T2 EX5 L1 (MEDCHEM ANTIDEPRESSANTS & ANXIOLYTICS) (JINWAL)

Diagnostic criteria for major depressive disorder?

SIGECAPS Questionnaire - Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicide

At least 5 symptoms must be consistently present over a 2-week period

T/F: Depression is associated with significant functional disability, morbidity, and mortality.

True

Monoamine hypothesis of major depressive disorder

A deficiency or imbalances in the monoamine neurotransmitters (serotonin, norepinephrine, dopamine) causes depression

Based on the monoamine hypothesis of MDD, how can we ameliorate depression

Increasing 5-HT and NE neurotransmission

Per the monoamine hypothesis of MDD, a ___________ synaptic concentration of 5-HT and/or NE causes depression.

A. Increased

B. Decreased

B. Decreased

Give me the rundown on the hypercholinergic hypothesis of depression

Hyperactivity of cholinergic system + excessive neuronal nicotinic acetylcholine receptor activity (nACHR) -> depression

What drugs are used to treat MDD according to the hypercholinergic hypothesis of depression?

Bupropion

Nicotinic transdermal patch

Give me the rundown on the postsynaptic receptor sensitivity hypothesis

Hypersensitivity of postsynaptic receptors due to low conc. in synaptic cleft -> decreased sensitivity and decreased number of receptors over time -> depression

Give me the rundown on the permissive hypothesis of MDD

The balance between NE and 5-HT in regulating mood and not the absolute levels of the neurotransmitters

Give me the rundown on the hormonal hypothesis of MDD

Hypothalamus-pituitary-adrenal axis (HPA): elevated CRH levels, corticosteroids modulate 5-HT synthesis, metabolism, and uptake

Neuroendocrine system: abnormal thyroid function test (low T3/T4)

Serotonin and norepinephrine regulate... (six)

1. Mood

2. Sleep-wake cycle

3. Motivation

4. Reward

5. Cognitive processing

6. Other physiological processes

Serotoninergic projections to the forebrain modulate... (three)

1. Mood

2. Cognition

3. Neuroendocrine function

The noradrenergic system modulates... (five)

1. Vigilance

2. Stress responses

3. Neuroendocrine function

4. Pain control

5. Sympathetic nervous system activity

Precursor to serotonin?

Tryptophan

Norepinephrine synthesis pathway? (three steps)

Tyrosine -> L-DOPA -> Dopamine

Which enzyme oxidizes tyrosine to L-DOPA?

Tyrosine hydroxylase

T/F: For all monoamines, the 1st synthetic step is rate-limiting.

True

T/F: The rate-limiting step enzymes involved in monoamine synthesis are regulated by feedback inhibition via autoreceptors located presynaptically.

True

Role of VMAT?

Transport 5-HT into vesicles (nonspecific)

Role of reserpine?

Bind irreversibly to VMAT, inhibits packaging of monoamine NTs into vesicles

Role of SERT/NET?

Serotonin/NE reuptake transporters

Recycle 5-HT/NE from extracellular space back into presynaptic terminals

5-HT is degraded by what enzyme?

Monoamine oxidase

Bonus points: COMT, but not so important for MDD

Two isoenzymes of MAO?

MAO A

MAO B

MAO-A preferentially deaminates... (four)

1. Serotonin

2. Norepinephrine

3. Epinephrine

4. Dietary vasopressors i.e. tyramine

MAO-B preferentially deaminates... (two)

Dopamine

Phenylethylamine

Four subclasses of MAO inhibitors?

Hydraxines

Non-hydraxines

Isocarboxazid

Selegiline

MOA of hydraxine MAOIs? (plus an example)

Phenelzine

Irreversible MAOI

MOA of non-hydraxine MAOIs? (plus an example)

Tranylcypromine

Irreversible MAOI

MOA of isocarboxazid MAOIs? (plus 3 examples)

Moclobemide, befloxatone, brofaomine

Reversible MAOI

Benefit of patch formulation for selegiline?

Less tyramine toxicity

Clinical applications for MAOIs?

Atypical depression OR non-responsive to other antidepressant therapy

MOA of MAOIs? (in general) (in detail)

Block deamination of monoamines by inhibiting the functional flavin moiety of MAO; increase available 5-HT and NE in cytoplasm of presynaptic neurons, which leads to increased uptake and storage of 5-HT and NE in synaptic vesicles and leakage into the extracellular space

Rate limiting enzyme in 5-HT synthesis?

Tryptophan hydroxlase

Rate limiting enzyme in NE synthesis?

Tyrosine hydroxylase

Adverse effects associated with MAOIs?

Systemic tyramine toxicity from foods -> uncontrolled catecholamine release -> hypertensive crisis

Headache, tachycardia, nausea, cardiac arrhythmia, stroke, etc.

Cardiac effects

Contraindications associated with MAOIs?

Concomitant use of sympathomimetic drugs, other MAOIs, L-DOPA, L-tryptophane, pretty much everything

CI in heart failure, liver disease

Explain the mechanism by which MAOIs can cause hypertensive crises

Block tyramine metabolism -> tyramine in circulation -> release of norepinephrine -> hypertension

Tyramine-containing food/drinks examples?

Fermented foods and drinks (wine, beers)

Aged cheese

Cured meat

Sauerkraut

Avocados?

Pickled meat or fish too

Secondary amine TCAs? (two)

Desipramine

Nortriptyline

MOA of secondary amine TCAs

Inhibit reuptake of 5-HT and NE from synaptic cleft

Block 5-HT and NE reuptake transporters

Preferentially inhibit NET to inc. NE

Desipramine dec. a1 adrenoceptors, desensitize a2 autoreceptors -> equilibration of NE system

Clinical applications of secondary amine TCAs?

Second-line for depression

Usable in pain, fatigue, etc.

Adverse effects associated with secondary amine TCAs?

Heart block (abnormal rhythm)

Cardiac arrhythmia

Orthostatic hypotension

Myocardial infarction

Explain how secondary amine TCAs can precipitate seizures

Binds to Na+ channels

Explain how secondary amine TCAs can cause urinary retention

Muscarinic blockage

Contraindications associated with secondary amine TCAs?

Concomitant use of MAOIs

Cardiac conduction system defects

Patients recovering from MI

Tertiary amine TCA examples? (four)

Clomipramine

Imipramine

Doxepin

Amitriptyline

T/F: Tertiary amine TCAs are not selective for any of the reuptake transporters.

True

Explain why tertiary amine TCAs have narrow therapeutic windows and many adverse effects

Non-selective, and so they bind to many neuro-receptors

Can cause many problems

T/F: Tertiary amine TCAs preferentially inhibit SERT, as opposed to NET.

False; non-selective, inhibit both SERT and NET.

Adverse effects associated with tertiary amine TCAs? (many)

Pharmacodynamic effects at...

H1

Muscarinic

A1-adrenergic

receptors

Blocks these receptors

Adverse effects associated with muscarinic receptor antagonism? (five)

1. Blurred vision

2. Dry mouth

3. Impaired memory

4. Constipation

5. Urinary retention

Adverse effects associated with dopaminergic (D2) receptor antagonism? (three)

1. Extrapyramidal movement disorders

2. Prolactinemia

3. Sexual dysfunction

Adverse effects associated with a1-adrenergic receptor antagonism? (two)

1. Postural hypotension, dizziness

2. Reflex tachycardia

Adverse effects associated with histaminergic (H1) receptor antagonism? (four)

1. Sedation

2. Drowsiness

3. Weight gain

4. Hypotension

T/F: SSRIs are first-line treatment drugs for MDD.

True

MOA of SSRIs?

Selectively inhibit reuptake of serotonin

Increase synaptic serotonin levels

Can also cause increased 5-HT receptor activation and enhanced postsynaptic responses

T/F: SSRIs selectively inhibit SERT but have a moderate affinity for NET/DAT.

False; minimal or no affinity for NET/DAT.

SSRI examples? (six)

Fluoxetine (Prozac)

Fluvoxamine (Luvox CR)

Paroxetine (Paxil)

Sertraline (Zoloft)

Citalopram (Celexa)

Escitalopram (Lexapro)

Clinical applications of SSRIs? (many)

Depression

Anxiety

OCD

PTSD

Panic disorders

Bulimia nervosa

Adverse effects associated with SSRIs? (two severe, several examples of more common less severe)

1. Serotonin syndrome (concomitant MAOI use) -> hyperthermia, muscle rigidity, myoclonus, rapid fluctuation in mental status and vital signs

2. Mania in bipolar patients

3. Sexual dysfunction, GI distress, vasospasm, sweating, anxiety etc.

Desipramine class?

Secondary amine TCA

Contraindications associated with SSRIs?

Concomitant MAOI use

Washout period recommended when transitioning from MAOI to SSRI?

10-14 days washout to allow regeneration of MAOI

SNRIs examples? (five)

1. Venlafaxine

2. Desvenlafaxine

3. Duloxetine

4. Milnacipran

5. Levomilnacipran

Clinical applications for SNRIs?

Depression

Anxiety

Pain

Fibromyalgia

Adverse effects associated with SNRIs?

May exacerbate mania/depression

Hypertension

Weight loss

GI stuff

Tachycardia

Hyponatremia

MOA of SNRIs?

Blocks SERT/NET in a concentration dependent manner

Contraindication associated with SNRIs?

MAOIs

MOA of NDRIs?

Norepinephrine and dopamine reuptake inhibitors

MOA of bupropion?

DA and NE reuptake inhibitor; induces release of DA and NE, and non-competitively antagonizes nAChR

Clinical applications of bupropion? (three)

1. Depression

2. Smoking cessation

3. Insomnia

Adverse effects associated with NDRIs?

Tachyarrhythmia

Hypertension (especially with NRT)

May exacerbate depression, mania

Liver failure

Hypotension

Blurred vision

Contraindications associated with NDRIs? (three)

1. Concomitant use of MAOIs

2. Patients undergoing abrupt discontinuation of alcohol or sedatives (including BZPs)

3. Seizure disorders and eating disorder (lowers seizure threshold)

Serotonin and a2-adrenergic receptor antagonist example?

Mirtazapine

MOA of mirtazapine?

Antagonizes 5-HT2 and 5-HT3 receptors as well as histamine receptors

Enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic a2-adrenergic autoreceptors and heteroreceptors

Clinical applications for mirtazapine? (three I guess unique scenarios?)

1. MDD (unipolar)

2. Effective in the elderly (65+)

3. Better tolerated than paroxetine?

T/F: Mirtazapine contraindicated in patients receiving linezolid or IV methylene blue.

True

Antidepressants with mixed serotonergic effects (three)

1. Trazadone

2. Vilazodone

3. Vortioxetine

MOA trazadone?

Serotonin antagonist and reuptake inhibitor

MOA vilazodone

Inhibits reuptake of 5-HT, partial agonist of 5-HT 1a

MOA vortioxetine (Trintellix)

Inhibits 5-HT reuptake, agonist of 5-HT 1z, partial agonist of 5-HT 1b, antagonist of 5-HT3, 5-HT7

Adverse effects associated with trazodone? (many)

Mainly GI

Adverse effects associated with volazodone?

GI + dizziness, insomnia

Adverse effects associated with vortioxetine (Trintellix)?

GI + dizziness, less sexual dysfunction than SSRIs/SNRIs

Mood stabilizers examples? (three)

1. Carbamazepine

2. Valproic acid

3. Lithium carbonate

MOA lithium?

Reduce neuronal activity in the brain by depleting the inositol pool available for re-synthesis

Increases 5-HT, but decreases NE and DA neurotransmission. Inhibits cAMP production

Clinical applications of lithium?

Bipolar affective disorder (manic depression)

Can be substituted by some antiepileptic drugs

Goal serum lithium concentration range? (mmol/L)

0.6-1.2 mmol/L

Adverse effects associated with lithium?

Vomiting

Renal failure

Neuromuscular dysfunction

Ataxia

Confusion

Delirium

Lots of bad stuff

Hypothyroidism weakness?

Hyperkalemia

Seizures?

Treatment options available for postpartum depression? (two)

1. Brexanolone

2. Zuranolone

T/F: Brexanolone administered IV.

True

Side effects associated with brexanolone? (one big one really)

Excessive sedation, sudden loss of consciousness

Side effects associated with zuranolone? (one big one)

Decreased ability to drive or do other dangerous activities

Talk to me about esketamine?

S-isomer of ketamine, NMDA receptor antagonist

Higher affinity than R-isomer

FDA approved for intranasal administration in treatment resistant depression

Clinical applications for esketamine

In conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults

Adverse effects associated with esketamine?

Ketamine side effects

MOA of brexanolone/zuranolone?

Positive allosteric modulators of the GABA-A receptors; hormonally derived

Describe anxiety disorders

Excessive fear and anxiety and related behavioral disturbances

T/F: Fear in anxiety disorders is more often associated with surges of autonomic arousal necessary for fight or flight, thoughts of immediate danger, and escape behaviors.

True

T/F: Anxiety in anxiety disorders is more often associated with muscle tension and vigilance in preparation for future danger and cautious or avoidant behaviors.

True