Antidepressants Dr. Layali Abbasi Psychiatrist Al-Balqa Applied University 5th year/Faculty of Medicine 2019-2020
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