major depressive disorder

list the symptoms of depression

D= SIG E CAPS

D= depressed mood

S= sleep disturbance

I= loss of interest

G= guilt

E= energy loss

C= concentration decreased

A= appetite and weight

P= psychomotor

S=suicide

DSM-5 Criteria for MDD

5 or more of the 9 Sx

present during the same 2 week period

represent a change from previous functioning

atleast 1 of the 5 sx must be either depressed mood or loss of interest

cause significant distress or impairment in social, occupational functioning

not better explained by the effects of a substance or general medical condition

not better accounted for as bereavement

is MDD more common in males or females

females (1.5-3X more common)

depression age of onset

any age but peak in 20’s

duration of episodes of untreated depression

6mo or more

duration of episodes of treated depression

3mo to remission

do people with depression usually obtain remission

yes- the norm

what is perisistent depressive disorder

20-30% of pts experience a chronic course lasting >2yrs

how many people with MDD have a 1st episode recurrence

60%

after a second MDD episode what is the % likelihood of recurrence

70%

% of people that relapse after 3rd episode of MDD

90%

Risk factors for MDD

Genetics: female sex, 2-4x risk with FD relative, 40% identical twins, 20% fraternal

Biologic: dysregulation of NE, 5HT, DA

psychosocial stressors: stressful life events (adverse childhood events, bereavement, gender dysphoria, job/income stress, etc) may precipitate episodes esp. 1st

secondary MDD causes

medical conditions: chronic illnesses (parkinsons, rheumatoid, alzheimers, epilepsy, stroke, cancers, insomnia), hypothyroidism, anemia, menopause

psychiatric conditions: anxiety disorders, schizophrenia, eating disorders, EtOH and substance use diagnosis

medications/substances: steroids, OC, substances of abuse, BB, CCB?

what is defined as response in MDD

>/=50% by 4-8 weeks

what is defined as partial response in MDD

20-49%

what is defined as non response in MDD

<20%

what is defined as remission in MDD

removal of all symptoms, back to baseline euthymia

considered remission for the first 3-9mo without symptoms (to be later defined as recovery if sustained for about 1yr)

Relapse vs Recurrence in MDD

relapse is when depression reoccurs within the 1st 9mo of treatment/remission- return of current episode

recurrence is when depression reoccurs once a patient has recovered (>1yr out)- second discrete episode

response rate of depression

1st line AD monotherapy: 2/3 have response by 8wks, 1/3 have remission by 3mo

¼ of nonremitters who receive 2nd AD will achieve remission

4 goals of efficacy in MD

1. early partial response (20% improvement in 2-4wks)

2. 50% decrease in 4-6 wks, closer to 8 if takes 1 wk to titrate

3. remission in 2-3mo

4. prevent relapse and recurrence

tolerability goals for depression

prevent and manage specific antid related side effects

prevent and manage drug interactions

avoid and manage other ae as indicated (ex: Tx emergent switch to mania, suicidality)

adherence goals for depression

select a Tx easy to take, effective, well tolerated and affordable/covered

to engage the pt in their Tx plan as much as possible (shared decision making)

to educate the pt re onset od effect/side effect/duration of Tx etc

First line meds for depression

SSRIs, SNRIs, NDRI (buproprion), NaSSA (mirtazepine), multi modal (vortioxetine, vilazodone)

second line meds for depression

TCAs, SARI (trazodone), quetiapine XR, RIMA (moclobemide)

third line meds for depression

IRIMA-MAOIs (phenelzine)

8 anti depressants with slight evidence of superiority

SSRI: escitalopram, paroxetine, sertraline
SNRI: venlafaxine XR

NDRI: bupropion

NASSA: mirtazepine

multimodal: vortioxetine

other: agomelatine

which antidepressants cause sedation

quetiapine, mirtazapine, fluvoxamine, TCA, paroxetine, citalopram

which antidepressants are activating

fluoxetine, sertraline, venlafaxine, bupropion

which antidepressants have anticholinergic ae

TCAs, paroxetine

which antid have LESS sexual dysfunction

bupropion, mirtazpine, moclobemide

which antid have more sexual dysfunction

SSRI, SNRI

which antid have metabolic issues/weight gain

quetiapine, mirtazapine, paroxetine

if someone has dementia which antid to avoid

anticholinergic agents (TCA, paroxetine)

if someone has high GI bleed risk which antid to avoid

SSRI

if someone has seizure disorder which antid to avoid

bupropion

if someone has parkisons or is a smoker which antid may be good for them

bupropion

if someone has conduction defects which antid to avoid

TCA (sodium channel block), citalopram (QT)

if someone has anxious distress which antid to use

SSRI or SNRI

if someone has catatonia what to add

add benzo

if someone has insomnia which antid to use

quetiapine, mirtazapine

if someone also has pain which antid to use

SNRI

if someone has cognitive symptoms which antid to use

bupropion, SNRI and vortioxetine may be superior to SSRIs

if someone has energy, fatigue and motivation issues which antid class to use

SNRI may be superior to SSRI

if someone is at suicide risk or if safety is a concern which antid to use

avoid TCAs bc 10 day supply can be lethal, SSRI prefered except can cause sexual dysfxn

citalopram has QT prolongation risk

escitalopram does not carry a clinically relevent QT prolongation risk

fluvoxamine kinetics drug int

potent 1A2 and 3A4i

which antidepressants are potent 2D6i

fluoxetine, paroxetine, bupropion

MAOI drug int concerns

pharmacodynamic int with tyramine containing foods and sympathomimetic amines to cause hypertensive crisis and with other serotonergic drugs to cause serotonin syndrome

SSRIs + chronic NSAIDs/ASA/clopidogrel issue

increased GI bleed risk, mitigate with PPI

SSRI + diuretic risk

increased risk of hyponatremia in elderly

unique thing about fluoxetine metabolism

active metabolite (norfluoxetine0 has 7 day half life

which antidepressants have less treatment emergent mood switch

bupropion and SSRIs (except paroxetine)

children/youth 1st line MDE

psychotherapy (mild-mod)

2nd line children/youth treatment for MDE

fluoxetine (level 1)

citalopram, escitalopram, sertraline (level 2)

3rd line children/youth treatment for MDE

venlafaxine, TCAs

pregnancy/lactation 1st line treatment for MDE

psychotherapy

pregnancy/lactation second line treatment for MDE

escitalopram, citalopram, sertraline

pregnancy/lactation third line treatment for MDE

bupropion, venlafaxine, desvenlafaxine, mirtazepine, fluoxetine

2 types of MDE in elderly

early onset MDE that has recurred later in life

later life depression (LLD)- first episode at age >60yrs

general principles of antidepressants in elders

1. low and slow dosing

2. more susceptible to falls, hyponatremia, GI bleeds, QT issues

3. may respond better to SNRIs than SSRIs

4. SSRIs modestly increase risk fractures/falls

how long does it take to titrate antidepressants

usually 1-2wks to get to atleast lower end of therapeutic range

general idea for a dosing target in elderly

around 50%

citalopram dose

20-40mg

escitalopram dose

10-20mg

quetiapine depression dose vs schizophrenic dose

dose is lower for depression than psychosis

what to do if someone experiences partial response (>/=20% reduction in Sx) in 2-4 weeks

carry on for 8 weeks total than reassess

what to do if someone does not experience partial response (>/=20% reduction in Sx) in 2-4 weeks

increase dose if not maximized and drug is well tolerated

otherwise consider a switch

should get response in 4-6 weeks

typical time course of improvements with antidepressants

Week 1: sleep improves

Week 2: appetite starts to pick up

Week 3: energy starts to return

Week 4: mood improves

TCA side effects

M1, H1, alpha 1 antagonism:

• constipation, dry mouth/eyes, blurred vision, urinary retention, delirium

• sedation, weight gain

• orthostasis and reflex tachycardia

sodium channel blocker- prolong conduction time

sexual dysfxn

least anticholinergic TCA

desipramine

least antiadrenergic TCA

nortriptyline

SSRI side effects

5Ht2A receptor mediated: anxiety, agitation, akathisia, insomnia, sexual dysfxn

5HT3 receptor mediated: anorexia, nausea, diarrhea

other: sweating, QT prolongation, weight gain, sedation

SNRI side effects

serotonergic side effects as with SSRIs (activation, insomnia, GI, sexual dysfxn, etc)

noradrenergic effects: increase in diastolic BP (dose related esp with venlafaxine, usually not clinically significant)

SARI side effects

less serotonergic side effects than SSRIs: antagonizes 5HT2a so no activation, insomnia, etc

5HT3 receptor mediated- headache, GI effects still possible

H1 antagonist- high affinity so sedation even at low doses

alpha1 antagonist- dose related orthostasis

side effects of NDRI

ae related to pro adrenergic activity: activation, insomnia, tremors, dose related lowering of seizure threshold

related to pro dopaminergic activity: not likely to cause sexual dysfxn, may cause/aggravate psychosis

top 3 ae of antidepressants for non adherence

weight gain, sedation, sexual dysfxn

why should you not double dose bupropion

dose related seizure threshold lowering

what very common side effect of most antidepressants does bupropion not cause

sexual dysfxn

NaSSA side effects

less serotonergic side effects than SSRIs: antagonizes 5HT2A and 5HT3 so no activation, insomnia, GI ae, headaches, etc

high affinity H1 antagonist therefore sedation

5HT2C antagonist (combined with H1) metabolic ae - weight gain, dyslipidemia

MAOI side effects

serotonergic ae: agitation, anxiety, akathisia, sexual dysfxn, insomnia

anticholinergic ae: dry mouth, constipation

antiandrenergic ae: orthostasis (high dose only)

MAOI drug interactions

hypertensive crisis- occipital h/a, nausea, stiff neck, sweating, htn

serotonin syndrome- altered mental status, muscle tone changes, autonomic instability

tyramine containing foods: cured meats, aged cheeses, kimchee, soy/tofu, tap beer

decongestants, stimulants, opioids including tramadol and methadone, triptans, typtophan, buspiron, antidepressants which increase NE or 5HT, SJW, selegiline, linezolid, DM, drugs of abuse (meth, LSD, MDMA, cocaine)

how many serotonin increasing drugs warrants extreme caution when combining due to serotonin syndrome risk

3+

what to do if first antidepressant treatment does not work

were they adherent? was the dose optimized + duration appropriate? diagnosis correct?

Options:

1. optimize dose

2. add psychotherapy

3. adjunct or switch:

   • esp if partial response + well tolerated

   • 1st line: aripiprazole, brexpiprazole

   • switch to another 1st line esp if no response + tolerability issues. can switch in class or out of class, definently try agent with superiority (super 7)

4. ECT

list the 4 ways to switch antidepressant meds

1. washout/start

2. stop/start

3. cross taper

4. delayed withdrawal

when would you do a start/stop switch when switching antidepressants

within class switch, sevre adr

most common method to switvh anti depressants

cross taper

how long to continue treatment in first episode

extend Tx for 6-12mo after remission

when is relapse risk highest post first episode depression

first 6mo following remission

risk factors for recurrent depression which may warrant longer treatment

persistent residual sx

Hx of childhood maltreatment

greater severity of episodes (psychosis, severe impairment/hospitalization, suicidality)

chronic depressive episodes

medical comorbidities (psychiatric or medical)

greater number of previous episodes

poor social supports

persistent stressful life events

strong family history

how long to Tx patients with risk factors for recurrence

2 years- long term

what are the two main reasons to taper antidepressants (instead of stopping abruptly)

1. to avoid relapse/recurrence

2. to avoid withdrawal phenomena or discontinuation syndrome. up to 50% experience when stopping long term use, esp abruptly

which classes of meds are most commonly associated with discontinuation syndrome, and which specific meds within the class

SSRis- paroxetine and SNRIs-venlafaxine

Sx of discontinuation syndrome

FINISH: flu like Sx, insomnia, nausea, imbalance, sensory disturbances (zaps) and hyperarousal

which antidepressant causes the least discontinuation syndrome

fluoxetine

which class of meds can have cholinergic rebound

TCAs

cholinergic rebound Sx

vomiting, sweating, salivation, diarrhea, irritability, dizziness, malaise

which antidepressant does not require tapering

fluoxetine

in general how long should it take to taper off an antidepressant

several weeks or months

if someone was on an antidepressant for less than 4 weeks how long to taper for

faster taper over 2 weeks

what to do if someone is experiencing withdrawal sx when tapering

return to previous dose and taper more slowly