Antidepressants

Antidepressants

Used to relieve symptoms of depression + anxiety, not used in uncomplicated bereavement

What is the most common psychiatric disorder?

Depression (affects 15 million ppl/yr)

Depression Incidence (Men vs Women)

Women have twice as high incidence compared to men

Clinical Features of Depression

Symptoms must be present most of the day, nearly every day, for at least 2 weeks

Contributing Factors to Depression

Genetic heritage, difficult childhood, chronic low-self esteem

Monoamine-Deficiency Hypothesis

Neurochemical imbalance in serotonin, norepinephrine, dopamine l/t depression

First-Generation Antidepressant Drug Examples

Tricyclic Antidepressants l/t decrease NE + 5HT reuptake

Second Generation Antidepressant Drug Examples 

SSRIs, SNRIs, Atypical Drugs

What 3 Antidepressant class drugs increase amine transmission?

First Generation, Second Generation, MAOi

NMDA Receptor Antagonist Example

Esketamine

Nonconventional Drugs for Depression Example

St John’s Wort

Onset of Antidepressant Drugs (1^st, 2^nd, MAOi)

1-3wks (no PRN use)

Efficacy of Antidepressant Drugs (1^st, 2^nd, MAOi)

Similar, thus we must select based on the patient’s needs

Black Box Warning of Antidepressant Drugs (1^st, 2^nd, MAOi)

Increase suicidal tendencies in <25yo (monitor patient closely)

After depression symptoms are in remission, how long should you continue the use of Antidepressant Drugs (1^st, 2^nd, MAOi)?

Continue treatment for 4-9months, discontinue use gradually over 6-8weeks to avoid withdrawal symptoms

Treatment Timeline of Antidepressant Drugs (1^st, 2^nd, MAOi)

Used for 8-12weeks, starting with low dose

Tricyclic Antidepressants (TCA) Drug Examples

Amitriptyline, Doxepin, Nortriptyline

Tricyclic Antidepressants MOA

Blocks reuptake of NE & Serotonin into nerve terminals l/t accumulation of neurotransmitters l/t increased activation of post-synaptic receptors

What can Tricyclic Antidepressants also block?

Histamine, muscarinic, alpha-adrenoceptors receptors (thus, contributes to many side effects)

Tricyclic Antidepressants Pharmacological Action

Elevates mood, improves mental alertness, increases physical activity, reduces morbid preoccupation

Pharmacokinetics of Tricyclic Antidepressants

Given at bedtime d/t sedating effect, orally administered, long/variable half-lives

Tricyclic Antidepressants Adverse Effects

Anticholinergic effect, cardiotoxicity, orthostatic hypotension, suicide risk/ideation, sedation

Clinical Manifestations of Tricyclic Antidepressants Toxicity

Dysrhythmias, tachycardia, mental confusion, agitation (overdose may l/t death)

Treatment of Tricyclic Antidepressants Toxicity

Intravenous sodium bicarbonate, gastric lavage, ingestion of activated charcoal

Tricyclic Antidepressants (TCA) Therapeutic Uses

First-line drug for depression, depressive episodes of bipolar disorders

Advantages of SSRI, compared to TCAs

Doesn’t cause orthostatic hypotension, sedation, doesn’t elicit anticholinergic effect, overdose doesn’t cause cardiac toxicity

SSRI Drug Examples

Fluoxetine, Sertraline, Paroxetine

SSRIs MOA

Blocks reuptake of serotonin into nerve terminals l/t serotonin accumulating in synapse l/t prolonged receptor stimulation

Pharmacological Effect of SSRIs

Just as potent as TCA (but with less side effects), onset of 1-3 weeks

Bruxism

Involuntary habitual grinding of teeth (typically during sleep)

SSRI Adverse Effects

Insomnia, sexual dysfunction, bruxism, long term use l/t weight gain, increased risk of suicidal tendencies, neuroleptic malignant syndrome, hyponatremia

SSRI Drug Interactions

Increased risk of serotonin syndrome when taken with MAOi, when taken together with TCA + lithium (SSRIs can elevate levels of those drugs)

Contraindications/Precautions of SSRIs

Pregnancy (l/t neonatal abstinence syndrome and persistent pulmonary hypertension of the newborn)

Therapeutic Uses of SSRIs

Fluoxetine is fist-line drug for depression (70% of patients respond after 6 weeks), OCD, panic disorder

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Drug Examples

Duloxetine, Venlafaxine, Desvenlafaxine

FDA Approved SNRI for Pain Management

Duloxetine

SNRIs MOA

Inhibit serotonin and norepinephrine reuptake, minimal effect on dopamine

Venlafaxine (SNRI) Side Effects

Mydriasis, oculuar damage in glaucoma, dizziness, sedation

SNRI Side Effects

Similar to SSRIs (sexual dysfunction, insomnia, suicide ideation, anorexia, tachycardia)

Therapeutic Uses of SNRIs

Low mood, irritability, feelings of worthlessness (effects develop over 6-8 weeks)

Atypical Antidepressants Drug Example

Bupropion

Bupropion Unique Properties

Used for smoking cessation, appetite suppressant, enhances libido, CNS stimulant, doesn’t cause weight gain, may induce seizures

Bupropion MOA

Inhibits reuptake of dopamine (may affect NE, little effect on serotonin)

Side Effects of Bupropion

Hallucinations, delusions, seizures, weight loss

Therapeutic Uses of Bupropion

Smoke cessation, major depression, alternative treatment to SSRI and SNRI in those unable to tolerate sexual dysfunction

Contraindications/Precautions of Bupropion

Seizure and eating disorder patients and pregnancy

MAOi Drug Examples

Phenelzine, Selegiline

Two Iso-Types of MAO Enzyme

MAOa Inhibitors (Antidepressants) and MAOb Inhibitors (= Anti-Parkinson’s Disease)

Effectiveness of MAOi

As effective as TCAs and 2^nd generation (but more hazardous d/t dietary interactions), 2^nd / 3^rd choice drugs for antidepressants

Phenelzine MOA

Inhibit MOA (enzyme that breaks down NE + Dopamine +Serotonin) (a-isotype) l/t neurotransmitter accumulation l/t increased activation of postsynaptic receptors

Pharmacokinetics of MAOi

Onset of minimum 2-4 weeks (slow), active orally

Contraindications of MAOi

Patients should avoid high tyramine foods d/t risk of hypertensive crisis

MAOa Inhibitors and Tyramine

Block breakdown of tyramine l/t excessive biosynthesis of NE that can induce hypertensive crisis

Side Effects of MAOi

Orthostatic hypotension, weight gain, CNS stimulation

Therapeutic Uses of MAOi

Depressed patients who are unresponsive or allergic to SSRIs + TCAs

Is it safe to use multiple classes of antidepressants simultaneously?

No

Serotonin Syndrome

D/t co-current administration of different classes of antidepressants l/t accumulation of serotonin in brain, beginning 2-72 hours after treatment

Signs and Symptoms of Serotonin Syndrome

Tachycardia, convulsions, coma, death, altered mental status

When switching from one class to another class of antidepressants, what is required?

An adequate “washout period of time” must be allowed to mitigate occurrence of serotonin syndrome

Esketamine MOA

Active isomer of ketamine, non-competitive inhibitor of NMDA receptor

Administration of Esketamine

Nasal spray that is used as adjunct to oral antidepressant for treatment-resistant depression in adults with major depressive disorder

Induction Phase of Esketamine Administration

Given 2x weekly for 1-4 weeks (evaluate benefits after 4 weeks before advancing to maintenance phase)

Maintenance Phase of Esketamine Administration

Give once weekly 5-8 weeks

After 9 Weeks of Esketamine Administration

Once every 2 weeks or weekly as needed

Side Effects of Esketamine (Black Box)

Sedation, dissociation, abuse potential, increased suicide ideation (watch patient for at least 2 hours after administration)

Precautions of Esketamine

Given by healthcare workers (wait 2hrs before leaving clinic), monitor BP before treatment and 40 minutes after, high BP should hold treatment

St. John’s Wort

Herbal product used for oral therapy of depression, superior to placebo in mild-moderate major depression (may be equal to TCAs), no evidence of efficacy on severe depression

St. John’s Wort and Serotonin Syndrome

St. John’s Wort potentiates SSRIs to cause serotonin syndrome as well (patients on SSRIs shouldn’t take this)

Bipolar Disorder

Cyclic disorder with recurrent fluctuations in mood and has episodes of mania and depression persist for months without treatment

Mood Stabilizer Examples

Lithium

Lithium MOA

Structural neuroprotection in the brain, increase GABA and decrease glutamate + dopamine,

Lithium

Drug of choice to relieve S&S of mania, narrow therapeutic index, active orally

Lithium Side Effects (Therapeutic Doses)

Teratogenesis, fine hand tremor, polyuria, GI upset

Lithium Side Effects (Excessive Doses Doses)

Coma, ECG changes, death, confusion, sedation

What does low plasma Na+ cause?

Retention of lithium and toxicity can occur (monitor Na+ intake, avoid Na+ free diet)