Depressive and Anxiety Disorder Pathophysiologies

ChAT

What is the synthetic enzyme of Acetylcholine (ACh)?

nAChR

mAChR: M1-M5

What are the acetylcholine receptors?

AChE

What is the degrading enzyme for acetylcholine?

Tyrosine hydroxylase

Dopa decarboxylase

What are the synthetic enzymes for Dopamine (DA)?

D1-D5

What are the receptors for Dopamine?

DAT

What it the transporter for Dopamine?

MAO, COMT

What are the degrading enzymes for Dopamine?

Dopamine beta-hydroxylase

What are the synthetic enzymes for Norepinephrine?

alpha-AR 1-2

beta-AR 1-2

What are the receptors for Norepinephrine?

NET

What is the transporter for Norepinephrine?

MAO, COMT

What are the degrading enzymes for Norepinephrine?

Tryptophan hydroxylase and decarboxylase

What are the synthetic enzymes for Serotonin (5-HT)?

5-HT1 - 5-HT-7

What are the receptors for Serotonin?

SERT

What is the transporter for serotonin?

MAO, COMT

What are the degrading enzymes for serotonin?

Histidine decarboxylase

What are the synthetic enzymes for Histamine?

H1-H4

What are the receptors for Histamine?

MAO, COMT

What are the degrading enzymes for Histamine?

Glutamine synthetase

What are the synthetic enzymes for Glutamate (Glu or E)?

mGluRs

iGluRs- NMDA-R, AMPA-R, KA-R

What are the receptors for Gultamate?

EAAT1-2

What is the transporter for Glutamate?

Glutamate decarboxylase

What is the synthetic enzyme for GABA?

GABA-A, GABA-B

What are the receptors for GABA?

GAT

What is the transporter for GABA?

GABA transaminase

What are the degrading enzymes for GABA?

Acetylcholine (ACh)

an imbalance in __________ can lead to disorders like: Psychosis with neurodegenerative diseases, Memory issues

dopamine

an imbalance in ________ can lead to disorders like: SUD, Schizophrenia, Delirium, Psychosis, Anxiety disorders, Depressive disorders

norepinephrine

an imbalance in _______ can lead to disorders like: Depressive disorders, Anxiety disorders

serotonin

an imbalance in __________ can lead to disorders like: Depressive disorders, Anxiety disorders, Obsessive compulsive disorders, ADHD

glutamate

an imbalance in ___________ can lead to disorders like: Schizophrenia, Depression, Seizures, Memory issues

GABA

an imbalance in _________ can lead to disorders like: SUD, Anxiety disorders, Sleep disorders, Seizures

1. Neurotransmitter synthesis

2. Neurotransmitter storage

3. Neurotransmitter release

4. Termination of neurotransmitter action

• Reuptake

• Degradation

• Diffusion

5. Receptor effects

What are the neurotransmission points of drug modulation?

dopamine

Synthesis of norepinephrine is largely dependent on _________ synthesis.

Tyrosine

is the precursor for dopamine

Tryptophan

the the precursor for serotonin

types of depressive disorders

-Major depression (MDD)

-Persistent (>2yr) depression

-Disruptive mood dysregulation

-Seasonal affective

-Peripartum depression

-Premenstrual dysphoric

-Atypical depression

-Bipolar disorder

major depression disorder

≥5 symptoms nearly every day for at least 2 weeks (DSM-5)

-Feeling sad, empty, hopeless

-Diminished interest or pleasure in all or almost all activities

-Significant weight loss or weight gain (when not dieting)

-Decrease/increase in appetite

-Insomnia or hypersomnia

-Restlessness or other psychomotor agitation

-Fatigue or loss of energy

-Feelings of worthlessness or excessive guilt

-Diminished ability to concentration

-Recurrent thoughts of death, suicidal ideation

basal ganglia

control of motor movement, routine behavoirs/routine learning, emotion

amygdala

emotions, fear, learning/memory

hippocampus

long term, short term, and spatial memory

thalamus

pain integration

prefrontal cortex

executive functions, planning, decision making, social behavoirs

there are multiple regions in the brain involved in depression which explains how you multiple effects not just sadness

Why is depression not just a change in mood?

1) monoamine dysregulation

2) neurotrophic loss

3) neuroendocrine dysfunction

What are the main hypotheses of mechanisms that underly depression?

monoamine hypothesis

Depression is caused by a deficit in the amount or function of the monoamines, especially 5-HT, NE, and DA in the cortical and limbic systems

increase

SERT polymorphisms _________ risk of MDD and suicidal behavior.

Reserpine

depletes monoamines, precipitates depressive symptoms

5-HT and NE

Post mortem analyses show reduced ____________ receptors in the brains of individuals which PMH of depression or suicidal thoughts.

monoamine system

nearly all available antidepressants target the __________

because tryptophan is the precursor for serotonin so low tryptophan equal low serotonin

Evidence suggests that some patients with depression who respond well to 5-HT based anti-depressants suffer relapse when changing to a low-tryptophan diet. WHY?

neurotrophic hypothesis

depression is due to a loss of neurotrophic support

MMD

is associated with a 5-10% volume loss in hippocampus

Worsens as disease progresses, esp if not treated

stress and pain

will result in decrease brain derived neurotrophic factor in hippocampus, cortex, and amygdala

chronic

While no therapies directly target BDNF signaling, almost all known antidepressants are associated with elevations in BDNF with ___________ administration

hypothalamus-pituitary adrenal axis

-dysfunction is common

-elevated cortisol and corticotrophin releasing hormone

-severity of MDD tends to associate with greater dysfunction of _________

hypothyroidism

-is a common comorbidity with MDD

-thyroid hormones are often used in conjunction with antidepressants

sex steroid deficiencies

are associated with depression

-hormone replacement therapies for both sexes improves mood and depression

HPA and neuroendocrine dysregulation

can contribute to reduction in brain derived neurotrophic factor (the binding of cortisol to glucocorticoid receptors in the hippocampus leading to decreased BDNF and decreased tissue volume in hippocampus)

-psychotherapy

-pharmacotherapies to counter NT imbalances

-brain stimulation

-exercise

What are the difference ways to treat depression?

psychotherapy

-Several forms of therapy increase metabolism in key brain regions (Martin Arch Gen Psych 2001, Paquette NeuroImage 2003, Goldapple Arch Gen Psych 2004)

-5-HT and DA signals change

-Neuronal structure also increases

pharmacotherapies to counter NT imbalances

-anti depressants

-mood stabilizers

exercise

-leads to an increase in DA, 5-HT, and BDNF

-maybe as effective as some pharmacotherapies

anxiety

-Natural response to stress= fear, worry, agitation, etc

-Common (natural) to experience anxiety occasionally

-Often a secondary response

-intense and debilitating anxiety may be a sign of an __________ disorder

generalized anxiety disorder

persistent and excessive worry about a number of things

agoraphobia

fear of public places

social anxiety disorder

fear of judgement in a social sistuation

separation anxiety disorder

recurrent and excessive distress about being away from home/loved ones

neurotransmitter imbalances

What is a common etiology of anxiety disorders?

serotonin imbalances with anxiety disorders

-5-HT levels are decreased in certain regions

-Alterations in SERT expression/function correlate with symptoms

-Presynaptic 5-HT1A agonism reduces anxiety

-Activation of some 5-HT2 subtypes increases anxiety

no major changes

What are imbalances with norepinephrine in anxiety disorders?

GABA imbalances in anxiety disorders

-GABA decreased in brain

-GABA-A receptors are decreased in brain

-increasing GABA-A activity reduces anxiety

tx of anxiety and anxiety like disorders

-removing triggers

-psychotherapy and cognitive behavioral therapy

-pharmacotherapies

-symptomatic tx

pharmacotherapies used in anxiety disorders

-anti-depressants

-sedatives

-serotonin receptor agonists

obsessions

Recurring and/or persistent thoughts that are difficult to ignore (unwanted and intrusive) and precipitate anxiety/distress

compulsions

Repetitive behaviors performed in response to an obsession in effort to reduce anxiety

types of obsessive compulsive and related disorders

-Obsessive Compulsive Disorder

-Hoarding Disorder

-Trichotillomania (hair pulling)

-Excoriation Disorder (skin picking)

-Body dysmorphic disorder

etiology of obsessive compulsive and related disorders

-decreased 5-HT signaling

-increased glutamatergic signaling

post traumatic stress disorder

fear and anxiety after experiencing and/or witnessing a shocking, scary or dangerous event

s/s of PTSD (for atleast 1 month)

-At least one re-experiencing symptom

-At least one avoidance symptom

-At least two arousal and reactivity symptoms

-At least two cognition and mood symptoms

Enuresis, mutism, attachment concerns

What is the presentation of children with PTSD?

etiology of PTSD

decreased 5-HT, HPA axis imbalances (cortisol), and imbalanced substance p and endorphin signaling

eating disorders

-Anorexia Nervosa

-Bulimia Nervosa

-Binge Eating Disorder

-Other specific feeding and eating disorder

-Avoidant Restrictive Food Intake Disorder

-Pica

-Rumination Disorder

patho of eating disorders

-Endocrine system

-Neurotransmitters- 5-HT, NE, DA, endocannabinoids, ghrelin, leptin, and other molecules

*Cause vs effect unclear

unknown

What is the etiology of eating disorders?

considerations for pharmacists when dealing with eating disorders

-potential alterations in pharmacokinetics

-potential alterations in pharmacodynamics

-meds that cause weight gain

-meds that may be abused