1. Tricyclic and Tetracyclic Antidepressants Pharmacology and Indications
Flavio Guzmán, MD

2. Overview
Chemical classification: tricyclics (secondary and tertiary) and tetracyclics
Pharmacology: SERT and NET inhibitors
Clinical uses: approved and non-approved uses
Role in depression: not first-line agents

3. Introduction

4. Some history: imipramine was the first TCA
1956: Dr. Ronald Kuhn studied imipramine as antipsychotic.
Lack of efficacy as antipsychotic.
Patients with schizophrenia who were also depressed improved depressive symptoms.
Switched to a new trial on depressive patients: improvement in 3 weeks
Nelson, JC "Triciclycs and Tetracyclics". Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

5. Chemical Classification of Tricyclics and Tetracyclics
Tertiary amines
Amitriptyline
Clomipramine
Doxepin
Imipramine
Trimipramine
Secondary amines
Desipramine
Nortriptyline
Protriptyline
Tetracyclic
Amoxapine
Maprotiline
Nelson, JC "Triciclycs and Tetracyclics". Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

6. Tertiary amines are metabolized to secondary amines
Imipramine
(tertiary amine)
Desipramine
(Secondary amine)

7. Tertiary amines are metabolized to secondary amines
Amitriptyline
(tertiary amine)
Nortriptyline
(Secondary amine)

8. Pharmacology

9. TCAs block NET and SERT
Tricyclics and tetracyclics block NET and SERT.
Presynaptic somatodendritic 5HT1A receptors are desensitized.
Upregulation of postsynaptic 5HT1A receptors.
Nelson, JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2009

10. Pharmacology of TCAs
Studies supporting the role of NE and 5HT in antidepressant effects.
Might not be central to the pathophysiology of depression.
Nelson, JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2009

11. Pharmacology of TCAs Desipramine Nortriptyline Clomipramine
Nelson, JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2009

12. Actions at other receptors
Antagonism at 5HT2A and 5HTC receptors
Could contribute to their therapeutc profile
Nelson, JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2009

13. Receptors associated with side effects
TCAs block other receptors:
Muscarinic
Alpha 1
Histamine 1
Fast sodium channels

14. Indications

15. Clinical uses of tricyclic antidepressants
FDA-Approved:
Major depressive disorder
OCD (clomipramine)
Enuresis (imipramine)

16. Clinical uses of tricyclic antidepressants
Non-approved :
Headache
Chronic pain syndromes
Insomnia
Yoshimura, M., & Furue, H. (2006). Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. Journal of pharmacological sciences, 101(2),

17. TCAs for major depressive disorder
Not first line agents
Effective for cases of severe depression (hospitalized patients) –especially effective-
Danish University Antidepressant Group. Psychopharmacology (Berl). 1986; 90:
Danish University Antidepressant Group. J Affect Disord. 1990; 18:

18. TCAs for major depressive disorder
Danish University Antidepressant Group (DUAG) studies found clomipramine to be more effective than paroxetine or citalopram in severely depressed patients.
In outpatients the designation of melancholia does not appear to predict an advantage for TCAs vs SSRIs
Danish University Antidepressant Group. Psychopharmacology (Berl). 1986; 90:
Danish University Antidepressant Group. J Affect Disord. 1990; 18:

19. TCAs: Therapeutic Dosage Range
mg/day
Nortriptyline
mg/day
Clomipramine
mg/day
Amitriptyline, desipramine, imipramine, doxepin, trimipramine
Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

20. TCAs: Therapeutic Dosage Range
mg/day
Nortriptyline
mg/day
Clomipramine
mg/day
Amitriptyline, desipramine, imipramine, doxepin, trimipramine
50mg/day
150mg/day
300 mg/day
Amitryptiline
Desipramine
Imipramine
Nortriptyline

21. Tetracyclics: Therapeutic Dosage Range
mg/day
Amoxapine
mg/day
Maprotiline
Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

22. TCAs: Therapeutic Drug Monitoring
Relationship between blood levels and efficacy in depression.
Clearest use: melancholic depression
Little or no relationship: depressed outpatients.
Demonstrated for imipramine, desipramine and nortriptyline.
Nelson, JC "Triciclycs and Tetracyclics". Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

23. TCAs: Therapeutic Drug Monitoring
When?
After achieving steady state: 5-7 days
Wait hours after the last dose
Nelson, JC "Triciclycs and Tetracyclics". Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

24. Indications: Clomipramine for OCD
SSRIs and clomipramine: first line agents (1)
Clomipramine is the most serotonergic of the tricyclics.
There are suggestions that clomipramine might be superior to SSRIs in OCD (2).
1. Koran, Lorrin, and H. Simpson. "Guideline Watch (March 2013): Practice Guideline for the Treatment of Patients With Obsessive-Compulsive Disorder."APA Practice Guidelines. American Psychiatric Publishing, Inc, 2013.
2. Greist JH et al Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Archives of general psychiatry. 1995;52(1):53-60.

25. Key Points
TCAs inhibit reuptake of serotonin and norepinephrine (SNRIs too)
TCAs interact with receptors associated with side effects
Use in depression:
Not first-line agents
Useful in severely depressed patients
Relationship between blood levels and efficacy