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Background Patients with schizophrenia can generally manifest a broad variety of primary negative symptoms. The current study aimed to assess the efficacy and tolerability of resveratrol add-on therapy in the treatment of negative symptoms in patients with stable schizophrenia. Methods In a randomized, double-blind, and placebo-controlled setting, schizophrenia patients were assigned to receive either 200 mg/d resveratrol or matched placebo in addition to a stable dose of risperidone for 8 weeks. Patients were assessed using the positive and negative syndrome scale, the extrapyramidal symptom rating scale, and Hamilton Depression Rating Scale over the trial period. The primary outcome was considered as the change in positive and negative subscale score from baseline to week 8 between the treatment arms. Results A total 52 patients completed the trial (26 in each arm). Baseline characteristics of both groups were statistically similar (P > .05). Despite the statistically similar behavior of positive symptoms between the groups across time (Greenhouse-Geisser corrected: F = 1.76, df = 1.88, P = .180), the resveratrol group demonstrated greater improvement in negative, general psychopathology, and total scores (Greenhouse-Geisser corrected: F = 12.25, df = 2.04, P Conclusion Adding resveratrol to risperidone can exhibit remarkable efficacy and safety in terms of management of schizophrenia-related negative symptoms.

What is known and objective The underlying pathophysiology of autism spectrum disorder (ASD) has been linked to immune dysregulation, oxidative stress and excitation-inhibition imbalance. Among associated symptoms of ASD, management of irritability has gained considerable attention as it complicates adjustment of ASD patients and thus necessitates its pharmacological treatment. Resveratrol is a plant phytoalexin, which has been demonstrated to have neuroprotective effects through its anti-inflammatory and antioxidant properties. This double-blind, placebo-controlled randomized trial was designed to assess the potential therapeutic effects of resveratrol plus risperidone on irritability of ASD patients. Methods Sixty-two patients were assigned randomly into two groups of resveratrol and placebo. Both groups were treated with risperidone twice daily starting at a dose of 0.5 mg with a dose increase of 0.5 mg per week (for the first 3 weeks). Resveratrol dosage was 250 mg twice per day from the beginning of the study. Using the Aberrant Behavior Checklist-Community (ABC-C), patients were assessed for ASD-related behavioural symptoms at baseline, week 5 and week 10. The frequency of adverse events was recorded using a checklist containing 25 possible side effects, including general, gastrointestinal, neurological and cardiovascular complications. Results and discussion Improvements in primary outcome measure (irritability) and three secondary outcome measures (lethargy/social withdrawal, stereotypic behaviour and inappropriate speech subscales) in the resveratrol group were statistically similar to those in the placebo group. The repeated measures analysis showed no time × treatment interaction on these subscale scores. In contrast, patients in the resveratrol group showed greater decline in hyperactivity/non-compliance score as a secondary outcome measure (mean difference [CI = 95%] = 4.51 [0.10-8.92], t = 2.04; P = .04), and repeated measures analysis showed significant effect for time × treatment effect on this subscale score (F = 3.81; df = 1.30; P = .043). There was no significant difference in number and severity of adverse events between the two groups. What is new and conclusion This clinical trial demonstrated no significant effect for adjunctive treatment with resveratrol on irritability of patients with ASD. However, it provided preliminary evidence indicating that resveratrol could improve hyperactivity/non-compliance of ASD patients.

Recent advances in clinical practice emphasize the utility of Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders (UP) as an effective intervention for targeting core processes underlying comorbid disorders. This study aimed to evaluate changes in psychopathological risk factors associated with the construct of neuroticism (i.e., negative affect, anxiety sensitivity, experiential avoidance, intolerance of uncertainty) within the UP to adults already on an optimal and stable dose of SSRIs. In a randomized controlled trial, a total of 39 adults (Mage = 27.51 [±8.43]; 56.4% female) on SSRIs with a diagnosis of comorbid anxiety and depressive disorder were randomly assigned to either UP + SSRI (n = 18) or continued SSRI-only (n = 21). Neuroticism dimensions were assessed at baseline, posttreatment, and 1-month follow-up. UP + SSRI condition demonstrated medium to large effect sizes for changes over time on facets of neuroticism including negative affect (Cohen's d = 1.12, 95% confidence interval [CI; 0.44, 1.80]), anxiety sensitivity (Cohen's d = 1.21, 95% CI [0.53, 1.90]), experiential avoidance (Cohen's d = 0.74, 95% CI [0.09, 1.04]), and intolerance of uncertainty (Cohen's d = 1.66, 95% CI [0.93, 2.39]). Post hoc analyses showed reductions in variables that were maintained at follow-up. Results adds to the growing body of literature and provide cross-cultural support for the utility of UP in targeting pathological risk factors as adjuncts to SSRI. Implications for future studies and limitations are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

This is a double-blind, placebo-controlled, parallel-grouped clinical trial, which was designed to investigate the potential effects of melatonin add-on treatment with lithium and risperidone on acute manic episodes in patients with bipolar disorder (BD). A total of 54 patients were included and randomly assigned into two groups of melatonin and placebo. The trial group received 3 mg/day risperidone, 900 mg/day lithium, and 6 mg/day melatonin. The placebo group received the same dose of risperidone and lithium plus placebo. The participants were evaluated at four sessions, consisting of baseline, weeks 1, 4, and 6. The manic symptoms and overall clinical improvement of the patients were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I), respectively. Two trial groups were matched based on all baseline characteristics. The patients in two trial groups had comparable serum lithium levels at weeks 1, 4, and 6. Our results from the general linear model repeated measures analysis showed a significant effect for time × treatment interaction on YMRS scores (P = 0.021 and F-value = 3.7). Furthermore, outcomes of the CGI-I rating scale demonstrated that patients in the melatonin group had better clinical improvements compared to the placebo group (P = 0.018). Our results provided preliminary evidence supporting melatonin as an effective adjunctive treatment leading to significant improvements in manic symptoms and overall clinical status in acute episodes of mania.

Although the pathogenesis of symptoms of schizophrenia is largely unknown, a variety of neurotransmitters are implicated, including serotonin and norepinephrine. Here we investigate the effectiveness of duloxetine as a serotonin-norepinephrine inhibitor in the treatment of negative symptoms.We performed a double-blind clinical trial on 64 patients with stable schizophrenia and no prominent symptoms of depression. Patients received risperidone (up to 6 mg/day) plus either duloxetine (60 mg/day) or placebo. Psychotic symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) at the onset of the trial, and at 2, 4, 6 and 8 weeks of therapy.Compared to the placebo group, the duloxetine group showed significantly higher improvement in negative symptoms (p0.001), PANSS total (p0.001), and the general psychopathology subscale scores (p=0.001), but no significant difference in positive symptoms (p=0.13). The side effect profiles of the 2 treatment regimens were not significantly different.Duloxetine adjuvant to risperidone seems to be a tolerable and efficacious treatment for primary negative symptoms of schizophrenia.

AIM The role of the glutamatergic system in the pathogenesis of obsessive-compulsive disorder (OCD) has been shown by numerous studies. The aim of the present randomized, double-blind, placebo-controlled, 12-week trial was to assess the efficacy and tolerability of amantadine as an adjuvant to fluvoxamine in the treatment of patients with moderate to severe OCD. METHODS One hundred patients diagnosed with moderate to severe OCD were randomized into two parallel groups to receive fluvoxamine (100 mg twice a day) plus placebo or fluvoxamine (100 mg twice a day) plus amantadine (100 mg daily) for 12 weeks. All patients received 100 mg/day fluvoxamine for 28 days followed by 200 mg/day for the rest of the trial, regardless of their treatment groups. Patients were evaluated for response to treatment using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and at Weeks 4, 10, and 12. The main outcome measure was to assess the efficacy of amantadine in improving the OCD symptoms. RESULTS Repeated-measure analysis of variance showed a significant effect for Time × Treatment interaction (Greenhouse-Geisser corrected: F = 3.84, d.f. = 1.50, P = 0.03) in the Y-BOCS total score and a significant effect for Time × Treatment interaction (Greenhouse-Geisser corrected: F = 5.67, d.f. = 1.48, P < 0.01) in the Y-BOCS Obsession subscale score between the two groups. CONCLUSION The results of this study suggest that amantadine may be effective as an augmentative agent in the treatment of moderate-to-severe OCD.

Objectives Recent research has focused on the inflammatory cascade as a key culprit in the etiology of bipolar disorder. We hypothesized that celecoxib, via its anti-inflammatory properties, may have a therapeutic role in mood disorder. Methods Forty-six inpatients with the diagnosis of acute bipolar mania without psychotic features participated in a parallel, randomized, double-blind, placebo-controlled trial, and underwent six weeks of treatment with either celecoxib (400 mg daily) or placebo as an adjunctive treatment to sodium valproate. Patients were evaluated using the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS). The primary outcome measure with respect to efficacy was the mean decrease in YMRS score from baseline to the study endpoint, which was compared between the two groups. Results A significant difference was observed in the change in YMRS scores on Day 42 compared to baseline in the two groups (p

This research aims to determine the mental health status of population aged 15 and over in the province of Kordestan in 2015.The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Kordestan in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Sanandaj, Divandareh and Bijar cities. The General Health Questionnaire-28 (GHQ-28) was used as a screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software.With the traditional scoring method used, 30.4% of the participants (38.1% of women and 22.9% of men) were suspected of having mental disorders. The suspected prevalence of mental disorder was higher in urban (32.5%) than rural areas (25.3%). The suspected prevalence of somatic symptoms and anxiety was greater than the suspected prevalence of social dysfunction and depression, and these disorders were more prevalent in women than men. The findings also showed that the suspected prevalence of mental disorder increased with age. The suspected prevalence of these disorders was higher in women, urban residents, the over 65 age group, the divorced and widowed subjects, the illiterate, the retired and the housewives compared to the other groups.The present findings showed that almost a third of the samples were suspected of mental disorder, and the prevalence of these disorders had increased from 21.8% in 1999 to 30% in 2015. The health authorities of the province should therefore take the necessary measures to protect and treat people with mental disorders and promote mental health in the community.

OBJECTIVE We aimed to evaluate the efficacy and tolerability of citicoline add-on therapy in treatment of negative symptoms in patients with stable schizophrenia. METHODS In a double-blind and placebo-controlled study, patients with stable schizophrenia (DSM-5) were randomized to receive either 2,500 mg/day citicoline or placebo in addition to risperidone for 8 weeks. The patients were assessed using the positive and negative syndrome scale (PANSS), the extrapyramidal symptom rating scale (ESRS), and Hamilton depression rating scale (HDRS). The primary outcome was the difference in PANSS negative subscale score reduction from baseline to week 8 between the citicoline and the placebo groups. RESULTS Sixty-six individuals (out of 73 enrolled) completed the trial. The citicoline group demonstrated significantly greater improvement in negative scores, F(1.840, 118.360) = 8.383, p = .001, as well as general psychopathology, F(1.219, 78.012) = 6.636, p = .008; change in general psychopathology did not remain significant after adjustment, and total PANSS scores, F(1.633, 104.487) = 15.400, p

Considering the role of neurohypophyseal peptides in normal development and function of higher cortical processes along with their proven abnormalities in schizophrenic patients, these pathways have recently attracted greater attention as treatment targets for schizophrenia. Desmopressin (DDAVP) is a synthetic analog of vasopressin. This study aimed to evaluate the efficacy and safety of DDAVP nasal spray as an adjunct to risperidone in improving negative symptoms of schizophrenia. In this randomized double-blind placebo-controlled clinical trial, forty patients aged 18-50 years with a DSM IV-TR diagnosis of chronic schizophrenia and a minimum score of 60 on positive and negative syndrome scale (PANSS) were equally randomized to receive DDAVP nasal spray (20mcg/day) or placebo in addition to risperidone for 8 weeks. Patients were partially stabilized and treated with a stable dose of risperidone (5 or 6mg/day) for at least four weeks prior to entry. Participants were rated by PANSS every two weeks and decrease in the PANSS negative subscale score was considered as our primary outcome. By the study endpoint, DDAVP-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=0.005 and P=0.003; respectively) compared to the placebo group. Treatment group was the strongest predictor of changes in negative symptoms (β=-0.48, t=-3.67, P=001). No serious adverse event or fluid/electrolyte imbalance was reported in this trial. In conclusion, DDAVP nasal spray showed to be an effective and safe medication for improving negative symptoms in patients with chronic schizophrenia.

We investigated the effects of simvastatin adjunctive therapy on the negative symptoms of schizophrenia. In this double-blind trial, inpatients with chronic schizophrenia were clinically stabilized on a constant dose of risperidone for at least 4 weeks before the study and were then randomized to receive risperidone (4-6 mg/day) plus either simvastatin (40 mg/day) (n=33) or placebo (n=33) for 8 weeks. The Positive and Negative Syndrome Scale was used to measure the negative, positive, and general symptoms of schizophrenia at baseline and every 2 weeks. The Hamilton Depression Rating Scale and the Extrapyramidal Symptom Rating Scale were used to measure depression and extrapyramidal symptoms at baseline and week 8. Difference in change in negative symptoms score from the baseline to week 8 was considered the single primary outcome. At baseline, negative symptoms scores were higher than positive symptoms scores in both simvastatin and placebo groups. There was no baseline difference between the two groups in terms of any of the measured variables. Compared with the placebo group, the simvastatin group showed a significantly higher reduction in negative symptoms scores from baseline to week 8 [mean difference: 95% confidence interval=-1.42 (-2.32 to -0.52), P=0.003]. Similar findings were observed for total scores [mean difference: 95% confidence interval=-1.85 (-2.87 to -0.83), P=0.001]. The results were not significant for positive symptoms or general psychopathology scores. We found a favorable effect of simvastatin on negative symptoms of patients with schizophrenia; however, future studies are warranted to confirm these results.

Objectives: Despite the burden of negative symptoms on quality of life in schizophrenic patients, no completely effective treatment has been developed to address such symptoms yet. Abnormalities in oxidative stress pathways have been recently demonstrated to be involved in the pathophysiology of schizophrenia, and a growing interest in antioxidant agents is emerging for targeting negative symptoms of schizophrenia. N-Acetylcysteine (NAC) is a potent antioxidant with neuroprotective properties. This study aimed to evaluate the possible effects of NAC as an adjunct to risperidone in treating negative symptoms of schizophrenia. Materials and Methods: In this randomized, double-blind, placebocontrolled, parallel-group study, 42 patients with chronic schizophrenia and a score of 20 or greater on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. The participants were equally randomized to receive NAC (up to 2 g/d) or placebo, in addition to risperidone (up to 6 mg/d) for 8 weeks. The participants were rated using PANSS every 2 weeks, and the decrease of PANSS negative subscale score was considered as our primary outcome. Results: By the study end point, NAC-treated patients showed significantly greater improvement in the PANSS total (P = 0.006) and negative subscale (P < 0.001) scores than that in the placebo group, but this difference was not significant for positive and general psychopathology subscales. There was no significant difference between the 2 groups in the frequency of adverse effects. Conclusions: NAC add-on therapy showed to be a safe and effective augmentative strategy for alleviating negative symptoms of schizophrenia.

We aimed to evaluate the efficacy of memantine add-on in the treatment of primary negative symptoms of patients with stable schizophrenia. In a double-blind placebo-controlled clinical trial, 40 patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who were stabilized on risperidone for a minimum of 8 weeks were randomized to either memantine (20 mg) or placebo in addition to risperidone, 6 mg/d, for eight weeks. Assessment was done using the Positive and Negative Syndrome Scale at baseline, week 4, and week 8. The Hamilton Depression Rating Scale and the Extrapyramidal Symptom Rating Scale at baseline and week 8 were used to assess depression and extrapyramidal symptoms, respectively. All 40 patients had at least one postbaseline measurement, and 38 patients completed the trial. Patients in the memantine group showed a significantly greater improvement on negative subscale than the placebo group at end point (P < 0.001). The same effect was observed for the total score (P < 0.001) and the general psychopathology subscale score (P = 0.002). There was no significant difference in reduction of positive symptoms score between the 2 groups (P = 0.757). Changes in the Hamilton Depression Rating Scale and the Extrapyramidal Symptom Rating Scale scores and frequency of adverse effects did not differ between the 2 groups. Our study showed that memantine is a tolerable and efficacious add-on treatment for primary negative symptoms of schizophrenia.

A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be of benefit in the treatment of negative symptoms in schizophrenia. 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. 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. Tropisetron resulted in greater improvement of the total PANSS scores [F(1.860,70.699) = 37.366, p

Objective To evaluate the efficacy and safety of cilostazol, a selective inhibitor of phosphodiesterase III, as an adjunctive to risperidone in alleviating the negative symptoms of schizophrenia. Methods Eighty-four in-patients with diagnosis of chronic schizophrenia participated in a randomized, placebo-controlled trial and underwent 8 weeks of treatment with either cilostazol (50 mg twice a day) or placebo as an adjuvant to risperidone. Participants were assessed using the positive and negative syndrome scale (PANSS) at baseline and at weeks 2, 4, 6, and 8. The primary outcome measure of the trial was to evaluate the efficacy of cilostazol compared to placebo in improving the PANSS negative subscale score. Result General linear model repeated measures demonstrated significant effect for time × treatment interaction on negative subscale scores (p

Objectives To investigate the effect of adding remifentanil to propofol used in the induction of anesthesia in efficacy, and to investigate the cognitive adverse effects of electroconvulsive therapy (ECT) in the treatment of patients with severe mania. Methods Thirty-eight patients' condition was diagnosed as manic episode by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and were prescribed ECT by their physicians were included in a double-blind study and were randomly allocated to receive premedication with either remifentanil-atropine (study) or saline-atropine (control). Induction of anesthesia was done with propofol (1 mg/kg) and succinylcholine (0.5 mg/kg) in all patients. Assessments included seizure duration, Young Mania Rating Scale (YMRS), Mini-Mental State Examination (MMSE), and immediate cognitive adverse effects. Results Twenty-nine patients with 98 ECT sessions completed treatment. There were no differences between the 2 groups in relation to age, sex, duration of disease, weight, marital status, seizure duration, YMRS, and MMSE. However, immediate cognitive adverse effects were significantly lower in remifentanil group.

Ginkgo biloba has been reported to affect the neurotransmitter system and to have antioxidant properties that could impact the pathogenesis of Autism Spectrum Disorder. Based on these studies, we decided to assess the effectiveness of Ginkgo biloba extract (Ginko T.D., Tolidaru, Iran) as an adjunctive agent to risperidone in the treatment of autism. Forty-seven outpatients with a DSM-IV-TR diagnosis of autism ages between 4 and 12 years were assigned to this double blinded clinical trial and were randomly divided into two groups. One group received risperidone plus Ginko T.D and the other received risperidone plus placebo. The dose of risperidone was 1-3 mg/day and the dose of Ginko T.D. was 80 mg/day for patients under 30 kg and 120 mg/day for patients above 30 kg. Patients were assessed using Aberrant Behavior Checklist-Community (ABC-C) rating scale and the side effect check list every 2 weeks until the endpoint. None of the 5 subscales of ABC-C rating scale showed significant differences between the two groups. Incidents of side effects were not significantly different between the two groups. Adding Ginkgo biloba to risperidone did not affect the treatment outcome of ADs. Nevertheless, further observations are needed to confirm this result.

It has been reported that mirtazapine would be helpful for treating negative symptoms in schizophrenia. Nevertheless, the results are contradictory so far. This study was designed to investigate the effect of mirtazapine added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial. Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 19 to 49 years. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion 20 to risperidone 6 mg/day plus mirtazapine 30 mg/day and 20 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). The mirtazapine group had significantly greater improvement in the negative symptoms and PANSS total scores over the eight-week trial. Therapy with 30 mg/day of mirtazapine was well tolerated and no clinically important side effects were observed. The present study indicates mirtazapine as a potential combination treatment strategy for chronic schizophrenia particularly for negative symptoms.

To date, no medication has been approved as an effective treatment for methamphetamine dependence. Topiramate has attracted considerable attention as a treatment for the dependence on alcohol and stimulants. Therefore, this study aimed to evaluate the effect of topiramate for methamphetamine dependence. This study was a double-blind, randomized, placebo-controlled trial. In the present investigation, 62 methamphetamine-dependent adults were enrolled and randomized into two groups, and received topiramate or a placebo for 10 weeks in escalating doses from 50 mg/day to the target maintenance dose of 200 mg/day. Addiction severity index (ASI) and craving scores were registered every week. The Beck questionnaire was also given to each participant at baseline and every 2 weeks during the treatment. Urine samples were collected at baseline and every 2 weeks during the treatment. Fifty-seven patients completed 10 weeks of the trial. There was no significant difference between both groups in the mean percentage of prescribed capsules taken by the participants. At week six, the topiramate group showed a significantly lower proportion of methamphetamine-positive urine tests in comparison with the placebo group (P = 0.01). In addition, there were significantly lower scores in the topiramate group in comparison with the placebo group in two domains of ASI: drug use severity (P < 0.001) and drug need (P < 0.001). Furthermore, the craving score (duration) significantly declined in the topiramate patients compared to those receiving the placebo. In conclusion, the results of this trial suggest that topiramate may be beneficial for the treatment of methamphetamine dependence.

Background The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of sustained-release methylphenidate (MPH-SR) in treatment of methamphetamine dependence. Methods Fifty-six individuals who met DSM-IV-TR criteria for methamphetamine dependence participated in this 10-week trial. The participants were randomly allocated into two groups and received 18 to 54 mg/day sustained-released methylphenidate or placebo for 10 weeks. Craving was evaluated by a visual analogue craving scale every week. Urinary screening test for methamphetamine was carried out each week. The Beck Depression Inventory-II (BDI-II) was used to monitor participant depressive symptoms at baseline and bi-weekly during the treatment period. Results At the end of the trial, the MPH-SR group was less methamphetamine positive compared to the placebo group and the difference was significant (p = 0.03). By the end of the study, MPH-SR group showed significantly less craving scores compared to the placebo group [MD (95% CI) = -10.28(0.88-19.18), t(54) = 2.19, p = 0.03]. There was greater improvement in the depressive symptoms scores in the intervention group compared to the placebo group [MD (95% CI) =2.03(0.31-3.75), t (54) =2.37, p = 0.02]. Conclusion Sustained-released methylphenidate was safe and well tolerated among active methamphetamine users and significantly reduced methamphetamine use, craving and depressive symptoms. Trial registration IRCT201202281556N38

Background Dysregulation of glutamate is implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Consistently, glutamate-modulating agents, such as riluzole and memantine have been used in OCD treatment. Previous research has identified some neuroprotective role for L-carnosine potentially via its modulatory effect on glutamate. Here, we assessed the efficacy of L-carnosine as adjuvant to fluvoxamine in OCD treatment. Methods Forty-four patients diagnosed with moderate to severe OCD were recruited in a randomized double-blind trial. Patients received either L-carnosine or placebo as adjuvant to fluvoxamine for 10 weeks. The Yale- Brown Obsessive Compulsive Scale (Y-BOCS) was used for assessing the severity of symptoms at baseline and at weeks 4, 8, and 10. Results General linear model repeated measure showed significant effects for Time × Treatment interaction on total Y-BOCS [F (2.10, 88.42) = 8.66, p

Increasing evidence suggest that the nitric oxide signaling system of the brain may contribute to the pathophysiology of schizophrenia, making this system a target for development of novel therapeutics. The objective of this study was to investigate the efficacy and safety of L-lysine as an adjunctive to risperidone in the treatment of patients with chronic schizophrenia during an 8-week trial. Seventy-two chronic schizophrenia inpatients with a Positive and Negative Syndrome Scale (PANSS) total score of ≥ 60 participated in a randomized, double-blind, placebo-controlled trial in the active phase of their disease and underwent 8 weeks of treatment with either L-lysine (6 g/day) or placebo as an adjunctive to risperidone. Patients were evaluated using PANSS and its subscales at baseline and weeks 2, 4, 6 and 8. The primary outcome measure was to evaluate the efficacy of L-lysine in improving schizophrenia symptoms. Repeated measures analysis demonstrated significant effect for time × treatment interaction on the PANSS total (P0.001), negative (P0.001) and general psychopathology (P0.001) subscale scores but not the PANSS positive subscale scores (P = 0.61). The frequency of adverse events (AEs) did not differ significantly between the two treatment groups and no serious AE was observed. The present study demonstrated that l-lysine can be a tolerable and efficacious adjunctive therapy for improving negative and general psychopathology symptoms in chronic schizophrenia. However, the safety and efficacy of higher doses of l-lysine and longer treatment periods still remain unknown.Iranian registry of clinical trials (www.irct.ir): IRCT201202201556N33.

Impairment of oxytocinergic function and/or oxytocin receptor genetic abnormalities has been demonstrated in patients with schizophrenia. Oxytocin reverses emotional recognition deficit and might restore sense of trust in patients with schizophrenia. Some short-term studies have shown efficacy and tolerability of oxytocin in patients with schizophrenia. However, there is a lack of evidence on the efficacy and tolerability of oxytocin in patients with schizophrenia beyond 3 weeks.The objective of this study was to assess the efficacy and tolerability of oxytocin intranasal spray (given as an adjuvant to risperidone) in patients with schizophrenia.This was an 8-week, randomized, double-blind, placebo-controlled study.Inpatients of two large referral psychiatric hospitals in Iran were recruited for the study.Forty patients (male and female gender) aged 18-50 years with a diagnosis of schizophrenia (DSM-IV-TR) who were on a stable dose of risperidone for a minimum of 1 month and who were chronically partially responsive to antipsychotic monotherapy were included in the study.The patients were randomly assigned to oxytocin intranasal spray (Syntocinon(®); Novartis, Basel, Switzerland) or placebo intranasal spray containing normal saline (ACER, Tehran, Iran) for 8 weeks. Oxytocin spray was administered as 20 IU (five sprays) twice a day for the first week followed by 40 IU (ten sprays) twice a day for the following 7 weeks. Placebo spray was administered at the same dose as the oxytocin spray. In addition, participants were on a stable dose of risperidone (5 or 6 mg/day).The patients were assessed using Positive and Negative Syndrome Scale (PANSS) at baseline and at weeks 0, 2, 4, 6 and 8. Primary outcomes were the differences in the PANSS scores between the two groups at the end of the trial. Adverse effects were recorded using a checklist and the Extrapyramidal Symptom Rating Scale (ESRS) at baseline and at weeks 1, 2, 4, 6 and 8.All patients had at least one post-baseline measurement and 37 patients (19 in the oxytocin and 18 in the placebo group) completed the study. Repeated measure analysis of variance showed significant effect for time X treatment interaction on the PANSS total [F(2.291,87.065) = 22.124, p0.001], positive [F(1.285,48.825) = 11.655, p = 0.001], negative [F(2.754,104.649) = 11.818, p0.001] and general psychopathology [F(1.627,61.839) = 4.022, p = 0.03] subscale scores. By week 8, patients in the oxytocin group showed significantly greater improvement on the positive (Cohen's d = 1.2, 20 % vs. 4 % reduction in score, p0.001), negative (Cohen's d = 1.4, 7 % vs. 2 % reduction in score, p0.001) and general psychopathology (Cohen's d = 0.8, 8 % vs. 2 % reduction in score, p = 0.021) subscales and total (Cohen's d = 1.9, 11 % vs. 2 % reduction in score, p0.001) PANSS scores than the placebo group. Adverse effects including the sodium concentration change were similar between the two groups.Oxytocin as an adjunct to risperidone tolerably and efficaciously improves positive symptoms of schizophrenia. In addition, effects on negative and total psychopathology scores were statistically significant, but likely to be clinically insignificant. The interesting findings from the present pilot study need further replication in a larger population of patients.

The objective of this study was to assess the efficacy and tolerability of minocycline add-on to risperidone in treatment of negative symptoms of patients with chronic schizophrenia. In a randomized double-blind placebo-controlled study, 40 patients with chronic schizophrenia who were stabilized on risperidone for a minimum duration of eight weeks were recruited. The patients were randomly assigned to minocycline (titrated up to 200 mg/day) or placebo in addition to risperidone (maximum dose of 6 mg/day) for eight weeks. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, and Extrapyramidal Syndrome Rating Scale were used. Thirty-eight patients completed the study. Significant time × treatment interaction for negative [F(2.254,85.638)=59.046, P0.001] general psychopathology [F(1.703,64.700)=6.819, P=0.001], and positive subscales [F(1.655,62.878)=5.193, P=0.012] as well as total PANSS scores [F(1.677,63.720)=28.420, P0.001] were observed. The strongest predictors for change in negative symptoms were the treatment group (β=-0.94, t=-10.59, P0.001) followed by the change in PANSS positive subscale (β=-0.185, t=-2.075, P=0.045). Side effect profiles of the two treatment regimens were not significantly different. Minocycline seems to be an efficacious and tolerable short-term add-on to risperidone for treatment of negative and general psychopathology symptoms of schizophrenia.

Some 5-HT3 antagonists such as ondansetron have shown beneficial effects on negative symptoms of patients with schizophrenia. We aimed to evaluate the efficacy of granisetron (another 5-HT3 antagonist) add-on therapy in the treatment of negative symptoms of patients with stable schizophrenia. In a randomized, double-blind, and placebo-controlled study, forty stable patients with schizophrenia (DSM-IV-TR), were randomized to either granisetron (1 mg twice daily) or placebo (twice daily) in addition to risperidone up to 6 mg/day for eight weeks. The patients were assessed using positive and negative syndrome scale (PANSS) and extrapyramidal symptom rating scale (ESRS) at baseline, week 4 and 8. Hamilton depression rating scale (HDRS) was used to assess depression at baseline and week 8. Thirty-eight patients completed the trial. Granisetron group showed a significantly greater improvement on negative subscale than the placebo group at endpoint [t(38) = 6.046, mean difference (±95% CI) = 3.2(1.8-3.7), P 0.001]. The same effect was observed for total score [t(38) = 4.168, mean difference (95% CI) = 3.2(1.6-4.7), P 0.001]. However the placebo and granisetron groups did not differ in their reduction of positive and general psychopathology symptoms scores. HDRS scores and its changes did not differ between the two groups. The ESRS score at week 4 was significantly lower in the granisetron than the placebo group while the two groups showed similar ESRS score at week 8. Frequency of other side effects was similar between the two groups. In summary, granisetron add-on can safely and effectively reduce the primary negative symptoms of patients with schizophrenia.

In recent years, evidence suggests that modafinil may be useful for certain symptom domains of schizophrenia, especially for the negative and cognitive symptoms. However, the results are not consistent. This study was designed to investigate the effect of modafinil added to risperidone in patients with chronic schizophrenia in a double blind and randomized clinical trial. Participants were inpatients males (35) and females (11), ages 20–49 years at two teaching psychiatric hospital in Iran. All patients were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion 23 patients to risperidone 6 mg/day plus modafinil 200 mg/day and 23 patients to risperidone 6 mg/day plus placebo. The principal measure of outcome was the positive and negative syndrome scale (PANSS). Patients were assessed by a psychiatrist at baseline and after 2, 4, 6 and 8 weeks after the start of medication. The modafinil group had significantly greater improvement in the negative symptoms as well as PANSS total scores over the 8-week trial. Therapy with 200 mg/day of modafinil was well tolerated and no clinically important side effects were observed. The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. Nevertheless, results of larger-controlled trials are needed before recommendation for broad clinical application can be made. This trial is registered with the Iranian Clinical Trials Registry (IRCT138903131556N16).

Objective It has been proposed that a deficit of adenosinergic activity could contribute to the pathophysiology of schizophrenia. The authors undertook this study to further evaluate the level of adenosine deaminase (ADA) in patients with chronic schizophrenia treated with monotherapy of haloperidol, risperidone or clozapine and correlation between the ADA level with response to treatment. Methods The trial was a prospective, 8-week, double blind study of parallel groups of patients with chronic schizophrenia. Eligible participants in the study were 51 patients with chronic schizophrenia with ages ranging from 20 to 45 years. All participants were inpatients, in the active phase of illness, and met DSM-IV-TR criteria for schizophrenia. Patients were randomly allocated (17 patients in each group) to risperidone (6 mg/day) or haloperidol 15 mg/day or clozapine (300 mg/day). Serum ADA activity was measured at baseline and week 8. Results The plasma levels of ADA in patients with chronic schizophrenia who received clozapine were significantly higher than patients who received haloperidol. In addition, response to treatment was positively correlated with plasma levels of ADA only in the clozapine group (r = 0.46 and p = 0.04). Conclusion The results indicate an increased activity of the enzyme ADA in the serum of schizophrenic patients being treated with clozapine and this increase may be correlated with clozapine's superior antipsychotic efficacy. Copyright © 2011 John Wiley & Sons, Ltd.

It has been suggested that phosphodiesterase 5 inhibitors such as sildenafil may be effective in the treatment of negative symptoms of schizophrenia.This study was designed to investigate the effect of sildenafil added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial.Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 18 to 45 years. All patients were inpatients and were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion: 20 to risperidone (6 mg/day) plus sildenafil (75 mg/day) and 20 to risperidone (6 mg/day) plus placebo. The principal measure of outcome was Positive and Negative Syndrome Scale (PANSS).Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and sildenafil showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores over the 8-week trial (between-subjects factor; F = 4.77, df = 1; P = 0.03; F = 5.91, df = 1, P = 0.02 respectively).Therapy with 75 mg/day of sildenafil was well tolerated, and no clinically important side effects were observed. The present study indicates sildenafil as a potential adjunctive treatment strategy for treatment of negative symptoms of schizophrenia. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N11).

Background Considerable amount of biochemical data supports the potential involvement of protein kinase C in the pathophysiology and treatment of bipolar disorder. The aim of this double-blind, placebo-controlled study was to investigate the efficacy and tolerability of tamoxifen as an adjunct to lithium for the treatment of acute mania in hospitalized bipolar patients. Methods Eligible participants were 40 inpatients, between the ages of 19 and 49 years with current manic episode. Patients were randomly allocated to lithium (1–1.2 mEq/L) + tamoxifen 80 mg/day (group A) or lithium (1–1.2 mEq/L) + placebo (group B) for a 6-week, double-blind, placebo-controlled study. The principal measure of outcome was the Young Mania Rating Scale. The raters used standardized instructions for Young Mania Rating Scale. Results Young Mania Rating Scale scores improved with tamoxifen. The difference between the two protocols was significant as indicated by the effect of the group, the between-subjects factor (F = 5.41, df = 1, p = 0.02). A significant difference was observed on the Positive and Negative Syndrome Scale total score at week 6 in the two groups. The difference between the two groups in the frequency of side effects was not significant except for fatigue that occurred more often in the tamoxifen group. Limitations Tamoxifen is an antagonist of estrogen receptor as well. Conclusion The results demonstrate that the combination of tamoxifen with lithium was superior to lithium alone for the rapid reduction of manic symptoms. The combined use of tamoxifen with lithium was well tolerated in these acutely manic patients.

The aim of this study was to evaluate the relationship between plasma levels of testosterone, FSH, LH and prolactin and the severity of negative symptoms in patients with chronic schizophrenia. Fifty-four male inpatients with chronic schizophrenia participated in this cross-sectional study. Twenty-five age-matched men without a history of psychiatric disorders or endocrine illnesses were used as controls. All patients were on risperidone 4 mg/day or haloperidol 10 mg/day and anticholinegic medication, biperidine 3 mg/day. The patients were assigned to groups with predominant negative and nonpredominant negative symptoms on the basis of their scores on the Positive and Negative Syndrome Scale (PANSS). Plasma levels of testosterone and free testosterone in the patients with predominant and nonpredominant negative symptoms were significantly lower than those in normal controls. Furthermore, plasma levels of FSH and LH, in the patients with predominant negative symptoms but not in the nonpredominant negative symptoms, were significantly lower than those in the normal controls. In contrast, plasma level of prolactin in the predominant negative symptoms group but not in the nonpredominant negative symptoms group was significantly higher than the aged matched normal males. Significant inverse correlation between negative subscale scores of PANSS and plasma levels of testosterone and free testosterone in the patients with predominant negative symptoms were detected. There was also a positive correlation between prolactin plasma levels and negative subscale scores. The present study indicates that assessment of sex hormones and function of hypothalamic-pituitary-gonadotropin axis could be an important biological marker for the severity of negative symptoms in schizophrenia and these findings may change the present pharmacotherapy for negative symptoms based on neuroendocrinology profiles of patients with schizophrenia.