Effectiveness and Safety of Haloperidol Add-on Methadone in Acute Opium Withdrawal Symptoms of Opioid-dependent Patients: A Double-blind Randomized Placebo-controlled Clinical Trial.

BACKGROUND: The aim of this double-blind clinical trial was to evaluate the efficacy and safety of haloperidol on acute opioid withdrawal symptoms. METHODS: In this randomized double-blind clinical trial, fifty-two eligible patients were assigned to two groups according to previous opioid consumption, low dose (LD) and high dose (HD). Then, patients in each group were randomly assigned to one of the two subgroups of haloperidol or placebo. Patients in the haloperidol subgroup in LD group received 2.5 mg and in HD group received 5 mg/day haloperidol with methadone. Methadone was discontinued ten days after the beginning of the study and haloperidol or placebo continued for up to two weeks after methadone discontinuation. The severity of opioid withdrawal symptoms was assessed with the Objective Opioid Withdrawal Scale (OOWS) every other day. FINDINGS: Although both treatment protocols either in LD or HD opioid consumption groups significantly increased the score of the OOWS over the trial period (all subgroups, P < 0.001), the combination of 2.5 mg/day of haloperidol and methadone in LD opioid consumption group showed a significant superiority over methadone alone in decreasing opium withdrawal symptoms during the study (P = 0.001). The frequency of adverse effects was comparable between two treatment protocols in both groups (P > 0.050). CONCLUSION: The results of this study suggest that 2.5 mg/day of haloperidol may be an effective adjuvant agent in the management of opium withdrawal symptoms in patients with LD opioid consumption. Nevertheless, results of larger controlled trials are needed before recommendation for a broad clinical application can be made.

Efficacy and Safety of Adding Olanzapine to the Standard Preventive Regimen for Chemotherapy-induced Nausea and Vomiting in Children: A Randomized Double-blind Controlled Trial.

This study aimed to assess the additive value of olanzapine to a combination of ondansetron and dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. A total of 40 patients between 4 to 18 years of age were enrolled in this randomized clinical trial. Both groups received a combination of ondansetron and dexamethasone, and 0.14 mg/kg olanzapine or matched placebo were administered for olanzapine and control groups, respectively. The primary end points were complete response and lack of nausea as far as three days after chemotherapy evaluated by the Common Terminology Criteria for Adverse Effects (CTCAE) v5.0 and the Multinational Association of Supportive Care in Cancer (MASCC) Anti-emesis Tool (MAT). Side effects of olanzapine were also analyzed. In patients receiving the standard regimen of ondansetron and dexamethasone, nausea was observed in 10.5% and 21% of patients according to MAT and CTCAE scales, respectively. In the olanzapine group, 37.5% (MAT scale) and 31.3% (CTCAE scale) of patients developed nausea. Complete response was observed in 84% (MAT scale) and 94.7% (CTCAE scale) of patients in the placebo group receiving ondansetron and dexamethasone. In comparison, it was observed in 87.5% (MAT scale) and 81.25% (CTCAE scale) for patients allocated to the olanzapine group. Neither acute nor delayed CINV was statistically different between placebo and olanzapine groups. The frequency of adverse effects was higher in the olanzapine group. Adding olanzapine to the standard regimen of CINV prophylaxis was only unhelpful in pediatric patients receiving moderately emetogenic chemotherapy but also associated with a higher rate of minor side effects.

Nanocurcumin as an Add-on to Antipsychotic Drugs for Treatment of Negative Symptoms in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE/BACKGROUND: It is well documented that one of the pathophysiological mechanisms of negative symptoms in patients with schizophrenia is hypofunction of N-methyl-d-aspartate receptors. This double-blind, placebo-controlled clinical trial was designed to assess the efficacy and safety of nanocurcumin as an adjuvant agent on psychotic symptoms, especially negative symptoms, in patients with chronic schizophrenia. METHODS/PROCEDURES: Fifty-six inpatients with stable chronic schizophrenia and predominant negative symptoms were randomized in a 1:1 ratio to nanocurcumin soft gel capsule (160 mg/d) and control groups, along with their antipsychotic regimen for 16 weeks. The efficacy of treatment was assessed by Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Clinical Global Impressions-Severity, and Clinical Global Impressions-Improvement scales. Extrapyramidal symptoms were evaluated by Simpson-Angus Scale and Barnes Akathisia Rating Scale. Patients were assessed at baseline and weeks 4, 8, 12, and 16 after the medication started. FINDINGS/RESULTS: No significant differences were observed in demographic or clinical variables between both groups at baseline. The nanocurcumin group showed significantly greater improvement on the negative subscale (P = 0.05), the general psychopathology subscale (P < 0.001), the positive subscale (P = 0.004), total Positive and Negative Syndrome Scale (P < 0.001), Clinical Global Impressions-Severity (P < 0.001), and Clinical Global Impressions-Improvement scores (P < 0.001) in comparison with the control group at the endpoint. Extrapyramidal symptom rating scales and Calgary Depression Scale for Schizophrenia and frequency of other adverse effects were comparable between 2 groups. IMPLICATIONS/CONCLUSIONS: The present study indicates nanocurcumin as a safe and potential adjunctive treatment strategy for treatment of primary negative symptoms of schizophrenia.

Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.

BACKGROUND AND OBJECTIVES: Cancer-related fatigue (CRF) is one of the most prevalent complications experienced by cancer patients during and after the process of treatment. Despite conducting a lot of studies, there is no approved therapy to help manage CRF. This study aims to investigate the efficacy of bupropion on CRF. MATERIALS AND METHODS: In this double-blind randomized placebo-controlled clinical trial, a total of 30 eligible cancer patients suffering from fatigue were randomly divided into two groups (15 patients in each group). Bupropion was administered 75 mg/day for the first three days and 150 mg/day (divided in two doses) till the end of the study at week 6. Fatigue as the primary outcome was measured by BFI (Brief Fatigue Inventory) and FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy) scales. Secondary outcomes included HADS (Hospital Anxiety and Depression Scale) and performance status (PS) measured by Karnofsky and ECOG (Eastern Cooperative Oncology Group) scales. Assessments were done at baseline, end of the second and sixth week. RESULTS: There was no significant difference between placebo and bupropion at baseline and the end of second week. Significant difference was seen between two groups at the end of week six (P = 0.006 based on BFI) in favor of bupropion. In-group assessment showed improvement in fatigue levels in both groups during study time (P = 0.000 based on BFI for both bupropion and placebo). Secondary outcomes (e.g., HADS and PS) were not different at baseline and the end of second week. However, at the end of week six, the difference was significant in favor of bupropion. CONCLUSION: A six-week trial of bupropion reduces the CRF and improves the PS of cancer patients. TRIAL REGISTRATION: Current Controlled Trials IRCT20090613002027N12, registration date: 2018-06-01.

Comparison of the Efficacy and Safety of Pregabalin and Duloxetine in Taxane-Induced Sensory Neuropathy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVE: Taxane-induced peripheral neuropathy (TIPN) is a main toxicity of taxanes with no effective treatment. This study aimed to compare the efficacy and safety of pregabalin (150 mg daily) and duloxetine (60 mg daily) for managing TIPN in breast cancer patients. METHODS: This randomized, double-blind, Phase II clinical trial was carried out at a chemotherapy center affiliated to Mazandaran University of Medical Sciences. Patients with breast cancer who received paclitaxel or docetaxel and had a grade 1 or more neuropathy (based on the National Cancer Institute Common Terminology Criteria for Adverse Events version (NCI-CTCAE v4.03), and who had score 4 or higher neuropathic pain severity [based on the visual analog scale (VAS)] were enrolled. Response to treatment was assessed based on improvements in the VAS, NCI-CTCAE, and Patient Neurotoxicity Questionnaire (PNQ) scores during a 6-week trial. RESULTS: Both interventions were effective in decreasing TIPN compared to baseline. At Week 6, the VAS scores were improved in 37/40 (92.5%) and 16/42 (38.1%) of the patients in the pregabalin and duloxetine groups, respectively (p < 0.001). Improvement in NCI-CTCAE sensory neuropathy was also more significant with pregabalin (37/40; 92.5%) in comparison to duloxetine (13/42; 31%) (p < 0.001). Pregabalin was also more beneficial than duloxetine in improving the PNQ scores by 36/40 (90%) and 13/42 (31%), respectively (p < 0.001). Both interventions were tolerated well with mild adverse events. CONCLUSIONS: Both pregabalin and duloxetine were well tolerated and efficacious in relieving neuropathic pain, however a 60 mg dose of duloxetine is inferior to a 150 mg dose of pregabalin.

Adjunctive Memantine Treatment of Schizophrenia: A Double-Blind, Randomized Placebo-Controlled Study.

PURPOSE/BACKGROUND: This double-blind, placebo-controlled clinical trial was designed to assess the efficacy and safety of memantine augmentation to standard regimen of antipsychotic treatment on psychotic symptoms and cognitive function in individuals with chronic schizophrenia for 8 weeks. METHODS/PROCEDURES: Forty stabilized individuals with chronic schizophrenia were randomized in a 1:1 ratio to memantine (20 mg/d) and control (placebo) groups, along with their antipsychotic regimen for 8 weeks. The efficacy of treatment was assessed by the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition Scale, and the safety was measured by the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale at baseline and at weeks 4 and 8. FINDINGS/RESULTS: No significant differences were observed in demographic or clinical variables between both groups at baseline. During the study, all subscales and total scores of PANSS decreased significantly within both groups, except the subscale score in memantine, which was found to be positive. Reduction in general subscale and total scores of PANSS was significantly higher in the control group compared with the memantine group. All subscale scores of the Brief Assessment of Cognition Scale increased significantly only in the memantine group. The increase in the Verbal Memory, Working Memory, Verbal Fluency Letter, and Verbal Fluency Total subscale scores was significantly higher in the memantine group than in the control group. There was no significant difference in the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale scores between the 2 groups during the study. IMPLICATIONS/CONCLUSIONS: This study showed that adjunctive memantine to antipsychotic regimen improved the verbal memory, learning, verbal letter fluency, and working memory without improvement on psychotic symptoms in individuals with chronic schizophrenia.

Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment.

Anti-psychotic medications are widely used to treat schizophrenia and bipolar disorder. Besides their medical applications, anti-psychotic drugs have other pharmacological properties which are involved in multiple intracellular functions including metabolism, cell stress, cell-cycle regulation, survival and apoptosis through modulation of cellular signaling pathways such as PI3K/Akt/GSK-3ß, STAT3 and wingless (Wnt)-related intracellular signaling. Also, anti-psychotics counteract the growth of tumor cells by stimulating the cellular immune system and natural killer cells. On the other hand, the positive charge and the lipophilicity of anti-psychotics have significant roles in the inhibition of P-gp pumps resulting in accumulation of chemotherapy drugs as well as increasing the cellular susceptibility to chemotherapy, autophagy, angiogenesis inhibition, stem cells differentiation induction and changing the expression of tumor suppressor genes and oncogenes. Overall, anti-psychotics are able to inhibit the proliferation of cancer cells through modulation of different cellular pathways. Anti-psychotics act as anti-cancer drugs and besides can increase the efficacy of anti-cancer agents in cancer cells. In this study, the anti-cancer effects of different anti-psychotic medicines on various malignant tumor cells and their molecular mechanisms have been discussed.

The effect of pregabalin and duloxetine treatment on quality of life of breast cancer patients with taxane-induced sensory neuropathy: A randomized clinical trial.

BACKGROUND: The primary side effect of adjuvant chemotherapy with taxanes is the taxane-induced peripheral neuropathy (TIPN), which may have substantial negative impacts on patients' quality of life (QOL). We investigated the effect of pregabalin and duloxetine on QOL of breast cancer patients who experienced TIPN. MATERIALS AND METHODS: This was a randomized, double-blind clinical trial conducted at a chemotherapy center of Mazandaran University of Medical Sciences, Sari, Iran. Breast cancer patients 18 or more years old were included if they received paclitaxel or docetaxel and experienced neuropathy grade one or higher; and neuropathic pain score of four or more. Patients were treated with pregabalin or duloxetine until 6 weeks. Assessment of sensory neuropathy and QOL was performed at baseline, and 6 weeks after the initiation of the treatment. RESULTS: At baseline, the mean score of global health status/QOL scale for pregabalin and duloxetine groups were 61 (standard deviation [SD]; 5.11) and 60.28 (SD; 5.44), respectively (P = 0.54). After 6 weeks, both interventions were associated with improvement of global QOL compared to baseline. The global health status/QOL score was not different between two groups after 6 weeks. While the emotional functioning was improved more favorably with duloxetine (P < 0.001); pregabalin was associated with more improvement in insomnia and pain scores (P = 0.05 and P < 0.001, respectively). CONCLUSION: Pregabalin as well as duloxetine improve the global QOL of breast cancer patients with TIPN. Different effects of treatments on subscale of QLQ-C30 could help clinicians to select the appropriate agent individually.

Alterations in oxidative stress markers and its correlation with clinical findings in schizophrenic patients consuming perphenazine, clozapine and risperidone.

BACKGROUND AND OBJECTIVE: Today, the role of oxidative stress in development of schizophrenia has gained attention. Also, some atypical antipsychotic agents showed antioxidant properties. Therefore, in this study, we evaluated the level of oxidative stress parameters between patients treated with perphenazine, clozapine and risperidone and their relationship with schizophrenia symptoms' severity. MATERIALS AND METHODS: This was a descriptive study on 100 patients with chronic schizophrenia. Patient selection was done based on the DSM-IV-TR criteria for at least 3 months regular use of clozapine or risperidone or perphenazine and a minimum period of 2 years of schizophrenia. Ten ml of patient's blood samples were used to assess serum levels of glutathione (GSH), protein carbonyl, lipid peroxidation (LPO), superoxide dismutase (SOD) and Ferric Reducing Ability of Plasma (FRAP). Also, the severity of symptoms was assessed with the positive and negative syndrome scale (PANSS scale). P-values of less than 0.05 were considered significant. RESULTS: The results showed a significant difference between clozapine and risperidone with perphenazine in all subscales of PANSS. Also, there was a positive correlation between MDA and PANSS all subscales in risperidone and perphenazine groups and a negative correlation between MDA and PANSS in all subscales in the clozapine group. Serum level of GSH and negative symptoms in patients receiving clozapine showed a negative correlation. The results also represented that clozapine significantly increased SOD levels in comparison to perphenazine and risperidone and reduced LPO in comparison to perphenazine and risperidone, While the protein carbonyl level did not show a significant difference between three groups (p-value = 0.8). CONCLUSION: This study showed that clozapine, as an atypical antipsychotic agent, has significant antioxidant effects compared to risperidone and perphenazine. Especially, it increased SOD and GSH levels and reduced LPO in patients with schizophrenia. Therefore, clozapine's antioxidant effect may be contributive to improving negative symptoms of schizophrenic patients.

Negative Correlation between Serum S100B and Leptin Levels in Schizophrenic Patients During Treatment with Clozapine and Risperidone: Preliminary Evidence.

Recently, extensive efforts have been made to understand the rate of energy expenditure and the weight gain associated with atypical antipsychotic treatment, including identification of markers of obesity risk. In recent years, leptin, an adipocyte hormone, has gained significant interest in psychiatric disorders. S100B has been considered as a surrogate marker for astrocyte-specific damage in neurologic disorders. Also, S100B has been detected in adipose with concentration as high as nervous tissue as a second release source. In this study we evaluated the relationship between S100B and leptin in schizophrenic patients under treatment with clozapine and risperidone.This study included 19 patients meeting the DSM-IV-TR criteria for schizophrenia, having body mass index (BMI) of 16- 25 kg/m(2) and suffering schizophrenia for more than 3 years and from this study. Twenty five healthy controls were group matched for age and gender whose BMI was 16-25 kg/m(2). Serum S100B and leptin levels and positive and negative symptom scale (PANSS) were assessed at admission and after six weeks. During the study, S100B showed a strong and negative correlation with leptin (r = -0.5, P = 0.01). Also, there were negative correlation between serum S100B level and PANSS negative subscale after 6 weeks of treatment (r = -0.048, P = 0.8). Positive correlation between leptin level and PANSS suggested a potential role for leptin which can mediate the link between antipsychotic induced weight gain and therapeutic response in schizophrenia.

Effectiveness of Vitamin D Supplement Therapy in Chronic Stable Schizophrenic Male Patients: A Randomized Controlled Trial.

In this study, the aim was to determine whether adding vitamin D to the standard therapeutic regimen of schizophrenic male patients with inadequate vitamin D status could improve some aspects of the symptom burden or not. This study was an open parallel label randomized clinical trial. Eighty patients with chronic stable schizophrenia with residual symptoms and Vitamin D deficiency were recruited randomly and then received either 600000 IU Vitamin D injection once along with their antipsychotic regimen or with their antipsychotic regimen only. Serum vitamin D was measured twice: first at the baseline and again on the fourth month. Positive and Negative Syndrome Scale (PANSS) was assessed at the baseline and on the fourth month. During the study, the vitamin D serum changes in vitamin group and control group were 22.1 ± 19.9(95%CI = 15.9-28.8) and 0.2 ± 1.7(95%CI = 0.2-0.8) (ng/mL) (p<0.001) respectively. The changes of PANSS positive subscale score (P) were -0.1±0.7 (95%CI =-0.3-0.1) and 0.00 ± 0.8 (95%CI = -0.2-0.2) in vitamin D and control group respectively (p=0.5). The changes of PANSS negative subscale score (N) were -0.1 ± 0.7 (95%CI = -0.3-0.05) and -0.1 ± 0.5 (95%CI = -0.2-0.04) in vitamin D and control group respectively (p = 0.7) and there was a negative but not significant correlation between serum vitamin D level changes and PANSS negative subscale score (r = -0.04, p = 0.7). We did not find a relationship between serum vitamin D level changes and the improvement of negative and positive symptoms in schizophrenic patients and more randomized clinical trials are required to confirm our findings.

Hypertonic saline solution reduces the oxidative stress responses in traumatic brain injury patients.

BACKGROUND: Oxidative stress processes play an important role in the pathogenesis of secondary brain injury after traumatic brain injury (TBI). Hypertonic saline (HTS) has advantages as being preferred osmotic agent, but few studies investigated oxidant and antioxidant effects of HTS in TBI. This study was designed to compare two different regimens of HTS 5% with mannitol on TBI-induced oxidative stress. MATERIALS AND METHODS: Thirty-three adult patients with TBI were recruited and have randomly received one of the three protocols: 125 cc of HTS 5% every 6 h as bolus, 500 cc of HTS 5%as infusion for 24 h or 1 g/kg mannitol of 20% as a bolus, repeated with a dose of 0.25-0.5 g/kg every 6 h based on patient's response for 3 days. Serum total antioxidant power (TAP), reactive oxygen species (ROS) and nitric oxide (NO) were measured at baseline and daily for 3 days. RESULTS: Initial serum ROS and NO levels in patients were higher than control(6.86± [3.2] vs. 1.57± [0.5] picoM, P = 0.001, 14.6± [1.6] vs. 7.8± [3.9] mM, P = 0.001, respectively). Levels of ROS have decreased for all patients, but reduction was significantly after HTS infusion and mannitol (3. 08 [±3.1] to 1.07 [±1.6], P = 0.001, 5.6 [±3.4] to 2.5 [±1.8], P = 0.003 respectively). During study, NO levels significantly decreased in HTS infusion but significantly increased in mannitol. TAP Levels had decreased in all patients during study especially in mannitol (P = 0.004). CONCLUSION: Hypertonic saline 5% has significant effects on the oxidant responses compared to mannitol following TBI that makes HTS as a perfect therapeutic intervention for reducing unfavorable outcomes in TBI patients.