IP8 Exam 1

What are the two divisions of the ANS? Describe them briefly.

-Parasympathetic: this is relaxed, like reading a book (low HR).

-Sympathetic: this is like running from a killer (adrenaline, increased HR).

T or F: No labs will tell you if you have depression, but can rule out other things.

T

What are the different types of depression? Why is it important we differentiate these despite symptom overlap?

Major depressive disorder (unipolar depression), bipolar, seasonal, postpartum, and premenstrual. Treatment for each is different, in particular bipolar disorder because treating it as unipolar is not best for the patient.

Define major depressive disorder (MDD).

affective disorder characterized by depressed mood and/or loss of interest or pleasure (dopamine) in almost all activities.

Define affect and mood.

-Affect: what you are presenting to the outside world as right now.

-Mood: this is more about how you feel longer them, but not as long term as personality.

Explain the epidemiology of depression.

-Overall lifetime prevalence of 7-15% (has been rising steadily and especially during the pandemic).

-Risk factors include:

• female sex (about 2-3 fold more common)

• <60 years old

• poverty

• non-white

• with family history

• adolescence (more common in girls & transgender youth)

T or F: the risk factors for depression ARE NOT the same risk factors for suicide.

T

Explain the epidemiology of depression across different countries.

No big difference between high-income and low-income countries, depression is a global phenomenon.

Describe depression during the COVID-19 pandemic.

Really big spike in women at about 20 years old and also around the ages women have children. Higher in women then men.

Describe anxiety during the COVID-19 pandemic.

High risk in adolescence and children having ages. Having kids and working at home complexed things during the pandemic. Higher in women then men.

What is considered the most common cause of death in patients with depression? What is the risk percentage if left untreated?

Suicide; 20%

T or F: Men who are depressed are more likely to commit suicide and be successful in that attempt.

T

List the predisposing factors to committing suicide with depression.

• Age > 65

  • Ideation is lower than age 65, completion greater than 65 (especially for white men who have easy access to things like handguns).

• Divorced

• Family history of suicide

• Male sex

• Prior suicide attempt

• Substance use disorder

• Unemployed

• White or Native American

List the factors for likelihood of death for suicide in patients with depression.

• Access to means

  • pharmacologic or physical means

• Acute recent extreme loss

• Exacerbation of medical or psychological condition

• Extent of pain

• Impulsiveness

List the protective factors for suicide in patients with depression.

• Children at home

• Marriage

• Religion

• Social support

Describe the etiology of major depressive disorder.

We really don’t know what causes depression. In many cases, an episode of depression arises after using a depressive substance like alcohol. About one-third of a person’s risk for getting depression is inherited.

List the epigenetic mechanisms in major depressive disorder etiology.

-Aversive: prenatal factors, childhood trauma, stress, medical illness, drug abuse (especially in childhood or adolescence).

-Protective: social support, coping, exercise (this is a huge protection, better than placebo in mild to moderate depression).

T or F: Depression is not just feeling sad; your suppression of emotions (happy or sad) is lowered and you have a literal holding down of effect in your brain that gives you no mood and no interest.

T

List the behavioral level, brain network level, and molecular level specifics of MDD etiology.

-Behavioral level: affective, cognitive, and somatic-vegetative symptoms.

-Brain network level: decrease in regional brain volumes, affective-salience circuit, and cognitive control circuit; increase in default mode network (can’t get out of your sadness).

-Molecular level: decrease in neurotransmission and neuroplasticity; increase in stress hormones and inflammation.

Describe drug-induced depression by listing the drug classes, specific drugs, and mechanism of those drugs.

Antiviral

• Efavirenz—>increases pro inflammatory cytokines

Cardiovascular

• Clonidine, methyldopa—>decreases NE output in CNS

• Beta blockers—>typical ADEs similar to some depressive symptoms (beta-blocker blues)

Anticonvulsants

• Phenytoin, phenobarbital—>decrease unbound tryptophan which decreases serotonin

• Topiramate—>increases GABA receptor activity

Corticosteroids

• Prednisone—>increase plasma cortisol levels

Hormonal Agents

• Contraceptives (both E + P and P-only)—>E augments GABA inhibition; P increases monoamine oxidase activity

Retinoic Acid Derivatives

• Isotretinoin—>alters serotonin, NE, and dopamine systems

Summarize the mechanisms that happen in drug-induced depression.

• Increasing inflammatory signaling directly (indirectly with corticosteroids)

• Affecting monoamines like NE and serotonin

• Facilitating GABA (this goes with alcohol)

Describe the monoamine hypothesis of depression.

-This originated from Reserpine, an antihypertensive agent that depletes monoamines (serotonin, dopamine, NE) and causes depression.

-In summary, this hypothesis states that monoamines are dramatically depleted. Depression is not this simple however because monoamines are very interregulated.

What are monoamine systems regulated by?

GABA, steroids, endogenous opioids, nutrition

Describe the neurotrophic hypothesis of depression.

-This is when you have depression secondary to chronic stress and inflammation. You are diverting resources NOT to your brain health and growth, which causes failure in neurite growth (less dendritic sprouts or neurites).

List the steps in the neurotrophic hypothesis of depression.

• Decreased BDNF

• Decreased allopregnalone

  • Increased with stress but overtime it becomes exhausted

1. Glutamate —> BDNF

2. BDNF decreases GABAergic neurons

   1. BDNF normally inhibits GABAergic neurons

3. GABA A/B leads to decreased serotonin and mixed effects NE

Explain the updated monoamine hypothesis of depression.

-This is a failure of homeostatic regulation, you become hypersensitive to NE and pre-synaptic serotonin signaling. Pre-synaptic serotonin is inhibitory and if you are too sensitive to it, then you are failing to perform. The sensitivity comes from having too many receptors on the membrane.

What does long-term treatment with antidepressants change?

• Desensitizes presynaptic serotonin1A receptors

  • Reduced receptors at membrane gives you reduced sensitivity, so NO HYPERSENSITIVITY

• Desensitization to NE which leads to reduced NE receptors at membrane and reduced NE-stimulated cAMP synthesis

• Increases dendritic sprouts, BDNF

Describe the pathophysiology of MDD

On notes pages 17-19

List the DSM-5 criteria for major depressive disorder and persistent depressive disorder.

MUST HAVE 5 OR MORE OF 9 SYMPTOMS (including at least 1 of depressed mood and loss of interest or pleasure) in the same 2 week period.

• Depressed mood (subjective or observed)

• Loss of interest or pleasure

• Change in weight or appetite

• Insomnia or hypersomnia

• Psychomotor retardation or agitation (observed)

• Loss of energy or fatigue

• Worthlessness or guilt

• Impaired consciousness or indecisiveness

• Thoughts of death or suicidal ideation or suicide attempt

List the things included in an assessment for MDD.

• Physical exam

• Basic Labs (CBC, thyroid function, electrolytes)

  • to rule out other primary causes

  • hyper secretion of cortisol and positive dexamethasone suppression tests are correlated with depression and suicide risk

    • REMEMBER: cortisol should normally inhibit its own synthesis.

  • labs that are not well supported: serum glutamate, BDNF, MTHFR, genotype

• Depression scales

• Disease history

• Medication history

• Suicidal ideation

List & describe the depression scales used in an assessment for MDD.

• PHQ-2

  • over the last 2 weeks, how often have you had little interest or pleasure in doing things/feeling down, depressed, or hopeless?

    • ranges from 0 (not at all) to 3 (nearly everyday)

• PHQ-9 (go to this if PHQ-2 score is 3 or greater)

  • 9 questions, all formatted from the DSM-5 criteria

    • ranges from 0 (no days) to 3 (nearly everyday)

Diagnose depression based on someone’s PHQ-9 score.

Minimal depression: 0-4

Mild depression: 5-9 (medications indicated here)

Moderate depression: 10-14

Moderately-severe depression: 15-19

Severe depression: 20-27

Describe the Edinburgh Postnatal Depression Scale (EPDS).

Lists symptoms that are associated with childbirth to evaluate if a mother has postpartum depression. 10 questions (score of 0-3 for each). If a patient scores >10, further evaluation is recommended.

T or F: all drugs for depression work equivalently and patient specific factors will help decide what is best for the patient.

T

Indications for use of SSRIs

• Generalized anxiety disorder

• Panic disorder

• PTSD

• Social anxiety disorder

• Eating disorders

• Premenstrual dysphoric disorder

_________ is an SSRI indicated for OCD.

Fluvoxamine

Explain the MOA of SSRIs

Inhibit the serotonin receptor (SERT) which increases serotonin availability in the synapse.

What ADEs do all SSRIs share?

• Sexual dysfunction

  • highest for all of the classes

• GI (diarrhea, nausea)

• Sleep disturbances

• Serotonin syndrome

Why do SSRIs cause sexual dysfunction?

Excess serotonin in the spinal cord—>no peaks and troughs of serotonin in the spinal cord—>more difficult to achieve an erection and orgasm.

What are the “class warnings” for SSRIs?

• QTc prolongation

• SIADH & hyponatremia

• Fall risk (BEERS List)

• Bleeding

Compare the different SSRIs

Fluoxetine

• Long half life

  • good for stable dosing of the drug, needs a long washout period if discontinuing

• CYP2D6 inhibition

• Self-tapers

Sertraline

• Lowest bioavailability

• Preferred if CV/QT risk

• Most likely to cause diarrhea

Paroxetine

• CYP2D6 inhibition

• Highest withdrawal risk

• Highest anticholinergic effects & sexual dysfunction risk

• Weight gain

Citalopram & Escitalopram

• Citalopram: racemic mixture

• Escitalopram: S-enantiomer of citalopram

• High doses can cause QT prolongation

Explain the MOA of SNRIs

Block serotonin transporter (SERT) and norepinephrine transporter (NET) which increases serotonin and NE availability in the synapse. In the short term increase synaptic levels, in the long-term cause desensitization.

What boxed warning do all antidepressants have?

Suicidal thoughts and ideations for people 24/25 and under. These are greatest during the first few weeks of therapy and first month after discontinuation of therapy.

What is a good counseling point for patients that start out on antidepressants?

They could have a lower low after initiation.

What are the class ADEs for SNRIs?

• HTN/tachycardia

• Sweating

• Sexual dysfunction

• Serotonin syndrome

  • esp. when combined with other serotonergic agents because that would result in vascular constriction

What are the “class warnings” of SNRIs?

• SIADH/hyponatremia

• Fall risk (BEERs list)

• Bleeding

Compare the different SNRIs.

Venlafaxine

• Acts like a SSRI with doses < 150 mg/day

• Has the highest withdrawal risk, QT prolongation

• Used for general anxiety disorder, social anxiety disorder, and panic disorder

Desvenlafaxine

• Active metabolite of venlafaxine

Duloxetine

• Be cautious in renal insufficiency

• Has a risk of hepatotoxcity

Levomilnacipran

• Greater selectivity for NE reuptake inhibition vs serotonin reuptake inhibition

What are the indications for SNRI use?

Everything that SSRIs are indicated for, PLUS:

• Vasomotor symptoms of menopause

• Diabetic peripheral neuropathy

• Fibromyalgia

Antidepressants typically increase ______ availability.

neurotransmitter

Describe bupropion.

MOA: inhibits dopamine transporter and NE transporter to increase DA and NE in the synapse

Warnings: do no use if risk of seizure because this drug has a stimulating effect.

ADEs: dry mouth, weight loss, insomnia (because stimulating effect), lower risk of sexual dysfunction

Uses: tobacco cessation (Zyban), weight management + naltrexone (Contrave)

Metabolism: inhibits CYP2D6

Describe dextromethrophan and bupropion (auvelity)

MOA:

• Dextromethrophan: noncompetitive NMDA receptor antagonist and a weak SERT inhibitor

  • SERT inhibitor comes into play with depression

• Bupropion: DAT/NET inhibitor

Warnings: cytochrome P450 2D6 poor metabolizers need to decrease dose by 50% or will have too much drug in system; 14 day washout period with MAOI.

ADEs: dizziness/falls, nausea, HTN, mania, seizures, suicidal ideation, some abuse risk (because of dopamine action)

Uses: major depressive disorder (improvement seen as soon as 1 week after treatment initiation)

• Prescribed for something quick in dire situations (probably)

Metabolism: dextrorphan via CYP2D6; bupropion is a CYP2D6 inhibitor, which will boost the levels of dextromethorphan

Describe mirtazapine.

MOA:

• Central presynaptic alpha-2 adrenergic antagonist—>increases NE and serotonin in the synpase

  • flood the synapse with NE

• Postsynaptic serotonin 2/3 and H1 antagonist

  • flood with serotonin

  • more specific H1 antagonist at lower doses

ADEs: sedation (more with lower doses vs. higher), weight gain, lower risk of sexual dysfunction (because not affecting serotonin as much).

Uses: elderly with depression, insomnia + depression because of sedative effects

Describe vortioxetine and vilazodone.

MOA: SSRI + 5-HT1A agonist (this is inhibitory pre-synaptic, so increases amount of serotonin that is released and blocking uptake).

ADEs: high risk of nausea with vortioxetine, insomnia, lower risk of sexual dysfunction

Describe trazodone.

MOA: inhibits SERT; blocks 5-HT2A, H1, and alpha-1 adrenergic receptors (lot more side effects due to this)

Warnings: additive QT prolongation

ADEs: sedating, non-habit forming hypnotic

Uses: primarily for insomnia (off-label), need high doses for depression (not really used for this though)

Dose: 50 to 100 mg for insomnia

Describe 2nd generation antipsychotic MOA and uses.

-Modulation of 5-HT and DA activity (all antagonize 5-HT2A)

-More so augmentation agents, often added on to SSRI or SNRI treatments.

List the ADEs of the 2nd generation antipsychotics.

• Metabolic changes (weight gain, increase A1c, lipid abnormalities)

• Extrapyramidal symptoms

• Increased risk of death in dementia patients

Compare the different 2nd generation antipsychotic agents.

Aripiprazole

• Partial agonist at D2, 5-HT1A

• High risk of dose-related akathisia

  • can decrease dose if this happens or switch to different agent in class

Brexpiprazole

• Partial agonist at D2, 5-HT1A

Cariprazine

• Partial agonist at D2, D3, 5-HT1A

• Antagonist at 5-HT2A 5-HT2B

• Falls due to orthostatic hypotension, increased risk of death in dementia patients

• Use caution in patients with renal/hepatic impairment

• Can be used as adjunctive therapy in adults with an inadequate response to antidepressants for treatment of unipolar MDD; bipolar + schizophrenia

Quetiapine XR

• Partial agonist at 5-HT1A

• Antagonist, in addition, at 5-HT27 and D2

• Causes sedation and risk for QT prolongation at high dose

• H1, alpha1?

Olanzapine + (Fluoxetine)

• Antagonist, in addition, at 5-HT2c, D1-4 (low affinity)

• Highest risk for weight gain and hyperglycemia

  • less desired because of this

• H1, alpha1?

• Also has antiemetic effects at 5-HT2C and 5-HT3

Describe cariprazine’s agonist/antagonist activities.

Functional agonist activity when NT levels are low; functional antagonist activity when NT levels are high. This removes the extremes, never going too high or low.

Describe esketamine.

MOA: really unknown, but speculated to have enhanced activity at post-synaptic AMPA receptors to increase neurotrophic signaling and synpatic function, increases BDNF, inhibits depolarization of GABAergic neurons, lowers cortical inhibitory tone

Warnings: C-III controlled substance

ADEs: dissociation (risk of patient not being able to be certain what is real and who they are is who they are), sedation, nausea, vertigo, HTN (increases in systolic and/or diastolic at all therapeutic doses)

Uses: for patients 18 to 65 years old with treatment-resistant depression (failure of at least 2 antidepressants)

Potential advantages: fast onset (immediate effect), few drug interactions, less frequent dosing (nasal dosage form administered by the patient themselves—do this in clinic & stay for 2 hours post-dose just in case of dissociative ADE), if currently considering suicide at a very high risk, can disrupt that with this.

Metabolism: CYP2B6 and CYP3A4

Describe brexanolone & zuranolone.

MOA:

• Brexanolone: synthetic allopregnanolone (positive allosteric modulator of GABA-A and GABA-A-P)

• Zuranolone: positive allosteric modulator of GABA-A

Warnings: risk of misuse (controlled); suicidal ideation <24 yo, do not combine with alcohol/sedatives, unknown if safe to breastfeed on these (must forgo nursing while on med)

ADEs: sedation, dizziness

Uses:

• Brexanolone: post-partum depression (severe cases); administered over 60 h continuous IV

  • do pulse oximetry to check for hypoxia

• Zuranolone: post-partum depression (severe cases); 50 mg QD for 14 days

What is the time to response for antidepressants?

Week 1-2: increased energy, improved sleep, improved appetite.

• Worry about suicide here because more energy to plan

Week 3-4: improved mood, increased interest in activities, decreased feelings of hopelessness/helplessness, increased self care, better concentration/memory

Week 5-8: relief of depressed mood

What is monoamine oxidase? What happens if this is inhibited?

This metabolizes monoamines (doesn’t synthesize them but metabolizes them out of the system). If this is inhibited, then we increase stability of monoamines and have more to pack into vesicles (NE, DA, serotonin, api).

What are the two types of monoamine oxidase? Where are they located?

A & B. Both in the brain, A is also important in digestion.

T or F: MAOIs have very extensive drug-drug interactions, so they are really only used when there is no response to other treatments.

T

Explain the MOA of MAOIs.

Non-selective inhibition of the MAO enzyme that leads to increased levels of epi, NE, DA, and 5-HT.

List the ADEs for MAOIs.

Serotonin syndrome, CNS stimulation, HTN

List the “class warnings” for MAOIs.

Avoid other serotonergic drugs, avoid drugs that increase epi, avoid tyramine-rich foods

List the class PK parameters for MAOIs.

These have an extensive first-pass and inhibition of MAO in the gut.

What is the outlier of MAOIs?

Selegiline

• Selectively inhibits MAO-B at lower doses (not as specific at high doses)

• Less concern with tyramine-rich foods

• Metabolite of note: methamphetamine

  • increases risk of acting as a stimulant and misuse

Which MAOIs are non-selective?

Isocarboxazid, Phenelzine, Tranylcypromine

Describe the basics of TCAs.

MOA: inhibits SERT and NET on presynaptic neuron. Structurally similar to muscarinic and histamine antagonists which leads to the side effects.

• Myocardial NA+ channel antagonism

  • Could have arrhythmias at high doses and lower seizure threshold

• Anticholinergic effect

• Alpha-adrenergic antagonism

  • causes orthostatic hypotension

• GABA antagonism

What are the indication for use of TCAs?

• Major depressive disorder

• Fibromyalgia

• Migraine prophylaxis

• Diabetic peripheral neuropathy

  • because of NE

• Postherpetic neuralgia

Describe the overdose risk of TCAs.

TCAs are narrower therapeutic index drugs.

• Toxic dose of 10 to 20 mg/kg

• Effect: coma, convulsions, cardiac arrhythmia

• Onset: 30 to 40 minutes after ingestion, toxicity by 2 hours.

Describe the common class features of TCAs.

ADEs: orthostatic hypotension, anticholinergic effects, weight gain, sedation

Warnings: QTc prolongation, fall risk (BEERs list), lethal in overdose

PK: all need CYP2D6 to become inactive so if poor metabolizer then will have too high of serum concentrations in the blood.

List the unique factors of the different TCAs.

Amitriptyline

• Tertiary amine

• More balanced NE and serotonin activity

• More side effects

Doxepin

• Tertiary amine

• More balanced NE and serotonin activity

• More side effects

• Used as a hypnotic, antihistamine

Nortriptyline

• Secondary amine

• More selective for NE

• Less anticholinergic than tertiary amines

  • Less side effects because metabolite of amitriptyline

• Use this if patient is CYP2C19 atypical

Clomipramine

• Tertiary amine

• More selective for 5-HT

Explain what to do if a patient is a CYP2D6 poor metabolizer and wants to be started on a TCA.

*4, 5, 6

Avoid TCA due to high side effects

Explain what to do if a patient is a CYP2D6 *N and wants to be started on a TCA.

*N—>extra copies, extra action! (not that the enzyme is really great, but just that you have extra of it)

Avoid TCA due to lack of efficacy

Explain what to do if a patient is a CYP2c19 poor metabolizer and wants to be started on a TCA.

*2, 3

Choose nortriptyline or despiramine

Explain what to do if a patient is a CYP2c19 ultra rapid metabolizer and wants to be started on a TCA.

*17—>super sufficient

Choose nortriptyline or despiramine

SSRIs are highly ______, which helps get them into the CNS.

lipophilic

SSRIs have low affinity for _________

histamine, acetylcholine, and alpha-adrenoceptors

Describe fluoxetine’s metabolism.

• Metabolized to norfluoxetine mostly by CYP2D6.

  • Quences CYP2D6, uses it all up and this is an issue if any other drugs are being metabolized by CYP2D6.

• Fluoxetine half-life is 1-6 days (longer if chronic use)

• Norfluoxetine half-life is 4-16 days

• Glucoronidated for excretion via UGT

Recommend an appropriate SSRI dose for a patient that is a CYP2D6 poor metabolizer.

*4, 5, 6

Leads to higher concentrations and more side effects.

Consider a 50% reduction in fluvoxamine and paroxetine.

Recommend an appropriate SSRI dose for a patient that is a CYP2D6*N

*N—>extra copies, extra action!

If on paroxetine, select an alternative drug.

Leads to lower plasma concentrations and treatment failure.

Recommend an appropriate SSRI dose for a patient that is a CYP2c19 poor metabolizer.

*2, 3

Leads to higher concentrations and more side effects.

Consider a 50% reduction in escitalopram.

Recommend an appropriate SSRI dose for a patient that is a CYP2c19 ultra rapid metabolizer.

*17

If on escitalopram, consider an alternative option.

When comparing the structures of desvenlafaxine and venlafaxine, what is the difference?

Desvenlafaxine is the removal of a single carbon group.

_________ is the active enantiomer of milnacipran.

Levomilnacipran

Duloxetine has elevations in ______, which is likely due to a _______.

ALT; toxic metabolite/byproduct

What are the treatment goals for depression?

-Remission: few to no remaining symptoms (adjusted back to “normal” life)

-Response: 50% reduction in symptoms from baseline

Why is immediate relief not saw with antidepressants?

Receptors need to be desensitized and downstream effects are occurring, such as remodeling and reconnection of neurons.

List & describe the different phases of antidepressant therapy.

1. Acute phase: symptom remission, 6-12 weeks.

2. Continuation phase: relapse prevention, 4-9 months.

3. Maintenance phase: prevention of future episode, 12-36 months.

What is the duration of therapy with antidepressants?

• With your first depressive episode, treatment should continue for at least 4 to 9 months after response is achieved.

• Risk of recurrent depression:

  • <40 years old and 2 or more previous depressive episodes OR

  • 3 or more previous depressive episodes

• If patient meets risks for recurrent depression, consider indefinite treatment (could be 1.5 years, could be lifelong)

What are some non-pharmacological options in the treatment of depression?

• Psychotherapy

• Electroconvulsive therapy (ECT)

  • This is done in the hospital and you basically get zaps of energy in your brain.

  • This is reserved for refractory cases and requires anesthesia because it is a bit more invasive.

  • 6 to 12 sessions annually.

  • Can cause retrograde amnesia.

• Transcranial magnetic stimulation (TMS)

  • Magnetic impulses delivered to targeted brain areas to reset the circuitry of your brain.

  • Less invasive

• Exercise

What are the first line options for antidepressant selection?

1. SSRIs

2. SNRIs

3. Bupropion

4. Mirtazapine

5. Vortioxetine

_______ & ______ have largely fallen out of favor for depression therapy. List the reasons why.

TCAs and MAOIs

TCAs

• Not selective and have off-target effects (anti-cholinergic effects, more sedation, orthostatic hypotension)

• Lethal in overdose (> 20 mg/kg)

  • could cause cardiac arrhythmias at those doses.

• Better choice if there are other co-morbidities

MAOIs

• Drug & food interactions can cause hypertensive crises that could be fatal.

• Better if not responding to other agents.

• Can’t be used with other antidepressants.

What are some monitoring/counseling points for SSRIs?

Citalopram & Escitalopram: QTc prolongation

Fluoxetine: avoid use in hepatic impairment due to long half-life; is stimulating (structurally similar to amphetamine)

Paroxetine: avoid abrupt discontinuation due to potential for withdrawal syndrome; strong anticholinergic and antihistaminic properties; causes weight gain and has a slow half-life

Sertraline: diarrhea

Fluvoxamine: only FDA approved for OCD

What are some monitoring/counseling points for SNRIs?

Venlafaxine: increases blood pressure; avoid abrupt discontinuation due to withdrawal symptoms; acts as a SSRI at doses < 150 mg daily

Duloxetine: may cause hepatotoxicity, so don’t use with alcohol use disorder

Desvenlafaxine: active metabolite of venlafaxine, has no metabolism through liver for activation.

Levomilnacipran: stronger inhibitor of NE reuptake, but no greater efficacy; has no metabolism through liver for activation.

What are some monitoring/counseling points for misc. agents?

Mirtazapine: sedation higher at lower doses because more selective for histamine receptors; causes weight gain

Bupropion: avoid with seizure history because can be stimulating (not good combo if patient also has anxiety)

SSRI + Vortioxetine: more nausea than other SSRIs

SSRI + Vilazodone: must be taken with food to ensure adequate absorption

What are augmentation options for depression?

• Bupropion

• 2nd generation antipsychotics

  • more for bi-polar/schizophrenia, not for monotherapy

• Thyroid hormone (T3)

• Lithium

  • bipolar drug but some data that it can be used in depression.