antidepressants

MAJOR DEPRESSIVE DISORDER (MDD)

• Endogenous depression

• A depression of mood without any obvious medical or situational causes, manifested by an inability to cope with ordinary events or experience pleasure

Reactive depression

A response to external event, including adverse life events, physical illness, and drugs

Depression is the most common of the affective disorders; ranging from very  mild, bordering on normality, to severe and psychotic depression, accompanied by

hallucinations and delusions

UNIPOLAR DISORDER

mood swings are always in the same direction (depression or mania)

BIPOLAR DISORDER

depression alternates with mania (opposite of depression)

BIPOLAR DISORDER

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lithium

Monoamine hypothesis / biogenic amine hypothesis

depression is due to a deficiency of NE, serotonin and dopamine in the synapses of the CNS; these NTs regulate functions that if altered may results to depression

Lack of NE

may be related to:

• alertness and energy

• Anxiety

• Attention

• lack of interest in life

Reduced serotonin

• anxiety 

• obsessions 

• compulsions

Low levels of Dopamine

reduced functions associated to: 

• Attention

• Motivation

• Pleasure

• Reward

• interest in life

Neurotrophic hypothesis

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

Nerve growth factor, like BDNF, is critical in regulating:

• neural plasticity

• Resiliency

• neurogenesis.

Affective Disorders (mood disorders):

• Panic disorder

• Generalized anxiety disorder (GAD)

• Post-traumatic stress disorder (PTSD)

• Obsessive compulsive disorder (OCD)

• Pre-menstrual dysphoric disorder (PMDD)

• Post partum depression

PATHOPHYSIOLOGY OF MAJOR DEPRESSION:

• The monoamine hypothesis

• Neurotrophic hypothesis

• Endocrine factors

Anxious and irritable patients should be treated with

SSRIs or norepinephrine reuptake inhibitors

patients that are experiencing a loss of energy and enjoyment of life should be treated with

norepinephrine- and dopamine-enhancing drugs.

In human & animal studies a drop in BDNF is also associated with

pain and stress.

Antidepressants increase levels of BDNF expression over time helping to

reverse neuronal damage and improve the mood of patient

Endocrine factors

depression is attributed to the loss of volume in the hippocampus which plays an integral role in emotional stimuli and attention function

psychotherapy

which involves talking with a mental health professional to address emotional and psychological issues

electroconvulsive therapy

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

anterior cingulate

plays a role in integration of emotional stimuli and attention function

Major Categories of Antidepressants

• Tricyclic Anti-depressants (TCA)

• Monoamine oxidase inhibitors (MAOIs)

• Serotonin-specific reuptake inhibitors (SSRIs)

• Selective Serotonin-NE reuptake inhibitors (SNRIs)

• 5-HT2 Modulators (antagonists)

• Tetracyclic and Unicyclic anti-depressants

• NMDA receptor Antagonist

• Allosteric GABAA modulators

Tertiary amine TCA

• Amitriptyline

• Imipramine – prototype

• Doxepin

• Clomipramine

• Trimipramine

Seconndary amine TCA

• Amoxapine

• Maprotiline

• Protriptyline

• Desipramine

• Nortriptyline

Monoamine oxidase Inhibitors (MAOIs)

non seleective

• Phenelzine

• Tranylcypromine

• Pargyline

• Hydrazines

• Iproniazid

Monoamine oxidase Inhibitors (MAOIs)

mao a

• moclobemide

• Clorgyline

Monoamine oxidase Inhibitors (MAOIs)

mao b

selegiline

Overall antidepressants are applicable in: 

• Panic disorder ̶

• Generalized anxiety disorder (GAD) 

• Post-traumatic stress disorder (PTSD) 

• Obsessive-compulsive disorder (OCD) 

• Premenstrual dysphoric disorder (PMDD)

• Postpartum depression 

• Neuropathic pain

• fibromyalgia and migraine prophylaxis

Postpartum depression 

which is depression after childbirth often due to hormonal and physical changes among others

Premenstrual dysphoric disorder (PMDD) 

which involves severe mood changes, irritability, and other symptoms that occur before menstruation. 

MAO

 mitochondrial enzyme that is involved in the metabolism of catecholamines or monoamine neurotransmitters of serotonin, norepinephrine, dopamine and even tyramine.

MAO - A

present in

• both dopamine and NE neurons

MAO - A

primarily found in

the brain, gut, placenta and liver

MAO - A

responsible for

the inactivation of monoamines that may leak out of presynaptic storage vesicles 

MAO - B

Found primarily in serotogenic and histaminergic neurons and distributed in the brain, liver and platelets

MAO - B

responsible for

metabolism of dopamine and acts primarily on dopamine, tyramine, phenylethylamine and benzylamine

MONOAMINE OXIDASE INHIBITORS (MAOIs)

Side Effects

• Peripheral autonomic sympathomimetic effects (dry mouth, blurred vision & urinary retention)

• Psychotic symptoms, confusion, delirium, fever

• Seizure threshold reduced (increased risk of seizures)

• Weight gain

• orthostatic hypotension

• hypertensive crisis (headache, htn, arrhythmias, stroke)

MONOAMINE OXIDASE INHIBITORS (MAOIs)

Mechanism of Action

• ring-closed amphetamine derivatives that reduces the breakdown of norepinephrine and serotonin in the presynaptic neurons

• By blocking the oxidative deamination monoamine oxidaseof dopamine, it leads to increased amounts of norepinephrine and serotonin are stored in the vesicles

MONOAMINE OXIDASE INHIBITORS (MAOIs)

Pharmacokinetics

• Fairly rapidly absorbed

• peak plasma level within two to three hours

• highly protein bound 

• undergo hepatic metabolism

MAOIs When given with other antidepressants like TCAs or SSRIs,

it will cause serotonin syndrome.

MAOIs When given with tyramine or tyramine-rich foods, it may result to

hypertensive crisis or cerebral stroke.

Reversible

• Moclobemide

• Clorgyline

Irreversible

• Phenelzine

• Isocarboxazid

• Tranylcypromine

• Pargyline

• Iproniazid

Can Tricyclics and MAOIs be given together for added benefit?

No, there is a chance of producing severe convulsions and coma

Why are SSRIs contraindicated to MAOIs?

Because both increases serotonin levels in the brain that may result in “serotonin syndrome”

“serotonin syndrome”

• Hyperthermia

• Muscle rigidity

• Myoclonus (Seizures)

• Rapid changes in mental status

  • Agitation

  • Restlessness

  • Confusion

  • Insomnia

• severe hypertension

Clinical Use of MAOIs

• Atypical depression

  • Phobia

  • Psychotic features

Precautions in Using MAOIs

Should not be administered for at least

• 2 weeks after discontinuing the use of most SSRIs

• 5 weeks after discontinuing the use of fluoxetine

Contraindications of MAOIs

• Sympathomimetic amines

• Foods and beverages containing amines (tyramine)

Increased levels of tyramine,

will release catecholamines from storage vesicles and therefore will act as a pressor agent

Secondary amines

– block NE uptake more than serotonin uptake

Tertiary amines –

primarily block serotonin uptake

Secondary amines less likely causes

• sedation

• hypotension

• anticholinergic effects

Secondary amines more likely to induce

psychosis

Do tricyclics elevate mood in normal individuals?

No, these drugs are not stimulant.

Which of the tricyclics are most efficacious?

All are equally efficacious

Clinical Indications of Tricyclics

• Mood disorders (major depressive disorder)

• Panic disorder

• Generalized anxiety disorder (GAD)

• Post-traumatic stress disorder (PTSD)

• Obsessive-compulsive disorder (OCD)- Clomipramine

• Pain disorders

When should a physician expect to see a change in the patient’s mood?

May require 2 to 3 weeks to become apparent

TRICYCLIC ANTIDEPRESSANTS (TCAs)

• It has a three fused ring system

• Non-selective reuptake inhibitors

TRICYCLIC ANTIDEPRESSANTS (TCAs)

PHARMACOKINETICS

• Well-absorbed, have a long half-life, often converted to active metabolite, dosed once daily at night

• Undergoes first-pass effect and extensive metabolism with 5% excreted unchanged in the urine

• High volume of distribution, not dialyzable

TRICYCLIC ANTIDEPRESSANTS (TCAs)

MECHANISM OF ACTION

• Inhibits the CNS neuronal reuptake of norepinephrine and serotonin

• Blocks multiple receptors including histamine (H1), muscarinic (Mm), and adrenergic (alpha) receptors

TRICYCLIC ANTIDEPRESSANTS (TCAs)

side effects (histamine blocking)

• sedation, 

• drowsiness, 

• weight gain

TRICYCLIC ANTIDEPRESSANTS (TCAs)
side effects (muscrarinic blocking)

• blurred vision, 

• dry mouth,

• constipation

TRICYCLIC ANTIDEPRESSANTS (TCAs)

side effects (alpha 1 antagonism)

priapism

TRICYCLIC ANTIDEPRESSANTS (TCAs)

side effects (alpha 2 antagonism)

• postural hypotension, 

• dizziness, 

• reflex tachycardia 

TRICYCLIC ANTIDEPRESSANTS (TCAs)

side effects (setotonin)

nausea

Common side-effects of TCA

• Marked autonomic effects including hypotension and sinus tachycardia

• Excessive sedation

• Reduced seizure threshold

• additive effect with ethanol

• antagonize methyldopa and clonidine effect

imipramine overdse

• overweight

• coma

• cardiac arrhythmias

• convulsions

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs

• are highly lipophilic, easy to use, safe (even in overdose), well tolerated, broad spectrum, and all are available with generic counterparts. 

Fluoxetine and Fluvoxamine

used for bulimia, as well as in OCD

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs

drugs

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs

pharmacokinetics: fluoxetine

metabolized to active product, Norfluoxetine

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs

pharmacokinetics: Fluoxetine and Paroxetine

• – potent CYP2D6 isoenzyme inhibitors

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs\

MECHANISM OF ACTION

• Highly selective action on serotonin transporters (SERT) by allosteric inhibition

• Minimal effects on the NE uptake or blocking action on adrenergic and cholinergic receptors

• Equally effective as the TCAs. However, SSRIs present advantages such as fewer sedative autonomic and cardiovascular side effects. 

• These drugs are also generally safer compared to your TCAs following an overdose.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs

side effects

• Extrapyramidal symptoms: 

  • Akathisia

  • Dyskinesia

  • dystonic reactions

• Serotonin syndrome

Fluoxetine, Sertraline, and Citalopram

exist as isomers and formulated in their racemic forms.

Paroxetine & Fluvoxamine-

not optically active

Clinical uses of SSRIs

• MDD, GAD, PTSD, OCD(fluoxetine, fluvoxamine), Panic disorder, PMDD and Bulimia

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

drugs

• Venlafaxine

• Desvenlafaxine (metabolite)

• Duloxetine

• Levomilnacipran

• Milnacipran

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

pharmacokinetics: Venlafaxine and desvenlafaxine

–  lowest protein binding

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

pharmacokinetics:Desvenlafaxine

– conjugated and undergoes extensive oxidative metabolism

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

pharmacokinetics: Duloxetine

– well-absorbed and have a half-life of 12 to 15 hours

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

moa

• Similar to TCAs but more specific to reuptake action

• Do not have blocking effects on peripheral tissues

• Binds to transporters for both serotonin and norepinephrine (SERT and NET)

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

moa Duloxetine

– used for depressive disorder, neuropathic pain, and diabetic neuropathy

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

moa Venlafaxine

– less affinity for norepinephrine than duloxetine

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

side effects

• increased blood pressure

• similar effects to SSRIs 

• withdrawal symptoms

HETEROCYCLIC ANTIDEPRESSANTS

drugs

• Mirtazapine

• Buproprion

HETEROCYCLIC ANTIDEPRESSANTS

moa

Acts like TCAs with fewer side effects

HETEROCYCLIC ANTIDEPRESSANTS

moa Mirtazapine (tetracyclic)

• – increases amine release from the nerve ending by antagonism of presynaptic alpha-2 adrenoceptor

• not commonly associated with sexual effects like bupropion

HETEROCYCLIC ANTIDEPRESSANTS

moa Bupropion (unicyclic)

• – NE-dopamine reuptake inhibitor

• NE-dopamine releasing agent

• nicotinic receptor antagonist

Buproprion (unicyclic)

• Has unicyclic aminoketone structure

• With CNS activating property (similar to amphetamine)

• No side effects related to sexual dysfunction

Amoxapine

- N-demethylated metabolite of loxapine (older anti-psychotic); similar SE to TCA’s

• Maprotiline-

SE similar to TCA’s

• Vilazodone

- multi ring structure that binds to Serotonin transporter (less with NET & DAT)

HETEROCYCLIC ANTIDEPRESSANTS

side effects

• Autonomic effects

• Anxiety

• Agitation

• Dry mouth

• Aggravation of psychosis

• Seizure at high doses

Mirtazapine: weight gain, sedation

5-HT2 RECEPTOR ANTAGONIST

drgs

• Nefazodone 

• Trazodone

5-HT2 RECEPTOR ANTAGONIST

moa

• Blocks 5-HT2A and 5-HT2C receptors

• Short-acting

Nefazodone 

• not used much anymore due to CYP3A4 activity and risk of hepatotoxicity

Trazodone

• Has a triazolo moiety

• Its active metabolite, m-chlorophenylpiperazine, is a potent 5-HT2 antagonist

• Used as a sleep aid