Tetracyclic antidepressants

Definition and Classification
Tetracyclic antidepressants (TeCAs) are a structurally distinct class of antidepressants characterized by a four-ring (tetracyclic) chemical structure. They exert their effects primarily through modulation of monoamine neurotransmitters, particularly serotonin (5-HT) and norepinephrine (NE), by antagonizing presynaptic alpha-2 adrenergic receptors and blocking specific serotonin and histamine receptors. While pharmacologically related to tricyclic antidepressants (TCAs), TeCAs differ significantly in their receptor profiles, side effect burdens, and clinical applications.

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Mechanism of Action

Tetracyclic antidepressants primarily work via:

1. Alpha-2 adrenergic antagonism:

   • Inhibits presynaptic auto- and heteroreceptors

   • Enhances release of norepinephrine and serotonin

2. Serotonin receptor antagonism:

   • Especially 5-HT2 and 5-HT3 antagonism, which may reduce anxiety and gastrointestinal side effects

3. Histamine H1 receptor antagonism:

   • Leads to pronounced sedative and weight gain effects

4. Minimal inhibition of serotonin or norepinephrine reuptake compared to TCAs or SSRIs

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Notable Generic Drugs and Brand Names

Generic Name	Brand Name(s)
Mirtazapine	Remeron
Maprotiline	Ludiomil
Amoxapine	Asendin
Setiptiline	Tecipul (Japan)
Loxapine*	Loxitane (antipsychotic use)
(Loxapine is structurally tetracyclic but used primarily as an antipsychotic)

Pharmacologic Characteristics

Drug	Key Mechanisms	Unique Properties
Mirtazapine	α2 antagonist, 5-HT2/5-HT3 antagonist, H1 blocker	Sedative, anxiolytic, appetite-stimulating
Maprotiline	NE reuptake inhibitor, H1 antagonist	High seizure risk, potent antihistamine
Amoxapine	NE reuptake inhibitor, DA antagonist	Antipsychotic features, extrapyramidal risks
Setiptiline	α2 antagonist, 5-HT2 antagonist, H1 blocker	Less commonly used, available in Japan only

Indications and Clinical Uses

1. Major Depressive Disorder (MDD) – especially in patients with:

   • Prominent anxiety

   • Insomnia

   • Poor appetite or weight loss

2. Generalized Anxiety Disorder (off-label, especially mirtazapine)

3. Post-traumatic Stress Disorder (PTSD)

4. Obsessive-Compulsive Disorder (adjunctive, limited use)

5. Sleep disorders – due to sedative effects of mirtazapine

6. Appetite stimulation – especially in cachexia or cancer-related anorexia

7. Chronic pain disorders – occasionally used off-label

8. Schizoaffective disorders – amoxapine may be used off-label for depressive symptoms with psychotic features

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Pharmacokinetics and Metabolism

• Absorption: Well absorbed orally

• Distribution: Highly lipophilic; extensive tissue distribution

• Metabolism:

  • Mirtazapine: Liver metabolism via CYP1A2, CYP2D6, CYP3A4

  • Maprotiline and amoxapine: Hepatic metabolism, active metabolites

• Elimination half-life:

  • Mirtazapine: 20–40 hours (once-daily dosing)

  • Maprotiline: 28–60 hours

  • Amoxapine: 8–15 hours

• Excretion: Mainly renal

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Adverse Effects and Safety Profile

System	Common Adverse Effects
CNS	Sedation, dizziness, drowsiness, tremors
Metabolic	Weight gain, increased appetite
Cardiac	QT prolongation (rare), orthostatic hypotension
Anticholinergic	Dry mouth, constipation, blurred vision (less than TCAs)
Hematologic	Rare: agranulocytosis (mirtazapine), leukopenia
Neurologic	Seizures (maprotiline), extrapyramidal symptoms (amoxapine)
Sexual	Less sexual dysfunction compared to SSRIs

Contraindications

• Hypersensitivity to the drug or any of its components

• Severe hepatic or renal impairment (dose adjustment needed)

• Concurrent use of MAO inhibitors or within 14 days of MAOI therapy

• Seizure disorders (especially with maprotiline)

• History of arrhythmia or prolonged QT interval (caution with mirtazapine)

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Precautions and Monitoring

• Suicidality risk: As with all antidepressants, monitor closely in early therapy

• Sedation: Avoid driving or operating heavy machinery until tolerance is known

• Weight and appetite: Monitor in patients with metabolic disorders or obesity

• Hematologic testing: Consider baseline and periodic CBC with mirtazapine

• ECG monitoring: For elderly or those with known cardiovascular conditions

• Withdrawal symptoms: Taper gradually, especially after prolonged use

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Drug Interactions

Interacting Agent	Clinical Implication
MAO inhibitors	Hypertensive crisis, serotonin syndrome
Benzodiazepines	Increased sedation, CNS depression
Alcohol	Additive sedative effects
SSRIs/SNRIs	Risk of serotonin syndrome (especially with mirtazapine, though lower than SSRIs)
CYP3A4 inhibitors	Increased levels of mirtazapine
Antihypertensives	Additive hypotensive effects
Antipsychotics	Risk of extrapyramidal effects (especially with amoxapine)
Tramadol	Increased seizure risk

Tetracyclic Antidepressants vs. Other Antidepressants

Feature	Tetracyclics (e.g., mirtazapine)	Tricyclics (e.g., amitriptyline)	SSRIs (e.g., fluoxetine)
Sedation	High (especially mirtazapine)	Moderate to high	Low to moderate
Anticholinergic	Moderate	High	Low
Seizure Risk	Maprotiline: high	Moderate	Low
Sexual Dysfunction	Low (mirtazapine)	Moderate	High
Weight Gain	High (mirtazapine)	High	Moderate
Onset of Action	1–2 weeks	2–4 weeks	2–6 weeks

Use in Special Populations

• Elderly:

  • Use low doses initially

  • Monitor for sedation, falls, orthostatic hypotension

• Pregnancy:

  • Mirtazapine: Category C (use only if benefit outweighs risk)

• Breastfeeding:

  • Mirtazapine is excreted in breast milk (use with caution)

• Pediatrics:

  • Not typically recommended due to lack of efficacy/safety data

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Dosing (Mirtazapine Example)

Indication	Initial Dose	Usual Maintenance Dose	Max Dose
Major Depression	15 mg once daily (bedtime)	15–45 mg/day once daily	45 mg/day

Note: Lower doses (15 mg) are often more sedating due to predominant antihistaminic effect. Higher doses may reduce sedation.

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Advantages of Tetracyclic Antidepressants

• Useful in depressed patients with insomnia, low appetite, or weight loss

• Lower incidence of sexual dysfunction compared to SSRIs/SNRIs

• Favorable in patients non-responsive to SSRIs

• Faster onset of appetite stimulation and sleep restoration

• Mirtazapine is often used as an adjunct in treatment-resistant depression

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Limitations and Cautions

• Weight gain and metabolic effects limit use in overweight patients

• Seizure risk restricts use of maprotiline and amoxapine in high-risk individuals

• Sedation can impair daily functioning

• Not recommended as first-line antidepressants in most current guidelines

• Some agents have limited availability (e.g., maprotiline, setiptiline)

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Guidelines and Clinical Recommendations

• American Psychiatric Association (APA) includes mirtazapine as second-line agent in MDD

• NICE (UK) recommends mirtazapine in patients intolerant to SSRIs or who need sedation

• Not typically first-line in children or adolescents

• May be combined with SSRIs or SNRIs in augmentation strategies (e.g., mirtazapine + venlafaxine)