Pharm II Week 5 (Antidepressants, Anxiolytics, Sedatives, Hypnotics)

Major Depressive Disorder

•Depressed mood or loss of interest ≥ 2 weeks with functional impairment

•DSM-5: ≥ 5 symptoms for ≥ 2 weeks, including depressed mood or anhedonia

Anxiety Disorders

•Persistent, excessive worry or fear causing distress or impairment

•DSM-5 (GAD): Excessive anxiety/worry most days for ≥ 6 months, difficult to control, with associated symptoms (e.g., restlessness, fatigue, poor concentration)

Insomnia Disorder

•Difficulty falling or staying asleep with daytime impairment

•DSM-5: Sleep difficulty ≥ 3 nights/week for ≥ 3 months, despite adequate opportunity for sleep

incidence MDD

8.3% of U.S. adults (~21 million) experience annually

Higher prevalence in women (10.3%) versus men (6.2%)

Highest rate in young adults (18-25 years)

incidence anxiety

19.1% of U.S adults experience annually

31% lifetime prevalence (nearly 1 in 3 adults)

Frequently coexists with depression

incidence insomnia

30-40% of adults report insomnia symptoms

Strongly associated with depression, anxiety, substance use disorders

Drivers of Increasing Rates

Strong Evidence: COVID-19 stressors; economic hardship; improved screening; reduced stigma

Moderate: Primary care recognition; social stress; sleep disruption

Mixed: Social media use; lifestyle changes

Overview of CNS Neurotransmitters

Serotonin (5-HT)

Mood regulation, anxiety control, sleep initiation, appetite regulation

Overview of CNS Neurotransmitters

Glutamate

Primary excitatory neurotransmitter, learning and memory, synaptic plasticity

Overview of CNS Neurotransmitters

Norepinephrine (NE)

Alertness, attention, stress response, sympathetic activation

Overview of CNS Neurotransmitters

Gamma-Aminobutyric Acid (GABA)

Primary inhibitory NT, reduces neuronal excitability, promotes relaxation and sleep

Overview of CNS Neurotransmitters

Dopamine (DA)

Motivation, reward pathways, focus and cognition

Pathophysiology of Depression

2 key parts

•Monoamine Deficiency Hypothesis (purple box): have less/ineffective toward 5HT, NE, and or DA. initiator.

•Neuroplasticity Changes: longer term effects. decreased brain-derived neurotrophic factor (BDNF), decreased neurogenesis, hippocampal atrophy, impaired synaptic signaling

Pathophysiology of Anxiety Disorders

GABA and Glutamate Imbalance - normal vs in anxiety?

Normal Balance

- GABA: inhibitory

- Glutamate: excitatory

In Anxiety

- Decreased GABA inhibition, increased excitatory neurotransmission, increased amygdala activity

- Manifests as restlessness, hypervigilance, muscle tension, sleep disturbance

Pathophysiology of Anxiety Disorders

Noradrenergic Overactivity

Increased norepinephrine causes: tachycardia, sweating, tremors, panic symptoms

Linked to locus coeruleus activation, sympathetic nervous system stimulation

Pathophysiology of Insomnia

Sleep-Wake Dysregulation

Normal regulation involves GABA-mediated sleep pathways, circadian rhythm control, melatonin release

Insomnia: Increased CNS arousal, decreased GABA activity, disrupted circadian rhythm control

hyperactivation of the stress response system with strong cognitive and behavioral component.

Neural Substrates: Related Brain Regions (what do they process?)

Amygdala

Prefrontal Cortex

Hippocampus

Locus coeruleus

Hypothalamus

Amygdala

Fear and threat processing

Prefrontal Cortex

Executive control and emotional regulation

Hippocampus

Memory and mood regulation

Locus coeruleus

Norepinephrine release center

Hypothalamus

Sleep and circadian regulation

Antidepressants: Big Picture

1.SSRIs 

2.SNRIs

3.Atypical antidepressants 

4.TCAs 

5.MAOIs

SSRIs: Mechanism & Role

-Block serotonin reuptake results in increased serotonin in synapse

-First-line for depression and anxiety disorders  

-Favorable safety profile compared to older agents 

SSRIs: common issues

• GI upset

• Sexual dysfunction: Major cause of nonadherence

• Activation or sedation: Activation can worsen anxiety early

• Discontinuation symptoms (dizziness, irritability, “brain zaps” Flu-like symptoms, insomnia)

• Do not stop abruptly: Slow taper

SSRIs: Additional Highlights

Time to Effect

takes time!!

Initial improvement: 1–2 weeks

Full response: 4–6 (up to 8) weeks

Early side effects often appear before benefit

Serotonin Syndrome Risk

SSRI + MAOI (contraindicated!)

SSRI + another (tramadol / linezolid / other serotonergics)

stop offending agent and monitor fluids, consider 5HT antagonist. can be fatal!

serotonin syndrome triad

Triad

1.Mental status changes

2.Autonomic instability (fever, tachyc)

3.Neuromuscular hyperactivity (tremors, seizures, etc.)

CYP Drug Interactions

Strong inhibitors: fluoxetine, paroxetine, fluvoxamine (strongest)

Lower interaction burden: sertraline, escitalopram

Can increase levels of many co-administered drugs (e.g., inc level of warfarin, BB, antipsychotics)

Comparing SSRIs / Overview

know the major pearls well! and halflife application with withdrawl.

fluoxatine: primary activator, very long half life (less discontinuation sdr)

sertraline: versatile! less SE

Paroxetine (Paxil): shortest! most withdrawl sx if quickly stopped

Escitalopram (Lexapro): better version of Citalopram. LESS SE. dual inidcation for ANX AND DEP.

Fluvoxamine (Luvox): MANY drug interactions. some usage in OCD.

Failure or intolerance of one SSRI does NOT mean?

Failure or intolerance of one SSRI does NOT mean failure of all SSRIs

SNRIs: Mechanism

Inhibit reuptake of serotonin (5-HT) and norepinephrine (NE)

NE effects become more prominent at higher doses

SNRIs Clinical Indications

• Major depressive disorder

• Generalized anxiety disorder

• Neuropathic pain (key differentiator from SSRIs) !!

• Fibromyalgia

• Diabetic peripheral neuropathy

• Musculoskeletal/chronic pain syndromes

Why choose an SNRI instead of an SSRI?

• Depression + pain symptoms

• Partial response to SSRI

• Prominent fatigue/low energy symptoms

• Comorbid anxiety + somatic symptoms

SNRIs ADRs

•Cardiovascular: hypertension, tachycardia, palpitations

•CNS / Systemic: insomnia or activation, sweating, anxiety, nausea

SNRIs Discontinuation Syndrome

•Particularly venlafaxine (most notorious)... bc SHORT HALF LIFE

•Can occur within 1–3 days of missed doses

•FINISH pneumonic

SNRIs Monitoring Recommendations

•Blood pressure (baseline and follow-up)

•Heart rate in symptomatic patients

•Monitor adherence closely

Comparing SNRIs

know the top 3 BEST

Venlafaxine (Effexor): MDD, GAD, panic disorder. highest BP risk

Desvenlafaxine (Pristiq): MDD only. fewer drug drug interactions.

Duloxetine (Cymbalta): Best SNRI for pain syndromes

Clinical Pearls for SNRIs

- Venlafaxine = highest withdrawal risk SNRI

- Always taper slowly when discontinuing

- Missing even 1-2 doses can trigger symptoms in sensitive patients

- Duloxetine preferred when pain is a major component

•Depression + pain → ?

•Depression + anxiety → ?

•Poor tolerance to venlafaxine → ?

•Need more NE effect → ?

•Depression + pain → Duloxetine

•Depression + anxiety → Venlafaxine

•Poor tolerance to venlafaxine → Desvenlafaxine

•Need more NE effect → Levomilnacipran

Overview of Drug Class - Atypical Antidepressants

Antidepressants that do not primarily act via serotonin reuptake inhibition (SSRIs) or serotonin/norepinephrine reuptake inhibition (SNRIs)

major agents - Atypical Antidepressants

Bupropion

Mirtazapine

Trazodone

indications for atypicals?

- Target specific symptom profiles

- Improve tolerability when SSRIs/SNRIs fail

- Manage side effects of SSRIs (e.g., sexual dysfunction, insomnia)

Buproprion MOA

Inhibits reuptake of dopamine (DA) and norepinephrine (NE)

Buproprion Clinical Uses

- Major depressive disorder

- Seasonal affective disorder

- Smoking cessation (Zyban)

- SSRI-induced sexual dysfunction (common switch/add-on strategy)

Buproprion Key Advantages

- No sexual dysfunction (major differentiator)

- Weight neutral or weight loss

- Activating (improves energy, motivation)

Buproprion ADRs

- Insomnia

- Anxiety/activation

- Lower seizure threshold (dose-related risk)

Buproprion Contraindications

Seizure disorder

Eating disorders (bulimia/anorexia)

Abrupt alcohol/benzodiazepine withdrawal

Mirtazapine MOA

α2 antagonism: ↑ norepinephrine + serotonin release

- Blocks 5-HT2 (reduces anxiety/insomnia) and 5-HT3 (reduces GI effects)

Strong H1 blockade → sedation

Mirtazapine Clinical Use

Depression with insomnia

Depression with weight loss or poor appetite

Frail or underweight patients

Mirtazapine Key Advantages

Strong sedation (especially at lower doses)

Appetite stimulation --> weight gain

Minimal sexual dysfunction

Mirtazapine ADRs

Sedation (dose-dependent pattern)

Weight gain

I

ncreased appetite

Rare neutropenia

Trazodone MOA

Weak serotonin reuptake inhibition

5-HT2 antagonism

Strong H1 and alpha 1 blockade

Trazodone Clinical Uses

Insomnia (most common use at low dose)

Depression (higher doses)

Trazodone ADRs

Sedation (avoid combining with other CNS depressants when used for sleep)

Orthostatic hypotension

Dizziness

Priapism (rare)

TCAs: Why Not First-Line?

work on a variety of receptors. variable and diverse drug --> many SE and toxicity concerns! such as:

1. Anticholinergic Toxicity

2. Narrow Therapeutic Index

3. Cardiovascular Toxicity

anticholinergic toxicity TCA symtoms

Dry mouth

Blurred vision

Constipation

Urinary retention

Confusion/delirium (especially elderly)

Strong reason TCAs are avoided in older adults

narrow therapeutic index - TCAs

High risk of overdose

“3 Cs of TCA overdose”:

•Coma

•Convulsions

Cardiotoxicity

Cardiovascular Toxicity - TCAs

Sodium channel blockade _ QRS widening

Orthostatic hypotension (_1 blockade)

Arrhythmias

QT prolongation risk

Important: dangerous in patients with cardiac disease

TCAs: Where are they used then?

Neuropathic Pain

Migraine Prophylaxis

Sleep (off-label)

TCAs - Neuropathic Pain

Diabetic neuropathy

Postherpetic neuralgia

Chronic pain syndromes

Migraine Prophylaxis - TCAs

Amitriptyline commonly used

Especially helpful in:

-- Chronic migraines

-- Patients with comorbid insomnia

Sleep (off-label) - TCAs

Sedating TCAs (amitriptyline) sometimes used at low doses

Comparing TCAs

Amitriptyline - Most commonly used TCA clinically

Nortriptyline - “Cleaner” TCA, better tolerated

Desipramine - Most activating TCA

Imipramine - Classic pediatric bedwetting drug

Clomipramine - Strong serotonergic activity

Doxepin - Very sedating; used for sleep

Protriptyline - Stimulating, less sedating

Monoamine Oxidase Inhibitors (MAOIs)

MOA

Inhibit monoamine oxidase (MAO-A and MAO-B)

Prevent breakdown of serotonin, norepinephrine, dopamine → ↑ synaptic monoamines

Where MAOIs Are Still Used

- Treatment-resistant depression

- Atypical depression (hypersomnia, hyperphagia)

- Parkinson disease (MAO-B inhibitors like selegiline)

Key MAOIs

• Phenelzine (nonselective, more sedating)

• Tranylcypromine (nonselective, more activating)

• Selegiline (MAO-B selective with low-dose; patch form reduces dietary restriction somewhat... minimizes ADRs)

MAOIs: High Risk

dietary restrictions

• Tyramine (aged foods) normally broken down by MAO

• MAOI → tyramine accumulation → hypertensive crisis

• High-risk foods: aged cheeses, cured meats (salami, pepperoni), fermented foods (soy sauce, kimchi), tap beer / draft beer

think charcuterie board stuff + soy sauce + beer

MOAIs - Drug Interaction Burden

Contraindicated combinations?

Contraindicated combinations:

SSRIs / SNRIs

Tramadol

Meperidine

Dextromethorphan

Linezolid

Safety Concerns MOAs

Hypertensive crisis (tyramine reaction)

Serotonin syndrome

Orthostatic hypotension

Weight gain, sexual dysfunction

 46-year-old male presents with:

Depressed mood, low energy 

Difficulty concentrating 

Diabetic neuropathic pain 

Requests medication that will “help mood and pain”

Current meds:

Metformin 

Tramadol PRN (think abt serotonin sdr here)

Best initial antidepressant?

A. Sertraline B. Bupropion C. Duloxetine D. Amitriptyline E. Not indicated

✅ Answer: C. Duloxetine

(Duloxetine)

💡Rationale:

Treats depression + neuropathic pain

SNRI dual mechanism ideal fit

46-year-old male follow-up:

Increased restlessness

Episodes of sweating and tremor

Recently increased tramadol use for pain

Current meds:

Metformin 

Tramadol PRN

Duloxetine

What is the most likely issue?

A. Serotonin syndrome B. Duloxetine toxicity C. Opioid withdrawal D. Hypoglycemia E. Not indicated

A. Serotonin syndrome

SNRI + tramadol = serotonergic overload risk

Always reassess new medications or dose changes

sx are indicative

Key Points for Antidepressants

Suicidality Warning (BBW)

BBW: ↑ SI risk in children, adolescents, young adults (<25)

•Highest risk: first weeks or dose changes

•Requires close follow-up, not avoidance of therapy

Key Points for Antidepressants

Pregnancy and Lactation

•Untreated depression also carries risk

•SSRIs commonly used when needed

•Avoid abrupt discontinuation (ESP in PREGNANCY)

Key Points for Antidepressants

Initiation and Titration

•Start low, go slow

•Early side effects common and do NOT equal failure... can switch to another class! esp SSRIs

Key Points for Antidepressants

Expected Timeline

• 1–2 weeks: side effects > benefit

• 2–4 weeks: early symptom improvement

• 4–6+ weeks: full therapeutic effect

Key Points for Antidepressants

when to switch meds

No response after adequate trial (4-6 weeks)

Intolerable side effects

Drug interactions or safety concerns

Key Points for Antidepressants

how to switch

Direct switch (most SSRIs / SNRIs)

Cross-taper (selected cases)

Washout required: MAOIs

• SSRI --> MAOI: 14 days (mitigate SE like serotonin sdr)

• Fluoxetine --> MAOI: ~5 weeks (logistically not great)

Key Points for Antidepressants

when to cross taper

High-dose antidepressant

Hx of discontinuation sx // Relapse risk is high!

Partial response to current med

Switching between different antidepressant classes (SSRI --> TCA, SNRI --> mirtazapine)... bridges

Concluding Thoughts on Antidepressants

know this well! be able to ID these based on need

Anxiety Disorders: Big Picture

Medication Categories

1. SSRIs/SNRIs (first-line long-term)

2. Benzodiazepines

3. Buspirone

4. Hydroxyzine

5. Pregabalin

6. Beta-blockers (situational anxiety)

•Benzodiazepines are not first-line long-term

•Goal: treat anxiety without creating dependence

Benzodiazepines MOA

Enhance GABA Activity

Benzodiazepines increase GABA, the brain’s main inhibitory neurotransmitter

Benzodiazepines Result

Result:

- Sedation

- Anxiolysis

- Muscle relaxation

- Anticonvulsant activity

Indications - Benzodiazepines

Acute anxiety

Panic attacks

Alcohol withdrawal

Status epilepticus

Procedural sedation

Nausea/vomiting

Catatonia

Benzodiazepines - Clinical Usage

- Short-term rescue medications

- Not ideal for chronic anxiety management

- Often used as bridge therapy while SSRIs take effect

Benzodiazepines - Adverse Effects

Sedation

Dizziness

Delirium

Memory impairment (anterograde amnesia)

Respiratory depression (especially when with opioids or alcohol)

Falls (especially elderly)

Dependence and withdrawal

Tolerance

Paradoxical reactions

Increased Risk Of  Withdrawal

Increased Risk Of  Withdrawal - Benzodiazepines

Higher doses

Longer duration

Shorter-acting agents

Withdrawal can be life-threatening and should not be stopped abruptly

Comparing Benzodiazepines - Agents and key clinical perals

•Lorazepam = safest all-around acute benzo

•Clonazepam = chronic panic control

•Diazepam = long-acting (withdrawal, muscle spasm)

•Alprazolam = fast but high dependence risk... short 1/2 life = high rebound anx

LOT drugs = metabolized by Glucuronidation so no active metabolites, thus have LESS drug drug interactions (from a CYP standpoint)

Non-Benzodiazepine Anxiolytics

Buspirone (Buspar) MOA

5-HT1A partial agonist

Modulates serotonin signaling

No GABA activity

Buspirone (Buspar) Clinical use

Generalized Anxiety Disorder (GAD)

Adjunct in SSRI-treated anxiety

***not great for acute scenarios

Buspirone (Buspar) Key Advantages

No dependence or withdrawal

No respiratory depression

No cognitive impairment (minimal sedation)

Buspirone (Buspar) Limitations

Delayed onset (2–4 weeks)

Not effective for acute anxiety or panic attacks

Less effective for severe anxiety compared to benzos

Hydroxyzine (Atarax, Vistaril) MOA

H1 receptor antagonist

Mild anticholinergic and sedative effects

Hydroxyzine (Atarax, Vistaril) Clinical Use

Short-term anxiety

Acute situational anxiety

Adjunct for insomnia related to anxiety

Agitation

Pre-procedural sedation (mild)

Hydroxyzine (Atarax, Vistaril) Key Advantages

No dependence

Works quickly (unlike buspirone)

Useful as PRN alternative to benzodiazepines

Hydroxyzine (Atarax, Vistaril) Limitations

Sedation (common)

Anticholinergic effects - dry mouth, blurred vision , urinary retention (caution in elderly)

Not for long-term anxiety control

Pregabalin (Lyrica) MOA

GABA analogue (binds alpha-2-delta subunit of voltage-gated Ca2+ channels)

Decreases excitatory NT release (glutamate, norepinephrine, substance P)

Pregabalin (Lyrica) Clinical Uses

Generalized Anxiety Disorder (GAD) (off-label in US; approved in some countries)

Neuropathic pain (diabetic neuropathy, post-herpetic neuralgia)

Fibromyalgia

Adjunct for partial seizure disorders

Pregabalin (Lyrica) Advantages

No benzodiazepine-type dependence pattern

No serotonin syndrome risk

Useful when anxiety + chronic pain overlap

Pregabalin (Lyrica) Limitations

Additive CNS depression - alcohol, opioids, benzos - dizziness, somnolence, blurred vision

Weight gain

Peripheral edema

Dose adjustment needed in renal impairment

Misuse potential exists (though lower than benzos)

Beta Blockers (Propranolol, Atenolol)

MOA

Block Beta-adrenergic receptors

Reduce sympathetic symptoms:

- Tachycardia

- Tremor

- Sweating

- Palpitations

*Does not treat psychological anxiety directly

Beta Blockers (Propranolol, Atenolol) - Clinical Use

Performance anxiety (stage fright)

Public speaking

Test-taking anxiety (situational)

Performance-related tachycardia/tremor

Beta Blockers (Propranolol, Atenolol) - Key Advantages

- Non-sedating

- No dependence or abuse potential

- Rapid onset (taken PRN before event)

Beta Blockers (Propranolol, Atenolol) -Limitations

Does NOT treat generalized anxiety disorder, panic disorder (core symptoms)

Can cause bradycardia, hypotension, fatigue, hypoglycemia (masks also)

Avoid in asthma/COPD (nonselective agents like propranolol)

40-year-old female presents with:

Daily anxiety

Palpitations in social situations

Muscle tension

Wants “non-addictive PRN option”

Medical history:

Mild intermittent asthma 

Uses albuterol PRN

Best PRN treatment?

A. Propranolol B. Buspirone C. Hydroxyzine D. Alprazolam E. Not indicated

✅ Answer: C. Hydroxyzine

(Hydroxyzine)

💡 Rationale:

Avoid beta-blockers due to asthma + albuterol use (so not A)

Non-addictive PRN option appropriate (so not D)

Buspirone long onset time (2-4 wks)