Unit 11: TCAs, MAOis, SSRIs, SNRIs

Question 1

Anxiety & Fear

Answer 1

Anxiety and Fear
- emotional states
- neuron circuitry that regulates these emotions is subcortical (subconscious)

Fear: an emotional state aroused by specific external stimuli, giving rise to defensive and evasive behaviours

Anxiety: a generalized response to an unknown threat or internal conflict—occurs when a person recognizes that they are not in control of a situation’s outcome

Question 2

Anxiety Disorders

Answer 2

Anxiety Disorders: psychiatric conditions characterized by:
- overactivity of the autonomic nervous system (ANS—fight or flight)
- expectation of an impending threat
- continuous vigilance for danger
- not caused by drug intoxication or withdrawal

Question 3

Types of Anxiety Disorders

Answer 3

1) Generalized Anxiety Disorder (GAD)
- persistant state of excessive worry and anxiety serious enough to cause a disruption in normal activities

2) Panic Disorder
- episodic periods of intense fear and ANS overactivation (fast heart beat, short breath, patients sincerely believe they are dying)

3) Anticipatory Anxiety
- a fear of having a panic attack; may lead to the development of agoraphobia

4) Agoraphobia
- a fear of being away from home or other safe places

5) Social Anxiety Disorder (SAD)
- excessive fear of being exposed to the scrutiny of other people that leads to avoidance of social situations

6) Post-Traumatic Stress Disorder (PTSD)
- a reaction to a terrifying event that occurs to, or is witnessed by, the patient
- characterized by flashbacks, nightmares, anxiety, compulsive thoughts about event

7) Obsessive Compulsive Disorder (OCD)
- characterized by intrusive, recurring, distressing thoughts, feelings, or ideas (obsessions)
- OCD drives the person to perform repetitive rituals/behaviours (compulsions) in order to subdue the intrusive thoughts

8) Separation Anxiety Disorder (SAD)
- generally occurs in children
- significant distress upon being separated from home or close attachment figures (eg: parents/guardians)
- excessive fear/worry of losing close attachment figures

Question 4

Anxiety Disorder Demographics

Answer 4

Anxiety Disorder Demographics
WHO
- females are twice as likely to develop an anxiety disorder—emphasizes a biological nature of the disorder, though gender may also play a role

WHAT
- a group of psychiatric disorders primarily characterized by some form of crippling anxiety

WHEN
- broad onset
- early childhood - adulthood (can happen anytime)

WHERE
- global; most prevalent psychiatric disorder
- lifetime prevalence: 20%

WHY
- genetics:
- low heritability—genetic factors account for 30% of cause

• environmental: 70%—many many factors
  
  • stress buildup
  • childhood trauma
  • trauma
  • low SES, etc

Question 5

Neurobiology of Anxiety Disorders

Answer 5

Neurobiology of AD
Technologies
(A) fMRI (functional magnetic resonance imaging)—measures small changes in blood flow occurring with brain activity
- activated brain regions have increased blood flow

(B) DTI (diffusion-tensor imagine)—newer technique—measures water molecule diffusion and its directionality
- allows us to study white matter tracts and connectivity

(1) Cortisol
- chronic psychological stress persistently increases level of stress hormone (cortisol), affecting neuron synapse numbers
- long term effects of high cortisol levels:
- increased blood pressure/risk of cardiovascular event
- immune suppression
- increased risk of type II diabetes
- synaptic degredation—reduces number of pathways
- damage to the hippocampus—important for memory; increased risk of developing dementia

(2) Amygdala
- patients with AD show an overactivation of the amygdala (region for fear/anger/negative emotions)
- reduced connectivity between frontal cortex (planning of appropriate behavioural responses) and amygdala (fear/anx)

Question 6

Treatment for Anxiety Disorders (AD)

Answer 6

Treatment for Anxiety Disorders
A) Psychotherapy:
- CBT (Cognitive Behavioural Therapy)
- DBT (Dialectical Behavioural Therapy)
- Exposure Therapy

B) Pharmacotherapy:
- first line treatment: SSRIs (Selective Serotonin Reuptake Inhibitors)
- benzodiazepines are used as alternative treatment for GAD and PD, but have limitations:
- tolerance
- withdrawal
- rebound effect
- abuse liability

Question 7

Major Depressive Disorder (MDD)

Answer 7

Major Depressive Disorder (MDD) (unipolar depression)
WHO
- affects women more than men
- in the 12-24 age group:
- highest in men at 5.2%
- highest in women at 9.6%

WHAT
- chronic depressed mood
- fatigue, avolition, anhedonia, changes in appetite and sleep, rumination, suicidality
- comorbid with anxiety disorders

WHEN
- onset often in adolesence/early adulthood but can occur anytime

WHERE
- high lifetime prevalence (approx. 15-20%)
- leading cause of disability worldwide
- cultural stigmas about depression vary—can prevent people from accessing diagnosis/therapies

WHY
- genetics (0.3-0.4)—30-40% of risk due to genetic factors
- environment—like AD, many environmental factors:
- psychological stress
- neurological imbalances
- SES/education, etc.

Question 8

Depression DSM-V Criteria

Answer 8

Depression Criteria: 5/9 symptoms for a minimum of two weeks

(1) Low Mood — depressed mood for most of the day
(2) Anhedonia — diminished interest or pleasure in all or most activities
(3) Apathy — lack of energy or motivation
(4) Weight — significant unintentional weight loss or gain
(5) Movement — noticeable agitation or psychomotor retardation
(6) Low Energy — fatigue or loss of energy
(7) Rumination — feelings of worthlessness or excessive guilt
(8) Brain Fog — diminished ability to think or concentrate, or indecisiveness
(9) Suicidality — recurrent thoughts of death and suicide

Question 9

Neurobiology of MDD

Answer 9

Neurobiology of MDD
Cortisol
- chronic stress induces depression
- overactive production of cortisol causes a decrease in the Brain Derived Neurotrophic Factor (BDNF) protein—related to nerve growth—causing:
- decrease in new neurons
- retraction of dendrites (sprout where neuron receives signal)

• antidepressants can reverse this process

Question 10

Treatment for MDD

Answer 10

Treatment for MDD
A) Psychotherapy—CBT (Cognitive Behavioural Therapy) is currently most effective

B) Pharmacotherapy:
- (1) Monoamine Oxidase Inhibitors (MOAi’s)
- (2) Tricyclic Antidepressants (TCA’s)
- (3) Selective Serotonin Reuptake Inhibitors (SSRI’s)
- (4) Serotonin/Norepinephrine Reuptake Inhibitors (SNRI’s)
- (5) Hallucinogens (ketamine, psilocybin, MDMA)

C) Electroconvulsive Therapy (ECT) and Transcranial Magnetic Stimulation (TMS)
- deep brain stimulation for treatment resistant individuals

Question 11

Monoamines

Answer 11

Monoamines
- endogenous monoamines derived from amino acids:
- dopamine (DA)
- norepinephrine (NE)
- serotonin (5HT)
- melatonin, histamine, trace amines

• monoamines regulate:
  
  • sleep
  • mood
  • appetite
  • peristalsis
  • arousal
  • sexual function
  • cognition
  • reward
  • motivation
  • aggression
• monoamines:
  
  • are all packaged into synaptic vesicles by VMAT2 (Vesicular Monoamine Transporter 2)
  • act on metabotropic, G-protein coupled receptors
  • are cleared from the synapse by plasma membrane transporters

Question 12

1) Monoamine Oxidase Inhibitors (MOAi)

Answer 12

1) Monoamine Oxidase Inhibitors (MOAi)
- monoamine oxidase is an enzyme that degrades monoamines (dopamine, norepi, serotonin, adrenaline, tyramine)
- MOAi’s were discovered in 1950—og a drug for tuberculosis

(A) Irreversible MOAi: Phenelzine
Target: MOA enzyme
Mechanism:
- once it binds to the MOA enzyme it permanently inactivates it
- highly effective, but not used unless all else fails

Adverse Effects—has many drug-drug interactions that cause:
- serotonin syndrome
- hypertensive crisis (really high blood pressure)—can also be caused by foods containing tyramine:
- cheese
- wine
- beer
- sauerkraut

(B) Reversible MOAi: Moclobemide
- also effective and much safer, but doctors are still reluctant to prescribe

Question 13

2) Tricyclics

Answer 13

2) Tricyclics
- discovered in 1956
- chemical compound G22355

Imipramine; Amitriptyline
Target: NE and 5HT
MOA: block the reuptake of both serotonin and norepi—antagonist for:
- 5HT2A/2C, 5HT6, 5HT7 receptors
- a1 adrenergic receptor
- histamine receptor
- cholinergic receptor (acetylcholine)
- voltage-gated sodium channels
- voltage-gated calcium channels