involve multiple psychological processes, such as perception (hallucinations), reality testing (delusions), thought processes (loose associations), feeling (flatness, inappropriate affect), behaviour (catatonia, disorganization), attention, concentration, motivation (avolition), and judgement. The characteristic symptoms of schizophrenia have often been conceptualised as falling into three broad categories including positive (hallucination, delision), negative (affective flattening, alogia, avolition) and disorganised (poor attention, disorganised speech and behaviour) symptoms. No single symptom is pathogonomonic of schizophrenia. These psychological and behavioural characteristics are associated with a variety of impairments in occupational or social functioning. Cognition impairments are also associated with schizophrenia. Since the original clinical description by Kraepelin and Bleuler, abnormalities in attentional, associative and volitional cognitive processes have been considered central features of schizophrenia. Long term memory deficits, attentional and executive dysfunctions are described in the neurocognitive profile of schizophrenic patients, with a large degree of severity. The pathophysiology of schizophrenia is not well known but may be better understood by neuronal dysfunctions rather than by a specific anatomical abnormality. Frontotemporal lobar degeneration (FTLD) is one of the most common causes of cortical dementia. FTLD is associated with an anatomical atrophy that can be generalised, with a frontotemporal or focal lobar predominance. Histologically there is severe neuronal loss, gliosis and a state of spongiosis. In a minority of case Pick cells and Pick bodies are also found. The usual clinical features of FTLD are divided in three prototypic syndromes: frontotemporal dementia (FTD), progressive non-fluent aphasia (PA) and semantic dementia (SD). FTD is the most common clinical manifestation of FTLD. FTD is first characterised by profound alteration in personality and social conduct, characterised by inertia and loss of volition or social disinhibition and distractibility. There is emotional blunting and loss of insight. Speech output is typically economical, leading ultimately to mutism, although a press of speech may be present in some overactive, disinhibited patients. Memory is relatively preserved in the early stage of the disease. Cognitive deficits occur in the domains of attention, planning and problems solving, whereas primary tools of language, perception and spatial functions are well preserved. PA is an initial disorder of expressive language, characterised by effortful speech production, phonologic and grammatical errors. Difficulties in reading and writing also occur but understanding of word meaning is relatively well preserved. In SD a severe naming and word comprehension impairment occur on the beginning in the context of fluent, effortless, and grammatical speech output. There is also an inability to recognise the meaning of visual percepts. The clinical syndromes of FTLD are associated with the brain topography of the degeneration. So considerable clinical overlap can exist between schizophrenia and FTLD and the object of the following case report is to remind the difficulty to make a differential diagnosis between these two pathologies. CASE REPORT: A 34 year old non-married man is admitted in mental health district of a general hospital for behavioural disturbances that include repeated aggressions towards his family. At initial interview visual and auditives hallucinations are described. The patient doesn't care about these abnormalities and a poverty of speech is observed. The affects, globally blunted, show some degree of sadness however. The patient's birth and early development were unremarkable. At the age of 26, the patient dismissed from his job because of poor performance and absenteeism. He spent a lot of time watching TV, showed poverty of speech and become sometimes angry and violent without an explanation. He was hospitalised for several months and a schizophrenia including predominant negative features, hallucinations and delusion was diagnosed. He was treated with bromperidol, could go back to home and was followed by a general practitioner for 8 years. The patient had a stereotyped way of life during these years with a poor communication and little activity. During the months preceding the current hospitalisation, these characteristics and avolition emphasised, urinary incontinence appeared. The patient receives risperidone 8 mg/day associated with citalopram 40 mg/day during several months of hospitalisation. No significant evolution is observed regarding apathic and stereotyped way of live. The capacity of communication remains very poor. Neurocognitive assessments reveal multiple and severe dysfunctions. Memory, executive and attentional tasks are extremely disturbed. Physical and neurological examinations reveal an isolated bilateral Babinski sign. Cerebral scanner and magnetic resonance show bifrontal atrophy and PET scan is normal. There are no significant abnormalities found on blood and urine samples and on lumbar puncture. The patient is sent to a chronic neuropsychiatric hospital and the treatment is stopped. One year later, a comparative evaluation is realised. The general clinical state shows no evolution. Neurocognitive assessments are repeated and severe dysfunctions are observed with more perseverations. DISCUSSION: A diagnosis of FTLD for this patient can be discussed regarding clinical features, neurocognitive testings and neuroradiological findings. Schizophrenia is a major differential diagnosis. Psychotic symptoms like hallucinations and age of onset are essential observations for the diagnosis of schizophrenia but can not exclude FTLD. Memory, intellectual functions, executive and attentional abilities may all be disturbed in schizophrenia and FTLD. Cerebral abnormalities well established in schizophrenia are lateral ventricles enlargements. Frontal lobar atrophy is a major argument for FTLD and is only a sporadic finding in schizophrenic populations. Schizophrenia and FTLD could be comorbid diseases by several ways. CONCLUSION: A differential diagnosis between schizophrenia and FTLD is difficult to establish. Schizophrenia is a heterogeneous disease with a large variety of cognitive dysfunctions. Neurocognitive tools may improve our knowledge of schizophrenia.

[The psychiatry department]. / Le Service de Psychiatrie.

The Department of Psychiatry was first opened in April 1978. It is one of the largest sector of the hospital and contains 90 beds including a sleep laboratory and an adolescent unit. The clinical activities are broad and multidisciplinary, including novel psychopharmacological and psychotherapeutic and psychosocial approaches. Educational and research activities have also been developed, in particular in the areas of behavioral genetics, sleep physiology, brain imaging and psychosocial research and training.

Brain glucose metabolism in eating disorders assessed by positron emission tomography.

OBJECTIVE: As anorectic and bulimic patients present similar clinical and neurobiological symptoms, the purpose of this study was to compare brain glucose metabolism at rest in these patients. METHODS: Positron emission tomography with (18-F)-fluorodeoxyglucose was used to evaluate cerebral glucose metabolism (CMRglu) in 10 normal-weight bulimic women, in 10 underweight anorectic patients, and in 10 age- and sex-matched healthy volunteers. RESULTS: Absolute global cortical glucose activity was significantly lower in anorectic patients compared with bulimic and control subjects. Anorectic patients compared with normal control subjects also showed higher relative CMRglu in the inferior frontal cortex and in the basal ganglia, and putamen and caudate relative hypermetabolism when compared with bulimic patients. Thus, both eating disorder groups differed from control subjects in low relative parietal values of glucose. DISCUSSION: While absolute global metabolism seems to be related to weight loss, we can hypothesize either a common parietal cortex dysfunction in eating disorders or a particular sensitivity of this cortex to consequences of eating disturbances.

Brain hypometabolism of glucose in low-weight depressed patients and in anorectic patients: a consequence of starvation?

As low-weight anorectic patients presented a global as well as a regional absolute hypometabolism of glucose, we investigated a population of ten age- and sex-matched low-weight depressed patients without anorexia nervosa to evaluate the impact of weight loss on cerebral glucose metabolism evaluated by positron emission tomography and [18F]-fluorodeoxyglucose. Ten age- and sex-matched healthy volunteers were used as controls. Absolute global and regional glucose activity was significantly lower in anorectic and low weight depressed patients than in control subjects. Anorectic patients compared with normal control subjects also showed lower relative metabolism of glucose in the parietal cortex. Within patients, absolute hypometabolism of glucose seems to be a consequence of low-weight while there is a positive correlation between absolute metabolism of glucose and body mass index.

Brain hypometabolism of glucose in bulimia nervosa.

OBJECTIVE: A cerebral function lateralization has been described in bulimic patients in positron emission tomography (PET) studies realized during a specific cognitive task. The purpose of this study was to evaluate, at rest, brain glucose metabolism in patients with bulimia nervosa. METHOD: PET with (18-F)-fluorodeoxyglucose was used to evaluate cerebral glucose metabolism in 11 normal-weight bulimic girls compared to 11 age- and sex-matched healthy volunteers. Patients were diagnosed following DSM-IV and were off psychoactive medication. RESULTS: In comparison with control subjects, bulimic patients showed global and regional absolute hypometabolism of glucose. In relative values, only parietal cortex metabolism was significantly lower in bulimic patients. No correlation was found within groups for absolute or relative cerebral glucose metabolic rates (rCMRglu) and body mass index (BMI), anxiety scores, or Hamilton scores of depression. DISCUSSION: Since previous studies have demonstrated similar disturbances in anorectic patients, we hypothesized that these observations could be a consequence of neurobiological perturbations following nutritional deficiencies or a particular cerebral dysfunction in eating disorders.

Brain glucose metabolism in anorexia nervosa and affective disorders: influence of weight loss or depressive symptomatology.

Relationships between eating and affective disorders remain complex and unclear. Brain glucose metabolism of anorectic patients has been demonstrated to be reduced both globally and regionally, with a particular relative hypometabolism in the parietal cortex. To explore the possible influence of weight loss or depressive symptomatology on brain metabolism, we studied age- and sex-matched low-weight anorectic and depressed patients, normal-weight depressed patients, and healthy volunteers. Absolute global and regional glucose activity levels were reduced in low-weight patients, with the lowest values being found for anorectic patients. In relative values, anorectic patients showed a significant parietal hypometabolism in comparison to control subjects while they had higher metabolism in the caudate nuclei when compared with the other groups. Absolute hypometabolism of glucose seems to be a consequence of low weight as it was found in both low-weight anorectic and low-weight depressive patients. In addition, absolute glucose values were significantly correlated with body mass index in all subjects. Future positron emission tomographic studies in psychiatric patients should control for alimentary parameters.

In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: a film and electronic autoradiographic study.

To further validate its use in positron emission tomography (PET), we studied the binding of [18F]altanserin, a specific 5HT2 radioligand, in the rat brain using in vivo autoradiography. Distribution of [18F]altanserin binding was comparable to the in vitro mapping of 5HT2 receptors reported in the literature. Selective displacers were used to test the reversibility and the selectivity of this radioligand. Specific binding of [18F]altanserin in the rat frontal cortex was quantified by direct counting with an electronic imaging system and by quantification on digitalized autoradiograms. Close results of about 30 pmol/g were obtained with both methods. Our data confirmed that [18F]altanserin is a valid tracer for 5HT2 receptors binding studies.

Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex.

BACKGROUND: Serotonin receptors may play an important role in the pathophysiology of affective disorders. We studied type-2 serotonin (5-HT2) receptors in the brain of patients with major depression. METHOD: Using positron emission tomography (PET) and the selective radioligand [18F]altanserin, we investigated 5-HT2 receptor distribution in eight drug-free unipolar depressed patients and 22 healthy subjects. Data were analysed using Statistical Parametric Mapping 95. RESULTS: In depressed patients, [18F]altanserin uptake was significantly reduced in a region of the right hemisphere including the posterolateral orbitofrontal cortex and the anterior insular cortex. A trend to similar changes was found in the left hemisphere. No correlation was found between the uptake and the Hamilton rating scale score. CONCLUSIONS: Pathophysiology of depression may involve changes in 5-HT2 receptor in brain regions selectively implicated in mood regulation.

Brain hypometabolism of glucose in anorexia nervosa: normalization after weight gain.

Using positron emission tomography and (18-F)-fluorodeoxyglucose, we studied cerebral glucose metabolism in 10 anorectic girls within their underweight state and after weight gain. Ten age- and sex-matched healthy volunteers were used as controls. Both groups were scanned during rest, eyes closed and with low ambient noise. In absolute values, the underweight anorectic patients, when compared to control subjects, showed a global (p = 0.002) and regional (p < or = 0.001) hypometabolism of glucose which normalized with weight gain. In relative values, no global difference could be assessed between underweight anorectic patients and controls but a trend can, nevertheless, be observed toward parietal and superior frontal cortex hypometabolism associated with a relative hypermetabolism in the caudate nuclei and in the inferior frontal cortex. After weight gain, all regions normalized for absolute and relative values, although a trend appears toward relative parietal hypometabolism and inferior frontal cortex hypermetabolism in weight gain anorectic patients. Absolute brain glucose hypometabolism might result from neuroendocrinological or morphological aspects of anorexia nervosa or might be the expression of altered neurotransmission following deficient nutritional state. As some differences exists in relative values in underweight patients and tend to persist in weight gain states, this could support a potential abnormal cerebral functioning, a different reaction to starvation within several regions of the brain or different restoration rates according to the region.

Interregional correlation of cerebral glucose metabolism in unmedicated schizophrenia.

To investigate metabolic relationships between different brain regions in schizophrenia, we measured regional brain metabolism using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) in 15 unmedicated schizophrenic patients and 15 healthy subjects. We analyzed correlations between glucose metabolism data of multiple brain regions using factorial analysis and correlation coefficient comparisons. Absolute regional intercorrelations in schizophrenic brains were found to be significantly stronger than in controls, in relationship to the greater variability of metabolic rates in schizophrenic patients. Variability of normalized metabolic rates and regional intercorrelations were not significantly different between schizophrenic patients and control subjects. We conclude that a global metabolic factor accounts for the variability of metabolic data in untreated schizophrenia.

Sex difference in 5HT2 receptor in the living human brain.

Serotonergic mechanisms are involved in gender-related behaviors and psychiatric conditions like aggression, eating disorders, depression, impulsivity or suicide. We studied gender differences in the living human brain type-2 serotonin receptor (5HT2r). Twenty-two healthy age-matched men and women were investigated using positron emission tomography and the selective radiotracer, 18F-labeled altanserin. Binding was quantified using a non-linear least-squares minimization procedure. We found significantly higher 5HT2r binding capacity in men than in women, especially in the frontal and cingulate cortices. Distinct liability for men and women to suffer from some psychiatric disorders responding to serotonergic agents may be related to differences in brain serotonin receptors.

Basal ganglia and frontal lobe glucose metabolism. A reproducibility positron emission tomography study.

Positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (FDG) is frequently used to study the metabolic correlates of movement and mental disorders. These studies generally focus on changes in the frontal cortex and the basal ganglia. The reproducibility of glucose metabolism estimates in these structures was tested in 13 normal subjects studied at rest using a standard and simple protocol. A reproducible dorsoventral metabolic gradient was demonstrated in the frontal cortex. Such a gradient was not present in the basal ganglia when the upper region of interest in the caudate nucleus, where the lower metabolic rate of glucose was probably attributable to partial volume effects, was not considered. Absolute values of glucose metabolic rates varied by 6.4 to 12.5% in the frontal cortex and by 6.8 to 14.7% in the basal ganglia. Variations in normalized values in the basal ganglia ranged from 4.0 to 8.6%. The number of subjects required to detect statistical differences in group comparison or in test-retest studies was calculated for different anticipated levels of change. With the variability detected in this experiment, less than 10 subjects were expected to be sufficient to detect a 15% change in most regions and in both types of studies.

Altered frontostriatal relationship in unmedicated schizophrenic patients.

Positron emission tomography with [18F]-fluoro-2-deoxy-D-glucose as tracer was used to investigate frontal glucose metabolism in 15 unmedicated schizophrenic patients and 15 healthy subjects under resting conditions. Although no difference in absolute frontal cerebral metabolic rates of glucose (CMRglu) were found between schizophrenic patients and control subjects, relative measures significantly differentiated the two groups. Whole frontal metabolism and frontocaudate ratio were significantly decreased in both hemispheres in the patients. The results confirm the existence of hypofrontality in unmedicated schizophrenia and indicate disturbances in metabolic relationships between the frontal cortex and the striatum in this disorder.

[Decrease in the frontal-superobasal metabolic ratio in unipolar depression]. / Réduction du rapport métabolique frontal supéro-basal dans la dépression unipolaire.

Cerebral frontal glucose metabolism was investigated in 12 unipolar depressed patients and compared to these of 12 healthy volunteers using Positron Emission Tomography (PET) and (F18) fluorodeoxyglucose. The PET investigation was made in a quiet room with a dimly light and each subject remained in a resting state with closed eyes. Results show a decreased in a frontal superobasal calculated ratio in depressed patients compared to control subjects for left and for right values. This reduction indicates an imbalance between the frontal and the superobasal region. This imbalance could relate to some particular depressive symptom profile.