Concurrent benzodiazepine use in older adults treated with antidepressants in Asia.

ABSTRACTBackground:Little is known about the combined use of benzodiazepines and antidepressants in older psychiatric patients. This study examined the prescription pattern of concurrent benzodiazepines in older adults treated with antidepressants in Asia, and explored its demographic and clinical correlates. METHODS: The data of 955 older adults with any type of psychiatric disorders were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Demographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. Both univariate and multiple logistic regression analyses were performed. RESULTS: The proportion of benzodiazepine and antidepressant combination in this cohort was 44.3%. Multiple logistic regression analysis revealed that higher doses of antidepressants, younger age (<65 years), inpatients, public hospital, major comorbid medical conditions, antidepressant types, and country/territory were significantly associated with more frequent co-prescription of benzodiazepines and antidepressants. CONCLUSIONS: Nearly, half of the older adults treated with antidepressants in Asia are prescribed concurrent benzodiazepines. Given the potentially adverse effects of benzodiazepines, the rationale of benzodiazepines and antidepressants co-prescription needs to be revisited.

Concurrent antipsychotic use in older adults treated with antidepressants in Asia.

AIM: Depressive disorders are common in old age. Antipsychotics (APs) are often used as an adjunctive treatment with antidepressants (ADs) in this population but its patterns of use in Asia are not known. This study explored the rate of combination of APs and ADs in older adult psychiatric patients in Asia. METHODS: This is a secondary analysis of the database of a multicentre study which recorded participants' basic demographical and clinical data in standardised format in 10 Asian countries and territories. The data were analysed using univariate and multivariate logistic regression analyses. RESULTS: A total of 955 older adult psychiatric in- and outpatients were included in this study. The proportion of concurrent AP and AD use was 32.0%, ranging from 23.3% in Korea to 44.0% in Taiwan. Multivariate logistic regression analysis found that younger age, inpatient status and diagnosis of schizophrenia, anxiety and other mental disorders were significantly related to a higher proportion of concurrent use of APs and ADs. CONCLUSION: Around a third of older adult psychiatric patients had concurrent AP and AD use in the Asian countries/regions surveyed. Considering the uncertain effectiveness and questionable safety of the AP and AD combination in this patient population, such should be cautiously used.

A History of the Pharmacological Treatment of Bipolar Disorder.

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade's experiments with lithium and the beginning of the so-called "Psychopharmacological Revolution" in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed.

Physical comorbidities in older adults receiving antidepressants in Asia.

BACKGROUND: The present study explored the patterns of physical comorbidities and their associated demographic and clinical factors in older psychiatric patients prescribed with antidepressants in Asia. METHODS: Demographic and clinical information of 955 older adults were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Standardized data collection procedure was used to record demographic and clinical data. RESULTS: Proportion of physical comorbidities in this cohort was 44%. Multiple logistic regression analyses showed that older age (OR = 1.7, P < 0.001), higher number of depressive symptoms (OR = 1.09, P = 0.016), being treated in psychiatric hospital (OR = 0.5, P = 0.002), living in high income countries/territories (OR = 2.4, P = 0.002), use of benzodiazepines (OR = 1.4, P = 0.013) and diagnosis of 'other psychiatric disorders' (except mood, anxiety disorders and schizophrenia) (OR = 2.7, P < 0.001) were significantly associated with physical comorbidities. CONCLUSIONS: Physical comorbidities in older patients prescribed with antidepressants were common in Asia. Integrating physical care into the treatment of older psychiatric patients should be urgently considered.

A Bibliometric Analysis of Scientific Production on Second-Generation Anti-Psychotic Drugs in Malaysia.

OBJECTIVE: We carried out a bibliometric study on the scientific papers related to second-generation antipsychotic drugs (SGAs) in Malaysia. METHODS: With the SCOPUS database, we selected those documents made in Malaysia whose title included descriptors related to SGAs. We applied bibliometric indicators of production and dispersion, as Price's law and Bradford's law, respectively. We also calculated the participation index of the different countries. The bibliometric data were also been correlated with some social and health data from Malaysia (total per capita expenditure on health and gross domestic expenditure on R&D). RESULTS: We found 105 original documents published between 2004 and 2016. Our results fulfilled Price's law, with scientific production on SGAs showing exponential growth (r = 0.401, vs. r = 0.260 after linear adjustment). The drugs most studied are olanzapine (9 documents), clozapine (7), and risperidone (7). Division into Bradford zones yields a nucleus occupied by the Medical Journal of Malaysia, Singapore Medical Journal, Australian and New Zealand Journal of Psychiatry, and Pharmacogenomics. Totally, 63 different journals were used, but only one in the top four journals had an impact factor being greater than 3. CONCLUSION: The publications on SGAs in Malaysia have undergone exponential growth, without evidence a saturation point.

Valproic Acid and Lithium Meditate Anti-Inflammatory Effects by Differentially Modulating Dendritic Cell Differentiation and Function.

Valproic acid (VPA), with inhibition activity mainly toward histone deacetylase (HDAC) and Glycogen Synthase Kinase (GSK)-3, and lithium, with inhibition activity mainly toward GSK-3, are both prescribed in clinical as mood-stabilizers and anticonvulsants for the control of bipolar disorder. This study aims to compare the immuno-modulation activities of VPA and lithium, especially on the differentiation and functions of dendritic cells (DC). Our data show that treatment with VPA or lithium effectively alleviated the severity of collagen-induced arthritis triggered by LPS in mice. Both agents reduced the serum level of IL-6 and IL-10 after LPS challenge in mice. VPA and lithium both induce significant down-regulation of group I CD1 expression and secretion of IL-6 during differentiation of human monocyte-derived immature DC, while they differ in the induction of CD83 and CD86 expression, secretion of IL-8, IL-10, and TNF-α. Upon stimulation of immature DC with LPS, VPA, and lithium both reduced the secretion of IL-6 and TNF-α. However, only lithium significantly increased the production of IL-10, while VPA increased the production of IL-8 but substantially reduce the secretion of IL-10 and IL-23. Treatment with VPA resulted in a reduced capacity of LPS-stimulated DC to promote the differentiation of T helper 17 cells that are critical in the promotion of inflammatory responses. Taken together, our results suggest that VPA and lithium may differentially modulate inflammation through regulating the capacity of DC to mediate distinct T cell responses, and they may provide a complementary immunomodulatory effects for the treatment of inflammation-related diseases. J. Cell. Physiol. 232: 1176-1186, 2017. © 2016 Wiley Periodicals, Inc.

Clinical Use of Mood Stabilizers With Antidepressants in Asia: Report From the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) Projects in 2004 and 2013.

OBJECTIVE: As most reports concerning treatment with combinations of mood stabilizer (MS) with antidepressant (AD) drugs are based in the West, we surveyed characteristics of such cotreatment in 42 sites caring for the mentally ill in 10 Asian countries. METHODS: This cross-sectional, pharmacoepidemiologic study used 2004 and 2013 data from the REAP-AD (Research Study on Asian Psychotropic Prescription Patterns for Antidepressants) to evaluate the rates and doses of MSs given with ADs and associated factors in 4164 psychiatric patients, using standard bivariate methods followed by multivariable logistic regression modeling. RESULTS: Use of MS + AD increased by 104% (5.5% to 11.2%) between 2004 and 2013 and was much more associated with diagnosis of bipolar disorder than major depression or anxiety disorder, as well as with hospitalization > outpatient care, psychiatric > general-medical programs, and young age (all P < 0.001), but not with country, sex, or AD dose. CONCLUSIONS: The findings provide a broad picture of contemporary use of MSs with ADs in Asia, support predictions that such treatment increased in recent years, and was associated with diagnosis of bipolar disorder, treatment in inpatient and psychiatric settings, and younger age.

A comparison of clinical characteristics of older adults treated with antidepressants in general and psychiatric hospitals in Asia.

AIM: This study compared the demographics, clinical characteristics, and antidepressant prescription patterns between Asian patients aged 50 years and older attending psychiatric hospitals and those attending general hospitals. METHODS: In total, 955 patients (604 in general hospitals, 351 in psychiatric hospitals) aged 50 years or older treated with antidepressants in 10 Asian countries and territories were examined. Patients' demographics, clinical features, and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: Binary logistic regression revealed that high income and diagnosis of schizophrenia were independently associated with psychiatric hospital treatment, whereas outpatient care, diagnosis of anxiety disorders, and multiple major medical conditions were independently associated with general hospital treatment. In addition, tetracyclic and noradrenergic and specific serotonergic antidepressants were more likely to be prescribed in general hospitals. CONCLUSION: Older adults treated with antidepressants showed different demographic and clinical features between general hospitals and psychiatric hospitals in Asia.

Tramadol-related psychosis in a patient with bipolar I disorder.

INTRODUCTION: Tramadol hydrochloride (HCl) is a centrally acting synthetic opioid analgesic. Psychotic symptoms are relatively rare in reported adverse events. Here, we report a patient who presented with tramadol-related psychotic symptoms. CASE: A 59-year-old female had underlying bipolar I disorder and received lithium treatment with stable affective status. 1 month before hospitalisation, she had been taking tramadol HCl/acetaminophen for joint pain. She then developed obvious persecutory delusion. However, her clinical picture did not meet the criteria of any mood episode. After treatment of risperidone in addition to lithium, she was discharged without any psychotic symptom. She remained euthymic without any psychotic symptom on monotherapy of lithium (300 mg) three tablets once daily. CONCLUSIONS: Tramadol HCl is commonly prescribed in clinical practice and psychotic symptoms related to it are uncommon. We should be careful about the rare but important adverse events while prescribing tramadol HCl.

Surgical adverse outcomes in patients with schizophrenia: a population-based study.

OBJECTIVE: To validate the global features of postoperative adverse outcomes for surgical patients with schizophrenia. BACKGROUND: Patients with schizophrenia were known to have a higher risk of complications during hospitalization. Quality of care has become the key factor in reducing their potential mortality afterwards. METHODS: We present a population-based study of 8967 schizophrenic patients receiving major surgery from the Taiwan National Health Insurance Research Database within the years 2004 and 2007 compared with 35,868 surgical patients without mental disorders. Eight major postoperative complications and mortality after complications were evaluated among schizophrenic patients with different severity. RESULTS: Schizophrenic patients had significantly higher risk for postoperative complications, including acute renal failure, pneumonia, bleeding, septicemia, stroke, and 30-day postoperative mortality (adjusted OR = 2.70; 95% CI: 2.08-3.49), than surgical patients without mental disorders. Among surgical patients with 1 to 2, 3 to 18, 19 to 48, and more than 49 schizophrenia-related outpatient visits within 24-month period preoperatively, the adjusted ORs of 30-day mortality ranged from 1.95 (95% CI: 1.25-3.02) to 3.97 (95% CI: 2.66-5.92) in a frequency-dependent pattern when compared with controls. When compared with surgical patients with schizophrenia-related outpatient services only, OR of 30-day postoperative mortality increased from 2.54 (95% CI: 1.93-3.34) to 3.69 (95% CI: 2.25-6.03) in surgical patients with preoperative hospitalization or emergency visit because of schizophrenia. CONCLUSIONS: Surgical patients with schizophrenia showed significantly higher postoperative adverse outcome rates with risk of 30-day mortality nearly threefold when compared with patients without mental disorders. Our findings suggest the urgency revising the protocol of postoperative care for this specific population.

Health-seeking behavior, alternative medicine, and quality of life in Taiwanese panic disorder patients.

OBJECTIVE: Panic disorder (PD) is an anxiety disorder characterized by spontaneous and unexpected panic attacks of varying frequency. Clinically manifest PD is widespread among the general population in developed countries worldwide. This study is aimed to identify factors influencing Taiwanese patients' decision to seek psychiatric help and to assess relationships between patients' health-seeking behaviors and quality of life (QOL). METHODS: One hundred patients from the outpatient psychiatric clinic of a university hospital in Taiwan were evaluated for PD. RESULTS: Delayed diagnosis of panic disorder, high comorbidity with other mental and physical disorders, and high utilization of health care services were identified. Thirty-three percent of PD patients sought alternative therapies, delaying their seeking psychiatric care. CONCLUSIONS: More PD patients in Taiwan seek care from family practitioners and alternative and complementary medicine than from psychiatrists. Taiwanese patients with PD who seek psychiatric consultation more than one year after disease onset have lower QOL and lower physical health scores.

Mapping the scientific research on atypical antipsychotic drugs in Spain: a bibliometric assessment.

OBJECTIVES: We carried out a bibliometric study on the scientific publications in relation to atypical antipsychotic drugs (AADs) in Spain. METHODS: We used the EMBASE and MEDLINE databases and we applied some bibliometric indicators of paper production and dispersion (Price's law and Bradford's law, respectively). We also calculated the participation index of the different countries and correlated the bibliometric data with some social and health data (total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 656 original papers published between 1988 and 2011. Our study results fulfilled Price's law with scientific production on AADs showing exponential growth (correlation coefficient r = 0.9693, vs. r = 0.9177 after linear adjustment). The most widely studied drugs were risperidone (181 papers), olanzapine (143), clozapine (94), and quetiapine (74). Division into Bradford zones yielded a nucleus occupied by the European Psychiatry and European Neuropsychopharmacology (70 articles). Totally 194 different journals were published, with 5 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on AADs in Spain have undergone exponential growth over the studied period, without evidence of reaching a saturation point.

Validation of apathy evaluation scale and assessment of severity of apathy in Alzheimer's disease.

AIM: Apathy is a well-recognized symptom of Alzheimer's disease (AD). The aim of the present study was to validate the Taiwanese version of the Apathy Evaluation Scale, clinician version (AES-C) and assess the severity of apathy in patients with AD. METHODS: Comprehensive evaluations were conducted in a total of 144 AD patients. This study used a cross-sectional comparative design. Data were collected from clinical interviews using the AES, the Mini-Mental Status Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the Clinical Dementia Rating Scale (CDR). RESULTS: Internal consistency was indicated by Cronbach's alphas of 0.85; test-retest reliability was 0.89 over a period of 3 days. Criterion-related validity was supported by the fact that AES-C significantly correlated with the apathy scores of the NPI. Factor analysis indicated a three-factor structure. Convergent validity was supported by a positive correlation between the AES-C score and the anxiety score of the NPI. Discriminant validity was supported by the fact that the AES-C scores did not correlate with the depression subscale of the NPI, and the correlation between the AES-C score and the euphoria score of the NPI score was negative. Known-group validity was supported by results showing that AD patients in a moderate stage of dementia (CDR = 2) had significantly higher scores on the AES-C than patients with mild-stage dementia (CDR = 1). CONCLUSION: The AES-C is a reliable and valid instrument for measuring symptoms of apathy among AD patients in Taiwan.

Modulation of the development of human monocyte-derived dendritic cells by lithium chloride.

Lithium has been used or explored to treat psychiatric and neurodegenerative diseases that are frequently associated with an abnormal immune status. It is likely that lithium may work through modulation of immune responses in these patients. Because dendritic cells (DC) play a central role in regulating immune responses, this study investigated the influence of lithium chloride (LiCl) on the development and function of DC. Exposure to LiCl during the differentiation of human monocyte-derived immature DCs (iDC) enhances CD86 and CD83 expression and increases the production of IL-1ß, IL-6, IL-8, IL-10, and TNF-α. However, the presence of LiCl during LPS-induced maturation of iDC has the opposite effect. During iDC differentiation, LiCl suppresses the activity of glycogen synthase kinase (GSK)-3ß, and activates PI3K and MEK. In addition, LiCl activates peroxisome proliferator-activated receptor γ (PPARγ) during iDC differentiation, a pathway not described before. Each of these signaling pathways appears to have distinct impact on the differentiating iDC. The enhanced CD86 expression by LiCl involves the PI3K/AKT and GSK-3ß pathway. LiCl modulates the expression of CD83 in iDC mainly through MEK/ERK, PI3K/AKT, and PPARγ pathways, while the increased production of IL-1ß and TNF-α mainly involves the MEK/ERK pathway. The effect of LiCl on IL-6/IL-8/IL-10 secretion in iDC is mediated through inhibition of GSK-3ß. We have also demonstrated that PPARγ is downstream of GSK-3ß and is responsible for the LiCl-mediated modulation of CD86/83 and CD1 expression, but not IL-6/8/10 secretion. The combined influence of these molecular signaling pathways may account for certain clinical effect of lithium.

ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment.

OBJECTIVE: ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood-brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood-brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD). METHODS: Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S-CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8. RESULTS: The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety. CONCLUSION: Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD.

Age, gender, depression, and sexual dysfunction in Taiwan.

INTRODUCTION: The effects of age and gender on sexual function have attracted much attention in recent years, though few studies have focused on this issue in Asian populations. AIMS: The Changes in Sexual Functioning Questionnaire (CSFQ) was used to: (i) assess the differences in sexual functioning between unmedicated outpatients with depressive disorders and healthy volunteers; and (ii) investigate the influences of gender and age on sexual functioning in both groups. MAIN OUTCOME MEASURES: The CSFQ was used to assess sexual dysfunction. METHODS: Two groups of subjects, 73 unmedicated patients with depressive disorders and 116 healthy volunteers, were recruited to the study, and changes in their sexual function were assessed using the CSFQ. Subjects' global depressive level and psychiatric morbidity were assessed using the Taiwanese Depression Questionnaire (TDQ) and the Chinese Health Questionnaire (CHQ). RESULTS: The depressed subjects had significantly lower total CSFQ scores than did the controls. A negative correlation between age and total CSFQ score was found in both genders of depressed patients. Age generally predicted the sum of the CSFQ scores for both genders in the depressed group after controlling for TDQ score; however, a positive correlation between age and total CSFQ score was identified in the female controls. We also found that the S-curve was the best-fit curve for both the male and female controls, the cut-off point for which was the age of 40. CONCLUSIONS: Our study confirmed that, as a screening tool for clinically significant sexual dysfunction, the CSFQ offered good sensitivity for both the healthy and depressed subjects. In addition, our findings suggested that age and gender differences should be taken into account when measuring sexual satisfaction. It is possible that the age of 40 could be an anchor point in sexual functioning for the female population of Taiwan.

Prevalence and identification of alcohol use disorders among severe mental illness inpatients in Taiwan.

AIMS: A higher prevalence of alcohol use disorders (AUD) among psychiatric patients has been reported previously and the identification rate is relatively low. This study was designed to investigate the prevalence and identification of AUD among acute psychiatric inpatients with severe mental illness in a psychiatric hospital in Taiwan. METHODS: In a two-phase case identification strategy, the Alcohol Use Disorders Identification Test (AUDIT) was used as the first phase screening tool and the Structured Clinical Interview for DSM-IV-TR as the second phase diagnostic interview. The definition of identification was diagnosis of AUD on medical record at discharge. RESULTS: Of 400 respondents, 42 screened positive and 358 screened negative. All screen-positive respondents and 35 screen-negative respondents entered the second phase interview. The weighted lifetime prevalence of alcohol dependence was 8.3% (95% confidence interval [CI]: 4.6-11.9%); alcohol abuse, 1.5% (95%CI: 0.2-2.8%); and AUD, 9.8% (95%CI: 5.7-13.8%). The overall identification rate of AUD by medical staff was 28.2% (0% for alcohol abuse and 33.3% for alcohol dependence). Patients with mood disorders were prone to being undetected as having AUD. CONCLUSION: AUD comorbidity was common among inpatients with severe mental illness in Taiwan and was easily neglected by medical staff. It is necessary to use a validated screening questionnaire, such as AUDIT, to detect high-risk patients and then give appropriate interventions to enhance treatment outcome.

Obsessive-compulsive symptoms in patients with schizophrenia: Relationships with olanzapine pharmacological parameters, psychopathology, and quality of life.

Obsessive-compulsive symptoms (OCS) occur in a substantial portion of schizophrenia patients and have significant impacts on clinical course. This study was intended to investigate the relationships of OCS with pharmacological parameters of olanzapine, psychopathology, and quality of life. Totally 151 schizophrenia patients were recruited, and rated using Yale-Brown Obsessive-Compulsive scale (YBOCS), Positive and Negative Syndrome Scale (PANSS), Montgomery-Åsberg Depression Rating Scale (MADRS), and World Health Organization Questionnaire on Quality of Life: Short Form (WHOQOL-BREF). The concentrations of olanzapine and N-desmethylolanzapine were determined by HPLC. Twenty-five patients (16.6%) revealed the presence of OCS. OCS group had significantly higher olanzapine dose, more numbers of past hospitalizations, higher PANSS total, positive, negative, and general psychopathology scores, and higher MADRS score than those in non-OCS group. The WHOQOL-BREF physical subscale score in schizophrenia patients with OCS was significantly lower. Olanzapine dose, PANSS score, and MADRS score were significantly correlated with YBOCS score. Our findings highlight that OCS is highly prevalent in schizophrenia patients under olanzapine treatment, especially those at high doses. Schizophrenia patients with OCS had higher severity of psychotic and depressive symptoms and poorer quality of life. Clinicians should monitor OCS in patients with schizophrenia receiving olanzapine treatment.

Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole.

Hyperprolactinemia is an important but neglected adverse effect of antipsychotic medication. All first generation antipsychotics and the second generation antipsychotics amisulpride and risperidone have been shown to cause marked elevation in serum prolactin levels, whereas most other second generation antipsychotics and aripiprazole appear to have little or no effect on serum prolactin levels. This study was aimed to assess the time course of changes in antipsychotic-induced hyperprolactinemia during the process of antipsychotic switching to aripiprazole. Twenty-three female schizophrenic subjects with risperidone- or sulpiride-induced symptomatic hyperprolactinemia were recruited into the study and 20 of them completed the trial. We added aripiprazole to the therapeutic dose first, then overlapped the preexisting antipsychotic treatment and aripiprazole, and finally tapered the preexisting antipsychotic treatment. Clinical status was assessed by using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity Scale (CGI-S). Assessment scales and serum prolactin levels were measured at baseline, during the combination treatment period, and four weeks after having completed discontinuation of the preexisting antipsychotic treatment. Switching antipsychotic drugs to aripiprazole was effective in reducing serum prolactin levels and restoring menstruation in schizophrenic patients who received prolactin-raising antipsychotics. Mean serum prolactin levels at baseline, during combination period, and after the switch were 97.0+/-69.0 ng/ml, 27.2+/-10.6 ng/ml (p<0.001, vs. baseline), and 12.2+/-5.3 ng/ml (p<0.001, vs. baseline), respectively. None of the study subjects experienced any serious adverse effects during the switching process. No significant changes were noted in the PANSS and CGI-S scores during the switching process. The prolactin-normalizing effects of aripiprazole are likely caused by the unique characteristics of the dopamine partial agonist with its high affinity for dopamine D2 receptors.

Pharmacokinetics of olanzapine in Chinese male schizophrenic patients with various smoking behaviors.

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose-plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers (n=9), light-smokers (1-4 cigarettes per day; n=9), and heavy-smokers (>or=5 cigarettes per day; n=9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers (n=9; 0.79; p=0.01) or combined with light-smokers (n=18; 0.62; p<0.01) between peak plasma olanzapine concentrations (Cmax) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC0-->120 by 45.1% in light-smokers. The mean C(max) and the mean area under the plasma concentration-time curve from time zero to 120 h (AUC0-->120) of the heavy-smoking patients was 9.3+/-4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4+/-167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50-100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.