Trimipramine's mechanism of action differs from other tricyclic antidepressants. It is only a moderate reuptake inhibitor of norepinephrine, and a weak reuptake inhibitor of serotonin and dopamin. The main effects are due to considerable postynaptic blockage as follows:

strong : 5-HT2, Muscarinic, H1, H2, Alpha1
moderate : D2
weak : 5-HT1, Alpha2

The spectrum of effects (strong antidepressant activity, sedation and anxiolysis) and side-effects (strong anticholinergic and antiadrenergic side-effcts) is the same as with Doxepin. It is also a more effective sedative than Amitriptyline. Trimipramine is the only effective drug against insomnia known so far that does not alter the normal sleep architecture. In particular, it does not suppress REM-sleep. Moreover, dreams are said to brighten during treatment. Its relatively strong antagonistic activity at postsynaptic D2-receptors led to a clinical study trying Trimipramine as atypical neuroleptic. There it exerted good antipsychotic activity with a low incidence of extrapyramidal and other side-effects. But this study encompassed only 28 patients, so the use of Trimipramine as a neuroleptic needs further confirmation and can currently not be recommended. Trimipramine shows also useful activity against chronic pain.

Indications

Endogenous and neurotic depression with prominent agitation and anxiety
Depressive and non-depressive insomnia (suitable for long-term treatment)
Adjunctive therapy of alcohol and opioid withdrawal
Chronic pain of malignant and non-malignant origin

Trimipramine is an efficient antidepressant, sedative, and anxiolytic comparable to Doxepin.

Contraindications

absolute :

concomittant treatment with MAO-Inhibitors
known hypersensitivity to Trimipramine or other Tricyclics
acute intoxication with alcohol, sedatives, analgesics and other psychoactive drugs
acute Delirum tremens
untreated closed angle glaucoma
hypertrophy of the prostate with urine retention
paralytic ileus

relative :

hypertrophy of the prostate without urine retention
reduced function of the bone marrow
organic brain disorders
increased risk of seizures, preexisting epilepsy
preexisting cardial damage, particular some arrhythmias (impulse conductive disorders)

Side Effects

See the article on Doxepin. All side-effects of Doxepin are noted also during Trimipramine use with approximately the same frequency and intensity in equivalent doses.

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Low-dose tricyclics effective for depression - Patient Oriented Evidence That Matters: practice recommendations from key studies
From Journal of Family Practice, 5/1/03 by R. Eugene Bailey

Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002; 325:991-995.

* PRACTICE RECOMMENDATIONS

Minimum effective dosage and ranges for antidepressants have not been established. While studies suggest that lower-dose tricyclic antidepressants (TCAs) may be as effective as higher-dose TCAs, dose comparison studies with other antidepressants have not been conducted.

Low-dose TCAs may not be as effective as standard doses, but they do have fewer treatment dropouts due to side effects, and thus patients may have better long-term compliance. Regular monitoring of patient rate of reduction in severity of depression should be used to help determine optimal individual dosing.

* BACKGROUND

Despite widespread marketing of selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants, TCAs are prescribed as often as SSRIs (albeit not all of these prescriptions are for major depressive disorder). Yet evidence regarding the efficacy of TCAs is limited.

Although many guidelines recommend TCAs in higher doses (100 mg/day to 125 mg/day), the effectiveness of lower doses of TCAs is not clear.

* POPULATION STUDIED

The authors performed a comprehensive search of the Cochrane Collaboration's Depression, Anxiety and Neurosis Controlled Trials Registry (a compilation of studies in MEDLINE, Embase, CINAHL, PsychINFO, PSYINDEX, and LILACS). They also searched major psychiatric and medical journals, ultimately identifying 2418 studies. After excluding trials that didn't meet their criteria, they had 39 double-blind, randomized-controlled trials for inclusion. Six of 39 trials compared low-dose TCAs with standard doses of TCAs (551 participants), and 35 of 39 trials compared low-dose TCAs with placebo (2013 participants).

TCAs studied included amitriptyline, imipramine, clomipramine, doxepin, dothiepin, trimipramine, and lofepramine. Ten studies focused on use of TCAs in primary care and 12 studies in psychiatric settings. Five studies examined patients aged >65 years, and 6 dealt with depression and comorbidities (migraine or rheumatoid arthritis).

* STUDY DESIGN AND VALIDITY

Two authors determined independently whether studies met inclusion criteria, and then graded the eligible studies for quality. The studies included were not consistent for population (primary care vs psychiatric, comorbidities, and definition of depression), medication and duration of treatment (4 to 52 weeks), and outcomes measured. Significant heterogeneity existed only for the response rates at 4 to 6 weeks in the TCA vs placebo groups. When the smallest 5 studies reporting the differences were excluded, the results were no longer heterogeneous.

The authors assessed individual study quality using the Cochrane Collaboration Handbook, focusing on allocation concealment and double-blinding. The authors used "per protocol" analysis, examining only data where patients stayed on the medication--dropouts were handled either by analyzing them by the primary study (last observation carried forward) or by worst-case scenario, intention-to-treat analysis.

* OUTCOMES MEASURED

Outcomes included response rates at 4 weeks, 6 to 8 weeks, and 3 to 12 months.

* RESULTS

Low-dose TCAs (75-100 mg/day) were more likely than placebo to bring about a response at 4 weeks (relative risk (RR)=1.65; 95% confidence interval [CI]=1.36-2.00, number needed to treat [NNT] [benefit]=6), 6 to 8 weeks (RR=1.47; 95% CI=1.12-1.94, NNT [benefit]=5), and 3 to 12 months (RR=2.14; 95% CI=1.41-3.26, NNT [benefit]=3).

Standard-dose TCAs were not significantly more effective at achieving response than low-dose TCAs at 4 weeks or at 6 to 8 weeks. In elderly people, TCAs were more likely to produce a result at 4 to 6 weeks but were also more likely to cause at least one side effect. Results were similar in primary care and psychiatric settings.

Overall, dropout rates were similar (24%) for placebo, low-dose, and standard-dose TCAs. Compared with placebo, low-dose TCAs caused more dropouts due to side effects; compared with standard-dose TCA, low-dose TCAs caused fewer dropouts due to side effects.

R. Eugene Bailey, MD, and Kenneth M. Johnson, III, MD, Center for Evidence-Based Practice, Department of Family Medicine, SUNY Upstate Medical University, Syracuse, NY. E-mail: baileye@upstate.edu.

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