Jeremy S. Daniel, PharmD, BCPS

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.