IDT Exam 2 Antidepressants

Neuroses

changes in mood and affect

abnormal or disproportionate emotional response

IE: MDD, GAD, OCD

MDD Sx

• Thoughts – Persistent gloomy, hopeless, helpless thoughts – Worry, dread, premonitions of doom – Worthlessness and guilt – Inability to concentrate, slowed thinking – Suicidal ideation (10-15% will attempt suicide) •

Emotions and Feelings – Unrelieved sadness – Persistent anxiety-50-70% comorbidity – Pain – Irritability – Anger (more “male”) – Anhedonia, & apathy •

Behaviors – Loss of appetite and libido – Insomnia & Disturbances in diurnal rhythm (sleep/wake cycle), – Inability to act/lack of will – Social withdrawal

Unipolar vs Bipolar depression definition and Tx

Uni: dips between normal and low mood

Tx: antidepressants

Bi: severe rise and drop in mood

Tx: mood stabilizers (antiepileptics/psychotics)

Is MDD genetic?

yes, 40%

Subcategories of depression

– Mild, moderate or severe

– Reactive depression, i.e. grief -- a normal response to circumstances

– Agitated depression -- fear, insomnia, extreme irritability, and restlessness

– Atypical depression—hypersomnia, hyperphagia, high anxiety

– Dysthymia--low level, long term (>2 yr) melancholy

– Premenstrual dysphoric disorder

– Post-partum depression -- up to 1 yr after delivery

– Psychotic depression -- perceptions of reality become altered

– Seasonal affective disorder

Tx

• Talk therapy

• Antidepressant medications (ADM)

• Exercise: reduces relapse

• Light therapy?

-ECT

5-HT-associated symptoms

anxiety, social withdrawal, mood, appetite & sleep disturbances

NE-deficit associated symptoms

lowered pain threshold, attention deficit, poor working memory, reduced alertness, low energy

Serotonergic and Noradrenergic projections

– Overlap to frontal cortex and limbic areas

– Cross-regulate

– Descending pathways modulate pain perception

Increased 5-HT transmission over weeks structural changes

increases neurotrophic agents such as BDNF increased neuronal sprouting structural changes improve mood (esp. hippocampus)

ECT also increases BDNF (brain derived neurotrophic factor)

Glutamate signaling seems to be altered downstream of increased 5-HT transmission blocking NMDA receptors may be a faster mechanism to block and remodel pathways in pain and suffering

TCA vs SNRI

TCA have more side effects

SSRIs place in therapy, MoA

– First line agents for depression AND anxiety

– Block re-uptake of 5-HT

– Much better side effects profile than older agents (TCAs)

• No affinity for  adrenergic, muscarinic, histamine, or dopamine receptors

– Not for neuropathic pain

SSRI are NOT used for

• No inhibition of NE reuptake

SNRIs (list)

Duloxetine (Cymbalta®) Venlafaxine (Effexor®) Desvenlafaxine (Pristiq®)

Common Adverse effects of SSRIs

• Common

– Nausea and headaches • Usually resolve after a few days or weeks

– Nervousness and insomnia

– Sexual dysfunction in men and women

– Discontinuation syndrome

• Nightmares, insomnia, confusion and/or vertigo

• Irritability, agitation

• Electrical sensations: “brain zaps”, “brain shivers” or “cranial zings”

– TAPER DOSE! – Usually resolves after several weeks

Rare SE of SSRIs

– Increased bleeding risk, esp with anti-coagulants

• Serotonin is involved in platelet aggregation • 1.5X increased risk of GI bleed, similar to risk with NSAIDs • Increased risk in combo with antiplatelet agents

– Hyponatremia from elevated vasopressin • mainly in elderly and/or patients with electrolyte imbalance such as bulimia or anorexia

– Hypomania/mania

– Heat sensitivity / overheating

– Serotonin syndrome

– Overdose toxicity— very rare • Seizures, leading to death, in combination with other drugs only

SSRI Age dependent suicidal ideation

• Suicidal ideation in youth, 1-2% on placebo versus 2-4% on SSRIs

• Huge increase in depression, reported sexual violence, and suicidality in teens in the last decade. Problem started earlier but exacerbated by COVID pandemic isolation.

“the risk posed by untreated depression —in terms of morbidity and mortality — has always been far greater than the very small risk associated with antidepressant treatment.” N EnglJ Med 2014; 371:1666-1668 DOI: 10.1056/NEJMp1408480

SNRI Place in Therapy

• All have affinity for both SERT and NET similar to TCAs

• Same efficacy as SSRIs—also used as 1st line for anxiety

• Used to treat neuropathic pain (some off-label)

• Low SE: No affinity for adrenergic or muscarinic receptors

• Adverse effects similar to SSRIs plus NE side effects – Increased NE may cause mild hypertension, dry mouth, increased HR, dilated pupils

• Bleeding risk is not established

• Abrupt discontinuation could have cardiovascular effects

– Serotonin syndrome

•e.g., triptans for migraine, SSRIs, meperidine (opioid analgesic) or dextromethorphan

• Similar to Malignant Hyperthermia – Hyperthermia, – Muscle spasticity, hyperreflexia (exaggerated reflexes), myoclonus (involuntary, rhythmic contractions) – Mental disorientation

• Dose dependent, usually quick onset, more likely with drug combos

• Treatment includes oxygen, sedation and a serotonin antagonist. – Cyproheptadine is recommended

Tricyclic Antidepressants (TCAs)

–Block NE and 5-HT transporters (old-timey SNRIs)

–Standard therapy prior to 1990

•Amitriptyline (Elavil®)

•Nortriptyline (Pamelor®)

•Doxepin (Sinequan®) – used mainly for sleep

•and many others

–Similar efficacies

–Useful for neuropathic pain

–Lots of side effects

TCA AEs

CV: Antagonism of a₁ adrenergic receptors (^HR)–Antagonism of muscarinic cholinergic receptors (^HR) •Least with doxepin. Most with amitriptyline

–NE activation of cardiac b-adrenergic receptors (^HR)

–Antagonism of histamine H1 receptors

•Drowsiness and sedation

•Weight gain – very common and significant

•Worst with amitriptyline and doxepin

–Decreased seizure threshold

–Sexual side effects related to serotonin including impotence and loss of libido

Overdose Toxicities with TCAs

•Lethal in overdose

•Toxic sedative effects in combination with alcohol, benzodiazepines, or barbiturates

•Toxic cardiac effects

•CNS anticholinergic psychosis

Monoamine oxidase inhibitors (MAO Is)

–Block NE and 5-HT breakdown

–Irreversible and very long lasting

•Phenelzine (Nardil®)- most common

•others

–Problematic side effects, drug-drug interactions and food drug interactions

–Reserved for treatment resistant or atypical depression

•High anxiety, phobias, hypersomnia, hyperphagia

–Useful in narcolepsy

MAOi AE

–Insomnia followed by daytime sleepiness

–Dry mouth

–Impotence and loss of libido

–Hepatotoxicity associated with phenelzine

–Long washout period- IRREVERSIBLE inh

–Dangerously prolong half-lives of oxidatively deaminated drugs

Toxic Food / MAO-I interactions:

“wine & cheese reaction”

•Foods high in Tyramine

–Aged cheese

–Aged meats (pepperoni, salami)

–Spoiled meats and fish (?)

–Sauerkraut

–Soy Sauce

–Fava beans

–Banana peels (?)

–Beers on tap 

–Red or white wine (4 oz or less)

–Bottled or canned beers

•Tyramine is normally rapidly metabolized by MAO. MAO-Is block metabolism and tyramine accumulates.

•High levels of tyramine force NE out of the nerve and can precipitate a sympathetic crisis of high BP and HR, leading to stroke in rare cases.

Selective MAO Is

–MAO-B inhibitor antidepressant for depression with Parkinson’s disease

•Selegiline (Eldepryl® or Emsam®)

•Mechanism: Interference with dopamine metabolism, may affect serotonin receptors OR even though MAO-A is selective for NE and 5-HT, MAO-B may still play a role

Atypical Antidepressants list

Mirtazapine

Bupropion

Esketamine nasal spray

Dextromethorphan + Bupropion

Zulranolone

St John’s Wort

Atypical Antidepressantos

–Mode of action is not well understood

• not SNRIs, SSRIs, MAO-Is, or 5HT modulators

Mirtazapine (Remeron®) Presynaptic autoreceptor antagonist

Bupropion (Wellbutrin®) NET, DAT and central Nicotinic receptor antagonist

Esketamine nasal spray (Spravato®) NMDA receptor antagonist

Dextromethorphan + Buproprion (Auvelity®) NMDA receptor antagonist + opioid agonist??

Zulranolone (Zurzuvae®) Progesterone metabolite/GABA_A receptor positive allosteric modulator

St. John’s Wort Herbal remedy

Newest, Faster Onset Atypical Antidepressants

•Dextromethorphan + Bupropion (Auvelity®)

–Faster onset than bupropion alone or other typical antidepressants

–2 weeks to good effects rather than 4 to 6 weeks

•Esketamine (Spravato®)

–fastest onset within hours

•Zuranolone (Zurzuvae®)

–Fast onset within days

Proporsed Mirtazapine MoA

Blocking autoreceptors cause »^ NT release

Neurosteroids

–Post-partum depression only per FDA

–First in class agents

•Brexanolone: IV only, 60 hrs clinic infusion, super expensive ($34K)

•Zuranolone (Zurzuvae®) : appr Aug 2023, orally active, ($14K for 14 days)

–Rapid antidepressant action within days, similar to SSRIs at 6 weeks

–Allopregnanolones-progesterone metabolite

•Rapid decrease in mothers at birth

•Positive allosteric modulators of GABA_A-receptor which is usually associated with anti-anxiety medications

–Major side effects are dizziness and somnolence with a Black box warning to not drive for 12 hours after a dose.

•Breastfeeding on Zurvuvae®? Small dose excretion in breastmilk.

–Does not appear to cause mania in bipolar depression

Post-partum depression

•6-20% of post-partum individuals globally

•2^nd most common cause of post-partum maternal mortality

•Persistent depression for more than 2 weeks after birth

–More than “baby blues” that should resolve in a few weeks

•Worth a check-in with new parents.

•Do not confuse with post-partum psychosis - a much more rare and different diagnosis

Anyone with depression prior to pregnancy should make a post-partum depression treatment plan prior to delivery with additional attention from their primary care provider.