Antidepressants and Treatment of Bipolar Disorder

Question 1

Indications for Antidepressant Agents (9)

Answer 1

1. MDD (17% lifetime prevalence in the US): can be associated with chronic pain; increased risk of CAD, DM, and stroke; MDD with other illness decreases quality of life and prognosis of effective treatment
2. Panic disorder
3. GAD
4. PTSD
5. OCD
6. Neuropathic pain, fibromyalgia
7. PMDD
8. Menopause symptoms
9. Stress incontinence

Question 2

General Principles of Treatment with Antidepressants (3) - Part 1

Answer 2

1. Before beginning therapy, rule out other medical causes of depression and drug-induced depression
2. Goals of treatment:
   A. Acute phase, 6-12 wks - resolution of current symptoms (remission)
   B. Continuation phase, 4-9 mo - eliminate residual symptoms or prevent relapse
   C. Maintenance phase, 12-36 months/may be lifelong depending on risk factors - prevention of further (separate) episodes of depression (recurrence)
3. Patient Adherence Concerns
   A. ADRs of antidepressants may occur prior to therapeutic effects
   B. Adherence to the treatment plan is essential for successful outcome

Question 3

General Principles of Treatment with Antidepressants (3) - Part 2

Answer 3

1. Antidepressants have similar efficacy in MDD
   A. Efficacy is similar between classes
   B. Selection of agent is driven by age, ADRs, and past history of response
2. All antidepressants carry risk on increased suicidality, especially pediatric patients
3. Choosing an initial drug is based upon:
   A. Patient preference
   B. Nature of prior responses to medication
   C. Safety, tolerability, and anticipated side effects
   D. Co-occurring psychiatric or general medical conditions
   E. Pharmacokinetic properties
   F. Cost

Question 4

Pathophysiology of MDD (3)

Answer 4

1. Monoamine hypothesis: MDD is associated with deficit in monoamine signaling in cortical and limbic regions. Antipsychotic agent popular in the 1950s, Reserpine, depleted monoamine NTs from secretory vesicles and was noted to also cause depression. Antidepressants increase levels of monoamines.
2. Glutamatergic hypothesis: Esketamine (an NMADAR antagonist) has been approved for the treatment of MDD.
3. Neurotrophic hypothesis: Depression is associated with the loss of neurotrophic support (low BNDF). Treatment of depression increases neurogenesis and synaptic connectivity.

Question 5

Why does the time-course of antidepressant action challenge the monoamine hypothesis?

Answer 5

Full antidepressant action often requires treatment for 6 weeks or longer. At the beginning of treatment, there is an acute, paradoxical mechanism of action involving auto-receptors (5-HT1A, 5-HT1B, alpha-adrenergic 2). Acute treatment activates inhibitory auto-receptors, which REDUCES the firing rate of serotonergic and noradrenergic neurons, by decreasing the amount of NT released.
Chronic treatment eventually down-regulates the inhibitory auto-receptors and the firing rate of serotonergic and noradrenergic neurons increase. The time-course of down-regulation is consistent with therapeutic response in patients. Delayed onset of action poses significant challenges to patient adherence. The initial reduction in monoamines during the start of treatment may explain the increased suicide risk.

Question 6

Classes of Antidepressant Agents (5)

Answer 6

1. Selective-Serotonin Reuptake Inhibitors (SSRIs)
2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
3. Tricyclic Antidepressants (TCAs)
4. Monoamine Oxidase Inhibitors (MAOIs)
5. Atypical Antidepressants

Question 7

Compare Typical vs. Atypical Antidepressants

Answer 7

Typical antidepressants: Thought to improve depressive symptoms by increasing monoamine levels. They generally inhibit the reuptake or degradation of monoamines. Targets serotonin, norepinephrine, and monoamine oxidase.
Serotonin classes: SSRI, SNRI, TCAs
Norepinephrine classes: SNRIs, TCAs, NRIs
Monoamine oxidase class: MAOIs

Atypical antidepressants: Generally target receptors and/or inhibit reuptake of monoamines.
Classes: DAT, nAChR, 5-HT2A, 5-HT2C

Question 8

SSRIs (General, Indications, Agents, Formulation, and ADRs)

Answer 8

General: Popular due to safety in overdose, relative tolerability, cost, and broad spectrum of use.

Indications: MDD, GAD, PTSD, OCD, Panic disorder, PMDD, Bulimia

Agents: fluoxetine (one of the most commonly prescribed antidepressants), sertraline, citalopram, escitalopram, paroxetine, fluvoxamine

Formulation: Available PO in once-daily or once-weekly (fluoxetine)

ADRs: Due to excessive stimulation of 5-HT receptors. 5-HT2 - anxiety, nervousness, insomnia, irritability, decreased libido, sexual dysfunction. 5-HT3 - nausea, vomiting, diarrhea. No CV side effects. No strong affinity for muscarinic, alpha-adrenergic, or H1 receptors.

Question 9

SSRIs (Serotonin Syndrome, SSRI Discontinuation/Withdrawal Syndrome, and Pharmacokinetics)

Answer 9

Serotonin Syndrome: Excess serotonin causes hyperthermia, muscle rigidity, myoclonus, hyperreflexia, tremors, autonomic instability-mydriasis, confusion, irritability, agitation. Can progress to coma and death. Occurs most frequently in a DDI setting- CYP2D6 and 3A4 inhibition can increase serotonin to dangerous levels, especially with a TCA.

SSRI Discontinuation/Withdrawal Syndrome: Dizziness, headache, nervousness, nausea, insomnia due to abrupt withdrawal of serotonin. Most intense for paroxetine due to shorter half-life. Less common with fluoxetine due to longer half-life.

Pharmacokinetics: Highly lipophilic and protein bound. Metabolized by CYP2D6 and 3A4. Metabolites renally cleared.

Question 10

SNRIs (General, Indications, Agents, Formulation, and ADRs)

Answer 10

General: SNRIs target serotonin and norepinephrine. Dual inhibition of 5-HT and NE reuptake may contribute to pain relief; milnacipran approved for treatment of fibromyalgia.

Indications: MDD, GAD, stress incontinence, vasomotor symptoms of menopause, neuropathic pain, fibromyalgia, binge-eating.

Agents: Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran

Formulation: Available PO (immediate or extended-release)

ADRs: Similar ADRs to SSRIs - anxiety, nervousness, insomnia, irritability, decreased libido, sexual dysfunction, N/V/D. ALSO increased BP or autonomic effects due to excess norepinephrine.

Question 11

SNRI (Pharmacokinetics and DDIs)

Answer 11

Venlafaxine and duloxetine are metabolized by CYP2D6 and 1A2. Relatively severe withdrawal syndrome has been reported with venlafaxine.
Milnacipran/levomilnacipran are excreted unchanged in the urine.
If patient has hepatic/renal impairment, venlafaxine dose reductions are suggested. Duloxetine is not recommended.

DDIs (serotonin syndrome) can occur with drugs that increase 5-HT levels (MAOIs, TCAs, etc.)

Question 12

Tricyclic Antidepressants (General, Indications, Agents, Formulation, and ADRs)

Answer 12

General: Not recommended as first-line agents due to risk of lethal overdose. Newer agents are more easily tolerated.

Indications: MDD refractory to SSRIs or SNRIs, pain, enuresis, insomnia.

Agents: Amitriptyline, nortriptyline, imipramine, desipramine, doxepin.

Formulation: Available PO, once-daily

ADRs: Similar ADRs to SSRIs and SNRIs + off-target effects due to affinity for muscarinic receptors - anticholinergic effects, alpha-adrenergic 1 receptors - orthostatic hypotension and sedation, and H1 receptors - sedation and weight gain. ALSO have quinidine-like effects on cardiac conduction - prolong QTc with overdose. ALSO lowers seizure threshold.

Question 13

Tricyclic Antidepressants (Pharmacokinetics, DDIs, and Overdose)

Answer 13

Pharmacokinetics: Metabolized by CYP2D6. Slow metabolizers at risk of toxicity. Narrow therapeutic index window. Dose adjustments required for response and plasma level.

DDIs: Serotonin syndrome can occur with drugs that increase 5-HT levels (MAOIs, TCAs, etc.) Pharmacodynamic DDIs occur with drugs of similar ADR profiles - anti-muscarinics, antihistamines, or alpha-adrenergic antagonists (e.g. antipsychotics)

Overdose: Patients may attempt suicide with TCAs - lifetime risk of completing suicide with MDD is high (up to 15%). Symptoms - lethal arrhythmias, VT and fibrillation, BP changes, anticholinergic effects, altered mental status, and seizures. Treatment - cardiac monitoring, airway support, and gastric lavage; sodium bicarbonate to displace TCA from cardiac sodium channels.

Question 14

Monoamine Oxidase Inhibitors (General, Indications, Agents, Formulation, and ADRs)

Answer 14

General: Efficacy equivalent to TCAs. Irreversibly inhibit MAOa and MAOb; inhibits metabolism of norepinephrine and serotonin.

Indications: Depression

Agents: Tranylcypromine, phenelzine, isocarboxazid, selegiline (specificity for MAOb at low doses and spares MOAa activity in the GI tract and elsewhere).

Formulation: Selegiline available as a transdermal patch (may reduce risk for diet-associated hypertensive reactions by bypassing first-pass metabolism)

Most prominent ADR: Hypertensive crisis (MOAs metabolize tyramine. Global inhibition of MAOs increases bioavailability of dietary tyramine, which induces norepinephrine release and causes marked increases in BP). Patients should avoid foods containing high amounts of tyramine and sympathomimetics.

Question 15

MAOIs (Pharmacokinetics and Overdose)

Answer 15

Pharmacokinetics: Metabolized by acetylation. Slow-acetylators are at a higher risk of toxicity. Irreversible MOA inhibition requires new MAO proteins to be synthesized, which takes up to 2 weeks for MOA activity to recover.

Overdose: Can produce a variety of effects - hyperadrenergic symptoms, autonomic instability, psychotic symptoms, confusion, delirium, fever, seizures. Management of overdoses involves cardiac monitoring, vital signs support, and gastric lavage.

Question 16

5-HT2 Receptor Modulators (General, Indications, Agents, Formulation, and ADRs)

Answer 16

General: Replaced by SSRIs in the 1980s. Thought to act primarily as antagonists at the 5-HT2 receptor, but also blocks serotonin and alpha-adrenergic 1 receptors.

Indications: MDD (especially with insomnia) and anxiety disorders. Off-label use as hypnotic (highly sedating and not associated with tolerance or dependence).

Agent: Trazodone

Formulation: Available PO, divided doses for tapering.

ADRs: Orthostatic hypotension, priapism in rare cases. Nefazodone was removed from the market due to cases of liver failure.

Question 17

5-HT2 Receptor Modulators (Pharmacokinetics and DDIs)

Answer 17

Pharmacokinetics: Metabolized by CYP liver enzymes.

DDIs: Occur with CYP3A4 substrates. Contraindicated in combination use with MAOIs due to risk of Serotonin Syndrome.

Question 18

Atypicals: Tetracyclic and Unicyclic Antidepressants (General, Indications, and Agents)

Answer 18

General: Atypical agents have varied structures and complex pharmacology. Mirtazapine has 5-HT2 activity, potent H1 antagonism, and some alpha-adrenergic 2 antagonism. Bupropion has an amphetamine-like structure that conveys CNS-activating properties; promotes synaptic release of norepinephrine and dopamine.

Indications: MDD (with insomnia [mirtazapine] or refractory [amoxapine]). Bupropion - seasonal depressive disorder, smoking cessation, ADHD, and off-label for neuropathic pain and weight loss.

Agents: Mirtazapine, bupropion, amoxapine

Question 19

Mirtazapine (ADRs and Pharmacokinetics)

Answer 19

ADRs: weight gain, somnolence, increased appetite. Rarely agranulocytosis. Not associated with sexual dysfunction.

Pharmacokinetics: Hepatically metabolized. CYP2D6, 3A4, 1A2. May require mutual dose reductions with DDIs. Long half-life, so dose changes are suggested no more often than 1-2 weeks. Dose adjustments for the elderly or patients with moderate-to-severe renal impairment.

Question 20

Bupropion (ADRs and Pharmacokinetics)

Answer 20

ADRs: anxiety, mild tachycardia, HTN, irritability, tremor, headache, nausea, dry mouth, constipation, appetite suppression, insomnia, and rarely aggression, impulsitivity, and agitation. AVOID in patients with SEIZURES. Contraindicated in patients with bulimia due to increased risk of seizure. Not commonly associated with sexual dysfunction.

Pharmacokinetics: Hepatically and renally eliminated. CYP2B6, inhibits CYP2D6. DDIs with SSRIs, beta-blockers, haloperidol, etc. Limit dose in patients with severe hepatic cirrhosis and renal impairment.

Question 21

How to evaluate response to antidepressant treatment (3)

Answer 21

1. Consider target signs and symptoms
2. Assess quality of life such as role, social, and occupational functioning
3. Inquire about the tolerability of the agent (risk of non-adherence)

Question 22

When/how to switch antidepressant agents due to non-response (3)

Answer 22

1. Due to delay in therapeutic effect, ensure time and dosage of medication is adequate before switching
2. Determine whether the patient has been medication adherent
3. “Wash out” period to allow old drug to be eliminated, e.g., at least two weeks after cessation with MAOI before starting SSRI, SNRI, TCA

Question 23

Goals of BPD Treatment and Factors that Affect Drug Choice (5)

Answer 23

1. Eliminate mood episode with complete remission of symptoms (acute symptoms): prevent recurrences of mood episodes (continuation phase) and promote a return to baseline psychosocial functioning
2. Maximize adherence with therapy and minimize ADRs (best tolerability and fewest drug interactions)
3. Treat comorbid substance use and abuse
4. Avoidance of stressors or substances that precipitate an acute episode
5. Some patients can be stabilized with monotherapy, other require combination therapy

Question 24

Drug classes used to treat mania and bipolar disorder (5)

Answer 24

1. Mood stabilizers
2. Atypical antipsychotics: Aripiprazole, olanzapine, quetiapine, risperadone, ziprasidone
3. Anticonvulsants
4. Lithium
5. Antidepressants should be used in conjunction with mood-stabilizers: monotherapy may precipitate a manic episode

Question 25

Dose-dependent efficacy of Antipsychotic agents in acute mania and bipolar depression (6)

Answer 25

1. All atypical antipsychotics are indicated for acute mania in adjunctive or monotherapy: EXCEPT clozapine, which is used in refractory mania
2. Acute mania responds to higher dosages
3. Bipolar depression responds to lower dosages: olanzapine - adjunctive and quetiapine - monotherapy.
4. Weight gain and metabolic ADRs should be monitored
5. Typical antipsychotics are avoided due to risk of EPS
6. Mood stabilizers combined with antipsychotics reduce risk of relapse

Question 26

Comparative efficacy for mood stabilizers (4)

Answer 26

1. Lithium: the most effective treatment for acute mania, prophylaxis, and bipolar depression. Clinical efficacy is universally accepted.
2. Valproate: for acute mania and prophylaxis
3. Carbamazepine: for acute mania and prophylaxis
4. Lamotrigine: for prophylaxis and bipolar depression

Question 27

Lithium (ADRs) - (6)

Answer 27

80% of patients on lithium experience ADRs.

1. Common ADRs: headache, dry mouth, fatigue, dermatologic reactions, weight gain and fluid retention
2. GI disturbances: nausea, vomiting, diarrhea (osmotic)
3. CNS: Benign- transient muscle weakness, lethargy, tremor, sedation. Toxic- coarse tremor, ataxia, seizures, coma, death
4. Thyroid and parathyroid: hypothyroid, goiter, hyperparathyroidism, adenoma
5. Renal: polydipsia, polyuria with or w/o nephrogenic diabetes insipidus (DI) - 30-50% of patients develop after treatment initiation, renal tubular acidosis, nephrotic syndrome
6. Cardiovascular: T-wave flattening or inversion, depressed sinus node, heart block, and syncope

Question 28

Lithium (Pharmacokinetics and DDIs)

Answer 28

Pharmacokinetics: Available in immediate release and extended release. Exclusively excreted renally.

DDIs: Fewer than carbamazepine, oxacarbazepine, and valproate. Drugs that DECREASE lithium clearance - thiazide diuretics NSAIDs, COX 2 inhibitors, ACE inhibitors (when in mild hypovolemic or reduced GFR state - these drugs compete for renal clearance with lithium). NEUROTOXICITY with antipsychotics, metronidazole, methyldopa, phenytoin, and verapamil - enhance monoamine signaling of CYP inhibition. Caffeine can ENHANCE the renal elimination of lithium when in a EUVOLEMIC and HYPERVOLEMIC state.

Question 29

Lithium Monitoring (4)

Answer 29

1. Lithium has a narrow therapeutic index
2. Dosing depends on patient’s age (lower in elderly), weight, tolerance to side effects, and indication/status: lower dose for prophylaxis (600 mg/day) and higher dose for acute mania (900-1200 mg/day).
3. Ideal steady state serum concentrations: 0.6-1.2 mEq/L. Less than increases risk of relapse. More than (up to 1.5 mEq/L) may be needed for acute mania.
4. Check levels after 2 weeks, if stable, every 3-6 months or as indicated clinically

Question 30

Lithium Toxicity (Factors and Symptoms)

Answer 30

Factors generally involve decreased ECF and higher plasma levels:

1. Sodium restriction (water follows salt)
2. Dehydration, vomiting, diarrhea
3. Age greater than 50
4. Heart failure, cirrhosis
5. Heavy exercise, sauna baths, hot weather, and fever can promote sodium loss (water follows salt): patients should be cautioned to maintain adequate sodium and fluid intake, avoid excess use of coffee, tea, cola, and other caffeine-containing beverages and alcohol

Symptoms: ataxia, slurred speech, coarse tremor, confusion, convulsions. Treatment - monitor in ER and discontinue lithium. Restore fluid balance, electrolyte changes, and neurologic changes. Gastric lavage and IV fluids may be needed.
Hemodialysis when: plasma levels are 2.5 mEq/L and moderate-severe neurologic toxicity, plasma levels are >4 mEq/L with renal impairment, plasma levels are >5 mEq/L regardless of clinical status, patient has lost consciousness due to lithium treatment at any plasma concentration.

Question 31

Baseline and Routine Laboratory Tests and Monitoring Frequency for Mood Stabilizers

Answer 31

Check values every 6-12 months

Question 32

Anticonvulsants as Treatment for Bipolar Disorder (3)

Answer 32

1. Valproate: acute manic or mixed episodes. Also for prophylaxis; used off-label for maintenance monotherapy.
2. Carbamazepine: commonly used for both acute and maintenance therapy.
3. Lamotrigine: indicated for maintenance treatment of Bipolar I disorder. Effective in prevention of relapse of depression. No efficacy against acute depression or mania.

Question 33

Valproate/Valproic Acid (Indications, MOA, Pharmacokinetics, ADRs)

Answer 33

Indications: Bipolar mania. More effective than lithium when treating bipolar with rapid cycling, mixed features, and comorbid substance abuse.

MOA: Ca2+ channel inhibitor, Na+ channel inhibitor, and GABA transaminase inhibitor.

PK: Metabolized by several CYP isoforms. Highly protein bound.

ADRs: GI distress, CNS depression, alopecia, pancreatitis (rare, but fatal), hepatotoxicity (BLACK BOX WARNING), thrombocytopenia (increased bleeding time), teratogenicity (causes significant cognitive delay and impairment).

Question 34

Carbamazepine (Indications, MOA, PK, ADRs, and Overdose)

Answer 34

Indications: Acute mania. Can treat mania in treatment-resistant patients when combined with lithium, valproate, or antipsychotics.

MOA: Inhibitor of Na+ channel on glutamatergic synapses. Oxacarbazepine is less potent.

PK: Induces CYPs, including 3A4

ADRs: 50% of patients experience side effects. Fatigue, nausea, diplopia, blurred vision, ataxia, skin rashes, mild leukopenia, mild liver enzyme elevations, mild thrombocytopenia. RARE, BUT FATAL - agranulocytosis, aplastic anemia, thrombocytopenia, hepatic failure, Stevens-Johnson syndrome (increased risk in patients of Asian ethnicity with HLA-B1502 polymorphism), and pancreatitis.

Overdose: Acute overdose potentially lethal. Serum level above 15 mcg/mL associated with ataxia, choreiform movements, diplopia, nystagmus, cardiac conduction changes, seizures, coma.

Question 35

Lamotrigine (Indications, MOA, PK, ADRs)

Answer 35

Indications: Maintenance treatment of Bipolar I disorder and treatment-resistance Bipolar I and II disorders. Low rates of switching to mania. Useful in prevention of bipolar depression.

MOA: Inhibitor of Na+ channel on glutamatergic synapses.

PK: Phase II metabolism in liver, excreted renally. DDIs with valproate, sometimes beneficial.

ADRs: RASH (hypersensitivity) - can be reduced through slow introduction - greater risk in pediatric patients. Stevens-Johnson syndrome risk greater in patients on high doses who suddenly skip. Headache, nausea, infection, dry mouth.