Anxiety Disorders and ADHD

physiologic symptoms of anxiety

rapid HR, sweating

types of anxiety disorders

Generalized Anxiety Disorder (GAD)

Panic Disorder

Separation Anxiety Disorder

Phobias

Social Anxiety Disorder

Agoraphobia (environment not safe)

Obsessive Compulsive Disorder

Post Traumatic Stress Disorder (PTSD)

Obsessions vs compulsions

Obsessions: repeated intrusive uncontrollable thoughts/impulses that cause distress

Compulsions: repeated physical/mental behaviors that are done in RESPONSE to an obsession

Chronic and long-term psychiatric disorder

Suffer from obsessions and compulsions

OCD

what hormone plays a fundamental role in the pathogenesis of OCD?

5-HT

4 types of PTSD symptoms

1. Intrusive memories (recurrent, unwanted distressing memories of traumatic event)

2. Avoidance (avoid talking, avoid places, activities or people that remind you of trauma)

3. Negative affect (anhedonia, hopelessness)

4. Emotional reactivity (anger, irritable, shame, easily frightened)

what are the two main brain regions involved in the neurobiology of anxiety?

amygdala

hippocampus

Hub for processing incoming sensory signals and interpreting signals

Alerts the brain about a threat and triggers a response

Fear associated emotional memories stored here

amygdala

happy and sad memories stored here

plays a role in flashbacks and retrieval of memories

hippocampus

what structure is smaller in victims of child abuse or military combat?

hippocampus

4 things that play a role in the neurobiology of anxiety

1. Brain structures (amygdala and hippocampus)

2. Neurotransmitters

3. Autonomic nervous system (sympathetic and parasympathetic)

4. Hypothalamic Pituitary Adrenal (HPA - stress axis)

how do anxiolytics work in treatment of anxiety?

they inhibit neuronal activity in brain structures that mediate fear and worry

they reduce symptoms of anxiety, panic attacks, extreme fear and worry

*** relieve symptoms - do not cure anxiety ***

classes of anxiolytics

1. sedatives: benzodiazepines and non-benzodiazepines

2. Buspirone

3. antidepressants

benefits and drawbacks of benzodiazepines

Benefits - effective in quickly relieving anxiety

Drawbacks - build up of tolerance when taken over a long period of time, requiring higher doses to get the same effect...dependency

***do not withdrawal quickly

Diazepam (Valium) Indications

-Anxiety

-Alcohol withdrawal

Diazepam MOA

positive allosteric modulator at benzodiazepine receptors; enhances GABA effects

Diazepam

Benzodiazepine for anxiety

Non-Benzodiazepine MOA and indications

Same mechanism of action as BDZs

Helps patients who have difficulty falling asleep, more effective as a sedative than anxiety med

Melatonin MOA

hormone produced by pineal gland to regulate circadian rhythm

melatonin receptor agonist --> promote sleep

first non-controlled sleep agent that targeted melatonin receptors

Ramelteon

Ramelteon MOA

Agonist at MT1 and MT2 melatonin receptors

___________ is a novel and selective MT1 and MT2 receptor agonist for treatment of insomnia characterized by difficulty in sleep onset

Ramelteon

10X more potent than MT in promoting sleep

Ramelteon

what drugs are first line for treatment of OCD?

SSRIs and TCAs

______________ was the first to show beneficial effects on OCD symptoms, however, it's is less well tolerated than the SSRIs

Clomipramine

Clomipramine

tricyclic antidepressant

Fluoxetine

SSRI (Prozac)

how long does it take to see benefits with SSRI treatment (OCD)?

10-12 weeks

Mechanism of action of SSRI (Fluoxetine) for OCD:

•Block 5-HT reuptake

•Results in increasing synaptic 5HT release in the orbitofrontal cortex and other brain areas

Which TCA is used for OCD?

Clomipramine

______________ are a commonly prescribed class of anti-anxiety medication that can help reduce the severity of panic attacks.

Benzodiazepines

Clonazepam and alprazolam are benzodiazepines indicated for __________

panic attacks

which benzodiazepines are indicated for panic attacks?

Clonazepam and alprazolam

Clonazepam and alprazolam MOA in treatment of panic attacks

BDZ agonists that modulate the activity of GABA (positive allosteric modulator)

By affecting the GABA receptors, clonazepam slows down the CNS, which decreases nervousness and agitation while eliciting a sense of calm and relaxation.

they act fast!

____________indicated for MDD, are the first line of therapy for anxiety disorders.

SSRIs

how long does it take for SSRIs to improve anxiety?

2-4 weeks

Venlafaxine - what is it and how can it treat anxiety?

Serotonin Norepinephrine Reuptake Inhibitor (SNRI)

MOA not fully understood

•Reduce the symptoms of depression that accompanies anxiety disorders

•GAD, PD, separation anxiety disorder

diagnosis/symptoms ADHD

For diagnosis, symptoms should present before age 12, present for at least 6 months & interfere with daily activities & in different settings

-Failure in sustaining attention

-Not following instructions

-Does not listen when spoken to

-Hyperactivity and Impulsivity

-Fidgets or taps hands or feet

can ADHD be cured?

ADHD can be effectively treated but NOT cured

ADHD triad of symptoms

impulsivity, inattention, hyperactivity

what is the main pharmacological goal in treatment of ADHD?

to increase central DA and NE activity (both DA and NE are low in patients with ADHD)

2 major classes of drugs for treatment of ADHD

•Psychostimulants

•Non-stimulants

psychostimulant MOAs

Block reuptake of dopamine (DA) and norepinephrine (NE): Inhibit DAT and NET, increasing DA and NE levels in the synapse.

Increase release of DA and NE: Inhibit VMAT2, causing more DA and NE to be released from storage vesicles into the synapse.

High DA levels → downregulation of D2 receptors: Too much dopamine leads the brain to reduce D2 receptor numbers to prevent overstimulation.

High NE levels → downregulation of alpha-2 receptors: Increased norepinephrine causes the brain to reduce alpha-2 receptor numbers to maintain balance.

Lisdexamphetamine - what is it and MOA

Lisdexamfetamine is a prodrug converted to dextroamphetamine.

The mechanism of action of dextroamphetamine in the treatment of ADHD is unknown.

Amphetamines cause the release of dopamine and norepinephrine at presynaptic nerve terminals and may block the reuptake of norepinephrine and dopamine by competitive inhibition.

Lisdexamfetamine - long acting or short acting?

long acting

Amphetamine/dextroamphetamine

Adderall; short acting

Amphetamines MOA

-Amphetamines competitively bind to DA and NE transporters

-Get transported into the presynaptic DA or NE terminal

-Inhibit VMAT2 to release DA and NE from vesicles

-High doses inhibit monoamine oxidase activity

Methylphenidate MOA

Methylphenidate acts as a NE and DA reuptake inhibitor (NDRI)

–Increases NE and DA in the synapse, prolonging their action

•No action on VMAT2

non-stimulants for treatment of ADHD

Antidepressants

•Atomoxetine

•TCAs

•Bupropion

Alpha2 Adrenergic Agonists

•Guanfacine

•Clonidine

what population are alpha2 adrenergic agonists more effective in for the treatment of ADHD?

More effective in children than adults

Atomoxetine indication

used for treatment of ADHD when stimulants cannot be tolerated in children or if they have anxiety

Atomoxetine MOA

selective NE reuptake inhibitor (SNRI); non-stimulant

Imipramine MOA for ADHD

NE reuptake blocker

TCA

first and only non-stimulant medication approved by FDA for treatment of ADHD

Atomoxetine

____________ is used for treatment of ADHD with patients who have co-existing conditions such as untreated glaucoma, structural heart defects, and uncontrolled seizures

Atomoxetine

_____________ can be additive to other second-line ADHD medications such as the alpha2 receptor agonist medications (guanfacine and clonidine)

Atomoxetine

Why doesn't atomoxetine have abuse potential like stimulants?

It doesn't increase NE or DA in the brain's reward center (nucleus accumbens), so it doesn't cause euphoria or hyperactivity.

How does a selective norepinephrine reuptake inhibitor (like atomoxetine) help with ADHD?

It increases norepinephrine (and indirectly dopamine) in the prefrontal cortex, improving focus and attention in patients with low NE/DA levels.

which is more selective for a2A receptors - Guanfacine or Clonidine?

Guanfacine

What is Guanfacine (Intuniv) and how is it used in ADHD treatment?

Guanfacine is a non-stimulant ADHD medication that directly stimulates post-synaptic α2A-adrenergic receptors to improve NE transmission in the prefrontal cortex.

How does Guanfacine improve ADHD symptoms?

By activating α2A receptors in the prefrontal cortex, it improves working memory and reduces inattention, hyperactivity, impulsivity, emotional reactivity, and insomnia.

why is Guanfacine considered a good option for some ADHD patients? what individuals might benefit?

It is not a controlled substance, has low abuse risk, and is helpful for patients who can't tolerate stimulants or have a history of substance abuse.

What is Clonidine approved for and how is it used in ADHD?

Clonidine is approved for hypertension but used off-label for ADHD, conduct disorder, oppositional defiant disorder, and Tourette's. It reduces inattention, hyperactivity, and impulsivity

When is Clonidine recommended in ADHD treatment?

It's recommended for patients who don't respond well to stimulants, and it can also be used with stimulants in severe ADHD cases.

What is the mechanism of action of Clonidine?

Clonidine is a nonselective alpha-2 adrenergic agonist that binds to α2A, α2B, and α2C receptors, and also to imidazoline receptors, contributing to its sedative and blood pressure-lowering effects.

What are common side effects of Clonidine?

Dry mouth, dizziness, constipation, low blood pressure, slow heart rate, drowsiness, allergic reactions, and potential heart issues