4.5 | Antidepressants

Major Depressive Disorder (MDD)

- Depression of mood without any obvious medical or situational causes

- inability to cope with ordinary events or experience pleasure

- modern and standardized diagnosis

Endogenous depression

older and descriptive term that likely refers to a melancholic subtype MDD

most common of the affective disorders

Depression

Depression

- range: very mild, bordering on normality, to severe and psychotic

- accompanied by hallucinations and delusions

Unipolar Disorder

- mood swings are always in the same direction

- [either] depression or mania

Bipolar Disorder

depression alternates with mania

Reactive depression

response to an external event e.g.:

1. life events

2. physical illness

3. drugs

MDD: Pathophysiology (3)

1. Monoamine hypothesis

2. Neurotrophic hypothesis

3. Endocrine factors

Monoamine hypothesis

deficiency of NE, 5-HT & DA in the synapses of the CNS

↓ NE

1. Alertness & energy

2. Anxiety

3. Attention

4. Lack of interest in life

↓ 5-HT

1. Anxiety

2. Obsessions

3. Compulsions

↓ DA

1. Attention

2. Motivation

3. Pleasure

4. Reward

5. Interest in life

Neurotrophic hypothesis

loss of neurotrophic support from the nerve growth factor like brain-derived neurotrophic factor (BDNF)

nerve growth factor like BDNF (3)

regulates:

1. Neural plasticity

2. Resiliency

3. Neurogenesis

Endocrine factors (2)

1. hippocampal volume loss

2. anterior cingulate

hippocampus & anterior cingulate

integral role in emotional stimuli & attention function

hippocampus ONLY

- hypothalamic-pituitary-adrenal (HPA) axis

- contextual memory

hippocampal volume loss

increases according to duration & if depression is left untreated

Depression: Treatment Options (2)

1. Psychotherapy

2. Electroconvulsive therapy

Psychotherapy

talking with a mental health professional

Electroconvulsive therapy

electrical stimulation of the brain under anesthesia to produce a controlled seizure

Antidepressant Classes (6)

1. Monoamine oxidase Inhibitors (MAOIs)

2. Tricyclic Antidepressants (TCAs)

3. Selective Serotonin Reuptake Inhibitors (SSRIs)

4. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

5. Heterocyclic Antidepressants

6. 5-HT2 Receptor Modulators

Antidepressants: Clinical Uses (8)

1. Panic disorder

2. Generalized anxiety disorder (GAD)

3. Post-traumatic stress disorder (PTSD)

4. Obsessive-compulsive disorder (OCD)

5. Premenstrual dysphoric disorder (PMDD)

6. Postpartum depression

7. Neuropathic pain

8. Fibromyalgia and migraine prophylaxis

*MAOIs

*Causes blockade of monoamine oxidase (MAO) A and B and increases monoamine content

MAOIs: Nonselective (2 + 3)

Phenelzine

Tranylcypromine

*Pargyline

*Hydrazines

*Iproniazid

MAOIs: Selective MAO-A (1 + 1)

Moclobemide

- for 5-HT, NE, Tyramine

*Clorgyline

MAOIs: Selective MAO-B

Selegiline

- for DA

*Reversible MAOI (2)

Moclobemid

*Clorygyline

*Irreversible MAOI (5)

Phenelzine

Tranylcypromine

*Pargyline

*Iproniazid

*Isocarboxazid

MAO

- mitochondrial enzyme

- involved in the metabolism of catecholamines or monoamine neurotransmitters of 5-HT, NE, DA, Tyramine

MAO - A

- primary substance 5-HT, NE, DA

- inactivation of monoamines (*5-HT or NE) that may leak out of presynaptic storage vesicles

MAO - A: Present in (4)

DA and NE neurons:

1. Brain

2. Gut

3. Placenta

4. Liver

MAO - B

- DA metabolism

- acts primarily on DA, Tyramine, Phenylethylamine, Benzylamine

MAO - B: Present In (4)

5-HT & H neurons:

1. Brain

2. Liver

3. Platelet

MAOIs: Pk (ADME)

A: fairly rapidly

D: peak plasma level within two to three hours, highly protein bound

E: hepatic metabolism

MAOIs: Structure

ring-closed amphetamine derivatives

MAOIs: MOA

- reduces NE & 5-HT breakdown in the presynaptic neurons

- ↑ NE & 5-HT in the vesicles

MAOIs: SEs (3)

1. Peripheral autonomic sympathomimetic effects

2. Psychotic symptoms, confusion, delirium, fever

3. ↓ Seizure threshold (↑ Seizure risk)

MAOIs: Peripheral autonomic sympathomimetic effects (3)

1. Dry mouth

2. Blurred vision

3. Urinary retention

*MAOIs: Clinical Uses

1. Atypical depression

2. Psychotic features

3. Phobia

*MAOIs & TCAs

- cannot be given together

- severe convulsions & coma

+ antagonize Methyldopa & Clonidine effects

*MAOIs & SSRIs

- SSRIs are contraindicated to MAOIs

- Serotonin syndrome

TCAs: Types (2)

1. Tertiary

2. Secondary

TCAs: Tertiary (3)

Imipramine

Amitriptyline

Doxepin

*Clomipramine

*Trimipramine

TCAs: Secondary (2)

Desipramine

Nortriptyline

*Amoxapine

*Maprotiline

*Protriptyline

TCAs: Pk (ADME)

A: well-absorbed, long half-life, qhs

D: high Vd, not dialyzable

M: first-pass, extensive metabolism

E: 5% excreted unchaterm-41nged

TCAs: Prototype

Imipramine

Imipramine

- TCAs prototype

- anticholinergic

- strong 5-HT & NE reuptake inhibitor (SNRI?)

*Imipramine BN

Tofranil

TCAs: metabolite of Imipramine

Desipramine

Desipramine

- less anticholinergic effects

- more potent & NE-selective

TCAs: MOA

Inhibits the CNS neuronal reuptake of NE & 5-HT

- blocks H1, Mm, and α receptors

TCAs: SEs with blocking H1 (3)

1. Sedation

2. Drowsiness

3. Weight gain

TCAs: SEs with blocking Mm (3)

1. Dry mouth

2. Blurred vision

3. Constipation

TCAs: SEs with blocking α-1

Priapism

TCAs: SEs with blocking α-2 (3)

1. Postural hypotension

2. Dizziness,

3. Reflex tachycardia

TCAs: SEs with blocking 5-HT

Nausea

TCAs: Other SEs (3)

1. Reduced seizure threshold

2. Additive effect with ethanol

3. Antagonize methyldopa and clonidine effects (*with MAOI)

Imipramine OD

1. Overweight

2. 3-Cs: Coma, Cardiac

arrhythmias, Convulsions

SSRIs

- highly lipophilic

- easy to use safe even in OD

- well-tolerated

- broad-spectrum

- have generic counterparts

SSRIs: Drugs (6)

Fluoxetine

Sertraline

Citalopram

Paroxetine

Fluvoxamine

Escitalopram

Prototype SSRI

Fluoxetine

Fluoxetine: Pk (ADME)

metabolized to active product, Norfluoxetine

Fluoxetine and Paroxetine: Pk (ADME)

potent CYP2D6 isoenzyme inhibitors

*Fluoxetine, Sertraline, Citalopram

exist as isomers & formulated in their racemic form

*Fluoxetine: BN

Prozac

*Sertraline: BN

Zoloft

*Citalopram: BN

Celexa

*Escitalopram

S-enantiomer of Citalopram

*Paroxetine & Fluvoxamine

not optically active

SSRIs: MOA

- highly selective action on SERT by allosteric inhibition

- Minimal effects on the NE uptake / blocking action on adrenergic and cholinergic receptors

SSRIs: SEs

1. EPS

2. Serotonin syndrome (*with MAOIs)

SSRIs: EPS (3)

1. Akathisia

2. Dyskinesia

3. Dystonic reactions

*SSRIs: Common SEs

1. Nervousness

2. Dizziness

3. Insomnia

*SSRIs: Other SEs

1. anticholinergic & antihistaminic effects

2. α-adrenergic blockade

3. impotence

4. priapism

5. Nausea & diarrhea

*SSRIs: Uses

1. MDD

2. GAD

3. PTSD

4. OCD

5. Panic disorders

6. PMDD

7. Bulimia

*SSRIs vs. TCAs

equally effective as the TCAs, but have pros:

1. fewer sedative, autonomic, and CV

SEs

2. safer than TCAs following OD

SNRIs: Drugs (5)

Venlafaxine

Desvenlafaxine

Duloxetine

Levomilnacipran

Milnacipran

SNRIs: metabolite

Desvenlafaxine

Venlafaxine & Desvenlafaxine: Pk (ADME)

lowest protein binding

Desvenlafaxine: Pk (ADME)

- conjugated

- extensive oxidative metabolism

Duloxetine: Pk (ADME)

- well-absorbed

- half-life: 12-15 hours

SNRIs: MOA

- Similar to TCAs but more specific to reuptake action

- NOT have blocking effects on peripheral tissues

- Binds to transporters: SERT (5-HT) & NET (NE)

Venlafaxine: MOA

less affinity for NE than Duloxetine

Duloxetine: Uses (3)

1. Depressive disorder

2. Neuropathic pain

3. Diabetic neuropathy

SNRIs: SEs (3)

1. ↑ BP

2. same with SSRIs

3. Withdrawal symptoms

Heterocyclic Antidepressants: Types (2)

1. Unicyclic

2. Tetracyclic

Unicyclic: Drug

Bupropion

*Bupropion: BNs (3)

Forfivo

Wellbutrin

Zypan

*Bupropion

- unicyclic aminoketone structure

- CNS activating property (like amphetamine)

- not commonly associated with

sexual effects

Tetracyclic: Drugs (4)

Mirtazapine

*Maprotiline

*Amoxapine

*Vilazodone

*Mirtazapine

like Bupropion: not commonly associated with

sexual effects

*Mirtazapine: BN

Remeron

*Maprotiline

similar SEs with TCAs

*Amoxapine

- N-demethylated metabolite of loxapine (older antipsychotic)

- similar SEs with TCAs

*Vilazodone

- multi ring structure

- binds to SERT (less with NET and DAT).

*Amoxapine: BN

Asendin

*Vilazodone: BN

Viibryd

Heterocyclic Antidepressants: MOA

like TCAs but fewer SEs