Trazodone and Levothyroxine Interaction: What You Need to Know

Does trazodone interact with levothyroxine?

Trazodone's label names the drugs it has clinically important interactions with: MAOIs, which are contraindicated; other serotonergic drugs; antiplatelet agents and anticoagulants; strong CYP3A4 inhibitors; strong CYP3A4 inducers; digoxin and phenytoin; CNS depressants such as alcohol and barbiturates; and other drugs that prolong the QT interval [2]. Levothyroxine is not on that list.

Levothyroxine's labels carry their own list, and it is mostly about absorption: calcium carbonate and ferrous sulfate, bile acid sequestrants and ion exchange resins, proton pump inhibitors, antacids, sucralfate, orlistat, and foods including soybean flour, cottonseed meal, walnuts, dietary fiber and grapefruit juice [1]. Trazodone is not named there either. The levothyroxine labels do name sertraline, another antidepressant, among drugs that may increase levothyroxine requirements [1].

Why levothyroxine has an absorption rule

Levothyroxine labels specify a single daily oral dose on an empty stomach, one-half to one hour before breakfast, and at least 4 hours before or after drugs known to interfere with its absorption [1]. The spacing differs by drug:

• Calcium carbonate and ferrous sulfate: the labels specify at least 4 hours apart. They say calcium carbonate may form an insoluble chelate with levothyroxine and ferrous sulfate likely forms a ferric-thyroxine complex [1].
• Bile acid sequestrants and exchange resins: the labels specify levothyroxine at least 4 hours before the binder, or monitoring TSH [1].
• Proton pump inhibitors, antacids and sucralfate: the labels give no fixed hour spacing. They say these can reduce absorption by affecting gastric acidity, and that patients should be monitored [1].

Studies behind those rules were small. In an uncontrolled study of 20 adults with hypothyroidism, 1,200 mg a day of elemental calcium taken with levothyroxine for 3 months lowered mean free T4 from 17 to 15 pmol/L and raised TSH from 1.6 to 2.7 mIU/L, with values returning toward baseline after calcium stopped [3]. In an uncontrolled study of 14 patients, ferrous sulfate 300 mg taken with thyroxine daily for 12 weeks raised mean TSH from 1.6 to 5.4 mU/L, and 9 patients had more hypothyroid symptoms [4]. In a 248-patient study of multinodular goiter, thyroxine requirements were 22% to 34% higher in people with H. pylori or atrophic gastritis, and omeprazole raised TSH in all 10 patients treated with thyroxine, an effect reversed by a 37% dose increase [5].

Do the two drugs share a metabolic pathway?

The labels describe different routes. Trazodone is a CYP3A4 substrate, and CYP3A4 forms its active metabolite, m-chlorophenylpiperazine [2][6]. The trazodone label says a strong CYP3A4 inhibitor raises trazodone exposure and the risk of adverse reactions including arrhythmia, so a lower dose should be considered; a strong CYP3A4 inducer lowers exposure, so a higher dose may be needed [2]. In 10 healthy volunteers, low-dose ritonavir cut trazodone's apparent oral clearance from 155 to 75 mL/min, lengthened half-life from 6.7 to 14.9 hours and raised peak levels from 842 to 1,125 ng/mL, with more sedation and fatigue [7].

Levothyroxine is handled differently: about 80% of a daily T4 dose is deiodinated to T3 and reverse T3, and the liver is the main site of degradation [1]. Trazodone's label does not describe trazodone as a CYP inhibitor or inducer; the only level-raising effects it lists are on digoxin and phenytoin, with no mechanism given [2].

Timing when taking both

Neither label sets a required interval between trazodone and levothyroxine. Levothyroxine labels specify an empty stomach, one-half to one hour before breakfast [1]. The trazodone tablet label says to take it shortly after a meal or light snack [2]. That label also notes that drowsiness may call for a major portion of the daily dose at bedtime, or a dose reduction [2]. Food changes trazodone's absorption profile: in 8 healthy volunteers, a 100 mg dose with food lowered peak concentration from 1.88 to 1.47 micrograms/mL and delayed the peak from 1.3 to 2.0 hours, without changing the total amount absorbed [8].

Some people take levothyroxine at bedtime. In a double-blind crossover trial that enrolled 105 adults with primary hypothyroidism and had 90 complete it, bedtime dosing lowered TSH by 1.25 mIU/L and raised free T4 by 0.07 ng/dL compared with morning dosing, with no significant difference in quality-of-life scores [9]. The levothyroxine labels still describe pre-breakfast dosing [1].

Safety points from each label

Trazodone. Orthostatic hypotension and syncope are label warnings; among outpatients treated for major depression, hypotension was reported in 4% on trazodone versus 0% on placebo and syncope in 5% versus 1% (157 versus 158 patients) [2]. The label says trazodone prolongs the QT interval, and postmarketing reports include torsades de pointes and ventricular tachycardia at doses of 100 mg a day or less [2]. Serotonin syndrome can occur with trazodone alone and becomes more likely with other serotonergic drugs [2]. Common side effects in the same outpatient trials were drowsiness (41% versus 20%), dry mouth (34% versus 20%) and dizziness or lightheadedness (28% versus 15%) [2].

Levothyroxine. Reactions are mainly those of excess thyroid hormone: palpitations, tachycardia, arrhythmias, angina, heart failure, tremor, nervousness, insomnia, heat intolerance, sweating, weight loss and diarrhea; over-replacement decreases bone mineral density [1]. The labels warn about cardiac reactions in older adults and people with heart disease, who are started below the full replacement dose, and about the risks of over- and under-treatment given the narrow therapeutic index [1].

Monitoring. The levothyroxine labels adjust the dose in 12.5 to 25 mcg steps every 4 to 6 weeks until TSH is normal, and note that the peak effect of a dose may take 4 to 6 weeks [1].

What is not known

A label that omits a drug is not a tested, neutral result for the pair. TSH is what the levothyroxine labels use to guide dose adjustment [1]. Fatigue is also a listed trazodone adverse reaction (6% versus 3% on placebo) [2], so a change in symptoms alone would not show that trazodone changed thyroid levels.