Family psychoeducation in schizophrenia and schizophrenia related disorder, treatment compliance, and suicidal risk reduction: questions about their relationship from a naturalistic observation.

Introduction: The Profamille V3.2 multi-family psycho-educational program directed at caregivers of relatives with schizophrenia or schizophrenia related disorder has been shown to decrease the annual prevalence of suicide attempts. It has been reported that psychoeducation of families can sometimes improve compliance with treatment. This study investigates whether the Profamille program improves compliance and thus reduces the risk of suicide among patients. Method: This is a retrospective study of 179 groups of family caregivers, encompassing 1946 participants enrolled in Module 1 of the Profamille program and followed up one year after completion of the module. Evaluations were conducted using questionnaires filled out by family caregivers at three distinct times: prior to beginning the program, upon its completion, and again one year following its conclusion. The annual prevalence of suicide attempts was measured both before the program began and one year after its conclusion, while compliance to treatment was evaluated at the start and end of the program. Result: After the Profamille program, the annual prevalence of suicide attempts fell by a factor of 2 (p-value = 0.00002) and patient compliance improved (p-value <0.000001). This reduction in suicide attempts was observed independently of improved compliance. Compliance seems to have an additional effect, but only after participation in the program. Conclusion: The Profamille program reduces patients' risk of suicide even when patients are not taking the treatment. When family psychoeducation is not proposed in schizophrenia or schizophrenia related disorder, this can represent a loss of chance for patients.

Metacognitive training for schizophrenia: a multicentre randomised controlled trial.

A psychotherapeutic approach for schizophrenia is now recommended as an adjuvant for psychopharmacology, since antipsychotic medications only have a partial impact especially as regards positive symptoms and insight. In addition, cognitive distortions and the lack of metacognitive skills might increase positive symptoms leading to poor social functioning. This underlines the need for specific approaches which target cognitive processes relevant for insight, and abilities in metacognition. Metacognitive training (MCT) is a structured group intervention, which enhances a patient's reflection on cognitive biases and improves problem-solving. The aim of our study was to assess MCTs' short term impact on insight, symptoms and quality of life. Fifty patients with schizophrenia or schizoaffective disorders and persistent positive symptoms (delusions or hallucinations) were enrolled in the study. After baseline assessment participants were randomised either to supportive therapy or MCT. Both groups used the same design (1h-session twice a week during 8weeks) although the basic knowledge given to participants was different between interventions. Participants were assessed at eight weeks based on the Scale to Assess Unawareness of Mental Disorder, Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scales, the Calgary Depression Scale for Schizophrenia and the Quality of Life Scale. Between-group differences were significant in favour of MCT on the PANSS positive scale. Between-group differences in post- and pre-test values showed a trend in favour of MCT for insight on hallucinations. Results of our study indicate that the MCT has an effect on reducing positive symptomatology, and a trend impact on insight and social functioning.

Active cyamemazine metabolites in patients treated with cyamemazine (Tercian®): influence on cerebral dopamine D2 and serotonin 5-HT (2A) receptor occupancy as measured by positron emission tomography (PET).

RATIONALE: Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D(2) receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin 5-HT(2A) receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine (N-desmethyl cyamemazine) has similar affinity for 5-HT(2A) receptors as cyamemazine, whereas its D(2) receptor affinity is eight times lower (Benyamina et al. in Eur J Pharmacol 578(2-3):142-147, 2008). Moreover, cyamemazine sulfoxide showed modest affinity for 5-HT(2A) receptors. OBJECTIVES: The objective of this study is to measure steady-state plasma levels of N-desmethyl cyamemazine and cyamemazine sulfoxide in patients treated with clinically relevant doses of cyamemazine and correlate them with dopamine D(2) and serotonin 5-HT(2A) receptor occupancies (RO) assessed by positron emission tomography (PET). METHODS: Eight patients received Tercian® 37.5, 75, 150, or 300 mg/day according to their symptoms. Dopamine D(2) and serotonin 5-HT(2A) RO were assessed at steady-state cyamemazine plasma levels using [(11)C]raclopride and [(11)C]N-methyl-spiperone, respectively, for PET. Plasma levels of cyamemazine metabolites were determined using a validated high-performance liquid chromatography (PerkinElmer) associated with a mass spectrometry detection (API 365, PE SCIEX). The apparent equilibrium inhibition constant (K (i)) was estimated by fitting RO with plasma levels of cyamemazine metabolites at the time of the PET scan. RESULTS: After 6 days of cyamemazine administration, plasma N-desmethyl cyamemazine reached steady-state levels at 2 to 12 times higher than those previously found for cyamemazine (Hode et al. in Psychopharmacology (Berl) 180:377-384, 2005). Plasma levels of N-desmethyl cyamemazine were closely related to striatal D(2) RO (r (2) = 0.942) and extrastriatal 5-HT(2A) RO (r (2) = 0.901). The estimated K (i(app)) value of N-desmethyl cyamemazine for striatal D(2) receptors was about fivefold higher than that for extrastriatal 5-HT(2A) receptors (48.7 vs. 10.6 nM). Striatal D(2) RO increased with the plasma levels of N-desmethyl cyamemazine but remained below 75% even at its highest levels. At steady state, plasma cyamemazine sulfoxide levels were about double those of N-desmethyl cyamemazine. However, these cyamemazine sulfoxide levels should not contribute significantly to in vivo 5-HT(2A) and D(2) receptor occupancy. CONCLUSIONS: In patients orally given cyamemazine, N-desmethyl cyamemazine, but not cyamemazine sulfoxide, should significantly contribute to in vivo frontal 5-HT(2A) and striatal D(2) receptor occupancy. The higher in vivo affinity of cyamemazine and its desmethyl metabolite for serotonin 5-HT(2A) receptors compared with dopamine D(2) receptors should explain the low incidence of extrapyramidal adverse effects.

One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: investigation of neural correlates with BOLD MRI.

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.

Functional magnetic resonance imaging characterization of CCK-4-induced panic attack and subsequent anticipatory anxiety.

The main objective of this work was to study the functional markers of the clinical response to cholecystokinin tetrapeptide (CCK-4). Twelve healthy male subjects were challenged with CCK-4 and simultaneously underwent functional magnetic resonance imaging (fMRI) recording. Since anticipatory anxiety (AA) is an intrinsic part of panic disorder, a behavioral paradigm, using the threat of being administered a second injection of CCK-4, has been developed to investigate induced AA. The study was composed of three fMRI scans according to an open design. During first and second scan, subjects were injected with placebo and CCK-4, respectively. The third scan was the AA challenge. CCK-4 administration induced physiological and psychological symptoms of anxiety that met the criteria for a panic attack in 8 subjects, as well as cerebral activation in anxiety-related brain regions. Clinical and physiological response intensity was consistent with cerebral activity extent and robustness. fMRI proved more sensitive than clinical assessment in evidencing the effects of the AA challenge. The latter induced brain activation, different from that obtained on CCK-4 and during placebo injection, that was likely related to anxiety. The method applied in this study is suitable for the study of anxiety using fMRI.

Human models as tools in the development of psychotropic drugs.

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.