Pharmacology of tricyclic antidepressants

Imipramine, first developed tricyclic antidepressant


Tricyclic Antidepressants (TCAs) were once the bread and butter of antidepressant treatment.  In the United States, however, TCAs are less and less frequently used and now most of the graduates of psychiatric residencies are quite unfamiliar with how to prescribe TCAs.

PL thinks this is unfortunate, since a number of studies strongly suggest that TCAs are more effective than SSRIs in the treatment of melancholia and refractory depression. I believe that a refractory unipolar depressed patient has not received adequate treatment if they fail to receive at least one trial of a TCA.  It is common today for a unipolar depressed patient to receive multiple trials of new antidepressants, often over years, and yet never receive a single trial of a TCA.  This reluctance often comes from the clinician, rather than the patient. 

A few simple rules

A few simple rules suffice to become comfortable with prescribing TCAs.  First, as background, it is important to distinguish between tertiary and secondary amines.  Tertiary amines are agents like amitriptyline and imipramine, and secondary amines are agents like their metabolites nortriptyline and desipramine, respectively.  Tertiary amines block the reuptake of serotonin and norepinephrine, while the secondary amines are more selective for norepinephrine reuptake.  The tertiary amines also block multiple other receptor systems, leading to a host of other side effects, while the secondary amines do so to a lesser degree.  Thus, as a rule, the secondary amines are more tolerable, though occasionally there may be increased efficacy with a tertiary amine.

In general, then, in using TCAs, it is wise to begin with a secondary amine, using a tertiary amine as a last resort.  In practice, tertiary amines are infrequently tolerated in full antidepressant doses for refractory depression because all TCAs except nortriptyline generally require a dose of 200-300 mg/d for optimal efficacy.  Nortriptyline is the only TCA with a definitive blood level (50-150 ng/ml, with 100 being ideal).  Usually, the same numbered dose produces that blood level (100 mg/d of nortriptyline tends to yield a blood level of 100 ng/ml).  A patient can thus be more readily and rapidly dosed to an effective amount with nortriptyline than with any other TCA.  Since it is also a secondary amine, PL prefers nortriptyline as the most effective and tolerable TCA. 

 Side effects

All TCAs have quinidine-like effects on cardiac muscle, which can cause or exacerbate conduction defects, resulting in prolongation of the QT interval.  In extreme cases, this can result in Torsades de Pointes and ventricular tachycardia, which is often fatal.  This effect is dose related, hence the potential fatal risk of overdose with TCAs.   As a general rule, a two-week or more prescription of a TCA poses a risk of fatality in overdose.

Some clinicians seem to think that low doses of TCAs for nondepressive indications are less harmful.  One continues to see low dose tertiary TCAs, like amitriptyline (Elavil) or doxepin (Sinequan), prescribed for insomnia.  However, this use of TCAs is inappropriate.  Many safe treatments for insomnia exist (e.g., trazodone).  There is no benefit to using a TCA for a sedating effect.  This use is harmful because even at low doses, some potential of cardiac arrhythmias exists, especially in the elderly and those with underlying cardiac disease.  Even a small exposure to such risk, when unnecessary, is too much exposure.  Also, a low dose of TCAs for insomnia is often the fourth or fifth drug in a polypharmacy cocktail; in almost all cases, the patient experiences sedation or some other side effect shared between TCAs and other agents in the mix.  In general, the low-dose TCA can be omitted altogether without any risk to the patient.

PL emphasizes the need to remain open to the use of TCAs in refractory unipolar depression. However, one still must be realistic that such patients mostly will not improve with any antidepressant:  the STAR*D study found about a 25% response rate after failure of other agents.  In such apparent, "treatment-refractory" cases, PL emphasizes the need to rethink the whole concept of "depression" in such cases, and examine the relevance of the older "manic-depressive illness" concept, and/or the use of bipolar spectrum concepts.  

 PL highly discourages the use of low-dose tertiary TCAs for non-depressive indications such as insomnia.

Common specific agents and their features

  • Imipramine: Tertiary amine, oldest of the class 
  •  Amitryptyline: Tertiary amine,  very sedating 
  • Desipramine: Secondary amine, often too stimulating, most noradrenergic drug available 
  • Nortriptyline: Secondary amine, most tolerable in TCA class
  • Clomipramine: Tertiary amine, most serotonergic in TCA class, useful in OCD 
  • Doxepin: Tertiary amine, most antihistaminic in TCA class, extreme sedation

General rules for TCA treatment

1.     Tertiary amines (like amitriptyline) are metabolized to secondary amines (like nortriptyline).

2.     Secondary amines are more specific to norepinephrine reuptake and are more tolerable.

3.     All TCAs need to be dosed to 200-300 mg/d for full efficacy, with the exception of nortriptyline.

4.     Nortriptyline is the only TCA with a definitive therapeutic blood level, 50-150 ng/dl.

5.     Nortriptyline is the most effective, tolerable TCA  and usually the best first-line agent.

Common receptor blockade effects of tertiary TCAs

  • anticholinergic effects:  dry mouth, constipation
  •  antiadrenergic effects:  sedation, sexual dysfunction, orthostatic hypotension
  • antihistaminic effects:  weight gain, sedation

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