Exam 1 - Antidepressants

Question 1

Depression Treatment Key Takeaways:

Medications are only one part of treatment

R/O bipolar disorders prior to initiating antidepressants

Certain medications may work for some people and not for others

Macro level data does not show superiority of any agent

Greater depressive sx predicts greater response to medication, in general

Side effects can often be troubling

Adherence issues are common

Treatment with more than one antidepressant or treatment with one antidepressant and one additional agent for augmentation is often reasonable

Question 2

Major Depressive Disorder

SIG-E-CAPS:

Sleep changes

Interest (loss of)

Guilt

Energy (lack of)

Cognition/concentration

Appetite

Psychomotor

Suicide/death thoughts** (high risk of this in depression, always assess)

Question 3

Treating Depression

Mild Depression: Non-pharmacologic interventions (e.g. CBT, guided self help, interpersonal psychotherapy and other lifestyle and psychosocial interventions.

Severe-chronic depression: Consider antidepressant

Depression w/ psychotic features: Antipsychotic and an antidepressant or ECT.

Question 4

Factors that impact antidepressant selection

Previous patient or family member response to antidepressants (if any)

Impact on psychiatric or medical comorbidities

Clinician familiarity

Patient preference

Safety in overdose

Availability

Cost

Drug to drug interaction

Top distressing side effects: Sexual dysfunctions, sleep disturbance, weight gain

Question 5

Theories of Depression: Monoamines

Monoamine hypothesis

Deficit of monoamines (serotonin, norepinephrine, dopamine)

Delayed onset of therapeutic response to antidepressants (2 to 6 weeks)

Changes in receptors takes time

Problems with the monoamine hypothesis

Question 6

Theories of Depression: Neurogenic

Neurogenic theory

Neurons become damaged, a neurodegenerative process

Genetic vulnerability + stress = disorder

Medication, therapy, etc. can Increases BDNF (brain-derived neurotrophic factor) “fertilizer for the brain cells” to help repair neurons and connections

BDNF can be increased via medication, therapy, or other interventions (exercise) to some extent

Question 7

Neurotransmitters/Monoamine Hypothesis

Depression=↓Serotonin; ↓Dopamine; ↓NE

Monoamine Hypothesis: Deficient brain 5HT and/or NE results in depression

Question 8

Antidepressants

Etiology:

Dysregulation in 1 or more biogenic amines (i.e. 5HT, NE, DA)

Low level precursor tryptophan

Target Symptoms: Depressed mood, sleep/rest distress, anxiety, irritability, impaired concentration/memory, appetite disturbances, agitation, anhedonia, impaired energy/motivation.

Classes: SSRI, SNRI, NDRI, SPARI, TCA, MAOI

Question 9

Antidepressants

General Information:

All antidepressants have similar response rates but differ in safety and side effect profiles.

60-70% of patient with MDD will respond to antidepressant meds.

Most antidepressants require a trial of at least 3-4 weeks for effect and in some cases 6-8 weeks for noticeable effects.

Maintenance therapy: 6-13 months

Most antidepressants have a withdrawal phenomenon= Educate patients not to stop abruptly

Dizziness, headaches, nausea, insomnia, anxiety, electric-like shocks “zaps”, malaise

Depends on dose and half-life

Question 10

Antidepressants

Factors affecting drug choice= Cost, patient symptoms, previous treatment of patient or family member, side effect profile, comorbid conditions, risk of suicide

Side Effects: Sexual dysfunction (25-30%), GI (nausea/diarrhea)-Give w/ food, insomnia, headaches, anorexia/weight loss, Akathisia

Lab Monitoring: TSH, CBC, Chemistry, Folate and vitamin B12 , UA

Question 11

STAR-D Study Implications

The longer a person goes without responding to treatment, the less likely response becomes overall

Switching medications to a different class or to a different SSRI is a reasonable strategy but provides only modest improvement for most

On a macro level, any antidepressant is just as likely to be effective as any other antidepressant
Individual responses can be hard to predict

High relapse rates for chronic depression

More complex individuals have more difficulty with response/remission (e.g. other psychosocial stressors, medical issues, etc.)

Question 12

The Major Categories

SSRIs – commonly used d/t safety and tolerability

SNRIs

Heterocyclic antidepressants (i.e. TCAs and tetracyclic)

MOAI

Atypical/Miscellaneous antidepressants

Question 13

Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism of Action:

Inhibit presynaptic serotonin reuptake pumps = ↑ availability of 5HT in synaptic clefts.
Cause downstream effects increasing brain plasticity – explains the delay of antidepressant effect.
1st line
Most prescribed class d/t
Low incidence of side effects – most resolve with time
No food restrictions
- Safer in overdose
Better tolerated
May initially worsen anxiety or panic attacks

Question 14

Selective Serotonin Reuptake Inhibitors (SSRIs)

Low incidence of side effects

Transient (lasting 1-2 weeks especially GI)

Side Effects: Sexual dysfunction (30-40%)- decreased libido, anorgasmia, delayed ejaculation – occurs weeks to months (typically do not resolve)

GI (nausea/diarrhea)-Give w/ food, insomnia, headaches, anorexia/weight loss, Akathisia, sedation, agitation, Hyponatremia / SIADH, decreased platelet aggregation-risk for bleeding and bruising

Seizures- rare

BLACKBOX WARNING: Increased suicidality in children, adolescents and young adults

NOTE: Remember FFPECS

Question 15

Common result of blocking serotonin reuptake is enhancement of postsynaptic serotonin activity at all serotonin receptors in the brain

5-HT1 = antidepressant and anxiolytic

5-HT2 and 5-HT3 = adverse effects

5-HT2 = insomnia, anxiety, agitation, and sexual dysfunction

5-HT3 = nausea

Question 16

The SSRIs

Fluoxetine(Prozac) 20-80mg

Longest half –life =2-3 days(no need to taper)

Safe in pregnancy

Approved in use of Child/Adolescent

Approved for Buliemia

Can be dosed 1x/wk

Can elevate levels of antipsychotics – watch for increased side effects

Consider in patients w/ poor adherence d/t long half life

Activating” or energizing effect (Stahl, 2013)

Combination with olanzapine for psychotic depression

Question 17

The SSRIs

Fluvoxamine(Luvox) 50-300mg

FDA approved for OCD

Common S/E: Nausea, vomiting

Question 18

The SSRIs

Paroxetine (Paxil) 20-50mg

Considered “dirty” -

Potent CYP26 Inhibitor = several drug to drug interactions

Common side effects – Anticholinergic and sexual dysfunction

Short half-life = withdrawal phenomenon

Fairly significant side effects including sexual s/e

“Paxil packs on the pounds”

Can be sedating, take around dinner time

Question 19

The SSRIs

Escitalopram (Lexapro) 10-20mg

Levo-enantiomer of citalopram, similar efficacy

Dose dependent QTc prolongation

Fewer drug –drug interactions.

Question 20

The SSRIs

Citalopram (Celexa)
20-40mg

Associated with dose dependent QTC prolongation in doses 40+mg

Max dose in Geriatrics= 20mg.

Fewer drug interactions

Most Lethal in OD

Question 21

The SSRIs

Sertraline(Zoloft) 50-200mg

Has the most GI side effects

Very few drug interactions

Give with food

Activating (Agitation, anxiety)

Favored during pregnancy and nursing (MCPAP for Moms, 2014)

Question 22

Activating Antidepressants – good for patients who want to avoid medications that cause tiredness – e.g. Fluoxetine

Advantage of SSRIs over other classes of meds

When choosing an SSRI= Consider the inhibition of CYP-450 isoenzymes (induction vs. inhibition) – be familiar with these concepts

Most lethal SSRI in overdose ? (Citalopram) consider cardiac effects

Question 23

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Consider w/ patients who have significant fatigue or comorbid chronic pain

Mechanism of Action: Inhibits dual reuptake of NE and 5HT = ↑ extracellular concentrations of NE and 5HT

Side Effects: Sustained elevation in BP Nausea, diarrhea, dizziness, anticholinergic

All SNRI can increase blood pressure, cause tremor (beta receptor stimulation)

Question 24

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)-

Venlafaxine (Effexor ) 75-375mg BID

MDD, GAD, neuropathic pain

Useful in treating anxiety and panic attacks in depressed patients

XR available

New form Desvenlafaxine (Prestiq)= expensive

Short half life

Very hard to taper and d/c

Question 25

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)- Duloxetine (Cymbalta) 40-120mg/day Can increase LFTs Used for depression, neuropathic pain and in fibromyalgia Hepatotoxicity (monitor LFTs)

Question 26

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)- Levomilnacipran(Fetzima) 20-120mg /day Associated w/ more side effects (HTN, decrease appetite, Palpitations, diaphoresis etc.)

Question 27

Norepinephrine- Dopamine Reuptake Inhibitor (NDRIs) Mechanism of Action: Inhibits reuptake of NE and DA Side Effects: Headache, tremors, tachycardia, insomnia, anxiety, decreased appetite Most helpful for target sx of low energy, anhedonia, low concentration, or if having sexual s/e from SSRI

Question 28

Norepinephrine- Dopamine Reuptake Inhibitor (NDRIs) Bupropion (Wellbutrin) 150-450mg Used in ADHD and smoking cessation d/t effects on DA Weight neutral Contraindicated in patients with seizure and eating disorders = Lowers seizure threshold (at higher doses) Lacks sexual side effects – add to other antidepressants to txt sexual dysfunction Other available forms: XR= 24 hours; SR= 12 hours Less GI distress Side effects: agitation, jitteriness, mild cog dysfunctions, insomnia

Question 29

Contraindicated in patients with seizure and eating disorders = Lowers seizure threshold (at higher doses) A. Tefretol B. Carbamazepine C. Buproprion D. Gabapentin

Answer 29

C. Buproprion

Question 30

Serotonin Partial Agonist Reuptake Inhibitor (SPARI) Vilazodone (Vibryd) In theory, may mitigate some sexual s/e but these still do occur Other s/e similar to SSRI class Fairly weight neutral and non-sedating

Question 31

Serotonin Receptor Antagonist and Agonist Trazodone (Desyrel) Acts on the Alpha –adrenergic receptors Used for MDD, anxiety and insomnia Main SE: nausea, dizziness, orthostatic hypotension, sedation, Priapism Low doses for sleep (50mg), higher doses antidepressant effects

Question 32

Serotonin Receptor Antagonist and Agonist Nefazodone (Serzone) BLACKBOX warning for serious liver failure= rarely used Off the market 

Question 33

Serotonin Receptor Antagonist and Agonist Mirtazapine (Remeron) 15-45mg Alpha 2 adrenergic and 5HT2 antagonist =↑ 5HT and NE Blocks H1 histamine receptors Sedating and promotes appetite(Used with patients who have weight loss and insomnia as primary symptoms of their depression) E.g. elderly SE: Sedation, weight gain, dizziness, tremor, dry mouth Inverse relationship between dose and sedation

Question 34

Tricyclic Antidepressants (TCAs) Mechanism of Action: Increases extracellular concentrations of 5HT and NE by inhibiting pre-synaptic reuptake High affinity to H1, H2 histamine receptors and muscarinic acetylcholine receptors 2nd line treatment for depression Side Effects Anticholinergic/Antimuscarinic: dry mouth, blurred vision, constipation, memory problems, urinary retention, narrow angle glaucoma Antiadrenergic: hypotension, orthostasis; dizziness, reflex tachycardia, arrhythmias, ECG changes – avoid in patients with pre-existing conduction abnormalities or recent MI Antihistaminic: sedation weight gain EKG changes and Cardiac dysrhythmias Seizure risk – related to the dose and serum level Lethal in overdose (give 1-week prescription especially in high-risk patients); Desipramine is the most lethal NOTE: 3Cs= Cardiotoxic (arrhythmia), Convulsions, Coma (caution w/ cardiac patients)

Question 35

Tertiary Amines Amitriptyline (Elavil) Used for chronic pain (neuropathy), migraines and insomnia

Question 36

Tertiary Amines Imipramine (Tofranil) IM form available Used for enuresis and panic disorder

Question 37

Tertiary Amines Clomipramine (Anafranil) Approved for the treatment of OCD

Question 38

Tertiary Amines Doxepine (Sinequan) Used for insomnia Used as sleep aid in low doses

Question 39

Tertiary Amines These are highly anticholinergic/antihistaminergic, antiadrenergic and with greater lethality in overdose.

Question 40

Secondary Amines Nortriptyline (Pamelor) Useful in treating chronic pain Useful to obtain therapeutic level Can be safely used in geriatric population

Question 41

Secondary Amines Desipramine (Norpramine) More activating/least sedating Least anticholinergic Used off label in ADHD

Question 42

Secondary Amines Amoxapine (Asendin) Metabolite of antipsychotic loxapine May cause EPS and has similar side effect profile to typical antipsychotics

Question 43

Secondary Amines Less anticholinergic/antihistaminic/antiadrenergic

Question 44

Side effects if TCAs (remember the 3 As) Indications for Tricyclic antidepressants TCA overdose= gastric aspiration is helpful, cardiac monitoring is important NOTE: Desipramine is the most lethal TCA

Question 45

Monoamine Oxidase Inhibitor (MAOIs) Mechanism of Action: Deactivate MOA-A and MOA-B (enzymes needed to deactivate 5HT, DA, tyramine) = increases the number of neurotransmitters in the synapses. Prevents the inactivation of biogenic amines (NE, 5HT, DA and tyramine) Selective and reversible MAO-A inhibitors are effective in treating major depression. Selective MAO-B inhibitors are used in the treatment of Parkinson's Disease and Alzheimer's Disease. Last resort secondary to dangerous food and drug interactions Used in refractory cases of depression Food restriction: Follow Tyramine free diet SE: Insomnia, weight gain, Anticholinergic, sexual SE, orthostatic hypotension, photophobia, drowsiness, sleep dysfunction Liver toxicity, seizures and edema (rare) Require washout period of 5 half-lives when switching Very dangerous interactions with other antidepressants and opioids, risk of serotonin syndrome

Question 46

Monoamine Oxidase Inhibitor (MAOIs) Hypertensive Crisis (Life threatening): When MAOI is taken with tyramine rich foods (inhibits catabolism of dietary amines) Sudden explosive headaches, high BP, facial flushing, palpitation, diaphoresis, fever, n/v, photophobia, autonomic instability , chest pain, arrhythmia and death Treatment: D/C medication Supportive care Phentolamine administration (NE antagonist) Tyramine rich foods: red wine, aged cheese, chicken liver, fava beans, cured meats Avoid the following: TCA’s Atypical antipsychotics, St. Johns Wort, Asthma meds, SSRI’s, decongestants, opiates (fentanyl, tramadol, meperidine) Serotonin Syndrome “SHIVERS”: When SSRI’s are taken w/ MAOIs NOTE: Wait at least 2 weeks before switching from SSRI to MAOI and at least 5-6 weeks with fluoxetine

Question 47

MAOIs Phenelzine (Nardil) Phenelzine has been shown to be more effective than placebo for MDD w/ atypical features, MDD w/ psychotic features and social phobia.

Question 48

MAOIs Selegiline (Emsam) Transdermal Patch DOES NOT REQUIRE DIETARY RESTRICTION 6mg/24hr or lower

Question 49

MAOIs should NOT be combined with psychotropic meds.

Question 50

Newer Antidepressants Most helpful in patients lacking response to initial SSRIs Vortioxetine=Trintellix or Brintellix Approved in 2013 Activates glutamate (excitatory NT) in the frontal cortex Effective in patients with cognitive deficits associated w/ MDD Theoretically fewer sexual s/e but clinically/anecdotally not necessarily so

Question 51

Newer Antidepressants Most helpful in patients lacking response to initial SSRIs Vilazodone=Viibryd Approved in 2011 Take with food to increase absorption and bioavailability

Question 52

Antidepressant Adverse Effects Sexual Dysfunction Highest with SSRI/SNRIs Impaired sexual motivation, desire, arousal and orgasm affecting men and women Highest with Venlafaxine and SSRIs Lowest with Bupropion, trazodone, nefazodone, mirtazapine Management First line- switch to bupropion(Wellbutrin) Use of phosphodiesterase -5 inhibitors such as sildenafil(Viagra) or tadalafil (Cialis)

Question 53

Antidepressant Adverse Effects Increased Suicidality Increased risk of suicidal thoughts and behavior with antidepressants primarily SSRIs Highest in persons younger than 25 Consider benefits vs. risks – patient education and documentation is critical

Question 54

SSRIs vs. TCAs and MAOIs Significantly fewer side effects d/t serotonin selectivity (i.e. not much activity on histamine, adrenergic or muscarinic receptors) Safer in overdose Many of the side effects resolve within a few days to weeks (including GI disturbance, insomnia, headache, weight changes)

Question 55

Antidepressant Withdrawal / Discontinuation Syndrome “FINISH” F= Flu like symptoms (aches, pains, chills) I= Insomnia N= Nausea I= Imbalance S= Sensory disturbance (tremors, sensation of electrical shock) H= Hyperarousal Gradual taper of medications Least likely with Fluoxetine and Vortioxetine (Trintellix/Brintellix) Symptoms usually begin within 5 days of treatment cessation Consider a 4-week taper (longer with Paxil and Effexor)

Question 56

Serotonin Syndrome “SHIVERS” Etiology: Excess. Serotonin in the body (single or multiple serotonergic agents) S=Shivering H=Hyperreflexia/Myoclonic jerks I = Increased Temp (Fever) V= Vitals Instability ( ↑↓BP; ↑RR; ↑HR) E= Encephalopathy ( Confusion) R= Restlessness S= Sweating ( Diaphoresis) Progression: Rhabdomyolysis, renal failure, convulsions, coma= DEATH Txt Stop medication Supportive care Cyproheptadine (5HT antagonist) ECT in emergencies

Question 57

Treatment Resistant Depression NOTE: Each relapse increases symptom severity, decreases treatment response and heightens risk of treatment resistance. Treatment Resistance: Inadequate response to 2+ antidepressants Treatment options Augmentation agents: Lithium, thyroid hormone, buspirone, atypical antipsychotics. Neurostimulation therapies Electroconvulsive therapy Ketamine and Esketamine

Question 58

Treatment Resistant Depression Neurostimulation Repetitive transcranial magnetic stimulation (rTMS) Nonpharmacologic approach Approved in 2008 Safe and effective

Question 59

Electroconvulsive Therapy (ECT) Effective in severe or refractory depression ECT generates electrical stimuli for seizure induction through electrodes applied to the scalp Patient is under general anesthesia and pre-medicated with a muscle relaxant Full ECT = at least 4-6 sessions over 2-3x/week S/E: Headaches; muscle soreness, nausea during ECT – transient ; loss of memory recall

Question 60

Who is eligible for ECT? First line for severe melancholic Catatonic Psychotic or refractory depression Patients who refuse to eat or drink High suicide risk or severe distress, Pregnant women with severe depression Previous positive ECT response

Question 61

Ketamine vs. Esketamine Ketamine N-methyl D-aspartate receptor (NMDA) antagonist Standardized subanesthetic dose (0.5mg/kg) IV over 40 minute infusion

Question 62

Ketamine vs. Esketamine Esketamine Ketamine derivative FDA approved in 2019 Administered via nasal spray given under direct supervision of a provider Monitor of adverse effects for at least 2 hours following administration Part of REMS program d/t potential for abuse and misuse

Question 63

Depression in Children and Adolescents Goal of treatment Remission of symptoms Return to baseline functioning. Treatment Choice Pharmacotherapy Psychotherapy Combination therapy (pharmacotherapy + psychotherapy)

Question 64

Depression in Children vs. Adolescents Depression in Children - May appear anxious and irritable - Psychomotor Agitation Depression in Adolescents - Hypersomnia - Hopelessness - Weight changes - Illicit drug use

Question 65

Depression in Children and Adolescents Factors affecting choice of initial treatment Illness severity and duration Presence of agitation, psychosis, suicidal and homicidal ideation, behavior, comorbidity Patient’s age and functioning Number of previous depressive episodes, response to and adherence with prior treatment Adverse effects Patient and family preference Clinical preference Familiarity with treatment options Cost

Question 66

Depression in Children and Adolescents Medication Choices First line: Fluoxetine Second line: Sertraline, escitalopram or citalopram; Venlafaxine Third line: Bupropion or duloxetine

Question 67

Depression in Children and Adolescents Pediatric Consideration Only Fluoxetine (Prozac) is FDA approved for use in treating depression in pediatric patients OCD in peds: Fluoxetine, Sertraline, Fluvoxamine and clomipramine Best results in pediatric population: Combination of pharmacotherapy and Cognitive-behavioral therapy (CBT) Multidisciplinary team approach d/t complexities involved with this population Monitor for: Agitation, irritability, suicidality, unusual behavior changes during first few months. Prescribe low dose, small quantities – to reduce the risk of OD.

Question 68

Depression in Children and Adolescents Patient Education Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults when the medicine is first started. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.