Hypnotic-induced Amnesia and Hypnotic-induced Amnesia and Complex BehaviorsComplex Behaviors

Kuang-Yang Hsieh, M.D. ph.D.Kuang-Yang Hsieh, M.D. ph.D.Department of PsychiatryDepartment of Psychiatry

Chimei Medical CenterChimei Medical Center

Amnesia automatismAmnesia automatism (amnestic complex automatic behavior)(amnestic complex automatic behavior)

Doing something automatically and not Doing something automatically and not remembering afterwards.remembering afterwards.

Aware of actions when confronted with evidence.Aware of actions when confronted with evidence. Usually induced by drugs, with a memory gap for Usually induced by drugs, with a memory gap for

a period shortly after taking the drug concerned.a period shortly after taking the drug concerned.

Sleep conversation (in person or on the phone), Sleep conversation (in person or on the phone), sleep walkingsleep walking

Sleep cooking, sleep eating, sleep sex Sleep cooking, sleep eating, sleep sex Sleep driving, sleep shoppingSleep driving, sleep shopping Robbery, assaultRobbery, assault

Examples of hypnotic-induced amnesia automatism

Hypnotic-induced amnesia automatism was once Hypnotic-induced amnesia automatism was once regarded as rare.regarded as rare.

However, cases increase with frequent use. However, cases increase with frequent use. In Mar 2007, the US FDA requested that In Mar 2007, the US FDA requested that

hypnotics should be labeled with new warnings hypnotics should be labeled with new warnings about the potential to cause these complex about the potential to cause these complex behaviors.behaviors.

Complex behaviors involving Complex behaviors involving nonbenzodiazepine hypnoticsnonbenzodiazepine hypnotics

17 case reports published during 1966-2007.17 case reports published during 1966-2007. 15 involving Zolpidem15 involving Zolpidem, 1 Zopiclone, 1 Zaleplon., 1 Zopiclone, 1 Zaleplon. DoseDose of drugs in these reports: Zolpidem 10-20 of drugs in these reports: Zolpidem 10-20

mg/d, Zopiclone 7.5-15 mg/d.mg/d, Zopiclone 7.5-15 mg/d. FrequencyFrequency of complex behaviors reported by of complex behaviors reported by

manufacturers:manufacturers:

Zolpidem 0.1-1%, Zaleplon <0.1%.Zolpidem 0.1-1%, Zaleplon <0.1%.

Complex behaviors involving Complex behaviors involving benzodiazepinesbenzodiazepines

It is difficult to identify published reports It is difficult to identify published reports because of differences in nomenclature. because of differences in nomenclature.

TriazolamTriazolam is the benzodiazepine associated with is the benzodiazepine associated with the largest number of complex behavior reports.the largest number of complex behavior reports.

Proposed mechanisms of hypnoticProposed mechanisms of hypnotic-induced amnesia automatism-induced amnesia automatism

Enhancement of GABA activity at αEnhancement of GABA activity at α11-GABA-GABAAA

receptorreceptor Inhibition of consolidation of short-term Inhibition of consolidation of short-term

memorymemory Pharmacokinetic drug-drug interactionPharmacokinetic drug-drug interaction Pharmacodynamic drug-drug interactionPharmacodynamic drug-drug interaction

GABA receptorsGABA receptors

GABAGABAAA receptor receptor: ligand-gated ion channel, : ligand-gated ion channel,

widely expressed in CNS.widely expressed in CNS. GABAGABABB receptor: G-protein-coupled receptor, receptor: G-protein-coupled receptor,

limitedly expressed.limitedly expressed.

GABAGABAAA receptor complex receptor complex

Heterogeneic pentamer containing 5 subunits.Heterogeneic pentamer containing 5 subunits. Identified subunits:Identified subunits:

αα11, α, α22, α, α33, α, α44, α, α55, α, α66

ββ11, β, β22, β, β33

γγ11, γ, γ22, γ, γ33

ρρ11, ρ, ρ22, ρ, ρ33,,

δ, ε, π, θδ, ε, π, θ

Structure of GABAStructure of GABAAA receptor complex receptor complex

BZD site

Effects of GABAEffects of GABAAA receptor activation receptor activation

depend on the type of subunits contained in depend on the type of subunits contained in the receptor complex.the receptor complex.

Activation of αActivation of α11-GABA-GABAAA receptor results in receptor results in

sedation and amnesia.sedation and amnesia. Activation of αActivation of α22-, α-, α33-, and α-, and α55-GABA-GABAAA

receptors results in anxiolytic, muscle receptors results in anxiolytic, muscle relaxant and alcohol potentiating effects.relaxant and alcohol potentiating effects.

Hypnotics differ in their GABAHypnotics differ in their GABAAA receptor receptor

subunit binding profiles. subunit binding profiles. Nonbenzodiazepine hypnotics bind to αNonbenzodiazepine hypnotics bind to α11--

GABAGABAAA receptors selectively. receptors selectively.

Benzodiazepines bind to αBenzodiazepines bind to α11-, α-, α22-, α-, α33-, and α-, and α55--

GABAGABAAA receptors with comparable affinity. receptors with comparable affinity.

The amnestic effect of hypnotics is The amnestic effect of hypnotics is proportional to their dose, proportional to their dose, and can be and can be attributed to enhancement of GABA attributed to enhancement of GABA activity at αactivity at α11-GABA-GABAAA receptor. receptor.

Inhibition of consolidation of Inhibition of consolidation of short-term memory by hypnoticsshort-term memory by hypnotics

hypnotics

Hypnotics interrupt the consolidation phase of Hypnotics interrupt the consolidation phase of memory formation, but not the input or recall.memory formation, but not the input or recall.

Transfer of short-term memory information Transfer of short-term memory information into long-term memory storage is blocked.into long-term memory storage is blocked.

Pharmacokinetic Pharmacokinetic drug-drug interactiondrug-drug interaction

CYP3A4 CYP3A4 is the major isoform of cytochrome is the major isoform of cytochrome P450 responsible for metabolism of many P450 responsible for metabolism of many benzodiazepines (triazolam, alprazolam, benzodiazepines (triazolam, alprazolam, diazepam) and nonbenzodiazepine hypnotics diazepam) and nonbenzodiazepine hypnotics (zolpidem, zopiclone).(zolpidem, zopiclone).

Lorazepam and zaleplon Lorazepam and zaleplon are mostly are mostly metabolized by non-CYP pathway.metabolized by non-CYP pathway.

There are no clinically important genetic There are no clinically important genetic polymorphisms of CYP3A4 reported so far.polymorphisms of CYP3A4 reported so far.

CYP3A4 inhibitors (ketoconazole) or CYP3A4 inhibitors (ketoconazole) or substrates substrates may increase the serum may increase the serum concentration of a hypnotic medication and concentration of a hypnotic medication and the risk of amnesia automatism.the risk of amnesia automatism.

Pharmacodynamic Pharmacodynamic drug-drug interactiondrug-drug interaction

Concomitant use of Concomitant use of another GABAergic another GABAergic medicationmedication (valproate, alcohol), (valproate, alcohol), antihistamines or sedative antidepressants antihistamines or sedative antidepressants (trazodone, TCAs) may increase the risk of (trazodone, TCAs) may increase the risk of hypnotic-induced amnesia automatism.hypnotic-induced amnesia automatism.

Treatment of hypnotic-induced Treatment of hypnotic-induced amnesia automatismamnesia automatism

Reducing the dose. Reducing the dose. Correcting any adverse drug-drug interaction.Correcting any adverse drug-drug interaction. Stopping the offending hypnotic medication.Stopping the offending hypnotic medication. Switching to another hypnotic medication less Switching to another hypnotic medication less

associated with amnesia automatism.associated with amnesia automatism. Switching to antihistamines or sedative Switching to antihistamines or sedative

antidepressants.antidepressants. Switching to cognitive-behavioral therapy.Switching to cognitive-behavioral therapy.

Thanks for attentionThanks for attention