Evidence-Based Reviews

Tricyclics: Still solid performers for the savvy psychiatrist

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Tricyclics played an important therapeutic role in the past and are still valuable treatments for depression, anxiety, pain syndromes, and other disorders. It’s time to re-examine TCAs and prescribe them when appropriate.



Recent practice guidelines generally do not position tricyclic antidepressants (TCAs) as first-line therapies because of concerns about side effects and safety issues.1-3 Yet these agents have important clinical uses—both for approved and off-label indications—and diverse pharmacologic properties that distinguish them from each other as well as from many of the “newer antidepressants.”

Eleven TCAs are available in the United States (Table 1). Here’s what the evidence says about when and how to use them to treat a variety of psychiatric disorders, along with our recommendations on how to reduce the risk of side effects.

Indications and off-label uses

TCAs’ pharmacologic properties make them very versatile (Box 1).4 Major depression and anxiety disorders (such as obsessive compulsive disorder [OCD]) are the principal FDA-approved indications for TCAs. Other approved indications are anxiety (doxepin) and childhood enuresis (imipramine). Common off-label uses supported by scientific literature include panic disorder, social phobia, insomnia, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), attention-deficit/hyperactivity disorder (ADHD), migraine headache, chronic pain syndromes, premature ejaculation, substance abuse disorders, and eating disorders, to name a few.

Major depression To treat major depressive disorder, the American Psychiatric Association recommends selective serotonin reuptake inhibitors (SSRIs), bupropion, venlafaxine, and the secondary amine TCAs desipramine and nortriptyline as “optimal” first-line therapy for most patients.1 The Texas Medication Algorithm Project recommends SSRIs, bupropion, nefazodone, venlafaxine, or mirtazapine as first-line therapy and lists TCAs as second- or third-line therapy for patients with partial or no response to initial therapy.2

Table 1


Generic nameBrand namesTherapeutic dosage range (mg/d)
AmitriptylineElavil, Endep150-300
DesipramineNorpramin, Pertofane150-300
ImipramineTofranil, Tofranil
PM Janimine, Sk-Pramine
* Dosage ranges are approximate. Dosage needs to be tailored by individual patient needs. The elderly, children, and the medically compromised may require lower dosages.

Box 1


The tricyclic antidepresants are a broad class of drugs that can be divided, based on the number of rings in their nucleus, into tricyclics and tetracyclics. The tricyclics can be further classified into tertiary and secondary amines, based on the number of methyl groups on the side chain. In addition, some clinicians include trazodone—an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents—in the broad class of TCAs.

TCAs were initially hypothesized to block the reuptake of norepinephrine (NE) or serotonin (5HT), thereby increasing the levels of these neurotransmitters at the postsynaptic receptor. More recent theories include effects on pre- and postsynaptic receptors and other neurotransmitters, such as histamine and acetylcholine, which explain the various side effects of TCAs.

The relative norepinephrine-reuptake-blocking effects versus serotonin-reuptake-blocking effects of the TCAs and each drug’s biochemical effects are summarized in Table 2. Except for clomipramine, TCAs are relatively weak 5HT reuptake blockers.

Although recommended as first-line therapies, SSRIs and other newer antidepressants exhibit no greater efficacy than TCAs in treating major depression.5,6 Three major meta-analyses7-9 reported no significant difference in efficacy between the two antidepressant classes. In the largest,9 published by the U.S. Department of Health and Human Services, 50% of inpatients and 52% of outpatients responded to TCAs, whereas 54% of inpatients and 47% of outpatients responded to SSRIs. Compared with SSRIs, TCAs also may be associated with higher rates of remission.7,8

Clomipramine—approved for OCD—has been used for decades to treat depression and resistant depression. Two meta-analyses by the Danish University Antidepressant Group7,8 showed that clomipramine produced a “significantly better therapeutic effect” compared with citalopram and paroxetine. In three major studies,5,7,8 TCAs showed greater effectiveness than SSRIs in treating melancholic depression.

The anticholinergic side effects of TCAs have been perceived to cause higher patient dropout and discontinuation rates, but studies have shown mixed results. In one meta-analysis comparing SSRIs and TCAs, the difference in dropout rates due to adverse effects was less significant than previously reported. When total dropout rates for any reason were examined, the difference was less than was originally expected.10

OCD In clinical practice, most patients with OCD are started on an SSRI. Clomipramine is another valuable option, however, especially for patients who fail one or more therapeutic trials with SSRIs. Clomipramine may produce significant therapeutic benefit in patients with OCD, possibly because of its potent 5-HT reuptake properties. In one study, patients with OCD symptoms who received clomipramine improved more than those receiving SSRIs when each class was compared with placebo.11

Panic disorder Although not approved for panic disorder, imipramine and desipramine provide effective treatment, even in nondepressed patients.12 Doses and plasma levels are the same as those used for treating depression. Start low (e.g., imipramine, 10 to 20 mg/d; desipramine, 10 to 25 mg/d) and increase gradually over several weeks to typical therapeutic dosages (Table 1). Do not escalate too rapidly, as this may increase anxiety or precipitate a panic attack. Uses in children TCAs have been used to treat children with ADHD, OCD, enuresis, and depression. The American Academy of Child and Adolescent Psychiatry (AACAP) does not recommend TCAs as first-line treatment for youths requiring pharmacotherapy for depressive disorders but acknowledges that some youths with depression may respond better to TCAs than to other medications.3