·In this issue·

·In this issue·

This issue begins with a meta-analysis by Zhu and colleagues[1]focused on the potential therapeutic effectiveness of the ‘psychological placebos’ used as control conditions in randomized controlled trials (RCTs)about the usefulness of cognitive behavioral therapy(CBT) in the treatment of generalized anxiety disorder.The unsurprising finding was that relaxation training,nondirective support groups, and similar non-specific interventions had a non-negligible therapeutic effect(compared to a wait list condition) that needs to be taken into consideration when designing or evaluating trials about the effectiveness of psychotherapy. A secondary finding of the study was the authors’ inability to identify any high-quality RCTs about CBT in low- and middle-income countries. Given the lack of such studies in their own settings, clinicians in these countries usually follow treatment guidelines based on psychotherapy research in high-income countries. Considering the very different sociocultural environment of their patients compared to patients in high-income countries, it is by no means certain that this is appropriate. Clearly, more high-quality psychotherapy research is needed in non-Western settings.

The more surprising, and potentially more important, finding of this meta-analysis was that the 12 RCTs of CBT included in the analysis had serious limitations in terms of risk of bias and quality of evidence. Eight of the 12 studies were considered at high risk of bias, in 6 of the 12 studies the main outcome depended on the results of self-rated scales (so the outcome assessment was not blinded), and the overall quality of evidence using the Cochrane GRADE (Grading of Recommendations Assessment, Development and Evaluation) tool[2]was judged as ‘moderate’, which indicates that future research could change the overall conclusion about the efficacy of CBT in the treatment of generalized anxiety disorder. Thus, despite the widely accepted conventional wisdom about the effectiveness of CBT,[3]it does not, apparently, meet the most rigorous criteria of effectiveness developed by the Cochrane Collaboration.

The first original research article in this issue by Zhou and Gu[4]reports on a 30-month, single-blind,randomized controlled trial of self-management training among 201 community-dwelling individuals with chronic schizophrenia. The results of this intervention– including 6 months of weekly skills training and 24 months of monthly booster sessions – are impressive. A total of 194 (95.6%) of the participants completed the 30-month follow-up, by which time only 2 of the 103(1.9%) intervention group patients had relapsed but 14 of the 98 (14.3%) control group patients (who received regular outpatient treatment) had relapsed. Assessment by blinded evaluators also found that the intervention group patients had significantly better medication adherence and insight into their illness. Further research is needed to assess the effect of this intervention on the social functioning and quality of life of patients. And cost-benefit analyses of this self-management training are needed to assess the feasibility of up-scaling this promising approach.

The second original research article by Zhang and Lan[5]randomly assigned 150 first-episode, drug-naive patients with schizophrenia to 8 weeks of treatment with olanzapine, quetiapine, or aripiprazole and assessed changes in glucose and lipid parameters over the 8 weeks. There were no significant differences in the clinical effectiveness of the three medications but there were differences in their effects on glucose and lipid metabolism: fasting glucose increased in the olanzapine group but not in the other two groups; and the increase in triglycerides and the decrease in highdensity lipoprotein were greater in the olanzapine and quetiapine groups than in the aripiprazole group.These results are similar to previous reports, but the great advantage of this study was that it was conducted in patients who had not previously taken antipsychotic medication, so it avoids the potential confounding effect of prior medication usage. Further study is needed to determine whether or not the more benign metabolic effects of aripiprazole compared to olanzapine and quetiapine persist when the medications are administered over longer periods oftime.

The third original research article by Hocaoglu and colleagues[6]is a cross-sectional study about sexual dysfunction among outpatients with schizophrenia in Turkey. The sexual functioning of patients is an increasingly important issue because of its potential effect on patients’ quality of life and, in some cases,on their adherence to medication. But the relative importance in the etiology of sexual functioning of the illness itself versus the chronic use of antipsychotic medication remains unclear. The authors assessed five components of sexual functioning – sex drive, sexual arousal, vaginal lubrication/penile erection, ability to achieve orgasm, and satisfaction with orgasm – using the Arizona Sexual Experience Scale (ASEX),[7]a simple self-completion instrument that has been validated in Turkey. This was administered to 101 stable outpatients(who had been ill for a mean of 15 years) and to 89 healthy controls of similar gender, age, and educational attainment to the patients. The authors found that male patients have a much higher prevalence of self-reported sexual dysfunction than male controls (46% vs. 8%),but the self-reported prevalence of sexual dysfunction was equally high in female patients (68%) and healthy females (68%). It appears that the very conservative attitudes and expectations about female sexuality in Turkey obscure any potential negative effects on sexual functioning of the schizophrenic illness and of antipsychotic medications. This result highlights the need to consider location-specific and gender-specific sexual norms when trying to assess the relationships between mental illness, psychiatric medications, and sexual functioning.

The Forum in this issue includes four separate comments[8-11]on the issue of antidepressant polypharmacy, an increasingly common practice that may or may not be a useful alternative approach for dealing with treatment-resistant depression. The lead piece in the section by Si and Wang[8]highlights the increasing realization by clinicians and researchers that the substantial proportion of individuals treated for depression who do not recover fully are suffering from a chronic, disabling condition. This realization has resulted in increased efforts to develop alternative or adjunctive interventions that can improve outcomes for this group of patients. There is, as yet, no universally accepted definition of ‘treatment-resistant depression,’but, given the multiple etiological pathways that lead to this condition, it is clear that an array of different approaches will be needed to increase the proportion of these individuals who can be effectively treated. The question addressed by the Forum is whether or not simultaneous treatment with multiple antidepressants that have different mechanisms of action should be one of the accepted strategies to be tried in these difficult-to-treat patients. Some authors think that these patients are so disabled that all approaches – including antidepressant polypharmacy – should be vigorously pursued, while others caution about the potential of severe side effects from combined treatment with multiple antidepressants. Some believe that the current tendency to prematurely use multiple antidepressants before rigorously assessing monotherapy with different types of antidepressants should be reversed. Others suggest that better sub-categorization of different types of treatment-resistant depression may help determine which types of patients would benefit from which types of augmented or alternative treatments. As one might expect, all commentators agree that more focused research is needed on the issue.

The case report in this issue by Yang and colleagues[12]discusses a patient with bipolar disorder who developed neuroleptic malignant syndrome (NMS)within days of changing his medication regimen from lithium plus clozapine to lithium plus haloperidol.The case revisits the debate about whether or not patients receiving the combination of lithium and an antipsychotic medication – a common treatment strategy for bipolar patients with psychotic symptoms– are at higher risk of developing NMS than those receiving monotherapy with an antipsychotic medication. It is clear that case reports will not resolve this question. NMS remains such a rare event and the number of potential confounding factors is so great that definitive resolution of this question about the potential increased risk of NMS when being treated with lithium must wait until ‘big data’ makes it possible to integrate high-quality treatment and adverse event information on millions of individuals being treated with antipsychotic medications.

The research methods article by Cheng and Phillips[13]discusses the advantages and disadvantages of conducting secondary analyses of existing data sets.There are several international initiatives aimed at improving the efficiency of the health research effort by increasing the access of qualified researchers to government-funded health research results and to health registry data so they can use existing data to address new problems rather than conducting new studies for each separate question of interest. But progress in developing widely available, high-quality data sets about important health issues is slow –particularly in low- and middle-income countries –because of the many legal, financial, and professional barriers that make many researchers and governments reluctant to share their data.

The biostatistics in psychiatry paper by Liu and colleagues[14]describes the developing analytic technology for the new wave of studies that employ dynamic treatment regimens (DTRs). Rather than simply assessing the effectiveness of a single treatment strategy – the goal of traditional clinical randomized controlled trials – these studies more closely parallel clinical practice by assessing a variety of sequenced treatment strategies in which each step in the sequence is partially determined by the outcome of the preceding step. These studies are called sequential multiple assignment randomized trials (SMARTs).Well-known studies in mental health that use this design are the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial[15]and the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)for treating schizophrenia.[16]The methods for analyzing data generated by such studies are still evolving and will probably require the involvement of biostatistical consultants (the analytic methods are too complex for most clinical researchers), but the potential utility of the results from such studies makes the added analytic burden well worth the effort.

1. Zhu ZP, Zhang L, Jiang JL, Li W, Cao XY, Zhou ZR, et al. 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.Shanghai Arch Psychiatry.2014; 26(6): 319-331. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214173

2. Higgins JPT, Green S (eds).Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011; Available from: www.handbook.cochrane.org

3. Hofmann SG, Smits JA. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials.J Clin Psychiatry. 2008; 69(4):621-632

4. Zhou B, Gu YW. Effect of self-management training on adherence to medications among community residents with chronic schizophrenia: a single-blind randomized controlled trial in Shanghai, China.Shanghai Arch Psychiatry. 2014; 26(6): 332-338. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214076

5. Zhang SF, Lan GH. Prospective 8-week trial of effect of olanzapine, quetiapine, and aripiprazole on blood glucose and lipids among individuals with first-onset schizophrenia.Shanghai Arch Psychiatry. 2014; 26(6): 339-346. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214037

6. Hocaoglu C, Celik FH, Kandemir G, Guveli H, Bahcecei B.Sexual dysfunction in outpatients with schizophrenia in Turkey: a cross-sectional study.Shanghai Arch Psychiatry.2014; 26(6): 347-356. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214101

7. McGahuey CA, Gelemberg AJ, Laukes CA, Moreno FA,Delgado PI, Mc Knight KM, Manber R. The Arizona Sexual Experience Scale (ASEX): reliability and validity.J Sex Marital Ther.2000; 26: 25-40. doi: http://dx.doi.org/10.1080/009262300278623

8. Si TM, Wang P. When is antidepressant polypharmacy appropriate in the treatment of depression?Shanghai Arch Psychiatry. 2014; 26(6): 357-359. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214152

9. Saah T, Garlow SJ, Rapaport MH. Provide optimized antidepressant monotherapy with multiple drugs before considering antidepressant polypharmacy.Shanghai Arch Psychiatry. 2014; 26(6): 360-362. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214182

10. Dunner DL. Combining antidepressants.Shanghai Arch Psychiatry. 2014; 26(6): 363-364. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214177

11. Peng DH, Fang YR. Evaluation of antidepressant polypharmacy and other interventions for treatmentresistant depression.Shanghai Arch Psychiatry. 2014;26(6): 365-367. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214180

12. Yang YF, Guo YH, Zhang AG. Neuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol.Shanghai Arch Psychiatry. 2014;26(6): 368-370. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214099

13. Cheng HG, Phillips MR. Secondary analysis of existing data: opportunities and implementation.Shanghai Arch Psychiatry. 2014; 26(6): 371-375. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214171

14. Liu Y, Zheng DL, Wang YJ. Use of personalized Dynamic Treatment Regimes (DTRs) and Sequential Multiple Randomized Trials (SMARTs) in mental health studies.Shanghai Arch Psychiatry. 2014; 26(6): 376-383. doi: http://dx.doi.org/10.11919/j.issn.1002-0829.214172

15. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH,Sackeim HA, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.Control Clin Trials. 2004; 25(1): 119-142. doi: http://dx.doi.org/10.1016/S0197-2456(03)00112-0

16. Schneider LS, Ismail MS, Dagerman K, Davis S, Olin J, McManus D, et al. Clinical antipsychotic trials of intervention effectiveness (CATIE): Alzheimer’s disease trial.Schizophr bull. 2003; 29(1): 57. doi: http://dx.doi.org/10.1093/schbul/sbj026

A full-text Chinese translation of this article will be available at www.shanghaiarchivesofpsychiatry.org on January 25, 2015.