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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


Issue 26, May 2014—Guest Commentator: Chi-Un Pae, MD, PhD, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea



Influence of RGS2 on Sertraline Treatment for Social Anxiety Disorder

Stein MB, Keshaviah A, Haddad SA, et al
Neuropsychopharmacology. 2013 Oct 24. doi: 10.1038/npp.2013.301. [Epub ahead of print]

: To evaluate several candidate genetic predictors of SSRI response in social anxiety disorder (SAD).

• 346 patients with SAD received an open-label treatment with sertraline (up to 200 mg/d) over 10 weeks.

• Efficacy was determined using a continuous measure of outcome (Liebowitz Social Anxiety Scale (LSAS) and dichotomous indicators of response (LSAS≤50) and remission (LSAS≤30).

• Predictors of efficacy were examined in multivariate regression models that included eight polymorphic variants in four candidate genes (four in RGS2, two in HTR2A, one in SLC6A2, and one in SLC6A4).

ResultsAdjusting for covariates, all four single-nucleotide polymorphisms (SNPs) in RGS2 predicted change in LSAS over time, at study-wise significance (p=0.00833), with the minor allele associated with less improvement over time. After adjusting for covariates, two of the four RGS2 SNPs (Table) predicted likelihood of remission at or just below study-wise significance (p=0.025). 

Likelihood of Remission


P Value

SNP rs4606

OR=0.49, 95% CI=0.27-0.90


SNP rs1819741

OR=0.50, 95% CI-0.28-0.92


Conclusions: Variation in RGS2, a gene previously shown to be associated with social anxiety phenotypes and serotonergic neurotransmission, may be a biomarker of the likelihood of substantially benefiting from sertraline among patients with SAD. 

Clinical Commentary
Approximately 30% of depressed patients remit with initial antidepressant treatment. For the remaining patients, risk of recurrence significantly increases with each subsequent treatment failure. In this context, the present pharmacogenetic data are in line with the unmet need for predictive biomarkers of SSRI response in SAD for identifying responders and nonresponders before starting a treatment in clinical practice. However, additional research is mandatory to support and replicate this finding.


Assessment of Plasma C-Reactive Protein as a Biomarker of Posttraumatic Stress Disorder Risk

Eraly SA, Nievergelt CM, Maihofer AX, et al
JAMA Psychiatry. 2014 Feb 26. doi: 10.1001/jamapsychiatry.2013.4374. [Epub ahead of print]


Objective: To determine whether plasma concentration of the inflammatory marker C-reactive protein (CRP) helps predict posttraumatic stress disorder (PTSD) symptoms

• The present study was a part of the Marine Resiliency Study (MRS)

• PTSD symptoms and various physiological and psychological parameters were assessed before deployment and at approximately 3 and 6 months following a 7-month deployment.

• Primary endpoint: Severity of PTSD symptoms 3 months after deployment assessed by the Clinician-Administered PTSD Scale (CAPS).

• Among consented subjects, 2,555 (85.8%) were included in the analysis.

Results: Baseline plasma CRP concentration were found to be a highly significant overall predictor of post-deployment CAPS scores (P=.002). Each 10-fold increment in CRP concentration was associated with an odds ratio of nonzero outcome (presence vs absence of any PTSD symptoms) of 1.51 (95% CI, 1.15-1.97; P=.003) and a fold increase in outcome with a nonzero value (extent of symptoms when present) of 1.06 (95% CI, 0.99-1.14; P=.09).

Conclusions: A marker of peripheral inflammation, plasma CRP may be prospectively associated with PTSD symptom emergence, suggesting that inflammation may predispose to PTSD.

Clinical Commentary
The present study is in line with the hypothesis that PTSD may be predisposed by a dysregulation of the stress axis resulting in disinhibition of pro-inflammatory pathways. The strengths of the study are a huge sample size, prospective design, and adjustment for multiple potential confounders. The present study at least indicates that treatment with dietary or lifestyle modifications, which are associated with a decrease of inflammation, may effectively ameliorate the severity of this disorder. Further, such interventions can be combined with traditional pharmacological treatments, possibly leading to better treatment outcomes.



A Meta-analysis of the Risk of Major Affective Disorder in Relatives of Individuals Affected by Major Depressive Disorder or Bipolar Disorder

Wilde A, Chan HN, Rahman B, et al
J Affect Disord. 2014;158:37-47. doi: 10.1016/j.jad.2014.01.014. Epub 2014 Feb 5.


Objective: To conduct a meta-analysis to estimate the incidence of major depressive disorder (MDD) and bipolar disorder (BD) in first-degree relatives (FDRs) of probands affected by MDD or BD.


• A systematic review of case-control and cohort studies, which were published between 1977 and 2012.

• Relative risks (RR) or odd ratios (OR) or equivalent raw data were reported.

• Data search was based on electronic MEDLINE and EMBASE and hand-searching.

• Estimates were derived from pooled data using random effects methods.

ResultsThe MEDLINE and EMBASE searches resulted in 241 records. Two additional reports were identified by hand search. After removal of 28 duplicates, 215 records remained. Of these studies, 22 studies were eventually included after excluding all irrelevant studies based on titles, abstract, and full-text reading. The pooled OR estimates for MDD or BD in FDRs of either one or two probands with either MDD or BD were OR=2.59 (95% CI 2.09–3.21, all studies). For FDRs of one proband with MDD compared to healthy control probands, pooled estimates for MDD were OR=2.14 compared to FDRs of healthy control probands from 13 studies (Table). The OR was increased to 3.23 for two MDD probands with data from five studies. For FDRs of one BD proband compared to healthy control probands, estimates for BD were OR=7.92 and OR=6.58 for FDRs of two BD probands.

First-degree Relatives


One MDD proband

OR=2.14 (95% CI 1.72-2.67)

Two MDD probands

OR=3.23 (95% CI 2.11-4.94)

One BD proband

OR=7.92 (95% CI 2.45-25.61)

Two BD probands

OR=6.58 (95% CI 2.64-16.43)

Clinical Commentary
This is the first meta-analysis investigating familial loading for BD, and the first meta-analysis of shared genetic vulnerability for MDD and BD, and risk of MDD in more than one proband. The present meta-analysis includes data from 22 case-control and cohort studies, which investigated odds of MDD or BD in 10,859 relatives of probands with diagnoses of MDD or BD. The present meta-analysis confirms that elevated family loading remains the best predictive risk factor for MDD and BD. The need of development of a vulnerability index tailored to familial loading of affective disorders would be necessary and very helpful for better understanding of those risk factors and future researches. 



Omega-3 Fatty Acids in the Prevention of Interferon-Alpha-Induced Depression: Results from a Randomized, Controlled Trial

Su KP, Lai HC, Yang HT, et al
Biol Psychiatry. 2014 Jan 24. pii: S0006-3223(14)00047-X. doi: 10.1016/j.biopsych.2014.01.008. [Epub ahead of print]


Objective: To investigate the effects of Omega-3 polyunsaturated fatty acids (FAs) in patients with interferon (IFN)-α induced depression since the lower erythrocyte levels of FAs were found to be associated with an increased risk of such clinical condition. 

• A 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo in 162 patients with IFN-α induced depression.

• Among participants, 152 patients were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis (weeks -2, 0, 2, 4, 6, 8, 12, 16, 20, and 24).

• The depressive and neuro-vegetative symptoms were assessed by Hamilton Rating Scale for Depression (HAMD) and Neurotoxicity Rating Scale (NTRS), respectively at each visit.

Results: The incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p=.037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p=.002). The EPA intervention significantly increased EPA (+32%, p=.009) and DHA levels (+17%, p=.016). The DHA intervention significantly increased DHA (+27%, p=.002) but not EPA levels (−5%, p=.6).

Conclusion: The EPA pretreatment significantly decreased the incidence of IFN-α-induced depression in HCV patients. In addition, both EPA and DHA pretreatment significantly delayed the onset of IFN-α-induced depression as compared with placebo pretreatment.

Clinical Commentary
Emerging evidence consistently support the utility of FAs in the treatment of patients with depression as one of promising complimentary medicines, in particular, for depressed patients with partial response or tolerability issues from antidepressant treatment. In this context, this is the first study to demonstrate the beneficial effects of FAs in the prevention of IFN-α-induced depression. This study has a direct clinical relevance in that HCV patients receiving IFN-α may have some limitations in the use of contemporary antidepressants such as SSRIs due to safety and tolerability issues; FAs may possibly provide such patients with a safe and well-accepted alternative antidepressant treatment. However, conclusive remark on the exact role of FAs in the treatment of IFN-α-induced depression should be cautious till today since these findings should need to be supported by more adequately-powered and well-designed clinical trials.



Effect of Anxiolytic and Hypnotic Drug Prescriptions on Mortality Hazards: Retrospective Cohort Study

Weich S, Pearce HL, Croft P, et al.
BMJ. 2014 Mar 19;348:g1996. doi: 10.1136/bmj.g1996.


Objective: To test the hypothesis that people taking anxiolytic and hypnotic drugs are at increased risk of premature mortality, using primary care prescription records and after adjusting for a wide range of potential confounders 

• Retrospective cohort study using General Practice Research Database based on 273 UK primary care practices.

• 34,727 patients aged 16 years and older first prescribed anxiolytic or hypnotic drugs, or both, between 1998 and 2001, and 69,418 patients with no prescriptions for such drugs (controls) matched by age, sex, and practice.

• Followed-up for a mean of 7.6 years

• Primary outcome was the all cause mortality ascertained from practice records.

Results: Physical and psychiatric comorbidities and prescribing of non-study drugs were significantly more prevalent among those prescribed study drugs than among controls. The age adjusted hazard ratio (HR) for mortality during the whole follow-up period for use of any study drug in the first year after recruitment was 3.46 (95% confidence interval 3.34 to 3.59) and 3.32 (3.19 to 3.45) after adjusting for other potential confounders. Dose-response associations were found for all three classes of study drugs [benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs)]; the HRs were largest for benzodiazepines (3.89 for any daily dose vs 3.5 for Z drugs and 2.18 for other study drugs). These numbers increased to 6.75, 4.83, and 3.34, respectively, for those prescribed more than 90 daily doses in the first year of follow-up. After excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription. Crude cumulative mortality in those given drugs was 26.46 per 100 people over the full follow-up period compared with 16.82 per 100 controls.

Conclusion: In this large cohort study, anxiolytic and hypnotic drugs were associated with significantly increased risk of mortality over a 7-year period, after adjusting for a range of potential confounders. These results are cautiously interpreted due to potential bias arising from unmeasured and residual confounding.

Clinical Commentary
The greatest strength of the present study is the use of a large data from the General Practice Research Database, based on its sample size, representativeness of the sample, data completeness, and duration of the follow-up. These findings are consistent with previous evidence of a statistically and clinically significant association between anxiolytic and hypnotic drugs and mortality. However, cohort studies are also prone to immortal time bias, which arises if the period participants are considered at risk differs between comparator groups.


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