History and Future of Antipsychotic Drugs / 신경정신의학

After the discovery of antipsychotic drugs, the nature of clinical practice entered a period of inexorable transition. The advances of psychopharmacotherapy have interacted in complex ways with clinical practice, and the economics and policy of mental health care systems. The study of the mechanisms of action of these drugs has guided the development of hopefully improved treatment, and stimulated biological research on the pathophysiology of severe mental disorders. Despite the considerable effort to modify and change existing antipsychotic drugs, progress has been modest. This review describes the history of antipsychotic drugs and their impact on clinical practice and the study of psychiatric disorders, and offer prospects for future developments. Although finding new knowledge and methodologies to bring innovative discovery is imperative, as of now, it is important to provide comprehensive care, including the optimal use of existing antipsychotic drugs.

Comparative Efficacy and Safety of Long-acting Injectable and Oral Second-generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review and Meta-analysis

We aimed to compare the efficacy and safety of long-acting injectable (LAI) and oral second-generation antipsychotics (SGAs) in treating schizophrenia by performing a systematic review and meta-analysis. MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library, as well as five Korean databases, were systemically searched to identify studies published from 2000 to 16 April 2015, which compared the efficacy and safety of LAI and oral SGAs. Using data from randomized controlled trials (RCTs), meta-analyses were conducted. In addition, the GRADE (the Grading of Recommendations, Assessment, Development and Evaluation) approach was applied to explicitly assess the quality of the evidence. A total of 30 studies including 17 RCTs and 13 observational studies were selected. The group treated with LAI SGAs was characterized by significantly lower relapse rates, longer times to relapse and fewer hospital days, but also by a higher occurrence of extrapyramidal syndrome and prolactin-related symptoms than that in the group treated with oral SGAs. Our findings demonstrate that there is moderate to high level of evidence suggesting that in the treatment of schizophrenia, LAI SGAs have higher efficacy and are associated with higher rates of extrapyramidal syndrome and prolactin-related symptoms. Additionally, the use of LAI SGAs should be combined with appropriate measures to reduce dopamine D2 antagonism-related symptoms.

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 anti-psychotic 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.

Long-Term Evolution of Metabolic Status in Patients with Schizophrenia Stably Maintained on Second-Generation Antipsychotics

OBJECTIVE: Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Despite the risk of MetS, SGAs may have to be continued with change in some patients. The aim of this study was to trace the evolution of MetS in these patients. METHODS: Patients with schizophrenia who had been maintained on a fixed SGA regimen for more than a year were followed-up without changing the regimen. Metabolic indicators were evaluated at baseline and at follow-up. Prevalence, incidence and spontaneous normalization rate of MetS were estimated. Risk factors that might have influenced the evolution were scrutinized. RESULTS: A total of 151 subjects were included. During the mean observation period of 389.9±162.4 days, the prevalence of MetS was increased from 35.1 to 45.0%. The incidence rate was 29.6%, while the normalization rate was 26.4%, risk factors affecting incidence were age (OR=1.09, 95% CI: 1.03–1.17), baseline continuous values of metabolic syndrome risk scores (cMetS, OR=1.77, 95% CI:1.29–2.55) and baseline body weight (OR=1.06, 95% CI: 1.01–1.13). Normalization was influenced by age (OR=0.74, 95% CI: 0.57–0.89) and baseline body weight (OR=0.85, 95% CI: 0.72–0.95). CONCLUSION: The prevalence of MetS steadily increased with the continuous use of SGAs. However, individual difference was extensive and about a quarter of the patients were able to recover naturally without specific measurements.

The study on the association of serum adiponectin and metabolic indicators associated with second senera-tion antipsychotic-induced weight gain in first-episode schizophrenic patients / 中国神经精神疾病杂志

Objective To investigate the effect of second generation antipsychotics (SGAs) on adiponectin (APN) and metabolic indicators and to explore the role of APN in the antipsychotic-induced weight gain (AIWG). Methods A total of 86 drug na?ve first episode schizophrenia patients and 88 sex-and age-matched healthy controls were collected. All patients received a single SGAs treatment for 8 weeks. In patient group, the level of weight, body mass index (BMI), waist-to-hip ratio (WHR), fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), APN and fasting insulin (FINS) were measured before and after 8-week treatment. While as the control group was only measured once after enroll?ment. Results The serum APN [(9.32 ± 0.76) μg/mL vs. (10.9 ± 0.66) μg/mL] was lower and FINS was higher [(20.27 ± 15.02)μIU/mL vs. (12.68±11.70)μIU/mL] in drug na?ve patients compared with healthy controls (P<0.05). After 8-weekSGAs treatment, patients showed significant increases in weight [(59.01 ± 10.56) kg vs. (63.80 ± 9.78) kg], BMI [(21.74 ± 3.57) kg/m2 vs.(23.49±3.44) kg/m2], WHR [(0.88±0.07) vs. (0.92±0.05)], TG [(0.94±0.92) mmol/L vs. (1.63±1.08) mmol/L] and FINS [(12.68 ± 11.70)μIU/mL vs. (20.27 ± 15.02)μIU/mL], and significant decreases in APN [(9.32 ± 0.76)μg/mL vs. (8.03±0.68)μg/mL] and FPG [(5.04±1.01) mmol/L vs. (4.46±0.57) mmol/L] (all P<0.05). In male patients, baseline APN levels were positively correlated with AIWG (r=0.548,P=0.005). Conclusion The serum APN levels in drug na?ve first episode schizophrenic patients are significantly lower than normal and are further decreased after SGAs treatment. Base?line APN may predict the AIWG in male patients.

Arterial Stiffness in Patients Taking Second-generation Antipsychotics

OBJECTIVE: That treatment with second-generation antipsychotics (SGAs) causes metabolic side effects and atherosclerosis in patients with schizophrenia and bipolar disorder (BD) is well-known. Increased arterial stiffness is an important marker of arteriosclerosis and has been identified as an independent risk factor for cardiovascular diseases. We measured pulse wave velocity (PWV) as a marker of arteriosclerosis in patients with schizophrenia and BD who use SGAs. METHODS: Patients and controls were collected from our psychiatry outpatient clinics or family medicine. Mental illness was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Mean age, gender, systolic and diastolic blood pressure, body mass index, Framingham risk score (FRS), etc. were determined. Simultaneous electrocardiography and pulse wave were recorded with an electromyography device. The photo-plethysmographic method was used to record the pulse wave. Inclusion criteria included use of SGAs for at least the last six months. Patients with diseases that are known to cause stiffness and the use of typical antipsychotics were excluded. RESULTS: Ninety-six subject (56 patients, 40 controls) were included in our study. There were 49 females, 47 males. Patients had schizophrenia (n=17) and BD (n=39). Their treatments were quetiapine (n=15), risperidone (n=13), olanzapine (n=15), and aripiprazole (n=13). Although differences in mean age, gender, and FRS in the patient and control groups were not statistically significant (p=1), PWV was greater in patients in the antipsychotic group (p=0.048). CONCLUSION: This study supported the liability to stiffness in patients with schizophrenia and BD. Using SGAs may contribute to arterial stiffness in these patients.

Simultaneous Comparison of Efficacy and Tolerability of Second-Generation Antipsychotics in Schizophrenia: Mixed-Treatment Comparison Analysis Based on Head-to-Head Trial Data

OBJECTIVE: Second-generation antipsychotics have been repeatedly shown to be superior to placebo. However, the comparative efficacy among these drugs has not been systematically evaluated. In this study, we used Mixed Treatment Comparison (MTC) procedures to elucidate the comparative efficacy and tolerability of second-generation antipsychotics. METHODS: Seven antipsychotics were selected based on the availability of the relevant data. Data were gathered from a series of review article published by the Cochrane Collaboration. Six outcome measures were analyzed: 1) percentage of no clinically important response as defined by the original authors, 2) PANSS total score change from baseline to endpoint, 3) percentage of akathisia, 4) percentage of antiparkinson medication use, 5) percentage of total body weight increase more than 7%, and 6) percentage of drop-out due to any reasons. RESULTS: All the second-generation antipsychotics included in this study showed fairly similar efficacy but widely different tolerability. In terms of efficacy, amisulpride, clozapine and olanzapine were ranked higher than aripiprazole, quetiapine and ziprasidone. Clozapine and olanzapine were superior in terms of akathisia and extrapyramidal symptom risk, but, far more prone to induce clinically important weight gain. CONCLUSION: Using MTC methodology, we could line up the second generation antipsychotics according to their hierarchical superiority in terms of efficacy and tolerability. Though the wide overlap among the confidence intervals and the inconsistency between the direct and indirect comparison results may limit the validity of these results, it may still allow the important insights into the relative merits of the available drugs.

Update on Medications in Schizophrenia

Antipsychotics are a pharmacologically heterogeneous group of compounds, but all act as D2 dopamine receptor antagonists, an action linked to their antipsychotic effect. Today, sixty years on since 1952, we have the FGAs and the SGAs. These medications continue to be useful, and continue to have some troubling adverse effects. As a class, the FGAs are more likely to be associated with EPS but this is primarily true of medications that bind tightly with D2 neuroreceptors, such as haloperidol, and less true of medications that bind weakly, such as chlorpromazine. Anticholinergic effects are especially prominent with weaker-binding FGAs, as well as with the SGA clozapine. As a class, the SGAs, especially clozapine and olanzapine generally tend to cause more problems relating to the metabolic syndrome, such as obesity and type 2 diabetes mellitus. All antipsychotic medications are associated with an increased likelihood of sedation, sexual dysfunction, postural hypotension, prolonged QT interval and sudden death. Primary care physicians need to be familiar with the individual adverse effect profiles of these medications.

Comparative study on negative symptoms of schizophrenia treated with amisulpride and other second-generation antipsychotics: a meta-analysis / 中华行为医学与脑科学杂志

Objective To compare the efficacy of amisulpride and other SGAs in treating the negative symptoms of Schizophrenia.Methods The randomized controlled trials (RCTs) about Schizophrenia treated with amisulpride and other SGAs from Jan 1995 to Mar 2013 were searched in The Pubmed,EMbase,Cochrane Library,WanFang Data,CNKI and VIP.Two reviewers independently screened the literatures,extracted the data,and evaluated the methodological quality.Than meta-analyses were conducted by using RevMan 5.1 and Stata 12.0 software.Results The totall3 RCTs were included.Among the 1814 patients involved.The results of meta-analyses showed that the score of PANSS-N was no significant differences between two groups (MD =-0.33,95％ CI:(-0.87,0.21),Z =1.20,P =0.23) ; and the score of SANS was no significant differences between two groups (MD =-0.21,95％ CI:(-1.51,1.50),Z =0.31,P =0.76).The side effects were more in other SGAs group than those in amisulpride group.Conclusion Amisulpride is as effective as other SGAs for the treatment of schizophrenia with predominantly negative symptoms,and it has more advantage than other SGAs in safety.

Trends in Scientific Literature on Atypical Antipsychotics in South Korea: A Bibliometric Study

OBJECTIVE: We have carried out a bibliometric study on the scientific publications in relation to atypical or second-generation antipsychotic drugs (SGAs) in South Korea. METHODS: With the EMBASE and MEDLINE databases, we selected those publications made in South Korea whose title included the descriptors atypic* (atypical*) antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied some bibliometric indicators of paper production and dispersion with Price's law and Bradford's law, respectively. We also calculated the participation index (PI) of the different countries, and correlated the bibliometric data with some social and health data from Korea (such as total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 326 original papers published between 1993 and 2011. Our results state fulfilment of fulfilled Price's law, with scientific production on SGAs showing exponential growth (correlation coefficient r=0.8978, as against an r=0.8149 after linear adjustment). The most widely studied drugs were risperidone (91 papers), aripiprazole (77), olanzapine (53), and clozapine (43). Division into Bradford zones yielded a nucleus occupied by the Progress in Neuro-Psychopharmacology and Biological Psychiatry (36 articles). A total of 86 different journals were published, with 4 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on SGAs in South Korea have undergone exponential growth over the studied period, without evidence of reaching a saturation point.