What causes depression?

• During the last decade, increased access to brain imaging technology has
allowed neuroscientists and hospital clinicians to view the brain in detail,
measure neural activity, and quantify neurotransmitter levels.
• Such studies have revealed many clues regarding the underlying
contributing factors of depression and the pathophysiology of this disease
 Serotonin: the happy neurotransmitter

• Various animal models have demonstrated that chronic stress causes low
serotonin levels in the brain. In patients, low brain serotonin activity
correlates with a higher risk for more violent attempted and successful
suicides. Serotonin levels have also been implicated in seasonal affective
disorder (SAD)
• According to a recent study, sunlight keeps serotonin levels high by
decreasing serotonin transporter (SERT) activity. Because serotonin-
releasing neurons use SERT to recapture released serotonin, limiting
SERT activity increases serotonin-dependent activity and downstream
neuronal signaling.
• For this reason, patients afflicted with SAD experience increased SERT
levels as nights lengthen, thereby diminishing active serotonin levels
while increasing the risk of depression.
Mechanism of Depresion
 Dopamine: a chemical for motivation
may be one of the reason of Dep???

• Reduced dopamine levels, too, may contribute to depression. Although

dopamine was thought initially to be crucial to the “reward” system in the
brain and the neurons that control feelings related to pleasure, it more
directly impacts the neurons that underlie motivation and habit formation.
• Dopamine motivates people to take action toward goals, desires, and
needs, and issues a surge of reinforcing pleasure once they’ve been
accomplished. Low dopamine levels make people and animal models less
likely to work toward achieving a goal.
 monoamine oxidase A (MAO-A),?? Cause
depression ???
• People with clinical depression often have increased levels of monoamine
oxidase A (MAO-A), an enzyme that breaks down key neurotransmitters,
resulting in very low levels of serotonin, dopamine and norepinephrine.
• In 2013, a team from Stanford using optogenetic mouse models showed
that inhibiting midbrain dopamine-releasing neurons induced depression-
like behaviors caused by chronic stress, reinforcing the link between low
dopamine and depression in patients
 Ketamine: A promising quick fix

• One of the most exciting, recent findings related to treatments for depression
was the discovery that ketamine, a glutamate NMDA receptor antagonist and
a FDA approved anesthetic, appears to counteract depression in a matter of
hours.
• Although ketamine may be an alternative treatment for many patients with
major depressive disorder who don’t get better with standard antidepressant
drugs, it hasn't been thoroughly studied for long-term safety and
effectiveness, and the FDA hasn't approved it to specifically treat mood
disorder
 Antidepressants
Antidepressants are medications that can help relieve symptoms of depression,
social anxiety disorder, anxiety disorders, seasonal affective disorder, and dysthymia,
or mild chronic depression, as well as other conditions.
They aim to correct chemical imbalances of neurotransmitters in the brain that are
believed to be responsible for changes in mood and behavior.
 Action mechanism/ Hypotheses
• SNRIs, SSRIs
• https://www.youtube.com/watch?v=uA6r4BINvE8
• https://www.youtube.com/watch?v=l3N8ThFbBvs
• Monoamine oxidase
• https://www.youtube.com/watch?v=T25jvLC6X0w
 Types
Antidepressants can be divided into five main types:
• Serotonin and noradrenaline reuptake inhibitors (SNRIs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• Noradrenaline and specific serotoninergic antidepressants (NASSAs)
 SNRIs and SSRIs

• Serotonin and noradrenaline reuptake inhibitors (SNRIs) are used to treat major depression, mood
disorders, and possibly but less commonly attention deficit hyperactivity disorder (ADHD), obsessive-
compulsive disorder (OCD), anxiety disorders, menopausal symptoms, fibromyalgia, and chronic
neuropathic pain.
• SNRIs raise levels of serotonin and norepinephrine, two neurotransmitters in the brain that play a key
role in stabilizing mood.
• Examples include duloxetine (Cymbalta), venlafaxine (Effexor) and desvenlafaxine (Pristiq).
• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants.
They are effective in treating depression, and they have fewer side effects than the other
antidepressants.
• ).
• SSRIs block the reuptake, or absorption, of serotonin in the brain. This
makes it easier for the brain cells to receive and send messages, resulting
in better and more stable moods.
• They are called “selective” because they mainly seem to affect serotonin,
and not the other neurotransmitters.
• Examples include citalopram (Celexa), escitalopram (Lexapro),
fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil)
and sertraline (Zoloft
There have been reports that people who use SSRIs and SNRIs, and especially those under
the age of 18 years, may experience thoughts of suicide, especially when they first start
using the drugs.

SSRIs and SNRIs may have the following side effects:

 hypoglycemia, or low blood sugar sweating nausea
dizziness
• tremor anxiety and agitation weight loss
constipation or diarrhea
• abnormal thinking insomnia sedation
dry mouth
• headache rash sexual
dysfunction
 (TCAs)

• Tricyclic antidepressants (TCAs) are so named because there are three

rings in the chemical structure of these medications. They are used to treat
depression, fibromyalgia, some types of anxiety, and they can help control
chronic pain.
• Examples include amitriptyline (Elavil), amoxapine- clomipramine
(Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine
(Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil) and
trimipramine (Surmontil).
• Tricyclics may have the following side effects:
• Seizures insomnia rash
urinary retention
• Anxiety arrhythmia, or irregular heartbeat
constipation
• Hypertension nausea and vomiting
increased pressure on the eye
• abdominal cramps sexual dysfunction
weight loss
 (MAOIs)

• Monoamine oxidase inhibitors inhibits the action of monoamine oxidase, a brain

enzyme. Monoamine oxidase helps break down neurotransmitters, such as
serotonin. If less serotonin is broken down, there will be more circulating serotonin.
• In theory, this leads to more stabilized moods and less anxiety. Doctors now use
MAOIs if SSRIs have not worked. MAOIs are generally saved for cases where
other antidepressants have not worked because MAOIs interact with several other
medications and some foods.
• Examples of MAOIs include phenelzine (Nardil), tranylcypromine (Parnate), is
ocarboxazid (Marplan) and selegiline (EMSAM, Eldepryl).
• Side effects include:
• blurred vision rash insomnia and drowsiness headache

• seizures edema dizziness

hypertension, or high blood pressure
• weight loss or weight gain sexual dysfunction fainting
or feeling faint when standing up
• diarrhea, nausea, and constipation anxiety
arrhythmia, or irregular heart rhythm
 (NASSAs)

• Noradrenaline and specific serotoninergic antidepressants are used to treat anxiety

disorders, some personality disorders, and depression.
• Examples include Mianserin (Tolvon) and Mirtazapine (Remeron, Avanza, Zispin.)
• Possible side effects include:
• Constipation dry mouth
• weight gain drowsiness and sedation
• blurred vision dizziness
• More serious adverse reactions include seizures, white blood cell reduction, fainting, and
allergic reactions.
• Antidepressants are a type of psychiatric medication used to
treat mental health disorders such as clinical depression,
obsessive-compulsive disorder (OCD), generalized anxiety
disorder (GAD), or post-traumatic stress disorder (PTSD). Some
types of antidepressants can also be used to treat chronic pain
• Although antidepressants are a commonly used medication,
their exact mechanisms are not fully understood. It is thought
that they improve low mood by increasing the amount of
neurotransmitter (chemical messengers such as serotonin or
noradrenaline) in the brain.
• NaSSAs work by increasing the amount of noradrenaline and
serotonin in the synaptic cleft (the space between neurons at
the nerve synapses through which neurotransmitters send their
messages) and blocking some serotonin receptors in order to
treat depression. They are thought to cause less sexual
dysfunction than other antidepressants.
• https://www.youtube.com/watch?v=uA6r4BINvE8
 Uses
These medications are used not only to treat depression but for other conditions too.
The primary, or approved, uses of antidepressants are to treat:

• agitation
• obsessive-compulsive disorders (OCD)
• childhood enuresis, or bedwetting
• depression and major depressive disorder
• generalized anxiety disorder
• bipolar disorder
• posttraumatic stress disorder (PTSD)
• social anxiety disorder
• Off-label uses of antidepressants include:
• Insomnia, pain, migraine