Can doxepin and trazodone be taken together? (+3 risks)

In this article, we will discuss whether doxepin and trazodone can be taken together. We will also discuss the potential risks of combining these drugs and other relevant information. 

Can doxepin and trazodone be taken together?

Doxepin and trazodone may or may not be taken together. The research on their concomitant use is limited. Trazodone and doxepin should not be used together unless prescribed by the healthcare provider. 

Doxepin and trazodone are both antidepressants and are used to manage major depressive disorder (MDD) along with other conditions. 

Trazodone is categorized as a serotonin antagonist and reuptake inhibitor (SARI) (1). Doxepin is categorized as a tricyclic antidepressant (TCA) (2). Concomitant use of SARIs and TCAs raises significant warnings and is discouraged. 

Trazodone increases serotonin levels and also acts as an antagonist of some serotonin receptors and histamine (H1) and alpha-1 adrenergic receptors (1) Doxepin increases serotonin and norepinephrine (NE) levels in the body (2).

Doxepin also functions as an antagonist and blocks histamine (H1 and H2), alpha-1 adrenergic, and muscarinic receptors. The interaction with multiple receptors of doxepin results in different side effects (2). 

Healthcare providers exercise caution while prescribing SARIs and TCAs together due to the enhanced risk of threatening side effects like serotonin syndrome. However, in some cases, antidepressants can be combined for better outcomes. 

Therefore, the decision to take doxepin and trazodone together depends on your healthcare provider. Careful dose adjustments must be done to make the combination beneficial. Without medical oversight this combination is dangerous. 

What are the indications of trazodone and doxepin?

Trazodone and doxepin are both antidepressants used for different conditions. Trazodone is approved by the FDA to treat MDD. Its off-label uses include (1):

  • anxiety
  • substance abuse
  • Alzheimer’s disease
  • bulimia
  • fibromyalgia
  • insomnia

Doxepin, available in various forms, has FDA approval for the treatment of the following (2):

  • major depressive disorder
  • anxiety
  • insomnia
  • skin pruritis 

Doxepin is used off-label for migraine prevention and management of neuropathic pain (2). 

What does research suggest?

Medication guides for trazodone mention several cautions and warnings for the concomitant use of TCAs like doxepin. Research suggests that using trazodone with TCAs raises the risk of serotonin syndrome, which is a lethal condition (3). 

Medication guides mention that strict monitoring is required if trazodone is used with serotonergic drugs like doxepin and the drugs should be discontinued if patients show signs of serotonin syndrome (3). 

The simultaneous use of medications that lead to arrhythmias and QT prolongation should be avoided as indicated in the trazodone medication guide (3). Trazodone and doxepin both are associated with these side effects (1,2)

Other resources mention that combining trazodone with TCAs should be avoided due to the risk of serotonin syndrome and enhanced side effects on the cardiovascular system (4). 

One study was conducted to determine the rate of trazodone prescription with selective serotonin reuptake inhibitors (SSRIs) and TCAs. The results revealed that the rate of trazodone prescription with SSRI is greater than with TCAs (5). 

The above-mentioned study shows that trazodone can be prescribed with TCAs like doxepin (5). However, the research on their concomitant use is limited, and further investigation is needed on their appropriate combination. 

What are the risks of combining doxepin and trazodone?

The concomitant use of doxepin and trazodone should be done with extreme caution due to the following risks: 

Risk of serotonin syndrome: 

Trazodone and doxepin both increase the levels of serotonin in the body. Higher than normal concentrations of serotonin in the body can escalate into a potentially life-threatening condition known as serotonin syndrome.

Taking trazodone and doxepin together can increase the risk of serotonin syndrome. Therefore strict monitoring is required if they are prescribed together. Symptoms of serotonin syndrome include (3):

  • agitation
  • hallucination
  • increased heart rate
  • dizziness
  • excessive sweating
  • excessive saliva production
  • hyperthermia
  • tremors
  • seizures
  • nausea
  • rigidity
  • coma

Increased sedation and drowsiness:

The sedative properties of trazodone make it useful for sleep disturbances. It is a hypnotic drug and induces sedation due to its antagonist effects on several receptors.

The use of trazodone as a sleep aid is not approved by FDA. It is a preferred option for patients experiencing depression along with insomnia (1).

Doxepin also causes sedation as it blocks the histamine (H1) receptors. It has FDA approval for insomnia and is preferred in patients experiencing depression along with sleep issues or anxiety (2). 

Thus, taking these drugs together will enhance the sedative effects and result in extreme dizziness and drowsiness. Taking them without medical oversight can be dangerous and will impact alertness and morning wakefulness. 

Increased cardiovascular side effects:

Trazodone is associated with the side effects of QT prolongation and arrhythmias because it blocks the hERG potassium channels in the heart and interferes with cardiac electrical activity. It can also cause orthostatic hypotension (1). 

Doxepin can also cause QT prolongation and tachycardia because it blocks sodium and potassium channels in the heart. It is also associated with the side effect of orthostatic hypotension (2). 

Thus, taking trazodone and doxepin together will enhance these cardiovascular side effects. Simultaneous use of drugs that cause QT prolongation should be avoided. 

Amplified side effects: 

Both trazodone and doxepin have their respective set of side effects. Taking them together increases the side effects and amplifies the shared side effects. The following are the side effects of trazodone (1):

  • headache
  • sleepiness
  • feeling tired
  • light-headedness 
  • dry mouth
  • priapism
  • suicidal ideation
  • acid reflux
  • visual hallucinations
  • QT prolongation
  • orthostatic hypotension
  • arrhythmias

Side effects of doxepin include (2): 

  • dizziness
  • increased weight
  • dry mouth
  • constipation
  • lightheadedness
  • suicidal thoughts
  • QT prolongation
  • orthostatic hypotension
  • tachycardia 

What are the dosing recommendations for doxepin and trazodone?

The action of trazodone and doxepin both rely on the dosage administered. Trazodone is given at low doses of 25-100 mg when it is needed only for sedation as it does not have an antidepressant effect within this range (6). 

For the antidepressant effect of trazodone, higher doses of 150-600 mg are required. At this dose, trazodone produces its antidepressant effect by saturating serotonin receptors (6). 

Doxepin is used in the dose of 3-6mg to address insomnia. For its antidepressant effect, the doses of 25-300 mg can be prescribed (2). Below the 25 mg dose, doxepin does not elicit antidepressant effects (7). 

Studies on doxepin have shown that low doses of doxepin of 3-6 mg are not associated with daytime drowsiness, anticholinergic side effects, suicidal thoughts, and cardiovascular side effects (7). 

Thus, careful dose adjustments of trazodone and doxepin can lead to beneficial effects without amplified side effects. However, the research on this area is limited and needs further exploration. 

Trazodone vs doxepin: which one is more effective?

The efficacy, safety, and tolerability of trazodone have been widely established in the literature. They both have their advantages and side effects. Your healthcare provider will select a drug based on your symptoms and individual characteristics. 

Thus, the healthcare provider decides the appropriate medication and dosage and whether to use two medications or not. You should not use two medications together without medical oversight. 

Trazodone and doxepin have similar efficacy in treating depression. A double-blind study compared the effects of trazodone and doxepin and demonstrated that their anxiolytic and antidepressive effects were equivalent (8). 

In the above-mentioned study, it is discussed that trazodone is associated with fewer side effects than doxepin (8). 

In my perspective, trazodone and doxepin should not be taken together unless prescribed by the healthcare provider. Concomitant use of trazodone and doxepin should be done with extreme caution. 

Combining trazodone with doxepin increases the risk of serotonin syndrome, and cardiovascular effects, and amplifies the side effects. The sedative effects of both drugs are also enhanced with combined use. 

Literature suggests that trazodone has been combined with other antidepressants including SSRIs and TCAs. However, the research on trazodone and doxepin combination is limited. 

Therefore, drugs with similar effects should not be used together unless prescribed by a healthcare provider. 

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