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Doxepin for insomnia
Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).1 FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.
Table 1
Doxepin: Fast facts
| Brand name: Silenor |
| Indication: Insomnia characterized by difficulty with sleep maintenance |
| Approval date: March 2010 |
| Availability date: September 7, 2010 |
| Manufacturer: Somaxon Pharmaceuticals |
| Dosage forms: 3 mg and 6 mg tablets |
| Recommended dosage: 3 mg or 6 mg once daily within 30 minutes of bedtime |
Clinical implications
Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)
How it works
Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.2 Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.3 However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.
Pharmacokinetics
When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.1-3
Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.1-3
Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.
Efficacy
Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).4,5 Clinical studies lasted up to 3 months.1-3,6-8
In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.4 In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7th and 8th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.
Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.4
The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.5 Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.
In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.5
Table 2
Evidence of effectiveness of doxepin for insomnia
| Study | Subjects | Dosages | Results |
|---|---|---|---|
| Roth et al, 20074; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 67 patients age 18 to 64 with chronic primary insomnia | 1, 3, or 6 mg given once daily at bedtime for 2 nights | Improvement vs placebo in PSG-defined WASO, TST, SE, and SE during the final third of the night. 6-mg dose significantly reduced subjective latency to sleep onset. Safety profile of all 3 doses was comparable to placebo. No difference in residual sedation |
| Scharf et al, 20085; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 76 patients age ≥65 with primary insomnia | 1, 3, or 6 mg at bedtime for 2 nights | Reduction vs placebo in WTDS and WASO at all 3 doses. Increase in TST and SE at all 3 doses. No difference in number of awakenings after sleep onset and latency to persistent sleep at all 3 doses. WTAS was reduced only at 3 and 6 mg doses. Patient-reported WTAS was decreased at all doses. Patient-reported latency to sleep onset decreased only with 6 mg. Safety profile of all 3 doses was comparable to placebo and there were no differences among placebo and all 3 doses doxepin in next-day sleepiness or psychomotor function |
| PSG: polysomnography; SE: sleep efficiency; TST: total sleep time; WASO: wake after sleep onset; WTAS: wake time after sleep; WTDS: wake time during sleep Source: References 4,5 | |||
Tolerability
Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.1 All reported adverse events were mild to moderate.
Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.1 Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.
Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.2-4
Symptoms of withdrawal and rebound insomnia—an increase in WASO compared with baseline after discontinuing the medication—were assessed in a 35-day double-blind study of adults with chronic insomnia.1 There was no evidence of withdrawal syndrome as measured by Tyler’s Symptom Checklist after doxepin 3 mg and 6 mg was discontinued. Discontinuation period-emergent nausea and vomiting was noted in 5% of patients taking 6 mg of doxepin, but not in those taking placebo or 3 mg of doxepin. There was no evidence of rebound insomnia after doxepin 3 mg and 6 mg was discontinued.1
Contraindications
Doxepin is contraindicated in patients with hypersensitivity to doxepin hydrochloride, with severe urinary retention, with narrow angle glaucoma, and who have used monoamine oxidase inhibitors (MAOIs) within the previous 2 weeks. Serious adverse effects, including hypertensive crisis and death, have been reported with coadministration of MAOIs and certain drugs, such as serotonergic antidepressants and some opioids derivatives. There are no reports of concomitant use of doxepin with MAOIs.1
Dosing
In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes before bedtime. For patients age ≥65, the recommended starting hypnotic dose is 3 mg 30 minutes before bedtime, which can be increased to 6 mg if indicated.1
Related Resources
- Doghramji K, Grewal R, Markov D. Evaluation and management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454.
- Psychiatric Clinics of North America. December 2006. All articles in this issue address sleep disorders encountered in psychiatric practice.
- National Sleep Foundation. www.sleepfoundation.org.
Drug Brand Names
- Amitriptyline • Elavil
- Cimetidine • Tagamet
- Desipramine • Norpramin
- Doxepin (3 mg and 6 mg) • Silenor
- Doxepin (10 to 150 mg, oral) • Sinequan
- Doxepin cream • Prudoxin
- Fluoxetine • Prozac
- Paroxetine • Paxil
- Ramelteon • Rozerem
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Silenor [package insert]. San Diego, CA: Somaxon; 2010.
2. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10(10):1649-1655.
3. Stahl SM. Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13(12):1027-1038.
4. Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561.
5. Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2008;69:1557-1564.
6. Hajak G, Rodenbeck A, Adler L, et al. Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia. Pharmacopsychiatry. 1996;29:187-192.
7. Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62:453-463.
8. Rodenbeck A, Cohrs S, Jordan W, et al. The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed by an open treatment for 3 weeks. Psychopharmacology. 2003;170:423-428.
Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).1 FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.
Table 1
Doxepin: Fast facts
| Brand name: Silenor |
| Indication: Insomnia characterized by difficulty with sleep maintenance |
| Approval date: March 2010 |
| Availability date: September 7, 2010 |
| Manufacturer: Somaxon Pharmaceuticals |
| Dosage forms: 3 mg and 6 mg tablets |
| Recommended dosage: 3 mg or 6 mg once daily within 30 minutes of bedtime |
Clinical implications
Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)
How it works
Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.2 Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.3 However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.
Pharmacokinetics
When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.1-3
Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.1-3
Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.
Efficacy
Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).4,5 Clinical studies lasted up to 3 months.1-3,6-8
In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.4 In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7th and 8th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.
Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.4
The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.5 Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.
In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.5
Table 2
Evidence of effectiveness of doxepin for insomnia
| Study | Subjects | Dosages | Results |
|---|---|---|---|
| Roth et al, 20074; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 67 patients age 18 to 64 with chronic primary insomnia | 1, 3, or 6 mg given once daily at bedtime for 2 nights | Improvement vs placebo in PSG-defined WASO, TST, SE, and SE during the final third of the night. 6-mg dose significantly reduced subjective latency to sleep onset. Safety profile of all 3 doses was comparable to placebo. No difference in residual sedation |
| Scharf et al, 20085; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 76 patients age ≥65 with primary insomnia | 1, 3, or 6 mg at bedtime for 2 nights | Reduction vs placebo in WTDS and WASO at all 3 doses. Increase in TST and SE at all 3 doses. No difference in number of awakenings after sleep onset and latency to persistent sleep at all 3 doses. WTAS was reduced only at 3 and 6 mg doses. Patient-reported WTAS was decreased at all doses. Patient-reported latency to sleep onset decreased only with 6 mg. Safety profile of all 3 doses was comparable to placebo and there were no differences among placebo and all 3 doses doxepin in next-day sleepiness or psychomotor function |
| PSG: polysomnography; SE: sleep efficiency; TST: total sleep time; WASO: wake after sleep onset; WTAS: wake time after sleep; WTDS: wake time during sleep Source: References 4,5 | |||
Tolerability
Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.1 All reported adverse events were mild to moderate.
Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.1 Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.
Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.2-4
Symptoms of withdrawal and rebound insomnia—an increase in WASO compared with baseline after discontinuing the medication—were assessed in a 35-day double-blind study of adults with chronic insomnia.1 There was no evidence of withdrawal syndrome as measured by Tyler’s Symptom Checklist after doxepin 3 mg and 6 mg was discontinued. Discontinuation period-emergent nausea and vomiting was noted in 5% of patients taking 6 mg of doxepin, but not in those taking placebo or 3 mg of doxepin. There was no evidence of rebound insomnia after doxepin 3 mg and 6 mg was discontinued.1
Contraindications
Doxepin is contraindicated in patients with hypersensitivity to doxepin hydrochloride, with severe urinary retention, with narrow angle glaucoma, and who have used monoamine oxidase inhibitors (MAOIs) within the previous 2 weeks. Serious adverse effects, including hypertensive crisis and death, have been reported with coadministration of MAOIs and certain drugs, such as serotonergic antidepressants and some opioids derivatives. There are no reports of concomitant use of doxepin with MAOIs.1
Dosing
In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes before bedtime. For patients age ≥65, the recommended starting hypnotic dose is 3 mg 30 minutes before bedtime, which can be increased to 6 mg if indicated.1
Related Resources
- Doghramji K, Grewal R, Markov D. Evaluation and management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454.
- Psychiatric Clinics of North America. December 2006. All articles in this issue address sleep disorders encountered in psychiatric practice.
- National Sleep Foundation. www.sleepfoundation.org.
Drug Brand Names
- Amitriptyline • Elavil
- Cimetidine • Tagamet
- Desipramine • Norpramin
- Doxepin (3 mg and 6 mg) • Silenor
- Doxepin (10 to 150 mg, oral) • Sinequan
- Doxepin cream • Prudoxin
- Fluoxetine • Prozac
- Paroxetine • Paxil
- Ramelteon • Rozerem
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).1 FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.
Table 1
Doxepin: Fast facts
| Brand name: Silenor |
| Indication: Insomnia characterized by difficulty with sleep maintenance |
| Approval date: March 2010 |
| Availability date: September 7, 2010 |
| Manufacturer: Somaxon Pharmaceuticals |
| Dosage forms: 3 mg and 6 mg tablets |
| Recommended dosage: 3 mg or 6 mg once daily within 30 minutes of bedtime |
Clinical implications
Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)
How it works
Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.2 Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.3 However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.
Pharmacokinetics
When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.1-3
Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.1-3
Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.
Efficacy
Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).4,5 Clinical studies lasted up to 3 months.1-3,6-8
In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.4 In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7th and 8th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.
Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.4
The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.5 Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.
In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.5
Table 2
Evidence of effectiveness of doxepin for insomnia
| Study | Subjects | Dosages | Results |
|---|---|---|---|
| Roth et al, 20074; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 67 patients age 18 to 64 with chronic primary insomnia | 1, 3, or 6 mg given once daily at bedtime for 2 nights | Improvement vs placebo in PSG-defined WASO, TST, SE, and SE during the final third of the night. 6-mg dose significantly reduced subjective latency to sleep onset. Safety profile of all 3 doses was comparable to placebo. No difference in residual sedation |
| Scharf et al, 20085; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 76 patients age ≥65 with primary insomnia | 1, 3, or 6 mg at bedtime for 2 nights | Reduction vs placebo in WTDS and WASO at all 3 doses. Increase in TST and SE at all 3 doses. No difference in number of awakenings after sleep onset and latency to persistent sleep at all 3 doses. WTAS was reduced only at 3 and 6 mg doses. Patient-reported WTAS was decreased at all doses. Patient-reported latency to sleep onset decreased only with 6 mg. Safety profile of all 3 doses was comparable to placebo and there were no differences among placebo and all 3 doses doxepin in next-day sleepiness or psychomotor function |
| PSG: polysomnography; SE: sleep efficiency; TST: total sleep time; WASO: wake after sleep onset; WTAS: wake time after sleep; WTDS: wake time during sleep Source: References 4,5 | |||
Tolerability
Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.1 All reported adverse events were mild to moderate.
Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.1 Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.
Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.2-4
Symptoms of withdrawal and rebound insomnia—an increase in WASO compared with baseline after discontinuing the medication—were assessed in a 35-day double-blind study of adults with chronic insomnia.1 There was no evidence of withdrawal syndrome as measured by Tyler’s Symptom Checklist after doxepin 3 mg and 6 mg was discontinued. Discontinuation period-emergent nausea and vomiting was noted in 5% of patients taking 6 mg of doxepin, but not in those taking placebo or 3 mg of doxepin. There was no evidence of rebound insomnia after doxepin 3 mg and 6 mg was discontinued.1
Contraindications
Doxepin is contraindicated in patients with hypersensitivity to doxepin hydrochloride, with severe urinary retention, with narrow angle glaucoma, and who have used monoamine oxidase inhibitors (MAOIs) within the previous 2 weeks. Serious adverse effects, including hypertensive crisis and death, have been reported with coadministration of MAOIs and certain drugs, such as serotonergic antidepressants and some opioids derivatives. There are no reports of concomitant use of doxepin with MAOIs.1
Dosing
In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes before bedtime. For patients age ≥65, the recommended starting hypnotic dose is 3 mg 30 minutes before bedtime, which can be increased to 6 mg if indicated.1
Related Resources
- Doghramji K, Grewal R, Markov D. Evaluation and management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454.
- Psychiatric Clinics of North America. December 2006. All articles in this issue address sleep disorders encountered in psychiatric practice.
- National Sleep Foundation. www.sleepfoundation.org.
Drug Brand Names
- Amitriptyline • Elavil
- Cimetidine • Tagamet
- Desipramine • Norpramin
- Doxepin (3 mg and 6 mg) • Silenor
- Doxepin (10 to 150 mg, oral) • Sinequan
- Doxepin cream • Prudoxin
- Fluoxetine • Prozac
- Paroxetine • Paxil
- Ramelteon • Rozerem
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Silenor [package insert]. San Diego, CA: Somaxon; 2010.
2. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10(10):1649-1655.
3. Stahl SM. Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13(12):1027-1038.
4. Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561.
5. Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2008;69:1557-1564.
6. Hajak G, Rodenbeck A, Adler L, et al. Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia. Pharmacopsychiatry. 1996;29:187-192.
7. Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62:453-463.
8. Rodenbeck A, Cohrs S, Jordan W, et al. The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed by an open treatment for 3 weeks. Psychopharmacology. 2003;170:423-428.
1. Silenor [package insert]. San Diego, CA: Somaxon; 2010.
2. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10(10):1649-1655.
3. Stahl SM. Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13(12):1027-1038.
4. Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561.
5. Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2008;69:1557-1564.
6. Hajak G, Rodenbeck A, Adler L, et al. Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia. Pharmacopsychiatry. 1996;29:187-192.
7. Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62:453-463.
8. Rodenbeck A, Cohrs S, Jordan W, et al. The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed by an open treatment for 3 weeks. Psychopharmacology. 2003;170:423-428.
Suicide risk assessment: Questions that reveal what you really need to know
You can make more-informed decisions about a patient’s acute suicide risk—such as over the phone at 3 AM—if you know what to ask the psychiatry resident or crisis worker. For suicide risk assessment—especially when you have not seen the patient—you need specific, high-yield questions to draw out danger signals from large amounts of data.
We are not suggesting that a short list of questions is sufficient for this extremely difficult task. Rather—because we recognize its complexity—we offer the questions we find most useful when evaluating patients with suicidal behaviors.
American Psychiatric Association practice guidelines1 provide a comprehensive discussion of assessing suicide risk. In addition, we teach clinicians we supervise to probe for high-risk and less-commonly explored “protective” factors.
High-risk factors
Mental health clinicians are more experienced in probing for high-risk factors than for protective factors. Because population studies offer limited help (Box 1),2 we ask clinicians these questions to evaluate the seriousness of a suicide attempt:
- Most studies of suicide risk factors focus on medium- to long-range risk
- Population-based risk factors (such as being Caucasian, over age 65, or depressed) apply to so many patients that their clinical usefulness is limited1
- Population-based risk factors often have high sensitivity but low specificity (recent loss is an important risk factor for attempting suicide, for example, but very few persons with a recent loss attempt suicide)
- In an acute situation, the positive predictive value of suicide risk factors—alone or in combination—is not known
Table
3 important questions to ask in overdose cases
|
What method was used? Methods other than taking an overdose or cutting the wrists may be more dangerous.
What amount was used? (in overdose or poisoning cases)
What treatment was needed? If the patient took an overdose of opioids and needs intubation, this indicates a relatively serious attempt. On the other hand, the psychiatric seriousness of an acetaminophen overdose depends on whether the patient realized the danger in taking high doses of acetaminophen. Additional questions can help determine the seriousness of suicide attempts by overdose (Table).
Was the attempt impulsive or planned? Planned attempts tend to be more serious.
What is the ‘risk-rescue ratio’? The potential lethality of the attempt and the likelihood of being saved must be evaluated together. Where did the attempt occur? In a setting where others were likely to intervene? Was the patient alone? Attempts in the presence of others may be considered less alarming.
What did the patient do immediately afterward? Did he tell anyone? How did he get to the hospital? Did he seek help on his own? Who called the ambulance?
How does the patient feel about the attempt now? Is she glad or disappointed she didn’t die? Does she regret the attempt?
Have there been past attempts? Does the patient have a history of suicide attempts or significant selfmutilation? If so, what was the most serious incident? Past attempts tend to predict future attempts.
Other considerations for patients who have attempted suicide and those who have not but are being evaluated for possible suicide risk include:
Mental state. To estimate a patient’s mental state and depth of negative affect, without having seen her yourself, three helpful questions are:
- Does she still look upset, depressed, or angry? Anger and agitation tend to increase risk.
- Can she smile or relax, even briefly?
- Does she feel things are likely to improve?
Access to firearms. Suicide by firearms accounts for 55% of all suicides.3 Does the patient have access to a gun and bullets? If so, get details. Does he now keep the gun on his person instead of in a locked cabinet, as he did earlier? We find that questions about guns are all too frequently omitted.
Contract for safety. Can the patient reliably contract not to harm himself and to call for help in a crisis? Although contracts for safety have limited value—as will be discussed—a patient’s refusal to contract for safety may indicate a higher suicide risk.
Some patients may refuse to contract for safety in order to be hospitalized for other reasons. They may say they can’t be sure what they will do if not admitted or declare that the clinician will be blamed for their death.
Protective factors
A patient’s high-risk clinical features must be balanced against factors that may reduce suicide risk.
How much social support? Can family or friends constantly stay with the patient, watch him closely, and get help if the situation worsens? This is the simplest and most relevant method to assess the availability of protective support.
How much mental health support? Does the patient have a good relationship with a psychiatrist or therapist who can see the patient soon?
Have circumstances changed? Has the stressor that led to suicidal behavior resolved, at least in part? For example, if a patient’s fight with her boyfriend led to her taking an overdose, have they made up?
Four common myths. Clinicians assessing patients for acute suicide risk often overestimate the protective value of some factors. They may tell you:
- The patient only tried to harm himself while he was intoxicated. He’s not intoxicated now and therefore is not at high risk. The patient will likely get intoxicated again, despite his protestations to the contrary. Substance intoxication and withdrawal tend to worsen depression and diminish inhibitions, making suicide more—not less—likely.
- The patient contracts for safety. A contract for safety may have some value,4 but its clinical and legal merits in suicide risk assessment are overestimated.5 We are concerned about how often we see clinicians judge that a contract for safety overrides numerous high-risk factors.
- The patient was only trying to get attention. It is difficult for mental health professionals—and even for patients—to reliably ascertain what motivates someone to attempt suicide. Multiple motivations and ambivalence are common.
- The patient is ‘just a borderline.’ Because patients with borderline personality disorder tend to make repeated suicide gestures, clinicians may not take their suicide attempts seriously. This statement reveals ignorance about the suffering of persons with borderline personality disorder; their rate of completed suicide is approximately 10%.6
- When a suicide assessment is inconclusive, draw two columns on a sheet of paper. List the patient’s high-risk factors on one side and protective factors on the other
- Seeing the information in black and white often helps clarify the assessment
- Consider both the number of factors in each column and your clinical sense of each factor’s importance and intensity. Place a check mark next to particularly important factors
- This balance sheet can remind you of further questions to ask and often reveals that either the high-risk or protective factors far outweigh the others in number and/or intensity
Practical advice
Distinguish short-term vs long-term risk. Based on the questions above, we often conclude that a patient is at high long-term risk of suicide, but the immediate risk is much lower. Acute hospitalization is unlikely to alleviate the long-term risk (though sometimes is the only way to get the patient into psychiatric treatment).
Consider the source. Never disregard the “gut feeling” of the person who interviewed the patient, but also factor in your assessment of that clinician’s judgment. Sometimes inexperienced staffs’ intuitions may derive more from countertransference than from objective assessment.
Write it down. In cases where suicide risk seems unclear, it may help to list a patient’s risk and protective factors (Box 2). We have found this technique to be a useful teaching tool as well.
Be flexible. Because no method for assessing shortterm suicide risk is foolproof, be ready to re-evaluate your assessment and—if you are unsure—to take action to protect the patient.
1. American Psychiatric Association. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Am J Psychiatry. 2003;160(11 suppl):1-60.
2. Fawcett J. Suicide risk factors in depressive disorders and in panic disorder. J Clin Psychiatry. 1992;53(suppl):9-13.
3. National Institute of Mental Health. Suicide facts. Available at: http://www.nimh.nih.gov/SuicidePrevention/suifact.cfm. Accessed June 3, 2004.
4. Stanford EJ, Goetz RR, Bloom JD. The no harm contract in the emergency assessment of suicidal risk. J Clin Psychiatry 1994;55(8):344-8.
5. Simon RI. The suicide prevention contract: clinical, legal, and risk management issues. J Am Acad Psychiatry Law 1999;27(3):445-50.
6. Paris J. Chronic suicidality among patients with borderline personality disorder. Psychiatr Serv 2002;53(6):738-42.
You can make more-informed decisions about a patient’s acute suicide risk—such as over the phone at 3 AM—if you know what to ask the psychiatry resident or crisis worker. For suicide risk assessment—especially when you have not seen the patient—you need specific, high-yield questions to draw out danger signals from large amounts of data.
We are not suggesting that a short list of questions is sufficient for this extremely difficult task. Rather—because we recognize its complexity—we offer the questions we find most useful when evaluating patients with suicidal behaviors.
American Psychiatric Association practice guidelines1 provide a comprehensive discussion of assessing suicide risk. In addition, we teach clinicians we supervise to probe for high-risk and less-commonly explored “protective” factors.
High-risk factors
Mental health clinicians are more experienced in probing for high-risk factors than for protective factors. Because population studies offer limited help (Box 1),2 we ask clinicians these questions to evaluate the seriousness of a suicide attempt:
- Most studies of suicide risk factors focus on medium- to long-range risk
- Population-based risk factors (such as being Caucasian, over age 65, or depressed) apply to so many patients that their clinical usefulness is limited1
- Population-based risk factors often have high sensitivity but low specificity (recent loss is an important risk factor for attempting suicide, for example, but very few persons with a recent loss attempt suicide)
- In an acute situation, the positive predictive value of suicide risk factors—alone or in combination—is not known
Table
3 important questions to ask in overdose cases
|
What method was used? Methods other than taking an overdose or cutting the wrists may be more dangerous.
What amount was used? (in overdose or poisoning cases)
What treatment was needed? If the patient took an overdose of opioids and needs intubation, this indicates a relatively serious attempt. On the other hand, the psychiatric seriousness of an acetaminophen overdose depends on whether the patient realized the danger in taking high doses of acetaminophen. Additional questions can help determine the seriousness of suicide attempts by overdose (Table).
Was the attempt impulsive or planned? Planned attempts tend to be more serious.
What is the ‘risk-rescue ratio’? The potential lethality of the attempt and the likelihood of being saved must be evaluated together. Where did the attempt occur? In a setting where others were likely to intervene? Was the patient alone? Attempts in the presence of others may be considered less alarming.
What did the patient do immediately afterward? Did he tell anyone? How did he get to the hospital? Did he seek help on his own? Who called the ambulance?
How does the patient feel about the attempt now? Is she glad or disappointed she didn’t die? Does she regret the attempt?
Have there been past attempts? Does the patient have a history of suicide attempts or significant selfmutilation? If so, what was the most serious incident? Past attempts tend to predict future attempts.
Other considerations for patients who have attempted suicide and those who have not but are being evaluated for possible suicide risk include:
Mental state. To estimate a patient’s mental state and depth of negative affect, without having seen her yourself, three helpful questions are:
- Does she still look upset, depressed, or angry? Anger and agitation tend to increase risk.
- Can she smile or relax, even briefly?
- Does she feel things are likely to improve?
Access to firearms. Suicide by firearms accounts for 55% of all suicides.3 Does the patient have access to a gun and bullets? If so, get details. Does he now keep the gun on his person instead of in a locked cabinet, as he did earlier? We find that questions about guns are all too frequently omitted.
Contract for safety. Can the patient reliably contract not to harm himself and to call for help in a crisis? Although contracts for safety have limited value—as will be discussed—a patient’s refusal to contract for safety may indicate a higher suicide risk.
Some patients may refuse to contract for safety in order to be hospitalized for other reasons. They may say they can’t be sure what they will do if not admitted or declare that the clinician will be blamed for their death.
Protective factors
A patient’s high-risk clinical features must be balanced against factors that may reduce suicide risk.
How much social support? Can family or friends constantly stay with the patient, watch him closely, and get help if the situation worsens? This is the simplest and most relevant method to assess the availability of protective support.
How much mental health support? Does the patient have a good relationship with a psychiatrist or therapist who can see the patient soon?
Have circumstances changed? Has the stressor that led to suicidal behavior resolved, at least in part? For example, if a patient’s fight with her boyfriend led to her taking an overdose, have they made up?
Four common myths. Clinicians assessing patients for acute suicide risk often overestimate the protective value of some factors. They may tell you:
- The patient only tried to harm himself while he was intoxicated. He’s not intoxicated now and therefore is not at high risk. The patient will likely get intoxicated again, despite his protestations to the contrary. Substance intoxication and withdrawal tend to worsen depression and diminish inhibitions, making suicide more—not less—likely.
- The patient contracts for safety. A contract for safety may have some value,4 but its clinical and legal merits in suicide risk assessment are overestimated.5 We are concerned about how often we see clinicians judge that a contract for safety overrides numerous high-risk factors.
- The patient was only trying to get attention. It is difficult for mental health professionals—and even for patients—to reliably ascertain what motivates someone to attempt suicide. Multiple motivations and ambivalence are common.
- The patient is ‘just a borderline.’ Because patients with borderline personality disorder tend to make repeated suicide gestures, clinicians may not take their suicide attempts seriously. This statement reveals ignorance about the suffering of persons with borderline personality disorder; their rate of completed suicide is approximately 10%.6
- When a suicide assessment is inconclusive, draw two columns on a sheet of paper. List the patient’s high-risk factors on one side and protective factors on the other
- Seeing the information in black and white often helps clarify the assessment
- Consider both the number of factors in each column and your clinical sense of each factor’s importance and intensity. Place a check mark next to particularly important factors
- This balance sheet can remind you of further questions to ask and often reveals that either the high-risk or protective factors far outweigh the others in number and/or intensity
Practical advice
Distinguish short-term vs long-term risk. Based on the questions above, we often conclude that a patient is at high long-term risk of suicide, but the immediate risk is much lower. Acute hospitalization is unlikely to alleviate the long-term risk (though sometimes is the only way to get the patient into psychiatric treatment).
Consider the source. Never disregard the “gut feeling” of the person who interviewed the patient, but also factor in your assessment of that clinician’s judgment. Sometimes inexperienced staffs’ intuitions may derive more from countertransference than from objective assessment.
Write it down. In cases where suicide risk seems unclear, it may help to list a patient’s risk and protective factors (Box 2). We have found this technique to be a useful teaching tool as well.
Be flexible. Because no method for assessing shortterm suicide risk is foolproof, be ready to re-evaluate your assessment and—if you are unsure—to take action to protect the patient.
You can make more-informed decisions about a patient’s acute suicide risk—such as over the phone at 3 AM—if you know what to ask the psychiatry resident or crisis worker. For suicide risk assessment—especially when you have not seen the patient—you need specific, high-yield questions to draw out danger signals from large amounts of data.
We are not suggesting that a short list of questions is sufficient for this extremely difficult task. Rather—because we recognize its complexity—we offer the questions we find most useful when evaluating patients with suicidal behaviors.
American Psychiatric Association practice guidelines1 provide a comprehensive discussion of assessing suicide risk. In addition, we teach clinicians we supervise to probe for high-risk and less-commonly explored “protective” factors.
High-risk factors
Mental health clinicians are more experienced in probing for high-risk factors than for protective factors. Because population studies offer limited help (Box 1),2 we ask clinicians these questions to evaluate the seriousness of a suicide attempt:
- Most studies of suicide risk factors focus on medium- to long-range risk
- Population-based risk factors (such as being Caucasian, over age 65, or depressed) apply to so many patients that their clinical usefulness is limited1
- Population-based risk factors often have high sensitivity but low specificity (recent loss is an important risk factor for attempting suicide, for example, but very few persons with a recent loss attempt suicide)
- In an acute situation, the positive predictive value of suicide risk factors—alone or in combination—is not known
Table
3 important questions to ask in overdose cases
|
What method was used? Methods other than taking an overdose or cutting the wrists may be more dangerous.
What amount was used? (in overdose or poisoning cases)
What treatment was needed? If the patient took an overdose of opioids and needs intubation, this indicates a relatively serious attempt. On the other hand, the psychiatric seriousness of an acetaminophen overdose depends on whether the patient realized the danger in taking high doses of acetaminophen. Additional questions can help determine the seriousness of suicide attempts by overdose (Table).
Was the attempt impulsive or planned? Planned attempts tend to be more serious.
What is the ‘risk-rescue ratio’? The potential lethality of the attempt and the likelihood of being saved must be evaluated together. Where did the attempt occur? In a setting where others were likely to intervene? Was the patient alone? Attempts in the presence of others may be considered less alarming.
What did the patient do immediately afterward? Did he tell anyone? How did he get to the hospital? Did he seek help on his own? Who called the ambulance?
How does the patient feel about the attempt now? Is she glad or disappointed she didn’t die? Does she regret the attempt?
Have there been past attempts? Does the patient have a history of suicide attempts or significant selfmutilation? If so, what was the most serious incident? Past attempts tend to predict future attempts.
Other considerations for patients who have attempted suicide and those who have not but are being evaluated for possible suicide risk include:
Mental state. To estimate a patient’s mental state and depth of negative affect, without having seen her yourself, three helpful questions are:
- Does she still look upset, depressed, or angry? Anger and agitation tend to increase risk.
- Can she smile or relax, even briefly?
- Does she feel things are likely to improve?
Access to firearms. Suicide by firearms accounts for 55% of all suicides.3 Does the patient have access to a gun and bullets? If so, get details. Does he now keep the gun on his person instead of in a locked cabinet, as he did earlier? We find that questions about guns are all too frequently omitted.
Contract for safety. Can the patient reliably contract not to harm himself and to call for help in a crisis? Although contracts for safety have limited value—as will be discussed—a patient’s refusal to contract for safety may indicate a higher suicide risk.
Some patients may refuse to contract for safety in order to be hospitalized for other reasons. They may say they can’t be sure what they will do if not admitted or declare that the clinician will be blamed for their death.
Protective factors
A patient’s high-risk clinical features must be balanced against factors that may reduce suicide risk.
How much social support? Can family or friends constantly stay with the patient, watch him closely, and get help if the situation worsens? This is the simplest and most relevant method to assess the availability of protective support.
How much mental health support? Does the patient have a good relationship with a psychiatrist or therapist who can see the patient soon?
Have circumstances changed? Has the stressor that led to suicidal behavior resolved, at least in part? For example, if a patient’s fight with her boyfriend led to her taking an overdose, have they made up?
Four common myths. Clinicians assessing patients for acute suicide risk often overestimate the protective value of some factors. They may tell you:
- The patient only tried to harm himself while he was intoxicated. He’s not intoxicated now and therefore is not at high risk. The patient will likely get intoxicated again, despite his protestations to the contrary. Substance intoxication and withdrawal tend to worsen depression and diminish inhibitions, making suicide more—not less—likely.
- The patient contracts for safety. A contract for safety may have some value,4 but its clinical and legal merits in suicide risk assessment are overestimated.5 We are concerned about how often we see clinicians judge that a contract for safety overrides numerous high-risk factors.
- The patient was only trying to get attention. It is difficult for mental health professionals—and even for patients—to reliably ascertain what motivates someone to attempt suicide. Multiple motivations and ambivalence are common.
- The patient is ‘just a borderline.’ Because patients with borderline personality disorder tend to make repeated suicide gestures, clinicians may not take their suicide attempts seriously. This statement reveals ignorance about the suffering of persons with borderline personality disorder; their rate of completed suicide is approximately 10%.6
- When a suicide assessment is inconclusive, draw two columns on a sheet of paper. List the patient’s high-risk factors on one side and protective factors on the other
- Seeing the information in black and white often helps clarify the assessment
- Consider both the number of factors in each column and your clinical sense of each factor’s importance and intensity. Place a check mark next to particularly important factors
- This balance sheet can remind you of further questions to ask and often reveals that either the high-risk or protective factors far outweigh the others in number and/or intensity
Practical advice
Distinguish short-term vs long-term risk. Based on the questions above, we often conclude that a patient is at high long-term risk of suicide, but the immediate risk is much lower. Acute hospitalization is unlikely to alleviate the long-term risk (though sometimes is the only way to get the patient into psychiatric treatment).
Consider the source. Never disregard the “gut feeling” of the person who interviewed the patient, but also factor in your assessment of that clinician’s judgment. Sometimes inexperienced staffs’ intuitions may derive more from countertransference than from objective assessment.
Write it down. In cases where suicide risk seems unclear, it may help to list a patient’s risk and protective factors (Box 2). We have found this technique to be a useful teaching tool as well.
Be flexible. Because no method for assessing shortterm suicide risk is foolproof, be ready to re-evaluate your assessment and—if you are unsure—to take action to protect the patient.
1. American Psychiatric Association. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Am J Psychiatry. 2003;160(11 suppl):1-60.
2. Fawcett J. Suicide risk factors in depressive disorders and in panic disorder. J Clin Psychiatry. 1992;53(suppl):9-13.
3. National Institute of Mental Health. Suicide facts. Available at: http://www.nimh.nih.gov/SuicidePrevention/suifact.cfm. Accessed June 3, 2004.
4. Stanford EJ, Goetz RR, Bloom JD. The no harm contract in the emergency assessment of suicidal risk. J Clin Psychiatry 1994;55(8):344-8.
5. Simon RI. The suicide prevention contract: clinical, legal, and risk management issues. J Am Acad Psychiatry Law 1999;27(3):445-50.
6. Paris J. Chronic suicidality among patients with borderline personality disorder. Psychiatr Serv 2002;53(6):738-42.
1. American Psychiatric Association. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Am J Psychiatry. 2003;160(11 suppl):1-60.
2. Fawcett J. Suicide risk factors in depressive disorders and in panic disorder. J Clin Psychiatry. 1992;53(suppl):9-13.
3. National Institute of Mental Health. Suicide facts. Available at: http://www.nimh.nih.gov/SuicidePrevention/suifact.cfm. Accessed June 3, 2004.
4. Stanford EJ, Goetz RR, Bloom JD. The no harm contract in the emergency assessment of suicidal risk. J Clin Psychiatry 1994;55(8):344-8.
5. Simon RI. The suicide prevention contract: clinical, legal, and risk management issues. J Am Acad Psychiatry Law 1999;27(3):445-50.
6. Paris J. Chronic suicidality among patients with borderline personality disorder. Psychiatr Serv 2002;53(6):738-42.