Exam 2 Lecture 21, Antidepressant I

Question 1

Monopolar Mood disorders (depression)

Answer 1

Continuous depression: Become and stay depressed

Recurrent depression: Bounce between depression and “normal”

Question 2

Bipolar Mood Disorder (manic-depressive illness)

Answer 2

Cycle of depression and mania: Bounce between elation and depression

Question 3

Major Depressive Disorder (MDD)

Answer 3

denotes 1 type of mood disorder, unipolar depression

Symptoms maybe secondary to adverse, distressing events in patients life (reactive) or may have no clear precipitating cause (endogenous)

lifetime prevalence in US is 17%, one of most common psych disorders

Associated with other med conditions; high co-morbidity with heart disease, diabetes, chronic pain and anxiety disorders

Economic cost $70 Billion

3.4% commit suicide

Question 4

Bipolar disorder

Answer 4

applied to recurrent cyclic episodes of mania and depression, used to be called “manic-depressive illness”

Form of psychotic disorder distinct from schizophrenia

1-3% prevalence in adult pop

Question 5

Trends in antidepressant use

Answer 5

Percentage of people using antidepressant has increased

Females tend to take more then men

Question 6

DSM-V criteria MDD

Answer 6

5 or more symptoms should have been present during at least a 2 week period and represent a change from previous functioning

Question 7

Symptoms of MDD

Answer 7

severely depressed mood for most of day

Anhedonia

Loss of interest or pleasure in normally enjoyable things

Feelings of extreme sadness, hopelessness, etc

Lost of self esteem; self depreciation

change in appetite with weight gain or loss

Suicidal thoughts

fatigue, decreased energy

early waking with trouble sleeping

Question 8

DSM-V criteria Biopolar disorder

Answer 8

3 or more of the following symptoms for >1 week and interfering with job or relationships

Question 9

Symptoms of Bipolar Disorder

Answer 9

inflated self-esteem and grandiosity

Extreme elation, tinged with dysphoria and irritability

Marked insomnia

Increased verbal and motor activity, increased goal-directed activities

Poor judgment

Mania alternates with depression, transition or “switch” can occur over a period of minutes to hours to days

Question 10

2 types of Bipolar disorder

Answer 10

Bipolar I disorder: at least 1 episode of mania

Bipolar II disorder: at least 1 episode of hypomania and 1 episode of depression

Question 11

Pathophysiology Depressive symptoms

Answer 11

symptoms traditionally sought to be associated with deficiencies of CNS monamine transmitters, specifically NE and/or 5HT.

Maybe disruption in linkage between the NE and 5HT systems

Question 12

Pathophysiology Manic symptoms

Answer 12

In bipolar disorder, were thought to be due to excessive monoaminergic transmission….especially by NE and DA

Question 13

Monoamine theory is…

Answer 13

Controversial, not all evidence fits

Current drug therapies based on this theory

Question 14

Definition Monoamine theory

Answer 14

Depression due to deficiency of monamine transmission by NE or 5-HT or both

Mania is due to an excess of monoamine neurotransmission

Question 15

Evidence supporting Monoamine theory

Answer 15

Reserpine (which depletes catecholamines) causes depression

MAO inhibitors (which prevent catecholamine and serotonin metabolism) are antidepressants

Drugs that block NE and 5HT reuptake (TCA and SSRIs) are antidepressants

Depressed patients excrete less catecholamine metabolites in urine, suggesting lower CNS catecholamine neuronal activity

Theory is based on mechanism of action of 1st effective antidepressant drugs….MAO inhibitors and TCA

Question 16

Where is 5HT produced

Answer 16

Rostral raphe nuclei and Caudal raphe nuclei

Question 17

Where is NE produced

Answer 17

Locus cerulean and Lateral tegmental NA cell system

Question 18

Issues with Monoamine theory

Answer 18

Some effective antidepressants do not block either NE or 5HT uptake by nerve terminals

Some drugs that do block catecholamine and serotonin uptake (blow and amphetamine) are poor antidepressants clinically

There is poor temporal correlation between the onset of the clinical antidepressants effect (3-4 weeks) and the blockade of re-uptake or MAO inhibition in brain (immediate)

Question 19

“Newer” evidence depression

Answer 19

suggests depression maybe due to loss of brain-derived neurotrophic factor (BDNF) in critical brain areas such as hippocampus and frontal cortex

BDNF normally promotes neurogenesis (birth of new neurons) in these regions, and BDNF deficiency is associated with fewer new neurons

Stress and pain = decrease BDNF levels, MDD patient have decreased hippocampal volume

Question 20

Neurotrophic hypothesis overview

Answer 20

BDNF critical for neural plasticity, exert neural growth via RTK B, Hippocampus to HPA (hypothalamus, pituitary, adrenal) axis, anterior cingulate, orbitofrontal cortex.

In animal models, direct infusion of BDNF alleviates major depression

BDNF in cerebral spinal fluid decreased in human with major depression

Question 21

Modification of theory addresses temporal discrepancy

Answer 21

chronic administration of antidepressants causes autoreceptor subsensitivity thereby increasing release of NE or 5HT from nerve terminals….

Dumbed down:

When NE reuptake blocked, more NE is in synapse that binds to alpha 2 auto receptors.

These receptors control negative feedback.

Since there is more NE to bind to the alpha 2, they become bound excessively and then they become internalized thereby reducing alpha 2 receptor density at presynaptic end.

Reduced density allows for more NE release since they would usually inhibit it but there are less alpha 2 auto receptors to inhibit release

Question 22

Reduced contacts at Dendritic spines and dendrites

Answer 22

Due to decreased Monoamines and BDNF acting on CREB dependent transcription, making less BDNF

Also Gluccocorticoids causes reduce in transcription that leads to neural development

Question 23

Neurotrophic Hypothesis

Answer 23

Chronic stress and/or genetic susceptibility overwhelms normal neuroplasticity and causes a decrease in neurogenesis in the hippocampus

BDNF is up-regulated with antidepressant use (in hippocampus)

BDNF and its receptor (TrkB) are required for antidepressant efficacy and hippocampal neurogenesis

Stress decreases BDNF production and neurogenesis

Question 24

Inflammation Hypothesis

Answer 24

Depression results from chronic inflammatory event

Increased cytokine levels damage glia and cause tryptophan to turn into the neurotoxin quinolic acid (QUIN) intreat of 5-HT

QUIN causes glutamate receptor activation and glutamate release, leading to excitotoxicity and decreased BDNF production

May explain why glutamate blockers (iu ketamine) have strong antidepressant effects

Question 25

Integration of all aspects theory of depression

Answer 25

HPA and steroid abnormalities may contribute to the suppression of BDNF gene expression

Binding of stress hormone in hippocampus leads to decreased BDNF synthesis, further results in decreased volume in hippocampus

Chronic activation of monoamine receptors by antidepressants down regulates HPA axis and appress to increase BDNF transcription

Question 26

Tricyclic structure

Answer 26

7 member ring middle, 2 6 member rings on each side

Question 27

Tricyclic Mechanism of Action

Answer 27

block reuptake of NE and/or 5HT by presynaptic terminals

Results in transmitters being more available at postsynaptic receptors, potentiating effects of released transmitter.

Reuptake block occurs quickly, within hours

Chronic use required to relieve depressive symptoms

Question 28

Tricyclic Chronic use

Answer 28

required to relieve depressive symptoms, must be secondary effect with delayed onset

Chronic use causes down-regulation of presynaptic a2 and 5HT autoreceptors on NE and 5HT nerve terminals, increasing release of NE and 5HT.

higher synaptic levels of these transmitters cause post-synaptic B-adrenergic receptor down regulation at about same time that antidepressant efficacy begins

Question 29

Tricyclic CNS effect

Answer 29

in normal (non-depressed) individuals, feelings of dysphoria, anxiety and sedation, difficult concentrating and thinking

In depressed patients mood is gradually elevated (2-3 weeks required for onset of effect)

Sleep disturbance corrected

Some sedation usually observed

Question 30

Tricyclic Autonomic effects

Answer 30

Anticholinergic effects: dry mouth, blurred vision, constipation, and urinary retention (due to blockade of muscarinic cholinergic receptors)

Cardiovascular effects:
Postural hypotension (due to peripheral a-adrenergic receptor blockade)

Tachycardia (due to cardia muascarinic receptor blockade and inhibitor of norepinephrine reuptake)

tendency to develop arrhythmias

Direct cardiac depressant

Serious cardio toxicity can result in patients with pre-exisitng cardiac disease

Question 31

Tricyclic other side effects

Answer 31

Excessive sweating
weight gain
risk of transition to manic excitement
Can precipitate glaucoma, especially in elders with narrow angle type
can rarely cause jaundice, agranulocytosis, teratogenic effects

Question 32

Tricyclic drug interactions

Answer 32

Potentiate effects of…

alcohol and CNS Depressants
MAO inhibitors
Biogenic amines (norepinephrine)
Anticholinergic drugs used in PD treatment, or anticholinergic effects of antipsychotic drugs

Question 33

Tricyclic absorption, distribution, fate

Answer 33

Well absorbed orally, peak plasma lvl 2-8 hrs

Widespread distribution, highly bound to plasma, long half life

t1/2 = 10 - 20 hrs imipramine, 80 hr protriptyline

due to long 1/2 life, serious toxicity at high plasma level, can be life threatening in those prone to suicide

NEVER DISPENSE MORE THAN A WEEK’S SUPPLY OF A TCA TO ACUTELY DEPRESSED PATIENT