UPDATE ON DEPRESSION
From New Frontiers in Depression Research and Treatment, presented by the University of California, San Francisco, School
of Medicine
Educational Objectives
| The goals of this program are to improve the management of depression, through a greater understanding of its neurobiolgic
etiology, and as it relates to cardiovascular disease. After hearing and assimilating this program, the clinician
will be better able to:
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 | 1. Explain how genetics, adverse events in early life, and stress contribute to depression.
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| 2. Describe how stress is transduced into depression.
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| 3. Determine whether depression is associated with neurotoxicity.
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| 4. Discuss the connection between mind and heart in cardiovascular disease.
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| 5. Identify and treat depression in patients with cardiovascular disease.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Wolkowitz
is on the Speakers’ Bureaus of and is consultant to Forest Labs and GlaxoSmithKline. Dr. Whooley and the planning
committee reported nothing to disclose.
Acknowledgements
Drs. Wolkowitz and Whooley were recorded at New Frontiers in Depression Research and Treatment, held February 21-
23, 2008, in San Francisco, CA, and sponsored by the University of California, San Francisco, School of Medicine.
The Audio-Digest Foundation thanks the speakers and UCSF School of Medicine for their cooperation in the production
of this program.
| NEUROBIOLOGY OF DEPRESSION —Owen M. Wolkowitz, MD, Professor of Psychiatry, and Director, Psychopharmacology
Assessment Clinic, University of California, San Francisco, School of Medicine
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| Primary questions: how do genetics, early adversity, and stress contribute to depression? how is stress transduced into
depression? is depression associated with neurotoxicity? do stress and depression accelerate cell aging, leading to poor
health? influences on depression include genetic vulnerability, adversity during early life, stress hormones, neurosteroid
hormones, brain growth factors, and cell aging (telomeres)
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| Genetic vulnerability: “gene-by-environment” interaction moderates effect of stress, leading to depression; serotonin
transporter pump gene (5HTT) has 2 alleles (long and short) that influence individual reactions to stress; person with 2
long alleles has 9% to 10% chance of developing depression in response to life stresses; person with 2 short alleles has
>40% chance of developing depression; people with 1 long and 1 short have intermediate chance of developing depression
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| Early life stresses: people who experienced more adverse events (eg, tumultuous family, witnessing parents abuse each
other, presence of drugs and guns in home, incarcerated family members, physical abuse, sexual abuse, emotional neglect)
before puberty more likely to develop depression in adulthood
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| Epigenetic transmission: in studies, rat DNA tested in newborns, who were then exposed to different levels of maternal
nurturing; when tested again in adulthood, rats that had been well nurtured had different DNA from those who had
been poorly nurtured, indicating that stressful environmental factors can produce long-lasting, perhaps even lifelong,
changes in DNA (poorly nurtured rats had higher levels of glucocorticoid receptor methylation than well-nurtured individuals);
conclusion that life experiences can change DNA structurally; other studies showed “remarkable parallelism between
what’s been described in rats and what’s been described in humans”
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| Cortisol and the brain: cortisol necessary hormone for life, but too much cortisol for too long can affect brain adversely
(genomically, nongenomically, trophically, or atrophically)
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| Genomic effect: in classic model, steroid hormones do not bind to receptors on cell membrane, but cross membrane and
bind to receptors in cytoplasm; when steroid hormone binds to cytoplasmic receptor, it can then translocate into nucleus
and influence synthesis and production of proteins
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| Nongenomic effect: no direct interaction with genes; neurosteroids (eg, estrogen, progesterone, allopregnenolone) synthesized
in brain neurons and bind to cell membranes of neurons, influencing neurotransmitters
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| Trophic and atrophic effects: in rats, extended exposure to excessive level of corticosterone (“rat’s version of cortisol”) kills
neurons; sublethal exposure damages neurons, but recovery possible; shows that there is system for replacing dead neurons
with new ones; hippocampal shrinkage—human studies showed that people exposed to high levels of cortisol (such
as occurs in major depression) have smaller hippocampal volumes than those not so exposed; the longer the exposure to
high cortisol levels, the greater the hippocampal shrinkage; factors that can lead to shrinkage of hippocampus include
early life traumas, decreased neurogenesis in brain, decreased levels of brain-derived neurotrophic factor (BDNF), and elevated
glucocorticoids; several studies have shown that treatments that lessen cortisol activity have antidepressant effect,
suggesting that if primary neurotransmitter involved in individual’s depression can be determined (eg, glucocorticoid,
norepinephrine, serotonin), pharmacotherapy can be aimed at that neurotransmitter
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| Cortisol receptor blockers: studies show significant benefit of cortisol receptor blockers and cortisol biosynthesis inhibitors
in nonpsychotic patients with depression; in psychotic patients, these drugs significantly affect psychotic symptoms,
but not depressive symptoms
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| Nongenomic neurosteroids: cholesterol can be metabolized to several steroid hormones, including pregnenolone, dehydroepiandrosterone
(DHEA), and allopregnenolone
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| DHEA: historically promoted as “extraordinary superhormone,” which appears to be true in rats, but no evidence to support
claim in humans; model suggests that stressed brain signals increase in cortisol; when stress long-term, DHEA and
allopregnenolone (protective neurosteroid hormones) levels decrease; therefore, long-term stress subjects individual
not only to increased neurotoxic effects of cortisone, but also to decreased neuroprotective effects of protective neurosteroid
hormones; several studies have found that DHEA has significant antidepressant effect, indicating that DHEA
blocks neurodegenerative effect of cortisol; however, data preliminary, and speaker advises against administering DHEA until
more information available
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| Allopregnenolone: synthesized in brain and has potent agonist effects at γ-aminobutyric acid A (GABA-A) receptors; in
depressed patients, allopregnenolone levels in cerebrospinal fluid (CSF) low (more depressed the patient, lower the allopregnenolone
levels); when clinical recovery occurred in depressed patients treated with antidepressants, allopregnenolone
levels rose (not to level of normal controls, but “significantly up”)
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| Neuroprotection: neuroprotective agents include DHEA, allopregnenolone, BDNF, and telomerase; neurotoxic agents
include prolonged exposure to elevated cortisol levels, oxidative stress, and shortening of telomeres; all effective antidepressant
treatments (eg, pharmacotherapy, electroconvulsive therapy, psychotherapy) increase neurogenesis in rat
hippocampus; not known if that contributes to therapeutic effects, but more studies in humans needed
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| Telomeres and telomerase: “end caps” of DNA that keep the DNA strand from unraveling; although telomerase works to
rebuild end of telomeres, telomere length decreases throughout lifespan; however, tremendous variability seen in individuals;
early research suggests long-term stress results in shorter telomeres and lower telomerase activity; depression
and early life adverse events result in shorter telomeres but increased telomerase activity; unknown whether these
trends can be reversed by psychotherapy or pharmacotherapy
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| CARDIOVASCULAR ASPECTS OF DEPRESSION —Mary A. Whooley, MD, Associate Professor of Medicine, Epidemiology,
and Biostatistics, University of California, San Francisco, School of Medicine, and Department of Veterans Affairs
Medical Center, San Francisco
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| Introduction: long known that depression significant risk factor for cardiovascular disease (CVD); depression associated
with increased incidence of developing CVD and increased incidence of poor outcomes in patients with established
CVD; hostility found to be major component of type A personality that increases CV risk; additional significant predictors
of CVD include depression, anger, and anxiety
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| INTERHEART study: examined risk factors for acute myocardial infarction (MI) in >25,000 patients from 52 countries;
found dyslipidemia most frequent risk factor, with psychosocial factors second; somewhat protective effect found
for exercise, regular use of small quantities of alcohol, and diets rich in fruits and vegetables
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| Other study findings: depressive symptoms predict mortality in patients with established coronary heart disease
(CHD); patients with depression more likely to develop heart failure than nondepressed patients
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| Heart and Soul study: cohort study of >1000 patients with CVD; goals to confirm that depression predicts adverse cardiac
outcomes, independent of disease severity at baseline, and to determine mechanisms responsible for this association;
≈20% of cohort had depression; compared to nondepressed patients, depressed patients younger, more likely to be
women, similar in race, and “a little bit sicker,” with more history of MI, diabetes, and smoking; at baseline, cardiac
function similar in both groups (ie, no evidence that depressed patients sicker at outset), as were prevalence of low ejection
fraction and inducible ischemia
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| Measures of health status: patients with low incidence of depressive symptoms had lowest incidence of poor health status,
and those with intermediate and highest incidence of depressive symptoms most likely to report poor health status in all
domains; on analysis, depressive symptoms strongest contributors to health-related quality of life (QOL); ejection fraction
and inducible ischemia not associated with health-related QOL, but exercise somewhat associated
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| Potential mechanisms: many proposals in literature to explain link between depression and cardiac events, including
physiologic (eg, levels of norepinephrine, cortisol, and inflammation) and behavioral mechanisms
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| Norepinephrine: depressed patients more likely to have norepinephrine levels in highest quartile and more likely than
nondepressed patients to have norepinephrine levels above normal range
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| Cortisol: patients with current depression exhibit higher mean cortisol levels than those with past depression or who had
never had depression
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| Inflammation: several inflammatory markers examined; depression not associated with increased white blood cell count,
CD 4 ligand, or platelets, but was associated with lower levels of C-reactive protein, fibrinogen, and interleukin-6; indicates
role of inflammation questionable
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| Exercise: patients with low depression scores least likely to have poor exercise capacity, and those with high depression
scores most likely to have poor exercise capacity
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| Medication adherence: depressed patients more likely to report not taking medications as prescribed, forgetting to take
medications, and skipping medications
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| Final results of Heart and Soul study: “it looks like most of it [CVD] is explained by lack of exercise [which]
opens up the possibility that we can actually help these people with behavioral interventions”
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| Identifying depression in cardiac patients: depression common in patients with heart conditions (incidence 20%
in patients with stable coronary disease, 35% in patients with heart failure, and “even higher” after coronary artery bypass
grafting [CABG] and acute coronary syndrome)
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| 2-Item Depression Screen: “during the past month, have you often been bothered by feeling down, depressed, or hopeless?”
and “during the past month, have you often been bothered by having little interest or pleasure in doing things?”
depression ruled out if patient answers “no” to both items; “yes” answer to either question 90% sensitive and 70% specific
for depression, indicating need for further screening
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| Patient Health Questionnaire-9 (PHQ-9): utilizes criteria from Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV), including presence of anhedonia, “feeling down,” problems with sleep, tiredness or lack of
energy, changes in appetite, bad feelings about self, moving or speaking so slowly that other people notice, and
thoughts that one would be better off dead; also offers more frequency distribution, ranging from “not at all” to “every
day”; score ≥10 90% specific, but only 54% sensitive for depression in patients with CVD
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| Rule out: normal grief reaction; side effects of medications (especially steroids, narcotics, and benzodiazepines; β-blockers
do not cause depression); bipolar disorder
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| Safe and effective therapies for depression in patients with CVD
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| Medications: selective serotonin reuptake inhibitors—citalopram (Celexa); fluoxetine (eg, Prozac); paroxetine (eg, Paxil);
and sertraline (Zoloft); dopamine reuptake inhibitors—bupropion (eg, Wellbutrin); serotonin antagonists—mirtazapine
(Remeron; beware of weight gain and interactions with other drugs, especially clonidine)
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| Psychotherapy: cognitive behavioral therapy (CBT) only psychotherapy proven safe in patients with CVD; data scanty
for other forms of psychotherapy; in ENhancing Recovery In Coronary Heart Disease (ENRICHD) trial, 2500 patients
with acute MI within past 30 days randomized to CBT or usual care; in group that received CBT, depression improved
in those with depression, and social support improved in those with low social support but no depression; “bad news”
that no difference in cardiac event-free survival (incidence of recurrent MI or death, 24.4% in intervention group and
24.2% in usual-care group); shortcomings of study—included patients with depression or low social support, so unclear
whether CBT intervention actually targeted at depression; intervention CBT with no pharmacotherapy, but “a lot”
of patients in both groups eventually treated with SSRI; both groups had equal access to drug therapy; unusually high
recovery rate in control group, suggesting that investigators waited longer after MI to determine which patients develop
depression and which need treatment; post hoc analysis showed that patients who had taken antidepressants, no matter
their group, much less likely to have recurrent MI or death; however, use of antidepressants not randomized, leaving
question of whether antidepressants have protective effect
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| Summary: depression present in 1 of 5 patients with heart disease; depression associated with worse CV outcomes; treating
depression in cardiac patients safe, reduces depression, and improves QOL; unknown whether treating depression in
cardiac patients reduces cardiac events
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Suggested Reading
Abramson J et al: Depression and risk of heart failure among older persons with isolated systolic hypertension. Arch Intern
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convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci 256:174, 2006; Barth J
et al: Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med
66:802, 2004; Blier P, Abbott FV: Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders
and pain. J Psychiatry Neurosci 26:37, 2001; de Jonge P et al: Differential association of cognitive and somatic depressive
symptoms with heart-rate variability in patients with stable coronary heart disease: findings from the Heart and
Soul Study. Psychosom Med 69:735, 2007; Gehi A et al: Depression and medication adherence in outpatients with coronary
heart disease: findings from the Heart and Soul Study. Arch Intern Med 165:2508, 2005; Gehi AK et al: Self-reported
medication adherence and cardiovascular events in patients with stable coronary heart disease: the Heart and Soul
Study. Arch Intern Med 167:1798, 2007; Otte C et al: Depression and 24-hour urinary cortisol in medical outpatients with
coronary heart disease: The Heart and Soul Study. Biol Psychiatry 56:241, 2004; Otte C et al: Depressive symptoms and
24-hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study.
Am J Psychiatry 162:2139, 2005; Reus VI, Wolkowitz OM: Antiglucocorticoid drugs in the treatment of depression.
Expert Opin Investig Drugs 10:1789, 2001; Ruo B et al: Depressive symptoms and health-related quality of life: the Heart
and Soul Study. JAMA 290:215, 2003; Sheline YI et al: Untreated depression and hippocampal volume loss. Am J Psychiatry
160:1516, 2003; Sheline YI: 3D MRI studies of neuroanatomic changes in unipolar major depression: the role of
stress and medical comorbidity. Biol Psychiatry 48:791, 2000; Videbech P, Ravnkilde B: Hippocampal volume and depression:
a meta-analysis of MRI studies. Am J Psychiatry 161:1957, 2004; Vythilingam M et al: Childhood trauma associated
with smaller hippocampal volume in women with major depression. Am J Psychiatry 159:2072, 2002; Weaver
IC et al: Epigenetic programming by maternal behavior. Nat Neurosci 7:847, 2004; Whooley MA et al: Depression
and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biol Psychiatry 62:314,
2007; Wolkowitz OM et al: Stress hormone-related psychopathology: pathophysiological and treatment implications.
World J Biol Psychiatry 2:115, 2001; Wolkowitz OM, Reus VI: Neurotransmitters, neurosteroids and neurotrophins:
new models of the pathophysiology and treatment of depression. World J Biol Psychiatry 4:98, 2003; Yusuf S et al: INTERHEART
Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52
countries (the INTERHEART study): case-control study. Lancet 364:937, 2004.
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