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PHAR253 > Major Depressive Disorder > Flashcards

Major Depressive Disorder Flashcards

1
Q

What is major depressive disorder?

A

persistent and abnormally low mood, characterized by feelings of sadness, emptiness or irritability, and accompanied by other somatic or cognitive changes that significantly affect the individuals capacity to function

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2
Q

What is the global lifetime prevalence of major depressive disorder?

A

11-18%

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3
Q

Where does major depressive disorder rank in worldwide disability?

A

2nd

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4
Q

Describe the disease burden of major depressive disorder.

A

2nd leading cause of disability worldwide
increased CVD risk & morbidity/mortality in those with established CVD
increased complications from other medical conditions
impaired QOL
impaired social & occupational functioning

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5
Q

Describe the onset of major depressive disorder.

A

average age of onset is late 20s
-can occur at any age
increase between ages 12-16, up to early 40s
can develop over weeks or suddenly
may occur after significant life stressor

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6
Q

What is the etiology of major depressive disorder?

A

complex, multifactorial
-genetics, neurobiological, developmental, biologic, environmental

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7
Q

What are the proposed theories for major depressive disorder?

A

monoamine hypothesis
neuroplasticity hypothesis
endocrine and immune system abnormalities
structural and functional alterations

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8
Q

Describe the monoamine hypothesis.

A

dysfunction in monoamine production
-5HT, NE, DA
dysregulation in monoamine activity

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9
Q

Describe the neuroplasticity hypothesis.

A

downstream effects–>altered cell growth and adaptation
brain-derived neurotrophic factor
-lower levels observed in ppl with depression
-chronic stress may suppress BDNF expression in hippocampus

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10
Q

What is BDNF?

A

brain derived neurotrophic factor
-growth factor that regulates survival of neurons, important for structural integrity & neuroplasticity

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11
Q

Describe the endocrine and immune system abnormalities theory of depression.

A

increased plasma cortisol, increased peripheral cytokine concentrations
overstimulation of HPA-axis

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12
Q

Describe the structural and functional alterations theory of depression.

A

changes in brain regions involving emotional processing
-reduced volume or hyperactivity in prefrontal cortex, cingulate cortex, hippocampus, amygdala

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13
Q

What is the key takeaway regarding the pathophysiology of major depressive disorder?

A

complex & not completely known

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13
Q

What are the risk factors for major depressive disorder?

A

genetics
-relatives with history of MDD, bipolar, alcoholism or complete suicide
life experiences
-traumatic/stressful events, relationship or financial problems
personality disorders
-low self-esteem, dependent, self-critical, pessimistic
substance use
-alcohol or recreational substances
medical comorbidities
-anemia, HIV, HF, thyroid, CVA, MS, epilepsy, Parkinsons, cancer, pain

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14
Q

What is the diagnostic criteria for major depressive disorder?

A

A:
-at least 5 symptoms
-at least 1 symptom must be depressed mood or anhedonia
-present nearly every day for at least 2 wk period
B: symptoms cause distress or impairment
C: episode not attributable to meds/substance
D: not explained by a different mental illness
E: never had a manic or hypomanic episode

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15
Q

Differentiate between mild and severe depression.

A

mild: 5 or 6 sx, minimal functional impairment
severe: nearly all sx, significant functional impairment or motor impairment

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16
Q

What are the symptoms of depression?

A

depressed mood
anhedonia
feelings of worthlessness or guilt
suicidal ideation, plan, or attempt
fatigue or loss of energy
sleep increase or decrease
weight or appetite increase or decrease
decreased ability to think or concentrate
psychomotor retardation or agitation

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17
Q

What is the abbreviation to help with remembering the symptoms of depression?

A

SIG E. CAPS
Sleep changes
Interest (loss)
Guilt (worthless)
Energy (lack of or fatigue)
Cognition/Concentration (reduced)
Appetite (wt. loss, usually declined)
Psychomotor (anxiety, lethargic)
Suicide

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18
Q

What is persistent depressive disorder?

A

aka dysthymia
depressive mood for >2yrs with symptom free period no greater than 2 months
-+2 additional depressive symptoms
-no MDD episode in first 2 years of onset

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19
Q

What is a substance/medication induced depressive episode?

A

prominent, persistent disturbance in mood predominates the clinical picture with diminished interest in almost all activities
symptoms develop during or shortly after substance intoxication or withdrawal and the substance is known to cause the disturbance

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20
Q

What are some conditions involved in the differential diagnosis process for MDD?

A

bipolar depression
-history of mania or hypomania
anxiety (may co-occur)
substance use disorder (may co-occur)
another medical condition
premenstrual syndrome
grief
irritable or labile emotions
feeling sad

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21
Q

What are some medications associated with MDD?

A

CV: clonidine, methyldopa, reserpine
anticonvulsants: phenobarbital, topiramate, vigabatrin
hormonal agents: CS, GnRH agonists, tamoxifen
immunologic: interferon alpha

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22
Q

What are some objective findings for MDD?

A

poor hygiene
changes in weight
social isolation
no lab test or imaging to confirm diagnosis

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23
Q

What are some standardized rating scales for measurement based care of depression?

A

PHQ-9
QIDS
Beck Depression Inventory
HAM-D
MADRS

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24
Q

Describe the PHQ-2.

A

screening tool for depression
high sensitivity in primary care
if patients answer yes to either of the two questions, further investigation is warranted

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25
Q

What are the two questions used in the PHQ-2?

A

little interest or pleasure in doing things?
feeling down, depressed or hopeless?

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26
Q

What does MDD increase the risk for?

A

suicide
-especially if untreated
-lifetime risk of untreated MDD is ~20%
-risk increases with each episode of depression

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27
Q

What should occur during all patient interactions regarding MDD?

A

assessment for suicide risk

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28
Q

What are the suicide risk factors?

A

IS PATH WARM
Ideation
Substance use
Purposelessness
Anxiety
Trapped
Hopelessness
Withdrawal
Anger
Reckless
Mood changes

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29
Q

Describe the prognosis of MDD.

A

40% recover within 3mo, 60% within 6mo, 80% within 12mo
40% have fluctuating course
20-30% experience residual symptoms
15% never achieve remission

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30
Q

Describe response to antidepressants.

A

40-60% response rate, 30-50% response rate to placebo
response declines with each subsequent treatment trial
some response typically seen within first 2 wks; peak clinical effect usually at 4-6wks, may take up to 12 wks

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31
Q

Describe recurrence of MDD.

A

25-40% will have recurrence within 2yrs, 50-80% have more than one episode in life
functioning usually returns to baseline between episodes

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32
Q

True or false: MDD is considered an acute disease

A

false
chronic disease

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33
Q

What is partial remission?

A

continued presence of some symptoms but full criteria not met

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34
Q

What is full remission?

A

absence of significant symptoms (return to baseline)

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35
Q

What is recovery?

A

full remission for at least 2 months

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36
Q

What is relapse?

A

new episode before achieve recovery

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37
Q

What is recurrence?

A

new episode any time after achieving recovery

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38
Q

What is chronic MDD?

A

full criteria for MDD met for a minimum of 2 years

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39
Q

What is treatment resistance?

A

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

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40
Q

What are the predictors of remission?

A

female sex
higher income
white race
higher level of education
employment

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41
Q

What are the consequences of failure to achieve remission?

A

brain changes
chronicity
increased relapse rates
increased # of chronic depressive episodes
impairment in work and relationships
increased use of medical services
increased mortality
increased medical comorbidity
suicidal attempts

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42
Q

What are the goals of therapy for acute treatment of MDD?

A

overall goal: symptom remission and restoration of premorbid functioning, within 8-12 wks
prevent harm, ongoing
restore optimal functioning, within 8-12wks

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43
Q

What is the overall goal of therapy for maintenance treatment of MDD?

A

prevent recurrence of mood episode

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44
Q

What are some general & important goals for psych conditions?

A

minimize adverse drug effects ongoing
maximize adherence ongoing
provide education to patient and family ongoing
identify and manage risk factors for comorbid conditions ongoing

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45
Q

What is involved in the initial assessment and approach to treatment of MDD?

A

complete history
physical exam & labs
mental status exam and suicide risk assessment
current medications and substance use
past psychotropic medications and response
identify target symptoms, treatment preferences and goals of treatment
develop safety plan
support education and self-management

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46
Q

What are the non-pharmacological treatment options for MDD?

A

positive lifestyle changes
natural products
psychological treatment
-self help, counselling, psychotherapy
neurostimulation

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47
Q

What are the pharmacological treatment options for MDD?

A

antidepressants
adjunct drugs

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48
Q

Describe St. Johns Wort.

A

monotherapy for mild-mod symptoms
evidence is modest
MOA: non-selective MAO inhibitor
AE: GI, sexual dysfunction, photosensitivity
CYP450 inducer=lots of drug interactions
increases risk of serotonin syndrome, bleeding

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49
Q

Describe S-Adenosyl Methionine.

A

adjunct for mild-moderate symptoms
evidence is weak/inconsistent
MOA: unknown
AE: GI, flatulence, dry mouth

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50
Q

Describe omega-3 fatty acids.

A

monotherapy or adjunct to antidepressants
evidence is weak/inconsistent
3-PUFA deficiency has been shown to be associated with depression

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51
Q

Describe folate/L-methylfolate.

A

adjunct to antidepressants if already on antidepressant
low risk intervention
efficacy is extremely limited
low folate levels found in depressed patients

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52
Q

Describe initial psychological treatment recommendations based on depression severity.

A

mild:
-psychological alone
moderate:
-psychological guidelines vary
-pharmacological treatment
severe:
-psychological plus pharmacological

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53
Q

Why is psychological treatment recommended for severe or moderate (?) depression?

A

seems to work about as well as antidepressants
antidepressants have a lot more side effects

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54
Q

Which psychological treatments have the best evidence available?

A

cognitive behavioral therapy
behavioral activation
interpersonal psychotherapy
mindfulness-based cognitive therapy

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55
Q

What is transcranial magnetic stimulation used for?

A

refractory depression

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56
Q

How does TMS work?

A

magnetic fields are used to stimulate nerve cells in regions of the brain involved in mood regulation and depression

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57
Q

How long is the course for TMS? What are some side effects?

A

4-6 weeks
headache, scalp discomfort

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58
Q

What is electroconvulsive therapy used for?

A

severe depression
depression with psychosis or catatonic features
severe SI

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59
Q

How effective is ECT for MDD?

A

80-90% (older patients have better outcomes)

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60
Q

What is the procedure for ECT?

A

electrodes placed on various scalp regions
electrical charge is applied to stimulate the brain and produce a seizure while patient under anesthetic
seizure lasts 1 minute

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61
Q

How many treatments are involved in ECT? How long does it take for a response?

A

6-12 treatments
10-14 days
may require maintenance

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62
Q

Which concurrent medications are significant if a patient is to undergo ECT?

A

anticonvulsants
-dose should be minimized and avoid/minimize benzos to improve efficacy
lithium
-may increase delirium risk, prolong seizure
can continue antidepressants but use bupropion can cause prolonged seizure risk

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63
Q

What are the adverse effects of ECT?

A

confusion during post-ictal period
impaired memory after procedure
headache
muscle ache

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64
Q

What did the Cipriani trial show us?

A

no strong evidence to conclude that any antidepressant is superior in efficacy
no impressive effect sizes
relatively higher response and lower dropout:
-escitalopram, sertraline, vortioxetine, mirtazapine, paroxetine
relatively lower response and higher dropout:
-trazodone, fluvoaxmine, clomipramine
individualize therapy

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65
Q

From meta-analyses, which antidepressants might have the best balance of efficacy and tolerability?

A

sertraline
escitalopram
vortioxetine
venlafaxine
mirtazapine

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66
Q

True or false: international guidelines agree there is insufficient evidence to routinely recommend one first-line drug over another

A

true

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67
Q

What did the STAR*D trial show us?

A

no difference in remission rates or times to remission
-between medication strategies at any treatment level
-between any of the switching options or between any of the augmenting options
longer time to remission, greater number of treatment steps=higher relapse rates
no difference in remission/response between primary or psychiatric care

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68
Q

What is the symptom response rate across all antidepressant trials?

A

40-60%
placebo response rates 30-50%

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69
Q

What are the CANMAT 2016 1st line interventions for mild depression?

A

psychoeducation
psychological treatment
self-management
pharmacotherapy
complimentary treatment
St Johns Wort

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70
Q

What are the CANMAT 2016 1st line interventions for moderate-severe depression?

A

psychoeducation
psychological treatment
pharmacotherapy
ECT

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71
Q

What are the CANMAT 2016 2nd line interventions for depression?

A

non-response
-alt antidepressant, TMS, ECT, light therapy, omega-3
partial response
-augment with 1st line adjunct, adjunctive exercise, SJW, omega-3, light therapy, yoga

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72
Q

What are the CANMAT 2016 3rd line interventions?

A

augment with other AD or different med
-brexpiprazole, bupropion, lithium, mirtazapine, modafinil, olanzapine, T3, stimulants, TCA, MAOI, ketamine
neurostimulation monotx or augmentation
adjunctive acupuncture

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73
Q

Which antidepressants have evidence for superior efficacy based on meta-analyses?

A

escitalopram
mirtazapine
sertraline
venlafaxine
citalopram

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74
Q

What are the factors to consider in selecting antidepressants?

A

patient
-clinical features and dimensions
-comorbid conditions
-response and AE from previous use of AD
-patient preference
medication
-comparative efficacy
-comparative tolerability
-potential drug interactions
-simplicity of use
-cost and availability

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75
Q

How can we provide patient-centered care with antidepressants?

A

shared decision making
psychoeducation
transparent, accurate medication education
empathy

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76
Q

What are the CANMAT 1st line agents for MDD?

A

5 SSRIs
-escitalopram, citalopram, sertraline, fluoxetine, paroxetine
2 SNRIs
-venlafaxine, duloxetine
5HT modulator
-vortioxetine
a2 antagonist, 5HT2 antagonist
-mirtazapine
NDRI
-bupropion

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77
Q

What are all the SSRIs available in Canada?

A

citalopram
escitalopram
sertraline
fluoxetine
paroxetine
fluvoxamine (not 1st line due to AE and DI)

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78
Q

What is the MOA of SSRIs?

A

inhibition of presynaptic 5HT reuptake by inhibition of the 5HT transport=increased 5HT in synaptic cleft

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79
Q

Describe the onset of action for SSRIs.

A

1st few days:
-decreased agitation & anxiety, improved sleep + appetite
1-3 weeks:
-increased activity + sex drive, improve self-care, concentration, memory, thinking, movements
2-4 weeks:
-relief of depressed mood, return of pleasure
-fewer hopeless feelings, suicidal thoughts

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80
Q

What is the acronym to remember the adverse effects of SSRIs?

A

HANDS
headache
anxiety (start at low dose, esp if comorbid anxiety)
nausea
diarrhea & other GI disturbances
sleep disturbances (insomnia, sedation)
also anticholinergic effects (dry mouth, constipation, etc)
usually dose related, transient (1-2wks)

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81
Q

Asides from HANDS, what are some other adverse effects of SSRIs?

A

sexual dysfunction (male or female)
-switch, dose decrease, use PDE5i
-may persist after dc
emotional blunting/detachment
other: tremor, yawning, sweating, enuresis
SIADH

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82
Q

What is SIADH?

A

syndrome of inappropriate antidiuretic hormone
symptoms: lethargy, mental changes, hyponatremia, hyperosmolar urine

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83
Q

What kind of drugs can cause SIADH?

A

carbamazepine
opioids
SSRIs
NSAIDs
SNRIs
mirtazapine

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84
Q

What is a warning/precaution for all antidepressants?

A

increased risk of suicide in children, adolescents, and young adults <24yo

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85
Q

What are some warnings/precautions for SSRIs?

A

suicidality risk if <24yo
fracture risk and decreased BMD (esp elderly)
QTc prolongation (citalopram, escitalopram)
-dose dependent

86
Q

Are SSRIs sedating?

A

most are non-sedating
-mild: sertraline and citalopram
most with paroxetine, take it hs

87
Q

Which SSRI poses the highest probability of weight gain?

A

paroxetine
-most are not associated with significant weight gain

88
Q

Which SSRI tends to cause more sweating and sedation?

A

paroxetine

89
Q

Which SSRI has a fairly long t1/2?

A

fluoxetine (4-6 days)

90
Q

Which SSRIs have higher rates of GI side effects?

A

fluvoxamine
sertraline

91
Q

Which SSRIs are found to have better acceptability?

A

escitalopram
sertraline
fluvoxamine is least tolerable

92
Q

What are some important drug interactions for SSRIs?

A

fluvoxamine: 1A2 potent inhibition
-clozapine, warfarin, theophylline
fluoxetine+paroxetine: 2D6 potent inhibition
NSAIDs, antiplatelets, anticoagulants
-increased bleeding risk
serotonergic agents
-risk of serotonin syndrome

93
Q

What are some relevant points to keep in mind regarding the PK of SSRIs?

A

absorption
-with or without food
-F of sertraline increases with food
metabolism
-hepatically by CYP enzymes
-fluoxetine, citalopram, sertraline form active metabolites

94
Q

What is the dosing for SSRIs?

A

all are once daily

95
Q

What is the MOA of vortioxetine?

A

serotonin reuptake inhibitor

96
Q

What are the adverse effects of vortioxetine?

A

headache
N/V/D
sexual dysfunction (less than SSRI)
seems to be better tolerated than other ADs

97
Q

What are the drug interactions of vortioxetine?

A

metabolized via CYP 2D6, CYP3A4
not a significant inducer or inhibitor of CYP450
-more clean for DIs

98
Q

Which SSRI is the most activating?

A

fluoxetine (increased 5HT, NE, and DA)
sertraline is mildly activating

99
Q

What is the “purest” SSRI?

A

escitalopram

100
Q

What are the SNRIs available in Canada?

A

venlafaxine
desvenlafaxine
duloxetine
levomilnacipran

101
Q

What is the MOA of SNRIs?

A

inhibit presynaptic 5HT and NE reuptake by inhibiting 5HT and NE transporters in CNS neurons
-thought to be more antidepressive and more pro-cognitive than SSRIs
-effective for neuropathic pain
-venlafaxine binds 5HT @<150mg, >150mg binds NE and 5HT

102
Q

Which SNRIs have higher incidence of dry mouth & constipation?

A

duloxetine and desvenlafaxine
-higher overall NET inhibition than venlafaxine
-both have equal affinity for NE and 5HT

103
Q

Describe the onset of action for SNRIs.

A

1st few days:
-decreased agitation & anxiety, improved sleep+appetite
1-3 weeks:
-increased activity+sex drive, improved self-care, concentration, memory, thinking, movements
2-4 weeks:
-relief of depressed mood, pleasure
-fewer hopeless feelings, suicidal thoughts

104
Q

What are the adverse effects of SNRIs?

A

similar to SSRIs
-HANDS
-anticholinergic-like (related to NE)
-sexual dysfunction (venlafaxine similar to SSRIs, desvenlafaxine + duloxetine less than SSRIs)
-SIADH (esp venlafaxine)
-risk serotonin syndrome, AD-induced suicidality
-dose related BP/HR and sweating

105
Q

Which risk associated with SSRIs appear to be less with SNRIs?

A

dont appear to be associated with increased risk of fractures
may have less emotional blunting than SSRIs

106
Q

What are some relevant points to keep in mind regarding the PK of SNRIs?

A

no effects from food
dose adjustments for renal impairment
venlafaxine and duloxetine hepatically metabolized

107
Q

What are important drug interactions for SNRIs?

A

CYP450 interactions
-duloxetine: moderate inhibitor+substrate of 2D6
-venlafaxine: weak inhibitor+substrate of 2D6
-desvenlafaxine: no significant CYP interactions
NSAIDs, antiplatelets, anticoagulants
-bleeding risk (less risk than SSRIs)
serotonergic agents
-risk of serotonin syndrome

108
Q

What are the warnings/precautions for SNRIs?

A

duloxetine CI in narrow angle glaucoma
increased suicide risk if <24yo
monitor for increased bp
caution if hx of HTN or narrow angle glaucoma
avoid abrupt withdrawal, esp venlafaxine

109
Q

What are some specific warnings/contraindications for duloxetine?

A

CI in narrow angle glaucoma
avoid in hepatic impairment or heavy alcohol use
risk of urinary retention

110
Q

Which SNRI is most effective for neuropathic pain?

A

duloxetine

111
Q

What is the MOA of bupropion?

A

inhibits NE and DA transporters increasing concentrations in the synapses
no 5HT effects

112
Q

What is the place in therapy for bupropion?

A

patients with psychomotor retardation, hypersomnia, ADHD type symptoms
-stimulating, activating
can be used to augment SSRI or SNRI in treatment resistance
less risk of sexual dysfunction, may alleviate sx when used as adjunct
possibly useful in stimulant use disorder

113
Q

What are the adverse effects of bupropion?

A

activating
-insomnia, agitation, tremor, ANXIETY
-may need to avoid if history of anxiety
sweating (NE reuptake inhibition)
reduced appetite/weight loss
-avoid in eating disorders
GI upset
psychosis/exacerbation of psychosis
urticaria and anaphylactoid reactions
seizures (dose-dependent)
less sexual dysfunction than SSRIs/SNRIs

114
Q

What is the onset of effect for bupropion?

A

similar to SSRIs/SNRIs

115
Q

How is bupropion metabolized and eliminated?

A

in liver by CYP2B6 to active metabolite
eliminated by the kidneys

116
Q

What are the drug interactions for bupropion?

A

Zyban for tobacco cessation
-its the same drug!
concurrent MAOI therapy=contraindicated
-hypertensive crisis
potent CYP 2D6 inhibitor

117
Q

What are the contraindications for bupropion?

A

seizure disorder
eating disorder
abrupt discontinuation of alcohol or sedatives

118
Q

What are warnings and precautions for bupropion?

A

increased suicide risk if <24yo
precautions:
-dependence on opioids, cocaine, stimulants
-concurrent use of seizure threshold lowering drugs
-head trauma history
-HTN
-unstable CVD/CAD
-psychosis
-anxiety
-insomnia
-overdose lethality

119
Q

What is the MOA of mirtazapine?

A

antagonism at 5HT2A, 5HT2C, 5HT3, a2, H1

120
Q

Describe the impact of mirtazapine on each of the receptors it interacts with.

A

a2
-increased NE and 5HT
5HT2A/2C
-lower anxiety, antidepressive, pro-cognitive
5HT3
-lower GI side effects
H1
-sedation, weight gain

121
Q

What is the place in therapy for mirtazapine?

A

useful as monotherapy and adjunctive treatment
consider in patients with insomnia, anxiety, reduced appetite
relatively safe in overdose

122
Q

What are the adverse effects of mirtazapine?

A

CNS: sedation (can last until morning even if supper dosing)
endocrine: increased TGs & weight gain
genitourinary: less sexual dysfunction vs SSRI/SNRI

123
Q

What are some revelant points regarding PK and drug interactions for mirtazapine?

A

onset similar to SSRIs/SNRIs
75% renally excreted
hepatic clearance decreased in cirrhosis
increased serotonin syndrome risk with serotonergic agents
caution with CNS depressants (benzos)

124
Q

At what dose is the sedation effect of mirtazapine typically lost?

A

doses starting at 30mg
-balance for insomnia and antidepressant activity ~22.5mg

125
Q

What are warnings and precautions for mirtazapine?

A

suicide risk if <24yo
caution:
-agranulocytosis (rare)
-orthostasis
-hyponatremia in elderly

126
Q

What are the CANMAT 2nd line agents?

A

TCAs
-amitriptyline
-clomipramine
-nortriptyline
1 SNRI
-levomilnacipran
1 reversible MAOI
-moclobemide
serotonin reuptake inhibitor/5HT2 antagonist
-trazodone
atypical antipsychotic
-quetiapine
serotonin reuptake inhibitor/5HT1 partial agonist
-vilazodone

127
Q

Differentiate between tertiary amines and secondary amines.

A

tertiary amines
-amitriptyline, clomipramine, doxepin, imipramine
secondary amines
-nortriptyline, desipramine

128
Q

What is the MOA of TCAs?

A

inhibits presynaptic 5HT and NE reuptake by inhibiting 5HT and NE transporters in CNS neurons
-tertiary amines=more 5HT activity
-secondary amines=more NE activity, better tolerated

129
Q

Why are TCAs considered to be the dirty antidepressants?

A

individual TCAs have varying affinity for other receptors
-adrenergic, histamine, muscarinic, Na channels

130
Q

What is the place in therapy for TCAs?

A

MDD with:
-insomnia
-anxiety
-chronic, non-cancer pain
-migraines/headaches
-OCD (clomipramine)

131
Q

What are contraindications to TCAs?

A

acute MI, heart block, CHF
severe liver impairment

132
Q

What are some cautions for TCAs?

A

any CVD
suicidal ideation
QT prolongation
seizure history/risk
risk of harm associated with antichol effects
elderly
bipolar disorder

133
Q

What are the adverse effects of TCAs?

A

common: sedation, anticholinergic, CV
CV effects: lethal in overdose
-cardiotoxicity is mechanism of overdose
-orthostatic hypotension
-tachycardia
-right bundle branch block
-QT prolongation
weight gain
tremors
sexual dysfunction
urine discolouration (amitriptyline)
rash
seizures, SIADH, fractures

134
Q

Do TCAs pose a high risk of lethal overdose?

A

yes
lethal dose is only 3x max therapeutic dose

135
Q

What are the drug interactions for TCAs?

A

interactions related to:
-additive CNS depression
-serotonin activity
-neurotoxicity with lithium
-seizure risk
-arrhythmias
most TCAs are substrates of CYP2D6
-clomipramine: 1A2 substrate

136
Q

What is the MOA of trazodone?

A

weak inhibition of SERT and NET
5HT2A and 5HT2C antagonism
a1 and H1 antagonism
other 5HT, alpha, DA receptor action

137
Q

What are the adverse effects of trazodone?

A

CNS: dizziness, sedation, headache, tremor
CV: orthostatic hypotension, prolonged QT, arrhythmias, CI if recent or acute MI
GI: nausea, constipation, dry mouth
rare: sexual dysfunction, seizures, bleeding, serotonin syndrome

138
Q

What is the depression dosing for trazodone?

A

usual range: 200-400mg/day
initial: 50mg BID, after meal

139
Q

What is the sedative dosing for trazodone?

A

50-200mg po HS

140
Q

What are some relevant points regarding the PK of trazodone?

A

food enhances, although delays peak concentration
metabolized to active metabolites by CYP 3A4
75% excreted via kidney

141
Q

What are the drug interactions for trazodone?

A

CYP3A4 inducers and inhibitors
antihypertensives

142
Q

What is the MOA of quetiapine?

A

atypical antipsychotic

143
Q

What dosage forms does quetiapine come as?

A

IR or XR

144
Q

What is the usual dosing of quetiapine for depression?

A

150-300mg/day
-max 300-600mg

145
Q

What are the MAOIs available in Canada?

A

moclobemide (reversible MAOa>MAOb)
irreversible MAOa+MAOb
-selegiline
-phenelzine
-tranylcypromine

146
Q

What is the MOA of moclobemide?

A

short-acting reversible inhibitor of MAO-A to decrease metabolism of DA, NE, 5HT

147
Q

What is the dosing of moclobemide?

A

300mg/d in 2 divided doses
-usual: 450-600mg/d
-high dose=900mg/d

148
Q

At what dose does moclobemide lose its specificity for MAO-A?

A

> 600mg/day
-caution regarding tyramine

149
Q

What are some foods rich in tyramine?

A

cheese
wine
meats
chocolate
smoked/pickled foods

150
Q

What are the drug interactions for moclobemide?

A

stop serotonergic drugs 2 wks before starting
-fluoxetine 5 wks before
if stopping, wait 2 wks before another AD
stop 2 days prior to local or general anesthesia

151
Q

What are the adverse reactions of moclobemide?

A

tachycardia
hypotension
sleep disturbances, agitation, nervousness, anxiety
less frequent than SSRI/SNRI
-NVD
-sexual dysfunction
-anticholinergic

152
Q

Differentiate between phenelzine and tranylcypromine.

A

phenelzine
-irreversibly binds and inhibits MAO-A and MAO-B
tranylcypromine
-irreversibly binds and inhibits MAO-A and MAO-B
-additional action similar to amphetamines

153
Q

Describe irreversible MAOIs.

A

DOA: time to synthesize new MAO enzymes (2-3 weeks)
CI:
-pheochromocytoma
-concurrent use of serotonergic and sympathomimetic agents
-tyramine foods
-dc 10 days before surgery
counseling very important
-diet and med restrictions
-disclose use to all HCPs

154
Q

What is the MOA of ketamine?

A

NMDA antagonism
-anesthesia, amnesia, analgesia, inhibited sensory perception
opioid agonism
-acute euphoric effects
AMPA agonism
-rapid antidepressant effects

155
Q

Describe how ketamine works in relation to the Chronic Stress Theory.

A

ketamine upregulates neurotrophic signaling–>increased protein synthesis and restoration of synaptic connectivity in the prefrontal cortex (synaptogenesis)

156
Q

What is the indication for racemic ketamine?

A

anesthesia

157
Q

Which mixture of ketamine is approved for treatment-resistance depression as a nasal spray?

A

S-ketamine

158
Q

What are the adverse effects of ketamine?

A

cardiovascular
-increased bp, HR
gastrointestinal
-nausea
CNS
-dissociation, dizziness, feeling drunk, sedation
genitourinary
dermatological
blurred vision
unknown impacts on fetus and dependency

159
Q

What are the general antidepressant adverse effects?

A

nausea
diarrhea
constipation
sexual dysfunction
QT prolongation
suicidality risk

160
Q

Describe nausea as an adverse effect of antidepressants and its management.

A

very common
-majority experience by 2nd week and up to 3 months into therapy
venlafaxine>SSRI>bupropion>moclobemide>mirtazapine
management:
-divide doses/reduce SSRI dose if stable
-take with food (ginger?)

161
Q

Describe diarrhea as an adverse effect of antidepressants and its management.

A

may be transient
-most experience by 2 wks and some will persist up to 3 months
management:
-should resolve on its own
-may use antidiarrheal agent
-may try probiotics and/or psyllium

162
Q

Describe constipation as an adverse effect of antidepressants and its management.

A

paroxetine has highest rates of SSRIs
common with TCAs
management:
-should resolve on its own (up to 3 months)
-adequate fiber, activity
-OTC/self-care

163
Q

What is the black box warning for all antidepressants?

A

increased risk of suicidality in those 18-24yrs during initial therapy (first 1-2 months)

164
Q

Which antidepressants are most associated with suicidality based on small RCTs and pooled analyses?

A

venlafaxine
paroxetine

165
Q

What is the shown effect of SSRIs on suicidality in those 18-24yrs in systematic reviews of observational studies?

A

ambiguous
monitor and discuss concerns

166
Q

What is the effect of antidepressants on suicidality in those age 25-64yrs?

A

neutral-protective
-mostly SSRIs or newer antidepressants

167
Q

What is the effect of antidepressants on suicidality in those older than 65yrs?

A

protective effect

168
Q

What is the management of the suicidality risk for all antidepressants?

A

consider hospitalization if reporting suicidal ideation (monitor closely)
closely monitor children and youth newly prescribed ADs
-frequent visits and family involvement
-HCP to follow up within 1 week
consider CBT or other forms of psychotherapy if severe MDD, suicidality, etc
if developing suicidality during treatment:
-consider dose reduction, switching or d/c agent

169
Q

Which classes of antidepressants are associated with an increased frequency of sexual dysfunction?

A

SSRIs
SNRIs
TCAs

170
Q

Which antidepressant has the lowest risk for sexual dysfunction?

A

bupropion
-mirtazapine, trazodone, moclobemide typically lower risk
-vilazodone and vortioxetine appear to be lower risk as well

171
Q

What are the options for managing sexual dysfunction related to an antidepressant?

A
  1. no intervention
    -some cases report spontaneous remission/improvement
    -may increase risk of non-compliance
  2. reduce dose
    -maintains efficacy as antidepressant but potential for relapse
  3. drug holidays or eliminating doses few days prior to sex
    -evidence for efficacy with sertraline, citalopram, paroxetine
    -disadvantages=withdrawal after missing 2 doses, relapse, non-adherence
  4. using medications to augment sexual side effects
    -adjunct AD (bupropion or mirtazapine)
    -sildenafil or tadalafil
  5. switching antidepressant (Halpapes favourite)
    -switch to agent with lower rates of sexual dysfunction
    -bupropion=greatest evidence
    -mirtazapine=some small RCTs show resolution
    -SNRI instead of SSRI
172
Q

True or false: there is a high risk of QT prolongation at therapeutic doses of antidepressants

A

false
generally safe at therapeutic doses

173
Q

Which antidepressants pose the greatest risk for QT prolongation?

A

TCAs=high risk at higher doses
citalopram, escitalopram, desvenlafaxine, mirtazapine risk with higher doses
-other SSRIs, bupropion, moclobemide=lowest risk

174
Q

What is the cause(s) of serotonin syndrome?

A

concomitant use of multiple serotonergic agents
-ADs: MAOIs, TCAs, venlafaxine, St Johns Wort
-others: linezolid, DM, meperidine, tramadol, opioids

175
Q

What is the triad of serotonin syndrome?

A

mental status changes
autonomic hyperactivity
neuromuscular abnormalities

176
Q

What is the treatment of serotonin syndrome?

A

supportive
discontinue serotonergic agents
cyproheptadine (serotonin antagonist)

177
Q

Which antidepressants are the worst for discontinuation syndrome?

A

venlafaxine
paroxetine

178
Q

What is the mechanism for discontinuation syndrome?

A

exact mechanism unknown
-risk appears to relate to affinity for serotonin transporter
more likely if treatment has been longer than 6-8wks

179
Q

What is the mnemonic to remember the symptoms associated with discontinuation syndrome?

A

FINISH
f=flu-like symptoms
i=insomnia
n=nausea
i=imbalance
s=sensory disturbances (paresthesia’s, electric-shock)
h=hyperarousal (anxiety, agitation)

180
Q

When do the symptoms tend to appear for discontinuation syndrome?

A

24-72hrs after AD stop

181
Q

When do the symptoms associated with discontinuation syndrome tend to resolve?

A

typically in 1-2 weeks (generally mild and transient)
-may persist for weeks to months

182
Q

How can we prevent discontinuation syndrome?

A

reduce the dose over ~2-4wks
-may be able to stop fluoxetine without taper due to long t1/2

183
Q

What should we do if discontinuation syndrome occurs?

A

consider restarting medication with a slow taper
if symptoms occur during tapering:
-consider restarting at original dose and taper slower
if slow tapering is poorly tolerated:
-consider substituting fluoxetine

184
Q

Describe monitoring and follow-up for antidepressants.

A

weeks 1-4: follow up q1-2wks, assess response, education, titration
weeks 2-8: follow up q2-4wks, assess response, education, adjustment prn
suicidal ideation: someone should monitor daily until resolved
in general: adherence, tolerability, response, suicidality

185
Q

When should we consider switching agents or augmenting therapy?

A

symptoms persist after an adequate trial of initial medication at an adequate dose
-after 6-8 weeks

186
Q

What proportion of people fail to achieve remission with initial pharmacotherapy?

A

2/3
->30% have a less than satisfactory response to 4 courses of ADs

187
Q

What are some possible reasons for non-response to antidepressants?

A

comorbid disorders including substance use
inadequate dose & duration
incorrect diagnosis
non-adherence
persistent AEs
PK and PD factors
psychosocial or psychological issues

188
Q

What is the decision point for augmenting/combining therapy or switching therapy?

A

augment:
-partial response (synergistic response)
switch:
-no response (less pill/cost burden, less AEs)

189
Q

What is the working definition of treatment resistant depression?

A

lack of improvement (<20% reduction in depression scores) following adequate trials of two or more antidepressants
-not a subtype of depression, it occurs along a spectrum

190
Q

What are the options for therapy with treatment resistant depression?

A

may switch antidepressant
may choose to augment therapy
-lithium, AAP, T3, other (buspirone, MPH, modafinil)
combine antidepressants
-SSRI/SNRI + mirtazapine
-SSRI/SNRI + bupropion
-SSRI + TCA

191
Q

Is there a difference in outcomes with switching within a class and between classes of ADs?

A

several studies have found comparable outcomes

192
Q

Describe switching between SSRI and SNRI.

A

direct switch (similar MOA)
-can also switch directly between duloxetine and venlafaxine
-often will cross taper

193
Q

How should we switch between antidepressants with different MOAs?

A

cross-tapering

194
Q

Describe the switch from an MAOI to a different antidepressant.

A

washout when switching from MAOI and other ADs
-2 wks
-5 wks between stopping fluoxetine and starting MAOI

195
Q

What are the adjunct medication options?

A

2nd generation antipsychotics=1st line
-most evidence=aripiprazole, quetiapine, risperidone
bupropion, mirtazapine=2nd line
lithium=2nd line
T3=2nd line
lisdexamphetamine, TCAs=3rd line
ketamine=experimental
non-pharm (psychotherapy, neurostimulation, exercise)

196
Q

What are the target lithium levels?

A

~0.5-1.0 mEQ/L (take 12h after dose)

197
Q

How long does it take to see a response from lithium?

A

3-4 weeks
-if patient responds, continue the combo for 6-9 months

198
Q

What is the effect of T3 for depression?

A

improves and accelerates antidepressant effect
may be preferred over lithium due to better tolerance

199
Q

What is the recommended trial of T3 for depression?

A

2 weeks at 50mcg/d
-rarely affects peripheral thyroid measures at this dose

200
Q

What are the adverse effects of T3?

A

tachycardia
insomnia
sweating
caution in patients with cardiac insufficiency or elderly

201
Q

What is the dose we use of atypical antipsychotics for depression?

A

lower doses than what is used for schizophrenia or bipolar disorder

202
Q

What are the phases of antidepressant treatment?

A

acute phase
continuation phase
-move from acute to continuation with significant improvement in symptoms (preferably complete remission)
-ADs should continue at same dosage as acute phase x 4-9mo
maintenance phase
-recommended if chronic symptoms or history of 3 or more episodes
-duration is indefinite and may be life long

203
Q

If someone had a response to an antidepressant after 4 weeks, when should we re-evaluate?

A

at 6, 8 and 12 weeks

204
Q

What are the common symptoms of depression in the elderly?

A

anhedonia
cognitive impairment
decreased appetite
increased irritability

205
Q

Why do we consider maintenance therapy in the elderly?

A

less likely to achieve remission with greater chance of relapse
-symptoms may also take longer to respond to treatment (>12wks)

206
Q

True or false: polypharmacy is preferred over monotherapy of depression in the elderly

A

false
increased risk of AEs, decreased elimination, more comorbidities and drug interactions

207
Q

What are the better choices of antidepressants in the elderly?

A

duloxetine, bupropion, sertraline
-SSRI, SNRI, TCA, mirtazapine on the BEERS list

208
Q

What is strongly recommended as 1st line therapy of depression in children/adolescents?

A

psychological treatments
-emphasize active monitoring rather than treatment right away

209
Q

Which antidepressant is approved by Health Canada for use in under 18yrs?

A

none
-FDA: fluoxetine, escitalopram
-off label: citalopram, sertraline
avoid SNRI, TCA
AE more common, titrate slowly with close monitoring

210
Q

What is the treatment of depression in pregnancy if symptoms are mild?

A

psychotherapy preferred

211
Q

What is the treatment of depression in pregnancy if symptoms are moderate-severe?

A

pharmacotherapy should be offered
-lowest effective dose
-higher doses>polypharmacy
-agents with less metabolites, protein binding and drug interactions

212
Q

Which antidepressants are first line in pregnancy?

A

SSRIs
-most safety data for sertraline, citalopram, escitalopram
-paroxetine may have higher risk of cardiac malformations
less data: SNRI, mirtazapine, bupropion

213
Q

Which antidepressants are first line if breastfeeding?

A

citalopram
nortriptyline
sertraline
paroxetine
low-to-undetectable serum concentrations

PHAR253 (16 decks)

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