Nagesh B Pai

Reducing olanzapine-induced weight gain side-effect by using betahistine: a study in the rat model

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H1 receptor agonist and H3 receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H3 receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H1 receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

The measurement of burden of care in serious mental illness: A qualitative review

Objective: Caring for someone with serious mental illness such as schizophrenia or bipolar disorder can result in considerable consequences for the caregiver. Carers often experience a range of negative emotions, impacts upon their physical and mental health, as well as financial strain. Resultant from these impacts, carers utilise medical services at a higher rate than their non-caregiving counterparts. Further, these consequences of caregiving can also impact upon the patient, resulting in an increase in psychopathology and relapse. Although the notion of burden has been studied for approximately 60 years, many flaws and inadequacies remain; most notably, a lack of agreement on the definition of the construct along with the poor psychometric properties of the burden assessment instruments. Method: This article reviews and evaluates the measures of burden of care that have been utilised with carers of people with a serious mental illness. A systematic search was conducted and all articles that had measured burden of care in schizophrenia or bipolar disorder in the database PUBMED were reviewed to ascertain the measure utilised. Results: Ten different measures were subsequently identified and eight were reviewed; two were excluded on the basis that they had only been utilised once. Conclusions: It was apparent that many of the measures lacked a strong theoretical basis and sound psychometric properties. Further, some of the measures lacked utility, feasibility and specificity. The article concludes with recommendations for future research.

Reason for clozapine cessation

Pai NB, Vella SC. Reason for clozapine cessation.

Preventing olanzapine-induced weight gain using betahistine: a study in a rat model with chronic olanzapine treatment

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.

Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways

Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.

Are there different neural mechanisms responsible for three stages of weight gain development in anti-psychotic therapy: Temporally based hypothesis

Weight gain as a result of atypical anti-psychotic treatment is a common issue with different atypical anti-psychotic treatments causing differing magnitudes of weight gain. Although differing amounts of weight gain result from different atypical agents little is known about the temporal course of weight gain in anti-psychotic treatment. Specifically is the time course of weight gain comparable across different agents. Therefore this article reviews the temporal course of weight gain for three common atypical anti-psychotics namely; clozapine, olanzapine and risperidone. It is evident that all three of these agents exhibit similar although at distinct magnitudes temporal courses of weight gain. That is an initial rapid increase from baseline to 3 months (stage 1), a steady increase from 3 months to 18 months (stage 2) and a plateau after this point (stage 3) with continued anti-psychotic treatment. It is postulated that each of these stages of weight gain result from distinct neural mechanisms. The hypothesized neural correlates for each stage of weight gain are reviewed and discussed. The article concludes with recommendations for future research.

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either olanzapine (1mg/kg), betahistine (2.7 mg/kg), olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce olanzapine-induced weight gain side-effects without affecting olanzapines actions on 5-HT2AR transmissions.

A Comparative Study of Sexual Dysfunction Involving Risperidone, Quetiapine, and Olanzapine

Background: With the advent of newer antipsychotic drugs, side effects such as sexual dysfunction have been a major contributor toward treatment compliance. There are only a few studies that have compared different atypical antipsychotic agents regarding sexual dysfunction. We have not come across any data in this area on Indian population. Aims: To determine and compare the frequency of sexual dysfunction associated with risperidone, olanzapine, and quetiapine, among patients with clinically stable schizophrenia. Settings and Design: It is a cross-sectional hospital-based study. The subjects were recruited for the study by the purposive sampling technique. Materials and Methods: The total sample size was 102, consisting of 25 each in the quetiapine and risperidone groups, 22 in the olanzapine group, and 30 healthy volunteers. A Brief Psychiatric Rating Scale and Sexual Functioning Questionnaire (SFQ) were administered. The Kruskal Wallis test was used to compare the variables in the demographic data and the mean chlorpromazine equivalent doses of the study groups. To analyze the sexual dysfunction, the mean scores on all the domains of sexual functioning in SFQ were compared across the study groups using the Chi square test, for proportions. Results and Conclusion: Twenty-three percent of the healthy volunteers had some impairment in one or more domains of sexual functioning. For the medication groups this was 96, 88, and 90%, respectively for risperidone, quetiapine, and olanzapine. However, there was statistically no significant difference across the study groups although it was relatively less with quetiapine.

Augmentation of clozapine with another pharmacological agent: treatment for refractory schizophrenia in the ‘real world’

Pai NB, Laidlaw M, Vella S‐C. Augmentation of clozapine with another pharmacological agent: treatment for refractory schizophrenia (SZ) in the ‘real world’.

Mental health literacy survey among Sri Lankan Carers of patients with Schizophrenia and Depression

INTRODUCTION Mental health literacy has been defined as knowledge and beliefs about mental disorders which aid their recognition, management or prevention. AIM Preliminary investigation on mental health literacy among Sri Lankan carers of patients with Schizophrenia and Depression. METHOD Cross sectional descriptive study investigated a convenience sample of 119 carers of a person with Depression or Schizophrenia attending a community clinic using vignettes adapted from an existing mental health literacy survey. RESULTS The Schizophrenia vignette was reported as a crisis by 28% and 35.6% reported the Depression vignette as a crisis. Schizophrenia and Depression were identified as mental illnesses by 72% and 64% respectively. Persons with Schizophrenia and Depression were reported to be more violent than a member of the community by 61% and 60%. Psychiatrists help was preferred as the therapeutic intervention in Schizophrenia (86.7%) and Depression (91.5%), whereas only 21.7% preferred traditional healers. Carers of persons with Schizophrenia (72%) and Depression (61%) held the attitude that the problem is a sign of personal weakness. Sixteen percent of carers wanted to avoid people with similar problems. DISCUSSION Carers had stigmatising attitudes such as persons with mental illness were violent and the illness was a sign of personal weakness. A minority wanted to avoid persons with similar problems, indicating that maintaining social distance was not a major issue. Carers had good knowledge of help seeking locations with a majority identifying psychiatrists and psychiatric wards in general hospitals. CONCLUSION The mental health literacy amongst the carers are lacking in certain areas. They have stigmatising attitudes towards people with mental illness.