Major Depressive Disorder - Part 1 and 2

Risk factors for Depression

• Gender

• Race

• Age

• Martial Status

• Finanical Status

• Psychiatric comorbidities

• Stress

• General Medical conditions

• Genetics

Monoamine Oxidase Inhibitors

Serotonin - increase

Norepinephrine - increase

Dopamine - increase

Tricyclic Antidepressants

Serotonin - Increase

Norepinephrine - Increase

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin - Increase

Serotonin Norepinephrine Reuptake Inhibitors

Serotonin - Increase

Norepinephrine - Increase

Norepinephrine Dopamine Reuptake Inhibitor

Norepinephrine - Increase

Dopamine - Increase

DSM-% Diagonistic Criteria

Major Depressive Disorder

• > 5 Symptoms in same two week period

• At least one symptom must be depressed mood or anhedonia

SPICE GAPS

S - Suicidal Ideation/suicide attempts/recurrent thoughts of death

P - Psychomotor agitation or retardation

I - Interest (loss of) or Depressed Mood

C - Concentration (diminished ability to think of concentrate or indecisions)

E - Energy (loss of) or fatigue

G - Guilt (excessive) or worthless

A - Appetite Changes (increase or decrease or >5% weight gain/weight loss in 1 month)

S - Sleep Changes

Differential Diagnoses

• Sadness

• Manic episodes with irritable mood or mixed episodes

• Adjustment disorder with depressed mood

• Attention-deficit/hyperactivity disorder (ADHD)

• Substance/medication-induced depressive disorder

– Alcohol, amphetamine/cocaine withdrawal

• Mood disorders due to another medical condition

– Hypothyroidism, anemia, HIV/AIDS, Cancer, Lupus, CHF, CAD

Acute Phase

Minimum of 6 to 12 weeks in duration

Goal: Remission, achieve baseline level of functioning

Remission: at least 2 months with no to minimal (1-2) depressive symptoms

Continuation Phase

4 to 9 months after remission

Goal: Eliminate residual symptoms, prevent relapse

Relapse: depressive symptoms return after partial recovery

Maintenance Phase

> 3 MDD episodes

• Chronic MDD

• Additional risk factors for recurrence (psychosocial stressors, family history,
  severity of MDD, early age at onset, elderly)

• Goal: Prevent recurrence

• Recurrence: return of depression

Mild to Moderate MDD

• Antidepressant

• Psychotherapy

  • Antidepressant + Psychotherapy

Moderate to Severe MDD

• Antidepressant + Psychotherapy

Mild Depression

Zero to few symptoms in excess of those required for diagnosed present

Intensity of symptoms distressing but manageable

Minor functional impairmen

Moderate Depression

Number of symptoms, intensity, and/or functional impairment between “mild” to “severe”

Severe Depression

Number of symptoms in excess of those required for diagnosis

Intensity seriously distressing and unmanageable

Marked interruption in social and occupational functioning

Non - Pharm Therapy

Psychotherapy

• Electroconvulsive Therapy (ECT)

• Treatment resistant depression (TRD)

• Vagal Nerve Stimulation (VNS)

• Treatment resistant depression (TRD)

• Trancranial Magnetic Stimulation (TMS)

  • Neurostar®

Selecting an Antidepressant

• Past AD trials

• Core Symptoms

• Psychiatric/medical co-morbidities

• Concomitant

• Age

• Patient Preference

• Family History

• Side Effects

• Drug Cost

Symptom Improvement: First Few Days

• Increased agitation/anxiety, nausea/vomiting, diarrhea

• Improvement in sleep and appetite

Symptom Improvement: 1-3 weeks

Increased activity, improved hygiene, normalization of memory and concentration, sleep and eating back to normal

Symptom improvement: After 2-4 weeks or Longer

Relief of depressed mood

Decreased hopelessness

Decreased thoughts of suicide

Increased enjoyment in activites

First line treatment

SSRIs, SNRIs, Bupropions, Vortioxetine

What is the adequate trial of antidepressant?

4 to 8 weeks

If symptoms persist after adequate trial?

Switch to a different antidepressant OR augment with antidepressant with different MOA, or SGA, or psychotherapy

• Unclear whether it is better to increase dose, augment, or switch if partial response to
  therapy

• Less tjam 50% improvement at 8 weeks, switching treatment is recommended

General Approach to Treatment

Goal of Treatment: Remission (absence of symptoms)

• Predictors of remission: female sex, Caucasian race, employment, higher level of education, higher income

Treatment resistance: episode that has failed to respond to 2 separate trials of an antidepressant of adequate dose and duration

Strategies for Partial or No Response to Treatment

Strategies

• Switching- preferred if little to no improvement after 4-8 weeks at

  adequate dose

  • Can switch within class or outside of class

    • Strategies for switching

    – Cross taper

    – Direct switch

• Augmentation: Addition of second AD ot other medication to existing AD treatment; preferred if partial response to treatment at 4-8 weeks

Antidepressant Issues

Black Box Warning: Suicidal Thoughts and Behaviors

BBW issued in 2004 for increased risk of suicidality (ideation and behavior) for those < 25 years of age

SSRIs that we need to know

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac, Prozac Weekly, Sarafem)

Fluvocamine (Luvox, Luvox CR)

Paroxetine (Paxil, Paxil CR)

Sertraline (Zoloft)

SSRIs: Indications

• MDD

• Panic disorder

• OCD

• GAD

• PTSD

• PMDD

• Social Anxiety Disorder

Escitalopram

S-enantiomer of Citalopram

Theorized to be 100 Xs more potent than R-enantiomer at Serotonin reuptake inhibition

Dose conversion not provided in PI

• Citalopram 20mg = Escitalopram 10mg

Both have side effects and no significant drug interactions

Citalopram and QT Prolongation

Dose-dependent QT prolongation

• Not recommended for use at doses > 40 mg/day!!

Maximum dose of 20 mg/day if:

• Age > 60

• Hepatic impairment

• CYP2C19 poor metabolizer (CYP2C19 substrate)

• Concomitant cimetidine or other 2C19 inhibitors (e.g. omeprazole)

Citalopram and QT Prolongation

Do not use in patients with:

• Congenital long QT syndrome

• Bradycardia

• Hypokalemia

• Hypomagnesemia

• Recent MI

• Uncomepensated heart failure

• Concomitant QT prolonging medications

Immediate action required if irregular heartbeat, SOB, dizziness, or fainting

EKG monitoring:

• D/C if persistent QTC measurement > 500 msec

Citalopram and QT prolongation (slide 31)

Fluoxetine (Prozac)

Long t ½ for parent and active metabolite

• Beneficial in patients: Non-adherent, atypical depression

Strong CYP2D6 Inhibitor

• Increase desipramine, dextromethorphan, atomoxetine

• Decreases metabolism of tamoxifen to active metabolite

Must wait 5 weeks after stopping before initiating a MAOI!

Formulations:

• Prozac weekly: 90mg delyaed-release capsule = 20mg daily

• Start 7 days after last 20mg dose

Sarafem

• Premenstrual Dysphoric Disorder (PMDD)

• Given daily or intermittently (start 14 days prior to menstrual cycel and through first full day of menses)

Sertraline (Zoloft)

Mild activating properties

• Improve hypersomnia and energy

SADHEART (Sertraline Antidepressant Heart Attack Randomized Trial)

• Safe for use in patients with recent MI or unstable angina

Few drug interactions

Paroxetine (Paxil, Paxil CR, Prexeva, Brisdelle)

Strong CYP2D6 inhibitors

• Formulations: CR: Good for nausea

  • Sedation

  • Sexual dysfunction

  • Anticholinergic side effects

  • Withdrawl syndrome

• Brisdelle - 7.5 mg caps PO for menopausal hot flashes

• Pregnancy CAT D due to cardiac defects

Fluvoxamine (Luvox, Luvox CR)

FDA approved for OCD, but effective for depression and anxiety

Dosing:

• IR: BID

• CR: Q day (QHS dosing preferred because sedating)

Strong CYP1A2 Inhibitor

• Increase clozapine, theophylline

SSRIs: Common Side Effects

GI: Nausea, vomiting, diarrhea

Activation/insomnia

Sedation

Neurological effects (headache)

Sexual side effects

Bone fractures

Orthostatic Hypotension

Weight gain

Pregnancy category C - persistant pulmonary hypertension; CAT D for paroxetine (heart defects)

SSRI Side Effects: HOWS G

Hypotension

Headache

Hyponatremia

Bone fractures

Ocular effects

Suicidal thinking

GI issues/GI bleed

Serotonin syndrome

Sexual dysfunction

Weight gain

SSRIs: Other adverse effects

Hyponatremia and Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

• Rare but fatal if untreated

• Sighs and Symptoms: lethargy, mental status changes, hyponatremia (serum sodium (135 mEq/L), elevated urinary sodium excretion

• Hyperosmolar urine (>300 mosmol/kg)

• Management: dc offending agent; water restriction (more severe cases: hypertonic NaCl)

SSRIs: Significant Drug Interactions

NSAIDs, anti-platelet, anticoagulants

• Increased risk of bleed

• Monitor for signs and symptoms of bleed

• Risk increases if concomitant NSAID therapy

• Exercise caution when combined with NSAIDs, aspirin, and warfarin

Serotonergic Agents

• Increased risk of of Serotonin Syndrome

• Serotonergic ADs, MAOIs, tramadol, triptans, methylphenidate, linezolid, methylene blue, dextromethorphan, MDMA, St Johns Wort, fentanyl, buspirone, lithium, ginseng

SSRIs: Other adverse effects

Serotonin Syndrome

• Results from increased serotonin levels

• Single agent, increase in dose, or combination of serotonergic agents

  • Rapid onsents (minutes to hours)

• Clinical triad of symptoms

  • Mental status changes, autonomic hyperactivity, neuromuscular abnormalities (MAN)!

• 2-12% mortality rate

• Many cases self-limiting

Discontinuation Syndrome

Abrupt cessation of AD Risk higher for agents with
short half-life (e.g. paroxetine) and lower with fluoxetine
– Onset within 1 to 3 days

• Anxiety, irritability, sadness,
  insomnia, headache, nausea,
  electric shock sensations
  – ↑ risk if treated with AD for
  > 5 weeks or on high dose
  AD
  – Resolves in ~ 10 days
  – To avoid or minimize
  withdrawal, taper AD dose
  no more rapidly than ~ 25%
  per week

SNRIs Drugs

Venlafaxine (effexor, effexor XR) '

Desvenlafaxine (Pristiq, Khedezla)

Duloxetine (Cymbalta, Irenka)

Milnacipran (Savella)

Levomilnacipran (Fetzima)

SNRIs: Indications

MDD, Fibromyalgia, Neuropathic Pain, Chronic Musculoskeletal pain, GAD, SAD, PD, OCD, PTSD, PMDD

Venlafaxine (Effexor, Effexor XR)

Dosing

• Inhibits reuptake of 5HT »NE

• 75 to 150-225mgL SSRI Activity only

• >150-250mg: duel SNRI activity

Formulations: IR: BID-TID

XR: QDAY

CRCL < 30ml/min decrease dose by 50%

Venlafaxine: Effexor: Adverse Effects

Withdrawl syndrome

GI side effects, headache, insomnia, agitation, sexual dysfunction

Increased Blood Pressure

• Dose dependent (doses > 300mg/day)

• Mean SBP and DBP increase from baseline by 3-4mmg Hg over 8-12 weeks

Desvenlafaxine Succinate (Pristiq, Khedezla)

S-isomer of Venlafaxine

5HT-NE reuptake inhibitor at all doses

PI recommends starting and maintenance dose of 50mg/day (max 400mg/day)

Potential advantage over venlafaxine: PK not altered by 2D6 inhibition

Patients may notice empty capsule in stool

Duloxetine (Cymbalta®, Irenka)

First SNRI approved for fibromyalgia and diabetic neuropathic
pain

• Inhibits serotonin and norepinephrine reuptake at all doses
  (5HT=NE reuptake inhibition); administered BID

• Avoid if CrCl< 30 mL/min, hepatic impairment, or substantial alcohol intake

• Side effects - Nausea, dry mouth, constipation, decreased appetite, sweating, insomnia

• ↑ mean SBP by up to 2.1 mm Hg and DBP by 2.3 mm Hg in clinical trials

Milnacipran (Savella)

FDA-approved for fibromyalgia

Titration schedule

• Day 1: 12.5 mg/day

• Day 2-3: 12.5 mg BID

• Day 4-7: 25 mg BID

• After Day 7: 50 mg BID – 100 mg BID (max: 200 mg/day)

• Avoid use in patients with substantial alcohol intake or chronic liver disease

• CrCl< 29 mL/min: decrease dose to a max of 50 mg BID

• ESRD: do not use

• Side effects - Nausea/vomiting, HA, constipation, dizziness, insomnia, increased HR, dry mouth, hypertension

Levomilnacipran ER (Fetzima)

Indicated for treatment of MDD (not approved for FM)
- Preferentially blocks reuptake of NE vs. 5HT (levo isomer of
milnacipran)

Dosing
- 20 mg PO once daily x 2 days then 40 mg once daily
- Can be increased in increments of 40 mg at intervals of ≥ 2 days
- Dose range: 40- 120 mg once daily
- Should be taken at same time each day
- CrCl 30-59: max 80 mg daily

CrCl 15-29: max 40 mg daily

• ESRD: do not use

Levomilnacipran ER (Fetzima)

Pharmacokinetics:

• Metabolism: hepatic (desenthylation and hydroxylation); 3A4 substrate

• Half life- 12 hours

DDIs

• 3A4 inhibitors

• Do not exceed 80mg/day

Common adverse effects:

• Nausea, constipation, hyperhidrosis, increased HR, erectile dysfunction, tachycardia, vomiting, and palpitations

Esketamine (Spravato): REMS

• Administration can only occur in healthcare setting that can ensure monitoring by healthcare provider for >2 hours

• Practitioners, healthcare settings, and pharmacies dispensing esketamine must be certified and cannot dispense it to patient

• Patient must enrolled in registry

SNRIs: Common Side Effects

All SNRIs need dose adjustments if renal/hepatic impairment

• GI: nausea, vomiting

• Activation

• Sexual dysfunction

• Noradrenergic side effects

  • Increase HR, BP

  • Dry mouth

  • Sweating

  • Constipation

  • Urinary retention

Serotonin Modulators

Vilazodone, trazodone, nefazodone

MOA: Antagonize postsynaptic serotonin receptors and block serotonin reuptake

All hepatically cleared

Vilazodone: Initial Dose: Range: Half Life: Metabolism: Preg Cat: How Supplied

10mg PO daily with FOOD

20-40 mg PO daily with FOOD

25hours

CYP3A4 (major); CYP2C19 and 2D6 minor

C

T

Trazodone: Desyrel: Initial Dose: Range: Half Life: Metabolism: Preg Cat: How Supplied

IR: 50mg PO BID; ER: Discontinued in the US

200-400mg/day

5--9hours

CYP3A4

Preg. C

T

Nefazodone (Serzone): Initial Dose: Range: Half Life: Metabolism: Preg Cat: How Supplied

100mg dose PO BID

150-600mg/day in two divided doses

2-4hours; active metabolite: 1.4-8hours

Metabolism: Hepatic

Preg C

T

Vilazodone (Viibryd)

Role in therapy: comorbid anxiety, treatment failure with SSRIs

MOA: Serotonin reuptake inhibitor, 5HT1A partial agonists

Administration: must take with food

Two-fold: increased Cmax and AUC

Dosing for Vilazodone (Viibryd)

10mg PO daily with food x 7days, max: 40mg daily with food

Drug Interactions (CYP3A4 substrate): Vilazodone (Viibryd)

Strong 3A4 inhibitors may ↑ concentration by 50%
- Management: decrease dose by 50% (max: 20 mg daily)
– 3A4 inducers may ↓ concentration
- Monitor for decompensation (max: 80 mg daily)

Adverse Effects of Vilazodone: Viibryd

Diarrhea, nausea, insomnia, vomiting

No weight gain

Trazodone (Desyrel): MOA

MOA: 5HT2A/C antagonist, 5HT reuptake inhibitor
– Alpha-1 antagonist (orthostasis, priapism) and H1 antagonist (sedation)

Trazodone (Desyrel): Dosing Insomnia

• Initial dose of 12.5-50mg QHS, range: 50-100mg QHS

• Immediate onset; no risk of dependence, tolerance, withdrawal

Trazodone (Desyrel): Depression

Initial: 50 mg PO BID; Target: 75-150 mg PO BID
– Use as adjunct to AD if sedation desired

Trazodone (Desyrel): Halflife, peak, metabolism

Half life: 5-9 hours

Peak: 30-100mins, delayed with food

Metabolism: CYP3A4 to active metabolite

Trazodone (Desyrel): Side effects

Sedation, nausea, orthostasis, dry mouth, priapism (rare)

No significant DDIs

Nefazodone (Serzone): Black Box Warning

Life threatening Hepatic Failure

1 case per 250,000-300,000 patient years of treatment

Do not initiate if active liver disease or elevated LFTs at baseline

Counsel patients on symptoms of liver dysfunction

Monitor LFTS periodically

• Disconinute if LFTs > 3x UNL

Do not re-challenge

Nefazodone (Serzone): Side effects

Sedation, dizziness, HA, agitation, nausea, constipation

Miratazapine: Initial dose, range, Half life, Metabolism, Preg Cat. How Supplied

15mg QHS

15-45mg/day

37 hours

Metabolism: CYP2D6, 1A2

Preg Cat. C

How supplied: T, ODT

Buproprion (Wellbutrin IR, SR, XL): Initial dose, range, Half life, Metabolism, Preg Cat. How Supplied

Initial Dose: 150mg/day

IR/ER: 300-450mg/day

SR: 300-400mg/day

Half Life: 21 hours

CYP2B6 (strong 2D6 inhibitor)

C

T

Vorioxetine (Trintellix): Initial dose, range, Half life, Metabolism, Preg Cat. How Supplied

Inital: 10mg/day

10-20mg/day

66 hours

2D6 (major), CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6

Preg Cat: Use not recommended

How supplied: T

Miratazapine (Remeron)

a-2 antagonist - increases serotonin and norepinephrine release

Miratazapine Post Synaptic Activity

• 5HT1A agonism: improved
  cognition, anxiolytic,
  antidepressant

• 5HT2A antagonism: improves
  sleep, no sexual dysfunction,
  antidepressant, anxiolytic

• 5HT2C antagonism: anxiolytic,
  antidepressant, weight gain

• 5HT3 antagonism: No GI
  problems

Miratazapine (Remeron): Side effects, DDIs, Formulations, Max Dose

Sedating at lower doses, more activating at doses ≥ 30 mg/day
- Adjunct to AD to treat anxiety, insomnia, sexual dysfunction, GI
side effects
- Side effects: dry mouth, sedation, weight gain, ↑ appetite,
hypertriglyceridemia
- Use with caution in patients stabilized on clonidine due to
rebound hypertension
- Available as orally disintegrating tablets
- Max dose: 45 mg/day

Bupropion (Wellbutrin SR, Wellbutrin XL, Aplenzin (ER), Forfivo XL, Zyban): MOA, Indications, Dose Range

Inhibits reuptake of dopamine and norephinephrine
- No indication for anxiety
- Dose range: 300-450 mg/day

Strong CYP 2D6 inhibitor
• Smoking cessation agent: 150 mg SR daily (Zyban ®)
• Formulations
– IR: TID
– SR: BID
– XL: QDAY
• Good augmentation agent
– Lack of weight gain, sedation, sexual dysfunction

Bupropion (Wellbutrin® IR, SR, XL): Side Effects

Side Effects
– ↓ Seizure threshold at doses ≥ 450 mg/day
• Use caution with other meds that ↓ seizure threshold
– Activation/agitation/insomnia
• SR: give PM dose no later than 5 PM
• XL: Dose in AM
– Weight loss, headache, nausea, tremors

Contraindications
– Seizure Disorder
– Anorexia or Bulimia
– Abrupt discontinuation of alcohol, sedatives, or anti-epileptic drugs
– Use of MAOI within 14 days

Vortioxetine (Trintellix): Indication and MOA

Indicated for treatment of MDD

MOA: SSRI, 5HT1A agonist, 5HT1B partial agonist
– 5HT3 and 5HT1D antagonist

Vortioxetine (Trintellix): Dosing

– Initial: 10 mg once daily
– Target: 20 mg once daily (max)
– Strong 2D6 inhibitors or poor metabolizers: reduce dose by 50%
– Strong CYP inducers: may need increase in dose

Vortioxetine (Trintellix): Pharmacokinetics

– Primarily CYP2D6 and other CYP enzymes
– Half-life: 66 hours

Vortioxetine (Trintellix): DDIs

Do not initiate MAOIs within 21 days of discontinuing treatment with
vortioxetine

Vortioxetine (Trintellix): Common Adverse Effects

Nausea, constipation, vomiting

Brexabolone (Zulresso): Indications and MOA

Indication: Postpartum Depression
Schedule IV controlled substance

MOA: GABA A receptor positive modulator -Mimics hormone (allopregnanolone) which interacts with GABA receptors; this hormone decreases around childbirth which may cause MDD

Brexanolone (Zulresso): Dosage

IV infusion (continuous infusion over 60 hours); improvement in MDD symptoms observed 24-48 hours after starting; duration of effect up to 30 days

Brexanolone (Zulresso): Monitoring Parameters

Extreme sleepiness, sudden loss of consciousness (monitor q 2 hours
while awake),and continuous pulse oximetry monitoring

Brexanolone (Zulresso): Why must patients be watched?

Patient must be accompanied during interactions
with children while receiving infusion because of
sedation and loss of consciousness potential

Brexanolone (Zulresso): Most Common Side Effects

Sedation/Somnolence, dry mouth, loss of consciousness, and flushing/hot flush

Avoid use in pregnancy (may cause fetal harm) and in end stage renal disease

Transferred through breastmilk; infant exposure is expected to be low but no data on effects in breastfed infant available

Boxed Warning: Brexanolone (Zulresso)

Excessive sedation or loss of consciousness

• Other precautions: suicidal thoughts and behaviors

REMS: Brexanolone (Zulresso)

Healthcare facility must be enrolled in program
- Healthcare provider must be available on-site to continuously monitor patient for the duration of the infusion

– Patient must be enrolled
– Pharmacies must be certified and can only dispense to healthcare facilities that are certified
– Wholesalers and distributors must be registered with program

Zuranolone (Zurzuvae)

FDA approved August 4, 2023 for postpartum depression in adults

• Currently pending controlled substance scheduling

Zuranolone (Zurzuvae): Black Box Warning

Impaired ability to drive or engage in other potentially hazardous activities

MOA of Zuranolone (Zurzuvae)

Neuroactive steroid GABA- A receptor positive modulator

Dosage and Administration:

• Administer with fat-containing food
  – Recommended dose: 50 mg PO once daily in the evening for 14 days
  – Can be used alone or as an adjunct to oral antidepressant therapy
  – Dosage adjustments required for renal and/or hepatic impairment

Warnings and Precautions: Zuranolone (Zurzuvae)

CNS depressant effects
– Suicidal thoughts and behaviors
– Embryo-fetal Toxicity (need to use contraception during treatment and for one week after final dose)

Common adverse effects: Zuranolone (Zurzuvae)

Somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, urinary tract infections

Esketamine (Spravato): MoA

CIII nasal spray
MOA: NMDA receptor antagonist

Esketamine (Spravato): Used alongside antidepressants

– Treatment Resistant Depression
– Depressive symptoms in adults with MDD
with suicidal thoughts or actions

Onset of Action for Esketamine (Avapro)

Clinical improvements of depressive symptoms seen within 24 hours

Esketamine (Avapro): Dosage form and strength

28 mg of esketamine per device; each nasal spray
device delivers two sprays (14 mg each; one
spray per nostril; total 28 mg)

Warnings and Precautions for Esketamine (Avapro)

Sedation, dissociative and perceptual changes, abuse
and misuse, suicidal thoughts and behaviors in adolescents and young adults, blood pressure changes, cognitive impairment, impairment in ability to drive/operate heavy machinery,
ulcerative or interstitial cystitis, potential teratogenicity