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PHAR 253 Exam 2 > MDD Therapeutics > Flashcards

MDD Therapeutics Flashcards

1
Q

Describe the mood spectrum

A

There is a spectrum of experienced moods, ranging from severe depression to severe elated mood (or mania)

Fluctuations in mood are normal (and again, some would say essential to a balanced and fulfilling life)

Persistent episodes in extreme ends of the spectrum, or rapid fluctuations that impair functioning are not normal (miss school school, contribute to relationships, work)

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2
Q

Define MDD

A

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

Impact on life: Socially, academically, etc.

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3
Q

Global Prevalence of MDD

A

Global lifetime prevalence ~ 11-18%

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4
Q

Annual prevalence of MDD. How many sought treatment?

A

Annual prevalence (Canada 2012) ~4-5%

63% sought treatment, 28% spent 27-52w depressed in past year

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5
Q

Sex differences in MDD?

A

~2x more likely in female > male sex

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6
Q

Average age of onset?

A

Avg age onset: mid-20s; 40% before age 20

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7
Q

Global Disease Burden of MDD?

A

depressive disorders 2nd leading cause disability worldwide

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8
Q

What is the dx burden of MDD?

A

(2nd leading cause of disability worldwide

↑ CVD risk & ↑ morbidity/mortality in those with established CVD

↑ complications from other medical conditions
(Chronic pain, diabetes, infections, malignancy, Parkinson’s disease, inflammatory bowel disorder)

Impaired QOL

Impaired social & occupational functioning

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9
Q

What is occupation dysfunction?

A

increase absenteeism, impaired concentration, depressed mood.

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10
Q

What is cognitive dysfunction?

A

more strongly association with loss of work place productivity than depression severity (affects attention, verbal/auditory processing, problem solving, processing speed/motor functioning)

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11
Q

Age of onset depression

A

Average age of onset is late 20s (can occur at any age)

Sharp increase between ages 12-16 years

Increases up to early 40s

Can develop over days to weeks but may develop suddenly

May occur after significant life stressor

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12
Q

What is the etyiology of MDD?

A

Complex, mulifactorial (developmental, biologic, environmental)

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13
Q

What are the proposed theories of MDD pathophysiology?

A

Monoamine Hypothesis (5HT, NE, DA)

Neuroplasticity Hypothesis

Endocrine and Immune System Abnormalities

Structural and Functional Alterations identified in brain regions involving emotional processing

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14
Q

Describe the monoamine hypothesis

A

Dysfunction in monoamine production (i.e. low 5HT = depression)

Dysregulation in monoamine activity (i.e. decreased 5HT activity in presynaptic areas = upregulated autoreceptors(negative feedback) = less 5HT in synapse)

Monoamines = serotonin, norepi, dopa

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15
Q

What theory are MDD medications based off of? Is it fully correct?

A

Monoamine Hypothesis

This is the oldest theory and the one most of our medications are based off of, even though it still fails to fully explain variability in response, delayed response, or lack of response

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16
Q

Describe the neuroplasticity hypothesis.What type of drugs work here?

A

Downstream effects -> altered cell growth and adaptation

E.g. Brain-derived neurotrophic factor (BDNF)
Growth factor that regulates survival of neurons, important for structural integrity & neuroplasticity

Lower levels BDNF observed in people with depression

Chronic stress may suppress BDNF expression in hippocampus

E.g. drugs that restore balance to glutamate/GABA

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17
Q

Describe endocrine and immune system abnormalities

A

increased plasma cortisol, increased peripheral cytokine concentrations

Chronic Stress Model- involves hypothalamic-pituitary-axis

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18
Q

Describe structural and functional alterations

A

Structural and functional alterations identified in brain regions involving emotional processing

Reduced volume or hyperactivity in prefrontal cortex, cingulate cortex, hippocampus, amygdala

Modulated by monoaminergic neurotransmission

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19
Q

What is the patho of MDD simple?

A

Complex and not completely known

It is now recognized that psychiatric symptoms correlate with malfunctioning brain circuits and that restoring neurotransmitter activity in these circuits leads to recovery.

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20
Q

What are some MDD risk factors?

A

Genetics
Blood relatives with a history of MDD, bipolar disorder, alcoholism or completed suicide

Life Experiences
Traumatic or stressful events such as physical/sexual abuse, death or loss of a loved one, relationship or financial problems

Personality Disorders
(30%)
Personality traits such as low self-esteem and being overly dependent, self-critical, or pessimistic

Substance Use
Alcohol or recreational substances

Medical Comorbidities (85%)
Anemia, HIV, heart failure, hypothyroidism, CVA, MS, epilepsy, Parkinson’s disease, cancer, pain

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21
Q

How is MDD diagnosed?

A

DSM-5

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22
Q

What are the symptoms of depression in DSM-5?

A
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23
Q

What is the diagnostic criteria of MDD in the DSM-5?

A

(A)
At least 5 sxs
At least 1 sx must be depressed mood or anhedonia
Present nearly every day for at least a 2 wk period

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

C)
Episode is not attributable to direct physiologic effects of a substance of another medication

D)
MDD is not better explained by a different mental illness

E)
There has never been a manic or hypomanic episod

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24
Q

DSM-5 Classification of MDD Severity

A

Mild= 5 or 6 sxs, minimal functional impairment

Severe = nearly all sxs, significant functional impairment or motor impairment

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25
Q

What is persistent depressive disorder?

A

Dysthymia

Depressive mood for > 2 years with sx free period no greater than 2 months

2+ additional depressive sxs (not full criteria for MDD) from (A) (influence duration of medications, not medications itself)

No MDD episode in first 2 years of onset
–> Depressive episodes can be superimposed after

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26
Q

What is substance/medication induced depressive disorder?

A

Prominent, persistent disturbance in mood with anhedonia

Sxs develop during or shortly after substance intoxication or withdrawal

the substance is known to cause disturbance

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27
Q

What are some differential diagnoses of MDD?

A

Bipolar depression
–>History of mania (BDI) or hypomania (BDII)
–> Complete Mood Disorders Questionnaire to rule out history of mania/hypomania

Anxiety (may co-occur)
–> Complete GAD-7
Substance use disorder (may co-occur)
Another medical condition
–> Thyroid abnormalities, glucose dysregulation, anemia, auto-immune, CVD, pain, sleep apnea, long COVID, etc.
Grief (adjustment disorder)
Premenstrual syndrome (premenstrual dysphoric disorder)
Irritable or labile emotions
Feeling sad

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28
Q

What are some examples of specific meds that may cause MDD? How?

A

CV: Clonidine, Methyldopa, Reserpine,
–> NE effects

Anticonvulsants:
Phenobarbital (Decrease tryptophan, thus decrease 5HT) , Topiramate, Vigabatrin (Increase GABA)

Hormonal:
CS’s (cortisol increase) GnRH agonists, tamoxifen (reduce estrogen)

Immunologic
interferon Gamma (Induction of IDO enzyme of tryptophan catabolism)

Benzodiazepines –> CNS depression
Beta-blockers –> (especially propranalol) –> Sympathetic activity blocking
Opiods
Anti-thyroid
Corticosteroids - increase plasma cortisol concnetration. May cause mania initially, on long term can cause depression

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29
Q

What are some objective findings of someone who may have MDD?

A

Patient may present with poor hygiene, changes in weight, social isolation

No laboratory tests or imaging studies are available to confirm diagnosis

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30
Q

What is the measurment based care: standardized rating scales for MDD?

A
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31
Q

What is the benefit of the PHQ-9?

A

PHQ-9 matches perfectly with the nine core symptoms listed in DSM 5

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32
Q

What is the scoring of the PHQ-9?

A

Scoring 20-27: severe,
15-19: moderately severe,
10-14: moderate,
5-9: minimal ,
< 5: no symptoms

Response: > or= 50% reduction in score
Remission: score < or = 5

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33
Q

What is the PHQ-2?

A

Screening tool for depression

High sensitivity in primary care - i.e. if a patient answers no to both questions, they are highly unlikely to have major depression

If patients answer yes to either of the two questions, further investigation is warranted (complete PHQ-9)

Total score of 3+ is a positive screen

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34
Q

What is the relationship between suicide and MDD?

A

Patients with MDD are at ↑ risk for suicide
–> Especially if untreated

Lifetime risk of suicide if untreated MDD is ~20%

Risk of suicide ↑ with each episode of depression

Formal or specific assessment for suicide risk should occur during all patient interactions

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35
Q

What is an important screening mechanism for all psychiatric disorders?

A

Formal or specific assessment for suicide risk should occur during all patient interactions

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36
Q

What are the risk factors for suicide?

A

Ideation
Substance use

Purposelessness
Anxiety
Trapped (feelings of no way out)
Hopelessness

Withdrawal
Anger
Recklessness
Mood changes (dramatic)

IS PATH WARM

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37
Q

What is a useful tool for pharmacists to screen for suicide? What is an important consideration?

A

Columbia community card for pharmacists is a brief and simple tool that can be used for suicide risk assessment

Do not leave a person alone. Stay with them until they are in the care of professional help.

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38
Q

What is the prognosis of MDD?

A

40% recover within 3 mon, 60% within 6 mon, 80% within 12 mon

40% have fluctuating course, 20-30% experience residual symptoms/chronic course, 15% never achieve remission

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39
Q

Describe the usual response to anti-depressants?

A

40-60% response (not remisison) rate to antidepressants, 30-50% response rate to placebo (strong placebo effect)

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40
Q

What is a critical factor to understand about subsequent treatment trials?

A

Response/remission declines with each subsequent treatment trial

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41
Q

When is the response to anti-depressants usually noticed?

A

some response typically seen within first 2 wks; peak clinical effect usually 4-6 wks, may take up to 12 wks

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42
Q

What is the relationship between MDD and recurrence?What happens between episodes?

A

25-40% will have recurrence within 2 years, 50-80% have more than one episode in lifetime

Functioning usually returns to baseline between episodes

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43
Q

What is MDD classified as

A

A chronic disease

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44
Q

Describe the phases of tx for MDD

A
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45
Q

What is partial remission?

A

Continued presence of some sxs but full criteria not met

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46
Q

What is full remission?

A

Absence of significant sxs (return to “normal”/baseline)

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47
Q

What is recovery?

A

Full remission for at least 2 months

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48
Q

What is relapse?

A

New episode before achieve recovery

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49
Q

What is recurrence?

A

New episode any time after achieving recovery

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50
Q

What is referred to as chronic in regards to MDD?

A

Full criteria for MDD met for a minimum of 2 years

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51
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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52
Q

What are some predictors of remission?

A

Female Sex
White Race
Employment
Higher Level of Education
Higher Income

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53
Q

What are the consequences of failure to achieve remission?

A

Increased:

Brain changes
Chronicity
Relapse Rates
Number of chronic depressive episodes
Impairement in work and relationships
Use of medical services
Mortality
Medical comorbitity
Suicide Attempts

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54
Q

What are the main areas of goals of therapy for MDD?

A

Acute Treatment
Overall Goal: Symptom remission and restoration of premorbid functioning, within 8-12 weeks

Remission: HAM-D score <or = 7; PHQ-9 < or =5

Response: HAM-D, PHQ-9 score > or = to 50% reduced from baseline

Prevent harm (e.g. suicide), ongoing

Restore optimal functioning, within 8-12 weeks

Improve quality of life to level similar to that prior to onset, all areas of functioning (social, psychological, physical, etc.)

Maintenance Treatment
Overall goal: prevent recurrence of mood episode

General Psych Conditions Goals
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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55
Q

What is the approach to MDD tx?

A

Complete history
Medical, family/social, psychiatric, previous hospitalizations, suicide attempts

Physical exam & labs
CBC, electrolytes, renal panel, thyroid panel

Mental status exam and suicide risk assessment

Current medications and substance use
Rx, Non-Rx, OTCs, herbals
Alcohol, tobacco, caffeine, recreational

Past psychotropic medications and response

Identify target sxs, tx preferences, and goals of tx

Develop safety plan

Support education and self-management

Approach him preciously, men can p* deep inside someone

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56
Q

What are the two forms of tx for MDD? Examples?

A

Non-pharmacological
–> Positive lifestyle changes
–> Natural products
–> Psychological treatment
Self-help, counselling, psychotherapy
–> Neurostimulation

Pharmacological
–> Antidepressants
–> Adjunct drugs

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57
Q

What are some natural products used for MDD?

A

St. John’s Wort

S-adenosyl Methionine

Omega-3 Fatty ACids

Folate L-methylfolate

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58
Q

Compare natural products

A
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59
Q

What are the treatment guidelines for recommedation of pharmacotherapy?

A

**Active monitoring suggested by some guidelines for patients who may recover with no formal intervention or who have mild depression and do not want drug therapy. Active support required; follow-up within 2 weeks.

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60
Q

When is psychological treatment recommended?

A

For moderate to severe depression or if patient prefers

Psychological treatment seems to work about as well as antidepressants (especially for less severe)

Antidepressants have a lot more side effects. Access to psychological tx is an issue however.

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61
Q

What are some psychological tx? Which one is the most effective?

A

cognitive behavioural therapy (CBT)(Most evidence)

behavioural activation (BA)

interpersonal psychotherapy (IPT)

Mindfulness-based cognitive therapy (MBCT)

Other options: guided self-help, counselling, group exercise, acceptance and commitment therapy (ACT)

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62
Q

What is TMS? When is ti used? What is the course of tx? A/e?

A

Used for refractory depression (tx-resistant)

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

Course: 4-6 weeks

Adverse events: headache, scalp discomfort

Meta-analysis suggests TMS is effective but unclear how long benefit lasts (~4 weeks)

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63
Q

When is ECT used? effectiveness?

A

Used for severe depression, depression with psychosis or catatonic features, severe Sucidialideation

80-90% effective for MDD
–> Older patients have better outcomes

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64
Q

What is the procedure of ECT (electric-convulsive therapy)?

A

Electrodes placed on various scalp regions
Electrical charge is applied to stimulate the brain and produce a seizure while patient under general anesthetic
Seizure lasts 1 minutes

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65
Q

What is the usual tx length of ECT? What is the time to response?

A

Typically 6-12 treatments
Time to response: 10-14 days
May require maintenance

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66
Q

What are the recommedations for ECT and concurrent medications?

A

Anticonvulsant dose should be minimized and avoid/minimize benzos to improve efficacy of tx

Lithium use is controversial: may increase delirium risk, prolong seizure

Can continue antidepressants but use caution with bupropion prolonged seizure risk

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67
Q

What are the adverse effects associated with ECT?

A

Confusion during post-ictal period
Impaired memory after procedure
Headache
Muscle ache

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68
Q

What were the main results of the Cipriani trial?

A

No strong evidence to conclude that any antidepressant is superior in efficacy

AD’sbetter than placebo

New medications not better than old ones

No impressive effect sizes

Relativelyhigher response and lower dropout:
escitalopram, sertraline, vortioxetine, mirtazapine, paroxetine

Relatively lower response and higher dropout:
trazodone, fluvoxamine, clomipramine

Individualize therapy

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69
Q

In regards to research, how should one select an initial anti-depressant?

A

International guidelines agree there is insufficient evidence to routinely recommend one first-line drug over another

From meta-analyses, these antidepressants MIGHT have the best balance of efficacy and tolerability: sertraline, escitalopram, vortioxetine, venlafaxine, mirtazapine

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70
Q

What were the main results of the STAR*D trial?

A

No difference in remission rates or times to remission
–> between medication strategies (switch or augmentation) at any treatment level
–> between any of the switching options or between any of the augmenting options in step 2-4
–> between switch to CT vs. meds or augment with CT vs meds

Longer time to remission, greater number of treatment steps = higher relapse rates during naturalistic follow up

Prognosis better for those achieving remission prior to follow-up phase compared to those with adequate response without remission

No difference in remission/response between primary or psychiatric care settings

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71
Q

The results of the STAR*D trial tell us that….

A

Pick your star
there are a lot of good options, no really outstanding options; no option out-shines another

Intolerance and relapse risk is high

Prognosis worsens with each partial or non-response
Notable drop after two trials

Possible predictors of non-response
–> Greater illness burden, more comorbidities, lower function/QoL,socioeconomic disadvantage

Patients may have clear preferences about treatment strategies

Depression can effectively be managed in primary care

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72
Q

Treatment response to antidepressants?

A

First treatment: ~30% remission, 10-15% no response

Across all antidepressant trials there is consistently a 40-60% symptom response rate

Placebo group response rates 30-50%

Greater magnitude of response over placebo for depression of greater severity(not that drugs work better, but that PBO works less)

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73
Q

What are the 1st line interventions for MDD according to CANMAT?

A
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74
Q

What are the second-line interventions for MDD according to CANMAT?

A
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75
Q

What are the 3rd line interventions listed by CANMAT used for?

A

Treatment Resistance

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76
Q

What are some factors to consider when selecting an anti-depressant?

A
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77
Q

What is a key takeaway for the mechanism of action of AD’s?

A

Oral anti-depress work on either neutransmitter transporters or pre-synaptic or post-synaptic receptors working on serotonin, norepinephrine or dopamine

Takes a bit longer, takes 2 months to see full response (mechanisms under this for MOA)

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78
Q

What is the role of the pharmacist in tx of MDD?

A

Provide patient-centred care
Shared decision making
Psychoeducation
Transparent, accurate medication education
Empathy

Ensure optimal efficacy and safety of medication use for MDD

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79
Q

What are the CANMAT 1st line agents?

A
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80
Q

What SSRI’s are avilable in Canada?

A

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

Fluvoxamine (Luvox):
Not often used due to drug interactions and decreased tolerability (NVD) Not listed as a 1st line agent in CANMAT guidelines

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81
Q

What is the MOA of SSRI’s?

A

Inhibition of presynaptic 5-HT reuptake by inhibition of the 5-HT transporter CNS neurons
(reuptake inhibition/transporter inhibition) Increased 5HT in synaptic cleft

Variable activity on other receptors

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82
Q

What is special about Paroxetine? What class is it?

A

SSRI

Paroxetine –> acts on Histamine and muscarinic receptors –> More anticholinergic and sedating

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83
Q

What is the onset of action for SSRI’s?

A
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84
Q

What is an issue with SSRI onset of action?

A

Super down, sucidial –> Energy by SSRI –> more likely to act on suicidal thoughts

Monitor for sucidiaty in first few weeks

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85
Q

What are the main adverse effects of SSRI’s?

A

Headache
Anxiety
Nausea
Diarrhea and other GI upset
Sleep disturbances (insomnia or sedation)

Anticholinergic (either due to muscarinic effects or NE effects): dry mouth, constipation, blurred vision
–> Paroxetine –> anti-cholinergic

Sexual Dysfxn 10-70%
Male/female (e.g. libido, arousal, orgasm, ejaculation)

Emotional blunting/detachment

Other: tremor, yawning, sweating, enuresis (should monitor for)

SIADH

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86
Q

SSRI’s Length of A/E

A

Usually dose related, usually transient (1-2 wks). Tolerability is variable

87
Q

Sexual Dysfx due to SSRI mangement.Important consideration?

A

Switch, ↓dose, use a PDE5 inhibitor
In some cases, may persist after discontinuation

88
Q

How to deal with emotional blunting due to SSRI

A

Reported phenomenon but hard to study accurately

Switch to AD with ↑NE/DA activity (e.g. bupropion), ↓dose.

Pt dependent

89
Q

What is SIADH?

A

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a condition in which the body makes too much antidiuretic hormone (ADH).

ADH is also called vasopressin. This hormone helps the kidneys control the amount of water your body loses through the urine.

SIADH causes your body to retain too much water.

90
Q

What are some physiologic causes of SIADH?

A
91
Q

What are some causes of SIADH (lecture slides)?

A

Pain, vomiting, CNS injury, inflammation, lung injury, carbamazepine, opioids, SSRIs, NSAIDs, SNRIs, mirtazapine

92
Q

What are some signs and symptoms of SIADH?

A

lethargy
change in mental status,
Na < 135 mEq/l,
hyperosmolar urine (>300 mosmol/kg)

93
Q

What is the management of SIADH?

A

usually inpatient care, discontinue offending agent, water restrictions

94
Q

What AD has the highest risk of SIADH?

A

ALL AD’s Higher correlation with SSRI’s and venlafaxine

95
Q

What is an important consideration in regards to monitoring for SIADH?

A

Electrolyte monitoring is very important in elderly, Na+ depleting meds, or brain damage

96
Q

What are some SSRI warnings/precautions?

A

Similar to all antidepressants: increased risk of suicide in children, adolescents, and young adults <24 y.o.

Increased fracture risk and decreased bone mineral density (especially elderly)

Citalopram, escitalopram have dose-dependent risk of QTc prolongation

97
Q

Which SSRI has a cardiac risk? Whatshould be monitored? Why?

A

Citalopram, escitalopram have dose-dependent risk of QTc prolongation

QTc interval monitoring –> Changes in cardiac function –> marker of progressing to arrthymias

98
Q

Which SSRI have a SERIOUS warning besides suicidality?

A

Citalopram

  • No longer prescribed at doses greater than 40 mg per day
  • 20 mg per day is the maximum recommended for patients with hepatic impairement, pts >65, pts who are CYP 2C19 poor metabolizers, or pts who are taking concomitant Cimetidine or another CYP 2C19 inhibitor
  • C.I. in pt’s with long QT syndrome or known QT prolongation
99
Q

Compare SSRI’s sedation. Counselling tip?

A

Most are non-sedating – can cause sedation and insomnia/stimulation in different patients

Mild sedation can occur with sertraline and citalopram; most with paroxetine(fluvoxamine most sedating- not 1st line)

Take it at bedtime

100
Q

Which SSRI is associated with wt gain?

A

Not usually associated with significant weight gain

Higher probability with paroxetine

101
Q

What are the main differences with paroxetine?

A

Most sedative

Higher probability of wt gain

More sweating and sedation

102
Q

Which SSRI is the most sedative?

A

Fluvoxamine
Paroxetine

103
Q

Which SSRI is the most associated with wt gain?

A

Paroxetine

104
Q

Which SSRI is associated with the most sweating?

A

Paroxetine

105
Q

In regards to SSRI’s, what is fluoxetine unique for?

A

Fluoxetine is most stimulating & long t1/2 4-6 days

106
Q

Which SSRI is the most stimulating?

A

Fluoxetine is most stimulating & long t1/2 4-6 days

107
Q

Which SSRI has the most G.I. side effects?

A

Fluvoxamine and sertraline have higher rates of nausea/diarrhea

108
Q

What is the comparitive ADE’s of SSRI”s in regards to overall tolerability?

A

Meta-analyses have found fluvoxamine least tolerable
–> Highest nausea, sedation, and constipation

Escitalopram and sertraline have better acceptability
–> Based on overall withdrawal rates and dropouts due to AEs

(Cipriani Trial)

109
Q

What are some potent drug interactions of SSRI’s?

A

CYP P450 Interactions –> INHIBITION

CYP 1A2 –> Fluvoxamine –> Avoid concomitant adminsitration with clozapine, warfarin and methylxanthines

CYP 2D6 –> Fluoxetine and Paroxetine
–> Avoid or use with caution with concomitant meds solely metabolized by 2D6 (e.g. metoprolol)

110
Q

What are some other critical drug interactions of SSRI’s?

A

NSAIDs, antiplatelets, anticoagulants
↑ bleeding risk secondary to ↓ platelet aggregation effects of SSRIs
- Not an absolute C.I.

Serotonergic agents
↑ risk of serotonin syndrome

111
Q

Describe the absorption of SSRI’s

A

Adequate with or without food
Sertraline bioavailability increases with food

112
Q

What is unique regarding absorption of sertraline?

A

Sertraline bioavailability increases with food

113
Q

Which SSRI has increased bioavilability when taken with food?

A

Sertraline

114
Q

What SSRI’s form activ emetabolites by the liver?

A

Only fluoxetine, citalopram, sertraline form active metabolites

115
Q

Describe the metabolism of SSRI’s by the liver. Worry?

A

All are metabolized hepatically by CYP enzymes to varying degrees

Note: Only fluoxetine, citalopram, sertraline form active metabolites

–> If liver cannot metabolize these efficiently, drug will not work well, or potentially cannot clear drugs effectively (poor hepatic function)
–> Concerning in liver dysfunction

116
Q

What is the dosing of SSRI’s?

A

All SSRIs are taken once daily

117
Q

What is the cost/availability of SSRI’s?

A

All SSRIs are on SK formulary and NIHB formulary

118
Q

What is the MOA of vortioxetine?

A

Serotonin reuptake inhibitor

5HT1A receptor agonist
5HT1B receptor partial agonist
5HT3+7 5HT1D receptor antagonist

119
Q

What are the available dosage forms of vortioxetine?

A

Dosage forms: 5, 10, 20mg

120
Q

What are the A/E of vortioxetine?

A

Headache, Nauseau (most common), Diarhhea, Sexual dysfx

  • More well tolerated than other AD’s (clinical experience, not shown in studies)
121
Q

What makes Vortioxetine unique besides MOA?

A

Less sexual dysfx than SSRI’s
Seems to be better tolerated than other AD’s

122
Q

Vortioxetine Metabolism D.I.

A

Metabolized via CYP2D6, CYP3A4
Not a significant inducer or inhibitor CYP450

123
Q

What is the cost of Vortioxetine?

A

$120-130 per month
- Newly added to SK formulary

124
Q

Which SSRI is most effective for OCD?

A

Fluvoxamine

125
Q

Which SSRI has the highest rates if sexual dysfx?

A

Paroxetine

126
Q

Which SSRI is the most activating?

A

Fluoxetine

127
Q

Which SSRI has the longest half-life?

A

Fluoxetine

128
Q

What antidepressant has “mild-activating properties?

A

Sertraline

129
Q

Which SSRI is refrred to as the “purest”?

A

Escitalopram

130
Q

Which SSRI has the fewest drug interactions?

A

Citalopram

131
Q

Which SSRI”s are studied in pregancy?

A

Fluoxetine, Sertraline

132
Q

What is unique about fluvoxamine for usage?

A

Has anxiolytic and antipsychotic properties

133
Q

What SNRI’s are available in Canada?

A

Venlafaxine (Effexor)
Desvenlafaxine (Pristiq) – 1st line, but not on sk formulary

Duloxetine (Cymbalta)

Levomilnacipran (Fetzima)
–> 2nd line agent in CANMAT guidelines (not on SK formulary)

134
Q

What is the MOA of SNRI’s?

A

Inhibit presynaptic 5-HT and NE reuptake by inhibiting 5-HT and NE transporters in CNS neurons

135
Q

Compre SNRI’s to SSRI’s

A

Thought to be more antidepressive and more pro-cognitive than SSRIs.

Also shown to be effective for neuropathic pain vs SSRIs.

136
Q

Compare the MOA of SNRI’s

A

Venlafaxine binds to 5-HT @ doses < 150mg/day, >150 binds to NE and 5-HT
Weakly inhibits DA transporter @ >450mg/day (dopamine)

Duloxetine & desvenlafaxine have about equal affinity for NE and 5-HT transporters
–> Higher overall NET inhibition than venlafaxine
–> Higher incidence of dry mouth & constipation

137
Q

What is the onset of action of SNRI’s?

A

Same as SSRI’s

138
Q

What are the adverse reactions of SNRI’s?

A

Headache
Anxiety
Nausea
Diarhhea
Sleep and sexual dysfx

Anticholinergic Effects (Dry mouth, constipation, sedation urinary retention)
–> Related to increased NE (no direct effect on M1 receptors)

SIADH

Serotonin Syndrome
AD-induced sucidality

Dose related ↑ BP/HR and sweating
Due to NE action

139
Q

SNRI sexual dysfx variation

A

Venlafaxine similar rates to SSRIs
Desvenlafaxine, duloxetine less than SSRIs

140
Q

SIADH SNRI Variation

A

More risk with venlafaxine

141
Q

What is a difference between SNRI’s and SSRI’s in regards to a/e?

A

Don’t appear to be associated with ↑ risk of fractures
May have less emotional blunting than SSRIs

142
Q

SNRI and SRRI Fracture Compariosn

A

Don’t appear to be associated with ↑ risk of fractures

143
Q

Effect of food on SNRI’s

A

No effects from food

144
Q

SNRI’s Relevant PK

A

Dose adjustments for renal impairment

Venlafaxine & duloxetine hepatically metabolized

145
Q

What are some drug interactions of SNRI’s?

A

CYP450 Interactions
Duloxetine
Moderate inhibitor & substrate of CYP2D6

Venlafaxine
Weak inhibitor & substrate of CYP2D6

Desvenlafaxine
No significant CYP drug interactions

NSAIDs, antiplatelets, anticoagulants – caution only
↑ bleeding risk secondary to ↓ platelet aggregation effects serotonin reuptake inhibition (less risk than SSRI)

Serotonergic agents
↑ risk of serotonin syndrome

146
Q

What are some warnings/precautions for SNRI’s?

A

Black box warning for ↑ suicide if < 24 y.o.
Monitor for ↑ blood pressure
Caution if hx of HTN or narrow angle glaucoma
Avoid abrupt withdrawal (hardest to taper off of)

147
Q

What are some specific warnings for Duloxetine?

A

Duloxetine is contraindicated in narrow angle glaucoma (NE makes it worst)

Avoid in hepatic impairment or heavy ETOH use

Risk of urinary retention

148
Q

Which SNRI is contraindicated in narrow angle glaucoma?

A

Duloxetine

149
Q

Which SNRI has signifcant withdrawal sx?

A

Venlafaxine

150
Q

Desvenlafaxine is________

A
  • ACtive metabolite of venlafaxine (less subject to genetic polymorphisms)
151
Q

Desvenlafaxine is particularily useful for…..

A

Menopausal vasomotor sx

152
Q

MDD efficacy Duloxetine doses

A

No greater efficacy for MDD at doses > 60 mg

153
Q

Which SNRI is most effective for neuropathic pain?

A

Duloxetine

154
Q

What is unique about duloxetine use?

A

Most effective for neuropathic pain

155
Q

What is unique about DUloxetine metabolism and PK?

A

Severe renal impairement can double AUC

Hepatic Impairement –> AUC increased 5-fold, half-life 3 fold

156
Q

What is the MOA of bupropion?

A

Inhibits NE and DA transporters increasing concentrations in the synapses

No 5-HT effects

157
Q

Bupropion is structuarlly similar to….

A

Amphetamine

158
Q

Where is bupropions place in therapy?

A

Useful for patients with psychomotor retardation, hypersomnia, ADHD type symptoms
–> Stimulating, activating

Can be used to augment SSRI or SNRI in treatment resistant cases

Much less risk of sexual dysfunction, and in some cases may alleviate sx when used as adjunct

Possibly useful in stimulant use disorder to reduce illicit use and cravings (misusing cocaine, meth)

159
Q

What are some A/E of bupropion?

A

Activating
Agitation, insomnia, tremor, and ANXIETY

Sweating due to NE reuptake inhibition

Reduced appetite/weight loss

GI upset

Psychosis/ exacerbation of psychosis (too much dopamine)

Urticaria and anaphylactoid reactions

Seizures

Less sexual dysfunction than SSRIs/SNRIs

160
Q

When should bupropion be avoided/C.I.?

A

May need to avoid if hx of anxiety

Avoid in eating disorders (also increased risk of seizures)
Minimal weight gain compared to others

161
Q

What is the onset of action of bupropion?

A

Onset of effect similar to SSRIs/SNRIs

162
Q

Describe the metabolism of bupropion?

A

Metabolized in liver by CYP2B6 to active metabolite

Hydroxybupropion 20-50% potency of bupropion

163
Q

What is the main elimination mechanism of bupropion?

A

Excretion of metabolites will be reduced in severe renal dysfunction

Renal dosing adjustments are not provided by manufacturer, but recommended

Clinical judgment

164
Q

What are some D.I. of bupropion?

A

Zyban for tobacco cessation is the same drug!!
Would not use both at the same time but use of Zyban for smoking cessation can be used for concurrent MDD

Concurrent MAOI therapy –> contraindicated –> hypertensive crisis

Potent CYP2D6 inhibitor
Increase level of CYP2D6 substrates

165
Q

What is the usual dose of bupropion? What formulations are available?

A

Usual Dose: 100-300 mg

SR formulation (OD or BID)

XL Formulation (OD)

166
Q

Use of bupropion is cautioned when?

A

Use with caution in renal and/or hepatic impairment

Consider reducing dose and/or frequency; avoid if severe

167
Q

C.I. of Bupropion

A

Seizure disorder

Eating disorders

Abrupt discontinuation of alcohol or sedatives (at risk of seizures)

168
Q

What are some warnings or precautions of bupropion?

A

Black box warning of ↑ risk of suicide if < 24 yrs old (as with all ADs)

Precautions:
Dependence on opioids, cocaine, stimulants
Concurrent use of seizure threshold lowering drugs
Head trauma hx
HTN
Unstable CVD/CAD
Psychosis
Anxiety
Insomnia
Overdose lethality

169
Q

What is mirtazapine MOA?

A

antagonism at: 5HT2A, 5HT2C, 5HT3,α2-adrenergic, H1

Presynaptic central alpha2-adrenergic autoreceptors (doses > 15 mg)
–> increased release of NE and 5HT (mirt = squirt)

5HT2A/2C receptors
–> Linked to lower anxiety, antidepressive, pro-cognitive; lower 5HT related Aes,

5HT3 receptors
–> Lower GI side effects (helps relieve N/V)

H1 histamine receptors (doses < 30 mg)
sedation, weight gain

Moderate peripheral alpha-adrenergic and muscarinic receptor antagonism

Exact clinical effect on depression is not clear

170
Q

Describe mirtazapines role in therapy?

A

Useful as monotherapy and adjunctive treatment

Consider in patients with insomnia, anxiety, reduced appetite

Relatively safe in overdose

171
Q

What is the onset of action of bupropion?

A

Onset similar to SNRI’s and SSRI’s

172
Q

What are some PK considerations of Mirtazapine?

A
  • Half-life is significantly longer in females than males
  • Extensive hepatic metabolism and mainly renally eliminated
173
Q

D.I. of Mirtazapine

A

Increased risk of serotonin syndrome in combination with serotonergic agent

Caution when combining with other CNS depressants
Example: benzodiazepines

174
Q

What are some critical considerations in Mirtazapine dosing?

A
  • Dosed HS
  • Titration q1-2 weeks
  • No adjustment required with renal or hepatic dysfunction – but use with caution as may accumulate

The sedation effect is typically lost (or at least much less pronounced) with doses starting at 30mg
Below 30 –> More sedating
Above 30 –> More stimulating

Balance for insomnia and antidepressant activity ~22.5mg

175
Q

Mirtazapine warnings/precautions

A

Black box warning for increased suicide risk if < 24 yrs old (as with all ADs)

Caution
Agranulocytosis cases reported (rare)
Orthostasis (orthostatic HTN)
Hyponatremia in elderly (SDIH)

176
Q

What are the 2nd line classes of AD’s and examples?

A
177
Q

What TCA’s are available in Canada?

A

Tertiary amines
Amitriptyline
Clomipramine
Doxepin
Imipramine

Secondary amines
Nortriptyline
Desipramine

178
Q

TCA’s MOA

A

Inhibit presynaptic 5-HT and NE reuptake by inhibiting 5-HT and NE transporters in CNS neurons

Tertiary amines = more 5-HT activity
Secondary amines = more NE activity, better tolerated

Individual TCAs have varying affinity for other receptors

Adrenergic (alpha-1 blockade, hypotension), histamine (sedation), muscarinic (anti-cholinergic), sodium channels blockade

THE DIRTY ANTIDEPRESSANTS

179
Q

What are the differences between secondary and tertiary amine TCA’s?

A

Tertiary amines = more 5-HT activity
Secondary amines = more NE activity, better tolerated

180
Q

What is the result of a TCA overdose? Why?

A

FATAL –> Sodium blockade

181
Q

Why are TCA’s second line?

A

Older and much less selective, but still have evidence they can work just as well

Second line largely due to tolerability and safety

182
Q

What are TCA’s place in therapy?

A

MDD with:

Insomnia
Anxiety (bit more relaxing)
Chronic, non-cancer pain (low back pain, neuropathic)
Migraines/headaches
OCD (clomipramine)

183
Q

TCA C.I.

A

Acute MI, heart block, CHF
Severe liver impairment

184
Q

Cautions of TCA Use

A

Any CVD (risk on heart)
Suicidal ideation (limit quantity dispensed!)
QT prolongation
Seizure history/risk
Risk of harm associated with antichol effects
Elderly
Bipolar disorder (risk that may induce mania)

185
Q

What are A/e of TCA’s?

A

Common: sedation, anticholinergic effects, CV

Weight gain
–> 5HT, His, ACh
Tremors
Sexual dysfunction
Urine discolouration (amitriptyline)
Rash; anticonvulsant hypersensitivity cross-rxn (rare)
Seizures, SIADH, fractures

186
Q

What are some CV effects of TCA’s?

A

Cardiotoxicity (e.g. ventricular tachycardia, heart block) is primary mechanism of overdose

Orthostatic hypotension

Tachycardia (increased NE)
–> May necessitate change to alternative antidepressant

Right bundle branch block (arrthymias blocks NA+ channels)
–> If occurs – stop TCA
–> If present – avoid TCA

QT prolongation (assess overall risk and monitoring regularly)

187
Q

What are the anti-cholinergic side effects notcied with TCA’s?

A
  • Increased body temp
  • Mydriasis (dilated pupils)
  • Dry mouth, eyes, decreased sweat
  • Flushed face
    -Delirium
188
Q

What is the lethal dose of TCA’s?

A

Lethal dose is only ~3x max therapeutic dose

189
Q

What adverse effect of TCA’s is specific to urine dicolouration?

A

Amitriptylline

190
Q

Specific a/e of amitriptylline

A

Urine discolouration

191
Q

TCA D.I.

A

MANY

Many potential interactions related to additive CNS depression, serotonin activity, neurotoxicity with lithium, seizure risk, arrhythmias

Most TCAs are substrates of CYP2D6
Clomip: 1A2 substrate

192
Q

What is the MOA of trazadone?

A

Weak inhibition of SERT and NET (doses > 200 mg)

5-HT2A and 5-HT2C(doses > 200 mg) receptor antagonism

Antagonist at alpha-1 adrenergic receptors and H1 histamine receptors(doses 25-200 mg)
–> Sedating - commonly used for insomnia
–> Also a primary reason for not being well tolerated

Plus multiple other serotonin, alpha, DA receptors!

193
Q

What is the primary reason that trazadone is not well tolerated?

A

Antagonist at alpha-1 adrenergic receptors and H1 histamine receptors(doses 25-200 mg)
–> Sedating - commonly used for insomnia
–> Also a primary reason for not being well tolerated

194
Q

What are the a/e of trazadone?

A

CNS: dizziness, sedation, headache, akathisia, myalgia, tremor

CV:
Orthostatic hypotension, syncope
Prolonged QT interval, arrhythmias

GI:
Nausea 21%, constipation 8%, dry mouth 14-34%

Rare:
*can cause priapism< 1%
Sexual dysfunction (less than with SSRI/SNRI)
Seizures, suicidal ideation, serotonin syndrome, bleeding

195
Q

Trazadone C.I.

A

CI if recent or acute MI

196
Q

What is trazdone used for and its respective dosing?

A

Depression –> BID
Sedation –> PO HS

197
Q

Trazodone with food?

A

Food enhances, although delays peak concentration

198
Q

Trazodone Elimination

A

Metabolized to active metabolites by CYP3A4
- m-chlorophenylpiperazine (m-CPP)
Has serotonergic activity
Blockage of CYP3A4 activity can interfere with action

75% excreted via kidney

199
Q

Trazodone D.I.

A

CYP3A4 inducers and inhibitors

Antihypertensives
Dose adjustment may be required since trazodone may cause hypotension (alpha-1 antagonism) –> Prazosin

200
Q

What is quietiapine?

A

Atypical antipsychotic (2nd and 3rd generation)

201
Q

Quietapine MOA

A

Antagonist at 5HT-1 & 2, D1 & 2, H1, alpha-1 & 2

202
Q

Quetiapine Formulations

A

IR or XR(ER)

203
Q

What are the avilable MAOI’s?

A

Moclobemine (Manerix) –> Reversible MAOA»MAOB

*Irreversible MAOA+MAOB
Selegiline
Phenelzine
Tranylcypromine

204
Q

What is the comparitive metabolism differences between MAOA and MAOB?

A
205
Q

Meclobemide MOA

A

Short- acting reversible inhibitor of MAO-A to ↓ metabolism of
5-HT, NE, DA

206
Q

What is critical to understand regarding the dosing of moclobemide?

A

BID

With doses >600mg/day, specificity for MAO-A is lost, and thus caution regarding tyramine is required (cautious around tyramine containing food)

207
Q

Describe the tyramine rxn

A

Inhibition of MAO allows for aborption of exogenous tyramine which displaces NE from storage vesicles in noradrenergic neurons

Moclobemide does not inhibit MAO-B, so tyramine absorbed from the gut can still be degraded (unless > 600) –> Loss specificity

208
Q

Moclobemide Metabolism

A

Metabolized by CYP2C19 (major) & CYP 2D6 (minor)

95% excreted in urine as metabolites

209
Q

Moclobemide Switching

A

Stop serotonergic drugs 2 weeks before starting MAOI to avoid precipitating a hypertensive reaction or serotonin syndrome
–> Stop fluoxetine 5 weeks prior to starting MAOI

If stopping MAOI, wait 2 weeks before starting another antidepressant

Stop MAOI at least 2 days prior to local or general anesthesia

210
Q

A/E of Moclobemide

A

Tachycardia
Hypotension
Sleep disturbance, agitation, nervousness, anxiety
Less frequent than SSRI, SNRI
–> N/V/D
–> Sexual dysfunction (low incidence compared to SSRI)
–> Anticholinergic effects

211
Q

What are the irreversible MAOI and there MOA?

A

Phenelzine
Irreversibly bind and inhibit MAO-A and MAO-B non-selectively increasing 5-HT, NE, DA

Tranylcypromine
Irreversibly binds and inhibits MAO-A and MAO-B
Additional action similar to amphetamines:
–> Increased 5-HT, DA, NE release in synapse
–> Inhibits DA and NE transporters

212
Q

What is the duration of action of Irreverisble MAOI’s?

A

Duration of Action: matches timeframe to synthesize new MAO enzymes (2-3 weeks)

213
Q

C.I. of Irreversible MAOI’s

A

Pheochromocytoma –> tumor secreting catecholamines

Concurrent use of serotonergic or sympathomimetic agents
–> High risk of serotonin syndrome & HTNsive crisis, respectively

Tyramine containing foods

Discontinue at least 10 days prior to surgery

214
Q

What are some important counselling tips for ireevrsible MAOI’s?

A

Adherence to dietary and medication restrictions
Disclose MAOI use to all HCPs

PHAR 253 Exam 2 (4 decks)

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