Mental Health: Major Depressive Disorder

Major depressive disorder onset

typically in mid-teens to late 20's

Peak prevalence in 30's-40's

Major depressive disorder more commonly affects

women (2-3x more common)

Genetic risk factors for major depressive disorder

2-3 times greater prevalence among first-degree relatives

MTHFR gene shows “meager significant association”

Environmental risk factors for major depressive disorder

High ACE (adverse childhood experience) score

Chronic medical illness/disability

Stressful life events (bereavement, divorce, unemployment, financial loss)

Major depressive disorder pathophysiology: neurotransmitter deficit hypothesis

Low Serotonin- depression and anxiety

Low Norepinephrine- depression

Low Dopamine- depression

Major depressive disorder pathophysiology: other correlations

Elevated cortisol levels

Thyroid hormone imbalance

Decreased hippocampus volume
Cortical thinning (temporal regions)

Major depressive disorder clinical presentation

Depressed mood, Anhedonia (lack of motivation), Sleep disturbance (insomnia or hypersomnia), Appetite changes (increased or decreased), Weight change (increased or decreased), Fatigue, Difficulty concentrating, Indecisiveness, Guilt, Worthlessness, Suicidal ideation

Major depressive disorder diagnosis

Clinical based on DSM-5 Diagnostic Criteria:

2 weeks of 5+ symptoms of depression (one of which must be depressed mood or loss of interest or pleasure)

Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning

Major depressive disorder diagnostic tools

Patient Health Questionnaire 9 (PHQ-9)

Initial screening and tracking progress

Depression score ranges according to the PHQ-9

5 to 9: mild

10 to 14: moderate

15 to 19: moderately severe

≥20: severe

Major depressive disorder specifiers: severity

mild, moderate, severe

Major depressive disorder specifiers: remission

partial, full

Major depressive disorder specifiers: seasonal pattern

AKA Seasonal Affective Disorder

Presence of depressive symptoms at the same season every year (typically winter)

Major depressive disorder specifiers: catatonic depression

Motor immobility, stupor, extreme withdrawal

Major depressive disorder non-pharmacologic management

•Improve diet
•Increase exercise
•Improve sleep routine
•Practice gratitude
•Meditation
•Invest in meaningful relationships
•Serve/volunteer
•Avoid drugs and alcohol

Major depressive disorder additional therapy

Psychotherapy

Cognitive Behavioral Therapy

Group Therapy

Major depressive disorder pharmacologic management

SSRI

SSRI MOA

inhibit Serotonin reuptake-> increased levels of Serotonin in the synaptic space

SSRI drugs

Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft)

SSRI that can cause QT prolongation

Citalopram

SSRI that has the longest half life and takes the longest to wash out

Fluoxetine

good for patients with bulimia or not taking medication out of non-compliance

SSRIs that are the safest to use in pregnancy

Sertraline and Escitalopram

SSRI time taken to induce a response

2-6 weeks of daily use

SSRI BBW

Suicide- Children, adolescents, and young adults (up to age 24) can have increased suicide risk during initial treatment

SSRI ADE

GI dysfunction- 6-18%, sexual dysfunction- 17%, drowsiness- 17%, weight gain- 12%, insomnia- 11%, headache- 10%

SSRIs and serotonin syndrome

Potentially life-threatening syndrome due to increased serotonergic activity in the CNS

Serotonin increasing drugs- SSRIs, SNRIs, TCAs, MAOIs, Triptans, St. Johns Wort, Amphetamines, Ergot derivatives, Tramadol

Serotonin syndrome symptoms

altered mental status, hyperthermia, diarrhea, tremors, clonus, dilated pupils, and/or flushed skin typically within 24 hours of adding a new serotonin increasing drug

Serotonin syndrome diagnosis

clinical based on Hunter Criteria

Serotonin syndrome management

1) d/c offending drugs

2) supportive care and Benzodiazepines

3) Cyproheptadine (Serotonin Antagonist)

SNRIs MOA

MOA- inhibits Serotonin and Norepinephrine reuptake-> increased levels of Serotonin and Norepinephrine in the synaptic space

SNRI to use first-line in patients with neuropathic pain and/or fibromyalgia

Duloxetine (Cymbalta)

SNRI drugs

Desvenlafaxine (Pristiq), Venlafaxine (Effexor), Duloxetine (Cymbalta)- with weak inhibition of Dopamine

SNRI BBW

Suicide- Children, adolescents, and young adults (up to age 24) can have increased suicide risk during initial treatment

SNRI side effects

nausea- 30%, insomnia- 17-24%, dizziness- 15%, drowsiness- 16%, reduced appetite- 8-22%, weight loss- 7-30%, diaphoresis- 11%, sexual dysfunction- 5-10%

NDRIs MOA

inhibits Norepinephrine and Dopamine reuptake-> increased levels of Norepinephrine and Dopamine in the synaptic space

NDRI indications

First or second choice for depression management

Very useful for MDD with fatigue and anhedonia

Also used to reduce addiction (ex: nicotine cessation)

NDRI drug

Bupropion (Wellbutrin)

NDRI BBW

Suicide- Children, adolescents, and young adults (up to age 24) can have increased suicide risk during initial treatment

NDRI ADE

insomnia- 11-40%, GI disturbance- 30%, headache 30%, dizziness 18%, weight loss 14-28%, tachycardia 11%, sexual dysfunction- 2%

NDRI contraindicated in patients with

Eating Disorder or Seizure Disorder

Bupropion HCl (Auvelity) MOA

CYP2D6 inhibitor to reduce the metabolism of dextromethorphan

Dextromethorphan MOA

antagonizes the NMDA receptor which reduces excitatory neurotransmission by Glutamate (reduces excitotoxicity)
uThird choice for depression management

Dextromethorphan HBr and Bupropion HCl (Auvelity) ADE

dizziness-16%, headache-8%, diarrhea-7%, somnolence-8%, dry mouth-6%, sexual dysfunction-6%, hyperhidrosis-5%

Dextromethorphan HBr and Bupropion HCl (Auvelity) contraindicated in

Eating Disorder or Seizure Disorder

Tricyclic Antidepressants (TCAs) MOA

Inhibits reuptake of Serotonin and Norepinephrine as well as block muscarinic M1, Histamine H1, and alpha-adrenergic receptors-> increased levels of Serotonin and Norepinephrine in the synaptic space as well as anticholinergic, antihistamine, and anti-adrenergic effects

TCAs choice for depression management

3rd line

Easy to overdose (lethal dose is only 8x the average therapeutic dose)

Teratogenic (Pregnancy category C)

TCA drugs

Amitriptyline (Elavil), Nortriptyline (Pamelor), Imipramine (Tofranil)

TCA BBW

Children, adolescents, and young adults (up to age 24) can have increased suicide risk during initial treatment

TCA ADE

sexual dysfunction, orthostatic hypotension, sedation, dry mouth, urinary retention, constipation, weight gain, cardiac toxicity, lower seizure threshold, cardiotoxicity, convulsions, coma

Monoamine Oxidase Inhibitors (MAOIs) MOA

inhibits Monoamine Oxidase from breaking down Serotonin, Norepinephrine, and Dopamine-> increase levels of Serotonin, Norepinephrine, and Dopamine in the synaptic space

MAOIs choice for depression management

3rd line

Teratogenic (Pregnancy category C)

MAOIs drugs

Selegiline (Zelapar), Phenelzine (Nardil)

MAOIs BBW

Suicide- Children, adolescents, and young adults (up to age 24) can have increased suicide risk during initial treatment

MAOIs ADE

sexual dysfunction, weight gain, CNS stimulation (anxiety, insomnia, mania), orthostatic hypotension, hypertensive crises if taken with dietary tyramine

Trazodone (Oleptro) MOA

mildly inhibits Serotonin reuptake and is an alpha-1 adrenergic antagonist

Used most often in patients with depression + insomnia

Trazodone (Oleptro)

Trazodone (Oleptro) ADE

somnolence, priapism (rare)

Mirtazapine (Remeron) MOA

increased release of Serotonin and Norepinephrine through blockade of alpha adrenergic receptors (which normally inhibit their release)

Used most often in patients with depression + insomnia + poor appetite

Mirtazapine (Remeron)

used often in elderly patients

Mirtazapine (Remeron) ADE

somnolence, weight gain, increased appetite

Ketamine MOA

antagonizes the NMDA receptor, which reduces excitatory neurotransmission by Glutamate (reduces excitotoxicity)

Used in resistant depression (3rd or 4th line option)

Ketamine

Ketamine PK

IV or Nasal Spray administration

Ketamine patient descriptors

dissociative "out of body" experience where they can process emotions efficiently

Ketamine peak effect

24 hours, but continues to be effective for 1-2 weeks after infusion

Ketamine repeat treatment schedule

Patients return every 2-4 weeks

Transcranial Magnetic Stimulation (TMS) MOA

hypothesized to change pathologic neural pathways

Used in resistant depression (3rd or 4th line option)

TMS

ECT- Electroconvulsive Therapy

Electrical current is passed through the brain while the patient is under general anesthesia

ECT MOA

hypothesized to sensitize neurotransmitter receptors

Used in resistant depression (3rd or 4th line option)

ECT

ECT effectiveness

Remission occurs in 70-90% of patients who receive ECT

60% of patients reach remission within 3 weeks (9 treatments)