[Suicidal risk prevention in schizophrenia: Importance of family psychoeducation]. / Prévention du risque suicidaire dans la schizophrénie : importance de la psychoéducation des familles.

OBJECTIVES: Although mortality by suicide in schizophrenia seems to have decreased in some countries over the last 30 years, it remains much higher than in the general population. Studies have shown this risk to impact around 5% of patients, corresponding to a risk almost 2.5 times higher than in the general population. Family psychoeducation in schizophrenia has been demonstrated to lead to symptom reductions and to an improvement of the quality of life, two factors that should contribute to decreasing the suicidal risk. Therefore, if families attend an efficient psychoeducation program, we can expect a decrease in the patient suicidal risk. Attending a family psychoeducation program at the beginning of the disease would also be associated with a stronger preventive effect on suicidal mortality. The objective of this study is to describe the suicide attempt rate of patients who suffer from schizophrenia before and one year after one of their relatives participated to the family psychoeducation program Profamille. METHOD: We performed a retrospective study on 1209 people who attended the Profamille (V3.2 version) Family Psychoeducation Program. This program has 2 modules: an initial training module of 14 weekly or fortnightly sessions, and a consolidation module of 4 sessions over 2 years. Sessions last 4 hours and follow a precise and structured course. Data were collected from 40 different centers in France, Belgium and Switzerland and were based on participants assessed at the beginning and one year after the first module. Self-assessment from the relatives participating in the program provided the measure of patients' suicide attempts. An assessment at T0 explored the attempts over the 12 months before the beginning of the program while the assessment at T1 analyzed those during the 12 months following the end of the Program. The Chi2 test was used to compare the suicide attempt rates for each period, using a significance threshold of 0.05. Since the risk of suicide is greater in the first years of the illness, rates of attempts are also calculated according to the age of disorder. The analysis was carried out with the statistical software R. RESULTS: The number of participants reporting that their relative had attempted suicide in the previous 12 months decreased from 41 to 21. The annual attempts rate was evaluated at 6.4 % before the Profamille program and decreased to 2.4 % a year after the end of the program (P=0.0003). The reduction of the attempt rate was observed even for patients with schizophrenia for more than 10 years. CONCLUSION: This study shows the positive impact of Profamille on reducing the rate of suicide attempts in patients with schizophrenia. It has been shown that the risk is highest at the beginning of the disorder. Therefore, based on our results, it would seem appropriate to propose the Profamille program at an early stage.

[Depression in relatives of patients with schizophrenia: 8-month longitudinal outcome of ProFamille Program]. / La dépression chez les proches de patients souffrant de schizophrénie : effets longitudinaux sur 8 mois du programme ProFamille.

INTRODUCTION: Mental illness such as schizophrenia is a major public health concern. In France, the economic cost of schizophrenia represents 2% of total medical expenditures. Schizophrenia has an impact on health and quality of life not only for patients but also for relatives. Family psychoeducation is a complementary therapeutic intervention to ordinary clinical care deigned to alleviate the burden of care among relatives of patients with schizophrenia. Literature suggests such programs including the patients' family members reduce the risk of relapse. Current studies also suggest that negative emotions expressed by family members have negative consequences on patients' mental health and need to be addressed. However, family psychoeducation is still underdeveloped in France. The objective of this study was to assess the longitudinal outcome on depression level of a psychoeducation program for relatives of schizophrenic patients. The program was held in Paris and Région Île-de-France "Cluster ProFramille Île-de-France" between 2012 and 2014. METHODS: Level of participant's depression was assessed by the Center for Epidemiologic Studies - Depression Scale (CES-D). Measures of depression were made for four time points: 2 months before joining the program (T1), at the beginning of the program (T2), at midpoint of the first program module (3 months, T3) and at the end of the first program module (6 months, T4). Repeated-measures ANOVA were performed to assess longitudinal change in a participant's level of depression. Type of coping strategies, knowledge about the disease, dominant thoughts and emotional progress are assessed by the program. Univariate correlation with CES-D differences between T1 and T4 were assessed. Variables with a significant association were included in a multivariate linear model to explain CES-D difference. RESULTS: Sixty-five relatives participated to the "Cluster ProFramille Île-de-France" between 2012 and 2014 and terminated with the first module of the program. Repeated-measures ANOVA on CES-D scores between T1 and T4 (8 months) showed a significant decrease in average scores for all participants. The mean of decrease was 7 points, equivalent to a 26.6% pre-post decrease level of depression. Significant univariate correlations with depression decrease over 8 months were with "psychomotor tiredness", "frequent worries" and "dealing with worries". Multivariate linear regression only confirmed the significant role of diminishing fatigue in relation to the decrease of depression. CONCLUSION: Our study's results showed that the ProFamille program was efficient in reducing the level of depression for its participants over an 8 month period. As the participants progressed on managing their fatigue, their depressed moods improved.

[Psychoeducation of patients and their family members during episode psychosis]. / Psychoéducation des patients et de leurs proches dans les épisodes psychotiques.

The concept of psychoeducation is close to the concept of therapeutic education and refers to a kind of education intervention targeting people with a mental health condition. In the framework of psychosis, psychoeducation can be offered to patients, family members or both. The efficacy of patient psychoeducation on treatment adherence or social functioning is well-established but only if the family benefits of a joint psychoeducational intervention. Family psychoeducation, even without patient psychoeducation has proven efficacy in reducing relapse rate. This reduction is of the same order of magnitude as that obtained with an antipsychotic medication.

A positron emission tomography (PET) study of cerebral dopamine D2 and serotonine 5-HT2A receptor occupancy in patients treated with cyamemazine (Tercian).

RATIONALE: Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT(2A) receptors, which was fourfold higher than its affinity for dopamine D(2) receptors (Hameg et al. 2003). OBJECTIVES: The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian. METHODS: Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D(2) and serotonin 5-HT(2A) receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [(11)C]raclopride and [(11)C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan. RESULTS: Cyamemazine induced near saturation of 5-HT(2A) receptors (RO=62.1-98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D(2) receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2-74.9%). The effective plasma level of cyamemazine leading to 50% of D(2) receptor occupancy was fourfold higher than that for 5-HT(2A) receptors. Accordingly, individual 5-HT(2A)/D(2) RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale. CONCLUSION: This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT(2A) receptors compared to dopamine D(2) receptors. In the dose range 37.5-300 mg, levels of dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.

Benevolent voices are not so kind: the functional significance of auditory hallucinations.

BACKGROUND: This study measures the impact of beliefs about auditory hallucinations on social functioning. SAMPLING AND METHODS: Twenty-nine subjects who met the ICD-10 criteria for schizophrenia or a schizo-affective disorder were included. Beliefs about voices and coping responses as measured by the Beliefs about Voices Questionnaire were compared with social functioning as assessed with the Life Skills Profile (LSP). RESULTS: The belief that voices are benevolent was associated with poor communication. Engagement with voices was correlated with the non-turbulence and the compliance factors of the LSP. Patients who held the belief that their voices were benevolent functioned significantly more poorly on the communication factor of the LSP than patients who interpreted their voices as malevolent. DISCUSSION: The results indicate that a positive relationship with voices may affect social functioning. However, the size of the sample is small and patients with benevolent voices are overrepresented. Nonetheless, these results have implications for the use of cognitive therapy for psychotic symptoms.

Long-term sequestration of fluorinated compounds in tissues after fluvoxamine or fluoxetine treatment: a fluorine magnetic resonance spectroscopy study in vivo.

Fluorine magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI) and proton anatomical magnetic resonance imaging (1H MRI) were performed on brains and lower extremities of six subjects in vivo concurrently with HPLC of serum to investigate tissue and plasma drug localization and withdrawal kinetics in humans treated with fluvoxamine or fluoxetine. 19F MRS signal was unexpectedly detected in the lower extremities months after complete disappearance of signal from plasma and brain. MRSI suggested that the lower extremity fluvoxamine signal originated mainly from bone marrow. Results suggest long-term sequestration of these drugs or their metabolites mainly in bone marrow and possibly in surrounding tissue and demonstrate the usefulness of MRS to reveal drug-trapping compartments in the body.

Morning and evening TSH response to TRH and sleep EEG disturbances in major depressive disorder.

1. The aim of this study was to investigate hypothalamo-pituitary-thyroid axis (HPTA) functioning and sleep EEG disturbances in major depressive disorder. 2. Thyroid function was evaluated by determination of TSH levels before and after 8 AM and 11 PM TRH administration on the same day in a sample of 113 consecutively-admitted DSM-IV major depressed inpatients (72 females aged 44.3 +/- 13.0 and 41 males aged 45.7 +/- 10.7) that underwent sleep EEG recordings. 3. A blunted TSH response occurred in 15.9% for 8 AM deltaTSH (maximum increment above baseline at the 8 AM TRH challenge), in 39.8% for 11 PM deltaTSH and in 77% for deltadeltaTSH (difference between 11 PM deltaTSH and 8 AM deltaTSH). A negative correlation between deltadeltaTSH and duration of awakenings after sleep onset, and a shorter sleep onset latency in patients with a blunted 11 PM deltaTSH were found, but these two significant relationships disappeared after controlling for the effects of gender and age. 4. The present findings do not support the hypothesis that, in major depression, HPTA dysfunctioning, as reflected in TSH response to TRH, may be related to sleep EEG disturbances.

Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy.

This investigation of fluvoxamine and fluoxetine-norfluoxetine distributions in vivo at steady-state and of quantitative kinetics in brain and plasma after drug therapy interruption was performed by fluorine nuclear magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI), and plasma HPLC on 12 subjects treated for depression. MRSI suggests a homogeneous distribution of 19F MRS visible fluvoxamine mainly in brain. Fluvoxamine steady-state brain concentrations (12 +/- 5 microM; n = 13) and brain-to-plasma concentration ratios (10 +/- 2; n = 12) were similar to those of combined fluoxetine-norfluoxetine (CF-norfluoxetine) (13 +/- 6 microM; n = 4 and 10 +/- 6; n = 4). Fluvoxamine brain elimination half-life (79 +/- 24 hours; n = 4) was significantly shorter than that of CF-norfluoxetine (382 +/- 48 hours; n = 2). Fluvoxamine brain-to-plasma-half-life-ratio was 2.2 +/- 0.3 (n = 4), contrarily to CF-norfluoxetine (1.0 +/- 0.3; n = 2). This study shows that quantitative pharmacokinetics in target organs by 19F MRS in vivo should prove useful for understanding and investigating outcome of treatment modifications and side effects.

Gamma-hydroxybutyric acid as a signaling molecule in brain.

Gamma-hydroxybutyric acid was synthesized 35 years ago to obtain a GABAergic substance that penetrates the brain freely. Since then, gamma-hydroxybutyric acid has been used in human beings for its sedative and anesthetic properties when administered at high doses, and most of the studies on gamma-hydroxybutyric acid have focused on its pharmacological effects. However, gamma-hydroxybutyric acid is also an endogenous substance, which is synthesized and released in the brain by specific neuronal pathways, implicated in the control of the GABAergic, dopaminergic, and opioid systems. This control is mediated by specific gamma-hydroxybutyric acid receptors with a unique distribution in brain and a specific ontogenesis and pharmacology. Stimulation of these receptors induces specific cellular responses. Taken together, these results suggest that gamma-hydroxybutyric acid possesses most of the properties required of a neurotransmitter/neuromodulator in the brain.

Prolactin response to D-fenfluramine and suicidal behavior in depressed patients.

Previous studies of the prolactin response to D-fenfluramine in depressed patients have yielded inconsistent results. This may be because they did not address the question of suicidality. We carried out this study to test the hypothesis that lower prolactin response to D-fenfluramine is more closely associated with suicidal behavior than with depression itself. A D-fenfluramine test was performed in a sample of 18 healthy control subjects and in 85 drug-free inpatients with a DSM-III-R diagnosis of major depressive episode (49 with a history of suicide attempt, 36 without). Depressed inpatients with a history of suicide attempt showed a significantly lower prolactin response to D-fenfluramine compared to depressed inpatients without such a history and compared to control subjects. Healthy control subjects and depressed inpatients without a history of suicide attempt showed comparable levels of prolactin after D-fenfluramine. Time elapsed since suicide attempt did not influence prolactin level (baseline or post-stimulation). Results show that in our depressed drug-free inpatient sample, prolactin response to D-fenfluramine seems to be a marker of suicidality, but not of depression itself. We suggest that it is a trait marker of suicidality.

Hypoexpression of benzodiazepine receptors in the amygdala of neophobic BALB/c mice compared to C57BL/6 mice.

The distribution of benzodiazepine receptors in the brain of neophobic BALB/c mice was studied by autoradiographic analysis using [3H]-diazepam and compared to that of the same receptors of the "nonemotional" C57BL/6 mice. This technique revealed no significant interstrain difference except for a lower density of diazepam binding sites in the amygdala of BALB/c mice. Therefore, the expression of benzodiazepine receptors in the amygdala of the two strains of mice were quantified by binding studies on brain membranes. The amygdala of BALB/c mice exhibited a fivefold decrease in the density of benzodiazepine receptors compared to C57BL/6 mice. These results suggest that the trait anxiety (neophobia) that characterizes BALB/c mice could be due, at least in part, to a genetic modulation of benzodiazepine receptor expression in the amygdala, a structure known to be strongly involved in fear behavior.

Sulpiride, but not haloperidol, up-regulates gamma-hydroxybutyrate receptors in vivo and in cultured cells.

Five days of gamma-hydroxybutyrate (GHB) administration (3 x 500 mg kg(-1) day(-1) i.p.) to rats resulted in a significant decrease in the density of GHB receptors measured in the whole rat brain without modification of their corresponding affinity. Similar administration of (-)-sulpiride (2 X 100 mg kg(-1) day(-1) i.p. for 5 days) induces an up-regulation of GHB receptors without change in their dissociation constants (Kd). Haloperidol (2 X 2 mg day(-1) i.p. for 5 days) showed no effect. Administered chronically via osmotic minipumps directly into the lateral ventricles, (-)-sulpiride (60 microg day(-1) for 7 days) and GHB (600 microg day(-1) for 7 days) up-regulated and down-regulated rat brain GHB receptors, respectively. Finally, in a mouse hybridoma cell line (NCB-20 cells) expressing GHB receptors, the treatment of these cells with 1 mM GHB, 100 microM (-)-sulpiride or 1 mM GABA decreases, increases and induces no change, respectively, in the density of GHB receptors after 3 days of treatments. These results indicate that chronic GHB treatment modifies the expression of its receptor and that sulpiride also induces plastic changes in GHB receptors perhaps via antagonistic properties.

gamma-Hydroxybutyrate receptor binding in rat brain is inhibited by guanyl nucleotides and pertussis toxin.

gamma-Hydroxybutyrate is an endogenous substance of mammalian brain which is primarily derived from GABA. This compound exhibits neuromodulatory influences on dopamine and serotonin synthesis and release in rat brain. These effects are mediated by specific brain receptors which are mainly distributed in the hippocampus, cortex and striatum. In order to characterize this type of receptor, we have studied the possibility that guanosine triphosphate (GTP) and/or pertussis toxin mediated modification of the affinity for gamma-hydroxybutyrate binding to the receptor. Results presented in this paper favor the presence of guanine nucleotide binding proteins (G0 or Gi family), which are coupled to the gamma-hydroxybutyrate receptor, modifying the high-affinity gamma-hydroxybutyrate binding. We conclude that the gamma-hydroxybutyrate receptor in brain belongs to the G-protein family of receptors.

Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics.

Since gamma-hydroxybutyrate receptor agonists exhibit dopaminergic regulatory properties and neuroleptic-like effects in neuropharmacological tests, the common neuroleptics were tested for [3H] gamma-hydroxybutyrate binding activity on rat brain membranes. (-)-Sulpiride, sultopride, amisulpride and prochlorperazine possess affinity for the gamma-hydroxybutyrate site(s), consistent with their therapeutic dosage. This study has revealed that gamma-hydroxybutyrate receptors represent an additional target for antipsychotics.

Association between schizophrenia and homozygosity at the dopamine D3 receptor gene.

Disturbances in dopamine neurotransmission have been postulated to underlie schizophrenia. We report data from two independent studies of a BalI polymorphism in the dopamine D3 receptor gene in patients with schizophrenia. In both studies, more patients than controls were homozygous (p = 0.005, p = 0.008). When pooled data were analysed, this difference was highly significant (p = 0.0001) with a relative risk of schizophrenia in homozygotes of 2.61 (95% confidence intervals 1.60-4.26).