The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults.

DNA methylation age has been used in recent studies as an epigenetic marker of accelerated cellular aging, whose contribution to the brain structural changes was lately acknowledged. We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. Using the multi-tissue method (Horvath S. DNA methylation age of human tissues and cell types. 2013. Genome Biol 14), epigenetic age was computed with saliva sample. Epigenetic age acceleration was derived from residuals after adjusting epigenetic age for chronological age. Multiple regression models were computed for 148 brain regions for surface area, cortical thickness, and volume using epigenetic age or accelerated epigenetic age as a predictor and controlling for sex. Epigenetic age was associated with surface area reduction of the left insula. It was also associated with cortical thinning and volume reduction in multiple regions, with prominent changes of cortical thickness in the left temporal regions and of volume in the bilateral orbital gyri. Finally, accelerated epigenetic age was negatively associated with right cuneus gyrus volume. Our findings suggest that understanding the mechanisms of epigenetic age acceleration in young individuals may yield valuable insights into the relationship between epigenetic aging and the cortical change and on the early development of neurocognitive pathology among young adults.

Supported employment for adults with severe mental illness.

BACKGROUND: People who suffer from severe mental disorder experience high rates of unemployment. Supported employment is an approach to vocational rehabilitation that involves trying to place clients in competitive jobs without any extended preparation. The Individual placement and support (IPS) model is a carefully specified form of supported employment. OBJECTIVES: 1. To review the effectiveness of supported employment compared with other approaches to vocational rehabilitation or treatment as usual.2. Secondary objectives were to establish how far:(a) fidelity to the IPS model affects the effectiveness of supported employment,(b) the effectiveness of supported employment can be augmented by the addition of other interventions. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (February 2010), which is compiled by systematic searches of major databases, handsearches and conference proceedings. SELECTION CRITERIA: All relevant randomised clinical trials focusing on people with severe mental illness, of working age (normally 16 to 70 years), where supported employment was compared with other vocational approaches or treatment as usual. Outcomes such as days in employment, job stability, global state, social functioning, mental state, quality of life, satisfaction and costs were sought. DATA COLLECTION AND ANALYSIS: Two review authors (YK and KK) independently extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated mean difference (MD) between groups and its 95% (CI). We employed a fixed-effect model for analyses. A random-effects model was also employed where heterogeneity was present. MAIN RESULTS: A total of 14 randomised controlled trials were included in this review (total 2265 people). In terms of our primary outcome (employment: days in competitive employment, over one year follow-up), supported employment seems to significantly increase levels of any employment obtained during the course of studies (7 RCTs, n = 951, RR 3.24 CI 2.17 to 4.82, very low quality of evidence). Supported employment also seems to increase length of competitive employment when compared with other vocational approaches (1 RCT, n = 204, MD 70.63 CI 43.22 to 94.04, very low quality evidence). Supported employment also showed some advantages in other secondary outcomes. It appears to increase length (in days) of any form of paid employment (2 RCTs, n = 510, MD 84.94 CI 51.99 to 117.89, very low quality evidence) and job tenure (weeks) for competitive employment (1 RCT, n = 204, MD 9.86 CI 5.36 to 14.36, very low quality evidence) and any paid employment (3 RCTs, n = 735, MD 3.86 CI -2.94 to 22.17, very low quality evidence). Furthermore, one study indicated a decreased time to first competitive employment in the long term for people in supported employment (1 RCT, n = 204, MD -161.60 CI -225.73 to -97.47, very low quality evidence). A large amount of data were considerably skewed, and therefore not included in meta-analysis, which makes any meaningful interpretation of the vast amount of data very difficult. AUTHORS' CONCLUSIONS: The limited available evidence suggests that supported employment is effective in improving a number of vocational outcomes relevant to people with severe mental illness, though there appears to exist some overall risk of bias in terms of the quality of individual studies. All studies should report a standard set of vocational and non-vocational outcomes that are relevant to the consumers and policy-makers. Studies with longer follow-up should be conducted to answer or address the critical question about durability of effects.

Region-based analysis of sensory processing using diffusion tensor imaging.

The caudate nucleus has been thought to be involved in the control of motor commands by the cerebrum, and recent studies suggest that it may play a role in the control of attachment behavior, cognition, emotion, and mental functions. Implied by the basal ganglia's involvement in the execution, planning and control of movement, the caudate nucleus functions in a situation-dependent manner where processing of external stimuli is important on the basis of learning and memory. Sensory processing, which determines the response to external stimuli, has been shown to be related to various brain regions but it remains unknown how sensory processing is associated with the structure of the caudate nucleus and white matter microstructures of the caudate. Using four diffusion parameters derived from diffusion tensor imaging (DTI) (i.e., fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), and radial diffusivity (RD)) and the Adolescent/Adult Sensory Profile (AASP) questionnaire of 99 healthy subjects [42 males and 57 females; mean age:26.9 years, standard deviation 6.9], we investigated the relationship between white matter structure in the caudate nucleus and sensory processing. In consistent with what had been suggested by the results of previous studies, we found significant correlations between AD, MD and tactile sensation. Furthermore, we found a significant correlation between AD, MD and tactile sensory avoidance, the AASP sub-scores regarding the tactile senses. To the best of our knowledge, this is the first study to show that DTI diffusion parameters correlate with AASP scores in specific brain regions.

Duloxetine versus other anti-depressive agents for depression.

BACKGROUND: Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant drugs remain the mainstay of treatment. Amongst antidepressants many different agents are available. Duloxetine hydrochloride is a dual reuptake inhibitor of serotonin and norepinephrine and has been licensed by the Food and Drug Administration in the US for major depressive disorder (MDD), generalised anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain. OBJECTIVES: To assess the evidence for the efficacy, acceptability and tolerability of duloxetine in comparison with all other antidepressant agents in the acute-phase treatment of major depression. SEARCH METHODS: MEDLINE (1966 to 2012), EMBASE (1974 to 2012), the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to March 2012. No language restriction was applied. Reference lists of relevant papers and previous systematic reviews were hand-searched. Pharmaceutical company marketing duloxetine and experts in this field were contacted for supplemental data. SELECTION CRITERIA: Randomised controlled trials allocating patients with major depression to duloxetine versus any other antidepressive agent. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and a double-entry procedure was employed. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. MAIN RESULTS: A total of 16 randomised controlled trials (overall 5735 participants) were included in this systematic review. Of these, three trials were unpublished. We found 11 studies (overall 3304 participants) comparing duloxetine with one selective serotonin reuptake inhibitor (SSRI) (six studies versus paroxetine, three studies versus escitalopram and two versus fluoxetine), four studies (overall 1978 participants) comparing duloxetine with a newer antidepressants (three with venlafaxine and one with desvenlafaxine, respectively) and one study (overall 453 participants) comparing duloxetine with an antipsychotic drug which is also used as an antidepressive agent, quetiapine. No studies were found comparing duloxetine with tricyclic antidepressants. The pooled confidence intervals were rather wide and there were no statistically significant differences in efficacy when comparing duloxetine with other antidepressants. However, when compared with escitalopram or venlafaxine, there was a higher rate of drop out due to any cause in the patients randomised to duloxetine (odds ratio (OR) 1.62; 95% confidence interval (CI) 1.01 to 2.62 and OR 1.56; 95% CI 1.14 to 2.15, respectively). There was also some weak evidence suggesting that patients taking duloxetine experienced more adverse events than paroxetine (OR 1.24; 95% CI 0.99 to 1.55). AUTHORS' CONCLUSIONS: Duloxetine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. No differences in terms of efficacy were found, even though duloxetine was worse than some SSRIs (most of all, escitalopram) and newer antidepressants (like venlafaxine) in terms of acceptability and tolerability. Unfortunately, we only found evidence comparing duloxetine with a handful of other active antidepressive agents and only a few trials per comparison were found (in some cases we retrieved just one trial). This limited the power of the review to detect moderate, but clinically meaningful differences between the drugs. As many statistical tests have been used in the review, the findings from this review are better thought of as hypothesis forming rather than hypothesis testing and it would be very comforting to see the conclusions replicated in future trials. Most of included studies were sponsored by the drug industry manufacturing duloxetine. As for all other new investigational compounds, the potential for overestimation of treatment effect due to sponsorship bias should be borne in mind. In the present review no trials reported economic outcomes. Given that several SSRIs and the great majority of antidepressants are now available as generic formulation (only escitalopram, desvenlafaxine and duloxetine are still on patent), more comprehensive economic estimates of antidepressant treatment effect should be considered to better inform healthcare policy.

Guided internet-based cognitive behavioral therapy for obsessive-compulsive disorder: A multicenter randomized controlled trial in Japan.

Few studies have compared the effectiveness of internet-based cognitive behavior therapy (ICBT) for obsessive-compulsive disorder (OCD) with treatment as usual (TAU). We investigated the effectiveness of guided ICBT for patients with OCD. This prospective, randomized, controlled, assessor-blinded, multicenter clinical trial was conducted at three facilities in Japan from January 2020 to March 2021. Thirty-one patients with OCD as the primary diagnosis participated in the trial and were randomly assigned to either the intervention group or the control group. The primary outcome was the Yale-Brown obsessive-compulsive scale score; the assessors were blinded. Results of the analysis of covariance among the groups were significantly different between the groups (p < 0.01, effect size Cohen's d = 1.05), indicating the superiority of guided ICBT. The results suggest that guided ICBT is more effective than TAU for treating OCD. RCT REGISTRATION: UMIN Clinical Trials Registry (UMIN000039375).

Distinct neuropsychological profiles of three major symptom dimensions in obsessive-compulsive disorder.

Recent neuroimaging studies have suggested that different symptom dimensions are mediated by partially distinct neural systems in obsessive-compulsive disorder (OCD). However, the correlations between neuropsychological profiles and symptom dimensions in OCD are unknown. The aim of this study was to examine the extent to which OCD symptom dimensions were associated with episodic memory and attention and executive functions. The symptom dimensions of 63 patients with OCD were assessed using both the Padua Inventory and the Y-BOCS symptom checklist. Then, we administered the Logical Memory (LM) subset of the Wechsler Memory Scale-Revised (WMR-R) test and evaluated inhibition (Stroop test, Trail Making test) and cognitive flexibility (Digit Symbol test, Letter Fluency, and Category Fluency). While associations were observed between scores on the contamination/cleaning dimension and better performances on the LM and Trail Making tests, associations were also observed between scores on the aggressive/checking dimension and poorer performances on the Trail Making test. In addition, we found that scores on the symmetry/ordering dimension were associated with poorer performances on the LM and Trail Making tests. Our results support the hypothesis that different symptoms may represent distinct and partially overlapping neurocognitive networks in OCD patients.

Mirtazapine versus other antidepressive agents for depression.

BACKGROUND: Mirtazapine has a unique mechanism of antidepressive action and is one of the commonly used antidepressants in clinical practice. OBJECTIVES: The aim of the present review was to assess the evidence on the efficacy and acceptability of mirtazapine compared with other antidepressive agents in the acute-phase treatment of major depression in adults. SEARCH METHODS: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis review group's specialised register (CCDANCTR), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years to April 2011), EMBASE, (1980 to July 2011) MEDLINE (1950 to July 2011) and PsycINFO (1974 to July 2011). Reference lists of the reports of relevant studies were checked and experts in the field contacted. The review was not limited to English-language articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) allocating participants with major depression to mirtazapine versus any other antidepressive agent. DATA COLLECTION AND ANALYSIS: Two authors independently checked eligibility and extracted data on an intention-to-treat basis. The primary outcome was response to treatment. The secondary outcomes included dropouts and individual adverse events.Meta-analyses were conducted using the random-effects model. MAIN RESULTS: A total of 29 RCTs (n = 4974), mostly following up the participants for six weeks in outpatient clinics and inadequately reporting the risk of bias, were included. In comparison with tricyclic antidepressants (10 trials, n = 1553) there was no robust evidence to detect a difference between mirtazapine and tricyclics in terms of response at two weeks (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.64 to 1.13) or at the end of acute-phase treatment (at 6 to 12 weeks) (OR 0.89, 95% CI 0.72 to 1.10). In comparison with selective serotonin reuptake inhibitors (SSRIs) (12 trials, n = 2626) mirtazapine was significantly more effective at two weeks (OR 1.57, 95% CI 1.30 to 1.88) and at the end of acute-phase treatment (OR 1.19, 95% CI 1.01 to 1.39). Mirtazapine was significantly more effective than a serotonin-noradrenaline reuptake inhibitor (venlafaxine only, two trials, n = 415) at two weeks (OR 2.29, 95% CI 1.45 to 3.59) and at the end of acute-phase treatment (OR 1.53, 95% CI 1.03 to 2.25).In terms of dropouts, there was no robust evidence to detect a difference between mirtazapine and other antidepressants. Mirtazapine was more likely to cause weight gain or increased appetite and somnolence than SSRIs but less likely to cause nausea or vomiting and sexual dysfunction. AUTHORS' CONCLUSIONS: Some statistically significant and possibly clinically meaningful differences between mirtazapine and other antidepressive agents were found for the acute-phase treatment of major depression. Mirtazapine is likely to have a faster onset of action than SSRIs during the acute-phase treatment. Dropouts occur similarly in participants treated with mirtazapine and those treated with other antidepressants, although the adverse event profile of mirtazapine is unique.

Elucidation of the relationship between sensory processing and white matter using diffusion tensor imaging tractography in young adults.

Sensory processing and behaviors are altered during the development of connectivity between the sensory cortices and multiple brain regions in an experience-dependent manner. To reveal the relationship between sensory processing and brain white matter, we investigated the association between the Adolescent/Adult Sensory Profile (AASP) and neural connectivity in the white matter tracts of 84 healthy young adults using diffusion tensor imaging (DTI). We observed a positive relationship between AASP scores (i.e., sensory sensitivity, sensation avoiding, activity level)/subscores (i.e., sensory sensitivity-activity level, sensation avoiding-touch) and DTI parameters in the cingulum-cingulate gyrus bundle (CCG) and between AASP subscores (i.e., sensory sensitivity-auditory) and a diffusion parameter in the uncinate fasciculus (UNC). The diffusion parameters that correlated with AASP scores/subscores and AASP quadrant scores (i.e., sensory avoiding and sensitivity) were axonal diffusivity (AD) and mean diffusivity (MD) in the CCG and MD in the UNC. Moreover, the increased sensory avoiding and sensitivity scores represent the sensitization of sensory processing, and the level of diffusivity parameters indicates white matter microstructure variability, such as axons and myelin from diffusivity of water molecules. Thus, the present study suggests that the CCG and UNC are critical white matter microstructures for determining the level of sensory processing in young adults.

Relationship between sensory characteristics and cortical thickness/volume in autism spectrum disorders.

Individuals with autism spectrum disorders (ASDs) exhibit atypical sensory characteristics, impaired social skills, deficits in verbal and nonverbal communication, and restricted and repetitive behaviors. The relationship between sensory characteristics and brain morphological changes in ASD remains unclear. In this study, we investigated the association between brain morphological changes and sensory characteristics in individuals with ASD using brain image analysis and a sensory profile test. Forty-three adults with ASD and 84 adults with typical development underwent brain image analysis using FreeSurfer. The brain cortex was divided into 64 regions, and the cortical thickness and volume of the limbic system were calculated. The sensory characteristics of the participants were evaluated using the Adolescent/Adult Sensory Profile (AASP). Correlation analysis was performed for cortical thickness, limbic area volume, and AASP scores. In the ASD group, there was a significant positive correlation between visual sensory sensitivity scores and the right lingual cortical thickness (r = 0.500). There were also significant negative correlations between visual sensation avoiding scores and the right lateral orbitofrontal cortical thickness (r = -0.513), taste/smell sensation avoiding scores and the right hippocampal volume (r = -0.510), and taste/smell sensation avoiding scores and the left hippocampal volume (r = -0.540). The study identified associations among the lingual cortical thickness, lateral orbitofrontal cortical thickness, and hippocampal volume and sensory characteristics. These findings suggest that brain morphological changes may trigger sensory symptoms in adults with ASD.

Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.

BACKGROUND: Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression. METHODS: We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis. FINDINGS: Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine. INTERPRETATION: Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.

Sulpiride augmentation for schizophrenia.

BACKGROUND: Sulpiride may be used in combination with other antipsychotic drugs in the hope of augmenting effectiveness - especially for those whose schizophrenia has proved resistant to treatment. OBJECTIVES: To evaluate the effects of sulpiride augmentation versus monotherapy for people with schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (July 2009) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. SELECTION CRITERIA: All relevant randomised clinical trials (RCTs). DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a fixed-effect model. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model. MAIN RESULTS: We included three short-term and one long-term trial (total N=221). All participants had schizophrenia that was either treatment-resistant or with prominent negative symptoms. All studies compared sulpiride plus clozapine with clozapine (+/- placebo), were small and at considerable risk of bias.Short-term data of 'no clinically significant response' in global state tended to favour sulpiride augmentation of clozapine compared with clozapine alone (n=193, 3 RCTs, RR 0.58 CI 0.3 to 1.09).People allocated to sulpiride plus clozapine had more movement disorders (n=70, 1 RCT, RR 48.24 CI 3.05 to 762.56) and an increase in serum prolactin (skewed data, 1 RCT), but less incidence of hypersalivation (n=162, 3 RCTs, RR 0.49 CI 0.29 to 0.83) and less weight gain (n=64, 1 RCT, RR 0.30 CI 0.09 to 0.99). The augmentation of clozapine by sulpiride also caused less appetite loss (n=70, 1 RCT, RR 0.09 CI 0.01 to 0.70, NNT 4 CI 4 to 12, Z=2.31, P=0.02) and less abdominal distension (n=70, 1 RCT, RR 0.10 CI 0.01 to 0.78, NNT 5 CI 4 to 19, Z=2.20, P=0.03).Long-term data showed no significant difference in global state (n=70, 1 RCT, RR 0.67 CI 0.42 to 1.08) and relapse (n=70, 1 RCT, RR 0.85 CI 0.5 to 1.3). AUTHORS' CONCLUSIONS: Sulpiride plus clozapine is probably more effective than clozapine alone in producing clinical improvement in some people whose illness has been resistant to other antipsychotic drugs including clozapine. However, much more robust data are needed.

Supported employment for adults with severe mental illness.

This is the protocol for a review and there is no abstract. The objectives are as follows: To review the effectiveness of supported employment compared to other approached to vocational rehabilitation and treatment as usual.Secondary objectives are to establish how far: fidelity to the IPS model affects the effectiveness of supported employment,the effectiveness of supported employment can be augmented by the addition of other interventions.

Fluvoxamine versus other anti-depressive agents for depression.

BACKGROUND: Fluvoxamine, one of the oldest selective serotonin reuptake inhibitors (SSRIs), is prescribed to patients with major depression in many countries. Several studies have previously reviewed the efficacy and tolerability of fluvoxamine for the treatment of major depression. However, these reviews are now outdated. OBJECTIVES: Our objective is to evaluate the effectiveness, tolerability and side effect profile of fluvoxamine for major depression in comparison with other anti-depressive agents, including tricyclics (TCAs), heterocyclics, other SSRIs, SNRIs, other newer agents and other conventional psychotropic drugs. SEARCH STRATEGY: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register. Trial databases and ongoing trial registers in North America, Europe, Japan and Australia, were handsearched for randomised controlled trials. We checked reference lists of the articles included in the review, previous systematic reviews and major textbooks of affective disorder for published reports and citations of unpublished research. The date of last search was 31 August 2008. SELECTION CRITERIA: We included all randomised controlled trials, published in any language, that compared fluvoxamine with any other active antidepressants in the acute phase treatment of major depression. DATA COLLECTION AND ANALYSIS: Two independent review authors inspected citations and abstracts, obtained papers, extracted data and assessed the risk of bias of included studies. We analysed dichotomous data using odds ratios (ORs) and continuous data using the standardised mean difference (SMD). A random effects model was used to combine studies. MAIN RESULTS: A total of 54 randomised controlled trials (n = 5122) were included. No strong evidence was found to indicate that fluvoxamine was either superior or inferior to other antidepressants regarding response, remission and tolerability. However, differing side effect profiles were evident, especially with regard to gastrointestinal side effects of fluvoxamine when compared to other antidepressants. For example, fluvoxamine was generally associated with a higher incidence of vomiting/nausea (versus imipramine, OR 2.23, CI 1.59 to 3.14; versus clomipramine, OR 2.13, CI 1.06 to 4.27; versus amitriptyline, OR 2.86, CI 1.31 to 2.63). AUTHORS' CONCLUSIONS: We found no strong evidence that fluvoxamine was either superior or inferior to any other antidepressants in terms of efficacy and tolerability in the acute phase treatment of depression. However, differing side effect profiles were evident. Based on these findings, we conclude that clinicians should focus on practical or clinically relevant considerations, including these differences in side effect profiles.

Changes after behavior therapy among responsive and nonresponsive patients with obsessive-compulsive disorder.

Neuroimaging studies have suggested that behavior therapy (BT) might change abnormal activity in the frontal-subcortical circuits of the brain in patients with obsessive-compulsive disorder (OCD). However, the results of these studies have been rather inconsistent. The aim of the present study was to use statistical parametric mapping (SPM) analysis to explore the effects of successful BT on regional cerebral blood flow (rCBF) in patients with OCD. Forty-five OCD patients who were treatment-resistant to a single serotonin reuptake inhibitor (SRI) trial were examined. Single photon emission computed tomography (SPECT) using 99mTc-ECD was performed before and after the completion of 12 weeks of BT. Although no significant differences in pre-treatment rCBF were observed between responders and nonresponders to BT, the post-treatment rCBF values in the left medial prefrontal cortex (Brodmann area 10) and bilateral middle frontal gyri (Brodmann area 10) were significantly lower in the responders than in the nonresponders. Furthermore, the baseline rCBF in the bilateral orbitofrontal cortex (OFC) was significantly correlated with the change in the Y-BOCS score among the responders. Our results support the hypothesis that while the OFC may be associated with the BT response, BT may result in changes in rCBF in the medial and middle frontal cortex.

Sulpiride versus placebo for schizophrenia.

BACKGROUND: Sulpiride is a relatively old antipsychotic drug reputed to have low incidence of adverse effects and an effect on the negative symptoms of schizophrenia. This relatively inexpensive antipsychotic drug has a similar neuropharmacological profile to several novel atypical drugs. OBJECTIVES: To evaluate the effects of sulpiride for schizophrenia and other similar serious mental illnesses in comparison with placebo. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (September 2008) and references of all identified studies for further trial citations. We contacted pharmaceutical companies and authors of trials for additional information. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing sulpiride with placebo for people with schizophrenia and other types of schizophrenia-like psychoses. The primary outcome of interest was clinically significant response in global state. DATA COLLECTION AND ANALYSIS: We independently inspected citations and abstracts, ordered papers, re-inspected and quality assessed these. IMO and JW extracted data. We analysed dichotomous data using random-effects relative risk (RR) and estimated the 95% confidence interval (CI) around this. Where continuous data were included, we analysed this data using random-effects weighted mean difference (WMD) with a 95% confidence interval. MAIN RESULTS: Two trials of short duration compare sulpiride with placebo (total n=113). As regards mental state, there were no clear differences between groups for either positive or negative symptoms (n=18, 1 RCT, WMD Manchester scale negative subscore -0.30 CI -1.66 to 1.06; n=18, 1 RCT, WMD SANS 2.90 CI -0.14 to 5.94). Few people left these studies by three months (n=113, 2 RCTs, RR 1.00 CI 0.25 to 4.00). One subscore finding found sulpiride improved social behavior (n=18, 1 RCT, WMD -2.90 CI -5.60 to -0.20). There were no data for many important outcomes such as general functioning, service use or adverse effects. AUTHORS' CONCLUSIONS: Sulpiride may be an effective antipsychotic drug but evidence of its superiority over placebo from randomised trials is very limited. Practice will have to use evidence from sources other than trials until better evidence is generated.

Milnacipran versus other antidepressive agents for depression.

BACKGROUND: Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs are frequently used as first-line treatment in primary and secondary care settings. Milnacipran, a dual serotonin-norepinephrine reuptake inhibitor (SNRI), is one of the antidepressant drugs that clinicians use for routine depression care. OBJECTIVES: To assess the evidence for the efficacy, acceptability and tolerability of milnacipran in comparison with tricyclic antidepressants (TCAs), heterocyclics, SSRIs and other newer antidepressive agents in the acute-phase treatment of major depression. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety & Neurosis review group Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) were electronically searched in August 2008. References of relevant trials and other reviews were also checked. Trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished trials were hand-searched in 2007. All relevant authors were contacted for supplemental data. No language restriction was applied. SELECTION CRITERIA: Randomised controlled trials comparing milnacipran with any other active antidepressive agents (including non-conventional agents such as herbal products like hypericum) as monotherapy in the acute phase of major depression were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently checked eligibility, assessed methodological quality and extracted data from the eligible trials using a standardised data extraction form. The number of participants who responded to treatment or those who achieved remission were calculated on an intention-to-treat basis. Random-effects meta-analyses were conducted, combining data from the included trials. MAIN RESULTS: A total of 16 randomised controlled trials (n=2277) were included in the meta-analysis.Despite the size of this sample, the pooled 95% confidence intervals were rather wide and there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressive agents. However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95%CI 0.35 to 0.85). There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs. AUTHORS' CONCLUSIONS: Currently, there is inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events (acceptability) and the rates of experiencing adverse events (tolerability). Information about other clinically meaningful outcomes such as cost-effectiveness and social functioning, including the ability to return to work, is lacking. Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression.

Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants : a systematic review and meta-analysis.

BACKGROUND: Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. OBJECTIVE: To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. METHODS: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers. Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged > or =18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities. Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. RESULTS: No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). CONCLUSIONS: The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.

The differential impact of executive attention dysfunction on episodic memory in obsessive-compulsive disorder patients with checking symptoms vs. those with washing symptoms.

Neuropsychological studies of obsessive-compulsive disorder (OCD) have pointed to memory and attention deficits among its sufferers, but these reports have largely ignored the possibility that cognitive disturbances may vary across OCD clinical subtypes, or that their interactions may differ between subtypes. The purpose of the present study was to determine whether "checkers" and "washers" demonstrate differences in their memory and executive attention function. Fifty-three outpatients with primary DSM-IV diagnosis of OCD with typical checking (n=27) or washing (n=26) rituals participated in the study. Patients were administered the Wechsler Memory Scale-Revised and a comprehensive neuropsychological battery to assess executive attention function. Various neuropsychological tests were then subjected to factor analysis. Neuropsychological test results and obtained factor scores were compared between "washers" and "checkers". Effects of these factor scores on memory by OCD subtypes were examined. No significant difference in terms of demographic and clinical variables was found between the two groups. Checkers displayed performance deficits on Stroop test, Trail Making Test, GO/NO GO test (commission errors) and category fluency. Three factors, inhibition, cognitive flexibility, and multi-tasking, were obtained. Statistically significant differences were observed between the two groups on the inhibition and the cognitive flexibility scores, but not on the general memory or the multi-tasking score. There was a statistically significant interaction between groups and the inhibition score. Only among "checkers", a significant correlation was noted between the inhibition factor and the general memory, while no such correlation was observed among "washers". Among "checkers", poor general memory was related to inhibition deficits.

Can pill placebo augment cognitive-behavior therapy for panic disorder?

BACKGROUND: In a number of drug and psychotherapy comparative trials, psychotherapy-placebo combination has been assumed to represent psychotherapy. Whether psychotherapy plus pill placebo is the same as psychotherapy alone is an empirical question which however has to date never been examined systematically. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) that directly compared cognitive-behavior therapy (CBT) alone against CBT plus pill placebo in the treatment of panic disorder. RESULTS: Extensive literature search was able to identify three relevant RCTs. At the end of the acute phase treatment, patients who received CBT plus placebo had 26% (95%CI: 2 to 55%) increased chances of responding than those who received CBT alone. At follow-up the difference was no longer statistically significant (22%, 95%CI: -10% to 64%). CONCLUSION: The act of taking a pill placebo may enhance the placebo effect already contained in the effective psychotherapeutic intervention during the acute phase treatment. Theoretically this is an argument against the recently claimed null hypothesis of placebo effect in general and clinically it may point to some further room for enhancing the psychotherapeutic approach for panic disorder.

Venlafaxine versus other anti-depressive agents for depression.

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the efficacy of venlafaxine in comparison with other anti-depressive agents in alleviating the acute symptoms of major depressive disorder.To review acceptability of treatment with venlafaxine in comparison with other anti-depressive agents.To investigate the adverse effects of venlafaxine in comparison with other anti-depressive agents.