Microsoft word - amp_online_journal_club_sept 2013.doc

Association of Medicine & Psychiatry
On-line Journal Club
Presented by AMP Scholarship & Research Committee
Editors: Glen L. Xiong, MD; Gaurav Jain, MD
September, 2013 Edition
[If you would like to submit a review, please contact
glen.xiong@ucdmc.ucdavis.edu ]

Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders.
Benros et al. JAMA Psychiatry. 2013 Aug 1;70(8):812-20.

[Reviewed by: Vineka Heeruman, M.D (PGY-3); Southern Illnois University, Springfield, IL]

Introduction/background/literature review
Inflammatory processes underlie the pathophysiology of infections and autoimmune
diseases. These inflammatory processes affect the brain as well and have been found
to increase the development of mood disorders. Studies show immunological changes
in people with mood disorders without other medical comorbidities thereby implying that
immune responses may play a role in mood disorders including changes in
neurotransmitters. The authors claim that this is the “first population-based register
study” to gauge the impact of infections and autoimmune diseases on the development
of mood disorders.
Design/ Data collection /Analysis: This is a prospective longitudinal study. The
Danish National Register was used whereby each Dane has a unique registration
number. Individuals born between 1945 and 1996 (3.56 million people) were followed
from 1/1/1977 to 12/31/2010. The study cohort included people had hospital contacts
with autoimmune diseases and infections and were followed up for hospital contacts
due to mood disorders (91,637 people). Authors used IRR (Incidence Rate Ratios) and
accompanying 95 % C.I. as measures of relative risk using the Poisson Regression in
the SAS statistical software.
Findings: Authors found autoimmune increased risk of mood disorders by 45%. An
infection increased mood disorder by 62%. Having a prior autoimmune disease and
infection increased mood disorders even further, implying a synergistic effect. The
number of infections and autoimmune disease increased mood disorders in a dose-
response relationship; that is, more mood disorders were seen with more frequent
exposure to infections. The authors concluded that autoimmune diseases and infections
are risk factors for subsequent mood disorders which could be explained by an
immunological response.
Compliments/Critiques/Comments: This study had a large sample size; however, the
Dane population may differ from the U.S population. The authors caution us about
careful interpretation of the results as the synergy index assumes that there are no
confounders, which is not realistic. The study is based on hospital contact for infections
and autoimmune disease so can this data be extrapolated for outpatient cases that do not require hospitalization? The authors mention about the psychological stressors that enhance immune responses so that increased mood disorders could be a parallel observation rather than a causal effect. The study found that people with a family psychiatric history of mood disorders are not prone to mood disorders, which is not the case as per genetic and social studies. It is still not clear how immunological processes could affect the pathophysiological mechanism of mood disorders so that more research would be indicated in the future. Comorbidities and Mortality in Bipolar Disorder: A Swedish National Cohort
Study.
Crump C, Sundquist K, Winkleby MA, Sundquist J. JAMA Psychiatry. 2013 ;70(9) :931-
939.
[Reviewed by Glen Xiong; University of California at Davis]

Previous studies have demonstrated that mental illness is associated with reduced life
expectancy or premature death. Bipolar disorder was associated with a two-fold
increase in cardiovascular mortality and 15-fold increase in suicide deaths. The present
study examined both inpatient and outpatient Swedish cohort of 6.5 million adults, of
which 6618 were diagnosed with bipolar disorder. Medication information were
obtained from the Swedish Pharmacy Registry from 2005-2009. Physical comorbidities
and mortality and all-cause mortality were followed from 2003-2009. Adjusted variables
included age, marital status, education level, employment, and substance use
disorders. Cox proportional hazards regression was used to estimate hazard ratios.
More than 60% of the bipolar group was 40-69 years old, 59.2% were women, 30.5%
were employed, 12.2% had alcohol use disorder, 9.8% had other substance use
disorders, and were more likely to be unmarried or to have lower education level.
The bipolar disorder group had 3 time more outpatient clinic visits per year, two times
more hospital admissions per year, and had increased risk of influenza or pneumonia
(2.4 and 1.9-fold), COPD, diabetes, CVD, and stroke. However, there was no elevated
risk of hypertension, lipid disorders, or cancer. Overall, women with bipolar disorder
died 9.0 years, and men died 8.5 years earlier than the general population. Suicide risk
was 10-fold higher in women and 8-fold in men with bipolar disorder, after adjustment
for age and sociodemographic factors. Although suicide had the highest hazard ratios,
it accounted for 7.2% of all deaths, cardiovascular disease and cancer accounted for
36.3% and 16.5% of all deaths, respectively. Both gender had increased risk of death
from influenza or pneumonia (3.7-fold for women, 4.4 for men), diabetes (3.6, 2.6), and
COPD (2.9, 2.6). Women with bipolar disorder had increased risk of death from stroke
(2.6), cancer (2.4), and colon cancer (2.1).
As for medication usage, compared to lithium, aripiprazole, quetiapine, or lamotrigine
was associated with significantly lower all-cause mortality, while sole of use olanzapine,
sole or any use of valproiac acid, risperidone, or carbamazepine was associated with
modestly increased mortality (HR 1.2-1.4). Bipolar disorder persons who used none of
the medications had higher (1.6-fold) all-cause mortality and increase suicide death
(aHR 2.06).
Commentary: This study adds to the existing literature, showing that people with
mental illness suffer increased mortality and reduced life expectancy. While the relative
risk of suicide death is clearly elevated, medical causes of death accounted for a much
higher burden in terms of prevalence. This study attempts to examine a causal
relationship between bipolar medication use and mortality risk. However, the study
lacks specificity on disease severity, duration of medication usage, and dose-response.
For example, the comparison group consisted of people who were “sole” users of
lithium, but we do not have information on how long these people were on lithium for the
study duration, their serum levels, and the duration between lithium use and observed
outcomes (death). Finally, people who are “sole” users of lithium may be a less
severely ill group, compared to people who in the lithium “plus others” group.


Exercise and pharmacological treatment of depressive symptoms in patients with
coronary heart disease. Results from the UPBEAT (Understanding the Prognostic
Benefits of Exercise and Antidepressant Therapy) study. J Blumenthal, PhD et al
JACC Vol. 60, No. 12, 2012 September 18, 2012:1053–63

[Reviewed by Sarah Rivelli, MD; Duke University Medical Center; Training Director,
Internal Medicine-Psychiatry Training Program]

Why did I read this? We were seeing a patient with admitted for an MI who was
depressed and the question came up, if we treat their depression, will they have better
cardiac outcomes?
Background: We know that depression is associated with increased risk of developing
CAD, is common among CAD patients and is associated with more than double the risk
for mortality and cardiac events after MI and unstable angina. This has led the AHA to
advise that patients with CAD be screened for depression. However, it’s unclear if
screening leads to any benefit, and which treatments are most effective in this patient
population. In fact, there are only a few RCTs looking at depression treatment in
patients with CAD and CHF and some pharmacological interventions have actually not
been significantly better than placebo in improving depression.
Exercise has been shown to reduce depressive symptoms and might improve not only
depression, but cardiovascular risk among patients with CAD. This study looked at the
impact of exercise on depression and some biomarkers of cardiovascular risk, including
heart rate variability (HRV), low baroreflex sensitivity (BRS), impaired endothelial
function, increased platelet activation and inflammation.
This study was conducted at Duke, led by Jim Blumenthal, PhD, of Medical Psychology.
All patients had depressive symptoms, but only 40% met criteria for major depression.
284 patients met initial criteria and 101 were randomized. Patients were randomized to
exercise, sertraline or placebo for a treatment period of 4 months in a 2:2:1 ratio. The
exercise intervention was 3 supervised aerobic sessions per week with 30 minutes at
70-85% maximal heart rate.
Patients in the exercise arm achieved significantly lower depression scores than
sertraline or placebo and exercise was also the most effective in reducing symptoms
among those with major depression. Not surprisingly, exercisers had significantly
improved peak oxygen consumption. Significantly more patients remitted their
depression in the exercise arm as well.
Biomarkers: Both sertraline and exercise lead to increased HRV; however there was no
improvement in BRS, nor chronic inflammation markers compared to placebo.
Endothelial function did not appear improved, which is at odds with prior studies of
exercise. More sexual dysfunction was reported in the sertraline arm of the study.
Commentary: This study was relatively small and was likely underpowered to detect
differences for all of the biomarkers, it was positive for the primary endpoints. Study
volunteers were highly educated and may not be representative of all patient with CAD
and depression. Exercise was supervised in a group setting, so social support may
have contributed to its benefit. The dose of sertraline was low (median 50mg) and may
not have been high enough for maximal effect. Lastly, patients were only moderately
depressed and most did not meet criteria for major depression, thus it is unknown if this
intervention would be effective with more severely depressed patients.
We should effectively treat depression in patients with CAD in its own right, but we are
less clear of the impact of interventions on cardiac outcomes. It does seem that 90
minutes per week of exercise can have significant benefits in improving depression, we
need to know more about its impact on improving biomarkers or mitigating the elevated
risk of negative CAD outcomes.


Neurodevelopment of Children Following Prenatal Exposure to Venlafaxine,
Selective Serotonin Reuptake Inhibitors or Untreated Maternal Depression
Nulman et al. Am J Psychiatry. 2012 Nov 1;169(11):1165-74. [Reviewed by: Trinadh Pilla, M.D. (PGY-5); Southern Illinois University, Springfield, IL] Introduction: SSRIs and SNRIs are known to cross the human placenta. This could
potentially interfere with the fetal brain development. However, untreated maternal
depression is associated with stillbirth, impaired growth, malformations, cognitive
deficits and psychopathology. To understand these connections and further evaluate
treatment safety, the study attempts to separate the effects of maternal depression on the fetus from the effects of the pharmacological treatment. The purpose of the study was to evaluate children’s neuro-cognitive and behavioral abilities following prenatal exposure to venlafaxine, SSRIs or untreated maternal depression. Research Design/ Data Collection: The study is a Cohort, quantitative study. The
authors collected data from women who called the Motherisk program at the Hospital for
Sick Children in Toronto to seek counseling on the pregnancy safety of medications.
Three groups of women with depression were selected: those who took venlafaxine
during pregnancy, those who took SSRIs during pregnancy, and those who
discontinued pharmacotherapy before conception.
Findings/Conclusions: Women who were not treated for depression or stopped taking
their medication experienced more severe depression during pregnancy. Among those
exposed to antidepressants, 11.3% received a diagnosis of poor neonatal adaptation
signs. The children’s intelligence test results revealed no statistically significant
difference in the children’s IQs between group 3 (the no treatment depressed women)
and the 2 treatment groups. Children from the non-depressed women had significantly
higher performance IQs. Children from the venlafaxine and SSRI groups did not differ
from children of mothers with untreated depression in any of the IQ or behavioral
measures. The children of the healthy women had higher IQs than those exposed to
antidepressants. Children from all three groups exposed to maternal depression had
more clinically problematic behavior and temperament scores than the children of the
non-depressed women. Although the study showed differences in full-scale, verbal and
performance IQs between the antidepressant-exposed children and those of healthy
mothers, the authors believe that the differences were accounted for by maternal IQ
and the child’s sex and not by drug exposure.
The authors feel that the study failed to find an effect of antidepressant medication on children’s intellectual or behavioral outcomes. Instead it documented that untreated depression is associated with a high risk for postpartum depression and that fetal and childhood exposure to maternal depression were significant predictors of child behavior problems and may represent risk for long-term child psychopathology. Further research is warranted to support these findings.

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