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Systematic review and meta-analysis

Metformin for treatment of clozapine-induced weight gain in adult patients with schizophrenia: a meta-analysis

Zhengrong LIU, Wei ZHENG, Shuai GAO, Zhisong QIN, Guannan LI, Yuping NING

Background: Long-term use of clozapine for individuals with schizophrenia carries a high risk for developing metabolic abnormalities, especially clozapine-induced weight gain. Previous studies suggest that metformin can decrease clozapine-induced weight gain, but the sample sizes of most of these studies are relatively small.
Methods: We identified randomized controlled trials (RCTs) published prior to December 15, 2015 about the use of metformin to treat clozapine-induced weight gain in adults with schizophrenia by searching several English-language and Chinese-language databases. Two independent researchers did the screening and data extraction. We used Revman 5.3 to conduct the meta-analyses, assessed the risk of bias (RoB), and assessed the strength of the evidence using the Cochrane Grades of Recommendation, Assessment, Development, and Evaluation (GRADE).
Results: Six studies with a pooled sample of 207 treatment-group patients and 207 control-group patients were included – three double-blind, placebo-controlled RCTs and three RCTs that did not use placebo controls and were not blinded. The meta-analysis found that compared to the control condition, patients receiving metformin experienced significantly greater reductions in body weight (mean difference [MD]=-2.89 kg, 95% CI: -4.20 to -1.59 kg) and body mass index (BMI) (MD=-0.81, 95% CI: -1.16 to -0.45), but there was no significant difference between the groups in the prevalence of side effects. Based on the GRADE scale, the strength of the evidence for the change in weight outcome was ‘moderate’ and that for the change in BMI outcome was ‘high’, but the strength of evidence about differences in side effects between groups was ‘low’ or ‘very low’.
Conclusions: Adjunctive treatment with metformin appears to be effective for treating clozapine-induced weight gain and elevations in BMI in adult patients with schizophrenia. However, the quality of the evidence about the safety of this treatment is low, follow-up time in the available studies is relatively short, and half of the studies did not employ blinded assessment of outcome measures. Larger studies with placebo controls that follow patients for at least 24 weeks and that make blinded assessments of a range of relevant outcome measures (weight, BMI, blood lipids, insulin resistance, etc.) are needed to confirm these results.
Keywords: metformin; clozapine; schizophrenia; clozapine-induced weight gain; meta-analysis [Shanghai Arch Psychiatry. 2015, 27(6): 331-340. doi:]

Original research article

Association of schizophrenia with the rs821633 polymorphism

Guoqin HU, Chengqing YANG, Jing ZHAO, Minghuan ZHU, Xiangqing GUO, Chenxi BAO, Si JIA1, Ahong XU, Yo

Background: Previous studies report that various single nucleotide polymorphisms (SNP) in the Disrupted-in- Schizophrenia 1 (DISC1) gene are closely associated with schizophrenia, but there are no studies that assess the relationship of age of onset of schizophrenia with these SNPs.
Objective: Investigate the relationship between the rs821633 SNP in the DISC1 gene and the occurrence and age of onset of schizophrenia in Han Chinese.
Methods: We used the TaqMan genotyping technology to examine the rs821633 SNP in the DISC1 gene among 315 individuals who developed schizophrenia prior to 19 years of age (‘early-onset’), 407 individuals who developed schizophrenia when 19 years of age or older (‘late-onset’), and 482 healthy controls. We used survival analyses to investigate the relationship between the rs821633(C) risk allele and the age of onset of schizophrenia.
Results: Compared to the prevalence in healthy controls, the prevalence of the C/C genotype of rs821633 and of the C allele in rs821633 were significantly greater in individuals with early-onset schizophrenia (X2=7.17, df=1, p=0.007; X2=7.20, df=2, p=0.032) and significantly greater in individuals with late-onset schizophrenia (X2=5.36, df=1, p=0.022; X2=6.58, df=2, p=0.041). However, there were no significant differences in the prevalence of the C/C genotype or the C allele between individuals with early-onset and late-onset schizophrenia. Kaplan-Meier survival analyses found no significant association between the rs821633(C) risk allele and age of onset in schizophrenia.
Conclusion: We confirm the association of polymorphism in the rs821633 SNP in the DISC1 gene with schizophrenia among Han Chinese, but we found no association between the rs821633(C) risk allele and the age of onset in individuals with schizophrenia.
Keywords: schizophrenia; DISC1 gene; transmission disequilibrium test; single nucleotide polymorphism; age of onset; China [Shanghai Arch Psychiatry. 2015, 27(6): 348-355. doi:]


Comorbid anxiety and depression in school-aged children with attention deficit hyperactivity disorder (ADHD) and self-reported symptoms of ADHD, anxiety, and depression amongparents of school-aged children with and without ADHD

Weiping XIA, Lixiao SHEN, Jinsong ZHANG

Background: Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children that can extend into adulthood and that is often associated with a variety of comorbid psychiatric disorders.
Aim: Assess the comorbidity of ADHD with anxiety disorders and depressive disorders in school-aged children, and the relationship of the severity of ADHD, anxiety, and depressive symptoms in children who have ADHD with the severity of the corresponding symptoms in their parents.
Methods: A two-stage screening process identified children 7-10 years of age with and without ADHD treated at the Xin Hua Hospital in Shanghai. ADHD and other DSM-IV diagnoses were determined by a senior clinician using the Schedule for Affective Disorder and Schizophrenia for School-Aged Children (K-SADS-PL). One parent for each enrolled child completed three self-report scales: the ADHD Adult Self Report Scale (ASRS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI). In total 135 children with ADHD and 65 control group children without ADHD were enrolled; parents for 94 of the children with ADHD and 63 of the children without ADHD completed the parental assessment scales.
Results: Among the 135 children with ADHD, 27% had a comorbid anxiety disorder, 18% had a comorbid depressive disorder, and another 15% had both comorbid anxiety and depressive disorders. Parents of children with ADHD self-reported more severe ADHD inattention symptoms than parents of children without ADHD and were more likely to meet criteria for adult ADHD. Mothers (but not fathers) of children with ADHD had significantly more severe trait anxiety and depressive symptoms than mothers of children without ADHD. Among children with ADHD, the severity of ADHD symptoms was not significantly correlated with the severity of ADHD symptoms in parents, but depressive symptoms and anxiety symptoms in the children were significantly correlated with the corresponding symptoms in the parents.
Conclusions: School-aged children with ADHD commonly suffer from comorbid anxiety and depressive disorders, and the severity of these symptoms parallels the level of anxiety and depressive symptoms in their parents. Self-reported symptoms of ADHD are significantly more common in parents of children with ADHD than in parents of children without ADHD. Longitudinal studies are needed to disentangle the genetic, biological, and social factors responsible for these complex inter-relationships.
Keywords: attention deficit hyperactivity disorder; anxiety; depression; comorbidity; heritability; correlation analyses; China [Shanghai Arch Psychiatry. 2015, 27(6): 356-367. doi:]


Comparison of the density of gamma-aminobutyric acid in the ventromedial prefrontal cortex of patients with first-episode psychosis and healthy controls

Zhilei YANG, Yajing ZHU, Zhenhua SONG, Li MEI, Jianye ZHANG, Tianyi CHEN, Yingchan WANG,Yifeng XU, K

Background: Abnormality in the concentration and functioning of gamma-aminobutyric acid (γ-aminobutyric acid, GABA) in the brain is not only an important hypothetical link to the cause of schizophrenia but it may also be correlated with the cognitive decline and negative symptoms of schizophrenia. Studies utilizing high field magnetic resonance spectroscopy (MRS) report abnormal density of GABA in the ventromedial prefrontal cortex (vmPFC) of patients with chronic schizophrenia, but these results may be confounded by study participants’ prior use of antipsychotic medications.
Aim: Compare the density of GABA in the vmPFC of patients with first-episode psychosis to that in healthy controls and assess the relationship of GABA density in the vmPFC to the severity of psychotic symptoms.
Methods: Single-voxel 1H-MRS was used to assess the concentration of GABA and other metabolites in the vmPFC of 22 patients with first-episode psychosis (10 with schizophrenia and 12 with schizophreniform disorder) and 23 healthy controls. Thirteen of the 22 patients were drug-naïve and 9 had used antipsychotic medication for less than 3 days. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of psychotic symptoms in the patient group.
Results: The mean (sd) GABA density in the vmPFC was significantly higher in patients than in controls (2.28 [0.54] v. 1.93 [0.32] mM, t=2.62, p=0.012). The densities of other metabolites – including N-acetylaspartic acid (NAA), glutamic acid (GLU), and glutamine (GLN) – were not significantly different between patients and controls. Among the patients, GABA density in the vmPFC was not significantly correlated with PANSS total score or with any of the three PANSS subscale scores for positive symptoms, negative symptoms, and general psychopathology. GABA concentration was not associated with the duration of illness, but it was significantly correlated with patient age (r=0.47, p=0.026).
Conclusions: Elevation of GABA density in the vmPFC of patients with first-episode psychosis confirms that this abnormality is independent of medication use. The failure to find a correlation of GABA density in the vmPFC with the severity of psychotic symptoms needs to be confirmed in larger studies, but it suggests that there are several intervening steps between brain pathology and clinical symptoms.
Keywords: first-episode psychosis; first-episode schizophrenia; drug-naïve; magnetic resonance spectroscopy; gamma-aminobutyric acid; ventromedial prefrontal cortex; China [Shanghai Arch Psychiatry. 2015, 27(6): 341-347. doi:]


Psychopharmacological treatment for schizophrenia: less is more

Chuanyue WANG

Summary: Antipsychotic polypharmacy in the treatment of schizophrenia is more common in China and other Asian countries than in Western countries. The reasons for this are unclear, but it may be related to an unsubstantiated belief among clinicians that multiple medications are more likely to achieve the desired clinical outcome. Antipsychotic medications are the mainstay of treatment for individuals with schizophrenia, but the use of antipsychotic polypharmacy and of high dosages of antipsychotic medication are associated with substantially increased risks without conferring improved clinical outcomes. It is generally accepted that high dosages of antipsychotic medications and the simultaneous use of multiple antipsychotics are associated with an increased prevalence, duration, and severity of adverse drug effects. More recent evidence also suggests that antipsychotic polypharmacy and the associated high overall dosage of antipsychotic medication lead to excessive striatal D2 receptor occupation (resulting in tolerance and drug withdrawal problems) and exacerbation of the impaired synaptic plasticity seen in schizophrenia (magnifying the cognitive impairment associated with the condition). Clinicians need to apply the ‘less is more’ principle in the psychopharmacological treatment of schizophrenia.
Keywords: antipsychotic polypharmacy; cognitive impairment; low-dose antipsychotic medication; synaptic plasticity [Shanghai Arch Psychiatry. 2015; 27(6): 368-370. Epub 2015 Nov 10. doi: j.issn.1002-0829.215086]


‘Less is more’ in the Chinese context

Yifeng XU

Summary: Excessive polypharmacy is a common problem around the world, particularly in the treatment of psychiatric disorders. In mainland China use of out-of-date treatment strategies by psychiatric professionals is one of the reasons; others include unrealistically high expectations about the effectiveness of medications, the dominant role of the doctor in doctor-patient negotiations about treatment, the practice of polypharmacy in Traditional Chinese Medicine (TCM), the profit-driven nature of medical institutions and individuals, the infiltration of pharmaceutical marketing, and a critical lack of relevant research. This commentary considers the cultural factors that need to be addressed when trying to reduce polypharmacy in psychiatry in China.
Keywords: polypharmacy; doctor-patient relationship; TCM; pharmaceutical companies; clinical guidelines; China [Shanghai Arch Psychiatry. 2015; 27(6): 371-373. Epub 2015 Nov 10. doi: j.issn.1002-0829.215106]

Case report

Panic attacks 10 years after heart transplantation successfully treated with low-dose citalopram: a case report

Chenyu YE, Yamin ZHUANG, Jianlin JI, Hao CHEN

Summary: Panic attacks are common among patients who have undergone heart transplantation, but there are no clinical guidelines for the treatment of panic attacks in this group of patients. This report describes a 22-year-old woman who experienced panic attacks 10 years after heart transplant surgery. The attacks started after she discovered that the average post-transplantation survival is 10 years. Treated with citalopram 10 mg/d, her symptoms improved significantly after 2 weeks and had completely resolved after 8 weeks. A positive physician-patient relationship with the doctors who regularly followed her medical condition was crucial to encouraging her to adhere to the treatment with citalopram. She continued taking the citalopram for 7 months without any adverse effects. When followed up 3 months after stopping the citalopram, she had had no recurrence of the panic attacks.
Keywords: heart transplantation; panic attacks; citalopram; China


Case report of eosinophilia induced by quetiapine

Liming CHEN, Pei TAN, Xiaolin TAN

Summary: An increase in the concentration of eosinophils in blood may lead to endocarditis, myocarditis, and pericarditis. When the absolute eosinophil count increases beyond 1.5 x 109/L, myocardial damage and even death can occur. This case report describes a 47-year-old male with an alcohol-induced psychotic disorder who developed eosinophilia 4 weeks after starting treatment with quetiapine 50-200 mg/d. His maximum recorded absolute eosinophil count was 7.63 x 109/L (normal range <0.5 x 109/L), but the level returned to normal over a 4-week period after stopping quetiapine and no myocardial damage was observed. This patient’s dramatic eosinophilia did not have any associated clinical symptoms; it was only identified as part of a routine blood test a few weeks after starting quetiapine. This is a reminder that all clinicians who treat patients with antipsychotic medications must be vigilant about the occurrence of such rare but life-threatening adverse events.
Keywords: eosinophilia; quetiapine; case report; China

Biostatistics in psychiatry

The debate about p-values


Summary: The p-value is the most widely used statistical concept in biomedical research. Recently, there are controversies over its utility and over the possible relationship between p-value misuse and the relatively high proportion of published medical research that cannot be replicated. In this paper, we introduce the p-value in layman’s terms and explain its randomness and limitations. However, we also point out that the available alternatives to p-value suffer similar limitations. We conclude that using p values is a valid way to test the null and alternative hypotheses in clinical trials. However, using the p-value from a single statistical test to judge the scientific merit of a research project is a misuse of the p-value; the results of inference tests using p-values need to be integrated with secondary results and other data to arrive at clinically valid conclusions. Understanding the variability and limitations of the p-value is important for the interpretation of statistical results in research studies.
Keywords: p-value; inferential statistics; hypothesis testing; statistical significance; scientific repeatability [Shanghai Arch Psychiatry. 2015; 27(6): 381-385. doi:]


Comorbid bipolar disorder and obsessive-compulsive disorder: state of the art in pediatric patients

Matteo TONNA, Andrea AMERIO, Anna ODONE, Brendon STUBBS, S. Nassir GHAEMI