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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 27, June 2014—Guest Commentator: Roger S. McIntyre, MD, FRCPC, University of Toronto, Ontario, Canada


Repeated ∆9Tetrahydrocannabinol Exposure in Adolescent Monkeys: Persistent Effects Selective for Spatial Working Memory

Verrico CD, Gu H, Petersen ML, et al.
Am J Psychiatry. 2014;171:416-425.

Objective: The authors sought to determine whether 6 months of repeated intravenous THC administration compared with vehicle would result in 1) persistent adverse effects on performance improvement on spatial versus object working memory tasks and 2) ultra-sensitivity to the acute effects of THC on these tasks.


  • Experimentally naïve Chinese origin rhesus monkeys 14–18 months of age (corresponding with adolescent age in humans).
  • Received THC 5 days/week for up to 6 months
  • During week 1 THC was administered at various doses (15–240 µg/kg) in an ascending order or vehicle
  • On the basis of findings during the first 17–22 weeks of repeated dosing, monkeys were assigned to 120–240 µg/kg 5 days/week.
  • The THC was provided in ethanol by the National Institute on Drug Abuse Drug Supply Program
  • Working memory for both spatial and object memory tasks were administered. The working memory and object memory tasks had been previously validated.
  • Cognitive assessments were measured 23 hours or 71 hours after the most recent administration of THC or vehicle.

: THC administration impaired spatial working memory but not object working memory. It was also noted that the adverse effect of THC on spatial memory was delay-dependent in so far as a greater effect was observed over time. Taken together, the results of the study determined that repeated THC administration impaired the age-and-practice related improvements in accuracy on spatial working memory tasks in a delay-dependent manner but did not impair improvement and accuracy on the object working memory task. It was also determined that neither tolerance nor sensitivity developed to the acute effects of THC on working memory performance. A limitation of this study is that cannabinoids were administered intravenously, which is not necessarily identical to smoking cannabis.

Conclusion: These intriguing findings provide powerful support for adolescent cannabis use as a risk factor for cognitive dysfunction. The deficits that were identified were selective for spatial memoranda and are persistent beyond the period of exposure.

Clinical Commentary
The percentage of high school students reporting cannabis use in the past 12 months was higher than the percentage who reported alcohol use in several recent studies. Clinicians frequently encounter patients who complain of cognitive difficulties across the transnosological spectrum (e.g., schizophrenia, bipolar disorder, major depressive disorder). During the last five years, legitimate access to marijuana has been increasing in many countries and jurisdictions. Clinicians are often asked to address the risks associated with cannabis use in their patients. The data herein suggests that repeat exposure to cannabinoids exerts a detrimental effect that persists on selective measures of cognition.


Structural Brain Development and Depression Onset During Adolescence: A Prospective Longitudinal Study

Whittle S, Lichter R, Dennison M, et al.
Am J Psychiatry. 2014 Feb 28. doi: 10.1176/appi.ajp.2013.13070920. [Epub ahead of print]. 

Objective: The aim of this study was to investigate whether the development of limbic and striatal volumes and prefrontal cortical thickness from early to mid-adolescence was associated with the onset of depressive disorders. The hypothesis was that adolescent onset depression was subserved by an abnormal developmental trajectory.


  • Community sample of adolescents (N=86; N=41 female) from Melbourne, Australia were enrolled as part of a longitudinal cohort study (i.e., the Origin Adolescent Development Study).
  • The aim of the broader study was to examine risk and protective factors for depression during adolescence
  • A sample of 415 adolescents was selected to participate for the original study.
  • Adolescents were between the ages of 12 and 18.
  • At each wave the K-SADS-PL was administered to assess current and past DSM Axis I disorders.
  • Depression, anxiety and externalizing symptoms were assessed at wave 1 using the CES-D, the Beck Anxiety Inventory, and the Child Behavior Checklist.
  • At wave 1, MRI scans were performed on 3-T MRI. Repeat measures of the volume and thickness for regions of interest (ROI) were carried out for the hippocampus, amygdala and striatum (putamen, caudate and pallidum), as well as mean thickness of prefrontal cortex.
  • Mean age at wave 1 was 11.4-13.7, while at wave 3 it was 15.0-17.5. MRIs were repeated at wave 3.

: Volumetric change in the hippocampus, amygdala, and putamen from early to mid-adolescence was associated with incident depression. There appeared to be an effect of larger hippocampal volume in the depressive group that was more pronounced in the left hemisphere. For females, increased growth of the amygdala was associated with incident depression, whereas for males reduced growth was associated with incident depression. Volumetric reduction in the putamen was greater in the comparison group compared to the depression group. The nucleus accumbens decreased in size over time and was smaller in the depression group only for female participants (Table).

Brain Region and Effect

F (df=1, 77)

P Value

   Group by time
   Group by hemisphere



   Group by sex
   Group by sex by time



Nucleus Accumbens
   Group by sex



   Group by time



Dorsolateral prefrontal cortex



Conclusion: This is the first study to use a longitudinal design to assess whether structural development of the brain is associated with incident depression during adolescence. The authors determined that the normative pattern of change in the hippocampus, putamen and amygdala volumes for ages 12-16 was associated with incident depression. No association in development between prefrontal cortex thickness and depression was noted. This study underscores the complex relationship between neural development, sex and vulnerability to depression in adolescence. The changes observed herein were captured with longitudinal change measurement, which is a methodological improvement over extant studies.

Clinical Commentary
Mood disorders are conceptualized along a developmental trajectory. Clinicians frequently encounter adolescents presenting with behavioural, affective and cognitive disturbances that interfere with functioning and result in significant interpersonal distress. The results of this study indicate for the first time that longitudinal changes can be identified in selective regions of interest before the declaration of the brain disorder. It is widely agreed that the health outcomes in psychiatric disorders are greater when accurate and timely detection occurs thwarting unnecessary illness progression. For myself as a clinician, these data provide an important piece of psychoeducation information for younger patients, underscoring that depressive disorders are brain disorders that are possibly progressive in some people. For many patients and families, but not all, the understanding of depression as a brain disorder mitigates against stigma, self-blame, and guilt. It is also hoped that destigmatization of the underlying causation of depression will enhance patient and family alliance with the multidisciplinary healthcare team, which is essential for optimal outcome.


Randomized Trial of Electronic Personal Health Record for Patients with Serious Mental Illnesses

Druss BG, Gi S, Glick G, et al.
Am J Psychiatry. 2014;171:360-368.

Objective: The authors sought to determine with a randomized trial design whether a mental health personal health record in a sample of patients with serious mental illness and comorbid medical disorders resulted in a better outcome than a control group. The overarching aim of this initiative is to facilitate improved health outcomes across both mental and physical domains that affect individuals with serious mental illness.


  • Investigators employed My Health Record, which is an adaptation of the Shared Care Plan, a community-based personal health record developed by providers and by patients with chronic medical conditions to self-manage their illnesses and interact with the health system.
  • 170 of 644 individuals were eligible and randomly assigned to the intervention arm or usual care arm.
  • Patients could have a diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, major depressive disorder, or post-traumatic stress disorder and one or more chronic medical conditions confirmed through chart review.
  • The outcome assessment was interviews and review of all medical and mental health charts conducted at baseline and the 12-month follow-up. Quality and service use indicators were assessed through review of all medical and mental health charts. Patient activation and health-related quality of life was assessed through patient interviews.
  • The primary study outcome was quality of medical care, which included quality of preventative services and quality of cardiometabolic care in people who had cardiometabolic morbidity.

: The total proportion of preventative services received increased in the personal health record group from 24% at baseline to 40% at 12 months of follow-up, compared with a decline in the usual care group from 25% to 18%. Compared with the usual care group, the personal health record group had significantly greater improvements in rates of physical examination, screening, vaccination, and education. In the personal health record arm there was a significant greater rate of care improvement for hypertension, but not for diabetes or hyperlipidemia. Both groups exhibited small improvements in patient activation, physical health-related quality of life, and mental health-related quality of life (Table).

Prediction of Service Change Between Baseline and Follow-up Interview


Without Adjustment for No. Of Outpatient Medical Visits

With Adjustment for No. Of Outpatient Medical Visits

Quality of Care





Preventive Services

Physical examination




















Preventive care for women





Preventive care for men





Total percentage of eligible services received





Cardiometabolic Services
















Total percentage of eligible services received





Conclusion: In this sample of adults with serious mental illness and comorbid medical disorders, a personal health record was associated with improved quality of preventative care and cardiometabolic care. The exchange of health information across providers along with patient portals increased the probability that care would be synchronized with clinical and laboratory data.

Clinical Commentary
The results of this randomized and thoughtful study are highly relevant to the comprehensive management of adults with severe mental disorders and comorbid medical conditions. It has been amply documented that individuals with serious mental disorder are differentially affected by cardiometabolic and other non-communicable and communicable disorders. Convergent evidence also indicates that the occurrence of medical comorbidity complicates the psychiatric presentation and decreases overall health outcomes. Mortality studies indicate that the most common cause of excess and premature mortality in adults with serious illness is excess cardiometabolic disorders. Academic studies have provided compelling evidence that multidisciplinary, integrated, and accountable care improves value outcomes. Unfortunately, because of the balkanization of most health care systems, access to integrated units of care is not available to many individuals. The strategy herein, i.e. a personal health record with multi-provider access and patient portal, significantly improves disparate measures of health outcomes. These data underscore the importance of patient self-management in chronic disease and provide an important vehicle to complement multidisciplinary care toward the fundamental aim of improving outcome.


Antidepressant Effects of Insulin in Streptozotocin Induced Diabetic Mice: Modulation of Brain Serotonin System

Gupta D, Kurhe Y, Radhakrishnan M. 
Physiology & Behaviour. 2014;129:73-78.

Objective: The primary aim of this preclinical study was to determine if insulin modulated serotonin signaling in an animal model for depression. The impetus for this study is provided by the cross-sectional and longitudinal literature documenting a bidirectional relationship between mood disorders and diabetes mellitus.


  • Albino mice, 3 months of age, either sex, were evaluated with two measures of behavioural despair thought to have predictive validity in depression (i.e., Forced Swim Test and Tail Suspension Test).
  • Animals received 200 mg/kg of streptozotocin, which results in the obliteration of insulin production in pancreas.
  • Exactly following administration of streptozotocin, animals exhibited a significant increase in behavioural despair.
  • After administration of streptozotocin the activity level of the MAO-A and MAO-B were measured. In addition, brain serotonin concentrations were measured using RH-HPLC.
  • Insulin was administered to determine the effect on whole-brain serotonin concentration.

Results: Diabetic rats exhibit an increase in both MAO-A and MAO-B activity. Diabetic rats also exhibited a significant decrease in central nervous system serotonin concentration levels. Chronic insulin treatment showed significant increases in brain serotonin levels with 78% increase compared to the diabetic mice without treatment.

Conclusion: These animal data provide a mechanistic understanding for the association between mood disorders and diabetes. Diabetic rats exhibit a significant decrease in central serotonin and increase MAO-A and MAO-B activity. This collection of observations could provide partial explanation for the increased susceptibility to depressive-like behavioural manifestations in animals rendered diabetic.

Clinical Commentary
Clinicians often encounter patients with depression and diabetes. These preclinical data replicate previous results underscoring the cross-talk between peripheral metabolism and brain neurochemistry. To achieve optimal outcomes in depression in an adult with comorbid diabetes, it is absolutely essential that diabetes management receive contemporaneous management with the mental health aspects. It is widely reported that insufficient attention to concurrent medical disorders, e.g. diabetes, in an adult with depression results in higher rates of non-recovery, chronicity of depression, as well as adverse diabetic outcomes. The take-away message is holistic, multidimensional care is not only a principal but is now embroidered by scientific data documenting the cross-talk between brain and body.


Castelli Risk Indexes 1 and 2 are Higher in Major Depression but Other Characteristics of the Metabolic Syndrome are Not Specific to Mood Disorders

Vargas HB, Nunes SO, Barbosa DS, et al.
Life Sci. 2014;102(1):65-71.  

Objective: The authors sought to delineate whether Castelli risk indexes 1 and 2 are biomarkers of major depression or bipolar disorder, and whether biomarkers of the metabolic syndrome (i.e., lipid profile, increased insulin, glucose, HbA1c) are characteristics of major depression or bipolar disorder.


  • The study design was cross-sectional. Participants had either major depressive disorder (N=92) or bipolar disorder (N=49); there were also normal controls (N=201).
  • Diagnosis was confirmed with SCID; metabolic syndrome was defined according to International Diabetes Federation (1) abdominal obesity using population and country specific definitions, 2) hypertriglyceridemia, 3) low HDL cholesterol, 4) average blood pressure, 5) elevated fasting glucose, or 6) an oral antidiabetic medication.

: Patients with bipolar disorder had a significantly higher BMI in comparison to control and individuals with major depressive disorder. There were no significant differences in systolic and diastolic blood pressure, and in waist and hip circumference in the three study groups. Plasma glucose insulin and HbA1c were not significantly different between the three study samples. There were not significant differences in total LDL cholesterol and triglycerides between the three study samples. HDL cholesterol was significantly lower in bipolar patients than healthy controls, while there were no significant differences between bipolar and depressed patients and between major depressive and controls. Castelli risk indices were significantly higher in major depression and bipolar disorder than in controls. There were no significant differences between major depression and bipolar disorder (Table).


Healthy Controls (SE)*


Bipolar Disorder

   Metabolic Syndrome†

No                       Yes

BMI (kg/m2)

27.7 (0.37)





Systolic BP (mm Hg)

127.5 (1.40)





Diastolic BP  (mm Hg)

81.7 (0.99)





Waist (cm)

93.6 (0.98)





Hip (cm)

106.8 (0.98)





Glucose (mg/dL)

94.7 (1.21)





Insulin (U/mL)

10.8 (0.41)





Hba1c (%)

6.0 (0.07)





Total (mg/dL)

196.1 (3.18)





HDL (mg/dL)

45.3 (1.00)





LDL (mg/dL)

123.0 (2.91)





Castelli risk index 1

4.7 (0.10)





Castellis risk index 2

3.0 (0.09)





Triglycerides (mg/dL)

145.7 (5.24)





Homocysteine (uM)

13.4 (0.35)





•Based on ANCOVA and adjusted for age, gender, and smoking status. SE indicates standard error.

† Adjusted for metabolic syndrome and the interaction between diagnosis and metabolic syndrome.


Conclusion: The major finding of this study is that major depression, but not bipolar disorder, is characterized by increased Castelli risk indices 1 and 2, which are more powerful coronary risk predictors than total cholesterol or HDL used separately. The implication of these findings is that major depressive disorder may increase atherogenic risk to a greater extent that bipolar disorder.

Clinical Commentary
Psychiatry is increasingly pressing the point that personalized care is warranted. In the absence of biological markers, clinicians are unable to provide bespoke medical approaches and instead are providing for patients a more stratified approach. These data remind us that patients with mood disorders are at elevated risk for cardiometabolic disorders, but add to our knowledge by suggesting that the atherogenic risk, as proxied by the Castelli risk indices, may be higher in major depression than bipolar disorder. If these results are replicated, the clinical translation would be that amplified attention to traditional and emerging risk factor for cardiovascular disease is warranted for all individuals with mood disorders, perhaps to a greater extent those with major depression.




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