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NEW YORK CITY -- Forensic psychiatrists have found it challenging to unravel the role of zolpidem (Ambien) in several brutal murders committed against loved ones -- and then to persuade attorneys, judges, and juries to take their conclusions seriously.

The cases may be the most extreme examples of an already known side effect of zolpidem -- that, even at recommended doses, people using the drug may get out of bed and do things while still effectively asleep, and don't remember it the next day.

Numerous reports have described people fixing meals, having sex, and even getting into their cars and driving away in the middle of the night, with no later recollection. A few "Ambien zombies" have wrecked their cars and even killed people in accidents.

But in at least three cases, a person with no apparent motive and no history of violence brutally murdered a spouse or close friend in the wee hours after taking more than the recommended dose of zolpidem along with other psychotropic medications.

A forensic psychologist and two psychiatrists who were involved in two of these cases discussed their experiences and how the law is evolving in this area at the .

Zolpidem was first approved in 1992. In 2007, after reports had piled up describing bizarre and dangerous activities undertaken by patients who had taken either high doses or regular doses in combination with other drugs such as alcohol, the warning of "sleep-driving" and other risks.

Last year, the agency went further, . This was based on in a substantial minority of patients who had taken the highest recommended dosages at the time.

The Crimes

The FDA announcements made no mention of murders committed by zolpidem users, but it had to have been aware of at least two of them. by , of Marymount Manhattan College and Kings County Hospital, and two psychiatrist colleagues -- , and , of Columbia University. They had worked for the defense teams in those cases and also were the speakers at the APA panel this week.

A third murder linked to zolpidem had been committed in April 2013, just before the agency ordered the new restrictions.

The two cases in the 2012 paper involved a 45-year-old man and a 62-year-old woman, both of whom had taken at least two 10-mg zolpidem pills (the current maximum dosage is 5 mg for women and 10 mg for men) and had received other prescription psychotropic drugs including paroxetine (Paxil) and, in the man's case, quetiapine (Seroquel).

Sometime in the night, these patients got up and killed their spouses. Mr. A, as he was called by Paradis and colleagues, stabbed his wife more that 20 times. Ms. B went into her garage, picked up a metal pipe, and returned to the bedroom where she bludgeoned her husband and then put a plastic bag over his head.

Both Mr. A and Ms. B stayed alone with the bodies for hours, and then seemed glassy-eyed and confused when they finally emerged. They consistently denied any recollection of the events and were initially incredulous that they could have done such things.

Also, in both cases, the perpetrators reported being still sleepless after taking one zolpidem and had therefore taken additional pills.

In the 2013 case, a young man in Littleton, Colo., a suburb of Denver, named Andrew McClay beat his female housemate to death with a hammer. , he had taken five zolpidem pills along with whiskey and naproxen. Other aspects of the crime and its aftermath were similar to those in the previous two cases.

Another similarity was that all three ended up criminally convicted. Mr. B was found guilty of second-degree murder at trial, and McClay pleaded guilty to the same charge; both received long prison sentences. Ms. B pled guilty to manslaughter in a deal with prosecutors and served 4-1/2 years before being paroled.

Amnesia and Responsibility

Kleinman told APA attendees that amnesia -- even if a jury can be persuaded that it's genuine -- does not absolve someone of a crime he or she has committed. The fact that a murderer later doesn't remember doing it does not mean that he or she wasn't fully aware of it and its implications at the time, he noted.

But, in some states, murderers can argue that, as a result of some medical condition or medication they were taking, they were not in control of their actions through no fault of their own. It's called "involuntary intoxication" or "automatism" -- although a person may undertake seemingly deliberate acts, he or she may be effectively unconscious and not responsible for those actions.

Kleinman said that is exceedingly hard to do -- it was completely unsuccessful in the case of Mr. A, only partly successful for Ms. B, and untested in McClay's case. His attorney told 番茄社区 that she thought they could win an involuntary intoxication acquittal, but McClay was afraid he would be convicted of first-degree murder and accepted the slightly lesser charge.

Siegel, who worked on Mr. A's case, also thought they had a winning argument.

He identified several features of the man's behavior before and after the killing that supported an involuntary intoxication defense.

The man had received electroconvulsive therapy (ECT) 3 days before the crime and it might be argued that it caused his amnesia. ECT is not known to foster sleep-walking or other active but unconscious behaviors, so it would not be a credible defense.

In interviewing Mr. A, Siegel found the man's memory intact right up until the time he took two zolpidem pills the night of the murder, "which is not typical of ECT amnesia," he said.

After the crime, Mr. A remained in the apartment -- which was in his parents' house -- with his wife's bloody body for some 12 hours before stumbling downstairs, talking incoherently and looking "catatonic," his parents said. When interviewed by police shortly afterward, he was still incoherent, which was documented on a videotape.

Siegel retrospectively diagnosed Mr. A with major depression with psychotic features, with his behavior the night of the murder a result of zolpidem combined with his other medications.

Pushback From Prosecutors

However, the psychotic features that were documented prior to the murder -- for example, he had told doctors that an ex-wife was controlling his thoughts through books left in his garage, which he then burned -- helped persuade the jury that he was violence-prone.

The prosecution's psychiatrist agreed with the medical diagnosis but stressed that Mr. A was "self-centered and aggressive," Siegel said. Prosecutors argued that the amnesia was fake, which in turn would suggest that Mr. A was well aware of the nature of his acts. The jury produced a guilty verdict after only a few hours of deliberation.

In their APA panel talk, the speakers skimmed over the case of Ms. B, but their account in the 2012 paper portrayed it as similar in many ways to that of Mr. A. Her husband had suffered a stroke some months before and become severely disabled, which led to her becoming anxious, depressed, and unable to sleep for which she was given a paroxetine prescription along with zolpidem for insomnia.

Like Mr. A, she had no history of violence but, because of her husband's condition, she could have had a motive for murder. Although she too was glassy-eyed and incoherent many hours after the murder, she did not deny responsibility for it.

The prosecution in her case was less hostile to the involuntary intoxication argument and allowed her to plead guilty to manslaughter.

Another case in which this defense had some impact was that of a heavily armed North Carolina man who, allegedly under the influence of zolpidem, burst into a nursing home where his estranged wife worked and in 2009.

He was still convicted of murder, but escaped the death penalty because North Carolina law does not allow it for people who commit crimes while intoxicated.

However, Kleinman noted that some states do not recognize involuntary intoxication as a defense. He described the case of a Mississippi man, Mark Andrew Fortune, who was charged with fondling his 11-year-old niece (not a murder). Fortune said he had taken gabapentin for pain and a single zolpidem pill and then lay on a couch with the girl to watch a movie.

He had no history of pedophilia or criminal sex offenses. He had been wounded in Iraq, with a concussion and other injuries, and had been diagnosed with post-traumatic stress and migraine.

The girl later told family members and the police that he had seemed groggy and had put his hands on her breasts and then her hands on his crotch -- then abruptly stopped when the movie ended. He claimed not to remember doing any of those things and that he frequently had memory lapses after taking medications.

Kleinman (who was not involved in the case) said the man's lawyers tried to introduce an involuntary intoxication argument, asking the judge to include it in the jury instructions. The judge denied the request and, which was a conviction on the molestation charge with a 2-year prison term.

Bottom Line

Kleinman said the law is still evolving in this area. The traditional legal view has been that if an individual is aware of an impairment, he or she is obliged to mitigate the risks.

"The legal issue is, did you realize at some point, prior to [for example] violating the law by speeding or, worse, having an accident, that you were suffering from the impact of having ingested one or more hypnotics? In many states, the law says that if you realize this, you have a legal obligation to stop driving and pull over," he said.

"The issue really is, does that logical description comport with the impact of the substance? What is the actual experience? Do they switch levels of awareness to diminished awareness? Awareness is also about judgment."

With regard to zolpidem, "we just don't know the answers," Kleinman said.

He also noted that states vary in the obligations that physicians and patients have to understand the risks associated with a medication.

In some places, it falls on the physician to inform the patient and tell them what they can and cannot do after taking a drug. If the patient isn't told, then a resulting intoxication may be considered involuntary.

But in other jurisdictions, it's the patient's responsibility. When the information on risks is available -- via a patient medication guide or published warnings, for example -- intoxication from a drug is presumed to be voluntary and any criminal acts performed under the influence can be prosecuted.

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