Prescribing Doxepin

At a glance

Two drugs by dose: at 3–6 mg a clean, non-addictive sleep-maintenance hypnotic; at 75–300 mg a full tricyclic antidepressant.

How to doseFull section

Comes as

Capsule10, 25, 50, 75, 100 mg

Silenor tablet3, 6 mg

Oral concentratenot on either label

Example photos; looks vary by maker. Click to enlarge.

In shortClinicians start depression at 25–50 mg at bedtime (10–25 mg if older or sensitive) and titrate every 5–7 days as tolerated toward 75–150 mg/day; for sleep, Silenor 6 mg at bedtime (3 mg if more sensitive or older, or if 6 mg over-sedates).

FDA labelIn practice

A row across both columns means the label and usual practice agree. Off-label marks the few places where practice goes beyond what the label allows.

Adultsdepression (MDD)

StartFDA label25 mg three times daily or 75 mg once dailyIn practice25–50 mg at bedtime; 10–25 mg in older or sensitive patients.

IncreaseFDA labelNo labeled doseIn practiceIncrease every 5–7 days as tolerated.

Usual doseFDA labelTarget 75–150 mg/day; may be given once daily or in divided doses.

MaximumFDA label100 mg three times dailyIn practiceUp to 300 mg/day for more severe or resistant depression; doses above 150 mg are typically divided and only for hospitalized or severe patients.

Side effectsFDA labelCapsules: if anticholinergic effects develop, such as dry mouth, blurred vision or constipation, reduce the dosage.In practiceDoses at the top of the range meaningfully increase anticholinergic and cardiac risk.

Adults with insomniasleep maintenance (trouble staying asleep)

SilenorFDA label6 mg once daily; a 3 mg once daily dose may be appropriate for some patients, if clinically indicated.In practice6 mg at bedtime; 3 mg in patients more sensitive or older, or where 6 mg over-sedates.

MaximumFDA labelTotal Silenor dose should not exceed 6 mg per day.In practiceGoing further moves into the antidepressant range, where the anticholinergic and cardiac effects are real.

Generic capsuleFDA labelNo labeled doseIn practice10 mg at bedtime, above the labeled 6 mg-a-day Silenor cap; or 3–6 mg from the 10 mg/mL concentrate if you want to match Silenor dosing exactly.

Older adultsFDA labelDepression: generally lower start than younger adults. Silenor: start 3 mg once daily; evaluate before increasing to 6 mg, if clinically indicated.In practiceDepression: start 10–25 mg at bedtime, titrate slowly, get a baseline ECG. Insomnia: 3 mg at bedtime.

Interacting drugs, poor metabolizersFDA labelCapsules: reduce the dosage based on doxepin plasma concentrations with strong CYP2D6 inhibitors or in known poor metabolizers.In practiceCYP2D6 and 2C19 inhibitors, including paroxetine, fluoxetine, bupropion, fluvoxamine or cimetidine, raise levels: start low and consider a level.

Liver impairmentFDA labelCapsules: consider obtaining doxepin concentrations in hepatic impairment and modifying the dosage as appropriate.In practiceUse lower doses and titrate cautiously; significant liver disease is a precaution.

Sleep dose timingFDA labelSilenor: within 30 minutes of bedtime, and not within 3 hours of a meal, to minimize next-day effects.In practiceFood substantially increases absorption and can raise next-day residual effects. Ensure a 7–8 hour sleep opportunity.

Stopping and switchingFDA labelCapsules: gradually reduce the dosage until discontinued. MAOI: at least 14 days in either direction.In practiceTaper antidepressant-range doses gradually; low-dose sleep use can generally stop without a formal taper.

Only Silenor carries the insomnia indication; generic doxepin for sleep is off-label.

Allow 14 days in each direction between doxepin and an MAOI.

IndicationsFull section

FDA-approved

Insomnia, sleep maintenance (Silenor 3, 6 mg)

Major depressive disorder

Anxiety ("depression and/or anxiety")

Pruritus of atopic dermatitis, LSC (5% cream)

Off-label, evidence-based

Melancholic depressionTreatment-resistant depressionPTSD-related sleep disruptionChronic urticaria, severe pruritus

Boxed warningsFull section

Suicidality in patients under 25Class antidepressant warning; monitor closely in early treatment and after dose changes

ContraindicationsFull section

MAOIs, current or within 14 daysAbsolute contraindication at any dose; 14-day washout each way

MonitorFull section

Low dose: residual sedationClinical check; morning fog means lower dose, earlier dosing or more distance from food

ECG (full dose)Baseline if >40 or cardiac history; repeat if dose pushed higher or a QT/interacting drug added

Orthostatic BP, weightFull dose: baseline and ongoing

Anticholinergic effectsFull dose: dry mouth, constipation, urinary hesitancy, blurred vision, cognition

Suicidality, mood switchEarly in treatment and after dose changes, especially under 25

Overdose risk (full dose)Assess first; weekly supply and family help if at risk; any overdose goes to the ED

Serum level (optional)Doxepin + nordoxepin ~100–250 ng/mL, loose guide; 8–12 h post-dose, ≥5–6 days at a steady dose

At 3–6 mg: no routine labs, levels or ECG in an otherwise healthy adult.

Drug interactionsFull section

Drug-drug

MAOIsSerotonin syndrome and hypertensive crisis, at any dose; 14-day washout each way

Paroxetine, fluoxetine, bupropion, quinidinePotent 2D6 inhibitors raise levels at full dose; start low, consider a level

Fluvoxamine, cimetidine2C19/1A2 inhibitors raise levels; start low, go slow, consider a level

Alcohol, benzos, opioids, antihistaminesAdditive sedation and respiratory depression; main hazard at hypnotic doses

SSRIs, SNRIs, triptans, tramadolSerotonin-syndrome risk when stacked; greater at full dose

QT-prolonging drugsAdditive conduction risk at full dose

Other anticholinergicsAdditive dry mouth, constipation, retention, confusion; cumulative load matters in the elderly

Sympathomimetics (pseudoephedrine)Hypertensive risk with tertiary-amine TCAs

CYP enzymes

CYP2C19Substrate (principal pathway)Inhibitors (fluvoxamine, cimetidine) raise levels

CYP2D6Substrate (principal pathway)Potent inhibitors raise levels; poor metabolizers run higher on standard doses

CYP1A2, 3A4Substrate (contributes)

Active metabolite nordoxepin (N-desmethyldoxepin) extends the duration of action.

Must counselFull section

DrowsinessThat's the point at bedtime; morning fog means we adjust the dose or timing

Taking the sleep doseWithin 30 minutes of bed, at least 3 hours after eating

Alcohol, other sedativesAvoid mixing with alcohol, opioids or sleeping pills

Dry mouth, constipationMainly at higher doses; water, fiber, sugar-free gum

Dizziness on standingHigher doses: get up slowly and stay hydrated

Suicidal thoughtsCall right away if new or worse, especially under 25

StoppingSleep dose: just stop, a few rough nights possible. Higher doses: we taper

PearlsFull section

The dose tells you which drug you are writing. Don't refuse 6 mg for sleep out of TCA fear, or reach 200 mg with no ECG because it's "the sleep drug."

Low dose is for staying asleep, not falling asleep: built for the 4 a.m. waker who needs something non-addictive with no morning fog.

Generic 10 mg or a few drops of the 10 mg/mL concentrate delivers what Silenor does at roughly 1–2% of the price.

A good hypnotic for older adults at 3–6 mg: sidesteps benzodiazepine falls and dependence with minimal anticholinergic load.

Full-dose niche: the depressed, anxious, insomniac patient. Little sexual dysfunction, a point in its favor.

Discouraged in breastfeeding: nordoxepin accumulates, with reports of infant sedation and respiratory depression.

Summary of this guide. Check the full sections before prescribing.

Photo credits

Doxepin capsules in blister pack, shown with a ruler: Żółwiciel, CC BY-SA 3.0, Wikimedia Commons

Doxepin 100 mg film-coated tablets, box and blister: Fimpelman, CC BY 3.0, Wikimedia Commons

Why Doxepin Matters, and Why You Have to Decide Which Doxepin You Mean

Doxepin is one of the more useful molecules in psychiatry because it is really two drugs under one name, separated by more than an order of magnitude of dose.

At 3–6 mg (branded Silenor, or far more cheaply a fraction of a generic 10 mg capsule), doxepin is the cleanest selective H1 antihistamine hypnotic we have. Its FDA indication names sleep maintenance alone rather than sleep onset: keeping people asleep through the back half of the night, the 3-to-6 a.m. early-morning-awakening window that Ambien and the benzodiazepines handle poorly. It is non-scheduled and non-addictive, it preserves sleep architecture, and at these doses it is practically free of the anticholinergic and cardiac liabilities that make tricyclics scary.

At 75–300 mg, doxepin is a classic tricyclic antidepressant (TCA), a tertiary-amine, norepinephrine-and-serotonin reuptake inhibitor with the full TCA burden: anticholinergic side effects, orthostasis, weight gain, quinidine-like cardiac conduction effects, and lethality in overdose. Here it behaves like its cousins amitriptyline and imipramine and deserves the same respect and the same monitoring.

If you keep one sentence from this guide, keep this one: the dose tells you which drug you are prescribing, and therefore which safety conversation you are having. Almost every prescribing error with doxepin comes from importing the fears of one dose range into the other: either refusing to use 6 mg for sleep because "TCAs are dangerous," or casually titrating to 200 mg for depression without an ECG because "it's just the sleep drug."

This guide is organized around that split. Read the low-dose hypnotic sections and the full-dose antidepressant sections as if they described related but distinct medications, because clinically they do.

The Split, at a Glance

Every clinical decision downstream of the prescription pad follows from which of these two columns you're in:

Part 1: Indications

FDA-Approved Uses

• Insomnia, specifically sleep maintenance (low-dose formulation: Silenor 3 mg and 6 mg)
• Major depressive disorder
• Anxiety (the historical label reads "depression and/or anxiety," including anxiety associated with organic disease and alcoholism)
• Topical doxepin cream (5%): pruritus of atopic dermatitis and lichen simplex chronicus (a dermatology product, not covered in depth here)

The Two Clinical Lives of Doxepin

Life one: the sleep-maintenance hypnotic (3–6 mg). This is doxepin's most distinctive and defensible modern role. Because it is an extraordinarily selective and potent H1 antihistamine at low dose, it produces sedation without engaging the muscarinic, adrenergic, or serotonergic systems in any meaningful way. The randomized, placebo-controlled pivotal trials (Scharf et al., J Clin Psychiatry 2008, and related work) showed 3 mg and 6 mg superior to placebo specifically for staying asleep and improving sleep in the final third of the night, with no residual next-morning impairment at 8 hours. That last finding is what sets it apart. Most hypnotics that work on the back half of the night leave a hangover, and in the studies low-dose doxepin did not.

Best-fit patients for low-dose doxepin:

• Early-morning-awakening insomnia / sleep-maintenance insomnia: arguably the drug of choice for keeping people asleep through the night.
• Depression or anxiety with comorbid insomnia, where you want to treat sleep without an SSRI's activating effect or a benzodiazepine's dependence. (Insomnia and mood/anxiety disorders travel together: in survey data, ~46% of people with insomnia have comorbid depression/anxiety versus ~9% of good sleepers, and insomnia frequently precedes, and predicts relapse of, depression.)
• Patients you want to keep off controlled substances: those with substance-use histories, or where long-term hypnotic use is anticipated and Z-drug/benzodiazepine dependence is unacceptable.
• PTSD-related sleep disruption and hyperarousal: used alone or added to an SSRI; preserves sleep architecture.
• Older adults who need a hypnotic but can't tolerate benzodiazepine falls/confusion, as long as the dose stays low.

Life two: the tricyclic antidepressant (75–300 mg). Here doxepin is a full TCA and inherits the class's evidence base and its niche. In the modern era TCAs are rarely first-line for depression (SSRIs/SNRIs are safer and better tolerated), but doxepin and its cousins remain valuable for:

• Melancholic depression: the subtype (pervasive anhedonia, ruminating guilt, appetite loss, early-morning awakening, psychomotor change) where TCAs tend to outperform SSRIs.
• Treatment-resistant depression: after SSRI/SNRI failure, before or alongside MAOIs.
• Depression with prominent anxiety and insomnia: doxepin's sedation and anxiolysis are useful here, which fits its original "depression and/or anxiety" indication.
• Chronic urticaria / severe pruritus: off-label, exploiting the potent antihistamine action, though dedicated antihistamines are usually preferred.

Doxepin is not a first choice for OCD (that's clomipramine) or for neuropathic pain (amitriptyline and nortriptyline own that space). Its comparative advantage within the TCA class is sedation and antihistamine potency, which explains why it has a low-dose hypnotic life at all.

Where Doxepin Is a Poor Choice

• Bipolar depression without a mood stabilizer: TCAs rank near the top for inducing mania and mixed states. Don't.
• Sleep-onset insomnia as the sole complaint: mismatch to its maintenance profile.
• Patients needing a stimulating antidepressant: doxepin is among the most sedating agents in psychiatry.
• Active, high-lethality suicidality on a full antidepressant dose: overdose danger; if you must use it, dispense small quantities.

Part 2: Before You Start: Workup and Candidacy

The workup scales entirely with the dose.

Low-Dose Hypnotic (3–6 mg, or Generic 10 mg)

• No routine baseline labs, drug levels, or ECG required in an otherwise healthy adult.
• Screen the history for the few conditions where even antihistamine anticholinergic tone matters at the margins: narrow-angle glaucoma, urinary retention / significant BPH, and severe constipation. At 3–6 mg these are rarely limiting, but a two-question screen costs nothing.
• Ask about other sedatives (alcohol, opioids, benzodiazepines): additive CNS depression is the main real-world hazard at low dose.
• Confirm a realistic 7–8 hour sleep window and that the dose won't be taken within 3 hours of eating.

Full-Dose Antidepressant (75–300 mg)

Treat this like starting any tricyclic:

Who Is a Poor Candidate for Full-Dose Doxepin

• Recent MI, unstable angina, significant conduction disease, or baseline QT prolongation
• Untreated narrow-angle glaucoma
• Significant urinary retention / BPH
• Uncontrolled seizure disorder
• Unstabilized bipolar disorder
• Active high-lethality suicidality (relative; dispense small quantities if used)
• Concurrent or recent (within 14 days) MAOI use: absolute contraindication

Part 3: How to Start and Dose

Formulations

Doxepin comes in enough forms to cover both of its clinical lives:

Why Bedtime Dosing Works for Doxepin

Doxepin's potent H1 antihistaminism makes it sedating, and its active metabolite nordoxepin (N-desmethyldoxepin) extends the duration of action. Concentrating the dose at night puts the sedation to work as sleep instead of daytime somnolence, and it simplifies adherence.

Dose Adjustments and Special Populations

• Hepatic impairment: hepatically metabolized (CYP2D6/2C19/1A2); use lower doses and titrate cautiously.
• Renal impairment: no fixed adjustment; use caution and monitor.
• Cardiac disease: antidepressant doses carry the usual TCA cautions (baseline ECG with cardiac history or in older adults, conduction effects, cardiotoxic in overdose); the 3–6 mg insomnia dose carries much less of that burden.
• Pediatric: not established under age 12 for depression; Silenor is not approved in children.

Stopping and Switching

Part 4: Monitoring

Low-Dose Hypnotic

• No routine drug-level, lab, or ECG monitoring.
• Reassess clinically: is sleep maintenance improved, is there any morning residual sedation (suggests dose too high, or taken too late / with food), and is there any new anticholinergic complaint?
• If used long-term, periodically confirm ongoing need and screen for daytime cognitive effects, especially in older adults.

Full-Dose Antidepressant

• ECG: at baseline for age >40 or cardiac history; repeat if the dose is pushed substantially higher or a new interacting/QT-prolonging drug is added.
• Serum levels (optional, situational): doxepin does not have the tidy, validated therapeutic window that nortriptyline (50–150 ng/mL) or imipramine (>200 ng/mL) do. Levels (doxepin plus nordoxepin) are worth checking mainly to confirm adherence, sort out toxicity versus subtherapeutic dosing in a poor or ultrarapid metabolizer, or navigate a suspected drug interaction. A combined therapeutic range of roughly 100–250 ng/mL is often cited, but treat it as looser guidance than the nortriptyline window; dose primarily to clinical response and tolerability. Draw levels 8–12 hours after the last dose, at least 5 half-lives (about 5–6 days) after reaching a steady dose.
• Clinical monitoring: anticholinergic symptoms (dry mouth, constipation, urinary hesitancy, blurred vision, cognition), orthostatic blood pressure, weight, sedation, and, early in treatment, activation, mood switch, and suicidality per the class boxed warning.

Part 5: Side Effects and How to Manage Them

As everywhere else in this guide, the dose decides: at 3–6 mg the side-effect profile is that of a clean antihistamine, and at 75–300 mg it is that of a full tricyclic. Manage accordingly.

Sedation

The intended effect at bedtime, and doxepin is among the most sedating agents in psychiatry.

• Low dose: if there's next-morning residual sedation, the dose is too high, was taken too late, or was taken too close to food. Drop to 3 mg, dose earlier relative to wake time, and separate from meals by 3+ hours.
• Full dose: consolidate the dose at bedtime; if still over-sedating during the day, lower the dose or slow the titration.

Anticholinergic Effects (Dry Mouth, Constipation, Urinary Retention, Blurred Vision, Cognitive Dulling)

• Low dose (3–10 mg): minimal; usually no intervention needed.
• Full dose: manage proactively: hydration and sugar-free gum/lozenges for dry mouth (also protects dentition); fluids, fiber, and stool softeners for constipation (watch for obstruction in the frail); reassurance for mild blurred vision; and dose reduction for cognitive dulling or confusion. In older adults, remember anticholinergic burden is associated with increased dementia risk, so keep the dose as low as effective, and screen cognition.

Cardiovascular

• Orthostatic hypotension / falls: primarily a full-dose problem (alpha-1 blockade). Start low, titrate slowly, check orthostatic vitals, counsel slow position changes and hydration; important in older adults.
• Conduction effects: TCAs have quinidine-like Type 1a antiarrhythmic activity and can prolong QT and slow conduction at full dose, hence the baseline ECG. Not a meaningful concern at hypnotic doses.

Weight Gain and Metabolic

A recognized full-dose TCA effect (antihistamine-driven appetite). Minimal at 3–6 mg. That is an advantage over mirtazapine, the other antihistamine-driven sleep/depression option, which causes more weight gain. Manage with diet/activity counseling; if weight is the dealbreaker at full dose, consider a less histaminergic agent.

Sexual Dysfunction

Unlike with SSRIs/SNRIs, this is not a major problem with doxepin, a point in its favor for patients whose nonadherence is driven by sexual side effects.

Seizure Threshold

TCAs lower the seizure threshold at full dose; use caution in seizure-prone patients (e.g., TBI). Not relevant at hypnotic doses.

Dermatologic

Photosensitivity can occur at full dose (as with related agents); advise sun protection. Topical doxepin cream can itself cause contact dermatitis and, over large body-surface application, systemic anticholinergic/sedative effects.

Part 6: Overdose and Toxicity

This section is about full doses. At 3–6 mg the ingested quantity is far too small to produce tricyclic toxicity; the low-dose formulation is one of the safer sleep agents in overdose. The danger is at antidepressant doses and in the patient who stockpiles capsules.

Why TCAs Are Dangerous in Overdose

Tricyclics are among the most lethal antidepressants in overdose. The mechanism is quinidine-like sodium-channel blockade (Type 1a antiarrhythmic effect) producing:

• Cardiac: QRS widening, QT prolongation, conduction blocks, ventricular arrhythmias, hypotension, cardiovascular collapse
• Anticholinergic: delirium, hyperthermia, mydriasis, ileus, urinary retention, tachycardia
• CNS: sedation progressing to coma, and seizures

The combination of a narrow therapeutic index and cardiotoxicity is what makes tricyclic overdose an emergency.

Management

Prescribing Implication

In patients with meaningful suicide risk who nonetheless need a full-dose tricyclic, dispense limited quantities (a weekly supply) and involve family in medication safekeeping. This is standard practice for all TCAs and applies to doxepin at antidepressant doses.

Boxed Warning (Class Antidepressant Warning)

Part 7: Drug Interactions

Interaction risk, like everything else, is driven by dose, but a few interactions matter even at low dose.

MAOIs: Absolutely Contraindicated

CYP450 and Doxepin Levels (Relevant at Full Dose)

Doxepin is metabolized hepatically, principally via CYP2C19 and CYP2D6 (with contributions from 1A2/3A4). Inhibitors of these enzymes raise doxepin levels and can convert a tolerated dose into a toxic one:

• Potent CYP2D6 inhibitors: paroxetine, fluoxetine, bupropion, quinidine
• CYP2C19/1A2 inhibitors: fluvoxamine, cimetidine
• Management: when adding an inhibitor to full-dose doxepin (or vice versa), start low, go slow, and consider a serum level before and after. Poor CYP2D6 metabolizers run higher levels on standard doses.
• Relatively "clean" antidepressant combinations that don't meaningfully raise TCA levels: citalopram, escitalopram, desvenlafaxine, mirtazapine, trazodone, vilazodone, vortioxetine.

Additive-Effect Interactions (Relevant at Any Dose)

• Other sedatives/CNS depressants (alcohol, benzodiazepines, opioids, other antihistamines): additive sedation and respiratory depression, the main real-world hazard at hypnotic doses.
• Other anticholinergics: additive dry mouth, constipation, retention, and confusion (full-dose primarily, but cumulative anticholinergic load matters in the elderly even at low dose).
• Serotonergic drugs: serotonin-syndrome risk when stacked with SSRIs/SNRIs/triptans/tramadol (greater at full dose).
• QT-prolonging drugs: additive conduction risk at full dose.
• Sympathomimetics (e.g., pseudoephedrine): hypertensive risk with tertiary-amine TCAs.

Part 8: Special Populations

Pregnancy

Doxepin is a tricyclic; TCAs as a class have decades of reproductive use and are not among the clearly teratogenic psychotropics (unlike valproate), but data are older and doxepin specifically is not a preferred agent when better-characterized options exist. Weigh untreated maternal illness (itself a real risk to mother and pregnancy) against modest, imperfectly quantified fetal risk. Neonatal exposure late in pregnancy can produce transient withdrawal/anticholinergic effects. Individualize with obstetrics; for depression, better-studied agents are usually chosen first, and for insomnia, non-pharmacologic approaches come first.

Lactation

Doxepin is generally discouraged in breastfeeding. Its active metabolite nordoxepin has a long half-life and accumulates, and there are case reports of infant sedation and respiratory depression. If a sedating antidepressant/hypnotic is needed in a nursing mother, better-characterized alternatives are preferred; if doxepin is used, monitor the infant closely for sedation, poor feeding, and respiratory changes.

Elderly

• Low-dose (3–6 mg) is a reasonable, often good, hypnotic choice: it sidesteps benzodiazepine falls and dependence and, at that dose, carries minimal anticholinergic load. Keep the dose at the low end.
• Full-dose antidepressant use requires real caution: orthostatic hypotension/falls, anticholinergic confusion and urinary retention, and cardiac conduction effects all rise with age. Start very low (10–25 mg), titrate slowly, get a baseline ECG, and screen cognition. When an older adult really does need a full tricyclic, the secondary amines (nortriptyline, desipramine) are usually better tolerated, but doxepin's sedation may still earn it a role when insomnia and anxiety dominate.

Renal and Hepatic Impairment

• Hepatic impairment: doxepin is hepatically metabolized; reduce dose and titrate cautiously; significant liver disease is a precaution.
• Renal impairment: no specific dose-defining data, but the active metabolite can accumulate; use conservative dosing and monitor.

Pediatrics

Not a first-line pediatric agent; efficacy and safety in young children are not established, and the antidepressant boxed warning (suicidality under 25) applies. The 10 mg/mL oral concentrate can enable precise low dosing by the drop, but that is a titration convenience, not an endorsement of routine pediatric use. Reserve for specialist settings.

Part 9: Discontinuation

• Low-dose hypnotic: doxepin is non-scheduled and non-addictive: the Silenor label found no indication of a withdrawal syndrome after stopping 3 mg or 6 mg (35-day study) and says doxepin does not appear to produce physical dependence. It can generally be stopped without a formal taper, though some patients get transient rebound insomnia for a few nights. Antidepressant-range capsule doses should be reduced gradually (capsule label). Warn them so they don't over-interpret it.
• Full-dose antidepressant: taper rather than stop abruptly. TCAs discontinued suddenly can produce a cholinergic-rebound withdrawal syndrome (nausea, malaise, sweating, headache, insomnia, vivid dreams) and abrupt cessation risks depressive relapse. CANMAT 2023 puts tricyclics in the moderate-risk group for discontinuation symptoms (only paroxetine and venlafaxine are high risk), so a gradual taper (over weeks, guided by dose and duration) remains the rule.

Part 10: Doxepin vs the Alternatives

As a Hypnotic (the Low-Dose Comparison)

As an Antidepressant (the Full-Dose Comparison)

Mechanism

Doxepin is a tertiary-amine tricyclic that inhibits reuptake of norepinephrine and serotonin (the classic dual-monoamine antidepressant mechanism, more noradrenergic than serotonergic). What sets it apart from every other TCA is its extraordinary potency as an H1 histamine antagonist. Doxepin is one of the most potent H1 blockers known, which is why it is uniquely sedating and why a dose as low as 3–6 mg, far below any antidepressant effect, is enough to produce clean, selective hypnotic action. At those low doses, H1 blockade is practically the only receptor action of clinical consequence, so the anticholinergic, adrenergic, and cardiac liabilities of the full tricyclic don't show up.

As the dose climbs into the antidepressant range, the other pharmacology switches on: muscarinic (anticholinergic) blockade, alpha-1 adrenergic blockade (orthostasis), and quinidine-like sodium-channel effects on cardiac conduction (the overdose danger). Metabolism is hepatic via CYP2C19 and CYP2D6, yielding the long-acting active metabolite nordoxepin (N-desmethyldoxepin); parent and metabolite together give doxepin its long tail of action, which is what you want for holding sleep across the night.

The Bedside Cheat Sheet