Major

Depressive
Disorder
IVORY DIANE C. AMANCIO, RPH CPH
 Introduction:
❖Major depression is classified as a unipolar mood disorder. Further,
major depression can be classified as when an emotional state, such
as sadness, becomes chronic and uncontrollable. It is the most
common mood disorder.
❖Mood disorders are still being studied due to the unclear nature of
how they occur due to the difficult availability of human brain tissue
for neurochemical measurement until patients are post-mortem.
Epidemiology
According to Age: Hereditary:
Adolescence – Mid50’s About 37% hereditary liability
◦ Women have 1.7-2.7 times greater prevalence than men. (8%-18% with MDD have at least
65 – 80 years old a degree relative with a history
◦ 20.4% prevalence in women of depression)
◦ 9.6% prevalence in men

Other Prevalence with: Environmental:

Comorbid substance abuse About 63% of the variance in
liability was due to an individual-
Suicide attempts
specific environment.
Death occurring frequently
MDD Etiology
Epigenetic mechanism of MDD:
1. Genome factor:
- a 2 to 3 times increase in lifetime risk of developing MDD among first-
degree relatives.
- 37% heritable
2. Environment:
- 63% environmental factor
2 types:
Aversive: Protective:
Prenatal factors Social support
Childhood trauma Coping
Stress Exercise
Medical Illness
Drug abuse
MDD Etiology Clinical Presentation:
• Affective symptoms
• Cognitive symptoms
Epigenetic mechanism of MDD: • Somatic-vegetative
symptoms
Genome
Pathophysiology:
Brain Network Level:
• Regional Brain volumes

MDD • Congnitive control

circuit
Molecular level:
• Neurotransmission
Environ • Neuropasticity
mental • Stress hormones
• Inflammation
Etiology Normal Physiology

The symptoms reported by MDD

patients consistently reflect changes
in Brain Monoamine
Neurotransmitters (NTs).
1. NTs carry messages between cells.
2. Each NT generally binds to a specific receptor,
and this coupling initiates a cascade of
events.
3. NTs are then absorbed back into nerve cells
by reuptake pumps(transporter molecules),
which may be recycled for later use or broken
down by enzymes.
4. Primary MAO of most antidepressants are
thought to inhibit the transporter molecules
and allow more NT to remain in the synapse.
Primary Hypothesis for the
Development of MDD:
Monoamine Hypothesis (Biogenic Amine Hypothesis)
❖Decreased levels and functional deficiencies of 5-HT, DA, and NE, which are
typically present in the brains of depressed patients
❖By improving neurotransmission in the central nervous system and increasing the
number of related monoamine neurotransmitters in the synaptic cleft, this class of
medications reduces the symptoms of depression
Primary Hypothesis for the
Development of MDD:
Neural Plasticity Hypothesis
❖The neurotrophic family includes brain-derived neurotrophic factor (BDNF), which regulates
neuronal plasticity. On the one hand, it might impact the development of synaptic structures,
such as axons and dendrites, and their growth and remodeling. On the other hand, it might
enhance the long-term synaptic transmission function of the hippocampus through pre- and
post-synaptic pathways.
❖The pathogenesis of depression is significantly influenced by neuroplasticity and remodeling
failure.
❖Decreased levels of BDNF have been found in brain samples from depressed patients. In
contrast, antidepressant treatment increases the expression of BDNF in the brains of depressed
patients. Therefore, it shows great potential in the treatment of depression as it increases BDNF
levels.
Primary Hypothesis for the
Development of MDD:
Neuroinflammatory hypothesis
❖Glial cells and cytokines play a role in the immune response known as neuroinflammation,
which occurs in the central nervous system.
❖Depression is an inflammation-related disease that worsens as inflammation increases and
progresses.
❖Glial cell activation in the brains of depressed patients results in the release of pro-
inflammatory cytokines such as interleukin-6 (IL-6), interleukin 1 beta (IL-1β), and tumor
necrosis factor-alpha (TNF-α), which can lead to neuroinflammation and neuronal death.
❖In addition, glial cells produce nitric oxide synthase (NOS), and cyclooxygenase-2 (COX-2)
could also induce neuroinflammation by promoting oxidative stress levels.
Neuroinflammation has emerged as a novel target for the t of depression
Primary Hypothesis for the
Development of MDD:
Hypothalamic-pituitary-adrenal (HPA) axis
The hypothalamus, pituitary, and adrenal glands work together as part of the
HPA axis to govern the body’s reaction to physiological or psychological
stimuli.
Patients with depression have been discovered to have HPA dysfunction,
resulting in high glucocorticoid (GC) levels, which in turn cause neuronal
dysfunction and structural changes in the hippocampus.
Clinical trials have established the antidepressant properties of glucocorticoid
receptor (GR) antagonists and the viability of targeting HPA regulation in the
treatment of depression
❖ The primary function of the HPA axis is to regulate the stress
response. When we experience something stressful, the
hypothalamus releases a hormone called corticotropin-releasing
hormone (or CRH).

❖ CRH signals the pituitary gland to secrete a hormone called

adrenocorticotropic hormone, or ACTH into the bloodstream.

❖ ACTH travels down to the adrenal glands where it prompts the release
of a hormone called cortisol from the cortex, or outer layer, of the
adrenal glands.

❖ The release of cortisol causes several changes that help the body to
deal with stress. For example, it helps to mobilize energy like glucose
so the body has enough power to cope with a prolonged stressor.

❖ When cortisol levels in the blood get high, this is sensed by receptors
in areas of the brain like the hypothalamus and hippocampus, which
leads to the shutting off of the stress response through what is known
as a negative feedback mechanism.
Function of
Neurotransmitters
Function of Neurotransmitters:
Dopamine: The most thrilling
Glutamate: main excitatory neurotransmitter plays a major role in
your brain’s reward system.
neurotransmitter in the central
nervous system Dopamine proved critical to central
nervous system functions such as
GABA (γ-aminobutyric acid): movement, pleasure, attention, mood,
and motivation.
main inhibitory neurotransmitter. It
reduces the activity in the central Adrenaline (Epinephrine):
nervous system and blocks certain neurotransmitter is responsible for your
signals from your brain. body’s fight or flight response.
Adrenaline is your body’s defense
mechanism against stress
Function of Neurotransmitters:
Serotonin: promotes satisfaction Acetylcholine: directly affects your
after eating and keeps your muscles. presence of
appetite in check. acetylcholine triggers an action
potential or command in the
muscle fiber. But acetylcholine
Oxytocin:“love hormone”. Two main makes your muscle contract
actions of oxytocin in the body instead of sending signals to a
are contraction of the womb (uterus) brain cell.
during childbirth and lactation.
Pathophysiology
of MDD
Neurochemical dysregulation
A deficit in the concentration of the brain’s norepinephrine, dopamine,
and/or serotonin resulting in depression. Antidepressant therapies focus on
increasing the monoamine neurotransmitter levels within the synapses
Downregulation of B-adrenergic receptors
accompanies the desensitization
Reserpine is lipid soluble and can penetrate
the blood-brain barrier. This agent binds and
inhibits the catecholamine pump on the
storage vesicles in central and peripheral
adrenergic neurons, thereby inhibiting the
uptake of norepinephrine, and dopamine
serotonin into presynaptic storage vesicles.
Beta-adrenergic blockers: Reserpine may
have additive orthostatic hypotensive effects
when used with beta-blockers due to
catecholamine depletion. Beta-blockers may
also interfere with reflex tachycardia,
worsening the orthostasis.
Neuroendocrine Dysregulation
❖Chronic activation of the Hypothalamic-pituitary-adrenal (HPA)
system and chronic glucocorticoid secretion are found in 30-70% of
individuals with major depression suggesting the correlation
between the dysfunctional system and depression.
❖Chronic cortisol release in the body results in the secretion of
pro-inflammatory cytokines which causes immunosuppression and
inflammation.
❖Results to neuronal atrophy of the hippocampus resulting in no cell
growth consequently causing a reduction of the hippocampal brain-
derived neurotrophic factor (BDNF)
Neuroanatomic and Function
Abnormalities
❖Depressed individuals’ post-mortem brains have shown a widespread decrease
in serotonin 5-HT1a receptor subtype binding in the frontal, temporal, and limbic
cortex.
❖Norepinephrine receptor alterations are found in the frontal cortex of some
suicide victims with depression. Alterations in norepinephrine systems may be
linked to attention or concentration difficulties as well as sleep and arousal
disturbances in depression.
❖Depressed individuals have also been found to have abnormalities in Cerebral
blood flow and glucose metabolism.
Clinical
Manifestations
Clinical Manifestations/Diagnostic
Criteria
❖To diagnose depression, symptoms must be present for at least two weeks.
❖There are unremitting feelings of sadness and despair.
❖Depressive episodes may occur or recur suddenly, gradually, or continue
from a few weeks to months.
To be diagnosed with Major Depressive Disorder, patients have
to have several, usually five or more, symptoms including low
mood that is present for at least two weeks:

1.Depressed or irritable mood

2.Loss of interests and pleasures – this includes
interpersonal relationships
3.Significant weight gain or loss (5%) in a month
4.Sleep Disturbances: Insomnia/Hypersomnia
To be diagnosed with Major Depressive Disorder, patients have
to have several, usually five or more, symptoms including low
mood that is present for at least two weeks:

1.Psychomotor agitation or retardation: Restlessness or agitation can

occur
2.Fatigue or loss of energy
3.Feelings of worthlessness or excessive guilt: Pessimistic/Negative
outcomes are perceived
4.Poor concentration or indecisiveness
5.Recent thoughts of suicide/death: Suicidal risk increases with
depression
Treatment
Plan
3 Phases for Treatment with MDD
ACUTE PHASE
◦ 6-12 weeks
◦ The goal is remission (absence of symptoms)

CONTINUATION PHASE
◦ 4-9 months
◦ After remission is achieved; the goal is to eliminate residual symptoms/prevent relapse
◦ Possible return of symptoms within 6 months of remission

MAINTENANCE PHASE
◦ 12-36 months
◦ The goal is to prevent recurrence
◦ Example is a separate episode of depression
◦ Duration of antidepressant therapy depends on the risk occurrence:
◦ Recommended lifelong maintenance therapy for persons at greater risk
for recurrence:
◦ Younger than 40 years of age with two or more prior episodes
◦ Persons of any age with three or more prior episodes.
Pharmacologic
Therapy
SSRIs (Selective Serotonin Reuptake
Inhibitors)
First-line treatment antidepressant due to safety in overdose and
tolerability.

SNRIs (Selective Norepinephrine Reuptake

Inhibitors)
TCAs (Tricyclic Antidepressants)
◦ Effective in treating all depressive subtypes
◦ Potentiate the activity of NE and 5-HT by blocking their reuptake.
◦ Because TCA affects other receptor systems, including Cholinergic, neurologic, and
cardiovascular systems, ADEs are reported frequently during TCA therapy.
New Generation SNRIs
Venlafaxine – inhibits 5-HT in low doses; inhibits NE at high doses
Desvenlafaxine – primary active metabolite of Venlafaxine
Duloxetine – SNRI with both 5-HT and NE reuptake inhibition across all doses.

Mixed Serotonergic Medications (Mixed 5-HT)

Tradozone and Nefazodone – dual actions on serotonergic neurons, acting as
both 5-HT antagonists and 5-HT reuptake inhibitors.

Trazodone – blocks b-adrenergic and histaminergic receptors (sedation and dizziness)

long-acting release of Trazodone was approved by the FDA
Nefazodone – decline due to hepatotoxic effect
◦ Block box labeling requirement from FDA warning describing rare cases of liver failure.
Serotonin and A-adrenergic Receptor
Antagonist
Metazapine – enhances central noradrenergic and serotonergic activity through antagonism of
central presynaptic a-adrenoceptor auto receptors and heteroceptors.
- Antagonizes 5HT receptors as well as Histamine receptors.
- It helps lower Anxiety and GI effects

Monoamine Oxidase Inhibitors

MOA: increases the concentration of NE, 5-HT, and DA within the neural synapse through inhibition
of the MAO enzymes. Chronic therapy causes changes in receptor sensitivity.

Phenelzine and Tranylcypromine – Nonselective MAOis (inhibitors of MAO-A and MAO-B)

Selegiline Transdermal patch – allows inhibition of MAO-A and MAO-B in the brain, yet has reduced
effects on MAO-A in the gut.
Algorithm
Treatment of
Uncomplicated MDD
Thank you!