Pierre Vidailhet

Functional mechanisms of episodic memory impairment in schizophrenia.

Objective: To achieve a better understanding of the functional mechanisms underlying episodic memory dysfunction in schizophrenia, which is a prerequisite for unravelling schizophrenias neural correlates in neuroimaging studies and, more generally, for developing an integrated approach to the pathophysiology of schizophrenia. It is also crucial for developing cognitive remediation. Method: This paper reviews empirical evidence of episodic memory dysfunction in schizophrenia obtained with reference to various theoretical models of episodic memory. Results: All the studies converge to show a significant impairment of the critical feature of episodic memory: conscious recollection. Schizophrenia is also associated with a defect of autobiographical memory. The episodic memory dysfunction results from a predominant failure of strategic processing at encoding, although an impairment of strategic processing at retrieval cannot be ruled out. The possibility that it is not the execution of the encoding strategies that is defective but, rather, their self-initiation by the patients is plausible. Conclusions: These findings may explain some behavioural abnormalities associated with schizophrenia, notably, inadequate functional outcomes in everyday life. They may also have implications for cognitive remediation and better social and work functioning of patients with schizophrenia.

Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory

The effects of diazepam and lorazepam on explicit memory and perceptual priming were studied 50, 130 and 300 min after drug administration. Sixty healthy volunteers were randomly assigned to one of five parallel groups (placebo, diazepam 0.2 or 0.3 mg/kg, lorazepam 0.026 or 0.038 mg/kg). The corresponding doses of benzodiazepines exerted a similar negative effect on explicit performance. Lorazepam markedly impaired priming performance, whereas the effect of diazepam was intermediate between that of placebo and that of lorazepam 0.038 mg/kg. The impairment was maximal at the theoretical peak plasma concentration. Contamination by explicit memory could account for the decrease in priming performance observed in the diazepam groups.

Effects of lorazepam and diazepam on conscious and automatic memory processes

Recent studies exploring benzodiazepine memory effects have used the distinction between explicit and implicit tasks. There is now increasing evidence that implicit tasks can be “contaminated” by conscious uses of memory and that unconscious (automatic) use of memory can contaminate explicit tasks, leading to mistaken estimates of their respective influences on memory performance. The aim of the present double-blind, double-placebo study was to assess the memory effects of diazepam and lorazepam using a process-dissociation procedure in a stem-completion task, this procedure providing uncontaminated estimates of conscious and automatic memory processes. The memory task was administrated to 60 healthy volunteers randomly assigned to one of three parallel groups (placebo, diazepam 0.3 mg/kg, lorazepam 0.038 mg/kg). Lorazepam markedly reduced conscious as well as automatic influences of memory. Diazepam also reduced conscious uses of memory, albeit to a lesser extent than lorazepam, but did not decrease the influence of automatic memory. Secondary analyses showed that when the deleterious effect on conscious uses of memory was equated between a diazepam subgroup and the lorazepam group, only lorazepam impaired the automatic use of memory. This study strongly suggests a qualitative difference in the memory effects of the two benzodiazepines. It has some implications regarding the relationships between states of consciousness and memory processes.

Lorazepam impairs both visual and auditory perceptual priming.

Abstract Rationale: Lorazepam has been repeatedly shown to impair both explicit memory and perceptual priming, a form of implicit memory, in the visual domain. However, the effects of this benzodiazepine on priming in other perceptual domains, such as auditory priming, have never been explored. Objective:The present study investigated whether the deleterious effects of lorazepam on perceptual priming are restricted to the visual domain, or if they could be extended to the auditory domain. Methods: Thirty-two healthy volunteers were randomly assigned to two parallel groups, placebo and lorazepam 0.038 mg/kg. The drug was administered orally, following a double-blind procedure. In the same subjects, perceptual priming was assessed in the auditory and visual domains using similar word-stem completion tasks, and explicit memory was explored using a free- recall task. Results: Lorazepam markedly reduced free-recall performance for visually and auditorily presented words. Lorazepam equally impaired visual and auditory priming. In the auditory word-stem completion task, prior presentation of a word facilitated perception of its stem in the placebo group. This facilitation effect was not observed in the lorazepam group. The lorazepam-induced impairment of priming was not due to sedation or explicit contamination. Conclusion: These results indicate that the deleterious effects of lorazepam on priming are not restricted to the visual modality, but extend to the auditory modality.

Effects of lorazepam on perceptual integration of visual forms in healthy volunteers

We tested whether lorazepam (a benzodiazepine) affects perceptual processes involved in the computation of contour information. Subjects matched incomplete forms whose contour was composed of line segments varying in their spacing and in their alignment. An initial centrally displayed object (a reference) was followed by two laterally displayed pictures, a target and a distractor. The distractor was the mirror-reversed version of the target. In one condition, the reference was always an outline drawing of an object. In another condition, the reference was either an outline drawing or an incomplete form. All subjects were run in both conditions. Lorazepam 0.038 mg/kg induced a larger increase in RTs than the placebo and lorazepam 0.026 mg/kg when the spacing between local contour elements was larger than 10.8′ arc and when the line segments were not aligned. Performance was improved in the 0.038 mg/kg lorazepam group when subjects started with the condition in which the reference was always an outline drawing. Performance was not correlated with sedation. These results show that lorazepam impairs visual perception. They are interpreted in terms of impaired binding processes, which can be compensated for by the use of stored object representations. This effect is consistent with electrophysiological studies showing that the neuromediator GABA is involved in perceptual processes.

A Prospective Flexible-Dose Study of Paliperidone Palmitate in Nonacute But Symptomatic Patients With Schizophrenia Previously Unsuccessfully Treated With Oral Antipsychotic Agents

PURPOSE The goal of this study was to explore the tolerability, safety, and treatment response of flexible doses of once-monthly paliperidone palmitate (PP) in the subset of nonacute but symptomatic adult patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents in the PALMFlexS (Paliperidone Palmitate Flexible Dosing in Schizophrenia) study. METHODS This was an interventional, single-arm, international, multicenter, unblinded, 6-month study performed in patients with schizophrenia. Patients were categorized according to reasons for switching. In patients switching because of lack of efficacy or for other reasons, primary efficacy outcomes were the proportion achieving treatment response (defined as ≥20% improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to last-observation-carried-forward end point) and maintained efficacy (defined as noninferiority in the change in PANSS total score at end point versus baseline [Schuirmanns test]), respectively. FINDINGS A total of 593 patients (intention-to-treat population) were enrolled: 63.1% were male; their mean (SD) age was 38.4 (11.8) years; and 78.6% had paranoid schizophrenia. The main reasons for transition to PP were patients wish (n = 259 [43.7%]), lack of efficacy (n = 144 [24.3%]), lack of compliance (n = 138 [23.3%]), and lack of tolerability (n = 52 [8.8%]) with the previous oral antipsychotic medication. The recommended PP initiation regimen (150 milligram equivalents [mg eq] day 1 and 100 mg eq day 8) was administered in 93.9% of patients. Mean PANSS total score decreased from 71.5 (14.6) at baseline to 59.7 (18.1) at end point (mean change, -11.7 [15.9]; 95% CI, -13.0 to -10.5; P < 0.0001). Sixty-four percent of patients showed an improvement of ≥20% in PANSS total score, and the percentage of patients rated mildly ill or less in Clinical Global Impression-Severity increased from 31.8% to 63.2%. Mean personal and social performance total score (SD) increased (ie, improved) significantly for all patients from baseline to end point (58.1 [13.4] to 66.1 [15.7]; P < 0.0001). IMPLICATIONS The PALMFlexS study is a pragmatic interventional study compared with randomized controlled trials, conducted in a large, more representative sample of patients with schizophrenia, and designed specifically to mimic real-world clinical situations. The findings support the results from randomized controlled studies. They also demonstrate that a clinically relevant treatment response is possible in patients who are considered to be clinically stable by their physician, supporting the use of flexibly dosed PP in such patients. Clinical trials.gov number: NCT01281527.

Metabolic syndrome, abdominal obesity and hyperuricemia in schizophrenia: Results from the FACE-SZ cohort

OBJECTIVE Abdominal obesity was suggested to be a better predictor than Metabolic Syndrome (MetS) for cardiovascular mortality, however this is has not been extensively studied in schizophrenia. Hyperuricemia (HU) was also suggested to be both an independent risk factor for greater somatic comorbidity and a global metabolic stress marker in patients with schizophrenia. The aim of this study was to estimate the prevalence of MetS, abdominal obesity and HU, to examine the association between metabolic parameters with HU in a cohort of French patients with schizophrenia or schizo-affective disorder (SZ), and to estimate the prevalence rates of treatment of cardio-vascular risk factors. METHOD 240 SZ patients (age=31.4years, male gender 74.3%) were systematically included. Metabolic syndrome was defined according to the International Diabetes Federation and HU if serum uric acid level was above 360μmol/L. RESULTS MetS, abdominal obesity and HU were found respectively in 24.2%, 21.3% and 19.6% of patients. In terms of risk factors, multiple logistic regression showed that after taking into account the potential confounders, the risk for HU was higher in males (OR=5.9, IC95 [1.7-21.4]) and in subjects with high waist circumference (OR=3.1, IC95 [1.1-8.3]) or hypertriglyceridemia (OR=4.9, IC95 [1.9-13]). No association with hypertension, low HDL cholesterol or high fasting glucose was observed. Only 10% of patients with hypertension received a specific treatment, 18% for high fasting glucose and 8% for dyslipidemia. CONCLUSIONS The prevalence of MetS, abdominal obesity and hyperuricemia is elevated in French patients with schizophrenia, all of which are considerably under-diagnosed and undertreated. HU is strongly associated with abdominal obesity but not with psychiatric symptomatology.

Atypical behavioural effects of lorazepam: clues to the design of novel therapies?

Aside from their pharmacokinetic properties, e.g. their speed of action and the duration of residual effects, benzodiazepines are still considered as equivalent in terms of their effects on cognition. Here we review evidence suggesting that certain benzodiazepines, especially lorazepam, differ in a number of respects, in particular with respect to their effects on cognition. We focus this review on memory, attention and visual perception, where impairments may be brought about by only a subset of benzodiazepines in spite of their administration at doses inducing similar sedative effects. This precludes an explanation in terms of sedation. Differences in the effects of benzodiazepines have also been found in electrophysiological and animal behavioural studies. These studies are important for therapeutic approaches for two reasons: first, effects of benzodiazepine prescription on cognitive functions will differ according to the benzodiazepine, contrary to what is usually believed. Less straightforwardly are the possible therapeutic implications of specific effects on cognition following treatment with lorazepam. Indeed, the specific effects this drug has on cognition may reveal not only side-effects but also effects of potential therapeutic value. Current research concentrates on a fine scale analysis of the effects of GABA on different sub-types of GABA(A) receptors. We suggest that from looking at what makes lorazepam different in a behavioural sense from other benzodiazepines we may be in a position to design innovative treatments for major aspects of complex disorders, including schizophrenia.

Akathisia: prevalence and risk factors in a community-dwelling sample of patients with schizophrenia. Results from the FACE-SZ dataset.

The main objective of this study was to determine the prevalence of akathisia in a community-dwelling sample of patients with schizophrenia, and to determine the effects of treatments and the clinical variables associated with akathisia. 372 patients with schizophrenia or schizoaffective disorder were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with validated scales. Akathisia was measured with the Barnes Akathisia Scale (BAS). Ongoing psychotropic treatment was recorded. The global prevalence of akathisia (as defined by a score of 2 or more on the global akathisia subscale of the BAS) in our sample was 18.5%. Patients who received antipsychotic polytherapy were at higher risk of akathisia and this result remained significant (adjusted odd ratio=2.04, p=.025) after controlling the influence of age, gender, level of education, level of psychotic symptoms, substance use comorbidities, current administration of antidepressant, anticholinergic drugs, benzodiazepines, and daily-administered antipsychotic dose. The combination of second-generation antipsychotics was associated with a 3-fold risk of akathisia compared to second-generation antipsychotics used in monotherapy. Our results indicate that antipsychotic polytherapy should be at best avoided and suggest that monotherapy should be recommended in cases of akathisia. Long-term administration of benzodiazepines or anticholinergic drugs does not seem to be advisable in cases of akathisia, given the potential side effects of these medications.

Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort

OBJECTIVES Depression and negative symptoms have been associated with impaired Quality of life (QoL) in schizophrenia (SZ). However, childhood trauma may influence both QoL and depression in SZ patients, with consequences for the management of impaired QoL in SZ patients. The aim of the present study was to determine if childhood trauma was associated with impaired QoL in schizophrenia. METHOD A sample of 544 community-dwelling stabilized SZ patients enrolled in FACE-SZ cohort were utilized in this study (74.1% males, mean aged 32.3years, mean illness duration 10.6years). QoL was self-reported with the S-QoL18 questionnaire. Childhood trauma was self-reported with the Childhood Trauma Questionnaire. Depression was measured by the Calgary Depression Rating Scale for Schizophrenia. Psychotic severity was measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Other clinical factors, treatments, comorbidities, functioning and sociodemographical variables were also recorded, with validated scales. RESULTS Overall, 151 participants (27.8%) had a current major depressive episode and 406 (82.5%) reported at least one episode of historical childhood trauma. In multivariate analyses, lower QoL total score was associated with a history of childhood trauma (β=-0.21, p<0.0001), psychotic negative symptoms (β=-0.11, p=0.04), current depression (β=-0.0.38, p<0.0001) and male gender (β=-0.16, p<0.0001). CONCLUSION Impaired QoL is independently associated with negative symptoms, depression and childhood trauma in schizophrenia.