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Systematic review and meta-analysis

Comparison of psychological placebo and waiting list control conditions in the assessment of cognitive behavioral therapy for the treatment of generalized anxiety disorder: a meta-analysis

Zhipei ZHU, Li ZHANG, Jiangling JIANG, Wei LI, Xinyi CAO, Zhirui ZHOU, Tiansong ZHANG

Background: There is ongoing debate about the efficacy of placebos in the treatment of mental disorders. In randomized control trials (RCTs) about the treatment of generalized anxiety disorder, the administration of a psychological placebo or placement on a waiting list are the two most common control conditions. But there has never been a systematic comparison of the clinical effect of these different strategies.
Aim: Compare the change in symptom severity among individuals treated with cognitive behavioral therapy, provided a psychological placebo, or placed on a waiting list using data from RCTs on generalized anxiety disorder.
Methods: The following databases were searched for RCTs on generalized anxiety disorder: PubMed, PsycInfo, EMBASE, The Cochrane Library, CNKI, Chongqing VIP, Wanfang, Chinese Biological Medical Literature Database, and Taiwan Electronic Periodical Services. Studies were selected based on pre-defined inclusion and exclusion criteria and the quality of each included study – based on the risk of bias and the level of evidence – was formally assessed. Meta-analysis was conducted using RevMan5.3 and network meta-analyses comparing the three groups were conducted using R.
Results: Twelve studies with a combined sample size of 531 were included in the analysis. Compared to either control method (placebo or waiting list), cognitive behavioral therapy was more effective for generalized anxiety disorder. Provision of a psychological placebo was associated with a significantly greater reduction of symptoms than placement on a waiting list. Eight of the studies were classified as ‘high risk of bias’, and the overall level of evidence was classified as ‘moderate’, indicating that further research could change the overall results of the meta-analysis.
Conclusions: RCTs about the treatment of generalized anxiety disorders are generally of moderate quality; they indicate the superiority of CBT but the results cannot, as yet, be considered robust. There is evidence of a non-negligible treatment effect of psychological placebos used as control conditions in research studies. This effect should be considered when designing and interpreting the results of randomized controlled trials about the effectiveness of psychotherapeutic interventions.
Keywords: placebo effect; cognitive behavioral therapy; generalized anxiety disorder; effectiveness; meta-analysis; randomized control trial [Shanghai Arch Psychiatry. 2014; 26(6): 319-331. doi:]

Original research article

Sexual dysfunction in outpatients with schizophrenia in Turkey: a cross-sectional study

Cicek HOCAOGLU1, Fatmagul H. CELIK, Gokhan KANDEMIR, Hulya GUVELI, Bulent BAHCECI

Background: Sexual dysfunction is one of several factors related to medication compliance in patients taking antipsychotic medication but the magnitude of this problem is unknown.
Aim: Compare the self-reported sexual functioning of clinically stable patients with schizophrenia taking antipsychotic medication to that of healthy controls using the Turkish version of the 5-item Arizona Sexual Experience Scale (ASEX). This scale, which has previously been validated in Turkey, assesses 5 components of sexual function: sex drive, sexual arousal, vaginal lubrication/penile erection, ability to achieve orgasm, and satisfaction with orgasm.
Methods: The Scale for the Assessment of Positive Symptoms, the Scale for Assessment of Negative Symptoms, and ASEX were administered to 101 clinically stable outpatients with schizophrenia (38 females and 63 males). The ASEX was also administered to 89 control subjects (41 females and 48 males) without a history of mental illness. Respondents were classified as having sexual dysfunction if ASEX total score (range 5-30) >18, if any ASEX item score (range 1-6) ≥ 5, or if 3 or more ASEX items ≥4.
Results: Male patients with schizophrenia have significantly more self-reported sexual dysfunction than healthy controls (46% vs. 8%). The prevalence of sexual dysfunction is higher in female patients than in male patients (68% vs. 46%), but it was also very high in healthy female controls (68%), so the sexual dysfunction of female patients cannot be attributed to their illness or to the medications they are taking. Within the patient group, there was no significant relationship between the severity of positive or negative symptoms and the severity of sexual dysfunction, and the severity of sexual function was not different between patients taking first-generation or second-generation antipsychotic medications.
Conclusions: The very different findings by gender in Turkey highlights the importance of assessing location-specific and gender-specific sexual norms when trying to assess the role of mental illness and medications on sexual functioning. Prospective studies are needed to distinguish the relative importance of cultural norms, the schizophrenic illness, and the use of antipsychotic medication in the etiology and course of sexual dysfunction among individuals with schizophrenia.
Keywords: antipsychotic medication; schizophrenia; sexual dysfunction; sexual norms; Turkey [Shanghai Arch Psychiatry. 2014; 26(6): 347-356. doi:]


Effect of self-management training on adherence to medications among community residents with chronic schizophrenia: a single-blind randomized controlled trial in Shanghai, China

Bin ZHOU, Yiwei GU

Background: Many community dwelling individuals with schizophrenia do not take medications regularly and, thus, are prone to frequent relapses.
Aim: Evaluate the effectiveness of self-management training on adherence to medications and relapse among individuals with chronic schizophrenia living in the community.
Methods: A total of 201 individuals with chronic schizophrenia living in the urban and rural communities of Shanghai Municipality were randomized into a treatment as usual control group (n=98) or a self-management intervention group (n=103) that received weekly self-management skills training for 6 months followed by 24 months of monthly group booster sessions in which a community health worker reviewed patients’ self-management checklists. Two psychiatrists blind to the treatment status of patients, assessed adherence to medications using the Morisky Medication Adherence Scale and patients’ insight into their illness using the Scale to Assess Unawareness of Mental Disorders (SAUMD) at baseline and 30 months after baseline. A total of 194 individuals (95.6%) completed the study.
Results: There were no differences between groups at baseline, but after 30 months the intervention group had significantly better medication compliance, significantly greater insight into their illness, and (by self-report) were using significantly higher dosages of antipsychotic medication. Only 2 (1.9%) of the 103 intervention group participants relapsed (i.e., experienced one or more re-hospitalizations) over the 30 months of follow-up, but 14 (14.3%) of the 98 control group subjects relapsed (X2=8.83, p=0.003).
Conclusions: Given the large sample size, relatively long follow-up, randomized design, and single-blind evaluation of outcomes the dramatic reduction in relapse and improvements in medication adherence and insight identified in this study are robust findings. These results extended our previous findings, which demonstrated the benefit of self-management training on improving the symptoms and social functioning of individuals with chronic schizophrenia living in the community. Cost-benefit studies are now needed to assess the feasibility of up-scaling this self-management intervention to a wide range of communities.
Keywords: schizophrenia; community mental health services; self-care; medication adherence; insight; relapse; re-hospitalization; randomized controlled trial; China [Shanghai Arch Psychiatry. 2014; 26(6): 332-338. Epub 2014 Nov 07. doi:]


Prospective 8-week trial on the effect of olanzapine, quetiapine,and aripiprazole on blood glucose and lipids among individuals with first-onset schizophrenia

Shufen ZHANG, Guanghua LAN

Background: Metabolic symptoms induced by antipsychotic medication have been widely documented but there have been few studies comparing the effect of commonly used atypical antipsychotics on blood glucose and lipids among individuals with first-onset schizophrenia. 

Methods: A total of 150 patients with first-onset schizophrenia were randomized into three groups and each group was treated with olanzapine, quetiapine, or aripiprazole for eight weeks. Blood glucose and lipids (including levels of triglyceride, total cholesterol, low-density lipoprotein, and high-density lipoprotein) were tested at baseline and at the end of the 8 weeks of treatment.
Results: Fasting blood glucose increased significantly over the 8 weeks in the olanzapine group but not in the quetiapine or aripiprazole groups. Based on a repeated measures analysis of variance, triglyceride levels increased significantly over the 8 weeks of treatment and high-density lipoprotein decreased significantly over the 8 weeks of treatment. The increase in triglyceride in the olanzapine and quetiapine groups was greater than that in the aripiprazole group, and the decrease in high-density lipoprotein was greater in the olanzapine and quetiapine groups than in the aripiprazole groups.
Conclusions: During the first 8 weeks of treatment of drug-naïve patients with schizophrenia, olanzapine has a greater effect on blood glucose than quetiapine or aripiprazole, and both olanzapine and quetiapine have a greater effect on blood lipids than aripiprazole.
Keywords: schizophrenia; first-episode; antipsychotic medication; lipid metabolism; carbohydrate metabolism; olanzapine; quetiapine; aripiprazole; China [Shanghai Arch Psychiatry. 2014; 26(6): 339-346. doi:]


Provide optimized antidepressant monotherapy with multiple drugs before considering antidepressant polypharmacy
Tammy SAAH, Steven J. GARLOW, Mark H. RAPAPORT
Summary: Many patients with chronic or recurring major depressive disorder have suboptimal responses to the wide range of antidepressant medications available. When confronted with these patients, clinicians may augment the original antidepressant with other medications, including adjunctive treatment with a second or third antidepressant. Although it is a widely-used practice among psychiatrists and primary care physicians in high-income countries, evidence for the benefits of this type of antidepressant polypharmacy is limited. Care should be taken to utilize this approach only after failure of optimized monotherapy with different classes of antidepressants.
Keywords: antidepressants; polypharmacy; augmentation; major depressive disorder; treatment-resistant depression [Shanghai Arch Psychiatry. 2014; 26(6): 360-362. doi:]
Evaluation of antidepressant polypharmacy and other interventions for treatment-resistant depression
Daihui PENG, Yiru FANG

Summary: There is on-going controversy about the definition and sub-classification of treatment-resistant depression (TRD) that makes it difficult to assess the effectiveness of different proposed strategies for treating this chronic, often disabling condition. Sub-classification of TRD in terms of symptom severity and in terms of demographic and clinical characteristics may help in the recognition of homogeneous TRD subgroups and in the development of subgroup-specific interventions. 

Key words: treatment-resistant depression; classification; adjunctive treatment; combined treatment [Shanghai Arch Psychiatry. 2014; 26(6): 365-367. doi:]
Antidepressant polypharmacy: When is antidepressant polypharmacy appropriate in the treatment of depression?
Tianmei SI, Ping WANG

Summary: Depression is a serious medical condition that is often only partially improved or completely unchanged after standard treatment with antidepressant medications. Various approaches have been developed to treat this subgroup of individuals with ‘treatment-resistant’ depression; but many individuals continue to live with chronic depressive symptoms that seriously affect their quality of life and overall functioning. One relatively new strategy is ‘antidepressant polypharmacy’ – simultaneously administering two or more antidepressant medications. Given the heterogeneity of the etiology of depression, this approach could improve therapeutic outcomes by concurrently activating multiple neurological pathways with different mechanisms of action, but there is also the risk that using multiple antidepressants would increase the prevalence and severity of side effects. Further work is needed to assess the potential benefits and risks of this strategy to managing treatment-resistant depression. 

Key words: depression; treatment-resistant depression; antidepressants; polypharmacy; adjunctive treatment; multimodal treatment [Shanghai Arch Psychiatry. 2014; 26(6): 357-359. doi:]
Antidepressant polypharmacy: Combining antidepressants

Summary: Treatment-resistant depression is a common problem encountered by psychiatrists. These patients are often difficult to treat effectively. Strategies for addressing patients with treatment-resistant depression include changing medications, adding another antidepressant (antidepressant polypharmacy), and augmenting treatment with a non-antidepressant. 

Keywords: Treatment-resistant depression; switching antidepressants; antidepressant polypharmacy; augmentation [Shanghai Arch Psychiatry. 2014; 26(6): 363-364. doi:]

Case report

Neuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol
Yanfen YANG, Yahui GUO, Aiguo ZHANG

Summary: A 39-year-old female with a 20-year history of bipolar disorder was admitted due to a recurrence of a manic episode with psychotic symptoms. She was treated with standard doses of lithium carbonate and clozapine. Three days after admission, she showed aggressive behavior and refused to take her medications so her oral clozapine was switched to intramuscular haloperidol. Three days later she developed a high temperature and exhibited symptoms of neuroleptic malignant syndrome (NMS) including excessive sweating, cramps and tremors in limb muscles, muscle rigidity, and impaired consciousness. The haloperidol and lithium were stopped immediately, symptomatic treatment was provided, and she was administered the dopamine agonist bromocriptine. The NMS symptoms resolved within three days but she continued to have severe psychotic symptoms. She was subsequently re-challenged with valproate and olanzapine but the NMS did not re-occur. After one month of this treatment she recovered and was discharged. Several case histories similar to this one suggest – but do not prove – that individuals concurrently receiving lithium and antipsychotic medications may be at higher risk of developing NMS than those receiving monotherapy with antipsychotic medication. 

Key words: lithium carbonate; haloperidol; neuroleptic malignant syndrome; China [Shanghai Arch Psychiatry. 2014; 26(6): 368-370. doi:]

Research methods in psychiatry

Secondary analysis of existing data: opportunities and implementation

Biostatistics in psychiatry

Use of personalized Dynamic Treatment Regimes (DTRs) and Sequential Multiple Randomized Trials (SMARTs) in mental health studies
Ying LIU, Donglin ZENG, Yuanjia WANG

Summary: Dynamic treatment regimens (DTRs) are sequential decision rules tailored at each point where a clinical decision is made based on each patient’s time-varying characteristics and intermediate outcomes observed at earlier points in time. The complexity, patient heterogeneity, and chronicity of mental disorders call for learning optimal DTRs to dynamically adapt treatment to an individual’s response over time. The Sequential Multiple Assignment Randomized Trial (SMARTs) design allows for estimating causal effects of DTRs. Modern statistical tools have been developed to optimize DTRs based on personalized variables and intermediate outcomes using rich data collected from SMARTs; these statistical methods can also be used to recommend tailoring variables for designing future SMART studies. This paper introduces DTRs and SMARTs using two examples in mental health studies, discusses two machine learning methods for estimating optimal DTR from SMARTs data, and demonstrates the performance of the statistical methods using simulated data. 

Keywords: SMART; dynamic treatment regimes; personalized medicine; O-learning; Q-learning; double robust estimation [Shanghai Arch Psychiatry. 2014; 26(6): 376-383. doi:]