A double-blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia

Rationale

Several recent studies have focused on glutamate modulating agents for symptoms relief in schizophrenia, especially negative symptoms which are resistant to conventional therapies.

Objectives

We aimed to assess the efficacy and tolerability of riluzole, an anti-glutamate agent with neuroprotective properties, as an adjunct to risperidone in improving negative symptoms of schizophrenia.

Methods

In this randomized double-blind placebo-controlled parallel-group study, 50 patients with chronic schizophrenia and a score of ≥20 on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. Participants were equally randomized to receive riluzole (100 mg/day) or placebo in addition to risperidone (up to 6 mg/day) for 8 weeks. Participants were rated by PANSS every 2 weeks. The primary outcome of this study was the difference in the decrease of PANSS negative subscale score from baseline to the study endpoint between the two groups.

Results

By the study endpoint, riluzole-treated patients showed significantly greater improvement in the negative symptoms (P?<?0.001) as well as the PANSS total and general psychopathology subscale scores (P?=?0.001 and P?<?0.001; respectively) compared to the placebo group. Treatment group was the only significant predictor of changes in negative symptom in this trial (β?=??0.56, P?<?0.001). No significant difference was observed between two groups in the frequency of side effects.

Conclusion

These preliminary findings suggest that riluzole may be a safe and effective medication for the treatment of negative symptoms in patients with chronic schizophrenia. Further research and replication of study findings is warranted.

Clinical trial registry name and registration number

Iranian registry of clinical trials www.irct.ir, IRCT201107281556N26     

A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia

Rational

A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be of benefit in the treatment of negative symptoms in schizophrenia.

Objective

The objective of this study was to assess the efficacy and tolerability of tropisetron add-on to risperidone on negative symptoms in patients with chronic stable schizophrenia.

Methods

In a double-blind, placebo-controlled 8-week trial, 40 patients with chronic schizophrenia who were stabilized on risperidone were randomized into tropisetron or placebo add-on groups. Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) every 2 weeks. Furthermore, extrapyramidal and depressive symptoms as well as side effects were assessed. The primary outcome measure was the difference in change from baseline of negative subscale scores between the two groups at week 8.

Results

Tropisetron resulted in greater improvement of the total PANSS scores [F(1.860,70.699)?=?37.366, p?<?0.001] as well as negative scores [F(2.439,92.675)?=?16.623, p?<?0.001] and general psychopathology [F(1.767,67.158)?=?4.602, p?=?0.017], but not positive subscale scores [F(1.348, 51.218)?=?0.048, p?=?0.893] compared to placebo. In a multiple regression analysis controlling for positive, extrapyramidal, and depressive symptoms, treatment group (standardized β?=??0.640) significantly predicted changes in primary negative symptoms. The side effect profile did not differ significantly between the two groups.

Conclusion

Tropisetron add-on to risperidone improves the primary negative symptoms of patients with chronic stable schizophrenia.     

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.     

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.     

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.     

The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats

Rationale

Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia.

Objective

This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model.

Method

Forty-five male Lister hooded rats were housed in groups of 3–4 (n?=?16) or singly (n?=?29) for 4 weeks immediately after weaning on postnatal day (PND) 22–24. On PND 51, novel cage-induced locomotor activity (LMA) was assessed to subdivide rats into groups balanced for behavioural response. On PNDs 58, 59, 65 and 72, rats received either vehicle (1 ml/kg; i.p.) or risperidone (0.2 or 0.5 mg/kg; i.p.) 30 min prior to testing in LMA, novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle and conditioned emotional response (CER) learning paradigms, respectively.

Results

Isolation rearing had no effect on PPI, but produced LMA hyperactivity and impaired NOD and CER compared to group-housed controls. Risperidone caused a dose-dependent reduction in LMA, irrespective of rearing condition, but selectively reversed the NOD deficit in isolation-reared rats. Risperidone did not reverse the isolation rearing-induced CER deficit.

Conclusions

Similar to its clinical profile, risperidone only partially reverses the schizophrenic symptomology; since it reversed some, but not all, of the learning and memory deficits induced by post-weaning isolation, the isolation rearing model may be useful to predict antipsychotic activity of novel therapeutic agents.     

Treatment of methamphetamine-induced psychosis: a double-blind randomized controlled trial comparing haloperidol and quetiapine

Rationale

To our knowledge, only a few double-blind randomized controlled trials with antipsychotic drugs have been conducted to examine the treatment of methamphetamine-induced psychosis (MAP).

Objectives

The aims of this study are to compare the antipsychotic and adverse events of quetiapine, an atypical antipsychotic drug, to haloperidol, a standard treatment for primary psychotic disorder, in individuals with MAP.

Methods

Eighty individuals with MAP were randomly assigned into two groups, i.e. treatment with quetiapine (n?=?36) and haloperidol (n?=?44). Sixty-eight patients (85 %) completed the study protocol, i.e. treatment with quetiapine at least 100 mg per day or haloperidol at least 2 mg per day orally once a day for 4 weeks. The doses were increased every 5 days until no psychotic symptom was observed from the Positive and Negative Syndrome Scale (PANSS). Data were analysed by survival analysis with Cox’s proportional regression analysis, general estimating equations and log-rank tests.

Results

Thirty-two (89 %) subjects from the quetiapine group and 37 subjects (84 %) from the haloperidol group met the remission criteria at the end of the study. Baseline PANSS total scores of quetiapine and haloperidol groups were 82.4?±?16.6 and 90.0?±?18.4, respectively (mean?±?SD; p?=?0.06). The change-from-baseline scores were ?47.8 for the quetiapine group and ?53.2 for the haloperidol group. There were no significant differences between the antipsychotic effects (coefficient value?=??2.6, p?=?0.32, 95%CI?=??7.6, 2.5) and the adverse effects of quetiapine and haloperidol.

Conclusions

Quetiapine may be used as an antipsychotic treatment for MAP with comparable therapeutic effects and adverse events to treatment with classical antipsychotic drugs.     

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory

Rationale

The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.

Objectives

To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D₂ receptor occupancy and changes in working memory.

Methods

Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [¹¹C]raclopride and [¹⁸?F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [¹⁸?F]FDG scan.

Results

The mean (±SD) D₂ receptor occupancies were 22.2?±?16.0 % in the 2 mg group, 35.5?±?3.6 % in the 5 mg group, 63.2?±?9.9 % in the 10 mg group and 72.8?±?2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t?=?2.705, df?=?14, p?=?0.017). Greater striatal D₂ receptor occupancy was related to greater decrease in frontal metabolism (r?=??0.659, p?=?0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r?=??0.597, p?=?0.019) under the greatest task load.

Conclusions

Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D₂ receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.     

Association between the brain-derived neurotrophic factor Val66Met polymorphism and therapeutic response to olanzapine in schizophrenia patients

Rationale

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a major role in neurogenesis and neuroplasticity, and in the modulation of several neurotransmitter systems including the dopaminergic system. There are mixed reports about the association between the BDNF Val66Met polymorphism, schizophrenia, and treatment response to antipsychotic drugs.

Objectives

The present study evaluated the association of the BDNF Val66Met polymorphism with treatment response to atypical antipsychotic olanzapine in schizophrenia and the possible predictive value of the BDNF Val66Met genotype status in treatment response to antipsychotic medication.

Methods

The study included 590 ethnically homogenous Caucasian patients with schizophrenia (diagnosed using the SCID), 40.2?±?12.0 years old, treated with olanzapine monotherapy (10–20 mg/day), or with other antipsychotics such as risperidone (3–6 mg/day), clozapine (100–500 mg/day), haloperidol (3–115 mg/day), fluphenazine (4–25 mg/day), and quetiapine (50–800 mg/day). Patients were subdivided into responders and non-responders according to a 50 % reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscale scores after 8 weeks of treatment.

Results

The results, corrected for possible effects of gender and age, showed a significant association between the BDNF Val66Met polymorphism and treatment response to olanzapine in patients. The Val/Val genotype was observed more frequently in treatment responders to olanzapine, and this genotype was associated with an improvement in clinical symptoms.

Conclusions

Our results suggest that BDNF Val66Met variants might influence the response to 8 weeks of monotherapy with olanzapine, in a relatively large sample of patients with schizophrenia.     

A placebo-controlled study of sildenafil effects on cognition in schizophrenia

Background

Phosphodiesterase 5 (PDE5) inhibitors increase cyclic guanosine monophosphate (cGMP) concentrations in the intracellular pathway activated by N-methyl-d-aspartic acid receptors which is believed to mediate long-term potentiation and memory consolidation. The PDE5 inhibitor sildenafil has been shown to enhance memory in animal models. In addition, neuronal nitric oxide synthase, another component of the NMDA/nitric oxide/cGMP intracellular pathway, has been reported to be dysregulated in schizophrenia patients.

Materials and methods

Seventeen adult schizophrenia outpatients treated with a stable dose of antipsychotic received a single oral dose of placebo, sildenafil 50 mg, and sildenafil 100 mg in random order with a 48-h interval between administrations. Psychiatric symptom ratings and a cognitive battery were performed at baseline and 1 hour following each administration of the study drug. In addition, memory consolidation was examined by testing recall 48 h later, prior to the next administration of the study drug.

Results

Fifteen subjects completed all three treatment conditions. One subject developed irritability and required hospitalization 2 days after receiving sildenafil 100 mg. Neither dose of sildenafil significantly affected cognitive performance or symptom ratings compared to the placebo.

Conclusion

Despite evidence for cognitive-enhancing effects of sildenafil in animal models, the strategy for treating putative NMDA receptor-mediated memory deficits in schizophrenia with sildenafil 50 and 100 mg was not successful. It is possible that the doses used in this study were not optimal or that repeated dosing may be necessary to achieve therapeutic effects. Agents under development that inhibit other subtypes of PDE remain promising for schizophrenia and dementia.     

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 risperidone, amisulpride and nicotine on eye movement control and their modulation by schizotypy

Rationale

The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers.

Objectives

We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia.

Methods

In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555–564, 1991)).

Results

AS error rate showed a main effect of Drug (p?<?0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p?=?0.04), indicating higher error rates in medium schizotypes (p?=?0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p?=?0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p?≤?0.01) indicating impaired performance with risperidone.

Conclusions

We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.     

Tobacco withdrawal components and their relations with cessation success

Rationale

Tobacco withdrawal is a key factor in smoking relapse, but important questions about the withdrawal phenomenon remain.

Objectives

This research was intended to provide information about two core components of withdrawal (negative affect and craving): (1) how various withdrawal symptom profile dimensions (e.g., mean level, volatility, extreme values) differ between negative affect and craving; and (2) how these dimensions relate to cessation outcome.

Methods

Adult smokers (N?=?1,504) in a double-blind randomized placebo-controlled smoking cessation trial provided real-time withdrawal symptom data four times per day for 4?weeks (2?weeks pre-quit and 2?weeks post-quit) via palmtop computers. Cessation outcome was biochemically confirmed 8-week point-prevalence abstinence.

Results

Examination of craving and negative affect dimensions following a cessation attempt revealed that craving symptoms differed from negative affect symptoms, with higher means, greater variability, and a greater incidence of extreme peaks. Regression analyses revealed that abstinence was associated with lower mean levels of both craving and negative affect and fewer incidences of extreme craving peaks. In a multivariate model, the increase in mean craving and negative affect scores each uniquely predicted relapse.

Conclusions

Real-time reports revealed different patterns of abstinence-related negative affect and craving and that dimensions of both predict cessation outcome, suggesting that negative affect and craving dimensions each has motivational significance. This underscores the complexity of withdrawal as a determinant of relapse and the need to measure its distinct components and dimensions.     

Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat

Rationale

Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies.

Objectives

This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone.

Methods

Forty-two male Lister-hooded rat pups received the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n?=?11 or PCP-treated n?=?10) or isolation (saline n?=?10 or PCP n?=?11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded.

Results

Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment.

Conclusions

Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.     

Raloxifene adjunctive therapy for postmenopausal women suffering from chronic schizophrenia: a randomized double-blind and placebo controlled trial

Background

Cumulative evidence from epidemiological, preclinical and clinical studies suggests estrogens may have psychoprotective effects in schizophrenic patients. Selective Estrogen Receptor Modulators could have therapeutic benefits in schizophrenia for both sexes without being hazardous to gynecological tissues or having feminizing effects. Few studies have been conducted regarding the effects of raloxifene on postmenopausal women suffering from schizophrenia. We conducted this placebo-controlled trial to compare the add-on effect of raloxifene to risperidone versus risperidone with placebo.

Methods

This was an 8-week, parallel-group, placebo-controlled trial undertaken at two universities affiliated psychiatric Hospitals in Iran. Forty-six postmenopausal women with the definite diagnosis of schizophrenia were enrolled in the study. Patients received risperidone (6 mg/day in 3 divided doses) combined with either placebo (N = 23) or 120 mg/day of raloxifene (N = 23) for 8 weeks. Patients were assessed by a psychiatrist at baseline and at 2 and 8 weeks after the start of medical therapy. Efficacy was defined as the change from baseline to endpoint in score on Positive and Negative Syndrome Scale (PANSS).

Results

For PANSS scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.77, p = 0.18]. For positive subscale scores, there was marginal significant interaction between intervention type and time [F (2, 47) = 2.93, p = 0.06] and there was substantial main effect for time [F (2, 47) = 24.39, p = 0.001] within both groups showing reduction in positive subscale scores across the three time periods. In addition, the main effect comparing two types of intervention was significant [F (1, 48) = 3.78, p = 0.02]. On the other hand, for negative subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.43, p = 0.23]. For general subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 0.03, p = 0.86].

Conclusions

According to our findings, raloxifene as an adjunctive treatment to risperidone was only superior in improvement of positive symptoms and it was not effective in treating negative and general psychopathology symptoms.

Trial registration

The trial was registered at the Iranian registry of clinical trials: IRCT201205131556N42     

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial

Rational

Autism is associated with activation of the inflammatory response system.

Objective

This study aims to assess the efficacy of a cyclooxygenase-2 inhibitor, celecoxib, as adjunctive therapy in the treatment of autism

Methods

In a 10-week randomized double-blind placebo-controlled study, 40 outpatient children with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision clinical diagnosis of autism were randomly allocated to celecoxib plus risperidone or placebo plus risperidone. The dose of risperidone and celecoxib were titrated up to 3 and 300 mg/day, respectively. Patients were assessed at baseline and after 2, 4, 6, and 10 weeks of starting medication using the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale. Primary outcome measure was the change in irritability subscale of ABC-C.

Results

Significant time?×?treatment interaction was observed for Irritability (F (1.658, 63.021)?=?13.580, P?<?0.001), Lethargy/Social Withdrawal (F (1.948, 74.032)?=?16.811, P?<?0.001), and Stereotypic Behavior (F(1.742, 66.198)?=?12.104, P?<?0.001), but not for Hyperactivity/Noncompliance (F (2.564, 97.424)?=?1.469, P?=?0.232), and Inappropriate Speech subscales (F (1.607, 61.075)?=?0.173, P?=?0.794). By week 10, patients in the celecoxib group showed significantly greater improvement in the Irritability (P?<?0.001), Lethargy/Social Withdrawal (P?<?0.001), and Stereotypic Behavior (P?<?0.00) but not in Hyperactivity/Noncompliance (P?=?0.202) and Inappropriate Speech (P?=?0.802) subscales than the placebo group. Complete response was achieved by four (20 %) patients in the placebo group and 11 (55 %) patients in the celecoxib group (χ ² (1)?=?5.227, P?=?0.022). Frequency of side effects was similar between the two groups.

Conclusions

Combination of risperidone and celecoxib was superior to risperidone alone in treating irritability, social withdrawal, and stereotypy of children with autism. (Registration, www.irct.ir; IRCT138711091556N2)     

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

Rationale

Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABA_A receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids.

Objective

The objective of this study is to conduct a randomized controlled trial of adjunctive pregnenolone in schizophrenia.

Methods

Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment—Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized.

Results

No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n?=?56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n?=?55), p?=?0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p?r _s?=?0.497, p?n?=?17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated.

Conclusions

Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia.     

Long-term (3-year) neurocognitive effectiveness of antipsychotic medications in first-episode non-affective psychosis: a randomized comparison of haloperidol, olanzapine, and risperidone

Introduction

The initially postulated superior neurocognitive effectiveness of second-generation antipsychotics is currently under debate.

Methods

A prospective, randomized, open-label study was carried out to compare the long-term neurocognitive effectiveness of haloperidol, olanzapine, and risperidone in the first episode of schizophrenia spectrum disorders. A final sample of 79 patients randomized to haloperidol (N?=?28), olanzapine (N?=?23), or risperidone (N?=?28) who completed clinical and cognitive evaluations at baseline and 3-year follow-up was included in the final analysis. Forty-one healthy individuals were also included in the final analysis. The main outcome measure was cognitive changes at 3-year follow-up. Due to the fact that some of the patients had switched their initially prescribed antipsychotic medication during the course of the study (6 out of 28 in haloperidol group, 18 out of 23 in olanzapine group, and 24 out of 28 in risperidone group continued with the initial study drug at 3-year assessment), we have also conducted a per protocol analysis.

Results

Overall, cognitive changes were similar in the three treatment groups and controls, although a greater improvement in Rey Auditory Verbal Learning Test, Digit Symbol, and Iowa Gambling Test was found in the treatment groups. The better performance observed on Rey Auditory Verbal Learning Test and Digit Symbol in olanzapine treatment group was likely explained by the lower prevalence of use of antimuscarinic drugs. These results were essentially similar to those found in the intention-to-treat analysis.

Conclusions

The major conclusion of this study is that haloperidol, olanzapine, and risperidone have not demonstrated substantial neurocognitive effectiveness, improving cognitive deficits present in the early phases of the illness. The study also underscores the importance of exploring new drugs for the treatment of cognitive impairments and associated functional disabilities in schizophrenia.     

Influence of risperidone on balance control in young healthy individuals

Rationale

It has previously been shown that impairment of postural stability is a side effect of typical antipsychotic drugs, which are largely administered to control psychosis and behavioral symptoms in elderly patients. Surprisingly, no study has yet addressed this problem with second-generation antipsychotics.

Objective

The objective of this study was to determine the extent to which risperidone at low doses altered balance control in healthy participants.

Methods

Twelve healthy young adults received, following a randomized double-blind crossover design, a single oral dose of placebo, 1 and 3?mg of risperidone on separate days at least 14?days apart. Evaluation of extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale-abbreviated scoring form (ESRS-A) and measures of postural sway using a force platform were assessed over 9?h following drug ingestion.

Results

There is a significant increase in the postural stability item of the ESRS-A parkinsonism subscale at 3 and 6?h following 3?mg of risperidone only when compared to placebo. With regard to balance control, body sway measures were increased at 1?mg of risperidone but more pronounced at 3?mg. The peak effects were observed at 3?h after administration of the drug and had not completely returned to baseline after 9?h.

Conclusions

Risperidone administered at low doses did not elicit clinically detectable EPS but had significant effects on balance control. A dose?Cresponse effect on impairment of balance was observed that followed the expected time course of the drug pharmacokinetics. These results are likely to apply to older or demented individuals who have pre-existing balance control deficit.