Antidepressants And Mood Stabilizers

Question 1

What are some other indications for antidepressants?

Answer 1

Nicotine withdrawal (bupropion)
Enuresis (imipramine)
Diabetic peripheral neuropathy, fibromyalgia, and chronic MSK pain (duloxetine)
Stress incontinence (duloxetine)

Question 2

What are serotonin-selective reuptake inhibitors (SSRI’s)?

Answer 2

They selectively inhibit pre-synaptic reuptake of serotonin via SERT
Result in enhanced, prolonged serotonergic neurotransmission to post-synaptic receptors

Question 3

Name SSRI’s

Answer 3

Citalopram
Escitalopram
Fluoxetine
Paraoxetine
Sertraline
Vilazodone
Vortioxetine

Question 4

Describe common side effects of SSRI’s

Answer 4

As a class, much less impact on histamine, muscarinic, and adrenergic receptors. Fewer SE vs TCA’s
Examples:
CNS (sedation or insomnia/agitation/nervousness)
Sexual dysfunction (libido/impotence)
Weight gain (adults)/weight loss (mild; adolescents)
Acute withdrawal reactions (like with all categories): flu-like symptoms (malaise, lethargy, generalized aches)

Question 5

Describe rare (toxic) side effects of SSRI’s

Answer 5

QT prolongation
Hyponatremia

Serious:
Serotonin syndrome
-Increased risk when given concurrently with other serotonin-affecting agents
-sweating, hyperreflexia, akathisia/myoclonus, shivering/tremors

Suicidality (attempts/completions)
-highest risk in children/adolescents/young adults

Question 6

What precipitates neuroleptic malignant syndrome?

Answer 6

Dopaminergic agents (antipsychotics)

Question 7

What are identical features of neuroleptic malignant syndrome and serotonin syndrome?

Answer 7

HTN, tachycardia, tachypnea, hyperthermia (>40C)

Hypersalivation

Question 8

What are overlapping features of neuroleptic malignant syndrome and serotonin syndrome?

Answer 8

Diaphoresis, pallor (neuro)
Coma
Stupor and alert (neuro); agitation (sero)
Lead-pipe rigidity in all muscle groups (neuro); increased tone esp in LE (sero)

Question 9

What are distinct features of neuroleptic malignant syndrome and serotonin syndrome?

Answer 9

Neuro:
Hypo-reflexia
Normal pupils
Normal or decreased bowel sounds

Serotonin:
Hyper-reflexia
Clonus
Dilated pupils
Hyperactivity of bowel sounds

Question 10

Describe drug-drug interactions with SSRI’s

Answer 10

High risk of drug-drug interactions

• *Most is fluoxetine (broad and strong inhibitor)
• *Least is citalopram and sertraline (mild inhibitors)

Question 11

What are serotonin-noradrenergic reuptake inhibitors (SNRI’s)? Tertiary vs secondary amine TCA’s?

Answer 11

Include TCA’s
Selectively inhibit presynaptic reuptake of serotonin via SERT and norepinephrine via NET
Tertiary TCA’s inhibit both NE/5-HT relatively equally (except clomipramine/amitriptyline, which impact 5-HT>NE)
Secondary TCA inhibit NE>5-HT

Question 12

Name SNRI’s

Answer 12

All TCA's
Desvenlafaxine
Duloxetine
Venlafaxine
Levomilnacipran

SNRI’s + dopamine antagonist: amoxapine

Question 13

**Only TCA-based SNRI’s have impact on what 3 key non-efficacy-related receptors?

Answer 13

Histamine (H1)
Muscarinic (cholinergic)
Alpha1 (adrenergic)

Question 14

Name the tertiary amine TCA’s

Answer 14

amitriptyline
Clomipramine
Doxepin
Imipramine

Question 15

Name the secondary amine TCA’s

Answer 15

Amoxapine
Desipramine
Nortriptyline

Question 16

*What are the 3 key TCA system side effects?

Answer 16

CV (alpha):
Tachycardia, orthostatic hypotension, dysrhythmias

Anticholinergic (muscarinic):
Dry mouth, urinary retention/constipation, blurred vision/increased IOP

CNS (histamine):
Sedation/fatigue, dizziness/seizures

Question 17

What are the 3 C’s from toxic ingestion of TCA’s?

Answer 17

Coma
Cardiotoxicity (conduction abnormalities) (quinidine-like effect)
Convulsions

Question 18

What do class 1 antiarrhytmics do?

Answer 18

In ventricular cells, slows phase 0 depolarization and conduction velocity (slows conduction), alters QRS complex

Subclass-specific changes in repolarization (Na+ channel blockade)
Class IA: moderate Na+ channel block and prolonged repolarization
Class IB: mild Na+ channel block and shortened repolarization
Class IC: marked Na+ channel block and no change in repolarization

Question 19

Describe side effects of non-TCA SNRI’s

Answer 19

Relatively similar to SSRI’s with less risk (in general) of sexual dysfunction
Higher with venlafaxine

Question 20

What are serotonin-adrenergic receptor antagonists (SARAs)?

Answer 20

Trazodone and nefazodone act like SSRI’s and also selectively block post-synaptic alpha1 receptors on noradrenergic (NE) neurons and post-synaptic 5-HT2A (and H1 blockade (sedation))

Mirtazapine selectively blocks presynaptic alpha2 receptors on NE and 5HT neurons. Blocks postsynaptic 5HT 2a/2b/3 receptors, no SERT/NET activity. H1 blockade (sedation)

Question 21

What are side effects (H1/alpha1) of SARA’s?

Answer 21

CNS (sedation) (most with trazodoe/mirtazapine)
Orthostatic hypotension (most with trazodone)
Weight gain (most with mirtazapine)

Question 22

What are noradrergic-dopamine reuptake inhibitors (NDRI’s)?

Answer 22

Bupropion

Selectively inhibits presynaptic reuptake of NE via NET and dopamine via DAT. Results in enhanced, prolonged NE and DA neurotransmission to postsynaptic receptors

May also enhance presynaptic release of NE and DA. Also shown to have effects on VMAT2

Question 23

What are side effects of NDRI’s?

Answer 23

Agitation/insomnia (stimulating) (hypertension, tachycardia, tremors)
Weight loss
**Seizures (dose-dependent or those at risk)

Question 24

What are monoamine oxidase inhibitors (MAOI’s)?

Answer 24

Inhibition of MOA (A/B) increases levels of monoamines in neuronal vesicles and increase amounts of NE, 5-HT, and DA released
All oral agents are irreversible (avg 14 days recovery. Tranylcypromine shortest at 3-5 days)
All agents Nonselective except selegiline (B-selective, becomes non-selective at high doses; antidepressant form is patch)

Tranylcypromine (stimulant analog) increases neurotransmitter release

Question 25

Name MAOI's

Answer 25

Isocarboxazid Phenelzine Selegiline Tranylcypromine

Question 26

What are side effects of MAOI's?

Answer 26

Orthostatic hypotension Sexual dysfunction Weight gain Insomnia/agitation/nervousness

Question 27

Describe drug-drug interactions of MAOI's with 5HT/NE affecting drugs

Answer 27

Some anti-hypertensives, amphetamines, SSRI's/TCAs/SNRI's *2 week wash-out period (fluoxetine; 5 wks) Risk of serotonin syndrome Risk of hypertensive crisis

Question 28

*The major risk of MAOI's is hypertensive crisis. Explain

Answer 28

Non-selective MAOI's inhibit MAO-A necessary in GI for tyramine metabolism Increased tyramine can induce significant catecholamine release and hypertensive crisis Selegiline (especially topical) minimally blocks MAO-A in GI tract at low doses; blockade increased to significant-blockade at high doses Dose-dependent inhibition Low risk with low dose selegiline patch

Question 29

*What are the signs and symptoms of hypertensive crisis due to MAOI's?

Answer 29

``` Severe headache Nausea/vomiting Sweating/severe anxiety Nosebleeds Tachycardia Chest pain Changes in vision Shortness of breath Confusion ```

Question 30

What are examples of tyramine containing foods/beverages?

Answer 30

Aged cheeses esp. those not pasteurized Fava/broad/soy beans or snow peas Fermented or pickled eats/poultry/fish (lox/salmon/herring) Processed, pickled, or cured meats/sausages (bologna, pepperoni, salami, summer sausage) Tap beer/beers not pasteurized, red wine, sherry, and liqueurs Yeast or protein extracts/spreads Over-ripe or spoiled fruit/foods Soy/fish/shrimp sauces

Question 31

Describe treatment modalities of depression

Answer 31

``` Pharmacotherapy (antidepressants, antipsychotics, mood stabilizers) Psychosocial therapies (pt and family) Electroconvulsive therapy (ECT) Deep brain stimulation (DBS) Transcranial magnetic stimulation (TMS) Light therapy ```

Question 32

What are the 5 R's for general antidepressant efficacy?

Answer 32

1. Response =/> 50% reduction in symptoms from baseline Not well. Just better. Partial response =/>25% reduction but <50% in symptoms from baseline 2. Remission = symptom-free (very low-to-no symptoms). Not only better but well. Healthy state of functioning 3. Recovery = 2-6 months of ongoing remission. Not cured 4. Relapse = return of symptoms after remission but before recovery 5. Recurrence = return of symptoms after recovery

Question 33

Describe general antidepressant efficacy

Answer 33

All agents effect but take 3-8+ weeks depending on disease severity/duration and dose. Majority see 50% reduction in first 3-4 weeks (response). Goal is remission/recovery. Minority reach remission on single agent. If pt does not respond in 8 weeks, switching to different MOA reasonable. If partial response, other drugs may be added. Mono-therapy with antidepressants only for unipolar depression, not depressive phase of bipolar disorder

Question 34

**Describe treatment of depression

Answer 34

ALL antidepressants either are or can be associated with withdrawal syndrome. Slow titration downward is recommended for most agents (t1/2) Symptoms include dizziness, headaches, nervousness, nausea, insomnia, and flu-like aches Lower risk with long-acting agents (fluoxetine, amitriptyline), yet even possible with XR-type products (venlafaxine xR)

Question 35

Describe proposed mood stabilizer action of Lithium

Answer 35

Inhibits calcium-dependent and depolarization-provoked release of NE & DA Inhibits inositol monophosphatase leading to decreased cerebral inositol (valproate decreases inositol via inhibition of myoinositol-1-phosphate synthase) Decreases functioning of protein kinases in brain like PKC (valproate, too) Long-term Li+ decreases cytoplasm-to-membrane translocation of protein kinase-C and reduces PKC stimulation-induced release of 5-HT (disrupts prefrontal cortical regulation of behavior. Valproate, too) Reduces expression of MARCKS protein (valproate, too) Inhibits GSK-3B activity (Increases B-catenin)(valproate, too) Facilitates 5-HT release (augments effects of antidepressants)

Question 36

What is the major side effect of lithium? Describe

Answer 36

Polyuria (polydipsia) Clinical picture of *nephrogenic diabetes insipidus Lithium is a monovalent ion and handled by kidneys similar to Na+/K+. Li+ competes with Na+ for kidney reabsorption. chronic Li+ ingestion can lead to resistance to ADH, resulting in in polyuria/polydipsia. Li+ enters principal cells of collecting duct via Na+ channels in luminal membrane. Accumulation in these cells interferes with ADH-mediated effects

Question 37

What are other side effects of Lithium?

Answer 37

Tremor Mental confusion/dizziness/sedation (take at bedtime) Thyroid goiter (hypothyroidism) (inhibits iodination of thyroid hormone) Leukocytosis (stimulates M-CSF, increasing granulocytes) Seizures and serotonin syndrome (rare but can be severe)

Question 38

**Describe drug interactions of lithium wth other agents impacting Na+/K+

Answer 38

Diuretics via preferential Na+ loss and Li+ reabsorption, especially thiazides (hydrochlorothiazide) ACEIs especially lisinopril (renally eliminated) NSAIDs through alteration of renal perfusion Narrow therapeutic agent (monitored at trough phase) 0.6-1.0 mEq/mL (up to 1.5 mEq/mL in refractory cases)

Question 39

What are indications for lithium?

Answer 39

Acute & maintenance treatment of mania/bipolar I disorder Augmentation in unipolar depressive pts with inadequate response to antidepressant therapy Off label: reduced risk of suicide and all-cause mortality in pts with mood disorders

Question 40

Describe uses/indications for mood stabilizers (anti-seizures) agents

Answer 40

Divalproex used for acute bipolar I (with or without psychotic features): 50-125 McGill/mL Carbamazepine used for acute and maintenance treatment of acute mania and mixed episodes (bipolar I). **Major CYP450 inducer** Lamotrigine used for maintenance of bipolar disorder I and II