Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study

Rationale

There is an unmet need in the treatment of schizophrenia for effective medications with fewer adverse effects.

Objective

This study aims to evaluate the efficacy and safety of lurasidone, an atypical antipsychotic, for the treatment of schizophrenia.

Methods

Patients with an acute exacerbation of schizophrenia were randomized to 6 weeks of double-blind treatment with once-daily, fixed-dose lurasidone 40 mg (N?=?50), lurasidone 120 mg (N?=?49), or placebo (N?=?50). The primary efficacy measure was mean change from baseline to day 42 (last observation carried forward) in the Brief Psychiatric Rating Scale derived (BPRSd) from the Positive and Negative Syndrome Scale (PANSS).

Results

Mean change in BPRSd was significantly greater in patients receiving lurasidone 40 and 120 mg/day versus placebo (?9.4 and ?11.0 versus ?3.8; p?=?0.018 and 0.004, respectively). Treatment with lurasidone 120 mg/day was superior to placebo across all secondary measures, including PANSS total (p?=?0.009), PANSS positive (p?=?0.005), PANSS negative (p?=?0.011), and PANSS general psychopathology (p?=?0.023) subscales and Clinical Global Impression of Severity (CGI-S; p?=?0.001). Treatment with lurasidone 40 mg/day was superior to placebo on the PANSS positive subscale (p?=?0.018) and CGI-S (p?=?0.002). The most common adverse events for patients receiving lurasidone were nausea (16.2 versus 4.0 % for placebo) and sedation (16.2 versus 10.0 % for placebo). Minimal changes in weight, cholesterol, triglyceride, and glucose levels were observed.

Conclusions

In this study, which was limited by a relatively high discontinuation rate, lurasidone provided effective treatment for patients with acute exacerbation of chronic schizophrenia and had minimal effects on weight and metabolic parameters.     

Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine–betahistine combination

Rationale

Combination treatment with reboxetine, a selective norepinephrine reuptake inhibitor, and betahistine, a histamine H1 receptor agonist/H3 antagonist, was developed to produce complementary action in CNS pathways regulating appetite and body weight. In the present placebo-controlled study, we evaluated whether a reboxetine–betahistine combination attenuates olanzapine-induced weight gain in schizophrenia patients.

Method

Forty-three inpatients with DSM-IV schizophrenic disorder participated in a randomized double-blind study. Reboxetine (4 mg/day) with betahistine (48 mg/day) (N?=?29) or placebo (N?=?14) was co-administered with olanzapine (10 mg/day) for 6 weeks. Mental status was assessed at baseline and endpoint with relevant rating scales. Intention-to-treat method was used for statistical analysis.

Results

Seven patients in the study group and four in the placebo group discontinued the trial. At the end of the trial, patients in the olanzapine/reboxetine + betahistine group gained significantly less weight than those in the olanzapine/placebo group [2.02?±?2.37 and 4.77?±?3.16 kg, respectively; t?=?2. 89, degrees of freedom (df)?=?41, p?=?0.006]. The weight-attenuating effect of this combination was twofold larger than the weight-attenuating effect previously demonstrated with reboxetine alone. Significantly fewer patients in the study group than in the comparison group increased their initial weight by >7 %, the cutoff for clinically significant weight gain [3/29 (10.3 %) and 6/14 (42.9 %), respectively; χ ²?=?6.03, df?=?1, p?=?0.014]. The reboxetine–betahistine combination was safe and well tolerated.

Conclusions

Reboxetine–betahistine combination produces a clinically meaningful attenuation of olanzapine-induced weight gain. These results justify direct comparison between the reboxetine–betahistine combination and reboxetine alone.     

Zonisamide for Bipolar Depression: A Randomized,Double Blind,Placebo-Controlled,Adjunctive Trial

Objective

This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar depression.

Experimental design

One hundred two patients with bipolar disorder, type I or II in the depressed phase of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases, a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. MADRS score was the primary outcome variable. Secondary outcome measures included the YMRS, CGI-S, CGI-I, Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also evaluated. Side effects were measured using the SAFTEE.

Principal observations

There were no statistically significant differences in response between subjects treated with adjunctive zonisamide vs. placebo controls for the primary or secondary outcome measures. There were also no differences between the groups with regard to response rate or remission rate.

Conclusions

In contrast to preliminary open label studies that suggested a role for zonisamide in bipolar depression, we could not confirm these results in a large double blind controlled study.     

Magnitude of change with antidepressants and placebo in antidepressant clinical trials using structured,taped and appraised rater interviews (SIGMA-RAPS) compared to trials using traditional semi-structured interviews

Rationale

Although newer interview methods such as Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA; MADRS) with audiotaping and Rater Applied Performance Scale (RAPS) appraisal have been introduced to improve reliability of ratings in antidepressant clinical trials, there is limited evidence that these methods actually improve trial outcome.

Objective

The objective of this study uis to evaluate outcome in four similarly designed trials of two recently approved antidepressants: two trials randomly used taped SIGMA interviews with RAPS appraisal and two trials used traditional semi-structured MADRS interviews.

Methods

We reviewed data from patients who were screened (N?=?243) and randomized (N?=?148), evaluating the magnitude of change with placebo and antidepressants on mean total MADRS score.

Results

Depressed patients assigned to placebo in trials using taped SIGMA interviews with RAPS appraisal had a significantly larger MADRS change score (M?=??11.5?±?12.7) compared to patients assigned to placebo in trials using traditional semi-structured interviews (?5.4?±?8.9; F(df?=?1.57)?=?5.58, p?=?0.022). The error variance was also significantly larger in the placebo arm of trials using SIGMA interviews (F?=?5.43, p?=?0.023). Depressed patients assigned to antidepressants had similar outcome in all of the four trials.

Conclusion

The recently suggested modifications in obtaining clinical data in antidepressant trials such as taped SIGMA interviews with RAPS rating appraisals may in fact result in a higher magnitude of placebo response and a lower magnitude of antidepressant-placebo differences compared to the traditional methods of collecting clinical data. These results were unexpected and indicate the necessity to test new methods prospectively, no matter how intuitively sensible they seem, prior to their implementation.     

Results of a proof-of-concept, dose-finding, double-blind, placebo-controlled study of RX-10100 (Serdaxin?) in subjects with major depressive disorder

Background

RX-10100 (Serdaxin?), a nonantibiotic small molecule beta-lactam compound, has shown potent antidepressant and anxiolytic activities in preclinical models. RX-10100 does not bind to the serotonin transporter or other receptors associated with monoamine activity. In microdialysis studies with rats, RX-10100 increased the release of dopamine and serotonin metabolites. A clinical proof-of-concept study was conducted to determine the clinical effectiveness of RX-10100 in treating depression.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled, parallel group study of people with depression (n?=?77; HAM-D-17 baseline score?≥?20). Eligible subjects were randomly assigned to receive RX-10100 (5, 10, or 15?mg twice daily) or placebo for 8?weeks. Change from baseline in the MADRS total score was the primary endpoint.

Results

Mean changes in MADRS scores were ?46.0%, ?37.9%, and ?41.4%, for 5, 10, and 15?mg RX-10100, respectively, as compared with 43.1% for placebo. In subjects with severe depression (baseline MADRS?≥?29; n?=?28) scores improved 55.6% with 5?mg RX-10100 but only 34% with placebo (p?=?0.041). In an analysis of responders (i.e., subjects with 50% change from baseline score), 64.3% of subjects treated with 5?mg RX-10100 responded. All doses of RX-10100 were well-tolerated.

Conclusion

In this proof-of-concept study, RX-10100 treatment (5?mg twice daily) improved MADRS scores in subjects with severe depression. RX-10100 does not appear to have many of the typical side effects of other antidepressants. These results indicate a need for larger studies further evaluating RX-10100 at 5?mg and lower doses.     

Paliperidone for irritability in adolescents and young adults with autistic disorder

Rationale

Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies.

Objectives

The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism.

Methods

This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months.

Results

Twenty-one (84 %) of 25 subjects ages 12–21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3–12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n?=?1; nonresponse, n?=?1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range ?3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p?≤?0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p?≤?0.0001).

Conclusions

Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.     

Higher dopamine transporter density in Parkinson’s disease patients with depression

Rationale

Depression is a frequent non-motor symptom in Parkinson’s disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is not clear since clinical matching was inappropriate and DAT reduction could be attributed to PD severity.

Objectives

To further examine the role of DAT in PD depression, this study compared thoroughly matched depressed vs. non-depressed PD patients (ndPD).

Materials and methods

Twenty PD patients (n?=?10 ndPD; n?=?10 dPD) matched for age and disease severity were submitted to brain SPECT imaging with [^99mTc]-TRODAT-1, a DAT radioligand. DAT-binding potential was calculated using regions of interest bilaterally drawn in the striatum, caudate, and putamen. Depression was defined according to Beck Depression Inventory (BDI; cut-off >18).

Results

Mean BDI scores were higher in dPD (25.0?±?5.6) than in ndPD patients (8.0?±?1.9, p?<?0.0001). DAT density was greater on dPD especially in the left caudate (dPD 0.87?±?0.19 vs. ndDP 0.69?±?0.18, p?=?0.02) and right putamen (dPD 0.37?±?0.07 vs. ndPD 0.28?±?0.13, p?=?0.03) than in ndPD patients.

Conclusion

Our results suggest that in vivo DAT density is increased in dPD patients as compared to ndPD, suggesting that DAT is implicated in the pathophysiology of PD depression.     

A prospective open-label trial of paliperidone monotherapy for the treatment of bipolar spectrum disorders in children and adolescents

Rationale

Treatment studies for the management of pediatric bipolar disorder are limited.

Objectives

This study evaluates the safety and efficacy of paliperidone monotherapy as an acute treatment of mania and related symptoms in youth with bipolar spectrum disorders.

Methods

An 8-week, prospective, open-label paliperidone monotherapy trial to assess effectiveness and tolerability in treating pediatric bipolar spectrum and related disorders (depression, psychosis, attention-deficit/hyperactivity disorder [ADHD]). Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impression scale (CGI), Children’s Depression Rating Scale-Revised (CDRS-R), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis.

Results

Fifteen youth with bipolar spectrum disorders (YMRS at entry: 32.8?±?6.1) were enrolled in the study and 11 (73 %) completed the 8-week trial. The total daily dose of paliperidone at study endpoint was 3 mg in 12 subjects and 6 mg in three subjects. Treatment with paliperidone was associated with statistically significant levels of improvement in mean YMRS scores (?18.7?±?13.9, p?<?0.001) at endpoint. Paliperidone treatment also resulted in significant improvement in the severity of ADHD and psychotic symptoms. Although treatment with paliperidone was generally well tolerated and was not associated with clinically significant change in cardiovascular or metabolic parameters, increases in body weight (4.1?±?5.5 lb) were substantial.

Conclusions

Open-label paliperidone treatment appears to be beneficial in the treatment of bipolar spectrum disorders and associated conditions in youth. Future placebo-controlled studies are warranted to confirm these findings.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

Effects of short-term varenicline administration on cortisol in healthy, non-smoking adults: a randomized, double-blind, study

Rationale

Varenicline is the most effective drug for smoking cessation, but its use decreased because of reports of depressogenic side effects. However, because smoking and smoking cessation on their own are associated with depression, it remains unclear whether reported depressogenic effects are attributable to varenicline, or to smoking, and/or smoking cessation themselves.

Objectives

Previously, we observed no depressogenic effects of varenicline on a psychological level. In the present study, we aimed at investigating potential depressogenic effects of the partial nicotinergic acetylcholine receptor agonist varenicline on a biological level. A possible pathway would be an effect of varenicline on the hypothalamic–pituitary–adrenal (HPA) axis, considering the relation between the HPA axis and (1) the cholinergic system and (2) depression.

Methods

In a randomized, double-blind design, we administered varenicline or placebo for 7 days (0.5 mg/day first 3 days, then 1 mg/day) to healthy never-smoking subjects, thereby eliminating bias by (previous) smoking status. We used repeated measures (before and after treatment) of the salivary free cortisol awakening response to measure HPA axis activity and flexibility.

Results

Salivary cortisol data of 34 subjects were included in the analysis. Results showed no effect of varenicline on height (F _1,32?=?0.405; P?=?0.529) or shape (F _2,31?=?0.110; P?=?0.164) of the cortisol awakening response.

Conclusions

Results do not suggest depressogenic effects of varenicline on the HPA axis. Although this does not preclude other biological depressogenic effects of varenicline, it seems that concerns about effects of varenicline on the HPA axis should not limit its potential to treat nicotine and related addictions.     

A randomized,placebo-controlled,double-blind trial of sertraline for postpartum depression

Rationale

Postpartum depression (PMD) occurs in roughly 10 % of postpartum women and negatively impacts the mother and her offspring, but there are few placebo-controlled studies of antidepressant treatment in this population.

Objective

The objective was this study is to compare the selective serotonin reuptake inhibitor (SSRI) sertraline to placebo for treating PMD.

Methods

This was a single-center, 6-week, randomized double-blind placebo-controlled trial of sertraline with a 1-week placebo lead-in. The participants (n?=?38) were women with depression onset within 3 months of delivery; a subset (n?=?27) met strict DSM-IV criteria for PMD (onset within 4 weeks of delivery). The participants were prescribed sertraline 50 mg or placebo daily to a maximum of 200 mg/day. Primary outcome variables were the Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impressions (CGI) scores, which were used to determine the rates of response and remission.

Results

Sertraline produced a significantly greater response rate (59 %) than placebo (26 %) and a more than twofold increased remission rate (53 % vs. 21 %). Mixed models did not reveal significant group by time effects, although in the subset of women who met the DSM-IV criteria, there was a statistically significant group by time effect for the HAM-D, Hamilton Anxiety Rating Scale (HAM-A), and CGI.

Conclusions

Women with PMD are more likely to have a remission of their depression with sertraline treatment, a finding that is more pronounced in women who have onset of depression within 4 weeks of childbirth. These data support the continued use of 4 weeks for the DSM-5 postpartum onset specifier for major depressive disorder.     

Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis

Purpose

Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders.

Methods

We searched MEDLINE and EMBASE for randomized controlled trials in which oral formulations of second-generation antipsychotic drugs were compared head-to-head or against placebo or against haloperidol. Trials had to be of at least 6 months duration to be included. We used a network meta-analysis to combine direct and indirect comparisons of the cognitive effects between antipsychotics.

Results

Nine studies were eligible. The median trial duration was 52 weeks. Quetiapine, olanzapine and risperidone had better effects on global cognitive score than amisulpride (p?<?0.05) and haloperidol (p?<?0.05). When memory tasks were considered, ziprasidone had better effect than amisulpride (0.28 [0.02–0.54]) and haloperidol (0.32 [0.09–0.55]). Quetiapine was better than other drugs (p?<?0.001) on attention and processing speed tasks, followed by ziprasidone (p?<?0.05) and olanzapine (p?<?0.05). The effects of quetiapine, risperidone and olanzapine were better than those of amisulpride (p?<?0.05) on executive functions.

Conclusions

Our results suggest differences between antipsychotics in their effect on the overall cognitive score in schizophrenia. Quetiapine and olanzapine had the most positive effects, followed by risperidone, ziprasidone, amisulpride and haloperidol in that order. Significant differences were also observed according to specific cognitive tasks.     

Relative sensitivity of the Montgomery-Asberg Depression Rating Scale,the Hamilton Depression rating scale and the Clinical Global Impressions rating scale in antidepressant clinical trials

Although early antidepressant clinical trials simply relied on a clinician's judgment as to whether a depressed patient clinically improved or not, the Hamilton Depression (HAM-D) rating scale has become the 'gold standard' to assess the efficacy of new antidepressants. The alternative Montgomery-Asberg Depression Rating Scale (MADRS) has not achieved general acceptance. However, its ease of use warrants evaluation as to whether it is comparable to HAM-D in its sensitivity in detecting antidepressant-placebo differences in antidepressant clinical trials. A retrospective chart review was performed on the records of 208 depressed adult patients that participated in eight randomized, placebo-controlled, double-blind antidepressant clinical trials at the Northwest Clinical Research Center between 1996 and 2000. We compared the effect sizes of the HAM-D, MADRS and Clinical Impressions Rating Scale (CGI-S for severity and CGI-I for improvement) for patients assigned to placebo or an established antidepressant. The effect size (measured as the mean change in rating with antidepressants minus the mean change for placebo divided by the pooled SD of change, adjusted for age, gender and initial scores) was 0.49 with MADRS, 0.53 with HAM-D, 0.55 with CGI-S and 0.59 with CGI-I. The four rating scales had similar effect sizes regardless of the type of antidepressant evaluated. These data suggest that MADRS is as sensitive an instrument as HAM-D for detecting antidepressant efficacy in clinical trials. Thus, MADRS may be a desirable tool in large-scale, pivotal antidepressant clinical trials.     

Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: A four-week,randomized, double-blinded,placebo-controlled study

This is a 4 week, randomized, double-blind, placebo-controlled study to examine the effects of methylphenidate as add-on therapy to mirtazapine compared to placebo for treatment of depression in terminally ill cancer patients. It involved 88 terminally ill cancer patients from University of Malaya Medical Centre, Kuala Lumpur, Malaysia. They were randomized and treated with either methylphenidate or placebo as add on to mirtazapine. The change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 3 was analyzed by linear regression. Changes of MADRS and Clinical Global Impression-Severity Scale (CGI-S) over 28 days were analyzed using mixed model repeated measures (MMRM). Secondary analysis of MADRS response rates, defined as 50% or more reduction from baseline score. A significantly larger reduction of Montgomery-Åsberg Depression Rating Scale (MADRS) score in the methylphenidate group was observed from day 3 (B=4.14; 95% CI=1.83–6.45). Response rate (defined as 50% or more reduction from baseline MADRS score) in the methylphenidate treated group was superior from day 14. Improvement in Clinical Global Impression-Severity Scale (CGI-S) was greater in the methylphenidate treated group from day 3 until day 28. The drop-out rates were 52.3% in the methylphenidate group and 59.1% in the placebo group (relative risk=0.86, 95%CI=0.54–1.37) due to cancer progression. Nervous system adverse events were more common in methylphenidate treated subjects (20.5% vs 9.1%, p=0.13). In conclusions, methylphenidate as add on therapy to mirtazapine demonstrated an earlier antidepressant response in terminally ill cancer patients, although at an increased risk of the nervous system side effects.     

Ketamine administration in depressive disorders: a systematic review and meta-analysis

Introduction

Ketamine’s efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine’s effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.

Methods

Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic.

Results

We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD?=??0.99; 95 % CI ?1.23, ?0.75; p?p?p?=?0.04; I2?=?52.4 %). The duration of ketamine’s effects was assessed in only two non-ECT studies and seemed to persist for 2–3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine’s use should remain cautious in patients with a cardiovascular history.

Conclusion

The present meta-analysis confirms ketamine’s efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.     

Olanzapine monotherapy for acute depression in patients with bipolar I or II disorder: results of an 8‐week open label trial

We evaluated the efficacy, tolerability, and safety of olanzapine monotherapy in 20 adult patients with bipolar I or II disorder, depressed phase. Patients received open‐label olanzapine monotherapy (mean modal dose, 15 mg/day) for 8 weeks. Assessments of psychopathology (Montgomery–Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology [QIDS‐SR‐16], Young Mania Rating Scale [YMRS]), clinical global state (Clinical Global Impressions [CGI] scale), and safety/tolerability were performed at baseline, and at 1, 2, 4, 6, and 8 weeks. Seventeen patients (85.0%) completed the study. Improvement in MADRS total scores was observed after the first week of treatment, and at all remaining follow‐up time points (p ≤ 0.005). Parallel improvement in QIDS‐SR‐16 (p < 0.001) and CGI‐Severity (p < 0.001) was observed between baseline and study endpoint. Nine (45%) subjects achieved positive treatment response, eight of whom (40%) also achieved symptom remission. There were significant increases in weight (+3.2 kg, p = 0.001) and body mass index (+1.1 kg/m², p = 0.001), but not fasting glucose or lipids, with the exception of reduced triglyceride levels in the overall sample, and reduced HDL cholesterol in females. Olanzapine may be an effective, well‐tolerated option for treating acute non‐psychotic depression across a variety of bipolar disorder subtypes. Copyright © 2009 John Wiley & Sons, Ltd.     

Association between initial morphine intake and body weight change,acoustic startle reflex and drug seeking in rats

Rationale

Although chronic use of opiates can induce physical dependence and addiction, individual differences contributing to these symptoms are largely unknown.

Objectives

Using intravenous morphine self-administration (MSA), we investigated whether individual differences in drug intake are associated with weight change, acoustic startle reflex (ASR), pre-pulse inhibition (PPI), and drug seeking during spontaneous withdrawal.

Methods

Male Sprague-Dawley rats self-administered morphine (0.5 mg/kg/infusion) or saline for 3 weeks (4–6 h/day, 5 days/week) and drug intake and body weight were monitored daily. The ASR and the PPI (baseline, 1 day and 1 week) and drug seeking (1 week) were measured during spontaneous withdrawal.

Results

Morphine animals did not gain weight (101 %?±?0.69), while the control animals did (115 %?±?1.06) after 3 weeks of self-administration. The ASR and the PPI were not significantly different between morphine and saline animals in 1-day or 1-week withdrawal. However, individual differences in initial (first 10 min), but not total (4–6 h), morphine intake of the daily sessions were positively correlated with weight change (r?=?0.437, p?=?0.037) and drug seeking (r?=?0.424, p?=?0.035) while inversely correlated with the ASR (r?=??0.544, p?=?0.005) in 1-week withdrawal from chronic morphine.

Conclusions

A subgroup of animals that self-administered a larger amount of morphine at the beginning of the daily sessions exhibited subsequent weight gain, reduced ASR, and enhanced drug seeking in morphine withdrawal. Thus, individual differences in initial morphine intake may reveal a novel behavioral phenotype in opioid addiction.     

N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: a randomized,double-blinded,placebo-controlled,clinical trial

Purpose

The aim of this study was to evaluate the effectiveness of oral n-acetyl cysteine, as a potential nephroprotective agent, in preventing and/or attenuating amphotericin B-induced electrolytes imbalances.

Methods

During a one year period, patients were to receive conventional amphotericin b for any indication for at least one week and were randomly allocated to receive either placebo or 600 mg oral n-acetyl cysteine twice daily during the treatment course of amphotericin b. Demographic and clinical data of the study population were gathered. Different aspects of amphotericin b nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, renal magnesium and potassium wasting were assessed. Each patient was monitored for any adverse reaction to n-acetyl cysteine. Sixteen and 14 patients in the n-acetyl cysteine and placebo groups completed the study, 3incidences of hypokalemia (75 % versus 70 %; P?=?0.724) and hypomagnesemia (30 % versus 20 %; P?=?0.468) did not differ significantly between placebo and NAC groups, respectively. Although the rate of AmB nephrotoxicity was higher in the placebo than in the NAC group (60 % versus 40 %), this difference was not statistically significant (P?=?0.209) even after adjusting for probable associated factors of amphotericin b nephrotoxicity (P?=?0.206). The incidence as well as time of onset of electrolyte abnormalities also did not differ significantly between placebo and n-acetyl cysteine groups. About 44 % of n-acetyl cysteine recipients experienced new onset nausea and a mild unpleasant taste during the study.

Conclusion

Oral n-acetyl cysteine during the amphotericin B treatment course was not significantly effective in preventing or mitigating different features of its nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, and renal potassium as well as magnesium wasting.     

Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes

Objective

There is accumulating evidence that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of patients with schizophrenia. Clinical studies show reductions in BDNF in schizophrenic patients treated with first generation antipsychotics or second generation antipsychotics. However, there have been few systematic studies to examine the relationship between BDNF levels and psychopathology in first-episode and drug-naïve patients with schizophrenia.

Materials and methods

Serum BDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 88 never-medicated first-episode and 90 healthy controls subjects matched for age and gender. The schizophrenia symptomatology and the depressive symptoms were assessed by the positive and negative syndrome scale (PANSS) and the Hamilton rating (HAMD) scale for depression.

Results

The results showed that BDNF levels were significantly lower in first-episode patients with schizophrenia than in healthy control subjects (9.0?±?4.2 ng/ml vs 12.1?±?2.2 ng/ml; F?=?37.6; df?=?1, 176; p?<?0.0001). A significant positive correlation between BDNF levels and PANSS positive subscore was observed (r?=?0.29; df?=?88; p?=?0.008). Furthermore, higher BDNF levels were observed in patients with paranoid subtype of schizophrenia. However, no significant correlation between BDNF and HAMD total score was found.

Conclusion

Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and perhaps, could be a candidate biological marker for positive symptoms.     

Effect of d-amphetamine on emotion-potentiated startle in healthy humans: implications for psychopathy and antisocial behaviour

Rationale

An emerging literature associates increased dopaminergic neurotransmission with altered brain response to aversive stimuli in humans. The direction of the effect of dopamine on aversive motivation, however, remains unclear, with some studies reporting increased and others decreased amygdala activation to aversive stimuli following the administration of dopamine agonists. Potentiation of the startle response by aversive foreground stimuli provides an objective and directional measure of emotional reactivity and is considered useful as an index of the emotional effects of different drugs.

Objective

We investigated the effects of two doses of d-amphetamine (5 and 10 mg), compared to placebo, for the first time to our knowledge, using the affect–startle paradigm.

Method

The study employed a between-subjects, double-blind design, with three conditions: 0 mg (placebo), and 5 and 10 mg d-amphetamine (initially n?=?20/group; final sample: n?=?18, placebo; n?=?18, 5 mg; n?=?16, 10 mg). After drug/placebo administration, startle responses (eyeblinks) to intermittent noise probes were measured during viewing of pleasant, neutral and unpleasant images. Participants’ general and specific impulsivity and fear-related personality traits were also assessed.

Results

The three groups were comparable on personality traits. Only the placebo group showed significant startle potentiation by unpleasant, relative to neutral, images; this effect was absent in both 5- and 10-mg d-amphetamine groups (i.e. the same effect of d-amphetamine observed at different doses in different people).

Conclusions

Our findings demonstrate a reduced aversive emotional response under d-amphetamine and may help to account for the known link between the use of psychostimulant drugs and antisocial behaviour.