Depression

Catherine Buck
Mohamed Elzarka
Hannah Hales
Wendy Lu
Bhargav Vemuri
"At least 16% of Americans will
have clinical depression in at
least some point in their lifetime."
- Andrea Peterson of the Wall
Street Journal

Epidemiology
37% hereditary
average age of onset: 32 years
progression of prevalence: 30-44 years, 45-59 years,
18-29 years, 60+ years
major depression more common in whites than blacks
or mexican americans; dysthymia more prevalent in
mexican americans and blacks
impact of poverty and lack of education
co-existing depression common among other mental
illness and substance abuse

Women are
70% more
likely than
men to suffer
from
depression

Types of Depression
Dysthymic disorder or dysthymia -- mild, chronic depression; inhibitory,
not disabling
Minor depression -- mild symptoms for 2+ weeks; risk of developing into
major, clinical depression if left untreated
Psychotic depression -- severe depression characterized by forms of
psychosis, hallucinations, delusions, etc
Postpartum depression -- hormonal/physical changes after giving birth
coupled with stress of caring for newborn (prolactin)
Seasonal affective disorder -- depression during winter/fall months,
usually lifts during spring/summer

Speculation of Cause
1. Monoamine deficiency hypothesis

lack of serotonin and norepinephrine

treat by inhibiting monoamine oxidase or
blocking reuptake of monoamines to nerve
endings

2. Network hypothesis
problems with information processing in neural
networks
treat by helping neural networks normalize

Symptoms (with large variability)

persistent negative mood or emotions -- monoamine
deficiency, NPY deficiency

anhedonia -- melanocortin absorption by MC4 receptors

involuntary changes in eating or sleeping habits -disrupted circadian rhythms and gene activity; seasonal depression

suicidal thoughts and/or actions

Fatigue
decreased cognitive abilities
complaints of physical illness

Areas of the Brain

Neurotransmitters - depression causes low levels of
certain neurotransmitters (dopamine, serotonin)
Hippocampus - 20% reduction in volume (memory and
learning)
Pineal Gland - doesn't produce adequate amounts of
melatonin (sleep)
Thalamus - possess roughly 30% more neurons (fear and
emotions)
Cerebral Cortex - thinning in right side (mood, attention,
personality)
Amygdala - more active in processing emotions

Medical Imaging

Decline in Cortex
Increase in Limbic System

Neurons Affected
Study by Prof. Karl Deisseroth and postdoc Melissa Warden (Stanford)
Slowing down of motivation in depressed patients as "psychomotor retardation."
- Find it hard to envision positive results of actions or may feel physically heavy
Will to act in prefrontal cortex (plan and coordinate action)
- Series of electrical signals, passing from neuron to neuron along countless
branching pathways until it reaches the nerves that directly implement movement.
Isolated pathways relevant to depression by stimulating specific brain cells in
rodents and observing changes in their behavior
Optogenetics - green algae produce channelrhodopsin protein that makes them
sensitive to sunlight. Embed gene to create neurons that respond to light
delivered from fiber-optic cables. Turn neurons on and off by sending bursts of
light to activate different areas and then observe the effects on behavior.
Instead of one switch in the prefrontal cortex that turns motivation on, multiple
switches work in concert.
Worked backward from the brainstem and find the exact pathway from neurons in
the prefrontal cortex that signal motivation.

Neurotransmitters
Decline in three neurotransmitters:
Serotonin
Dopamine
Norepinephrine
Decrease in these neurotransmitters
leads to observable symptoms:
persistent sadness, anxiety, pessimism, guilt,

worthlessness
irritability or restlessness
Fatigue and decreased energy
Decreased cognitive abilities
involuntary changes in eating or sleeping habits -disrupted circadian rhythms and gene activity

Origin
Heritability is probably 40-50%, and might be higher for severe
depression.
~50% genetic / ~50% psychological or physical factors
Environmental Risk Factors:
severe childhood physical or sexual abuse childhood
emotional and physical neglect
severe life stress
losing a parent early in life
"If someone has a parent or sibling with major depression, that person
probably has a 2 or 3 times greater risk of developing depression
compared with the average person."
combinations of genetic changes predispose some people
dont know how many genes are involved; doubtful that any one
gene causes depression
hard to genetically engineer against
people with depression may have differences in serotonin
transporter gene length.
o homozygous long form less likely / heterozygous or
homozygous short more likely

Molecular Basis
Serotonin seems to act as a signal of
"repletion" or "satisfaction" (ex. satiation after
eating)
In the brain, serotonin exerts a suppressive
effect on both the reward system and
punishment system.
Serves as a ligand (signal)
Transduction pathway can send variety of
signals to the brain for processing.
SSRI's being used to inhibit reuptake as a
mechanism to combat depression

Treatment
Medication

Tricyclic Antidepressants
o TCAs block the absorption of
serotonin and epinephrine into the
nerve cells

Imipramine (Tofranil)

Amitriptyline (Elavil)

Desipramine (Norpramin)

Nortriptyline (Pamelor)

Monoamine Oxidase Inhibitors (MAOIs)

o Block the effects of the enzyme monoamine oxidase, that breaks down
serotonin, epinephrine, and dopamine.

Emsam

Treatment
Medication

Selective serotonin reuptake inhibitors (SSRIs)

o

Fluoxetine (Prozac)

Sertraline (Zoloft)

Escitalopram (Lexapro)

Paroxetine( Paxil)

Citalopram (Celexa)

Serotonin and norepinephrine reuptake inhibitors (SNRIs)

o

Venlafaxine (Effexor)

Duloxetine (Cymbalta)

How SSRIs (Prozac) work

Efficacy
TCAs and SSRIs have comparable antidepressant efficacy is based on the fact that they
both produce overall response rates of about 60%. Both the SSRIs and the TCAs
produce a 20% higher response rate than placebo
The efficacy of antidepressants is controversial- many studies illustrate they have a
minimal effect in patients with mild and moderate depression
SSRIs induce significantly less anticholinergic, antihistaminergic and cardiotoxic side-effects than
TCAs
Side Effects
o Cardiovascular effects- arrhythmias, blood pressure abnormalities, congestive heart
failure, heart rate increase, postural hypotension and slight prolongation of the
intraventricular conduction time and QT interval.
o Anticholinergic effects- dry mouth, blurred vision, drowsiness, constipation, and difficulty in
urination
o Weight gain, appetite increasing effects
o Sexual effects- Sexual dysfunction such as decreased sexual desire, erectile difficulties
and delayed ejaculation
o Central Nervous System effects - headache, dizziness, agitation, insomnia and tremor
o Nausea
o Gastro-intestinal effects.

 Psychotherapy
o Cognitive behavioral therapy
o Interpersonal therapy

Electroconvulsive therapy
Vagus Nerve Stimulation
Repetitive Transcranial Magnetic
Stimulation

Current Research

Current Treatment: Meds vs Cognitive Behavioral Therapy (CBT) X 1-2

months (trial and error)

New research into biomarkers that will predict who responds to CBT vs
Meds

One type of biomarker is PET scan of brain.

Recent study (June, 2013) from Emory University using PET scan:

Low activity in insula: + CBT, - SSRI

High activity in insula: -CBT, + SSRI

Patient/Family
Most troubling symptoms: patient
-sadness
- trouble concentrating
- reduced involvement
- tense/ uptight
- reduced sleep or sleeping too much
- negative thoughts
- inability to feel emotion
- changed appetite
- fatigue and lack of energy
- feeling hopeless, worthless or guilty
- delusions or hallucinations

How these symptoms impact the patient's life:

Symptoms can lead to- unemployment
- loss of family connection
- socially ostracized
- loss of relationships outside the family
- inability to care for themselves
- Inability to care for their families
- worsening of other conditions
- lower quality of life
- increased problems associated with aging
- reduced life expectancy

How these symptoms impact the family:

- negative thought patterns can trigger pessimism in the house
- feelings of rejection
- abuse
- feelings of responsibility and guilt
- patient health and well being
- financial
- anxiety
- marriage/ relationship conflicts
Most pressing concerns:
- risk of suicide (15% in depressed patients)
- increased risk for alcohol and drug abuse
- caring for the patient
- engaging the patient without overwhelming

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