Psych 01: Major Depression Disorder: Pathophysiology

Depression Sx on the DSM-5

• Feeling sad or having a depressed mood

• Loss of interest or pleasure in activities once enjoyed

• Appetite changes -weight loss or gain unrelated to dieting

• Sleep issues Trouble sleeping or sleeping too much

• Increased fatigue, lack of energy

• Changes in speech or other motor activities: Increase in purposeless physical activity (e.g., handwringing or pacing) or slowed movements and speech (actions observable by others)

• Feeling a sense of guilt or worthlessness

• Cognitive impairment, concentration, and decision making

• Recurring thoughts of death or suicide

What is required for Depression Dx?

1. at least 5 Sx on the DSM-5 must be present, can vary from mild to severe and must last a minimum of 2 continuous weeks

2. one of the 5 Sx must be from the first 2 on the list

What medical conditions may mimic some depression sx?

• thyroid problems

• a brain tumor

• vitamin deficiency

When does depression present?

any time, but usually in late teens to mid-20s

M vs W in depression

Women > men experience depression

Depression: mood/interest, self-esteem, and sudden loss of loved one.

mood/interest: constantly low

self esteem: Feelings of worthlessness & self-loathing are common

sudden loss of loved one: Can intensify existing MDD

Bereavement: mood/interest, self-esteem, and sudden loss of loved one.

mood/interest: "Painful" waves occur intermixed with positive memories of deceased

self esteem: Usually maintained

sudden loss of loved one: Can precipitate MDD

Depression RFs

1. Neuro-chemistry/physiology: Biogenic Amine Theory, Overactive Hypothalamic Axis

2. Genetics: If one identical twin has depression, another is very likely (>70 %) to experience depression.

3. Environmental factors: Continuous exposure to violence, neglect, abuse or poverty also increase vulnerability

What is the monoamine theory of depression?

• An abnormality in the receptors for monoamine neurotransmitters leads to depression

• This is caused by: - A depletion of monoamine NTs - Abnormalities in NT receptor - Problems with signal transduction

What are the biogenic amines of interest in depression?

5-HT, NA, DA

Which brain structures are implicated in normal regulation of affective behavior? (VVLAD)

1. ventromedial prefrontal cortex (VMPFC)

2. ventral striatum, amygdala, and hippocampus

3. lateral orbital prefrontal cortex (LOPFC),

4. anterior cingulate cortex (ACC)

5. dorsolateral prefrontal cortex (DLPFC)

What areas are hyperactive in MDD brains?

VMPFC & LOPFC underlying ↑ in pain, anxiety, tension.

- shown by blood studies

What areas are hypoactive in MDD brains?

DLFPC manifesting as apathy, ↓ in attention, memory and psychomotor activities

What happens to connectivity in MDD brains?

↓ in connectivity between ACC & amygdala

How does hippocampal volume change in MDD brains?

decreases --> memory issues

Hypothalamic-Pituitary-Cortisol System in MDD

1. high levels of stress hormone cortisol --> alters GRs

2. High density of GR --> hippocampal dysfunction and shrinkage --> down-regulation of GR sensitivity.

3. When chronic stress continues unabatedly, GR signalling cannot contain the stress response, i.e., GR negative feedback fails

4. Over-activity in HPA & amygdala follows --> ↑ in sympathetic tone

What is the result of increased sympathetic tone in MDD brains?

1. ↑ in sympathetic tone → cytokine & macrophage release

2. Cytokines diminish neurotrophic support and monoamine neurotransmission that can lead to neuronal death and glial cell* damage.

What are some manifestations of cytokine and macrophage release?

- fatigue

- ↓ appetite

- ↓ libido

- ↓ pain thresholds

What is Brain derived neurotrophic factor (BDNF) involved in?

- neuron survival

- stimulates and controls neurogenesis

- BDNF acts in the hippocampus

How do corticosteroids effect BDNF levels?

BDNF levels decrease when corticosteroid levels rise

How do monoaminergic levels effect BDNF levels?

BDNF levels decrease when monoaminergic transmission decreases

BDNF levels in MDD vs non MDD brains

levels in CSF and plasma/serum in MDD patients are lower than non-depressed individuals

What are depressogenic meds?

Drugs that have been linked with behavioural manifestations of symptoms of depressed mood

Cardiac depressogenic

Beta blockers, clonidine, methyldopa

CNS depressogenics

Alcohol, amphetamines, benzodiazepines, narcotics, cannabis

Antihistamine depressogenics

Diphenhydramine, brompheniramine

Chemo depressogenics

Tamoxifen

Steroid depressogenics

Glucocorticoids, Ocs

Other depressogenics

Isoretinoin, interferon, efavirenz (non-nucleoside reversetranscriptase inhibitor - NNRTI).

Non pharm tx of MDD

• Cognitive behavioral therapy

• Interpersonal therapy

• Dialectical behavior therapy

• Acceptance and commitment therapy

What is Electroconvulsive shock therapy (ECT)?

Brief pulses (~800 mA) applied bilaterally over ~ 1-6 s that are repeated 2-3 times per week over a course of 2-4 weeks.

When might ECT be used to treat MDD?

Reserved for MDD patients resistant to above treatment options

ECT AEs

retro- anterograde amnesia, especially few weeks before treatment

- post op amnesia and cognitive impairment

Therapeutic effect of ECT on depression

rapid relief of severe depression that is also accompanied by a rapid reduction in suicide drive.