Dietary Habits Modify the Association of Physical Exercise with Cognitive Impairment in Community-Dwelling Older Adults.

BACKGROUND: Previous studies have confirmed that both healthy diets and physical exercise have preventive effects with respect to cognitive decline with aging. The aim of this study was to investigate whether the associations of physical exercise with cognitive impairment differ in community-dwelling older adults with different dietary habits. METHODS: In the 2008/2009 wave of the Chinese Longitudinal Healthy Longevity Survey, 14,966 community-dwelling older adults (≥65 years) were included for analyses. Dietary habits (including daily intake of fruits, vegetables, tea, meat, fish, eggs, food made from beans, salt-preserved vegetables, sugar, garlic, milk products, nut products, mushroom or algae, vitamins and medicinal plants) and physical exercise were assessed. Cognitive impairment was evaluated using the Chinese version of the MMSE in the 2008/2009 and 2011/2012 waves. The effect modifications of physical exercise on cognitive impairment by dietary habits were estimated using logistic regression models. RESULTS: Older adults who practiced physical exercise exhibited a trend of decreased probability of cognitive impairment at baseline and follow-up (OR = 0.92, 95% CI = 0.80-1.06, p = 0.273; OR = 0.83, 95% CI = 0.65-1.05, p = 0.123, respectively) compared with those who did not practice physical exercise. When stratified by dietary habits, physical exercise had a protective effect with respect to prevalent cognitive impairment in older adults who ate fruits (OR = 0.74, 95% CI = 0.58-0.94, p = 0.016), ate food made from beans (OR = 0.76, 95% CI = 0.62-0.93, p = 0.007), did not eat sugar (OR = 0.81, 95% CI = 0.68-0.98, p = 0.028) and ate milk products (OR = 0.75, 95% CI = 0.57-0.97, p = 0.030); in the longitudinal analyses, physical exercise had a protective effect with respect to incident cognitive impairment in older adults who ate fruits (OR = 0.63, 95% CI = 0.41-0.98, p = 0.040) and milk products (OR = 0.57, 95% CI = 0.35-0.94, p = 0.027). Fruits, food made from beans and milk products modified the associations of physical exercise with prevalent cognitive impairment (p values for interaction = 0.008, 0.005 and 0.082, respectively). CONCLUSIONS: The associations of physical exercise with cognitive impairment could be modified by certain dietary habits. Physical exercise was not found to be significantly protective with respect to cognitive impairment in older adults unless they had specific dietary habits. Thus, dietary habits should be emphasized when investigating the beneficial effects of physical exercise on cognitive function in community-dwelling older adults.

Modified acupuncture therapy, long-term acupoint stimulation versus sham control for weight control: a multicenter, randomized controlled trial.

Objective: Long-term acupoint stimulation (LAS), also called embedding acupuncture, is a modified acupuncture technique. The preliminary results have demonstrated its efficacy in body-weight control. However, the low quality of available trials limited its application. This study aimed to evaluate the efficacy and safety of LAS in body-weight control by using a randomized, parallel, sham-controlled clinical trial design. Methods: This was a randomized, single-blind, sham-controlled clinical trial including 84 adult participants (18-60 years) with a body mass index (BMI) of ≥ 24 kg/m2 conducted in three general hospitals in Shanghai, China. Participants were equally assigned to receive LAS or sham LAS (SLAS) once per 10 days, eight times in total. After completion, an additional intervention with a 3-month follow-up period was set to examine the continued effect of LAS. The primary outcome was the change in body weight from baseline to treatment endpoint within the intention-to-treat (ITT) analysis. Secondary outcomes contained changes in waist-to-hip ratio (WHR), lipid metabolism, and visceral and subcutaneous adipose tissues. Results: From 14 May 2018 to 03 November 2019, 84 participants out of 201 screened individuals met the eligibility criteria, were randomized, and were analyzed (42 participants in each group). From baseline to treatment endpoint, the body-weight reduction in the LAS group was significantly larger than in the sham control (net difference: 1.57 kg, 95% CI: 0.29-2.86, p = 0.012). The superior weight reduction effect persisted in the follow-up period (net difference: 3.20 kg, 95% CI: 1.17-5.21, p = 0.001). LAS therapy also showed improvement in triglyceride and subcutaneous adipose tissue (SAT) compared with sham control. One participant in the LAS group reported a slightly uncomfortable and tingling sensation after the additional intervention. No other adverse events (AEs) were documented. Conclusion: LAS, a modified acupuncture technique, is safe and effective in body-weight control. It could be used as an alternative choice to classical acupuncture for obesity management. Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR1800015498].

Automatic auditory processing features in distinct subtypes of patients at clinical high risk for psychosis: Forecasting remission with mismatch negativity.

Individuals at clinical high risk (CHR) for psychosis exhibit a compromised mismatch negativity (MMN) response, which indicates dysfunction of pre-attentive deviance processing. Event-related potential and time-frequency (TF) information, in combination with clinical and cognitive profiles, may provide insight into the pathophysiology and psychopathology of the CHR stage and predict the prognosis of CHR individuals. A total of 92 individuals with CHR were recruited and followed up regularly for up to 3 years. Individuals with CHR were classified into three clinical subtypes demonstrated previously, specifically 28 from Cluster 1 (characterized by extensive negative symptoms and cognitive deficits), 31 from Cluster 2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 33 from Cluster 3 (characterized by the mildest symptoms and cognitive deficits). Auditory MMN to frequency and duration deviants was assessed. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired using TF analysis. Predictive indices for remission were identified using logistic regression analyses. As expected, reduced frequency MMN (fMMN) and duration MMN (dMMN) responses were noted in Cluster 1 relative to the other two clusters. In the TF analysis, Cluster 1 showed decreased theta and alpha ITC in response to deviant stimuli. The regression analyses revealed that dMMN latency and alpha ERSP to duration deviants, theta ITC to frequency deviants and alpha ERSP to frequency deviants, and fMMN latency were significant MMN predictors of remission for the three clusters. MMN variables outperformed behavioral variables in predicting remission of Clusters 1 and 2. Our findings indicate relatively disrupted automatic auditory processing in a certain CHR subtype and a close affinity between these electrophysiological indexes and clinical profiles within different clusters. Furthermore, MMN indexes may serve as predictors of subsequent remission from the CHR state. These findings suggest that the auditory MMN response is a potential neurophysiological marker for distinct clinical subtypes of CHR.

Temporal and time-frequency features of auditory oddball response in distinct subtypes of patients at clinical high risk for psychosis.

Individuals at clinical high risk (CHR) for psychosis exhibit a reduced P300 oddball response, which indicates deficits in attention and working memory processes. Previous studies have mainly researched these responses in the temporal domain; hence, non-phase-locked or induced neural activities may have been ignored. Event-related potential (ERP) and time-frequency (TF) information, combined with clinical and cognitive profiles, may provide an insight into the pathophysiology and psychopathology of the CHR stage. The 104 CHR individuals who completed cognitive assessments and ERP tests were recruited and followed up between 2016 and 2018. Individuals with CHR were classified by three clinical subtypes demonstrated before, specifically 32 from Cluster-1 (characterized by extensive negative symptoms and cognitive deficits, at the highest risk for conversion to psychosis), 34 from Cluster-2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 38 from Cluster-3 (characterized by the mildest symptoms and cognitive deficits). Electroencephalograms were recorded during the auditory oddball paradigm. The P300 ERPs were analyzed in the temporal domain. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired by TF analysis. A reduced P300 response to target tones was noted in Cluster-1 relative to the other two clusters. Moreover, the P300 amplitude of Cluster-1 was associated with speed of processing (SoP) scores. Furthermore, the P300 amplitude of Cluster-3 was significantly correlated with verbal and visual learning scores. In the TF analysis, decreased delta ERSP and ITC were observed in Cluster-1; delta ITC was associated with SoP scores in Cluster-3. The results indicate relatively disrupted oddball responses in a certain CHR subtype and a close affinity between these electrophysiological indexes and attention, working memory, and declarative memory within different CHR clusters. These findings suggest that the auditory oddball response is a potential neurophysiological marker for distinct clinical subtypes of CHR.

Magnetic seizure therapy for treatment-resistant depression.

BACKGROUND: Magnetic seizure therapy (MST) is a potential alternative to electroconvulsive therapy (ECT). Reports to date on use of MST for patients with treatment-resistant depression (TRD) are limited. OBJECTIVES: To evaluate the effects of MST in comparison with sham-MST, antidepressant, and other forms of electric or magnetic treatment for adults with TRD. SEARCH METHODS: In March 2020, we searched a wide range of international electronic sources for published, unpublished, and ongoing studies. We handsearched the reference lists of all included studies and relevant systematic reviews and conference proceedings of the Annual Meeting of the American College of Neuropsychopharmacology (ACNP), the Annual Scientific Convention and Meeting, and the Annual Meeting of the European College of Neuropsychopharmacology (ECNP) to identify additional studies. SELECTION CRITERIA: All randomised clinical trials (RCTs) focused on MST for adults with TRD. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. For binary outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). For continuous data, we estimated mean differences (MDs) between groups and 95% CIs. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. Our main outcomes of interest were symptom severity, cognitive function, suicide, quality of life, social functioning, dropout for any reason, serious adverse events, and adverse events that led to discontinuation of treatment. MAIN RESULTS: We included three studies (65 participants) comparing MST with ECT. Two studies reported depressive symptoms with the Hamilton Rating Scale for Depression (HAMD). However, in one study, the data were skewed and there was an imbalance in baseline characteristics. Analysis of these two studies showed no clear differences in depressive symptoms between treatment groups (MD 0.71, 95% CI -2.23 to 3.65; 2 studies, 40 participants; very low-certainty evidence). Two studies investigated multiple domains of cognitive function. However most of the outcomes were not measured by validated neuropsychological tests, and many of the data suffered from unbalanced baseline and skewed distribution. Analysis of immediate memory performance measured by the Wechsler Memory Scale showed no clear differences between treatment groups (MD 0.40, 95% CI -4.16 to 4.96; 1 study, 20 participants; very low-certainty evidence). Analysis of delayed memory performance measured by the Wechsler Memory Scale also showed no clear differences between treatment groups (MD 2.57, 95% CI -2.39 to 7.53; 1 study, 20 participants; very low-certainty evidence). Only one study reported quality of life, but the data were skewed and baseline data were unbalanced across groups. Analysis of quality of life showed no clear differences between treatment groups (MD 14.86, 95% CI -42.26 to 71.98; 1 study, 20 participants; very low-certainty evidence). Only one study reported dropout and adverse events that led to discontinuation of treatment. Analysis of reported data showed no clear differences between treatment groups for this outcome (RR 1.38, 95% CI 0.28 to 6.91; 1 study, 25 participants; very low-certainty evidence). Adverse events occurred in only two participants who received ECT (worsening of preexisting coronary heart disease and a cognitive adverse effect). None of the included studies reported outcomes on suicide and social functioning. No RCTs comparing MST with other treatments were identified. AUTHORS' CONCLUSIONS: Evidence regarding effects of MST on patients with TRD is currently insufficient. Our analyses of available data did not reveal clearly different effects between MST and ECT. We are uncertain about these findings because of risk of bias and imprecision of estimates. Large, long, well-designed, and well-reported trials are needed to further examine the effects of MST.

Altered functional connectivity of the thalamus induced by modified electroconvulsive therapy for schizophrenia.

BACKGROUND: Electroconvulsive therapy (ECT) has been shown to be effective in schizophrenia (SZ), particularly in drug-refractory cases or when rapid symptom relief is needed. However, its precise mechanisms of action remain largely unclear. To clarify the mechanisms underlying modified electroconvulsive therapy (mECT) for SZ, we conducted a longitudinal cohort study evaluating functional connectivity of the thalamus before and after mECT treatment using sub-regions of thalamus as regions of interest (ROIs). METHODS: Twenty-one SZ individuals taking only antipsychotics (DSZ group) for 4 weeks and 21 SZ patients receiving a regular course of mECT combining with antipsychotics (MSZ group) were observed in parallel. All patients underwent magnetic resonance imaging scans at baseline (t1) and follow-up (t2, ~4 weeks) time points. Data were compared to a matched healthy control group (HC group) consisting of 23 persons who were only scanned at baseline. Group differences in changes of thalamic functional connectivity between two SZ groups over time, as well as in functional connectivity among two SZ groups and HC group were assessed. RESULTS: Significant interaction of group by time was found in functional connectivity of the right thalamus to right putamen during the course of about 4-week treatment. Post-hoc analysis showed a significantly enhanced functional connectivity of the right thalamus to right putamen in the MSZ group contrasting to the DSZ group. In addition, a decreased and an increased functional connectivity of the thalamus to sensory cortex were observed within the MSZ and DSZ group after 4-week treatment trial, respectively. CONCLUSION: Our findings suggest that changes in functional connectivity of the thalamus may be associated with the brain mechanisms of mECT for schizophrenia.

Aberrant resting-state functional connectivity of salience network in first-episode schizophrenia.

The disruption of salience network (SN) has been consistently found in patients with schizophrenia and thought to give rise to specific symptoms. However, the functional dysconnectivity pattern of SN remains unclear in first-episode schizophrenia (FES). Sixty-five patients with FES and sixty-six health controls (HC) were enrolled in this study and underwent resting-state functional magnetic resonance imaging (rs-fMRI). The eleven regions of interest (ROIs) within SN were derived from the peaks of the group independent component analysis (gICA). Seed-based whole-brain functional connectivity (FC) analyses were performed with all SN ROIs as the seeds. Both hyper- and hypo-connectivity of SN were found in the FES. Specifically, the increased FC mainly existed between the SN and cortico-cerebellar sub-circuit and prefrontal cortex, while the reduced FC mainly existed within cortico-striatal-thalamic-cortical (CSTC) sub-circuit. Our findings suggest that FES is associated with pronounced dysregulation of SN, characterized prominently by hyperconnectivity of SN-prefrontal cortex and cerebellum, as well as hypoconnectivity of CSTC sub-circuit of the SN.

Laparoscopic inguinal ligament suspension with uterine preservation for pelvic organ prolapse: A retrospective cohort study.

OBJECTIVE: To introduce an alternative surgical technique of laparoscopic inguinal ligament suspension (LILS) with uterine preservation and evaluate its efficacy and safety for patients with severe pelvic organ prolapse (POP). METHODS: Between June 2014 and December 2015, 35 patients with symptomatic stage III or IV were treated by LILS with uterine preservation. The perioperative parameters including surgical time, blood loss, hospital stay and complications were recorded. The anatomical cure rate was evaluated according to the Pelvic Organ Prolapse Questionnaire (POP-Q) assessment. The anatomical points were analyzed by dynamic Magnetic Resonance Imaging (MRI). Validated questionnaire of the Pelvic Floor Distress Inventory (PFDI-20), the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Pelvic organ prolapse urinary Incontinence Sexual Questionnaire (PISQ-12) were recorded to evaluate the symptom severity, quality of life and sexual activity. RESULTS: The mean surgical time was 163.8 ±â€¯42.3 min (range: 120-280 min), the mean estimated blood loss was 48.6 ±â€¯60.5 ml (range: 10-200 ml), and the mean hospital stay was 5 days (range: 3-7 days). No intra-operative complications were encountered. The anatomical success rate at postoperative 6-month and 12-month was 97.1% and 94.3%, respectively. The postoperative anatomical points on straining showed a significant improvement on dynamic MRI as compared to baselines. The symptom severity, quality of life and sexual activity also presented significant improvement both 6-month and 12-month after surgery. After a minimal 12 months follow-up, no postoperative complications occurred and the recurrence prolapse were low. CONCLUSION: LILS with uterine preservation is a feasible, effective and safe surgical alternative in the treatment of POP for patients who desire to reserve uterus. Longer follow-up data from larger studies are required to confirm the benefits of LILS with uterine preservation as a minimally invasive surgical approach.

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia.

Published reports of functional abnormalities in schizophrenia remain divergent due to lack of staging point-of-view and whole-brain analysis. To identify key functional-connectivity differences of first-episode (FE) and chronic patients from controls using resting-state functional MRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functional-connectivity differences in prodromal, FE (mostly drug naïve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (343 patients). Brain-wide functional-connectivity analysis was performed in different datasets and the results from the datasets of the same stage were then integrated by meta-analysis, with Bonferroni correction for multiple comparisons. Prodromal patients differed from controls in their pattern of functional-connectivity involving the inferior frontal gyri (Broca's area). In FE patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Broca's area, and these changes were correlated with delusions/blunted affect. For chronic patients, functional-connectivity differences extended to wider areas of the brain, including reduced thalamo-frontal connectivity, and increased thalamo-temporal and thalamo-sensorimoter connectivity that were correlated with the positive, negative, and general symptoms, respectively. Thalamic changes became prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across FE and chronic stages of schizophrenia. Importantly, abnormalities in the frontal language networks appear early, at the time of disease onset. The identification of stage-specific pathological processes may help to understand the disease course of schizophrenia and identify neurobiological markers crucial for early diagnosis.

Tanshinone IIA reduces the risk of Alzheimer's disease by inhibiting iNOS, MMP­2 and NF­κBp65 transcription and translation in the temporal lobes of rat models of Alzheimer's disease.

Tanshinone IIA (Tan IIA), one of the major active constituents of the medicinal herb Salvia miltiorrhiza, has been reported to possess neuroprotective effects against the pathological features of Alzheimer's disease (AD), but the molecular mechanism underlying this effect remains unclear. To examine the effect of Tan IIA on AD, as well as the underlying molecular mechanisms, in vivo animal experiments and in vitro molecular biology investigations were employed in the present study. Firstly, a rat model of AD was successfully established by direct injection of the amyloid beta protein (Aß) and then these rats were administered an interventional treatment of Tan IIA. The learning and memory ability of rats was evaluated in four groups (Control, Sham, AD and Tan IIA) utilizing a Morris water maze test. Quantitative (q)PCR was employed to detect the mRNA expression of inducible nitric oxide synthase (iNOS), matrix metalloproteinase­2 (MMP­2) and nuclear transcription factor kappa (NF­κBp65) in temporal lobe tissues and protein expression was determined with western blot analysis. In addition, association analyses between iNOS, MMP­2 and NF­κBp65 at a transcriptional and translational level were performed utilizing Spearman's correlation analysis. In the present study, the results revealed that rats in the AD group demonstrated significant disruptions in learning and memory ability, and the symptoms were evidently reduced by Tan IIA. Furthermore, the upregulation of iNOS, MMP­2 and NF­κBp65 at a transcriptional and translational level in AD rats was distinctly inhibited by Tan IIA. Therefore, it was concluded that iNOS, MMP­2 and NF­κBp65 are involved in AD development, and Tan IIA may reduce AD risk by inhibiting transcription and translation of these genes. Furthermore, the positive correlation of iNOS and MMP­2 with NF­κBp65, respectively, provides evidence supporting the hypothesis that Tan IIA reduces AD risk by inhibiting iNOS and MMP­2 at a transcriptional and translational level through the NF­κB pathway. In summary, Tan IIA is an effective neuroprotective agent for AD therapy, and iNOS, MMP­2 and NF­κBp65 may be the potential molecular targets for manipulating this effect therapeutically.

Decreased P300 current source density in drug-naive first episode schizophrenics revealed by high density recording.

Decreased P300 amplitude has been reported in schizophrenics during their first episode. The brain sources that contribute to this abnormality have not yet been well documented, and were investigated in the present study using high density EEG recordings. Nineteen drug-naive first episode schizophrenics were compared to 25 normal controls. Auditory P300 was elicited using an oddball paradigm. The brain sources of P300 ERP were reconstructed by performing low resolution of electromagnetic tomography (LORETA) analysis. No group difference in P300 latency was found. P300 amplitude was smaller for schizophrenics than for controls. Topographical analysis revealed that P300 amplitude reduction in schizophrenics was significant over left and medial regions of interest (ROIs). LORETA analysis of the P300 peak revealed that, the brain sources of P300 were symmetrically distributed over left and right hemispheres among the normal controls, but were asymmetrically distributed among the patients, with a reduction predominantly over the left temporal area. Statistical non-Parametric Mapping analysis identified 29 voxels of a significant group difference, which focused on left insula, left superior temporal gyrus (STG) and left postcentral gyrus (PCG). In addition, the mean P300 current source density over left insula, left STG and left PCG correlated inversely with the patients' Positive and Negative Syndrome Scale scores. The neural substrates that contributed to the decreased P300 amplitude in drug-naive first episode schizophrenia relatively focused on left STG and its nearby areas. These areas are probably involved in the pathogenesis of schizophrenia, and possible mechanisms for pathology need to be further clarified.

[Anxiety disease: decreased of functional connectivity in left superior temporal gyrus (GTs) and right GTs].

OBJECTIVE: Neuronal circuits involved in the pathophysiology of anxiety are not yet fully understood. We used functional connectivity MRI to explore the characteristic of functional connectivity in anxiety disorders patient and the neural mechanism of this disease. This work was selected as an oral presentation in 2006 ISMRM. METHODS: Twenty right-handed subjects were included in this study, and were divided into two groups. The anxiety (P) group (n = 10; 7 male, mean age 42 years) consisted of patients meeting DSM-IV criteria for a principal diagnosis of anxiety disorder. The control (C) group consisted of volunteers free of psychiatric symptoms, and was matched on age and gender (n = 10; 7 male) with the panic patients. The subjects underwent noninvasive functional magnetic resonance imaging while listening actively to (1): emotionally neutral word alternating with no word as the control condition (CN, PN), and (2): threat-related words alternating with emotionally neutral word as the experimental condition (CT, PT). Each word was presented in pseudorandom order in each 16 s block of 12 words of the same type. Eight alternating blocks of neutral words were presented for about 256 s. The subject was only asked to passively listen to each word. All MRI data were obtained on a 1.5-Tesla scanner Data analysis was performed with SPM99 to find significant activations in two tasks for two groups. Based on group t-test, we chose two anatomically defined regions: left superior temporal gyrus (GTs) and right GTs. Then, based on individual t-map, the voxel with the largest t-value within two regions was taken as the subject-specific peak voxel. We define clusters based on faces and edges, but not corners, so each voxel has 18 neighbors. Subject-specific averaged time series were extracted by averaging the time series of 19 voxels. Since healthy control subjects showed no significant activation (corrected, P < 0.05) during processing of anxiety word to neutral word, region of interest during processing of neutral word to no word was used as substitution. The connectivity degree eta(i j) between the node i and the node j is used to identify the change of the functional connectivity associated with differential tasks, which calculated by using the methods that have developed by ourselves. Moreover, we just consider coherence in low-frequency (0-0.15 Hz). RESULTS: The activation brain regions have been reported in our previous work. Patients were significant different from normal controls on two experiments. The connectivity degree of left Gts and right Gts in two tasks across all subjects was calculated. Comparing during processing neutral word to blank, a significant decrease (P < 0.001) in functional degree was observed during processing of threaten word to neutral word (eta = 0.5636 for CN, eta = 0.555 for CT, eta = 0.5616 for PN, eta = 0.4926 for PT). Especially, the greater decrease connectivity degree was identified for patient group compared with normal control during threat-related words alternating with emotionally neutral word condition. The connectivity degree identifies that functional interactions change with differential task. CONCLUSION: This result suggests decreased functional connectivity among left superior temporal gyrus and right GTs during processing of anxiety word to neutral word in anxiety patients. This dysfunction may mediate the neural mechanism of this sort of disease.

Valproate for schizophrenia.

BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used; valproate is one of these. OBJECTIVES: To review the effects of valproate for the treatment of schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register (last update February 2007). This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted a pharmaceutical company and authors of relevant studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials comparing valproate to antipsychotics or to placebo (or no intervention), whether as the sole agent or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible, abstracts, ordered papers and re-inspected and quality assessed these. Data were extracted independently by at least two reviewers. We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We analysed continuous data using weighted mean differences. Where possible we calculated the number needed to treat (NNT) or number needed to harm statistics. MAIN RESULTS: The update search identified two further relevant studies, thus the review currently includes seven studies with a total of 519 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With one exception the studies were small, short-term and incompletely reported. Adding valproate was as acceptable as adding placebo to antipsychotic drugs (6 RCT, n=270, RR leaving the study early 1.7 CI 0.9 to 3.2). No significant effect of valproate as an adjunct to antipsychotic medication on the participants' global state or the general mental state at the endpoint was evident. However, one study showed a quicker onset of action in the combination group (Casey 2003). A single small study found the participants in the valproate group to be less aggressive than the control group (n=30, WMD -3.8, CI -5.1 to -2.5). Participants receiving valproate more frequently experienced sedation than those in the placebo group. In a single small study valproate significantly reduced tardive dyskinesia (n=30, WMD -3.3, CI -4.9 to -1.7). The effects of valproate on important subgroups such as those with schizophrenia and aggressive behaviour or those with schizoaffective disorder are unknown. AUTHORS' CONCLUSIONS: Based on currently available randomised trial-derived evidence, there are no data to support or to refute valproate as a sole agent for schizophrenia. There is some evidence for positive effects on aggression and tardive dyskinesia, but given that these results were based on only a single small study they cannot be considered robust. Given the paucity of the available database further large, simple well-designed and reported trials are necessary. Ideally these would focus on people with schizophrenia and aggression, on those with treatment resistant forms of the disorder and on those with schizoaffective disorders.