Depression

Question 1

Antidepressant Class BBW

Answer 1

Increased risk of suicidal thoughts and behaviors in young adults 18-24 years of age (and younger children or teens) especially at the early stage of treatment.

What to do?
• Counsel patients/families to monitor closely at beginning of treatment
• Possible ADRs could include agitation
• Deal with the subject of suicide directly
• Get help immediately

Question 2

Which CYP enzymes are most involved in SSRI/SNRI metabolism? How about antipsychotics?

Answer 2

CYP2D6 - SSRI, SNRI
CYP1A2 - Antipsychotics

Question 3

SSRIs (name the agents)

Answer 3

Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)

Question 4

SNRI (name the agents)

Answer 4

Desvenlafaxine
Duloxetine
Venlafaxine
Levominacipran

Question 5

Serotonin Modulators (name the medications)

Answer 5

Gepirone
Nefazodone
Trazodone
Vilazodone
Vortioxetine

Question 6

Tricyclic Antidepressants (TCAs) and other norepinephrine reuptake inhibitors

Answer 6

Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine

Question 7

Monoamine Oxidase Inhibitors (MAO-I) (name the agents)

Answer 7

Selegiline
Rasagiline
Phenelzine
Tranylcypromine

Question 8

Miscellaneous Antidepressant Agents (name the medications)

Answer 8

Brexanolone
Bupropion
Esketamine
Mirtazapine
Zuranolone

Question 9

Second Generation Antipsychotics (SGA) Agents with MDD FDA Approval

Answer 9

All also have schizophrenia FDA approval! All but Rexulti also have Bipolar Disorder

Aripiprazole (Abilify)
Brexpiprazole (Rexulti)
Olanzapine (Zyprexa) - Only approved for MDD if used with Fluoxetine (Prozac)
Quetiapine (Seroquel)

None of these agents are to be used alone, they should be used with an antidepressant

Question 10

Comparative Efficacy of Antidepressants. Which work best?

Answer 10

All antidepressants are considered equally efficacious for treatment of MDD; other factors should guide the selection of treatment options

Question 11

Antidepressant Pharmacological Issue - Antidepressant Use in Bipolar Disorder

Answer 11

Unopposed use of AD in pt with underlying BPD (bipolar disorder) may precipitate a manic/mixed episode
Beware of a spontaneous recovery <2 weeks of starting the new agent as these agents take a while to work. May mean the pt has BPD or something else

Question 12

General Approach to Treatment

Answer 12

• Psychotherapy considered for mild/moderate depression and psychoeducation a key component for all patients
• First line medication: SSRI, SNRI, bupropion, mirtazapine, vortioxetine
• If response to treatment (50% reduction of symptoms) has been reported after 4 weeks, AD should be continued at an optimal dose and reevaluated at 6, 8 and 12 weeks
• If symptoms persist after an adequate trial (4-8 weeks) at an adequate dose, guidelines suggest:
– Switching to alternate antidepressant (AD) OR AUGMENTING with an AD with an alternative MOA, a second generation antipsychotic (SGA) or psychotherapy

Question 13

How to discontinue SSRIs

Answer 13

Taper if possible (except fluoxetine with long t1/2).

Discontinuation Syndrome can cause “electric shock sensations”

Question 14

SSRI Class Effect - Rare, Serious ADEs (2 of many)

Answer 14

Hyponatremia and SIADH (rare but serious); monitor for increased lethargy mental status changes and serum sodium less than 135mEq/L

Question 15

SSRI Patient Education / Therapy Adjustment Decisions

Answer 15

• Insomnia or sedation
– take in morning or switch to another with less insomnia

• Sexual dysfunction
– may need to switch to another agent such as bupropion

• Serotonin syndrome counsel on symptoms
– Mental status changes
– Autonomic instability
– Neuromuscular abnormality
– GI symptoms

Question 16

Patient Education - How to Avoid Serotonin Syndrome

Answer 16

• Avoid concomitant use of serotonergic drugs
• Others:
– Triptan migraine agents
– Pain medications: fentanyl and tramadol
– Nausea products: zofran and reglan
– Buspirone
– Linezolid
– Ritonavir
• Drugs that impair the metabolism of serotonin

Question 17

SSRIs other DDIs other than Serotonin Syndrome

Answer 17

– QTC prolongation with concomitant medications
– Increased risk of bleeding for patients on NSAIDS, anti-platelets and anticoagulants

Question 18

SSRIs - Other Issues

Answer 18

– SSRI/SNRI hyponatremia (SIADH)
– Sexual side effects
– Withdrawal syndrome
– Generally require caution/dose modifications with hepatic impairment (renal is less common, but confirm status)

Question 19

Universal SSRI precautions

Answer 19

Discontinuation syndrome (except fluoxetine b/c longer half life), abnormal bleeding due to 5-HT reuptake on platelets, hyponatremia, serotonin syndrome, potential cognitive and motor impairment.
Most have some degree of QTc prolongation effects.
More likely energy boosting than sedating

Question 20

Citalopram

Answer 20

SSRI
Doses >40mg not recommended (older adults 20mg)
FDA released QTc warning in 2023
Available as ODT
Maximum Daily Dose 20mg for:
- Those 60 years or older
- CYP 2C9 PM
- Hepatic Impairment

Question 21

Escitalopram

Answer 21

SSRI
Benefit of 20 mg over 10 mg not established
Isomer of citalopram
Currently not labeled with same FDA QTc warning and dose requirements as citalopram - still not safest agent for patients with this risk
Maximum Daily Dose: 10mg for hepatic impairment
Pediatric Approved Dosing: 12-17 years old
Maximum Daily Dose of 10mg for Hepatic Impairment

Question 22

Fluvoxamine

Answer 22

SSRI
Caution in Elderly - one of the most sedating, also can be anticholinergic (less tolerable than many other agents)
Many drug interactions (CYP 1A2) - recall CI with Ramelteon from sleep lectures

Question 23

Fluoxetine

Answer 23

SSRI

• Majority of patients will not require >20 mg/d
• 40 mg/day or more should be divided in 2 or more doses
• Only SSRI approved for once weekly administration
• Available as liquid
• Inhibits CYP 2D6 (TCAs), CYP 3A4 (carbamazepine)
• Anorexia
• Anxiety and Insomnia

Question 24

Paroxetine

Answer 24

SSRI - Paxel

• Short half-life but CR available
• sedating & anticholinergic careful in the elderly
• Avoid in pregnancy
• Akathisia
• Reports of bone fracture

Question 25

Sertraline

Answer 25

SSRI - Zoloft Concentrate can be mixed with ONLY water, ginger ale, lemon/lime soda, lemonade or orange juice

Question 26

SNRI Class Adverse Effects

Answer 26

Abnormal bleeding due to 5-HT reuptake on platelets, potential for increased risk of activation of mania, elevated blood pressure, hyponatremia and serotonin syndrome and discontinuation syndrome. Tend to be more energy boosting than other AD Also share with SSRI: serotonin syndrome, variable seizure and QTc risks bleeding risk, hyponatremia, anticholinergic effects (glaucoma, urinary retention, etc)

Question 27

MAOi Class Adverse Effects

Answer 27

Must wait 4 to 5 half-lives of drug or active metabolite after D/C interacting drug: for example: • Fluoxetine and Vortioxetine have the longest T1/2 of the SSRIs so need to wait longer than 2 weeks before start of an MAOI – Fluoxetine: 5 weeks – Vortioxetine: 3 weeks • Dietary restrictions of **Tyramine Containing foods** – Aged products, smoked and pickled products, yeast extracts – Risk life threatening **hypertensive crisis** • Other side effects: postural hypotension, diarrhea, anticholinergic drying effects, sexual dysfunction • Monitor for potential DDI-primarily related to hypertensive crisis risk: – Amphetamines, decongestants, methylphenidate… • Serotonin syndrome – dextromethorphan, etc Irreversible nature of the medication • Clinician should wait 2 weeks before switch to new drug • Typically reserved for ‘last resort’

Question 28

Nefazodone

Answer 28

Serotonin Modulator Hepatic BBW Risk of priapism

Question 29

Trazodone

Answer 29

Serotonin Modulator Sedating Risk of priapism More anticholinergic and bleeding risk compared to nefazodone

Question 30

Vortioxetine (Trintellix)

Answer 30

Serotonin Modulator Reduce dose by 50% for CYP2D6 poor metabolizers Long half life (recall: 3 weeks off this agent before starting MAOi)

Question 31

Gepirone

Answer 31

Serotonin Modulator approved for MDD High Fat meals increase absorption - counsel to keep meals consistent Extensively metabolized by CYP3A4 • Dosing alerts for: – Older adults – Hepatic impairment (but severe=CI) – Renal impairment Shares universal precautions: FDA boxed warnings for suicide, QTc prolongation, serotonin syndrome, MAO washout **(New agent) May offer improvement: reduced sexual side effects, less weight gain**

Question 32

Bupropion

Answer 32

Miscellaneous Antidepressant Many brand names with different uses **Wellbutrin CONTRAINDICATED in patients with risk of SEIZURE or seizure disorder** Caution in patients with eating disorders or alcohol use disorders (because electrolyte abnormalities) Hypertension, insomnia, activation and anxiety, neuropsychiatric events with smoking cessation (warnings downgraded)

Question 33

Mirtazapine (Remeron)

Answer 33

Miscellaneous Antidepressant Sedating Cholesterol elevation Significant weight gain (>7%) common - stimulates appetite ODT option Transaminase increases possible - monitor LFTs Agranulocytosis has been reported Sometimes better for older adults because of these adverse effects

Question 34

Esketamine (Spravato)

Answer 34

Miscellaneous Antidepressant - Nasal Spray C3 Scheduled Controlled Substance Indicated for *Treatment Resistant Depression* in adults **in combination with an antidepressant** – **Failure of at least two other drugs required** • Non-competitive N-methyl D-aspartate (NMDA) receptor antagonist • CI: history of aneurysmal vascular disease, and intracerebral hemorrhage • Can lead to increased blood pressure, cognitive impairment, *impaired ability to drive or operate machinery*, embryo-fetal toxicity • Boxed warning: Sedation, dissociation; abuse and misuse; suicidal thoughts and behaviors • Adverse reactions: dissociation, dizziness, N/V, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, and feeling drunk • Only available through the SPRAVATOR **REMS** program – Dispensed in a REMS certified healthcare setting to patients enrolled in the program – *Administered in the direct observation of a healthcare provider* – **Monitored for two hours after administration** – Pharmacies must be certified by REMS and only dispense to REMS certified healthcare facilities

Question 35

Zuranolone

Answer 35

Zurzuvae Used to treat **postpartum depression** • Can be used alone or as an adjunct to oral antidepressant therapy • 50 mg taken **orally once daily in the evening for 14 days** • *Administer with fat-containing food* (e.g., 400 to 1,000 calories, 25% to 50% fat) Boxed warning: Advise patients not to drive or engage in other potentially hazardous activity until at least 12 hours after administration

Question 36

Brexanolone

Answer 36

Zulresso Used to treat **postpartum depression** **IV continuous infusion given over 60 hours (2.5 days)** **Hypoxia** - monitor via continuous pulse oximetry, D/C if profound hypoxia occurs **Excessive Sedation** - monitor q2h during wake hours. D/C infusion until symptoms resolve then resume at same or decreased dose PRN

Question 37

Which Medication Class to avoid in: Seizure Disorders? Substance Abuse? Cardiac Complications? GI Bleeding and Anticoagulation?

Answer 37

Bupropion Benzodiazepines TCAs SSRIs

Question 38

Elderly Population Treatment of Depression

Answer 38

• SSRI usually best choice as initial treatment • Second choices often bupropion and venlafaxine • Evidence of mirtazapine benefits on anxiety, sleep, and appetite stimulation (watch cholesterol) • Avoid TCA

Question 39

Elderly BEERS List

Answer 39

Chronic Seizures or Epilepsy - Bupropion Delirium - All TCAs History of Fractures/Falls - TCAs and SSRIs

Question 40

Children Depression Treatment Options

Answer 40

Fluoxetine is the only medication approved for tx of children 8 years and older as well as for adolescent depression Escitalopram is FDA approved for children over 12 years old

Question 41

Pregnancy Treatment of Depression

Answer 41

Pregnancy does not protect against depression and untreated, can result in relapses SSRIs are the most commonly used and best tolerated medication during pregnancy, but these too carry a small but significant risk (**AVOID PAROXETINE**)

Question 42

Augmentation Agents

Answer 42

Lithium - first line augmenting agent (best studied by augmenting TCAs) Triiodothyronine - used regardless of thyroid status, but may cause hyperthyroidism SGAs Buspirone, stimulants (mixed results with these)

Question 43

Neuroleptic Malignant Syndrome (NMS) vs. Serotonin Syndrome (SS)

Answer 43

NMS: • Dopamine antagonists • Onset variable ~1-3 days • **Lead pipe rigidity** in all muscle groups • Hyp**o**reflexia • **Normal** pupils • **Normal or decreased** bowel sounds • **Increased CPK values** SS: • Serotonin agents • Onset variable < 12 hours • Hyp**er**reflexia, clonus • **Dilated** pupils • **Hyperactive** bowel sounds