-Intro

Welcome to the chapter on Atypical Antidepressants, an essential component of your preparation for the Pharmacy Examining Board of Canada (PEBC) Evaluation Exam (EE). This chapter is meticulously designed to provide an in-depth understanding of atypical antidepressants, a unique and diverse class of medications used in the treatment of depression and other mental health disorders. Unlike their counterparts, atypical antidepressants do not fit into the conventional categories of antidepressant drugs due to their varied mechanisms of action and pharmacological profiles. This knowledge is not only vital for passing the PEBC EE but also for your future career in pharmacy, where you will encounter a wide range of patients with complex needs.

Bupropion

Mechanism of Action: Acts as a dopamine and norepinephrine reuptake inhibitor (NE/D/RI), increasing the availability of these neurotransmitters in the brain.

Indication: Primary treatment for major depression, with additional applications for smoking cessation (marketed as Zyban), ADHD, and countering SSRI-induced sexual dysfunction.

Side Effects:

• Tachycardia (increased heart rate).

• Insomnia, headaches, agitation, dizziness, and the risk of seizures.

• Potential for weight loss.

• Dry mouth (Xerostomia), constipation, nausea, vomiting.

• Tremors.

• Blurred vision.

Additional Considerations:

• Stimulant effects can include tachycardia and agitation.

• May aggravate psychosis or lower the seizure threshold, leading to seizures.

• Notably, it does not cause weight gain or sexual dysfunction, differentiating it from many other antidepressants.

Contraindications:

• Seizure disorders or conditions increasing seizure risk (e.g., arteriovenous malformation, severe head injury, severe stroke).

• History of eating disorders like anorexia or bulimia.

• Abrupt discontinuation of alcohol or sedatives.

• Binge drinking.

• Use alongside MAOIs, linezolid, methylene blue, thioridazine.

• Hypersensitivity to bupropion.

Example:

A patient with major depressive disorder who is also attempting to quit smoking may be prescribed bupropion for its dual efficacy in treating depression and aiding smoking cessation. However, a thorough medical history is necessary to rule out contraindications like a seizure disorder or a history of bulimia.

• Mirtazapine

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• Classification:

• Mirtazapine is categorized as a NaSSA (Noradrenergic and Specific Serotonergic Antidepressant) and also as a SARI (Serotonin Antagonist and Reuptake Inhibitor).

• Mechanism of Action:

• It blocks presynaptic alpha-2 receptors, which increases the release of norepinephrine.

• It blocks somatodendritic 5-HT (serotonin) autoreceptors, leading to an increase in serotonin release in the brain.

• It antagonizes the 5HT3 receptors, which can help prevent nausea and vomiting.

• It antagonizes both 5HT2A and 5HT2C receptors.

• It also blocks histamine H1 receptors, which results in sedation.

• Therapeutic Use:

• At lower doses, it's used to treat insomnia.

• It is metabolized by CYP enzymes 1A2, 2D6, 3A4 without producing active metabolites.

• Side Effects:

• Sedation, primarily due to its antagonism of H1 receptors.

• It has a lower incidence of sexual dysfunction compared to some other antidepressants.

• Other common side effects include drowsiness, weight gain, increased serum cholesterol, dry mouth (xerostomia), increased appetite, and constipation.

• Administration Notes:

• Mirtazapine should be taken with food to ensure proper absorption.

Example:

For example, a patient suffering from depression who also has trouble sleeping may be prescribed a low dose of Mirtazapine not only to address their depressive symptoms but also to help improve their sleep, thanks to its sedative effects. Due to its mechanism of action, which differs from typical SSRIs, it may also be a suitable option for patients who experience undesirable side effects like sexual dysfunction or nausea with other antidepressants. However, due to its sedative effects, patients may need to adjust their schedule to accommodate increased drowsiness, and they should be counseled on potential weight gain as a side effect.

• Trazodone

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• Classification:

• Trazodone is classified as a Serotonin Modulator and falls under the category of atypical antidepressants.

• Therapeutic Use:

• It is primarily used to treat depression and insomnia.

• Mechanism of Action:

• Inhibits serotonin reuptake, increasing serotonin availability in the brain.

• Blocks the 5HT2 receptors and histamine 1 receptors, which can help alleviate anxiety and promote sleep.

• Also blocks alpha-1 receptors, which can lead to some of its side effects.

• Side Effects:

• Drowsiness, dizziness, headache, nervousness, fatigue.

• Priapism (a prolonged erection).

• Dry mouth (xerostomia), nausea & vomiting.

• Blurred vision.

• Stuffy nose.

• it is less commonly associated with serotonin syndrome.

• Usage Notes:

• Can be combined with SSRIs, but may lead to excessive sedation.

• As a sleep aid, it is typically prescribed at lower doses (50-100 mg) than for depression (300-400 mg daily).

• It serves as an alternative to benzodiazepines (BZD) for insomnia.

• Metabolism:

• Trazodone is metabolized by the liver enzyme CYP3A4.

• Warnings:

• It carries a risk of causing suicidal thoughts, particularly significant in certain populations.

Example:

A patient with depression who also suffers from insomnia may be prescribed trazodone due to its dual-action as an antidepressant and a sleep aid. However, the healthcare provider must monitor for any signs of increased suicidal thoughts, especially when initiating treatment.

Vilazodone

• Vilazodone acts as a selective serotonin reuptake inhibitor (SSRI) and a partial agonist at the 5-HT1A receptor.

• For optimal absorption, vilazodone should be taken with food.

• The drug is metabolized by the CYP3A4 enzyme in the liver.

Side Effects: Nausea and diarrhea are the most common side effect but headaches and insomnia can also occur.

Key points about vilazodone:

• Dual mechanism as SSRI and 5-HT1A partial agonist

• Taken with food for optimal absorption

• Metabolized by CYP3A4 enzyme

• Common side effects include nausea, diarrhea, headaches, insomnia

• Designed to have faster onset than SSRIs due to 5-HT1A activity

Vortioxetine 

Classification and Action:

• Vortioxetine is an antidepressant with a multimodal mechanism.

• Acts as a selective serotonin reuptake inhibitor (SSRI).

• Increases serotonin availability by blocking its reabsorption (inhibition of SERT).

Receptor Activity:

• Serves as a partial agonist at the 5-HT1A receptor, enhancing serotonin signaling.

• Antagonizes the effects of 5-HT3 and 5-HT7 receptors.

• Additionally, it has a partial agonistic effect on the 5-HT1B receptor.

Metabolic Pathway: Metabolized mainly by the CYP2D6 enzyme found in the liver.

Side Effects Profile:

• Gastrointestinal: Primarily causes nausea and constipation.

• Sexual Dysfunction: Has a lower rate of sexual side effects compared to similar medications.

• Other Effects: Can cause headaches and difficulties in sleeping (insomnia).

Pharmacological Significance: Vortioxetine's action on multiple serotonin receptors and the serotonin transporter distinguishes it from other classes of antidepressants, earning it the label of a "multimodal antidepressant."

Clinical Implications: Due to its unique profile, vortioxetine may be chosen for patients who have not responded to or have had side effects with other SSRIs or SNRIs. It offers a balance between efficacy in treating depression and a tolerable side effect profile, particularly regarding sexual function and gastrointestinal discomfort.