Ch 13: Antidepressants

Major depressive disorder

Classified as a major affective disorder (aka mood disorders)

Disordered feelings; disturbances in mood/emotion

Normal life experiences (ups and downs) should not be confused with

Mood disorders (serious medical illnesses)

Different kinds of depressive mood disorders

Bipolar disorder (manic-depressive illness), post partum depression, psychosis and clinical depression/ unipolar disorder (most common)

Mood disorders

Very real illness

Can have serious/ sometimes fatal results

Affect entire body, not just mind

Many people never realize they are suffering from depression

Physical symptoms of mood disorders

Range from fatigue to stomach complaints or muscle and joint pain

Major depressive episode 2012 to 2022 (past year)

4.7% to 7.6%

Lifetime of major depressive episode 2012 to 2022

11.9 to 14%

In order to have a diagnosis of major depressive disorder

Five or more of the symptoms must be present for at least 2 weeks

One must be from first two

Symptoms of major depressive disorder (9)

1) Sense of sadness, despair, hopelessness, emptiness or feeling down

2) loss of interest in things that were once pleasurable

3)change in appetite/ body weight

4) Sleep disturbances

5) Psychomotor disturbances (excessive or lack of motor activity)

6) Tired/ devoid of energy

7) Worthlessness/ unwarranted guilt

8) Inability to focus, think clearly, or make decisions

9) Thoughts of suicide/ attempts

DSM

Guide to diagnosis of mental disorders

Neuroimaging differences in depression

PFC/ hippocampus decrease in size

Amygdala increases in size

Imaging techniques

Help identify regions but tell us nothing about neurochemical abnormalities found in depression

Monoamine theory of depression

Mood is related to functioning of the monoamines; particularly 5-HT and NE (DA may play a role)

Depression is the result of reduced levels of activity in these systems

5-HT

Seratonin

Early evidence for monoamine theory

Drugs that enhance monoamine neurotransmission make people feel good (coke, amphetamine)

Decreased transmission at monoamine synapses is associated with depression

Depression with Parkinson’s

Reserpine

Depression is the most common psychiatric condition in individuals with what?

Parkinson’s disease (loss of dopamine neurons in pathway)

Individuals treated with reserpine

Showed improvement in hypertensive symptoms

Developed severe depression

Reserpine

Irreversibly blocks the vesicular monoamine transporter (VMAT)

Normally transports free intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal into presynaptic vesicles for subsequent release into the synaptic cleft

(Transporters package neurotransmitter into vessible, this drug blocks these transporters, less neurotransmitters getting released)

Glucocorticoid theory of depression

Chronic overactivation of glucocorticoid receptors causes changes in brain structure/ function

Stress triggers hypothalamus to release

CRH (corticotropin releasing hormone)

CRH signals pituitary to release

ACTH (adrenocorticotropic hormone)

ACTH signals adrenal gland to release

Glucocorticoids (cortisol)

Catecholamines (epinephrine, norepinephrine, aldosterone)

High levels of cortisol activates

Receptors in pituitary/ hypothalamus (2 negative feedback pathways)

The theory is basically that the

Negative feedback is disfunctional

What is a frequently observed abnormality in patients with major depression

Hypercortisolemia

Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis

Reduces hippocampal volumes

Reduces prefrontal cortex (PFC) activity

Disrupts homeostasis within the neurocircuitry of depression

How do the two theories go hand in hand

Monoamine releasing neurons have glucocortical receptors

How do antidepressants generally work

By increasing activity in one or more of the monoamine systems of the brain (but other transmitter systems may be affected)

Classification of Antidepressants

First Generation

Second Generation

Third Generation

First generation antidepressants

MAOIs (monoamine oxidize inhibitors)

TCAs (tricyclase)

MAOIs

Inhibit activity of MAO (enzyme that breaks down monoamines)

Thus molecules of DA, NE and 5-HT that float freely in cytoplasm are not destroyed but are available for vesicle storage and later release

Steps of MAOIs

1) Dopamine produced

2) Packaged into vesicles (quickly to not get destroyed by MAOs)

*MAOI drugs inhibit this enzyme, more dopamine not getting destroyed

TCAs

Block reuptake of 5-HT and NE

Also affect other transmitter systems - non selective (antagonize muscarinic, histamine, adrenergic receptors)

Second generation antidepressants

SSRIs (selective seratonin reuptake inhibitor)

SSRIs

Block reuptake of 5-HT (with minimal effect on other monoamines or other transmitter systems)

Still side effects like sexual dysfunction

Third generation antidepressants

SNRIs (selective norepinephrine reuptake inhibitors)

Atypicals (all other antidepressants)

SNRIs

Block reuptake of 5-HT, NE (and dopamine)

Atypicals

Mechanism of action varies, depends on drug

Possible mechanism of action may include blocking monoamine reuptake; antagonist for autoreceptors (NE, 5-HT) (Preventing inhibitory feedback)

TCA time to maximal blood concentrations

1-3 hours

SSRI, SNRI, Atypicals time to maximal blood concentration

4-8 hours

First pass metabolism

Destroys a significant proportion of the dose of most antidepressants (absorbed from GI system)

Why should you not mix first gen antidepressants with alcohol

First pass metabolism is inhibited by alcohol

(End up with way more drug molecule in blood stream than intended)

Antidepressant distribution

Readily cross blood brain barrier

MAOIs half life

2-4 hrs

TCAs half life

24 hours

Second/ third gen half lives

15-25 hrs

Side effects of MAOIs

Tremors, weight gain, blurry vision, dry mouth, lowing of blood pressure and postural hypotension

Cheese effect

Seratonin syndrome

Postural hypotension

Blood pressure bottoms out when changing position (pass out when stand up)

“Cheese effect”

MAO required for break down of tyramine

Tyramine has no way of breaking down → side effects mimic sympathetic

Tyramine

High in foods like fermented cheese

Causes effects that mimic sympathetic nervous system activation (sweating, nausea, increased blood pressure, internal bleeding, stroke and death)

Older MAOIs

Non selective (a/b) and irreversible

Strict diet

Newer MAOIs

“Safer”

Reversible and target only one kind of MAOs

Have to be mindful of diet but not strict

Seratonin syndrome

Often described as a clinical triad of abnormalities (cognitive, autonomic, somatic effects)

Can occur from many medications

Mild symptoms of serotonin syndrome

Mydriasis (constricting pupils)

Shivering

Sweating

Tachycardia (inc HR)

Moderate symptoms of seratonin syndrome

Altered mental status (agitation, disorientation, excitement)

Autonomic Hyperactivity (rigidity, tachycardia, hyperthermia of >40 degrees)

Neuromuscular Abnormalities

Life threatening symptoms of seratonin syndrome

Delirium

Hypertension

Hyperthermia

Muscle rigidity

TCAs effects on body

Can affect autonomic nervous system function (blocking cholinergic receptors)

Inhibit parasympathetic division (dry mouth, constipation, blurred vision, excessive sweating, tremors)

Why can TCA cause dizziness, irregular heartbeat and postural hypotension

TCAs has influence on adrenergic receptor function

Why can TCA cause increased appetite/ sweet tooth

Has influence on histamine activity

SSRIs effects on the body

Fewer nonspecific actions on systems outside of seratonin (less unpleasant effects)

May cause nausea, GI problems, headache, dizziness, sweating, nervousness and agitation (tend to dissipate with time)

5HT1a vs 5HT2

5HT1a: therapeutic effects

5HT2: side effects

Third generation side effects

Increased appetite, weight gain, changes in blood pressure, dizziness, dry mouth, GI problems, restlessness, agitation, tremors, nausea, dry mouth, sedation

What causes side effects of third generation

Due to antagonism of acetylcholine and histamine and enhancement of 5-HT2-3 receptor activity

Tolerance to therapeutic effectives

Some individuals may show tolerance after a few months, but extent and clinical significance in unclear

Tolerance to many side effects

Occurs within several weeks (Except for tiredness reported with SSRIs)

Withdrawal

Antidepressants should not be abruptly discontinued (physical dependence)

TCAs withdrawal symptoms

Restlessness, anxiety, chills, akathisia (Compulsion to move) and muscle aches

SSRIs withdrawal

Dizziness, lightheadedness, insomnia, fatigue, anxiety, nausea, headache and sensory disturbances

Serotonin Discontinuation Syndrome

FINISH

(Any that target serotonin system)

FINISH

Flulike symptoms

Insomnia

Nausea

Imbalances

Sensory disturbances (brain zaps)

Hyperarousal

Some drugs still show seratonin discontinuation symptoms after

Tapering/ not sudden discontinuation

Efficacy rates

Roughly similar for all classes (individual differences as to which works best)

Differences in way that different types of depression respond to different antidepressants

Approximately 60-70% of individuals with major depression

Get some relief from antidepressants

Only about 30-50%

Show full remission of symptoms

Limitations in Antidepressant drug

All antidepressant drugs have lengthy response time

Treatment - resistant depression

Lengthy response time

Clinically significant effects occur after two weeks of treatment; full effects after four weeks

Treatment resistant depression

Successive failed attempts at significantly reducing depressive symptoms

(29-46% of patients are treatment resistant)

Depression symptoms overview

1) Sad

2) Loss of interest

3) Appetite

4) Sleep

5) Psychomotor

6) Tired

7) Worthlessness

8) Focus

9) Suicide