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Homicidal Ideation Causally Related to Therapeutic Medications

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Five patients with hepatitis C (HCV), three of whom were treated with interferon alpha2 (IFN) and two who were not treated with IFN, developed homicidal ideation (HI) during a 4-year period. Following accepted rules for determining causation, there appeared to be a causal relatedness between IFN use and the development of homicidal ideation for those patients taking IFN. None of these patients attempted a homicidal act while on treat- ment with IFN, nor in the follow-up period after treatment. The incidence of HI while treated with IFN in our patient population is estimated to be less than 1%. The ability of prescription medication to cause homicidal ideation is reviewed, and legal implications are discussed.
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Ethical Human Psychology and Psychiatry, Volume 10, Number 3, 2008
134 © 2008 Springer Publishing Company
DOI: 10.1891/1559-4343.10.3.134
Homicidal Ideation Causally Related
to Therapeutic Medications
Donald H. Marks, MD, PhD
Cooper Green Mercy Hospital, Birmingham, AL
Wallace Kettering Neuroscience Institute, Kettering, OH
Peter R. Breggin, MD
Ithaca, New York
Derek Braslow, Esq
Pogust, Braslow & Millrood, LLC
Conshohocken, PA
Five patients with hepatitis C (HCV), three of whom were treated with peginterferon
alfa-2 (IFN) and two who were not treated with IFN, developed homicidal ideation (HI)
during a 4-year period. Following accepted rules for determining causation, there appeared
to be a causal relatedness between IFN use and the development of homicidal ideation
for those patients taking IFN. None of these patients attempted a homicidal act while
on treatment with IFN, nor in the follow-up period after treatment. The incidence of HI
while treated with IFN in our patient population is estimated to be less than 1%. The abil-
ity of prescription medication to cause homicidal ideation is reviewed, and legal implica-
tions are discussed.
Keywords: homicide; murder; violence; adverse effect; interferon
T he ability of medications to affect the central nervous system (CNS) is well known
(Brunton, Lazo, & Lazo, 2005). In some cases, the effects are desired—for exam-
ple, medications designed to treat seizures, depression, or Alzheimer’s disease. In
other cases, the effects are unwanted—for example, decreased coordination and problems
when operating machinery when taking anxiolytics. Recently, there has been an increased
awareness of the ability of antidepressant medications to cause a paradoxical increase in
depression and, in some cases, suicidal ideation (SI) (Breggin, 2003, 2008; Food and Drug
Administration, 2005a; Healey, Herxheimer, & Menkes, 2006; Khan, 2002; Marks, 2004).
The clinical pharmacology and mechanism of the later effect may be related to the known
ability of medications in the SSRI class to cause or exacerbate levels of anxiety, agitation,
irritability, akathisia, aggression, hostility, emotional blunting, and disinhibition. Clini-
cally all of these phenomena have been associated with violence. It is reasonable from a
psychological perspective to understand how a medication that can induce or increase feel-
ings of anxiety, agitation, akathisia, aggression, hostility, irritability, and/or disinhibition
could lead toward self-directed or outwardly directed violence in a predisposed individual.
In at least one product liability case ( Tobin v. SmithKline Beecham, 164 F. Supp.2d 1278
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Homicidal Ideation and Therapeutic Medications 135
[D.Wy. 2001]), the courts have accepted a causal relatedness of an SSRI medication and
homicidal acts.
The prescribing information for Pegasys and Peg-Intron, interferon alpha 2 antiviral
medications used to treat hepatitis C, caution that:
Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving therapy
with [Pegasys or Peg-Intron] and include suicide, suicidal ideation, homicidal ideation, depres-
sion, relapse of drug addiction, and drug overdose. These reactions may occur in patients with
and without previous psychiatric illness. [Pegasys or Peg-Intron] should be used with extreme
caution in patients who report a history of depression. Neuropsychiatric adverse events observed
with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar
disorders, and mania.
Because these adverse events can reasonably be thought to be precursors to or exacer-
bate preexisting SI or HI, a causal relatedness between IFN and HI is plausible. This article
describes the occurrence of HI in fi ve patients with HCV at a hepatitis clinic based in a
large inner-city hospital.
METHODS
Medical records of over 460 patients seen at an inner-city hepatitis clinic, all of whom
were patients of the fi rst author, were reviewed for complaints of HI and other neuropsy-
chiatric problems, predisposing conditions, and correlated with IFN use. Entered into a
database were patient demographics; viral load at start of, during, and after treatment;
decision to treat; risk factors for drug response; urine drug screens; adverse effects; and
other data for all patients with viral hepatitis seen in the hepatitis clinic at Cooper
Green Mercy Hospital for the 4-year period 2004 to 2007. A directed search of the
data for HI and SI was prepared; no change in therapeutic decision was based on the
collection of this data. The hospital institutional review board approved the use of
anonymous demographic and incidence data collection for the purpose of preparing this
publication.
ASSESSMENT OF CAUSATION
A determination of causal relatedness between the administration of IFN and the develop-
ment of HI was made by means of universally accepted algorithms (Marks, 2005). Factors
considered included temporality of the HI to IFN use; preexisting HI or other psychiat-
ric problems; criminal history; absence of alternative explanations; and the challenge,
dechallenge, rechallenge phenomenon. Causal relatedness was divided into fi ve catego-
ries: defi nite, probable, possible, unlikely, or unrelated.
In addition to IFN, the prescribing information for all medications was searched
using electronic databases (www.PDR.net and www.Medscape.com), and the occur-
rence of specific relevant keywords related to psychological adverse effects was
prepared.
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136 Marks et al.
RESULTS
Since 2004, over 460 patients have been seen at the hepatitis clinic at Cooper Green
Mercy Hospital, including 408 patients with HCV, of whom treatment was initiated
in 134. Of those 134 patients, 5 reported having experienced homicidal ideations (see
Table 1), 8 reported suicidal thought (Marks, 2008), and 4% of all cases experienced
signifi cant new or worsening depression (Marks, Adineh, Wang, & Gupta, 2007).
Patients 48, 97, and 123 stated that they did not experience HI immediately before IFN,
that they did have HI that began after starting IFN, and that their HI resolved once IFN was
stopped. None of these three patients carried out a homicidal act. The three persons who
experienced HI while taking IFN were accessed as having had a probable causal relatedness,
using standard accepted defi nitions of pharmaceutical specifi c causation (Marks, 2005).
Patients 130 and 189 also experienced HI during the study period, but were not taking
IFN or any other medication (see Table 2) with a reported association to HI.
The possibility of experiencing HI during treatment with IFN is not unexpected and is
warned of in the prescribing information. Similarly, increases in depression and anxiety
due to IFN were expected and have been reviewed elsewhere (Marks et al., 2007).
For comparison, the prescribing information for most prescription medications was
searched using electronic databases (www.PDR.net and www.Medscape.com), looking for
TABLE 1. Individuals With Hepatitis C Who Developed Homicidal Ideation
Case ID 48 97 123 130 189
Sex M M M F F
Age 46 61 55 48 25
DSB Yes, and due to IFN No Remote Yes No
Drug abuse Yes Yes Yes Yes No
History of
mental health
problem
Yes No No No N o
Current legal
problems
Yes No No No N o
Relative to
IFN, and
degree
Homicidal ideation
on IFN
Anger, homi-
cidal ideation,
irritability,
aggression on
IFN
Homicidal
ideation on
IFN
HI not on
IFN
HI not on
IFN
Outcome Stopped for psycho-
logical adverse events
Stopped for
psychological
adverse events
Concurrent
Medications
SSRI Lortab, fosino-
pril, propranolol,
glipizide
Hydrocodone,
acetamino-
phen
Metoprolol None
Note. HI = homicidal ideation; IFN = interferon alpha 2; SSRI = selective serotonin reuptake inhibitor.
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137
TABLE 2. Some Frequently Used Medications With Serious Central Nervous System Adverse Events
Medication Anxiety Depression
Aggressive
and/or Violent
Behaviors Hallucination Impulsivity Paranoia Irritability Psychosis Suicidal Homicidal
Drug
Seeking
Behavior Seizures
Accutane X X X X
Adderall X Restlessness X X
Antiseizure
(Neurontin,
Lyrica) X
Chantix X X Infrequent Rare Agitation X And
mood
swings,
abnormal
thinking
Rare
Cymbalta SSNRI X X X and hostility X Mania X
Peginterferon
alfa-2
XX X XXXX
Lariam mefl oquine X X X and
confusion
X X Rare
Reglan
metoclopramide X X Rare Restlessness X Reports
Corticosteroids*XX
SSRI X X and hostility Agitation X Mania X
Note. SSRI = selective serotonin reuptake inhibitor.
SSNRI = selective serotonin norepinephrine reuptake inhibitor.
*
Pope & Katz, 1990; Porcerelli & Sandler, 1998.
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138 Marks et al.
the adverse event keywords listed in Table 3. These specifi c keywords were chosen because
of a potential inciting effect on homicidal ideation.
This directed search revealed that a wide range of medications in varied therapeutic
categories was associated with adverse CNS events. Some of these, alone or in combina-
tion, can reasonably have relevance to initiating or exacerbating HI. More specifi cally, the
prescribing information for medications in use at Cooper Green Mercy Hospital, including
the hepatitis patient population, were searched using the same electronic database, con-
centrating on those keywords listed in Table 3, and the results are listed in Table 2.
The fi ndings illustrate a wide range of potential CNS adverse events with relevance to
the development or exacerbation of SI or HI to patients from medications available in a
hospital formulary.
A literature search was also performed of illicit drugs associated with a number of CNS
effects that could initiate or exacerbate SI or HI. A number of illicit medications and alco-
hol, with some prevalence of use in hepatitis patients, can be associated with HI or cause
neuropsychiatric effects that might reasonably lead to HI.
DISCUSSION
Recent years have seen increased concern about suicidality induced by prescription medi-
cations. Suicidality and violence are closely connected clinically and often occur in the
same individual at the same or at different times. This known clinical phenomenon is
refl ected in the frequent use of the phrase “violence toward self or others.”
Paroxetine provides an example of a drug associated with both suicidality and violence.
Based on a reanalysis of placebo-controlled clinical trials, Kraus (2006) concluded on
behalf of GlaxoSmithKline, the manufacturer, that paroxetine caused a 6.4 times increase
in the rate of suicidal behavior compared to placebo (11/3,455 [0.32%] versus 1/1,978
[0.0.5%]) in adults of all ages with major depressive disorder. This information was later
included in the FDA-approved label (Paxil, 2006, p. 1531).
TABLE 3. Frequency of Specifi c Adverse Events Appearing in Prescribing Information
Keyword for Adverse Event Number of Citations in Prescribing Information
Agitation 214
Aggression 22
Hallucination 46
Homicide 1 (prescribing information for Effexor, reports for SSRI, IFN)
Irritability 117
Nightmare 8
Psychosis 84
Restlessness 152
Suicidal 49
Note. IFN = interferon alpha 2; SSRI = selective serotonin reuptake inhibitor.
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Homicidal Ideation and Therapeutic Medications 139
Violence, including homicide, as a reported adverse event, has a lower reported frequency
than suicidality and has more rarely been demonstrated in placebo controlled clinical trials.
Nonetheless, aggressive and violent behaviors (Dealberto, 2006) are often reported in associa-
tion with drugs such as paroxetine that are more defi nitively implicated in suicidality. In fact,
the class warnings for antidepressants, as illustrated by paroxetine, contain the following
FDA-mandated statement (Paxil, 2008 ; also see Food and Drug Administration, 2005a):
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggres-
siveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. (Paxil, 2008, p. 1531)
Nearly all of the symptoms described above are related to the potential for violence toward
others , including anxiety (Schwartz, 2005), agitation, irritability, impulsivity, aggre ssiveness
panic attacks (Korn et al., 1997), and hostility. They are commonly found as adverse effects
of drugs that cause violence or suicide. In addition, akathisia (American Psychiatric Associa-
tion, 2000, p. 801) and mania (American Psychiatric Association, 2000, p. 359) are associ-
ated with both depression and aggressive behavior, and suicidal ideation (Shaw, 1986).
Atomoxetine (Strattera), a drug with a black box warning that “identifi ed an increased
risk of suicidal thinking” (Strattera, 2008; Food and Drug Administration, 2005b), also has
been associated with aggressive and violent behavior (Henderson & Hartman, 2004 ). A
review of 153 sequential children treated at two clinics with atomoxetine revealed an
extreme amount of disturbed and hostile behavior: “We have observed extreme irritability,
aggression, mania, or hypomania induction in 51 cases (33%)” (Henderson & Hartman,
2004). Of the 51 cases, 88% displayed aggression; 49%, physical aggression; and 96%, irri-
tability. The researchers described examples of extreme aggression, including punching,
strangling, and brandishing a weapon.
Numerous nonpsychiatric drugs also carry FDA warnings concerning suicidality together
with violence. In the warnings section under psychiatric disorders, the Accutane label
states “Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide
attempts, suicide and aggressive and/or violent behaviors” (Accutane, 2008, p. 2707).
Levetiracetam (Keppra ) is an antiepileptic agent. In placebo-controlled clinical trials,
“non-psychotic behavior disorders (reported as abnormal behavior, aggression, conduct
disorder, and irritability) occurred in 11.4% of Keppra-treated patients compared to 3.6%
of placebo patients” (Keppra, 2008, p. 3252). This is one of the few demonstrations of
medication-induced aggression and aggressive-like behavior in placebo controlled clinical
trials. The label also warns about depression and suicidality, once again indirectly linking
harm to self and others.
Although not confi rmed in placebo-controlled clinical trials, many FDA-approved
labels include warnings about reported aggression, including the label on Peg-Intron,
which describes “homicidal ideation” in patients with and without a psychiatric history
(Peg-Intron, 2008, p. 2995). In our patient population, peginterferon alfa-2 was associated
with depression, SI, and HI, and has been reported previously (James & Savini, 2001).
Many researchers and clinicians have noted the association between benzodiazepines
and aggression or violence. Dukes (1980) addressed the question of whether the benzodi-
azepines can unleash violence and pointed to more than a dozen articles confi rming the
tendency of the drugs to produce irritability, defi ance, hostility, aggression, and rage. In an
unpublished in-house study utilizing the FDA’s spontaneous reporting system, Wise (1989)
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140 Marks et al.
found increased reporting rates for hostility on alprazolam, a short-acting benzodiazepine,
compared to temazepam and fl urazepam, two longer-acting benzodiazepines. The study
was conducted in response to six reports to the agency within 1 year concerning rage,
agitation, anger, aggression, and similar behavioral disturbances. Five of the six reports
involved murderous impulses, some of which were acted upon.
Psychoactive medications produce violence by causing a variety of clinical syndromes
that are associated with this behavior, including agitated depression, irritability, dyscon-
trol, mania, and aggression. Often activation or stimulation is involved.
The fi ndings reported here support the potential for HI arising from the use of a wide
range of common therapeutic medications. Violent behavior has been reported to occur
as a known adverse effect of certain medications, and, when it occurs in temporal associa-
tion with treatment, the violence should not automatically be attributed to an underlying
psychiatric abnormality or to past criminal behavior. Specifi cally, if a patient treated with
any of the medications listed in Table 4 develops SI or HI, the possibility should always be
entertained that these thoughts could arise from an adverse effect of those medications,
rather than simply attributed to a manifestation of an underlying psychiatric or personality
state. Adverse medication effects one could reasonably associate as potential precursors
or exciting factors for HI include anxiety, depression, aggressive or violent behavior, hal-
lucination, impulsivity, paranoia, irritability, psychosis, drug-seeking behavior, or seizures.
Persons who develop a substance-induced mood disorder, as described by the Diagnostic and
Statistical Manual of Mental Disorders ( DSM-IV; American Psychiatric Association, 1994),
may be more likely to develop a new onset of HI or perhaps a destabilization of HI.
The prescribing information for Pegasys states, “ Life-threatening or fatal neuropsychiatric
reactions may manifest in patients receiving therapy with PEGASYS and include suicide,
suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug over-
dose. These reactions may occur in patients with and without previous psychiatric illness.
Patients being treated for hepatitis who develop aggressive behavior, psychoses, hallucina-
tions, bipolar disorders, or mania, all potential precursors of SI or HI, should be questioned
(as encouraged by the prescribing information) about the occurrence of SI or HI. Medica-
tion dose adjustments, discontinuation, or psychiatric intervention may be needed.
The treating/prescribing physician of medications that have the potential to cause CNS
adverse events should perform an adequate medical and psychiatric history and evalua-
tion to ascertain the risk for using these medications in each patient. Professional help
should be sought from psychiatrists with a good knowledge of psychopharmacology and
substance-induced mood disorder. Consideration should be given to the consequences in
each patient of inducing increased anxiety, aggression, agitation, anger, depression, halluci-
nations, impulsivity, irritability, paranoia, or suicidal or homicidal ideation. It would seem
reasonable that all patients who receive these listed drugs and their immediate family and
caregivers be given specifi c caution and warning about the potential for induction of CNS
adverse events, including HI. Patients receiving these listed medications should be queried
at regular intervals for the development of CNS adverse events, and appropriate follow-up
should be performed. If a person receiving these medications develops new or heightened
HI, it is important for the treating/prescribing physician to determine whether the medica-
tion should be discontinued. Patients developing CNS adverse events should be questioned
concerning their degree of risk to themselves and others, and they should be requested to
notify anyone who may be at risk from their actions. Professional psychiatric input should
be considered. All these actions should be documented in the medical records.
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TABLE 4. Some Illicit/Addictive Drugs With Serious Central Nervous System Adverse Events
Anxiety Depression
Aggressive
and/or
Violent
Behaviors Hallucination Impulsivity Paranoia Irritability Psychosis Suicidal Homicidal DSB Seizures
Cocaine X Agitation,
insomnia
X Paranoia X and
homicidal
X
Heroin X X
Methamphetamine X Agitation,
violence
XX X
Alcohol X X X X
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142 Marks et al.
Patients undergoing treatment for hepatitis C have a higher background rate of alcohol
and illicit drug use. These drugs can be associated with a number of CNS effects that could
initiate or exacerbate SI or HI. It is also well characterized that illicit drugs and alcohol
could exacerbate CNS adverse events experienced from prescription medications. It is
important to take a thorough drug and alcohol history when evaluating CNS adverse
events possibly related to therapeutic medications
LEGAL IMPLICATIONS
The potential for prescription medications to cause violence, including suicide, has wide-
reaching implications in the law (Whitehead, 2003).
First, if a crime is committed as a result of ingesting a prescription medication, many
states have statutes that allow for the defense of involuntary intoxication (Myers &
Vondruska, 1998). This has generally been defi ned as intoxication with a prescription medi-
cation without foreknowledge that the medication can cause abnormal behavior.
While mens rea or “guilty mind” is usually one of the necessary elements of a crime,
states vary regarding the requirements for proving this mental state, sometimes requiring
the accused to meet legal criteria for insanity. Some states require negligent prescription
of the medication or require the individual to have taken the drug as prescribed in order
to qualify for the defense. In most cases, involuntary intoxication can serve as a complete
defense to the charges, similar to the insanity defense. Signifi cantly, even if the accused is
convicted of the crime, the sentencing judge could and should take into account the fact
that the criminal behavior was caused by or aggravated by a prescription medication. As
a result, the judge could conclude that the individual does not pose a danger to society
absent further exposure to the offending agent.
Just as individuals convicted of crimes while taking psychoactive medications may argue
that they are no longer at risk of perpetrating after becoming medication free, individuals
adjudicated incompetent while under the infl uence of a prescribed medication may argue
that they are no longer at risk of being incompetent after withdrawal from the agent.
Second, if a patient is injured as a result of ingesting a prescription medication, the pre-
scribing physician may be liable for money damages. In medical malpractice suits against
prescribing physicians, the failure to warn a patient that a medication may cause violent
and suicidal behavior, particularly if the medication’s label directly warns the prescribing
physician of this risk, may be grounds for negligence.
Third, if the pharmaceutical manufacturer failed to properly warn physicians of the
true risks of suicide or violence associated with a medication, a patient may have a civil
claim against the manufacturer in a product liability suit. Specifi cally, a pharmaceutical
company’s failure to properly evaluate whether a drug can cause suicidal or violent behav-
ior may be grounds for negligence.
CASE EXAMPLES
In several dozen individuals deemed to suffer from involuntary intoxication, none of them
repeated their crimes after withdrawal from the offending medication (Breggin, 2008). In
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Homicidal Ideation and Therapeutic Medications 143
addition to that series, here are two additional cases in which the author (PRB) testifi ed
as a psychiatric expert:
In the State of Connecticut v. Christopher DeAngelo, February 2000, a man with no criminal record
committed a series of robberies over a period of a few days, including a bank robbery from which
he fl ed by car amid a hail of police bullets. He was charged with fi rst-degree robbery and larceny.
He had been prescribed and was taking fl uoxetine (Prozac) for obsessive-compulsive disorder and
alprazolam (Xanax) for anxiety disorder. Two psychiatric experts concluded that the combination
of drugs caused him to experience a manic psychosis with uncontrollable bizarre behavior. For
example, he robbed his wife’s bank and the drug store he regularly patronized without wearing
a disguise. The defendant waived a jury trial, and the judge found him not guilty by reason of
mental disease or defect due to intoxication with the two medications.
In Commonwealth of Virginia v. Amnulla Khaliqi, 1997, Mr. Khaliqi, a young adult with no his-
tory of violence, was taking multiple psychiatric drugs when he cursed and kicked a policeman
who shook him awake from a deep sleep in his bed at home. The judge allowed testimony from a
psychiatrist concerning the adverse disinhibiting mental effects of numerous prescribed medica-
tions that he was taking simultaneously, including antidepressants, benzodiazepine tranquilizers,
and antipsychotic drugs. The defendant was acquitted of assault on the grounds of involuntary
intoxication. This was the fi rst application of the involuntary intoxication defense in Virginia.
In February 1998, 60-year-old husband, father, and grandfather Donald Schell, complained of
diffi culty sleeping. As a result, he went to see his physician, who diagnosed him as having anxiety
and prescribed him Paxil. Forty-eight hours later, Mr. Schell shot and killed his wife, his daugh-
ter, and his granddaughter before shooting himself. Three years later, in June 2001, a Wyoming
federal jury awarded $8 million in damages after fi nding, by a preponderance of the evidence,
that “Paxil can cause some individuals to commit suicide and/or homicide,” and “Paxil was a
proximate cause of the homicides and suicides involved in this litigation” ( Tobin v. SmithKline
Beecham, 164 F. Supp.2d 1278 [D.Wy. 2001]). This case remains, however, the only civil damage
award against a manufacturer of an antidepressant for a suicide/homicide.
CONCLUSIONS
Even though our data concerning interferon alpha 2 is preliminary and concerns a small
number of subjects, the incidence of IFN-induced HI, as was the case for IFN-induced
depression and SI, is very low but real in this treatment population. The rate of HI in IFN-
treated patients may be representative of the expected incidence rate for the population
in general, although our numbers were too low to allow statistical comparison. It will be of
clinical value to practitioners to know more precisely the extent of IFN-induced HI and
to predict increased mood disorders. Besides interferon, a wide range of therapeutic pre-
scription medications have been associated with reports of HI, for which there is a dearth
of information concerning individual or group causation. Nevertheless, for many of the
medications discussed in this article, it is probable, due to the known adverse effect pro-
les, that suffi cient agitation and irritability could cause HI in certain individuals. Indeed,
the antidepressants and numerous other drugs report aggression and hostility in association
with their use (Food and Drug Administration, 2005a). Further, when considering motive
during the sentencing of criminals, it can be instructive to consider the potential role of
medication use at the time of homicide. In someone who fi ts the pattern of a substance-
induced mood disorder according to the DSM-IV (American Psychiatric Association,
1994), the potential for an element of iatrogenic responsibility may exist.
3072-148-002.indd 1433072-148-002.indd 143 12/30/2008 8:54:41 AM12/30/2008 8:54:41 AM
144 Marks et al.
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... Since serious neurotoxicity from varenicline is rare, Pfizer objected to the characterization of the drug as meriting a "boxed warning." In 2016, the FDA demoted the labeling to "warnings and precautions" [19,20], largely on the strength of the EAGLES Trial. European regulators had rescinded the warning in May 2016 [10]. ...
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