1. Hypnotic-induced Amnesia and Complex Behaviors Kuang-Yang Hsieh, M.D. ph.D. Department of Psychiatry Chimei Medical Center

2. Amnesia automatism (amnestic complex automatic behavior) Doing something automatically and not remembering afterwards. Doing something automatically and not 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 a period shortly after taking the drug concerned. Usually induced by drugs, with a memory gap for a period shortly after taking the drug concerned.

5. Sleep conversation (in person or on the phone), sleep walking Sleep conversation (in person or on the phone), sleep walking Sleep cooking, sleep eating, sleep sex Sleep cooking, sleep eating, sleep sex Sleep driving, sleep shopping Sleep driving, sleep shopping Robbery, assault Robbery, assault Examples of hypnotic-induced amnesia automatism

6. Hypnotic-induced amnesia automatism was once regarded as rare. Hypnotic-induced amnesia automatism was once regarded as rare. However, cases increase with frequent use. However, cases increase with frequent use. In Mar 2007, the US FDA requested that hypnotics should be labeled with new warnings about the potential to cause these complex behaviors. In Mar 2007, the US FDA requested that hypnotics should be labeled with new warnings about the potential to cause these complex behaviors.

8. Complex behaviors involving nonbenzodiazepine hypnotics 17 case reports published during 1966-2007. 17 case reports published during 1966-2007. 15 involving Zolpidem, 1 Zopiclone, 1 Zaleplon. 15 involving Zolpidem, 1 Zopiclone, 1 Zaleplon. Dose of drugs in these reports: Zolpidem 10-20 mg/d, Zopiclone 7.5-15 mg/d. Dose of drugs in these reports: Zolpidem 10-20 mg/d, Zopiclone 7.5-15 mg/d. Frequency of complex behaviors reported by manufacturers: Frequency of complex behaviors reported by manufacturers: Zolpidem 0.1-1%, Zaleplon <0.1%. Zolpidem 0.1-1%, Zaleplon <0.1%.

10. Complex behaviors involving benzodiazepines It is difficult to identify published reports because of differences in nomenclature. It is difficult to identify published reports because of differences in nomenclature. Triazolam is the benzodiazepine associated with the largest number of complex behavior reports. Triazolam is the benzodiazepine associated with the largest number of complex behavior reports.

11. Proposed mechanisms of hypnotic -induced amnesia automatism Enhancement of GABA activity at α 1 -GABA A receptor Enhancement of GABA activity at α 1 -GABA A receptor Inhibition of consolidation of short-term memory Inhibition of consolidation of short-term memory Pharmacokinetic drug-drug interaction Pharmacokinetic drug-drug interaction Pharmacodynamic drug-drug interaction Pharmacodynamic drug-drug interaction

12. GABA receptors GABA A receptor: ligand-gated ion channel, widely expressed in CNS. GABA A receptor: ligand-gated ion channel, widely expressed in CNS. GABA B receptor: G-protein-coupled receptor, limitedly expressed. GABA B receptor: G-protein-coupled receptor, limitedly expressed.

13. GABA A receptor complex Heterogeneic pentamer containing 5 subunits. Heterogeneic pentamer containing 5 subunits. Identified subunits: Identified subunits: α 1, α 2, α 3, α 4, α 5, α 6 α 1, α 2, α 3, α 4, α 5, α 6 β 1, β 2, β 3 β 1, β 2, β 3 γ 1, γ 2, γ 3 γ 1, γ 2, γ 3 ρ 1, ρ 2, ρ 3, ρ 1, ρ 2, ρ 3, δ, ε, π, θ δ, ε, π, θ

14. Structure of GABA A receptor complex

16. BZD site

17. Effects of GABA A receptor activation depend on the type of subunits contained in the receptor complex. Effects of GABA A receptor activation depend on the type of subunits contained in the receptor complex. Activation of α 1 -GABA A receptor results in sedation and amnesia. Activation of α 1 -GABA A receptor results in sedation and amnesia. Activation of α 2 -, α 3 -, and α 5 -GABA A receptors results in anxiolytic, muscle relaxant and alcohol potentiating effects. Activation of α 2 -, α 3 -, and α 5 -GABA A receptors results in anxiolytic, muscle relaxant and alcohol potentiating effects.

18. Hypnotics differ in their GABA A receptor subunit binding profiles. Hypnotics differ in their GABA A receptor subunit binding profiles. Nonbenzodiazepine hypnotics bind to α 1 - GABA A receptors selectively. Nonbenzodiazepine hypnotics bind to α 1 - GABA A receptors selectively. Benzodiazepines bind to α 1 -, α 2 -, α 3 -, and α 5 - GABA A receptors with comparable affinity. Benzodiazepines bind to α 1 -, α 2 -, α 3 -, and α 5 - GABA A receptors with comparable affinity.

19. The amnestic effect of hypnotics is proportional to their dose, and can be attributed to enhancement of GABA activity at α 1 -GABA A receptor. The amnestic effect of hypnotics is proportional to their dose, and can be attributed to enhancement of GABA activity at α 1 -GABA A receptor.

20. Inhibition of consolidation of short-term memory by hypnotics hypnotics

21. Hypnotics interrupt the consolidation phase of memory formation, but not the input or recall. Hypnotics interrupt the consolidation phase of memory formation, but not the input or recall. Transfer of short-term memory information into long-term memory storage is blocked. Transfer of short-term memory information into long-term memory storage is blocked.

22. Pharmacokinetic drug-drug interaction CYP3A4 is the major isoform of cytochrome P450 responsible for metabolism of many benzodiazepines (triazolam, alprazolam, diazepam) and nonbenzodiazepine hypnotics (zolpidem, zopiclone). CYP3A4 is the major isoform of cytochrome P450 responsible for metabolism of many benzodiazepines (triazolam, alprazolam, diazepam) and nonbenzodiazepine hypnotics (zolpidem, zopiclone). Lorazepam and zaleplon are mostly metabolized by non-CYP pathway. Lorazepam and zaleplon are mostly metabolized by non-CYP pathway.

23. There are no clinically important genetic polymorphisms of CYP3A4 reported so far. There are no clinically important genetic polymorphisms of CYP3A4 reported so far. CYP3A4 inhibitors (ketoconazole) or substrates may increase the serum concentration of a hypnotic medication and the risk of amnesia automatism. CYP3A4 inhibitors (ketoconazole) or substrates may increase the serum concentration of a hypnotic medication and the risk of amnesia automatism.

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

25. Treatment of hypnotic-induced amnesia 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 associated with amnesia automatism. Switching to another hypnotic medication less associated with amnesia automatism. Switching to antihistamines or sedative antidepressants. Switching to antihistamines or sedative antidepressants. Switching to cognitive-behavioral therapy. Switching to cognitive-behavioral therapy.

26. Thanks for attention