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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 32, November 2014: Guest Commentator‎Angelo Sambunaris, MD, Medical Director at Institute for Advanced Medical Research

Adipokines as Emerging Depression Biomarkers:  A Systematic Review and Meta-Analysis

Carvalho, AF, et. al.
J Psychiatr Res. 2014 AUG 19. pii:  S0022-3956(14)00238-6. (Epub ahead of print)



Adiponectin, leptin and resistin are hypothesized to play a role in the pathophysiology of major depressive disorder (MDD).   The purpose of this study was to determine if adipokines are biomarkers using a meta-analysis approach across diagnostic studies and intervention studies. 



  • A meta-analyses was performed of diagnostic studies (i.e., MDD subjects versus healthy controls) and intervention investigations (i.e., pre-vs. post-antidepressant treatment) in MDD.


  • Differences in peripheral levels of these hormones are inconsistent across diagnostic and intervention studies.
  • Adiponectin (N = 1278; Hedge's g = -0.35; P = 0.16) and leptin (N = 893; Hedge's g = -0.018; P = 0.93) did not differ across diagnostic studies. 
  • Meta-regression analyses revealed that gender and depression severity explained the heterogeneity observed in adiponectin diagnostic studies, while BMI and the difference in BMI between MDD individuals and controls explained the heterogeneity of leptin diagnostic studies.
  • Subgroup analyses revealed that adiponectin peripheral levels were significantly lower in MDD participants compared to controls when assayed with RIA, but not ELISA.
  • Leptin levels were significantly higher in individuals with mild/moderate depression versus controls.
  • Resistin serum levels were lower in MDD individuals compared to healthy controls (N = 298; Hedge's g = -0.25; P = 0.03).
  • Leptin serum levels did not change after antidepressant treatment.However, heterogeneity was significant and sample size was low (N = 108); consequently meta-regression analysis could not be performed. 
  • Intervention meta-analyses could not be performed for adiponectin and resistin (i.e., few studies met inclusion criteria).
  • In conclusion, this systematic review and meta-analysis underscored that relevant moderators/confounders (e.g., BMI, depression severity and type of assay) should be controlled for when considering the role of leptin and adiponectin as putative MDD diagnostic biomarkers.


Cytokines are immunomodulating agents and some consider adipokines to be cytokines but there is disagreement as to their placement in this category of potential biomarkers as they do not react within the immune system.  The question then is whether they should be considered adipose tissue derived hormones and what roles do these hormones play in depression.  Interestingly, in order for a meta-analysis to occur there should be standardization of the data collection process.  In this case there was variance including diagnosis, treatment interventions, ELISA versus RIA tests, severity of disease, BMI, gender, etc.

The search for biomarkers in the field of depression research is important but uniformity of data collection and size of datasets is critical to the establishment of a biomarker that withstands the rigors of time. The collection of larger datasets with uniform testing of samples might fall under the purview of academic networks or the NIMH rather than relying on interpretation based on meta-analyses of small datasets.   Perhaps RDOC criteria could also play a role in minimizing variance and thus moving the field along.

Although the work is important there is need for standardization before interpretations can be made.


Seasonal Variation of Depressive Symptoms in Unipolar Major Depressive Disorder.

Cobb, BS et. al
Comp Psychiatry 2014 AUG 4. pii:  S0010-440x(14)00190-4.



Retrospective and cross-sectional studies of seasonal variation of depressive symptoms in unipolar major depression have yielded conflicting results. This study examined seasonal variation of mood symptoms in a long-term prospective cohort - the Collaborative Depression Study (CDS).


Two hundred ninety-eight CDS participants from five academic medical centers with a prospectively derived diagnosis of unipolar major depression were included in this sample that were followed for at least ten years of annual or semi-annual assessments.  Generalized linear mixed models were utilized to investigate the presence of seasonal patterns.  In a subset of 271 participants followed for at least 20 years, the stability of a winter depressive pattern was assessed across the first two decades of follow-up.


  • A small increase in proportion of time depressed was found in the months surrounding the winter solstice.
  • The greatest symptom burden was seen in December through April with a peak in March.
  • The relative burden of winter depressive symptoms in the first decade demonstrated no relationship to that of the second decade.
  • The onset of new episodes was highest October through January, peaking in January.


A very interesting trial with results that would be expected based on one’s clinical experience.  The beauty of this design was borne out of necessity, to find enough patients to follow over a span of ten years or more.  Although the n is small for such a trial the results are still interesting.  There are many other questions to address in a program such as this such as: how many unipolar patients were found to be bipolar and if bipolar which type, I or II; how many were lost to follow-up; what was data on medication compliance versus non-compliance over these winter months.  It would be interesting to see if sub-group analyses provide a clinician with any additional guidance on diagnosis, treatment, and follow-up through the winter months versus summer months for patients with unipolar depression.


Improvement in Suicidal Ideation after Ketamine Infusion: Relationship to Reductions in Depression and Anxiety.

Ballard, ED, et. al.
J Psychiatr Res. 2014 NOV;58:161-6.



Suicide is a psychiatric emergency. There are no approved pharmacologic treatments for suicidal ideation.  Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal ideation as well as depression and anxiety, but the dynamic between these symptoms is not known. The aim of this analysis was to evaluate whether ketamine has an impact on suicidal thoughts, independent of depressive and anxiety symptoms.


133 patients with treatment-resistant depression (major depressive disorder or bipolar I/II disorder) received a single sub-anesthetic infusion of ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAMA) focusing on 230 min post-infusion.


  • At 230 min post-infusion, correlations between changes in suicidal ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to 19% in the variance of ideation change.
  • Correlations with anxiety ranged from 0.23 to 0.40 (p < .05), accounting for similar levels of variance.
  • Ketamine infusion was associated with significant reductions in suicidal ideation compared to placebo, when controlling for the effects of ketamine on depression (F1,587 = 10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004).


Another interesting study emanating from the Zarate lab at NIMH and providing more data in support of  ketamine as a putative approach to the treatment of depression.   The trial size is large although it must be difficult to calculate the power analysis for programs of this specific focus, suicidal ideation.  The objectives note that there are no approved pharmacologic treatments for suicidal ideation.  Many clinicians might beg to differ stating that antidepressants and other psychopharmacologic agents prevent suicide but the key point here is that approval is a regulatory item and the FDA has not given approvals for symptomatology but rather gives approvals for treatments of diagnoses. 

Thus a question is raised as to whether the correlation in this trial between improvement in depression and anxiety was due to changes in somatic anxiety symptoms or due to alleviation of psychic symptoms or due to a simple improvement in depression (sub-items) raises an interesting question.  A new study comparing Ham-A to MADRS would be a possibility but Zarate and colleagues could also remove confusion by focusing on items from the Bech subscale in order to correlate change to strictly depression or other items.  An item analysis would also be beneficial.

So although questions arise as to why the change the data are important as well as the change in the mindset of the FDA allowing symptomatology to be tested rather than a diagnostic entity.


Effectiveness of a Smartphone App for Guiding Antidepressant Drug Selection.

Man, C. et. al.
Fam Med 2104 Sep: 46(8); 626-30


The purpose of this study was to assess the impact of a mobile application on the confidence level of family physicians in treating depression.


The smartphone application was provided to 14 family medicine residents and attending physicians from the O'Connor Family Medicine Residency Program in San Jose, CA.  Participants were asked to use the software as drug reference and clinical decision support during patient care activities.  Three surveys were administered over a 12-week period to assess provider characteristics, outcome measures (i.e. confidence in managing depression and choosing an initial antidepressant based on patient symptoms, medical comorbidities, potential side effects, and drug interactions), and fund of antidepressant knowledge.


  • The average confidence levels in managing depression, starting an antidepressant on a patient with depression, and choosing an initial antidepressant based on patient symptoms increased significantly within the period of smartphone application usage.
  • The average scores on the antidepressant knowledge tests also improved.


Computer programs have been used to assist in educational settings and as well as in development and use of algorithms.  In a mobile society the smartphone application fits well into the requirements of the on-the-go physician.  Being readily available and easy to use one would expect it to be an effective tool for both increasing confidence in depression treatment and educating physicians. Future studies on the impact on medical education are warranted.


Assessment and Lifestyle Management of Patients with Obesity:  Clinical Recommendations from Systematic Reviews.

Kushner, RF, Ryan, DH
JAMA 2014 Sep 3;312(9):943-52


To describe current best practices for assessment and lifestyle management of obesity and to demonstrate how the updated Guidelines (2013) for Managing Overweight and Obesity in Adults based on a systematic evidence review sponsored by the National Heart, Lung, and Blood Institute (NHLBI) can be applied to an individual patient.


Systematic evidence review conducted for the Guidelines (2013) for Managing Overweight and Obesity in Adults supports treatment recommendations in 5 areas (risk assessment, weight loss benefits, diets for weight loss, comprehensive lifestyle intervention approaches, and bariatric surgery); for areas outside this scope, recommendations are supported by other guidelines (for obesity, 1998 NHLBI-sponsored obesity guidelines and those from the National Center for Health and Clinical Excellence and Canadian and US professional societies such as the American Association of Clinical Endocrinologists and American Society of Bariatric Physicians; for physical activity recommendations, the 2008 Physical Activity Guidelines for Americans); a PubMed search identified recent systematic reviews covering depression and obesity, motivational interviewing for weight management, metabolic adaptation to weight loss, and obesity pharmacotherapy.


  • The first step in obesity management is to screen all adults for overweight and obesity. A medical history should be obtained assessing for the multiple determinants of obesity, including dietary and physical activity patterns, psychosocial factors, weight-gaining medications, and familial traits.
  • Emphasis on the complications of obesity to identify patients who will benefit the most from treatment is more useful than using body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) alone for treatment decisions.  The Guidelines (2013) recommend that clinicians offer patients who would benefit from weight loss (either BMI of ≥30 with or without comorbidities or ≥25 along with 1 comorbidity or risk factor) intensive, multicomponent behavioral intervention. Some clinicians do this within their primary care practices; others refer patients for these services.
  • Weight loss is achieved by creating a negative energy balance through modification of food and physical activity behaviors. The Guidelines (2013) endorse comprehensive lifestyle treatment by intensive intervention.
  • Treatment can be implemented either in a clinician's office or by referral to a registered dietitian or commercial weight loss program. Weight loss of 5% to 10% is the usual goal. It is not necessary for patients to attain a BMI of less than 25 to achieve a health benefit.


Excellent review.  The Primary Care setting is the first line in healthcare consideration and treatment recommendation with regard to this problem.  Some Primary Care providers may elect to refer patients out for treatment but this review suggests that screening criteria, and the initial discussion, should begin in the PCP setting.

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