Tetracyclic antidepressant

Not to be confused with Tetracycline or Tricyclic antidepressant.

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their tetracyclic chemical structure, containing four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.

Chemical structure of the TeCA mirtazapine. Notice its four rings fused together.

List of TeCAs

Marketed

• Maprotiline (Ludiomil) – can also be classified as a TCA and grouped with the secondary amines
• Mianserin (Tolvon)
• Mirtazapine (Remeron)
• Setiptiline (Tecipul)

Drugs that contain four rings not all fused together but are sometimes still classified as TeCAs include:

• Amoxapine (Asendin) – often classified as a TCA and grouped with the secondary amines
• Quetiapine (Seroquel) - an atypical antipsychotic sometimes used as an adjunct antidepressant

Miscellaneous

• Benzoctamine (Tacitin) – a tetracyclic compound and is closely related to maprotiline, with the two compounds differing only in the length of their side chain, but benzoctamine is not used as an antidepressant and is instead used as an anxiolytic
• Loxapine (Adasuve, Loxitane) – a typical antipsychotic that produces amoxapine as a major metabolite and is said to have antidepressant effects, but it is not usually regarded as a TeCA

Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:

• Mazindol (Mazanor, Sanorex) – a monoamine reuptake inhibitor used as an appetite suppressant and with potential antidepressant effects, but not classified as a TeCA

Never marketed

• Aptazapine (CGS-7525A) – a close analogue of mirtazapine
• Esmirtazapine (ORG-50,081) – the (S)-(+) enantiomer of mirtazapine
• Oxaprotiline (C 49-802 BDA) – a close analogue of maprotiline

Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:

• Ciclazindol (WY-23,409) – a close analogue of mazindol

Pharmacology

See also: Pharmacology of antidepressants

TeCAs have diverse pharmacology and differ from TCAs in a number of ways. With the exception of amoxapine, TeCAs do not inhibit the reuptake of serotonin^{[citation needed]}. However, aside from mirtazapine, they do inhibit the reuptake of norepinephrine^{[citation needed]}. TeCAs block the serotonin 5-HT₂ receptors similarly to TCAs. Besides mirtazapine, they also block the α₁-adrenergic receptor^{[citation needed]}. Conversely, whereas TCAs have relatively low affinity for the α₂-adrenergic receptor, mianserin and mirtazapine potently antagonize this receptor, and this action is thought to be involved in their antidepressant effects^{[citation needed]}. TeCAs block the histamine H₁ receptor similarly to the TCAs, but tend to be even stronger antihistamines than TCAs^{[citation needed]}. On the other hand, in contrast to almost all TCAs, TeCAs have only low affinity for the muscarinic acetylcholine receptors, and for this reason, are associated with few or no anticholinergic side effects^{[citation needed]}. Mianserin and mirtazapine are far less toxic than TCAs in overdose.^[1][2]

Binding profiles

See also: Tricyclic antidepressant § Binding profiles

The binding profiles of various TeCAs in terms of their affinities (K_i, nM) for various receptors and transporters are as follows:^[3]

Compound	SERTTooltip Serotonin transporter	NETTooltip Norepinephrine transporter	DATTooltip Dopamine transporter	5-HT1A	5-HT2A	5-HT2B	5-HT2C	5-HT3	5-HT6	5-HT7	α1	α2	D2	H1	H2	mAChTooltip Muscarinic acetylcholine receptor
Amoxapine	58	16	4,310	ND	0.5	ND	2.0	ND	6.0–50	41	50	2,600	3.6–160	7.9–25	ND	1,000
Maprotiline	5,800	11–12	1,000	ND	51	ND	122	ND	ND	50	90	9,400	350–665	0.79–2.0	776	570
Mianserin	4,000	71	9,400	400–2,600	1.6–20	1.6–55	0.63–6.5	5.8–300	55–81	48–56	34	3.8–73	≥2,100	0.30–1.7	437	820
Mirtazapine	>10,000	≥4,600	>10,000	≥3,330	6.3–69	200	8.9–39	7.9	ND	265	316–1,815	18–88	>5,454	0.14–1.6	>10,000	670
Setiptiline	>10,000	220	>10,000	ND	ND	ND	ND	ND	ND	ND	ND	24	ND	ND	ND	ND
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

The TeCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters.

See also

• List of antidepressants
• Noradrenergic and specific serotonergic antidepressant

References

1. Shaw, W. L. (1980-01-01). "The comparative safety of mianserin in overdose". Current Medical Research and Opinion. 6 (sup7): 44–51. doi:10.1185/03007998009114803. ISSN 0300-7995.
2. Waring, W. Stephen; Good, Alison M.; Bateman, D. Nicholas (2007-01-01). "Lack of significant toxicity after mirtazapine overdose: A five-year review of cases admitted to a regional toxicology unit". Clinical Toxicology. 45 (1): 45–50. doi:10.1080/15563650601005837. ISSN 1556-3650. PMID 17357381. S2CID 28546654.
3. Roth, BL; Driscol, J. "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.