Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia.

Few magnetic resonance imaging studies of schizophrenia have investigated brain tissue volumes and their relation to clinical symptoms in patients with an early age at illness onset. The twofold purpose of the study was to investigate both gray and white matter volumes in schizophrenic men with an early age at illness onset, and to determine whether clinical features correlated with tissue volume changes, using an automated voxel-by-voxel image analysis procedure. Twenty male patients with DSM-IV diagnoses of schizophrenia, and an early age at onset (m+/-SD=19+/-2) were compared with 20 age-matched health men. Magnetic resonance (1.5-T) scans were obtained with an Inversion-Recovery prepared fast gradient echo sequence enhancing gray and white matter contrast. Statistical Parametric Mapping was used for image segmentation and comparison. Patients had significant gray matter reductions in medial frontal gyri, left insula, left parahippocampus, and left fusiform gyrus; bilateral white matter reductions in frontal lobes, and increased total cerebrospinal fluid volume were also observed. Negative symptom scores were negatively related to white matter volumes in cingulate regions, and in the right internal capsule. These findings emphasize a pattern of left-hemisphere gray matter abnormalities, and suggest that fronto-paralimbic connectivity may be altered in men with early onset schizophrenia.

Altered hemispheric functional dominance during word generation in negative schizophrenia.

Functional brain imaging studies have reported decreased frontal activations in schizophrenia, but hemispheric dominance for language has rarely been assessed. To investigate regional activation and lateralization during word production, we determined normalized regional cerebral blood flow (rCBF) variations with positron emission tomography (PET) and H2(15)O (water labeled with the isotope oxygen 15) in 14 negative schizophrenia patients and 14 volunteers. Subjects were scanned during two trials of three conditions: rest, vocalized verbal fluency, and spontaneous word production. Images were analyzed using an anatomical volumes of interest method, and the two groups' changes were compared, using rest as a baseline. Differences in the lateralization of changes were detected in homologous frontal and inferior parietal regions. The lateralization effects in patients arose from lower activations in the left frontal regions, abnormal right inferior frontal activations, and weaker right inferior parietal deactivation, during the word production tasks. The right hemisphere changes correlated negatively with the performance in verbal fluency. Thus in negative schizophrenia patients, while the activations were less focused on the left hemisphere regions usually engaged in word generation, rCBF changes in the right hemisphere might reflect a compensatory functional pattern.

Working memory control in patients with schizophrenia: a PET study during a random number generation task.

OBJECTIVE: The authors' goal was to investigate brain regions involved in the deficiency of working memory control processes in patients with schizophrenia. METHOD: Regional cerebral blood flow was measured with positron emission tomography in eight men with stabilized schizophrenia and eight healthy men while they were performing a graded random number generation task. Twelve scans were made for each subject. Covariations between randomness of responses and regional activation were analyzed. RESULTS: The pattern of covariation between randomness of responses and activation in the anterior cingulate and superior parietal regions differed between patients and healthy subjects. CONCLUSIONS: These results suggest a cinguloparietal dysfunction underlying the impairment of working memory control processes during a random number generation task in patients with schizophrenia.

The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.

BACKGROUND: Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients. METHODS: Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls. RESULTS: There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions. CONCLUSIONS: These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET.

To investigate putative abnormalities of cortical 5-HT2A receptor density in schizophrenia, we used positron emission tomography and [18F]setoperone, a high-affinity 5-HT2A receptor radioligand, in 14 neuroleptic-free or -naive schizophrenic patients and in 15 normal controls. No significant difference between the groups was observed in the whole or regional cortical binding potential of [18F]setoperone, indicating an absence of major 5-HT2A receptor cortical density abnormalities in schizophrenics.

Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients.

OBJECTIVE: This study examined the binding to cortical serotonin 5-HT2A receptors of conventional doses of the typical neuroleptic chlorpromazine in comparison with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific dopamine D2-D3 blocker. METHOD: Seventeen schizophrenic patients treated with chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A binding was estimated by reference to the values for 14 antipsychotic-free schizophrenic subjects with the use of positron emission tomography and [18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors. RESULTS: A dose-dependent decrease in the number of available cortical binding sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the highest dose, there was a virtual lack of sites available for binding. A very low percentage of available binding sites was also observed in the clozapine-treated patients at all doses. This suggests a high level of 5-HT2A blockade with both clozapine and high doses of chlorpromazine. No significant binding of amisulpride to 5-HT2A receptors was detected. CONCLUSIONS: A high level of 5-HT2A receptor blockade does not appear specific to clozapine in comparison with high doses of chlorpromazine, suggesting that the distinct clinical profiles of both drugs are unrelated to 5-HT2A blockade itself.

[Seasonal depression]. / Les dépressions saisonnières.

Seasonal affective disorder (SAD) is characterized by annual major depressive episodes. It occurs most commonly in young women during autumn and winter with full remission during the following spring. The patient's mood is a combination of depression and anxiety accompanied by fatigue, loss of libido, and a reduction of socialization. Most of these patients complain of atypical vegetative symptoms (e.g. hypersomnia, carbohydrate craving, and weight gain). Hypotheses on the underlying mechanisms of these behavioural disorders indicate that environmental variables, e.g. climate, latitude, light, and changes in neurotransmitter function that occur naturally with the seasons, may be important. Phototherapy is being used increasingly for the treatment of SAD. The antidepressant response is contingent on the exposure of the patients' eyes to light. The biological basis of the diverse psychological and biological changes in SAD and the underlying mechanism of action of phototherapy are still unclear and require further study.

Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors.

To investigate adaptative changes of 5-HT2A receptors induced by SSRIs, six patients chronically treated for a depressive episode (four with fluoxetine, two with fluvoxamine) were studied with PET and [18F]setoperone. They were compared to eight untreated depressive patients. The mean frontal to cerebellum radioactivity concentration ratio, an index of the [18F]setoperone specific binding to 5-HT2A receptors, was higher in treated than in untreated patients, when age was taken into account. This suggests that chronic treatment by SSRIs could induce an up-regulation of the 5-HT2A receptors, and that 5-HT2A receptor down-regulation is not a common mechanism for the therapeutic effects of all serotoninergic antidepressive drugs.

Controlled efficacy study of fluoxetine in dysthymia.

BACKGROUND: There have been very few controlled studies of antidepressants in dysthymia, particularly in samples diagnosed reliably and with an adequate length of follow-up. In this investigation, we measured the long-term outcome in a large group of patients meeting DSM-III-R criteria for dysthymia. This study was designed to investigate whether fluoxetine is effective in the treatment of dysthymia. METHOD: This randomised study including 140 patients, compared fluoxetine (91 patients) and placebo (49 patients) on a double-blind basis in two distinct phases: a short-term end-point (3 months with 20 mg/day fluoxetine) and a medium-term end-point (6 months) where the initial responders continued double-blind treatment unchanged and non-responders received an additional treatment of 20 mg/day fluoxetine. RESULTS: After three months of treatment, response was seen more frequently in the fluoxetine group (42/72) than in the placebo group (14/39, P < 0.0001). Improved patients at 3 months were still improved at 6 months. Furthermore, 50% of the nonresponders at 3 months improved and rated as responders at 6 months, after fluoxetine was increased to 40 mg daily. CONCLUSIONS: This study showed the significant and persistent action of fluoxetine on dysthymia. The finding that 50% of the non-responders at 3 months were improved at 6 months, after fluoxetine dosage was increased to 40 mg daily, argues in favour of treating dysthymic patients for at least 6 months, and with a higher dosage if the initial doses are ineffective.

Presynaptic dopaminergic function in the striatum of schizophrenic patients.

The dopaminergic hypothesis of schizophrenia postulates increased brain dopaminergic activity. Two previous studies reported increased 18F-DOPA uptake with positron emission tomography in schizophrenic patients (n = 5, n = 7). In the present study, striatal dopaminergic function was assessed in vivo in six untreated schizophrenics and seven control subjects, comparable for age and sex. The 18F-fluoro-L-DOPA (18F-DOPA) uptake rate constant Ki was determined in the caudate and putamen using coregistered positron emission tomography and magnetic resonance imaging. No difference between groups for mean Ki was found. The variability of the 18F-DOPA uptake values was higher in the caudate (p < 0.01) and in the putamen (p < 0.001) in schizophrenic patients than in control subjects, suggesting that schizophrenia is a disorder involving heterogeneous states of the striatal presynaptic dopaminergic function.

[Role of associations in bipolar patients]. / Rôle des associations de patients bipolaires.

Providing information to the patients and their families represents one of today's new conditions in the management of the depressed. It will help their adaptation to the illness and its effects. It will maintain a good therapeutic alliance among patients and practitioners, and will enhance their treatment adherence thus improving their quality of life. Several aspects are essential in the transmission of this information: it must be available to every patient, easily accessible, concise, repeated and revised as necessary, discouraging self-diagnosis and self-prescription. This education must be given personally by the physicians and the pharmacists. Depressed patients may also have an access to complementary sources: books, magazines and more rarely scientific journals. Patients' associations provide another potential source of information, offering a comprehensive approach to the patient and the illness. France-Déxpression is a depressive and manic-depressive patients association. Its goals are to provide information and support to the patients and their families, promoting a better understanding and recognition of depressive and manic-depressive illness.

[Seasonal depression]. / Dépressions saisonnières.

Seasonal affective disorder (SAD) is a condition characterized by annually occurring major depressive episodes which was described by Rosenthal et al. in 1984. It occurs most commonly in women and the onset usually being in early adulthood. These episodes are regularly occurring in fall and winter with full remission during the following spring and summer. The patient's mood is a combination of depression and mild anxiety accompanied by fatigue, loss of libido, and a profound reduction of socialisation. During winter depression, most of these patients complain of atypical vegetative symptoms accompanied by hypersomnia, hyperphagia, carbohydrate craving, and weight gain. Hypotheses on the underlying mechanisms of these behavioral and neurovegetative disorders indicate that environmental variables, e.g., climate, latitude, light, and changes in neurotransmitter fraction that naturally occur with the seasons may be important. Phototherapy is being increasingly used for the treatment of seasonal affective disorder. The antidepressant effect of light therapy in the treatment of SAD has been widely shown. The response in patients with SAD is contingent on the exposure of the patients' eyes to light. Further important factors are the duration of daily treatment and light intensity. However, the role of timing of phototherapy remains controversial. The biological basis of the diverse psychological and biological changes in SAD and the underlying mechanisms of action of phototherapy are still unclear and require further study.

[Electroconvulsive therapy and aortic aneurysm: apropos of a case]. / Electroconvulsivothérapie et anévrisme aortique: a propos d'un cas.

The adverse effects of electroconvulsive therapy (ECT) become rare due to the increased progress specially in avoiding cardiovascular side effects. In fact, several studies report ECT treatment performed with success and without side effects, in depressive patients presenting serious cardiovascular diseases (aortic anevrysm, cerebral venous angioma, cerebral infarct, aortic dissection...). Occurrence of cardiovascular complications can be prevented if an elevation of blood pressure or an arythmia occurring during the seizure are previously and correctly detected and managed. Hence an adequate anaesthetic premedication must be implemented. Usual protocols use atropine, hydralazine and hydro-chlorothiazide. However, ECT treatment should be avoided in patients requiring urgent surgical correction of their cardiovascular abnormalities. Also, patients and families must be informed on the benefit derived from ECT treatment and reassured on the therapeutic issue when ECT treatment is correctly managed. This case report concerns an 89 year old woman presenting a melancholic depressive state complicated with an aortic anevrysm, successfully treated with ECT.

[Familial psychosis and filiation]. / Psychose familiale et filiation.

Since the last decade of the nineteenth century, psychiatric nosology has been dominated by Kraepelin's binary system: the notion that the distinction between manic-depressive illness and schizophrenia identifies two separate diseases with differing symptom patterns and outcomes. However, Kraepelin recognised that intermediate states, as exemplified by Kasanin's concept of "schizoaffective" illness are common. In contrast to Kraepelin's separation of manic-depressive illness from schizophrenia, the concept of a continuum of psychosis implies that there are gradations of illness between unipolar depressive, through bipolar affective and schizoaffective illness, to schizophrenia. This concept is strongly supported by the majority of family studies. Moreover, no simple clinical demarcations of affective from schizophrenic illnesses can be made. The family findings are compatible with the hypothesis that the same gene or genes contribute to susceptibility to both schizophrenia and affective disorder: a single locus that may be variable between generations, and that is represented by homologous loci on the X and Y chromosomes.

Loss of brain 5-HT2 receptors in Alzheimer's disease. In vivo assessment with positron emission tomography and [18F]setoperone.

Using [18F]setoperone and positron emission tomography (PET), alterations in serotonergic 5-HT2 receptor binding were studied in cerebral cortex of nine unmedicated patients with probable Alzheimer's disease and 37 healthy controls. The kinetics of unchanged radioligand in plasma and 18F-radioactivity in blood and brain were obtained for 90 min following tracer injection. The specific binding of [18F]setoperone to 5-HT2 receptors in the cerebral cortex was quantitated by subtraction using cerebellum as reference. In controls, a significant reduction in specific binding was associated with age and similar linear regression slopes were obtained in all the cortical regions studied. No significant difference was observed between patients with Alzheimer's disease and age-matched controls in the injected mass of setoperone, percentage of unmetabolized [18F]setoperone in plasma, 18F-radioactivity in blood fractions and cerebellar 18F-radioactivity concentration, indicating similar non-specific brain kinetics and metabolism of the radioligand. In contrast, there was a significant reduction in specific [18F]setoperone binding in the cerebral cortex in patients with Alzheimer's disease relative to control values (temporal, 69%; frontal, 69%; parietal, 55%; temporo-parietal, 54%; occipital cortex, 35%). The results demonstrate that the loss in 5-HT2 receptor binding in the cerebral cortex of patients with Alzheimer's disease, long documented by post-mortem studies, can now be assessed in vivo using PET.

Left prefrontal glucose hypometabolism in the depressed state: a confirmation.

The resting-state cerebral metabolic rates for glucose of 10 severely depressed patients (seven bipolar and three unipolar) were compared, before and after treatment with tricyclic antidepressants, to those of 10 control subjects of similar age by means of positron emission tomography and the fluorodeoxyglucose method. Significant left-right prefrontal asymmetry was present in the patients before but not after successful treatment, suggesting that medication can reduce this asymmetry. Also, significant hypofrontality and whole-cortex hypometabolism were found in the patients in the depressed state and persisted in the treated state, despite clinical improvement, suggesting that these abnormalities are not state dependent.

[Seasonal affective disorders, a new clinical category]. / Les troubles affectifs saisonniers, une nouvelle catégorie clinique.

Seasonal affective disorders have recently been individualized by American authors. According to these authors, this subgroup of affective diseases deserve to be regarded as a clinical category owing to its specific symptoms, its epidemiological features and its response to treatment. They are characterized by the triad: hypersomnia, hyperoxia, weight gain, associated with usual symptoms of depression. Moreover, contrary to the bipolar manic-depressive psychosis, they seem to predominate among women. Finally, phototherapy, the various protocols of which are discussed here, is said to be effective. The influence of latitude combined with the effectiveness of phototherapy has led to original pathogenic hypotheses, among which the presence of a chronobiological disorder (abnormality of the season-induced circadian rhythm), although attractive and supported by a strict clinical study, has yet to be demonstrated. Also hypothetical is the role played by melatonin: is this hormone the principal "mediator" or an epiphenomenon?