Major Depressive Disorder- Krysiak

Major Depressive Disorder (MDD) is a _____ disorder compared to schizophrenia which is a thought disorder.

mood

What is the monoamine hypothesis for MDD?

decreased brain levels of NE, 5-HT, DA associated with depressive symptoms

What hypothesis is now emphasized for MDD, focusing on a molecular problem with signal transduction rather than neurotransmitter depletion?

Dysregulation hypothesis

What is Brain-Derived Neurotrophic Factor (BDNF)? How does it relate to depression?

BDNF—> growth factor protein that regulates neuronal survival—> its dysregulation is connected with depression

What are 3 main classifications of depression based on severity and duration?

• bipolar/ unipolar depression—> opposite ends of an affective or mood spectrum

• major depression—> most common, single episode or recurrent episodes

• dysthymia—> less severe but often longer lasting form of depression (>2yrs)

What are some drugs that can cause depression?

What are the emotional, physical, cognitive, psychotic, and atypical symptoms of depression?

• i would just recognize> memorizing

According to DSM-5, what are the criteria for diagnosing MDD?

5 or more of the following symptoms have been present during the same 2 week period and is a change from previous functioning, at least one of the symptoms must be the red/underlined ones:

• depressed mood

• markedly diminished interest or pleasure in all/almost all activities

• significant weight loss or weight gain (can also be increase/decrease in appetite)

• insomnia or hypersomnia

• psychomotor agitation or retardation

• fatigue/ loss of energy

• feelings of worthlessness or excessive or inappropriate guilt

• diminished ability to think or concentrate or indecisiveness

• recurrent thought of death, recurrent suicidal ideation, suicide attempt, or plan to commit suicide

What does the “SIG E CAPS” mnemonic for depression symptoms stand for?

S- sleep disorder

I- interest deficit

G- guilt

E- energy deficit

C- concentration deficit

A- appetite disorder

P- psychomotor

S- suicide

What does the IS PATH WARM mnemonic for suicide stand for?

Depression rating scales are useful for what? What are some examples of scales?

• idk how imp

• useful for taking subjective info and making it more objective

• helps establish a baseline for the pt.

• examples: HAM-D, MADRS, BDI

What are the three phases of depression treatment?

• how long (weeks/month) is each phase?

• goal of each phase?

1. acute phase (6-12 weeks)—> goal to achieve remission (absence of sx)

2. continuation phase (4-9 months)—> goal to eliminate residual symptoms, prevent relapse

3. maintenance phase (12-36 months)—> goal is to prevent recurrence

Duration of antidepressant therapy depends on the risk of recurrence.

Lifelong maintenance is used for what age groups?

• pts. <40 w/ 2+ episodes

• any age with 3+ episodes

Definition of each of the following in the context of depression tx:

• nonresponse

• partial response

• response

• remission

• recovery

• relapse

• recurrence

• nonresponse: <25% decrease in baseline symptoms

• partial response: 26-49% decrease in baseline symptoms

• response: 50% reduction in symptoms

• remission: at least 3w of the absence of sad mood+ reduced interest and no more than 3 symptoms

• recovery: removal of all symptoms for >6-12m

• relapse: depression returns within 6m of remission

• recurrence: returns after recovery

What is treatment resistance in the context of MDD?

Episode that has failed to respond to 2 separate trials of different antidepressants of adequate dose and duration

What are non-pharmacologic treatment options for MDD?

• Electroconvulsive Therapy (ECT)

• Transcranial Magnetic Stimulation (TMS)

• Vagal Nerve Stimulation (VNS)

• psychotherapy

  • cognitive behavioral therapy (CBT)

  • Interpersonal Therapy (IPT)

• CAM

  • St. John’s Wort

  • S-adenosyl Methionine (SAMe)

  • Folate and L-methylfolate

What are the recommended uses for electroconvulsive therapy (ECT)?

Severe depression, depression with psychosis or catatonic features, and treatment of choice for patients with severe suicide ideation or food refusal.

What are the common side effects of Transcranial Magnetic Stimulation (TMS)?

Headache and transient scalp discomfort.

What is the indication for VNS?

adjuctive long-term chronic/recurrent depression lasting at least 2 yrs and not responding to 4 trials of antidepressants (not for pts <18)

What is the indication for Psychotherapy?

How does Cognitive Behavioral Therapy (CBT) address depression?

• idk how imp

How does Interpersonal Therapy (IPT) address depression?

• idk how imp

• indication: monotherapy for mild/acute depression or in combo with pharm tx for severe depression

• CBT—> Aims to address psychosocial stressors and psychological factors associated with mood episodes by focusing on the impact of thoughts on emotions and actions

• IPT—> improves communication skills and dealing with difficult emotions or relationships by focusing on building current interpersonal relationships

SSRIs are only FDA approved for what?

only approved for use in OCD, rarely used alone for depression

List the SSRIs:

• citalopram

• escitalopram

• fluoxetine

• fluvoxamine

• paroxetine

• sertraline

• vilazodone

MOA of SSRIs

inhibit presynaptic serotonin reuptake (but each SSRI has it’s unique properties)

Difference between citalopram and escitalopram?

• which enantiomer is responsible for efficacy? ADRs?

• which is more efficacious?

• citalopram—> R and S enantiomer

• escitalopram—> ONLY S enantiomer—> most efficacious, best tolerated SSRI ❤

• R enantiomer= mild antihistaminic properties

• S enantiomer= blocks 5-HT reuptake

Answer the following about Citalopram (an SSRI):

• max dose <60 yr old

• max dose >60 yr old

• FDA MEDWATCH and BBW for what?

• max dose <60 yr old= 40mg

• max dose >60 yr old= 20mg

• FDA MEDWATCH for QT prolongation

  • BBW for warning dose-dependent QTc prolongation and increased risk of torsades de pointes

Answer the following about Fluoxetine (Prozac) (an SSRI):

• helpful for what pt. population?

• recommended as continuation or initial tx?

IDK HOW IMP IDK HOW IMP

• helpful with pts. suffering from hypersomnia and fatigue

• recommended as continuation therapy vs. initial

Paroxetine is preferred for what symptoms?

anxiety symptoms

Vilazodone and Vortioxetine are thought to have what advantage compared to other SSRIs? (even tho there isn’t a lot of evidence)

thought to have faster ONSET of therapeutic response (and for Vortioxetine lower GI ADRs)

MOA of Vilazodone and Vortioxetine?

• i don’t think imp—> austin covers this

• Vilazodone—> 5-HT1A receptor partial agonist

• Vortioxetine—> 5-HT1A receptor agonist, 5-HT3 antagonist

What is the ONLY SSRI with an active metabolite?

Which SSRI has the longest t ½ ?

FLUOXETINE!!!!!!!!!!!!!—> t ½ of 4-6 days

SSRIs interact with what drugs?

• NSAIDs

• antiplatelets

• anticoagulants

With SSRIs, which are potent CYP inhibitors? of what enzyme?

• Fluvoxamine—> CYP1A2

• Fluoxetine, Paroxetine—> CYP2D6

BBW for all SSRIs and SNRIs?

increased risk of suicide in children, adolescents, and young adults age 24 or younger

ADRs of SSRIs:

• common

  • GI (n/d, anorexia)

  • neurologic (anxiety, insomnia, HA)

  • sexual dysfunction (decreased libido, delayed ejaculation, anorgasmia, ED)

• withdrawal syndrome

• hyponatremia

List the SNRIs:

• Venlafaxine

• Desvenlafaxine

• Duloxetine

• Levomilnacipran

MOA of SNRIs

• results?

• 5-HT reuptake inhibition + NE reuptake inhibition

  • boosts 5-HT and NE in the brain

  • boosts DA in the brain bc of NE inhibition

Answer the following about Venlafaxine (an SNRI):

• what are the dose dependent effects?

• metabolized to what?

• MAY CAUSE DOSE-RELATED WHAT?

• low doses—> most potent 5HT reuptake inhibition

• high doses—> inhibits DA transporter

• metabolized to DESvenlafaxine

• May cause dose-related INCREASE in blood pressure

Answer the following about Duloxetine (Cymbalta):

• MECHANISM IN ADDITION TO 5-HT and NE effects

• FDA approved for what?

• C/I?

• Mechanism

• FDA approved for MDD, DPN, fibromyalgia, and chronic musculoskeletal pain

• not used in hepatic insufficiency or severe renal impairment (CrCl <30ml/min)

  • avoid in pts. with history of heavy alcohol use as well

Why is Levomilnacipran (SNRI) not really used in practice?

• risk of seizures, urinary retention

• associated with tachycardia/palpitations

Drug and CYP interactions with SNRIs?

• LIKE SSRIs!!!!!!!—> NSAIDs, antiplatelets, anticoagulants

• CYP

  • Duloxetine, Venlafaxine, CYP2D6

  • Desvenlafaxine—> no CYP interactions

  • Levomilnacipran—> CYP3A4

SNRIs should be used in caution in pts. with a history of…

hypertension and narrow angle glaucoma

ADRs of SNRIs:

• common

  • similar to SSRIs—> nausea, sexual dysfunction, insomnia

  • neuro (sedation, somnolence, hypersomnia, dizzy)

  • anticholinergic

  • withdrawal syndrome

  • diaphoresis

  • CV (increase BP)

List the Tricyclic antidepressants (TCAs):

• Amitriptyline

• Clomipramine

• Doxepin

• Imipramine

• Desipramine

Active metabolite of Amitriptyline is…

nortriptyline

ALL TCAs are substrates of WHAT CYP?

CYP2D6

Interactions with TCAs:

• idk how imp

BBW and warnings associated with TCAs:

• BBW: increased risk of suicidality

• warning: TCAs are lethal in overdose—> don’t use if severely suicidal

  • overdose sym: hypotension, confusion, hyperthermia, arrhythmias, seizure, coma etc.

TCAs ADRs:

• common:

  • sedation

  • anticholinergic effects

  • CV effects (cardiotoxicity, ortho hypotension, tachycardia,)

• note: secondary amines are better tolerated!!!—> tertiary are more sedative and anticholinergic than secondary

List the MAOIS:

• Phenelzine

• Selegiline transdermal

• tranylcypromine

• Isocarboxazid

MOA of MAOIs:

• difference between MAO-A and MAO-B?

• block MAO enzyme—> which is responsible for breakdown of 5-HT, NE, DA

• inhibits BOTH subtypes MAO-A, MAO-B

  • MAO-A—> located in intestinal epithelium and is responsible for breakdown of tyramine and prevents absorption

  • MAO-B—> metabolizes trace amines

Why do we never use MAOIs?

• interactions?

• foods?

• INTERACTS WITH EVERYTHING

  • sympathomimetics

  • HYPERTENSIVE CRISIS

  • serotonin syndrome

• dietary restrictions

  • foods with tyramine—> MAO-A destroys it—> then we can’t increase NE

BBW with MAOIs:

increased risk of suicidality

List the Triazolopyridines:

• trazodone

• nefazodone

Although Trazodone isn’t really used in practice for depression, and is more used for sleep/sedation it’s still an option in depression, what is it’s MOA?

• i don’t think that important!

• weakly inhibits 5-HT and NE reuptake

• weak a1 antagonist

• serotonin 5HT2 antagonist

BBW, warnings, and interactions with Trazodone and Nefazodone:

• interactions:

  • serotonin syndrome

  • nefazodone—> CYP3A4 inhibitor

  • Trazodone—> CYP3A4 substrate

• BBW: increased suicide risk

• BBW: nefazodone and live threatening liver failure—> must monitor LFTs

• others:

  • ortho hypotension

  • increased QTc prolongation

  • risk of priapism

HOW IS THE MOA OF BUPROPION UNIQUE? benefits to use?

• UNIQUE—> NO EFFECT ON SEROTONIN

• MOA: weak reuptake inhibitors of DA and NE

• benefits:

  • generally activating—> good for pts. with sedation

  • DOES NOT CAUSE SEXUAL DYSFUNCTION

BBW, warnings, risks, interactions with Bupropion (Wellbutrin)?

• what CYP?

• risk of what?

• BBW

• C/I

• monitor?

• CYP2D6 substrate and inhibitor—> D/I

• RISK OF SEIZURES increased

• BBW—> increased risk of suicidality

• C/I in seizures and anorexia

• must monitor BP

HOW IS THE MOA OF MIRTAZAPINE UNIQUE? benefits to use?

• UNIQUE: increases 5HT release BUT DOES NOT CAUSE SEXUAL DYSFUNCTION

• MOA: increases 5HT and NE through a2 antagonism + 5HT2 and 3 receptor antagonist

• benefits: no sexual dysfunction, reduce n and GI problems, relieves insomnia

ADRs of Mirtazapine:

• sedation

• weight gain

• hypertriglyceridemia

• dry mouth

For MAOIs you MUST have a wash-out period due to risk of serotonin syndrome.

• What is the wash-out period if d/c a MAOI and wanting to start a serotonin agent?

• What is the wash-out period if you are on a SSRI and want to start a MAOI?

  • exception?

• 2 weeks after d/c a MAOI—> may start serotonergic agent

• 2-4 weeks after d/c a SSRI—> may start MAOI

  • exception: 5 WEEKS for FLUOXETINE

What is the triad of symptoms seen with serotonin syndrome

(I don’t like the way Krysiak described the triad of symptoms for serotonin syndrome so I’m taking from Austin’s lectures)

• cognitive- mental status change, HA, hallucinations

• somatic- hyperreflexia, tremor, myoclonus

• autonomic: hyperthermia, n/v/d, tachycardia, sweating

Are there any lab findings used to confirm Serotonin syndrome?

no!!!

Tx for serotonin syndrome?

• removal of precipitating agents- most important

• supportive care

• control agitation

• administer 5HT2A antagonist

  • cyproheptadine

  • atypical antipsychotic

• control hyperthermia

Augmenting agents are used in depression in addition to an antidepressant to improve response. What are some agents used?

• Which is considered the gold standard?

• LITHIUM—> gold standard for augmenting

• thiiothyronine

• SGAs—>FDA approved ones include:

  • Aripiprazole

  • brexipiprazole

  • olanzapine

  • quetiapine

  • cariprazine

  • risperidone (not FDA approved)

Monitoring for thiiothyronine?

thyroid—> may lead to hyperthyroidism

an adequate trial of antidepressants is ___-___ weeks at max dose.

4-8

Preferred drugs for acute tx phase?

monotherapy with:

• SSRI

• SNRI

• mirtazapine

• buproprion

What did the STAR*D trial results suggest?

• less than 1/3 of pts. achieve remission with initial SSRI monotherapy

• switching or augmentation are good strategies

• changing may be a good option for pts. that can’t tolerate or do not respond

• augmentation may be a good option for partial responders

What are the 1st and 2nd line tx for depression in the elderly?

• 1st line: SSRIs

• 2nd line: Mirtazapine, Buproprion

For moderate to severe depression in children/adolescents, what drugs have age considerations?

• idk how imp

• fluoxetine 8-18yrs old

• escitalopram >12 yrs old

• sertraline not FDA approved but used

• Desipramine—> has several cases of sudden death in children

How is depression during pregnancy and lactation managed?

• weight the risks (suicide, preeclampsia, low birth weight) and benefits

• tx should include psychotherapy (maybe even ECT)—> pharm therapy recommended for those with mod/severe depression

• medications in preg

  • SSRIs associated with pulmonary HTN especially in 3rd trimester

  • paroxetine is Cat D and associated iwht septal wall defects

  • SSRIs associated with withdrawal syndrome in babies

  • buproprion, mirtazapine—> cat C

• lactation—> paroxetine or sertraline preferred