L5 Antidepressants, Anxiolytics, Sedatives

Antidepressant Medication Classes

1. Selective Serotonin Reuptake Inhibitors (SSRI)

2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

3. Tricyclic Antidepressants (TCA)

4. Monoamine Oxidase Inhibitors(MAOIs)

5. Atypical antidepressants

SSRI Names

1. Citalopram, Escitalopram

2. Fluoxetine, Paroxetine

3. Fluvoxamine

4. Sertraline

What is the first line antidepressant?

SSRIs - better side effect profile and safer in overdose than TCAs and MAOIs

Other Indications for SSRIs

1. Anxiety, eating disorders

2. Menopausal hot flashes

3. OCD disorders

4. PTSD

5. Premature ejaculation

6. PMDD

7. Somatic sxs disorder

MOA of SSRIs

Increase serotonergic activity, decreasing the presynaptic reuptake pump

By decreasing the action of the presynaptic serotonic reuptake pump, what happens?

1. Increases length serotonin is available

2. Increases post synaptic serotonin receptor occupancy

How long does SSRIs take to benefit?

2-8 weeks

ADE of SSRIs

1. Nausea (MC)

2. Dry mouth/HA

3. Insomnia/Somnolence

4. Loose stools/diarrhea - early on

5. Sexual dysfunction

6. Diaphoresis

7. Tremor

8. Anxiety/agitation

9. Modest weight gain

Rare ADE of SSRIs

1. Suicidal ideation (greatest risk in people <25)

2. Mania/hypomania

3. Hyponatremia

4. QT prolongation

5. Serotonin syndrome

6. Lower seizure threshold

7. Increase risk of bleeding

Fluoxetine Key Points

1. Lowest risk of SSRI discontinuation syndrome

2. Most likely to cause sedation/drowsiness

3. Least likely to cause weight gain

4. Most likely to be activating

Sertraline Key Points

1. Known for diarrhea as an early side effect (squirt-raline), safest in cardiac dz

2. Least likely to cause weight gain after fluoxetine

Paroxetine Key Points

Most associated with weight gain and cardiac abnormalities

Citalopram Key Points

More likely to cause QT prolongation

If a patient experiences a particular side effect on one SSRI, will they have the same issue with a different one?

They may or may not have the same issue with an alternative SSRI

SNRIs Meds

1. Venlafaxine (Effexor)

2. Duloxetine (Cymbalta)

3. Desvenlafaxine (Pristiq)

SNRIs MOA

Block presynaptic serotonin and norepinephrine transporter proteins; increase postsynaptic receptors

When are SNRIs used?

2nd line after failing SSRI (Replaces SSRI)

ADE of SNRIs

1. Nausea (MC)

2. Decreased appetite and weight loss

3. Dizzy/diaphoresis/HA

4. HTN

5. Sexual dysfunction

6. Increased bleeding

7. Hyponatremia

8. Low seizure threshold

9. Serotonin syndrome

10. Mania/hypomania

When would SNRIs be used?

1. Depression/anxiety with pain (neuropathic)

2. Depression/anxiety with Fibromyalgia

3. Depression/anxiety with Fatigue

4. Vasomotor sxs of menopause - Venlafaxine

Tricyclic Antidepressants

1. Amitriptyline

2. Imipramine

3. Doxepin

4. Nortriptyline

5. Clomipramine

MOA of TCAs

1. Block neuronal re-uptake of NE and serotonin (5-HT)

2. Increases transmitters at CNS synapses

3. Increases transmitter effects

ADE of TCAs

1. Tachycardia

2. Sedation

3. Anticholinergic effects

4. Increased seizure risk

5. Cardiac toxicity

6. Weight gain

7. Sexual dysfunction

8. Serotonin syndrome

9. Mania/hypomania

What cardiac effects does TCAs have?

1. increased risk of dysrhythmias

2. Everyone should have ECG before and periodically after

3. QT prolongation

When are TCAs used?

1. Depression with pain

2. Depression with insomnia

3. Treatment resistant depression

4. Catatonia

5. Insomnia

6. Enuresis (bedwetting) in children resistant to others

7. Migraine prophylaxis

What TCA is used for migraine prophylaxis?

Amitriptyline

What TCA is used for insomnia?

Doxepin <6mg

What TCA is used for enuresis in children?

Imipramine

Monoamine Oxidase Inhibitors (MAOIs)

1. Isocarboxazid

2. Phenelzine

3. Tranylcypromine

4. Selegiline (Emsam patch)

MOA of MOAIs

1. Inhibiting MAO-A in nerve terminals

2. Increase amounts of NE and serotonin available for release

3. Intensify transmission at noradrenergic and serotonergic junction

ADE of MAOIs

1. CNS stimulation

2. Orthostatic hypotension

3. Mania/hypomania

4. Serotonin Syndrome

5. HTN crisis with dietary tyramine

Hypertensive Crisis of MAOIs

1. Educate patient against ingesting tyramine-rich foods

2. Give detailed list of food and beverages to avoid

What foods to avoid when taking MAOIs?

1. Aged cheese

2. Figs

3. Avocados

4. Fermented foods

5. Beer, Chianti wine

6. Soy sauce

DDI with MAOIs

1. Minimum 2-week washout before resuming an SSRI or other antidepressant

2. Minimum 2-week washout from other antidepressants before starting MAOI with exception of fluoxetine (6 weeks)

What combinations of medications with MAOIs can lead to HTN crisis?

1. Sympathomimetics

2. TCAs - amitriptyline

What sympathomimetics can't be taken with MAOIs?

1. Pseudoephedrine

2. Phenylephrine amphetamine

3. Cocaine

Serotonin Syndrome MAOIs

1. Begins 2-72 hours after med

2. Triad - AMS, autonomic instability, neuromuscular abnormalities

3. Incoordination, myoclonus, diaphoresis, tremor, fever, death

What are medications that increase the risk of Serotonin syndrome if currently taking MAOI?

1. SSRI/SNRI/TCA

2. Bupropion

3. Trazodone/Tramadol

4. Amphetamines/Cocaine

5. Dextromethorphan

6. Cyclobenzaprine

7. Buspirone

8. Triptans/Fentanyl/Lithium

How do we treat serotonin syndrome?

1. Lower provoking agent dose

2. Cyproheptadine (5HT-2 antagonist)

When are MAOIs used?

1. Treatment resistant depression (last line)

2. Atypical depression

3. Treatment resistant anxiety disorders

4. Phobias or social anxiety (resistant)

5. Melancholic depression

Atypical Antidepressants - Norepinephrine and Dopamine Reuptake Inhibitors (NDRI)

Bupropion (wellbutrin)

MOA of Bupropion

Blockade of dopamine or NE uptake

Use of Bupropion

1. Major depressive disorder

2. prevention of seasonal affective disorder

Additional Use/Benefits of Bupropion

1. Counteract hypoactive sexual desire caused by SSRIs

2. Energizing (always dosed in morning)

3. Can aid in quitting smoking

4. Doesn't cause weight gain

5. Used off-label for adult ADHD

ADE of Buproprion

1. Seizure risk

2. Weight loss (don't use in anorexia or bulimia)

3. Hallucinations, delusions

4. Dry mouth/nausea

5. Insomnia/dizziness

6. Anxiety/agitation

7. dyspepsia/tremor

MOA of Mirtazapine (Remeron) - Atypical Antidepressant

1. Blockade of presynaptic a2-adrenergic receptors, histamine receptors

2. Increase release of serotonin and NE

3. block H1 receptors = sedative

Use of Mirtazapine (Remeron)

1. MDD

2. GAD

3. Tension headaches

ADE of Mirtazapine (Remeron)

1. Sedation

2. Drowsiness

3. Increased appetite

4. Weight gain

5. Dry mouth

Additional Uses of Mirtazapine (Remeron)

1. Insomnia

2. Appetite issues

3. Anxiety symptoms

4. Treatment resistant depression

5. Sexual dysfunction (less sexual side effects)

Goals and Plan for Treating MDD

1. Remission - resolution of sxs and restoring baseline function (monitor w/ PHQ-9)

2. Start with combo of pharmacotherapy and psychotherapy

PHQ-9 Scores and Depression Severity

1. 0-4 = no depression

2. 5-9 = mild depression

3. 10-14 = moderate depression

4. 15-19 = mod-severe depression

5. 20-27 = severe depression

How do symptoms resolve with antidepressants?

1. Slowly

2. Initial response - 1-2 weeks

3. Most of the response - 4-6 weeks

4. Max response - possibly up to 12 weeks

Do not consider an antidepressant drug trial failed if ____.

Not taken > 1mo

How do we select antidepressants?

1. All are equally effective - done when PHQ-9 >14

2. Select based on - tolerability, safety, symptom profile/comorbidities

What are the usual drugs of choice for antidepressants?

1. SSRIs, SNRIs

2. Bupropion

3. Mirtazapine

Managing Treatment for Depression

1. Use drug for 4-8 weeks to assess efficacy, start low

2. If initial dose/drug not effective assess next steps

What are the next steps of an antidepressant dose/drug is not effective?

1. increase the dosage

2. Switch to another drug in the same class

3. Switch to another drug in a different class

4. Add a second drug, such as an atypical (Bupropion)

If a patient's depression is in remission, what do we do?

Continue treatment for at least 4-9 mo (reduce relapse if taken for 1yr)

How do we discontinue antidepressants?

1. Taper dosage gradually over several weeks

2. Abrupt discontinuation = withdrawal syndrome

Initial Preferred Medication for MDD

SSRI

How do we choose medication for MDD?

1. FMHX response to antidepressants

2. Safety/side effect profile

3. Specific depressive sxs

4. Comorbid illness/concurrent meds and potential DDI

5. Ease of use/preferrence/cost/response

Withdrawal Syndrome with Antidepressants

1. Abrupt d/c (after >6 week of use)

2. Occurs days to weeks of last dose

3. Persists for 1-3 days

4. Resumption of meds will make sxs subside

What are the symptoms of withdrawal syndrome with antidepressents?

1. Flu-like symptoms

2. Insomnia

3. Nausea

4. Imbalances

5. Sensory disturbances

6. Hyperarousal

How do we taper antidepressants?

Slowly over 2-4 weeks when d/c

What antidepressants have the least and most risk for withdrawal syndrome?

1. Least - fluoxetine

2. Most - paroxetine, sertraline

What risk do all antidepressants carry?

1. SUICIDE

2. Pt <18yo - first 1-2 mo of tx

2. High risk in pt 18-24 yo

Types of Anxiety

1. GAD

2. Panic disorder

3. Obsessive-Compulsive Disorder

4. Social anxiety

5. PTSD

Characteristics of GAD

1. Uncontrollable worrying

2. Least likely to go into remission

3. Many pts have depression also

Symptoms of GAD

1. Unrealistic/excessive worrying >6mo

2. Tension

3. Apprehension

4. Poor concentration

5. Difficulty falling/staying asleep/restlessness

6. Trembling/muscle tension

7. Tachycardia/palpitations

8. Sweating/cold clammy hands

First Line Treatment for GAD

SSRI or SNRI

How long does GAD tx take to benefit?

1. Initial - 1-2 weeks

2. Optimal 4-6 weeks

3. Cannot be used PRN

Duration for GAD Tx

Often indefinitely, needs to be at least 12mo

If a patient has severe anxiety and cannot wait until SSRI/SNRI take effect?

Bridge with Benzodiazepine

Second Line Treatment for GAD

1. Buspirone

2. Benzodiazepines

What are the advantages and disadvantages of using Buspirone as a second line GAD tx?

1. A - no abuse potential and not a CNS depressant

2. D - anxiolytic effect develops slowly, not for PRN

What are the advantages and disadvantages of using Benzodiazepines as a second line GAD tx?

1. A - onset is immediate

2. D - sedative, abuse potential, physical dependence, withdrawal symptoms

MOA of Buspirone

1. Partial serotonin agonist

2. Not a CNS depressant

3. No abuse potential

4. Comparable efficacy to benzo

How long does Buspirone take to tx GAD?

2-4 weeks

ADE of Buspirone

1. Dizziness/sedation

2. Nausea

3. HA/lightheadedness

4. Nervousness/excitement

When are benzodiazepines used for GAD?

SEVERE anxiety not general life stress

Benzodiazepines

1. Alprazolam

2. Clonazepam

3. Diazepam

4. Lorazepam

5. Midazolam

MOA of Benzodiazepines

1. Potentiate actions of GABA

2. Not a direct GABA agonist

3. Doesn't directly mimic GABA, just enhances GABAergic transmission

Benzos for Anxiety

1. Alprazolam

2. Diazepam

3. Lorazepam

4. Clonazepam

Benzos for Insomnia

1. Lorazepam

2. Temazepam

Benzos for Seizures & Status Epilepticus

1. Clonazepam

2. Diazepam

3. Lorazepam

Benzos for Muscle Spasms

Diazepam

Benzos for EtOH Withdrawal

1. Diazepam

2. Chlordiazepoxide (Librium)

Benzos for Anesthesia

Midazolam

Alprazolam

1. Intermediate onset

2. Intermediate duration of action

Lorazepam

1. Intermediate onset

2. Intermediate duration of action

Clonazepam

1. Intermediate onset

2. Long acting duration

Diazepam

1. Fast onset

2. Long acting

ADE of Benzos

1. CNS depression

2. Anterograde amnesia/confusion

3. Complex sleep behaviors "Sleep driving"

4. Ataxia

5. Abuse potential

What CNS depression symptoms does Benzos cause?

1. Sedation

2. Hypnosis

3. Stupor

Benzodiazepines Effect on CV System

1. Oral - no effect on the heart

2. IV - profound hypotension and cardiac arrest

Benzodiazepines Effect on Hepatic System

1. Most metabolized by CYP450 system

2. Exceptions - outside the liver - Oxazepam, Temazepam, Lorazepam

Which benzodiazepines are safer in liver disease?

Oxazepam, Temazepam, Lorazepam

Benzodiazepines Effect on Respiratory System

1. Little or no respiratory depression by themselves

2. Can be lethal when taken concurrently with other CNS depressants

Who is most likely to abuse Benzos?

1. Patients with substance abuse hx

2. Patients with mod alcohol use that doesn't meet AUD

3. Patients 18-25yo

Tolerance of Benzos

1. Prolonged use - decreased antiseizure effects

2. Less tolerance to anxiolytic effects

Tx of Benzo OD

Flumazenil