Antidepressants · antidepressants' delay in therapeutic effects. Since there are less 5HT1A...

Antidepressants

Dr. Layali Abbasi Psychiatrist

Al-Balqa Applied University

5th year/Faculty of Medicine 2019-2020

• Selective Serotonin Reuptake Inhibitors(SSRIs)

• Serotonin and Norepinephrine Reuptake Inhibitors(SNRIs)

• Tricyclic and tetracyclic antidepressants (TCAs)

• Bupropion

• Mirtazapine

SSRIs

• Paroxetine

• Fluoxetine

• Fluvoxamine

• Sertraline

• Citalopram

• Escitalopram

The Mechanism of Action of SSRIs

• Antidepressant effects are generally not seen

until 2 to 4 weeks of continuous treatment.

• The role of 5HT1A receptor downregulation in the mechanism of action of SSRIs.

This image shows a serotonergic neuron. We can see the somatodendritic region, the axon and the presynaptic terminal. Here is also depicted a postsynaptic neuron that is stimulated by the serotonergic neuron

There are 14 subtypes of serotonin receptors, the 5HT1A is one of them. When this receptor is stimulated it inhibits firing of serotonergic neurons, this means that it works as an autoreceptor that inhibits serotonergic activity.

Here 5HT1A receptors are expressed in the somatodendritic region of a serotonergic neuron. This picture is a schematic representation that emphasizes the role of 5HT1A receptors as inhibitory autoreceptors.

The serotonin transporter (SERT) is a monoamine transporter protein. This is a membrane protein that transports serotonin from synaptic spaces into presynaptic neurons

Selective serotonin reuptake inhibitors and other antidepressants block the SERT transporter. The result is an increased availability of serotonin in the synaptic space.

If you pay attention there is an important difference with the previous slides: there are less 5HT1A receptors, this is, 5HT1A receptors are downregulated. As a response to serotonin stimulation, the serotonergic neuron reduces the number of 5HT1A receptors, this phenomenon is known as downregulation. Since downregulation is mediated by genomic mechanisms, the reduction of 5HT1A receptors is not immediate, this occurs in weeks. This has been proposed as a possible explanation of antidepressants' delay in therapeutic effects.

Since there are less 5HT1A receptors expressed in the somatodendritic region, the neuron is now disinhibited. As a consequence, firing rate is increased. This in turn increases serotonin release to the synaptic space, which stimulates postsynaptic serotonin receptors. In summary, inhibition of serotonin reuptake increases serotonin concentration, which causes a downregulation of 5HT1A receptors. After the number of 5HT1A receptors is reduced, the neuron is disinhibited to release more serotonin in the synaptic space.

Side effects of SSRIs

Many clinicians see it as suitable for anxious depression

Sexual dysfunction

Discontinuation syndrome

Weight gain

Paroxetine - Overview

Inhibits SERT

Muscarinic blockade: anticholinergic properties.

Potentially problematic in the elderly

At high doses: NET inhibition

Paroxetine Pharmacodynamics

FDA-approved indications for paroxetine

Nausea Headache Somnolence

Dry mouth Sweating

Common side effects

• Sexual dysfunction more problematic with paroxetine than with other SSRIs

• Dose dependent side effect

SSRI-induced sexual dysfunction

Weight gain

• Weight gain needs to be considered when choosing paroxetine

• One of the antidepressants with highest risk of weight gain

Discontinuation syndrome

Discontinuation syndrome with

paroxetine

1/3 of patients after

abrupt cessation

Short half life

No active metabolites

• Paroxetine is labeled as pregnancy risk category D (this means that there is positive evidence or risk to human fetus).

Fluoxetine - Overview

First AD of the SSRI class

Activating properties

Long half-life / Weekly capsule

Potent CYP2D6 inhibitor

Fluoxetine

• Fluoxetine has activating properties that make

it a good option for patients with retarded depression or atypical depression. However, we should avoid activation in patients with insomnia and agitation.

Fluoxetine

Fluoxetine

Fluvoxamine

Fluvoxamine

Fluvoxamine

Major depressive disorder

Panic disorder

Premenstrual dysphoric disorder

Posttraumatic stress disorder

Social anxiety disorder

Obsessive compulsive disorder

Sertraline FDA-Approved Indications

Off-label uses

• Depression associated with Parkinson’s disease

• Generalized anxiety disorder

Sertraline

Indication Citalopram Escitalopram

Depression X X

Generalized anxiety disorder

x

FDA-Approved Indications

Citalopram and Escitalopram

• OCD

• Panic disorder

• PTSD

• Social anxiety disorder

• Premenstrual dysphoric disorder

Off-label uses

Citalopram and Escitalopram

• Most common side effects:

– Nausea and vomiting

– Increased sweating

– Dry mouth

– Headache

• Pregnancy category C

Citalopram and Escitalopram

SNRIs

• Venlafaxine and Desvenlafaxine

• Duloxetine

• SNRIs combine the robust SERT inhibition of the SSRIs with various degrees of inhibition of the norepinephrine transporter (or NET).

Venlafaxine

• FDA-approved indications:

-Major depressive disorder

-Generalized anxiety disorder

-Social anxiety disorder

-Panic disorder

Venlafaxine is one of the antidepressants most commonly associated with discontinuation syndrome.

Tricyclic and tetracyclic antidepressants (TCAs)

• Amitriptyline

• Clomipramine

• Imipramine

• Desipramine

• Nortriptyline

Tricyclic and tetracyclic antidepressants (TCAs)

• Block the reuptake pumps for norepinephrine (i.e., NET), or for both norepinephrine and serotonin (i.e., SERT).

• Some tricyclics have equal or greater potency for SERT inhibition (e.g., clomipramine); others are more selective for NET inhibition (e.g., desipramine, maprotiline, nortriptyline, protriptyline).

• Most, however, block both serotonin and norepinephrine reuptake to some extent.

• In addition, some tricyclic antidepressants have antagonist actions at 5HT2A and 5HT2C receptors which could contribute to their therapeutic profile.

• Tricyclic antidepressants are not merely antidepressants, since one of them (clomipramine) has anti-obsessive–compulsive disorder effects and many of them have anti-panic effects at antidepressant doses and efficacy for neuropathic and low back pain at low doses.

Side effects of tricyclic antidepressants (TCAs)

• Because of their side effects and potential for death in overdose, tricyclic antidepressants have fallen into second-line use for depression.

• Contraindications: Absolute contraindications: MI (until 6 months after the MI) Narrow-angle glaucoma Relative contraindications: Cardiac disease ( a baseline ECG is recommended). Prostatic hypertrophy or other obstructive uropathy ( secondary to anti-cholinergic side effects).

Norepinephrine Dopamine Reuptake Inhibitor (NDRI)

Used for depression and smoking cessation

Different side effects profile:

• lack of sexual side effects

• risk of seizures

Bupropion - Overview

Mechanism of Action

• Reuptake inhibition of:

– Norepinephrine transporter (NET)

– Dopamine transporter (DAT)

• MOA may involve the presynaptic release of NE and DA.

Mechanism of Action - Pharmacology

• Non competitive antagonist of nAch receptors

• Might contribute to antidepressant effects as well as effectiveness in smoking cessation

Bupropion for depression

Efficacy comparable to SSRIs and venlafaxine

Effective doses: 150-300 mg/day

Not sedating

•Retarded depression: decreased energy, interest and pleasure

Mildly stimulating properties

Bupropion and sexual side effects

• Sexual dysfunction not a side effect when using bupropion.

Adverse Effects

Lack of anticholinergic, antihistaminic and orthostatic hypotensive effects.

Restlessness Activation Tremors

Insomnia Nausea

Adverse Effects - Seizures

• IR: 0.4% at doses up to 450 mg/day

• SR: 0.1% for doses up to 300 mg/day

Incidence of seizures:

Dose dependent effect

• Screen for seizure disorder or other organic brain conditions

Before prescribing bupropion:

Mirtazapine

Mirtazapine- Overview

NaSSA (Noradrenergic and specific serotonergic antidepressant)

H1 antagonist

Sedation and weight gain

Used in the elderly population

No significant interactions

Used as augmenting agent

Mirtazapine Pharmacology

• No monoamine reuptake inhibition

• Serotonergic and noradrenergic antidepressant

• Antagonist at: • a2

• H1

• 5HT2A, 5HT2C, 5HT3

Mirtazapine: a2 antagonist

a2 receptors – Autoreceptors: noradrenergic neurons

– Heteroreceptors: serotonergic neurons

Mirtazapine blocks a2 presynaptic autoreceptors

a2 presynaptic blockade

Loss of inhibition

Increased NE release

Mirtazapine blocks a2 somatodendritic receptors in 5HT

neurons = activation

Mirtazapine blocks 5HT3 receptors in the CTZ

Kast, R. E., and K. F. Foley. "Cancer chemotherapy and cachexia: mirtazapine

and olanzapine are 5‐HT3 antagonists with good antinausea effects." European Journal of Cancer Care 16.4 (2007): 351-354.

Effects on other 5HT receptors

• Antagonist at:

– 5HT2A

– 5HT2C

Croom, Katherine F., Caroline M. Perry, and Greg L. Plosker. "Mirtazapine.“ CNS drugs 23.5 (2009): 427-452.

FDA-Approved Indications

Indication Dosage range

Depression 15-45 mg/day

Remeron (Mirtazapine) [Prescribing Information] NJ: Merck & Co., Inc. Accessed June 2014

Mirtazapine: tolerability profile

Sedation:

• 50% of patients during first week of treatment

Increased appetite: weight gain

• 15-25% of patients

- Dry mouth - Premarketing studies: agranulocytosis, association not established

Mirtazapine: side effects profile

Significantly lower frequency of:

– Antidepressant-induced sexual dysfunction

– Gastrointestinal disturbances – Insomnia Very low risk of sexual

dysfunction

Antidepressant Discontinuation Syndrome

What to do ? 1. Provide reassurance to the patient • Reversible, not life threatening, will run its course within 1 to 2 weeks. 2. Consider restarting the medication with a slow dose taper • If symptoms occur during tapering: Consider restarting at the original dose and then taper at a slower rate. • If slow tapering is poorly tolerated: Consider substituting with fluoxetine

THE END