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Doxepin chemical structure

11-(3-(Dimethylamino) propylidene)-6H-dibenz(b,e)oxepine
IUPAC name
CAS number
ATC code


Chemical formula {{{chemical_formula}}}
Molecular weight 279.376 g/mol
Bioavailability Absolute = 25%.
When main metabolite desmethyldoxepin is included: 31%
Metabolism Hepatic
Elimination half-life Doxepin 17h, main metabolite Desmethyldoxepin 51h
Excretion Renal
Pregnancy category Not recommended.
Animal studies have shown embryotoxic properties.
Legal status Rx-only
Routes of administration Oral, intramuscular injection, intravenous infusion

Doxepin is a psychotropic agent with tricyclic antidepressant and anxiolytic properties, known under many brand-names such as Aponal®, the original preparation by Boehringer-Ingelheim, now part of the Roche group; Adapine®, Sinquan® and Sinequan® (Pfizer Inc.).


Doxepin inhibits the reuptake of serotonin and noradrenaline from the synaptic cleft (dual action). The reuptake-inhibition of dopamine is very weak.

It has antagonistic effects (blockade) on a variety of postsynaptic receptors:

  • Extremely strong : H1, H2
  • Strong : 5-HT2, Alpha1, Muscarinic
  • Moderate : 5-HT1
  • Weak : D2, Alpha2

These effects account for the actions as well for most side-effects (sedation, hypotension, anticholinergic side-effects, massive weight gain). Doxepin shows strong antagonism against the effects of Reserpin (amine depletion) in the animal model. Like other 'classical' antidepressants it has a sodium channel blocking activity, possibly accounting for its analgesic action. Additionally, Doxepin exerts a strong local-anesthetic action.

Peak plasma levels are seen 2 to 3 hours after oral dosing.


acute toxicity:

  • Mouse : i.v. 15 - 20 mg/kg body weight, oral 148 - 178 mg/kg body weight
  • Rat : i.v. 13 - 19 mg/kg body weight, oral 346 - 460 mg/kg body weight
  • Human : Not exactly known, clinical experience indicates a rather high acute toxicity, as is the case with other tri-/tetracyclics. Fatal dose in sensitive adults may be as low as 500 to 1,000 mg oral (7 to 14 mg/kg). In children below 12 yrs. of age any oral intake is to be considered as serious.

chronic toxicity

  • Dog and Rat : Fat deposits in liver cells and decrease of triglyceride levels in plasma
  • Human : Data not available


Approved uses may vary by country. In the United States, the only Food and Drug Administration (FDA) approved use of doxepin in the treatment of depression. All other uses are considered off-label.

  • Depression
  • Anxiety disorder, longterm-treatment is possible.
  • Insomnia, also suitable for longterm-treatment (see Hajak et al., 2001).
  • Alleviation of the symptoms of alcohol and drug withdrawal (N.B.: Doxepin does not suppress seizure activity in alcoholics ('rum fits'). Cotreatment with benzodiazepines or barbiturates is needed to treat seizures effectively.
  • Gastrointestinal ulceration and other GI-problems (e.g. irritable bowel syndrome), whether part of depression or not. The action is due to strong H2-receptor antagonism. The efficiacy is comparable to H2-Receptor-Inhibitors.
  • Chronic pain, particular tension headaches, whether associated with depression or not
  • Topical (external) treatment of itching skin disease with Zonalon® and Xepin®
  • low dose doxepin (3 to 6 mg) is currently on phase 3 as "new" treatment for insomnia (Silenor® see [1])


absolute :

  • known hypersensitivity to doxepin or other dibenzoxepines or other ingredients of the drug
  • acute intoxication with alcohol, sedatives, analgesics and other psychoactive drugs
  • acute delirium 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 (e.g. sinoatrial blockage)

special caution is needed :

  • other forms of preexisting cardiac damage (other arrhythmias, insufficience)
  • MAO-Inhibitors of the irreversible type (tranylcypromine among others) : These drugs should normally be stopped at least 2 weeks before therapy with doxepin is started.

Children under 12 years of age should not be treated, because no sufficient clinical experience exists for this group of age. Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, doxepin should be administered with extreme caution to patients with a history of cardiovascular disease, those with circulatory lability and elderly patients. In such cases, treatment should be initiated with low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels. Since tricylic agents are known to reduce the seizure threshold, doxepin should be used with caution in patients with a history of convulsive disorders. Concurrent administration of ECT and doxepin may be hazardous and, therefore, such treatment should be limited to patients for whom it is essential. Close supervision is required when doxepin is given to hyperthyroid patients or those receiving thyroid medication because of the possibility of cardiovascular toxicity. At doses above 150 mg/day, it may block the antihypertensive effect of guanethidine and related compounds.


Before initiation of treatment a complete and differentiated blood count should be taken. If any value is pathologic, the blood count should be monitored closely under therapy with doxepin. If values are normal, blood counts should be taken during therapy in regular intervals (recommended: weekly during first month of therapy, monthly during the next 2 months, every 3 months afterwards).

Liver-function studies should be performed periodically.

Pregnancy and Lactation[]

If Doxepin is used chronically during pregnancy, the newborn may show a withdrawal syndrom with agitation, impaired cardio-respiratory functions, disturbed urination and defecation. Caution should be exerted in treating pregnant women on a regular basis.

Doxepin is found in significant amounts in the milk of lactating women. If therapy is necessary, lactation should be interrupted during treatment.


  • Central Nervous System : fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, insomnia, seizures (infrequently), delirium, rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side-effects (rarely), abuse in patients with polytoxikomania (rarely)
  • Anticholinergic : dry mouth, obstipation, even ileus (rarely), difficulties in urinating, sweating, precepitation of glaucoma
  • Antiadrenergic : hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinus-tachycardia, bradycardia, av-blockade)
  • Allergic/toxic : skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely)
  • Others : frequently increased appetite, massive weight gain, rarely nausea, frequently impaired sexual function in men (impotence, ejaculation-difficulties), rarely hypertension, rarely polyneuropathy, in both sexes breast-enlargement and galactorrhea (rarely)

Suicidal Patients[]

Patients with suicidal thoughts, or those with previous suicidal attempts, should be monitored closely under treatment with Doxepin. Perhaps, the decision is made to hospitalize high risk patients until remission or to prescribe an additional sedating drug like a benzodiazepine or chlorprothixene for 2-4 weeks of initial treatment with Doxepin (until significant remission). At least, the smallest amount of Doxepin should be prescribed at one time to minimize the risk of deliberate overdose.

Drug Abuse and Dependence[]

Doxepin has an extremely low potential for abuse and psychological dependence (mostly noted with polytoxicomaniacs, possibly due to the strong anxiolytic action of Doxepin).

Withdrawal symptoms frequently seen when treatment with doxepin is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of Doxepin gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. Lorazepam, Clonazepam, or Alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Other remarks[]

Doxepin may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued.

With Zonalon® and Xepin; in most countries an external form (cream) is available for the treatment of itching skin disease; the effect is probably due to the affinity of doxepin for H1 and H2 receptors and action on muscarininc receptors.


  • Irreversible MAO-Inhibitors : agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. potentially fatal. N.B. Treatment-resistant hospitalized patients may be treated concomitantly with an MAO-inhibitor, if they are closely monitored by an expert and the initial dose of both drugs is low.
  • Increased drug actions :
  • other antidepressants, barbiturates, narcotics, sedating antihistaminics, anticonvulsive drugs, alcohol - resulting in increased central depression
  • anticholinergics (antiparkinsonian agents, tri- and tetracyclic antidepressants) - resulting in increased anticholinergic action (dry mouth, obstipation etc.)
  • Cimetidine : impairs the excretion of Doxepin - increased central depression and anticholinergic effects
  • Sympathomimetics (also those used in local anesthetics like Noradrenaline) : sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc)
  • Nitrates and Antihypertensives (e.g. Beta-Blockers) - increased antihypertensive action with pronounced fall in blood pressure
  • Decreased drug actions :
  • Guanethidin, Reserpin, Guanfacin : antihypertensive effects decreased
  • Clonidin : antihypertensive effects decreased and risk of (massive) rebound hypertension.


  • Depending on the disease to be treated, clinical condition, age, weight and liver function :

Initial doses may be as low as 5 mg in the evening for treatment of insomnia or as high as 100 mg oral as bedtime single dose or in divided doses in severely agitated depressive patients. Patients with severe opioid withdrawal symptoms often even require 3 times 50 mg or more in the first few days. Generally, initial doses should be low and increased step by step. Outpatients should not receive more than 150 mg daily. Hospitalized patients may receive up to 300 mg orally in divided doses. Up to 150 mg may be given as single bedtime dose. The dose for i.m.-injections and i.v.-infusions is usually 1/2 or less of the oral dose. Infusions should be given very slowly and the patient should lie during the infusion and for some hours afterwards in order to avoid severe postural hypotension.

It has been shown that Doxepin is able to decrease the risk of relapse of serious depression when given as longterm treatment after the remission is stable. If this applies for you, your physician will determine as well the daily dose and the duration of longterm treatment. The daily dose might be lower than the dose needed for full remission of your depression.

  • External use : As directed by physician.


Main article: Tricyclic antidepressant

If overdose is suspected, local poison control centers or emergency departments can provide advice. United States residents can call the US national poison hotline at 1-800-222-1222. Other worldwide poison centers can be found at the World directory of poisons centers.

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.


Doxepin was synthesized by Stach and Spingler from the German drug manufacturer C. F. Boehringer & Söhne GmbH in Mannheim. It was tested from 1963 to 1968 in different German and Swiss psychiatric institutions and was approved in Germany and elsewhere thereafter. The antidepressive effects were found to be excellent. Strong anxiolytic and sedative properties were also demonstrated. Doxepin has been in clinical use for several decades. The drug plays an important role in many indications today, not only in psychiatry/neurology.

Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine, Modafinil
Norepinephrine-dopamine reuptake inhibitors Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine
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