Current Psychiatry

The long-held dogma that “anatomy is destiny” is fraying at the edges. The traditional nature vs nurture debate has also undergone a major transformation into a gene-by-environment interaction, abbreviated as GxE in the medical literature.^1,2 This is as true for psychiatric brain disorders as for any other medical illness.

The pessimistic determinism of “anatomy is destiny” has given way to a much more optimistic perspective, especially for the most plastic of all organs, the human brain. While genes are essential to construct one’s anatomy, environmental factors can significantly modulate gene expression. A person’s life experiences, good or bad, can wield a lasting influence on one’s brain structure and function, often transcending what is coded by the genome. For the mind, its thoughts, emotions, and cognition, the neurogenetic “tyranny” can be curbed or modified by one’s experiences. This epigenetic process is alive and well and known to be mediated by DNA methylation and histone modifications.

Consider the following examples of how genes are not the sole determinants of one’s mental health:

• A landmark study conducted in New Zealand³ followed a cohort of 847 individuals from age 3 to 26. Researchers recorded stressful life events for each participant, including romantic breakups, grief, medical illness, or employment problems, between age 21 and 26. Participants were evaluated for depressive episodes and hospitalizations and their genes tested for whether each individual carried the short (S) or long (L) allele of the serotonin transporter (5-HTT) gene. They found that when life stresses occurred, the probability of depression was much higher among the subgroup who were SS homozygous than among the LL homozygous subgroup. Thus, the genetic vulnerability to depression did not manifest itself unless adverse environmental events occurred. This is a classic example of GxE interaction, where genes alone are insufficient to produce a psychiatric disorder without environmental events interacting with them and triggering the psychopathology.
• In the same cohort described above, investigators showed that some children who were abused at an early age developed antisocial behavior as adults, while others did not.⁴ They discovered that a high expression of a polymorphism in the gene that codes for monoamine oxidase A had a protective effect that decreased the likelihood of developing antisocial traits in children who experienced trauma. In this case, the life experience failed to worsen a child’s behavior in the presence of elevated levels of a genetically determined protective enzyme.
• Schizophrenia is a heterogeneous neurodevelopmental syndrome caused by numerous genetic factors (risk genes, copy number variants, and de novo mutations) and a wide variety of perinatal complications. Concordance for schizophrenia in monozygotic twins who have identical genes is only 50%, not 100% as would be expected.⁵ Obviously, nongenetic factors during fetal life must play a role in disrupting the neurodevelopment of the affected twin, but not in the healthy twin. Examples of such factors may include differential distribution of blood during fetal life, leading to low birthweight and hypoplastic brain volume in the affected twin. It may also be due to labor complications, where one twin has an uneventful vaginal delivery while the other experiences hypoxia, a brain insult, due to a complicated breech delivery. Thus, despite having the same genes, the postnatal outcome in a discordant monozygotic twin pair diverges dramatically.
• A recent study⁶ identified somatic mutations in monozygotic twins discordant for psychiatric disorders, including schizophrenia and delusional disorder. Such somatic mutations have also been found in Van der Woude syndrome, which includes cleft palate. However, skillful surgeons can repair the cleft palate and allow the affected twin to have a normal facial appearance and oral functions, offsetting the abnormal genetic code.
• A monozygotic twin pair (one of whom was a patient of mine) born to a mother with bipolar disorder and adopted at birth by different families developed bipolar disorder due to genetic transmission, but eventually had very different outcomes. One twin was promptly and successfully treated with lithium at the first manic episode and became a successful teacher and author, while his twin did not receive treatment, became addicted to drugs, was repeatedly incarcerated for assaultive behavior, and later completed suicide at a young age. The appropriate environment and experiences of a person who inherits a psychiatric disorder can dramatically alter the prognosis for the better.

The GxE neurobiological equation is a central feature in many of our patients. As clinicians, we can modulate the patient’s environment by providing timely therapeutic biopsychosocial interventions to our patient to catalyze the GxE equation and veer it towards health, resilience, and wellness. Psychiatric practice can effectively help our patients overcome their genetically and neurobiologically driven maladaptive behavior and enable them to recover from the ravages of neuropsychiatric illness. Thus, psychiatric care represents the ultimate “E” that can interact with and modulate the “G” and effectively demonstrate that anatomy is not destiny.

The long-held dogma that “anatomy is destiny” is fraying at the edges. The traditional nature vs nurture debate has also undergone a major transformation into a gene-by-environment interaction, abbreviated as GxE in the medical literature.^1,2 This is as true for psychiatric brain disorders as for any other medical illness.

The pessimistic determinism of “anatomy is destiny” has given way to a much more optimistic perspective, especially for the most plastic of all organs, the human brain. While genes are essential to construct one’s anatomy, environmental factors can significantly modulate gene expression. A person’s life experiences, good or bad, can wield a lasting influence on one’s brain structure and function, often transcending what is coded by the genome. For the mind, its thoughts, emotions, and cognition, the neurogenetic “tyranny” can be curbed or modified by one’s experiences. This epigenetic process is alive and well and known to be mediated by DNA methylation and histone modifications.

Consider the following examples of how genes are not the sole determinants of one’s mental health:

• A landmark study conducted in New Zealand³ followed a cohort of 847 individuals from age 3 to 26. Researchers recorded stressful life events for each participant, including romantic breakups, grief, medical illness, or employment problems, between age 21 and 26. Participants were evaluated for depressive episodes and hospitalizations and their genes tested for whether each individual carried the short (S) or long (L) allele of the serotonin transporter (5-HTT) gene. They found that when life stresses occurred, the probability of depression was much higher among the subgroup who were SS homozygous than among the LL homozygous subgroup. Thus, the genetic vulnerability to depression did not manifest itself unless adverse environmental events occurred. This is a classic example of GxE interaction, where genes alone are insufficient to produce a psychiatric disorder without environmental events interacting with them and triggering the psychopathology.
• In the same cohort described above, investigators showed that some children who were abused at an early age developed antisocial behavior as adults, while others did not.⁴ They discovered that a high expression of a polymorphism in the gene that codes for monoamine oxidase A had a protective effect that decreased the likelihood of developing antisocial traits in children who experienced trauma. In this case, the life experience failed to worsen a child’s behavior in the presence of elevated levels of a genetically determined protective enzyme.
• Schizophrenia is a heterogeneous neurodevelopmental syndrome caused by numerous genetic factors (risk genes, copy number variants, and de novo mutations) and a wide variety of perinatal complications. Concordance for schizophrenia in monozygotic twins who have identical genes is only 50%, not 100% as would be expected.⁵ Obviously, nongenetic factors during fetal life must play a role in disrupting the neurodevelopment of the affected twin, but not in the healthy twin. Examples of such factors may include differential distribution of blood during fetal life, leading to low birthweight and hypoplastic brain volume in the affected twin. It may also be due to labor complications, where one twin has an uneventful vaginal delivery while the other experiences hypoxia, a brain insult, due to a complicated breech delivery. Thus, despite having the same genes, the postnatal outcome in a discordant monozygotic twin pair diverges dramatically.
• A recent study⁶ identified somatic mutations in monozygotic twins discordant for psychiatric disorders, including schizophrenia and delusional disorder. Such somatic mutations have also been found in Van der Woude syndrome, which includes cleft palate. However, skillful surgeons can repair the cleft palate and allow the affected twin to have a normal facial appearance and oral functions, offsetting the abnormal genetic code.
• A monozygotic twin pair (one of whom was a patient of mine) born to a mother with bipolar disorder and adopted at birth by different families developed bipolar disorder due to genetic transmission, but eventually had very different outcomes. One twin was promptly and successfully treated with lithium at the first manic episode and became a successful teacher and author, while his twin did not receive treatment, became addicted to drugs, was repeatedly incarcerated for assaultive behavior, and later completed suicide at a young age. The appropriate environment and experiences of a person who inherits a psychiatric disorder can dramatically alter the prognosis for the better.

The GxE neurobiological equation is a central feature in many of our patients. As clinicians, we can modulate the patient’s environment by providing timely therapeutic biopsychosocial interventions to our patient to catalyze the GxE equation and veer it towards health, resilience, and wellness. Psychiatric practice can effectively help our patients overcome their genetically and neurobiologically driven maladaptive behavior and enable them to recover from the ravages of neuropsychiatric illness. Thus, psychiatric care represents the ultimate “E” that can interact with and modulate the “G” and effectively demonstrate that anatomy is not destiny.

The long-held dogma that “anatomy is destiny” is fraying at the edges. The traditional nature vs nurture debate has also undergone a major transformation into a gene-by-environment interaction, abbreviated as GxE in the medical literature.^1,2 This is as true for psychiatric brain disorders as for any other medical illness.

The pessimistic determinism of “anatomy is destiny” has given way to a much more optimistic perspective, especially for the most plastic of all organs, the human brain. While genes are essential to construct one’s anatomy, environmental factors can significantly modulate gene expression. A person’s life experiences, good or bad, can wield a lasting influence on one’s brain structure and function, often transcending what is coded by the genome. For the mind, its thoughts, emotions, and cognition, the neurogenetic “tyranny” can be curbed or modified by one’s experiences. This epigenetic process is alive and well and known to be mediated by DNA methylation and histone modifications.

Consider the following examples of how genes are not the sole determinants of one’s mental health:

• A landmark study conducted in New Zealand³ followed a cohort of 847 individuals from age 3 to 26. Researchers recorded stressful life events for each participant, including romantic breakups, grief, medical illness, or employment problems, between age 21 and 26. Participants were evaluated for depressive episodes and hospitalizations and their genes tested for whether each individual carried the short (S) or long (L) allele of the serotonin transporter (5-HTT) gene. They found that when life stresses occurred, the probability of depression was much higher among the subgroup who were SS homozygous than among the LL homozygous subgroup. Thus, the genetic vulnerability to depression did not manifest itself unless adverse environmental events occurred. This is a classic example of GxE interaction, where genes alone are insufficient to produce a psychiatric disorder without environmental events interacting with them and triggering the psychopathology.
• In the same cohort described above, investigators showed that some children who were abused at an early age developed antisocial behavior as adults, while others did not.⁴ They discovered that a high expression of a polymorphism in the gene that codes for monoamine oxidase A had a protective effect that decreased the likelihood of developing antisocial traits in children who experienced trauma. In this case, the life experience failed to worsen a child’s behavior in the presence of elevated levels of a genetically determined protective enzyme.
• Schizophrenia is a heterogeneous neurodevelopmental syndrome caused by numerous genetic factors (risk genes, copy number variants, and de novo mutations) and a wide variety of perinatal complications. Concordance for schizophrenia in monozygotic twins who have identical genes is only 50%, not 100% as would be expected.⁵ Obviously, nongenetic factors during fetal life must play a role in disrupting the neurodevelopment of the affected twin, but not in the healthy twin. Examples of such factors may include differential distribution of blood during fetal life, leading to low birthweight and hypoplastic brain volume in the affected twin. It may also be due to labor complications, where one twin has an uneventful vaginal delivery while the other experiences hypoxia, a brain insult, due to a complicated breech delivery. Thus, despite having the same genes, the postnatal outcome in a discordant monozygotic twin pair diverges dramatically.
• A recent study⁶ identified somatic mutations in monozygotic twins discordant for psychiatric disorders, including schizophrenia and delusional disorder. Such somatic mutations have also been found in Van der Woude syndrome, which includes cleft palate. However, skillful surgeons can repair the cleft palate and allow the affected twin to have a normal facial appearance and oral functions, offsetting the abnormal genetic code.
• A monozygotic twin pair (one of whom was a patient of mine) born to a mother with bipolar disorder and adopted at birth by different families developed bipolar disorder due to genetic transmission, but eventually had very different outcomes. One twin was promptly and successfully treated with lithium at the first manic episode and became a successful teacher and author, while his twin did not receive treatment, became addicted to drugs, was repeatedly incarcerated for assaultive behavior, and later completed suicide at a young age. The appropriate environment and experiences of a person who inherits a psychiatric disorder can dramatically alter the prognosis for the better.

The GxE neurobiological equation is a central feature in many of our patients. As clinicians, we can modulate the patient’s environment by providing timely therapeutic biopsychosocial interventions to our patient to catalyze the GxE equation and veer it towards health, resilience, and wellness. Psychiatric practice can effectively help our patients overcome their genetically and neurobiologically driven maladaptive behavior and enable them to recover from the ravages of neuropsychiatric illness. Thus, psychiatric care represents the ultimate “E” that can interact with and modulate the “G” and effectively demonstrate that anatomy is not destiny.

The CURESZ Foundation was founded in 2016 to bring hope to people suffering from schizophrenia and those who love and care for them. CURESZ was established by Bethany Yeiser and her psychiatrist, Current Psychiatry Editor-in-Chief Henry Nasrallah, MD, and was inspired by Bethany's complete recovery from schizophrenia after 4 years of delusions, hallucinations, homelessness, and disability. Bethany returned to her normal life and graduated from college with honors, thanks to clozapine, which cured her symptoms when several other medications did not work (for more of Bethany’s story, see From the Editor, Current Psychiatry. October 2014, p. 21,24-25).

We previously assembled a panel of clozapine experts  to whom the CURESZ Foundation would refer patients who have never had a trial of clozapine despite ongoing delusions or hallucinations.  We now have a panel of 80 clozapine experts around the country who are willing to receive referrals.

 In an unexpected turn of events, after several years of receiving clozapine, Bethany developed tardive dyskinesia (TD) which,  fortunately,  was successfully treated. Bethany would not have been able to recover from  her TD had it not been for the recent FDA approval of effective treatments.   The embarrassing personal experience of oro-buccal TD movements  that Bethany went through before she improved led her and me to establish a panel of experts in the recognition and treatment of TD around the country. It is estimated that hundreds of thousands of patients with schizophrenia, schizo-affective disorders, bipolar disorder and major depression, all of whom receive first or second generation antipsychotic agents, currently have TD that is not being diagnosed or treated.

We are therefore calling for psychiatric practitioners who have had experience in recognizing TD movements and have treated patients with FDA-approved treatments,  to contact the CURESZ Foundation. Henry Nasrallah, MD, the Scientific Director of the CURESZ Foundation, who has had many years of federally funded research experience  in TD, will serve as the Chair of this TD Panel. 

This is a call for readers of Current Psychiatry who are treating TD  and who practice in settings that can accommodate additional patients seeking treatment for their involuntary TD muscle movements in their face, trunk, and extremities. We hope to assemble between 50 to 100 experts to join this national TD panel.

If you would like to be a member of this national CURESZ TD Panel, please go to  https://curesz.org/tardive-dyskinesia-panel/ and enter your name, email, work address, and office phone number. We will later organize the list by state and city so that patients and families around the country can contact the nearest expert to get an evaluation for assessment and treatment of their TD.

Thank you and we look forward to working with the experts who say “YESZ” to joining the TD Panel, sponsored by the CURESZ Foundation.

The CURESZ Foundation was founded in 2016 to bring hope to people suffering from schizophrenia and those who love and care for them. CURESZ was established by Bethany Yeiser and her psychiatrist, Current Psychiatry Editor-in-Chief Henry Nasrallah, MD, and was inspired by Bethany's complete recovery from schizophrenia after 4 years of delusions, hallucinations, homelessness, and disability. Bethany returned to her normal life and graduated from college with honors, thanks to clozapine, which cured her symptoms when several other medications did not work (for more of Bethany’s story, see From the Editor, Current Psychiatry. October 2014, p. 21,24-25).

We previously assembled a panel of clozapine experts  to whom the CURESZ Foundation would refer patients who have never had a trial of clozapine despite ongoing delusions or hallucinations.  We now have a panel of 80 clozapine experts around the country who are willing to receive referrals.

 In an unexpected turn of events, after several years of receiving clozapine, Bethany developed tardive dyskinesia (TD) which,  fortunately,  was successfully treated. Bethany would not have been able to recover from  her TD had it not been for the recent FDA approval of effective treatments.   The embarrassing personal experience of oro-buccal TD movements  that Bethany went through before she improved led her and me to establish a panel of experts in the recognition and treatment of TD around the country. It is estimated that hundreds of thousands of patients with schizophrenia, schizo-affective disorders, bipolar disorder and major depression, all of whom receive first or second generation antipsychotic agents, currently have TD that is not being diagnosed or treated.

We are therefore calling for psychiatric practitioners who have had experience in recognizing TD movements and have treated patients with FDA-approved treatments,  to contact the CURESZ Foundation. Henry Nasrallah, MD, the Scientific Director of the CURESZ Foundation, who has had many years of federally funded research experience  in TD, will serve as the Chair of this TD Panel. 

This is a call for readers of Current Psychiatry who are treating TD  and who practice in settings that can accommodate additional patients seeking treatment for their involuntary TD muscle movements in their face, trunk, and extremities. We hope to assemble between 50 to 100 experts to join this national TD panel.

If you would like to be a member of this national CURESZ TD Panel, please go to  https://curesz.org/tardive-dyskinesia-panel/ and enter your name, email, work address, and office phone number. We will later organize the list by state and city so that patients and families around the country can contact the nearest expert to get an evaluation for assessment and treatment of their TD.

Thank you and we look forward to working with the experts who say “YESZ” to joining the TD Panel, sponsored by the CURESZ Foundation.

The CURESZ Foundation was founded in 2016 to bring hope to people suffering from schizophrenia and those who love and care for them. CURESZ was established by Bethany Yeiser and her psychiatrist, Current Psychiatry Editor-in-Chief Henry Nasrallah, MD, and was inspired by Bethany's complete recovery from schizophrenia after 4 years of delusions, hallucinations, homelessness, and disability. Bethany returned to her normal life and graduated from college with honors, thanks to clozapine, which cured her symptoms when several other medications did not work (for more of Bethany’s story, see From the Editor, Current Psychiatry. October 2014, p. 21,24-25).

We previously assembled a panel of clozapine experts  to whom the CURESZ Foundation would refer patients who have never had a trial of clozapine despite ongoing delusions or hallucinations.  We now have a panel of 80 clozapine experts around the country who are willing to receive referrals.

 In an unexpected turn of events, after several years of receiving clozapine, Bethany developed tardive dyskinesia (TD) which,  fortunately,  was successfully treated. Bethany would not have been able to recover from  her TD had it not been for the recent FDA approval of effective treatments.   The embarrassing personal experience of oro-buccal TD movements  that Bethany went through before she improved led her and me to establish a panel of experts in the recognition and treatment of TD around the country. It is estimated that hundreds of thousands of patients with schizophrenia, schizo-affective disorders, bipolar disorder and major depression, all of whom receive first or second generation antipsychotic agents, currently have TD that is not being diagnosed or treated.

We are therefore calling for psychiatric practitioners who have had experience in recognizing TD movements and have treated patients with FDA-approved treatments,  to contact the CURESZ Foundation. Henry Nasrallah, MD, the Scientific Director of the CURESZ Foundation, who has had many years of federally funded research experience  in TD, will serve as the Chair of this TD Panel. 

This is a call for readers of Current Psychiatry who are treating TD  and who practice in settings that can accommodate additional patients seeking treatment for their involuntary TD muscle movements in their face, trunk, and extremities. We hope to assemble between 50 to 100 experts to join this national TD panel.

If you would like to be a member of this national CURESZ TD Panel, please go to  https://curesz.org/tardive-dyskinesia-panel/ and enter your name, email, work address, and office phone number. We will later organize the list by state and city so that patients and families around the country can contact the nearest expert to get an evaluation for assessment and treatment of their TD.

Thank you and we look forward to working with the experts who say “YESZ” to joining the TD Panel, sponsored by the CURESZ Foundation.

Mr. F, age 35, is homeless and has a history of cocaine and alcohol use disorders. He is admitted voluntarily to the psychiatric unit because he has homicidal thoughts toward Ms. S, who works in the shelter where he has been staying. Mr. F reports that he is thinking of killing Ms. S if he is discharged because she has been rude to him. He states that he has access to several firearms, but he will not disclose the location. He has been diagnosed with unspecified depressive disorder and exhibited antisocial personality disorder traits. He is being treated with sertraline. However, his mood appears to be relatively stable, except for occasional angry verbal outbursts. The outbursts have been related to intrusive peers or staff turning the television off for group meetings. Mr. F has been joking with peers, eating well, and sleeping appropriately. He reports no suicidal thoughts and has not been physically violent on the unit. However, Mr. F has had a history of violence since his teenage years. He has been incarcerated twice for assault and once for drug possession.

How would you approach assessing and managing Mr. F’s risk for violence?

We all have encountered a patient similar to Mr. F on the psychiatric unit or in the emergency department—a patient who makes violent threats and appears angry, intimidating, manipulative, and/or demanding, despite exhibiting no evidence of mania or psychosis. This patient often has a history of substance abuse and a lifelong pattern of viewing violence as an acceptable way of addressing life’s problems. Many psychiatrists suspect that more time on the inpatient unit is unlikely to reduce this patient’s risk of violence. Why? Because the violence risk does not stem from a treatable mental illness. Further, psychiatrists may be apprehensive about this patient’s potential for violence after discharge and their liability in the event of a bad outcome. No one wants their name associated with a headline that reads “Psychiatrist discharged man less than 24 hours before he killed 3 people.”

The purported relationship between mental illness and violence often is sensationalized in the media. However, research reveals that the vast majority of violence is in fact not due to symptoms of mental illness.^1,2 A common clinical challenge in psychiatry involves evaluating individuals at elevated risk of violence and determining how to address their risk factors for violence. When the risk is primarily due to psychosis and can be reduced with antipsychotic medication, the job is easy. But how should we proceed when the risk stems from factors other than mental illness?

This article reviews risk factors for violence, discusses targeted violence against a specific victim, and offers practical tips for assessing and managing risk, particularly when the risk for violence is not due to mental illness.

Violence and mental illness: A tenuous link

Violence is a major public health concern in the United States. Although in recent years the rates of homicide and aggravated assault have decreased dramatically, there are approximately 16,000 homicides annually in the United States, and more than 1.6 million injuries from assaults treated in emergency departments each year.³ Homicide continues to be one of the leading causes of death among teenagers and young adults.⁴

The most effective methods of preventing widespread violence are public health approaches, such as parent- and family-focused programs, early childhood education, programs in school, and public policy changes.³ However, as psychiatrists, we are routinely asked to assess the risk of violence for an individual patient and devise strategies to mitigate violence risk.

Continue to: Although certain mental illnesses...

Although certain mental illnesses increase the relative risk of violence (compared with people without mental illness),^5,6 recent studies suggest that mental illness plays only a “minor role in explaining violence in populations.”⁷ It is estimated that as little as 4% of the violence in the United States can be attributed to mental illness.¹ According to a 1998 meta-analysis of 48 studies of criminal recidivism, the risk factors for violent recidivism were “almost identical” among offenders who had a mental disorder and those who did not.⁸

Approaches to assessing violence risk

Psychiatrists can assess the risk of future violence via 3 broad approaches.^9,10

Unaided clinical judgment is when a mental health professional estimates violence risk based on his or her own experience and intuition, with knowledge of violence risk factors, but without the use of structured tools.

Actuarial tools are statistical models that use formulae to show relationships between data (risk factors) and outcomes (violence).^10,11

Continue to: Structured professional judgment

Structured professional judgment is a hybrid of unaided clinical judgment and actuarial methods. Structured professional judgment tools help the evaluator identify empirically established risk factors. Once the information is collected, it is combined with clinical judgment in decision making.^9,10 There are now more than 200 structured tools available for assessing violence risk in criminal justice and forensic mental health populations.¹²

Clinical judgment, although commonly used in practice, is less accurate than actuarial tools or structured professional judgment.^10,11 In general, risk assessment tools offer moderate levels of accuracy in categorizing people at low risk vs high risk.^5,13 The tools have better ability to accurately categorize individuals at low risk, compared with high risk, where false positives are common.^12,14

Two types of risk factors

Risk factors for violence are commonly categorized as static or dynamic factors. Static factors are historical factors that cannot be changed with intervention (eg, age, sex, history of abuse). Dynamic factors can be changed with intervention (eg, substance abuse).¹⁵

Static risk factors. The best predictor of future violence is past violent behavior.^5,16,17 Violence risk increases with each prior episode of violence.⁵ Prior arrests for any crime, especially if the individual was a juvenile at the time of arrest for his or her first violent offense, increase future violence risk.⁵ Other important static violence risk factors include demographic factors such as age, sex, and socioeconomic status. Swanson et al⁶ reviewed a large pool of data (approximately 10,000 respondents) from the Epidemiologic Catchment Area survey. Being young, male, and of low socioeconomic status were all associated with violence in the community.⁶ The highest-risk age group for violence is age 15 to 24.⁵ Males perpetrate violence in the community at a rate 10 times that of females.¹⁸ However, among individuals with severe mental illness, men and women have similar rates of violence.^19,20 Unstable employment,²¹ less education,²² low intelligence,¹⁶ and a history of a significant head injury⁵ also are risk factors for violence.⁵

Continue to: Being abused as a child...

Being abused as a child, witnessing violence in the home,^5,16 and growing up with an unstable parental situation (eg, parental loss or separation) has been linked to violence.^16,23,24 Early disruptive behavior in childhood (eg, fighting, lying and stealing, truancy, and school problems) increases violence risk.^21,23

Personality factors are important static risk factors for violence. Antisocial personality disorder is the most common personality disorder linked with violence.¹⁷ Several studies consistently show psychopathy to be a strong predictor of both violence and criminal behavior.^5,25 A psychopath is a person who lacks empathy and close relationships, behaves impulsively, has superficially charming qualities, and is primarily interested in self-gratification.²⁶ Harris et al²⁷ studied 169 released forensic patients and found that 77% of the psychopaths (according to Psychopathy Checklist-Revised [PCL-R] scores) violently recidivated. In contrast, only 21% of the non-psychopaths violently recidivated.²⁷

Other personality factors associated with violence include a predisposition toward feelings of anger and hatred (as opposed to empathy, anxiety, or guilt, which may reduce risk), hostile attributional biases (a tendency to interpret benign behavior of others as intentionally antagonistic), violent fantasies, poor anger control, and impulsivity.⁵ Although personality factors tend to be longstanding and more difficult to modify, in the outpatient setting, therapeutic efforts can be made to modify hostile attribution biases, poor anger control, and impulsive behavior.

Dynamic risk factors. Substance abuse is strongly associated with violence.^6,17 The prevalence of violence is 12 times greater among individuals with alcohol use disorder and 16 times greater among individuals with other substance use disorders, compared with those with no such diagnoses.^5,6

Continue to: Steadman et al...

Steadman et al²⁸ compared 1,136 adult patients with mental disorders discharged from psychiatric hospitals with 519 individuals living in the same neighborhoods as the hospitalized patients. They found that the prevalence of violence among discharged patients without substance abuse was “statistically indistinguishable” from the prevalence of violence among community members, in the same neighborhood, who did not have symptoms of substance abuse.²⁸ Swanson et al⁶ found that the combination of a mental disorder plus an alcohol or substance use disorder substantially increased the risk of violence.

Other dynamic risk factors for violence include mental illness symptoms such as psychosis, especially threat/control-override delusions, where the individual believes that they are being threatened or controlled by an external force.¹⁷

Contextual factors to consider in violence risk assessments include current stressors, lack of social support, availability of weapons, access to drugs and alcohol, and the presence of similar circumstances that led to violent behavior in the past.⁵

How to assess the risk of targeted violence

Targeted violence is a predatory act of violence intentionally committed against a preselected person, group of people, or place.²⁹ Due to the low base rates of these incidents, targeted violence is difficult to study.^7,30 These risk assessments require a more specialized approach.

Continue to: In their 1999 article...

In their 1999 article, Borum et al³⁰ discussed threat assessment strategies utilized by the U.S. Secret Service and recommended investigating “pathways of ideas and behaviors that may lead to violent action.” Borum et al³⁰ summarized 3 fundamental principles of threat assessment (Table 1³⁰).

What to do when violence risk is not due to mental illness

Based on the information in Mr. F’s case scenario, it is likely that his homicidal ideation is not due to mental illness. Despite this, several risk factors for violence are present. Where do we go from here?

Scott and Resnick¹⁷ recommend considering the concept of dangerousness as 5 components (Table 2¹⁷). When this model of dangerousness is applied to Mr. F’s case, one can see that the magnitude of the harm is great because of threatened homicide. With regard to the imminence of the harm, it would help to clarify whether Mr. F plans to kill Ms. S immediately after discharge, or sometime in the next few months. Is his threat contingent on further provocations by Ms. S? Alternatively, does he intend to kill her for past grievances, regardless of further perceived insults?

Next, the frequency of a behavior relates to how often Mr. F has been aggressive in the past. The severity of his past aggression is also important. What is the most violent act he has ever done? Situational factors in this case include Mr. F’s access to weapons, financial problems, housing problems, and access to drugs and alcohol.¹⁷ Mr. F should be asked about what situations previously provoked his violent behavior. Consider how similar the present conditions are to past conditions to which Mr. F responded violently.⁵ The likelihood that a homicide will occur should take into account Mr. F’s risk factors for violence, as well as the seriousness of his intent to cause harm.

Continue to: Consider using a structured tool...

Consider using a structured tool, such as the Classification of Violence Risk, to help identify Mr. F’s risk factors for violence, or some other formal method to ensure that the proper data are collected. Violence risk assessments are more accurate when structured risk assessment tools are used, compared with clinical judgment alone.

It is important to review collateral sources of information. In Mr. F’s case, useful collateral sources may include his criminal docket (usually available online), past medical records, information from the shelter where he lives, and, potentially, friends or family.

Because Mr. F is making threats of targeted violence, be sure to ask about attack-related behaviors (Table 1³⁰).

Regarding the seriousness of Mr. F’s intent to cause harm, it may be helpful to ask him the following questions:

1. How likely are you to carry out this act of violence?
2. Do you have a plan? Have you taken any steps toward this plan?
3. Do you see other, nonviolent solutions to this problem?
4. What do you hope that we can do for you to help with this problem?

Continue to: Mr. F's answers...

Mr. F’s answers may suggest the possibility of a hidden agenda. Some patients express homicidal thoughts in order to stay in the hospital. If Mr. F expresses threats that are contingent on discharge and declines to engage in problem-solving discussions, this would cast doubt on the genuineness of his threat. However, doubt about the genuineness of the threat alone is not sufficient to simply discharge Mr. F. Assessment of his intent needs to be considered with other relevant risk factors, risk reduction strategies, and any Tarasoff duties that may apply.

In addition to risk factors, consider mitigating factors. For example, does Mr. F express concern over prison time as a reason to not engage in violence? It would be more ominous if Mr. F says that he does not care if he goes to prison because life is lousy being homeless and unemployed. At this point, an estimation can be made regarding whether Mr. F is a low-, moderate-, or high-risk of violence.

The next step is to organize Mr. F’s risk factors into static (historical) and dynamic (subject to intervention) factors. This will be helpful in formulating a strategy to manage risk because continued hospitalization can only address dynamic risk factors. Often in these cases, the static risk factors are far more numerous than the dynamic risk factors.

Once the data are collected and organized, the final step is to devise a risk management strategy. Some interventions, such as substance use treatment, will be straightforward. A mood-stabilizing medication could be considered, if clinically appropriate, to help reduce aggression and irritability.³¹ Efforts should be made to eliminate Mr. F’s access to firearms; however, in this case, it sounds unlikely that he will cooperate with those efforts. Ultimately, you may find yourself with a list of risk factors that are unlikely to be altered with further hospitalization, particularly if Mr. F’s homicidal thoughts and intent are due to antisocial personality traits.

Continue to: In that case...

In that case, the most important step will be to carry out your duty to warn/protect others prior to Mr. F’s discharge. Most states either require or permit mental health professionals to take reasonable steps to protect victims from violence when certain conditions are present, such as an explicit threat or identifiable victim (see Related Resources).

Once dynamic risk factors have been addressed, and duty to warn/protect is carried out, if there is no further clinical indication for hospitalization, it would be appropriate to discharge Mr. F. Continued homicidal threats stemming from antisocial personality traits, in the absence of a treatable mental illness (or other modifiable risk factors for violence that can be actively addressed), is not a reason for continued hospitalization. It may be useful to obtain a second opinion from a colleague in such scenarios. A second opinion may offer additional risk management ideas. In the event of a bad outcome, this will also help to show that the decision to discharge the patient was not taken lightly.

The psychiatrist should document a thoughtful risk assessment, the strategies that were implemented to reduce risk, the details of the warning, and the reasoning why continued hospitalization was not indicated (Table 3).

CASE CONTINUED

Decision to discharge

In Mr. F’s case, the treating psychiatrist determined that Mr. F’s risk of violence toward Ms. S was moderate. The psychiatrist identified several static risk factors for violence that raised Mr. F’s risk, but also noted that Mr. F’s threats were likely a manipulative effort to prolong his hospital stay. The psychiatrist carried out his duty to protect by notifying police and Ms. S of the nature of the threat prior to Mr. F’s discharge. The unit social worker helped Mr. F schedule an intake appointment for a substance use disorder treatment facility. Mr. F ultimately stated that he no longer experienced homicidal ideas once a bed was secured for him in a substance use treatment program. The psychiatrist carefully documented Mr. F’s risk assessment and the reasons why Mr. F’s risk would not be significantly altered by further inpatient hospitalization. Mr. F was discharged, and Ms. S remained unharmed.

Continue to: Bottom Line

Use a structured approach to identify risk factors for violence. Address dynamic risk factors, including access to weapons. Carry out the duty to warn/protect if applicable. Document your decisions and actions carefully, and then discharge the patient if clinically indicated. Do not be “held hostage” by a patient’s homicidal ideation.

Related Resources

• Dolan M, Doyle M. Violence risk prediction. Clinical and actuarial measures and the role of the psychopathy checklist. Br J Psychiatry. 2000;177:303-311.
• Douglas KS, Hart SD, Webster CD, et al. HCR-20V3: Assessing risk of violence–user guide. Burnaby, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University; 2013.
• National Conference of State Legislatures. Mental health professionals’ duty to warn. http://www.ncsl.org/research/health/mental-health-professionals-duty-to-warn.aspx. Published September 28, 2015.

Drug Brand Names

Sertraline • Zoloft

Mr. F, age 35, is homeless and has a history of cocaine and alcohol use disorders. He is admitted voluntarily to the psychiatric unit because he has homicidal thoughts toward Ms. S, who works in the shelter where he has been staying. Mr. F reports that he is thinking of killing Ms. S if he is discharged because she has been rude to him. He states that he has access to several firearms, but he will not disclose the location. He has been diagnosed with unspecified depressive disorder and exhibited antisocial personality disorder traits. He is being treated with sertraline. However, his mood appears to be relatively stable, except for occasional angry verbal outbursts. The outbursts have been related to intrusive peers or staff turning the television off for group meetings. Mr. F has been joking with peers, eating well, and sleeping appropriately. He reports no suicidal thoughts and has not been physically violent on the unit. However, Mr. F has had a history of violence since his teenage years. He has been incarcerated twice for assault and once for drug possession.

How would you approach assessing and managing Mr. F’s risk for violence?

We all have encountered a patient similar to Mr. F on the psychiatric unit or in the emergency department—a patient who makes violent threats and appears angry, intimidating, manipulative, and/or demanding, despite exhibiting no evidence of mania or psychosis. This patient often has a history of substance abuse and a lifelong pattern of viewing violence as an acceptable way of addressing life’s problems. Many psychiatrists suspect that more time on the inpatient unit is unlikely to reduce this patient’s risk of violence. Why? Because the violence risk does not stem from a treatable mental illness. Further, psychiatrists may be apprehensive about this patient’s potential for violence after discharge and their liability in the event of a bad outcome. No one wants their name associated with a headline that reads “Psychiatrist discharged man less than 24 hours before he killed 3 people.”

The purported relationship between mental illness and violence often is sensationalized in the media. However, research reveals that the vast majority of violence is in fact not due to symptoms of mental illness.^1,2 A common clinical challenge in psychiatry involves evaluating individuals at elevated risk of violence and determining how to address their risk factors for violence. When the risk is primarily due to psychosis and can be reduced with antipsychotic medication, the job is easy. But how should we proceed when the risk stems from factors other than mental illness?

This article reviews risk factors for violence, discusses targeted violence against a specific victim, and offers practical tips for assessing and managing risk, particularly when the risk for violence is not due to mental illness.

Violence and mental illness: A tenuous link

Violence is a major public health concern in the United States. Although in recent years the rates of homicide and aggravated assault have decreased dramatically, there are approximately 16,000 homicides annually in the United States, and more than 1.6 million injuries from assaults treated in emergency departments each year.³ Homicide continues to be one of the leading causes of death among teenagers and young adults.⁴

The most effective methods of preventing widespread violence are public health approaches, such as parent- and family-focused programs, early childhood education, programs in school, and public policy changes.³ However, as psychiatrists, we are routinely asked to assess the risk of violence for an individual patient and devise strategies to mitigate violence risk.

Continue to: Although certain mental illnesses...

Although certain mental illnesses increase the relative risk of violence (compared with people without mental illness),^5,6 recent studies suggest that mental illness plays only a “minor role in explaining violence in populations.”⁷ It is estimated that as little as 4% of the violence in the United States can be attributed to mental illness.¹ According to a 1998 meta-analysis of 48 studies of criminal recidivism, the risk factors for violent recidivism were “almost identical” among offenders who had a mental disorder and those who did not.⁸

Approaches to assessing violence risk

Psychiatrists can assess the risk of future violence via 3 broad approaches.^9,10

Unaided clinical judgment is when a mental health professional estimates violence risk based on his or her own experience and intuition, with knowledge of violence risk factors, but without the use of structured tools.

Actuarial tools are statistical models that use formulae to show relationships between data (risk factors) and outcomes (violence).^10,11

Continue to: Structured professional judgment

Structured professional judgment is a hybrid of unaided clinical judgment and actuarial methods. Structured professional judgment tools help the evaluator identify empirically established risk factors. Once the information is collected, it is combined with clinical judgment in decision making.^9,10 There are now more than 200 structured tools available for assessing violence risk in criminal justice and forensic mental health populations.¹²

Clinical judgment, although commonly used in practice, is less accurate than actuarial tools or structured professional judgment.^10,11 In general, risk assessment tools offer moderate levels of accuracy in categorizing people at low risk vs high risk.^5,13 The tools have better ability to accurately categorize individuals at low risk, compared with high risk, where false positives are common.^12,14

Two types of risk factors

Risk factors for violence are commonly categorized as static or dynamic factors. Static factors are historical factors that cannot be changed with intervention (eg, age, sex, history of abuse). Dynamic factors can be changed with intervention (eg, substance abuse).¹⁵

Static risk factors. The best predictor of future violence is past violent behavior.^5,16,17 Violence risk increases with each prior episode of violence.⁵ Prior arrests for any crime, especially if the individual was a juvenile at the time of arrest for his or her first violent offense, increase future violence risk.⁵ Other important static violence risk factors include demographic factors such as age, sex, and socioeconomic status. Swanson et al⁶ reviewed a large pool of data (approximately 10,000 respondents) from the Epidemiologic Catchment Area survey. Being young, male, and of low socioeconomic status were all associated with violence in the community.⁶ The highest-risk age group for violence is age 15 to 24.⁵ Males perpetrate violence in the community at a rate 10 times that of females.¹⁸ However, among individuals with severe mental illness, men and women have similar rates of violence.^19,20 Unstable employment,²¹ less education,²² low intelligence,¹⁶ and a history of a significant head injury⁵ also are risk factors for violence.⁵

Continue to: Being abused as a child...

Being abused as a child, witnessing violence in the home,^5,16 and growing up with an unstable parental situation (eg, parental loss or separation) has been linked to violence.^16,23,24 Early disruptive behavior in childhood (eg, fighting, lying and stealing, truancy, and school problems) increases violence risk.^21,23

Personality factors are important static risk factors for violence. Antisocial personality disorder is the most common personality disorder linked with violence.¹⁷ Several studies consistently show psychopathy to be a strong predictor of both violence and criminal behavior.^5,25 A psychopath is a person who lacks empathy and close relationships, behaves impulsively, has superficially charming qualities, and is primarily interested in self-gratification.²⁶ Harris et al²⁷ studied 169 released forensic patients and found that 77% of the psychopaths (according to Psychopathy Checklist-Revised [PCL-R] scores) violently recidivated. In contrast, only 21% of the non-psychopaths violently recidivated.²⁷

Other personality factors associated with violence include a predisposition toward feelings of anger and hatred (as opposed to empathy, anxiety, or guilt, which may reduce risk), hostile attributional biases (a tendency to interpret benign behavior of others as intentionally antagonistic), violent fantasies, poor anger control, and impulsivity.⁵ Although personality factors tend to be longstanding and more difficult to modify, in the outpatient setting, therapeutic efforts can be made to modify hostile attribution biases, poor anger control, and impulsive behavior.

Dynamic risk factors. Substance abuse is strongly associated with violence.^6,17 The prevalence of violence is 12 times greater among individuals with alcohol use disorder and 16 times greater among individuals with other substance use disorders, compared with those with no such diagnoses.^5,6

Continue to: Steadman et al...

Steadman et al²⁸ compared 1,136 adult patients with mental disorders discharged from psychiatric hospitals with 519 individuals living in the same neighborhoods as the hospitalized patients. They found that the prevalence of violence among discharged patients without substance abuse was “statistically indistinguishable” from the prevalence of violence among community members, in the same neighborhood, who did not have symptoms of substance abuse.²⁸ Swanson et al⁶ found that the combination of a mental disorder plus an alcohol or substance use disorder substantially increased the risk of violence.

Other dynamic risk factors for violence include mental illness symptoms such as psychosis, especially threat/control-override delusions, where the individual believes that they are being threatened or controlled by an external force.¹⁷

Contextual factors to consider in violence risk assessments include current stressors, lack of social support, availability of weapons, access to drugs and alcohol, and the presence of similar circumstances that led to violent behavior in the past.⁵

How to assess the risk of targeted violence

Targeted violence is a predatory act of violence intentionally committed against a preselected person, group of people, or place.²⁹ Due to the low base rates of these incidents, targeted violence is difficult to study.^7,30 These risk assessments require a more specialized approach.

Continue to: In their 1999 article...

In their 1999 article, Borum et al³⁰ discussed threat assessment strategies utilized by the U.S. Secret Service and recommended investigating “pathways of ideas and behaviors that may lead to violent action.” Borum et al³⁰ summarized 3 fundamental principles of threat assessment (Table 1³⁰).

What to do when violence risk is not due to mental illness

Based on the information in Mr. F’s case scenario, it is likely that his homicidal ideation is not due to mental illness. Despite this, several risk factors for violence are present. Where do we go from here?

Scott and Resnick¹⁷ recommend considering the concept of dangerousness as 5 components (Table 2¹⁷). When this model of dangerousness is applied to Mr. F’s case, one can see that the magnitude of the harm is great because of threatened homicide. With regard to the imminence of the harm, it would help to clarify whether Mr. F plans to kill Ms. S immediately after discharge, or sometime in the next few months. Is his threat contingent on further provocations by Ms. S? Alternatively, does he intend to kill her for past grievances, regardless of further perceived insults?

Next, the frequency of a behavior relates to how often Mr. F has been aggressive in the past. The severity of his past aggression is also important. What is the most violent act he has ever done? Situational factors in this case include Mr. F’s access to weapons, financial problems, housing problems, and access to drugs and alcohol.¹⁷ Mr. F should be asked about what situations previously provoked his violent behavior. Consider how similar the present conditions are to past conditions to which Mr. F responded violently.⁵ The likelihood that a homicide will occur should take into account Mr. F’s risk factors for violence, as well as the seriousness of his intent to cause harm.

Continue to: Consider using a structured tool...

Consider using a structured tool, such as the Classification of Violence Risk, to help identify Mr. F’s risk factors for violence, or some other formal method to ensure that the proper data are collected. Violence risk assessments are more accurate when structured risk assessment tools are used, compared with clinical judgment alone.

It is important to review collateral sources of information. In Mr. F’s case, useful collateral sources may include his criminal docket (usually available online), past medical records, information from the shelter where he lives, and, potentially, friends or family.

Because Mr. F is making threats of targeted violence, be sure to ask about attack-related behaviors (Table 1³⁰).

Regarding the seriousness of Mr. F’s intent to cause harm, it may be helpful to ask him the following questions:

1. How likely are you to carry out this act of violence?
2. Do you have a plan? Have you taken any steps toward this plan?
3. Do you see other, nonviolent solutions to this problem?
4. What do you hope that we can do for you to help with this problem?

Continue to: Mr. F's answers...

Mr. F’s answers may suggest the possibility of a hidden agenda. Some patients express homicidal thoughts in order to stay in the hospital. If Mr. F expresses threats that are contingent on discharge and declines to engage in problem-solving discussions, this would cast doubt on the genuineness of his threat. However, doubt about the genuineness of the threat alone is not sufficient to simply discharge Mr. F. Assessment of his intent needs to be considered with other relevant risk factors, risk reduction strategies, and any Tarasoff duties that may apply.

In addition to risk factors, consider mitigating factors. For example, does Mr. F express concern over prison time as a reason to not engage in violence? It would be more ominous if Mr. F says that he does not care if he goes to prison because life is lousy being homeless and unemployed. At this point, an estimation can be made regarding whether Mr. F is a low-, moderate-, or high-risk of violence.

The next step is to organize Mr. F’s risk factors into static (historical) and dynamic (subject to intervention) factors. This will be helpful in formulating a strategy to manage risk because continued hospitalization can only address dynamic risk factors. Often in these cases, the static risk factors are far more numerous than the dynamic risk factors.

Once the data are collected and organized, the final step is to devise a risk management strategy. Some interventions, such as substance use treatment, will be straightforward. A mood-stabilizing medication could be considered, if clinically appropriate, to help reduce aggression and irritability.³¹ Efforts should be made to eliminate Mr. F’s access to firearms; however, in this case, it sounds unlikely that he will cooperate with those efforts. Ultimately, you may find yourself with a list of risk factors that are unlikely to be altered with further hospitalization, particularly if Mr. F’s homicidal thoughts and intent are due to antisocial personality traits.

Continue to: In that case...

In that case, the most important step will be to carry out your duty to warn/protect others prior to Mr. F’s discharge. Most states either require or permit mental health professionals to take reasonable steps to protect victims from violence when certain conditions are present, such as an explicit threat or identifiable victim (see Related Resources).

Once dynamic risk factors have been addressed, and duty to warn/protect is carried out, if there is no further clinical indication for hospitalization, it would be appropriate to discharge Mr. F. Continued homicidal threats stemming from antisocial personality traits, in the absence of a treatable mental illness (or other modifiable risk factors for violence that can be actively addressed), is not a reason for continued hospitalization. It may be useful to obtain a second opinion from a colleague in such scenarios. A second opinion may offer additional risk management ideas. In the event of a bad outcome, this will also help to show that the decision to discharge the patient was not taken lightly.

The psychiatrist should document a thoughtful risk assessment, the strategies that were implemented to reduce risk, the details of the warning, and the reasoning why continued hospitalization was not indicated (Table 3).

CASE CONTINUED

Decision to discharge

In Mr. F’s case, the treating psychiatrist determined that Mr. F’s risk of violence toward Ms. S was moderate. The psychiatrist identified several static risk factors for violence that raised Mr. F’s risk, but also noted that Mr. F’s threats were likely a manipulative effort to prolong his hospital stay. The psychiatrist carried out his duty to protect by notifying police and Ms. S of the nature of the threat prior to Mr. F’s discharge. The unit social worker helped Mr. F schedule an intake appointment for a substance use disorder treatment facility. Mr. F ultimately stated that he no longer experienced homicidal ideas once a bed was secured for him in a substance use treatment program. The psychiatrist carefully documented Mr. F’s risk assessment and the reasons why Mr. F’s risk would not be significantly altered by further inpatient hospitalization. Mr. F was discharged, and Ms. S remained unharmed.

Continue to: Bottom Line

Use a structured approach to identify risk factors for violence. Address dynamic risk factors, including access to weapons. Carry out the duty to warn/protect if applicable. Document your decisions and actions carefully, and then discharge the patient if clinically indicated. Do not be “held hostage” by a patient’s homicidal ideation.

Related Resources

• Dolan M, Doyle M. Violence risk prediction. Clinical and actuarial measures and the role of the psychopathy checklist. Br J Psychiatry. 2000;177:303-311.
• Douglas KS, Hart SD, Webster CD, et al. HCR-20V3: Assessing risk of violence–user guide. Burnaby, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University; 2013.
• National Conference of State Legislatures. Mental health professionals’ duty to warn. http://www.ncsl.org/research/health/mental-health-professionals-duty-to-warn.aspx. Published September 28, 2015.

Drug Brand Names

Sertraline • Zoloft

Mr. F, age 35, is homeless and has a history of cocaine and alcohol use disorders. He is admitted voluntarily to the psychiatric unit because he has homicidal thoughts toward Ms. S, who works in the shelter where he has been staying. Mr. F reports that he is thinking of killing Ms. S if he is discharged because she has been rude to him. He states that he has access to several firearms, but he will not disclose the location. He has been diagnosed with unspecified depressive disorder and exhibited antisocial personality disorder traits. He is being treated with sertraline. However, his mood appears to be relatively stable, except for occasional angry verbal outbursts. The outbursts have been related to intrusive peers or staff turning the television off for group meetings. Mr. F has been joking with peers, eating well, and sleeping appropriately. He reports no suicidal thoughts and has not been physically violent on the unit. However, Mr. F has had a history of violence since his teenage years. He has been incarcerated twice for assault and once for drug possession.

How would you approach assessing and managing Mr. F’s risk for violence?

We all have encountered a patient similar to Mr. F on the psychiatric unit or in the emergency department—a patient who makes violent threats and appears angry, intimidating, manipulative, and/or demanding, despite exhibiting no evidence of mania or psychosis. This patient often has a history of substance abuse and a lifelong pattern of viewing violence as an acceptable way of addressing life’s problems. Many psychiatrists suspect that more time on the inpatient unit is unlikely to reduce this patient’s risk of violence. Why? Because the violence risk does not stem from a treatable mental illness. Further, psychiatrists may be apprehensive about this patient’s potential for violence after discharge and their liability in the event of a bad outcome. No one wants their name associated with a headline that reads “Psychiatrist discharged man less than 24 hours before he killed 3 people.”

The purported relationship between mental illness and violence often is sensationalized in the media. However, research reveals that the vast majority of violence is in fact not due to symptoms of mental illness.^1,2 A common clinical challenge in psychiatry involves evaluating individuals at elevated risk of violence and determining how to address their risk factors for violence. When the risk is primarily due to psychosis and can be reduced with antipsychotic medication, the job is easy. But how should we proceed when the risk stems from factors other than mental illness?

This article reviews risk factors for violence, discusses targeted violence against a specific victim, and offers practical tips for assessing and managing risk, particularly when the risk for violence is not due to mental illness.

Violence and mental illness: A tenuous link

Violence is a major public health concern in the United States. Although in recent years the rates of homicide and aggravated assault have decreased dramatically, there are approximately 16,000 homicides annually in the United States, and more than 1.6 million injuries from assaults treated in emergency departments each year.³ Homicide continues to be one of the leading causes of death among teenagers and young adults.⁴

The most effective methods of preventing widespread violence are public health approaches, such as parent- and family-focused programs, early childhood education, programs in school, and public policy changes.³ However, as psychiatrists, we are routinely asked to assess the risk of violence for an individual patient and devise strategies to mitigate violence risk.

Continue to: Although certain mental illnesses...

Although certain mental illnesses increase the relative risk of violence (compared with people without mental illness),^5,6 recent studies suggest that mental illness plays only a “minor role in explaining violence in populations.”⁷ It is estimated that as little as 4% of the violence in the United States can be attributed to mental illness.¹ According to a 1998 meta-analysis of 48 studies of criminal recidivism, the risk factors for violent recidivism were “almost identical” among offenders who had a mental disorder and those who did not.⁸

Approaches to assessing violence risk

Psychiatrists can assess the risk of future violence via 3 broad approaches.^9,10

Unaided clinical judgment is when a mental health professional estimates violence risk based on his or her own experience and intuition, with knowledge of violence risk factors, but without the use of structured tools.

Actuarial tools are statistical models that use formulae to show relationships between data (risk factors) and outcomes (violence).^10,11

Continue to: Structured professional judgment

Structured professional judgment is a hybrid of unaided clinical judgment and actuarial methods. Structured professional judgment tools help the evaluator identify empirically established risk factors. Once the information is collected, it is combined with clinical judgment in decision making.^9,10 There are now more than 200 structured tools available for assessing violence risk in criminal justice and forensic mental health populations.¹²

Clinical judgment, although commonly used in practice, is less accurate than actuarial tools or structured professional judgment.^10,11 In general, risk assessment tools offer moderate levels of accuracy in categorizing people at low risk vs high risk.^5,13 The tools have better ability to accurately categorize individuals at low risk, compared with high risk, where false positives are common.^12,14

Two types of risk factors

Risk factors for violence are commonly categorized as static or dynamic factors. Static factors are historical factors that cannot be changed with intervention (eg, age, sex, history of abuse). Dynamic factors can be changed with intervention (eg, substance abuse).¹⁵

Static risk factors. The best predictor of future violence is past violent behavior.^5,16,17 Violence risk increases with each prior episode of violence.⁵ Prior arrests for any crime, especially if the individual was a juvenile at the time of arrest for his or her first violent offense, increase future violence risk.⁵ Other important static violence risk factors include demographic factors such as age, sex, and socioeconomic status. Swanson et al⁶ reviewed a large pool of data (approximately 10,000 respondents) from the Epidemiologic Catchment Area survey. Being young, male, and of low socioeconomic status were all associated with violence in the community.⁶ The highest-risk age group for violence is age 15 to 24.⁵ Males perpetrate violence in the community at a rate 10 times that of females.¹⁸ However, among individuals with severe mental illness, men and women have similar rates of violence.^19,20 Unstable employment,²¹ less education,²² low intelligence,¹⁶ and a history of a significant head injury⁵ also are risk factors for violence.⁵

Continue to: Being abused as a child...

Being abused as a child, witnessing violence in the home,^5,16 and growing up with an unstable parental situation (eg, parental loss or separation) has been linked to violence.^16,23,24 Early disruptive behavior in childhood (eg, fighting, lying and stealing, truancy, and school problems) increases violence risk.^21,23

Personality factors are important static risk factors for violence. Antisocial personality disorder is the most common personality disorder linked with violence.¹⁷ Several studies consistently show psychopathy to be a strong predictor of both violence and criminal behavior.^5,25 A psychopath is a person who lacks empathy and close relationships, behaves impulsively, has superficially charming qualities, and is primarily interested in self-gratification.²⁶ Harris et al²⁷ studied 169 released forensic patients and found that 77% of the psychopaths (according to Psychopathy Checklist-Revised [PCL-R] scores) violently recidivated. In contrast, only 21% of the non-psychopaths violently recidivated.²⁷

Other personality factors associated with violence include a predisposition toward feelings of anger and hatred (as opposed to empathy, anxiety, or guilt, which may reduce risk), hostile attributional biases (a tendency to interpret benign behavior of others as intentionally antagonistic), violent fantasies, poor anger control, and impulsivity.⁵ Although personality factors tend to be longstanding and more difficult to modify, in the outpatient setting, therapeutic efforts can be made to modify hostile attribution biases, poor anger control, and impulsive behavior.

Dynamic risk factors. Substance abuse is strongly associated with violence.^6,17 The prevalence of violence is 12 times greater among individuals with alcohol use disorder and 16 times greater among individuals with other substance use disorders, compared with those with no such diagnoses.^5,6

Continue to: Steadman et al...

Steadman et al²⁸ compared 1,136 adult patients with mental disorders discharged from psychiatric hospitals with 519 individuals living in the same neighborhoods as the hospitalized patients. They found that the prevalence of violence among discharged patients without substance abuse was “statistically indistinguishable” from the prevalence of violence among community members, in the same neighborhood, who did not have symptoms of substance abuse.²⁸ Swanson et al⁶ found that the combination of a mental disorder plus an alcohol or substance use disorder substantially increased the risk of violence.

Other dynamic risk factors for violence include mental illness symptoms such as psychosis, especially threat/control-override delusions, where the individual believes that they are being threatened or controlled by an external force.¹⁷

Contextual factors to consider in violence risk assessments include current stressors, lack of social support, availability of weapons, access to drugs and alcohol, and the presence of similar circumstances that led to violent behavior in the past.⁵

How to assess the risk of targeted violence

Targeted violence is a predatory act of violence intentionally committed against a preselected person, group of people, or place.²⁹ Due to the low base rates of these incidents, targeted violence is difficult to study.^7,30 These risk assessments require a more specialized approach.

Continue to: In their 1999 article...

In their 1999 article, Borum et al³⁰ discussed threat assessment strategies utilized by the U.S. Secret Service and recommended investigating “pathways of ideas and behaviors that may lead to violent action.” Borum et al³⁰ summarized 3 fundamental principles of threat assessment (Table 1³⁰).

What to do when violence risk is not due to mental illness

Based on the information in Mr. F’s case scenario, it is likely that his homicidal ideation is not due to mental illness. Despite this, several risk factors for violence are present. Where do we go from here?

Scott and Resnick¹⁷ recommend considering the concept of dangerousness as 5 components (Table 2¹⁷). When this model of dangerousness is applied to Mr. F’s case, one can see that the magnitude of the harm is great because of threatened homicide. With regard to the imminence of the harm, it would help to clarify whether Mr. F plans to kill Ms. S immediately after discharge, or sometime in the next few months. Is his threat contingent on further provocations by Ms. S? Alternatively, does he intend to kill her for past grievances, regardless of further perceived insults?

Next, the frequency of a behavior relates to how often Mr. F has been aggressive in the past. The severity of his past aggression is also important. What is the most violent act he has ever done? Situational factors in this case include Mr. F’s access to weapons, financial problems, housing problems, and access to drugs and alcohol.¹⁷ Mr. F should be asked about what situations previously provoked his violent behavior. Consider how similar the present conditions are to past conditions to which Mr. F responded violently.⁵ The likelihood that a homicide will occur should take into account Mr. F’s risk factors for violence, as well as the seriousness of his intent to cause harm.

Continue to: Consider using a structured tool...

Consider using a structured tool, such as the Classification of Violence Risk, to help identify Mr. F’s risk factors for violence, or some other formal method to ensure that the proper data are collected. Violence risk assessments are more accurate when structured risk assessment tools are used, compared with clinical judgment alone.

It is important to review collateral sources of information. In Mr. F’s case, useful collateral sources may include his criminal docket (usually available online), past medical records, information from the shelter where he lives, and, potentially, friends or family.

Because Mr. F is making threats of targeted violence, be sure to ask about attack-related behaviors (Table 1³⁰).

Regarding the seriousness of Mr. F’s intent to cause harm, it may be helpful to ask him the following questions:

1. How likely are you to carry out this act of violence?
2. Do you have a plan? Have you taken any steps toward this plan?
3. Do you see other, nonviolent solutions to this problem?
4. What do you hope that we can do for you to help with this problem?

Continue to: Mr. F's answers...

Mr. F’s answers may suggest the possibility of a hidden agenda. Some patients express homicidal thoughts in order to stay in the hospital. If Mr. F expresses threats that are contingent on discharge and declines to engage in problem-solving discussions, this would cast doubt on the genuineness of his threat. However, doubt about the genuineness of the threat alone is not sufficient to simply discharge Mr. F. Assessment of his intent needs to be considered with other relevant risk factors, risk reduction strategies, and any Tarasoff duties that may apply.

In addition to risk factors, consider mitigating factors. For example, does Mr. F express concern over prison time as a reason to not engage in violence? It would be more ominous if Mr. F says that he does not care if he goes to prison because life is lousy being homeless and unemployed. At this point, an estimation can be made regarding whether Mr. F is a low-, moderate-, or high-risk of violence.

The next step is to organize Mr. F’s risk factors into static (historical) and dynamic (subject to intervention) factors. This will be helpful in formulating a strategy to manage risk because continued hospitalization can only address dynamic risk factors. Often in these cases, the static risk factors are far more numerous than the dynamic risk factors.

Once the data are collected and organized, the final step is to devise a risk management strategy. Some interventions, such as substance use treatment, will be straightforward. A mood-stabilizing medication could be considered, if clinically appropriate, to help reduce aggression and irritability.³¹ Efforts should be made to eliminate Mr. F’s access to firearms; however, in this case, it sounds unlikely that he will cooperate with those efforts. Ultimately, you may find yourself with a list of risk factors that are unlikely to be altered with further hospitalization, particularly if Mr. F’s homicidal thoughts and intent are due to antisocial personality traits.

Continue to: In that case...

In that case, the most important step will be to carry out your duty to warn/protect others prior to Mr. F’s discharge. Most states either require or permit mental health professionals to take reasonable steps to protect victims from violence when certain conditions are present, such as an explicit threat or identifiable victim (see Related Resources).

Once dynamic risk factors have been addressed, and duty to warn/protect is carried out, if there is no further clinical indication for hospitalization, it would be appropriate to discharge Mr. F. Continued homicidal threats stemming from antisocial personality traits, in the absence of a treatable mental illness (or other modifiable risk factors for violence that can be actively addressed), is not a reason for continued hospitalization. It may be useful to obtain a second opinion from a colleague in such scenarios. A second opinion may offer additional risk management ideas. In the event of a bad outcome, this will also help to show that the decision to discharge the patient was not taken lightly.

The psychiatrist should document a thoughtful risk assessment, the strategies that were implemented to reduce risk, the details of the warning, and the reasoning why continued hospitalization was not indicated (Table 3).

CASE CONTINUED

Decision to discharge

In Mr. F’s case, the treating psychiatrist determined that Mr. F’s risk of violence toward Ms. S was moderate. The psychiatrist identified several static risk factors for violence that raised Mr. F’s risk, but also noted that Mr. F’s threats were likely a manipulative effort to prolong his hospital stay. The psychiatrist carried out his duty to protect by notifying police and Ms. S of the nature of the threat prior to Mr. F’s discharge. The unit social worker helped Mr. F schedule an intake appointment for a substance use disorder treatment facility. Mr. F ultimately stated that he no longer experienced homicidal ideas once a bed was secured for him in a substance use treatment program. The psychiatrist carefully documented Mr. F’s risk assessment and the reasons why Mr. F’s risk would not be significantly altered by further inpatient hospitalization. Mr. F was discharged, and Ms. S remained unharmed.

Continue to: Bottom Line

Use a structured approach to identify risk factors for violence. Address dynamic risk factors, including access to weapons. Carry out the duty to warn/protect if applicable. Document your decisions and actions carefully, and then discharge the patient if clinically indicated. Do not be “held hostage” by a patient’s homicidal ideation.

Related Resources

• Dolan M, Doyle M. Violence risk prediction. Clinical and actuarial measures and the role of the psychopathy checklist. Br J Psychiatry. 2000;177:303-311.
• Douglas KS, Hart SD, Webster CD, et al. HCR-20V3: Assessing risk of violence–user guide. Burnaby, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University; 2013.
• National Conference of State Legislatures. Mental health professionals’ duty to warn. http://www.ncsl.org/research/health/mental-health-professionals-duty-to-warn.aspx. Published September 28, 2015.

Drug Brand Names

Sertraline • Zoloft

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm³, and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder.¹ The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS.² Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs).^1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART.³

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection.³ Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously.³ These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued.³

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6.⁴

Continue to: The DDIs arise because...

Table 1,^6-14,19-28 Table 2,^15-28 Table 3,^6-14,19-28 and Table 4^15-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.

These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.^19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.^6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.

Continue to: Consider adverse effect profiles

Consider adverse effect profiles

When selecting an antipsychotic agent for a patient receiving HIV therapy, also consider adverse effect profiles. The emergence of adverse effects can greatly impact patients’ quality of life, leading to consequences of medication nonadherence and exacerbation of mental illness.

Extrapyramidal symptoms. Patients with HIV have a higher sensitivity to treatment-emergent EPS from antipsychotics.² This sensitivity is generally thought to arise from the involvement of HIV on the basal ganglia. Historically, psychotic symptoms in HIV have been managed with second-generation antipsychotics (SGAs) at the lowest effective dose because these medications are less likely to cause EPS.^1,29 The antipsychotic with the lowest rate of EPS is clozapine, followed by quetiapine, olanzapine, ziprasidone, and aripiprazole. Conversely, high-potency first-generation antipsychotics (FGAs) have the highest rates of EPS, followed by intermediate-potency FGAs and risperidone.³⁰

Metabolic disturbances are another concern with concomitant antipsychotic/antiretroviral therapy. Patients with HIV who are receiving NRTIs or PIs can present with drug-induced lipodystrophy syndrome, which is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, and ultimately may cause metabolic syndrome.²⁹ The prevalence of metabolic syndrome in patients receiving PI therapy has a vast range—2% to 84%—which can be attributed to inconsistent definitions, criteria, and assessment methodology.²⁹ Use of a PI is considered to be the most prominent risk factor for developing lipodystrophy.²⁹ Among the PIs, metabolic disturbances in regards to lipids are most often seen with lopinavir/ritonavir (LPV/r), saquinavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir.³¹ In comparison with LPV/r, darunavir showed improvement in lipids.³² Atazanavir (ATV) boosted with ritonavir has not shown clinically significant adverse effects on lipids.³¹ Additionally, amprenavir, LPV/r, and ritonavir demonstrated more glucose uptake inhibition via blockade of the glucose transporter type 4 than ATV.³¹ Of the NRTIs, lipodystrophy syndrome is most commonly seen with stavudine, which is used minimally in practice.²

The rates of metabolic disturbance with antipsychotic use range from 2% to 36%.² The American Psychiatric Association recommends selecting one of the SGAs least likely to affect metabolic parameters.²⁹ Aripiprazole and ziprasidone are associated with the lowest risk of weight gain, hyperglycemia, and hyperlipidemia. They are followed by risperidone and quetiapine, which are associated with moderate risk, and then clozapine and olanzapine, which are associated with high risk.^2,30,33

Continue to: Management of metabolic adverse effects involves...

Management of metabolic adverse effects involves switching the antiretroviral agent and/or antipsychotic agent to an alternative associated with lower metabolic risk. Antipsychotics with low metabolic risk include aripiprazole, lurasidone, and ziprasidone. Lifestyle modifications are encouraged. Additionally, medication interventions, such as metformin, are also recommended in patients meeting criteria for pre-diabetes or type 2 diabetes mellitus.² Lipid panels and metabolic parameters should be monitored periodically, according to guidelines.^25,34

Bone marrow toxicity and blood dyscrasias. Lastly, consider the risk of bone marrow suppression. Patients receiving clozapine for treatment-resistant schizophrenia should be closely monitored for neutropenia and agranulocytosis. Although zidovudine is rarely used, its use is associated with adverse myelosuppressive effects, and the combination of clozapine and zidovudine could pose danger to the patient.^2,35,36

CASE CONTINUED

Because Mr. S’s diagnosis of HIV puts him at a higher risk of developing EPS, and because he is already experiencing increased wrist rigidity, the treatment team decides to switch his antipsychotic therapy to an agent with a lower risk of EPS. His comorbidities, including type 2 diabetes mellitus, hypertension, and hyperlipidemia, are taken into account, and an SGA with a benign metabolic profile is considered. Aripiprazole and ziprasidone are favorable options. However, because efavirenz, ATZ, and ritonavir may cause QTc prolongation, ziprasidone, the SGA with the highest rate of QTc prolongation, is not the preferred option.

Mr. S’s SGA therapy is switched from risperidone to aripiprazole. Because potential CYP-related interactions between aripiprazole and Mr. S’s current antiretroviral therapy could lead to increased aripiprazole levels. Mr. S is started on a low dose (5 mg/d) with the goal to titrate based on response and tolerability. Increased levels of aripiprazole may increase the risk of akathisia, drowsiness, headaches, and fatigue. Mr. S is monitored closely for improvement of EPS, adverse effects of medication, and metabolic parameters. Furthermore, if the treatment team believes there is a more preferred antipsychotic for the patient that it did not prescribe because of the risk of DDIs, it may be worthwhile to consider discussing the HAART regimen with the patient’s infectious disease treatment team.

Continue to: Acknowledgements

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

Related Resources

• Cohen MA. HIV: How to provide compassionate care. Current Psychiatry. 2013;12(6):19-23,A,B.
• Khan AY, Zaidi SN. Reducing morbidity and mortality from common medical conditions in schizophrenia. Current Psychiatry. 2016;15(3):30-32,34-38,40.

Drug Brand Names

Abacavir • Ziagen
Amlodipine • Norvasc
Amprenavir • Agenerase
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz
Brexpiprazole • Rexulti
Bupropion ER • Wellbutrin SR
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Darunavir • Prezista
Delavirdine • Rescriptor
Didanosine • Videx EC
Efavirenz • Sustiva
Efavirenz/emtricitabine/tenofovir disoproxil fumarate • Atripla
Enfuvirtide • Fuzeon
Emtricitabine • Emtriva
Etravirine • Intelence
Fluphenazine • Prolixin
Fosamprenavir • Lexiva
Gabapentin • Neurontin
Glipizide • Glucotrol
Haloperidol • Haldol
Iloperidone • Fanapt
Indinavir • Crixivan
Lamivudine • Epivir
Lopinavir/ritonavir • Kaletra
Loxapine • Loxitane
Lurasidone • Latuda
Maraviroc • Selzentry
Metformin • Glucophage
Metoclopramide • Reglan
Molindone • Moban
Nelfinavir • Viracept
Nevirapine • Viramune
Olanzapine • Zyprexa
Paliperidone • Invega
Perphenazine • Trilafon
Pimozide • Orap
Pravastatin • Pravachol
Quetiapine • Seroquel
Raltegravir • Isentress
Rilpivirine • Edurant
Risperidone • Risperdal
Ritonavir • Norvir
Saquinavir • Invirase
Stavudine • Zerit
Tenofovir disoproxil • Viread
Thioridazine • Mellaril
Thiothixene • Navane
Tipranavir • Aptivus
Trifluoperazine • Stelazine
Zidovudine • Retrovir
Ziprasidone • Geodon

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm³, and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder.¹ The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS.² Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs).^1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART.³

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection.³ Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously.³ These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued.³

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6.⁴

Continue to: The DDIs arise because...

Table 1,^6-14,19-28 Table 2,^15-28 Table 3,^6-14,19-28 and Table 4^15-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.

These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.^19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.^6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.

Continue to: Consider adverse effect profiles

Consider adverse effect profiles

When selecting an antipsychotic agent for a patient receiving HIV therapy, also consider adverse effect profiles. The emergence of adverse effects can greatly impact patients’ quality of life, leading to consequences of medication nonadherence and exacerbation of mental illness.

Extrapyramidal symptoms. Patients with HIV have a higher sensitivity to treatment-emergent EPS from antipsychotics.² This sensitivity is generally thought to arise from the involvement of HIV on the basal ganglia. Historically, psychotic symptoms in HIV have been managed with second-generation antipsychotics (SGAs) at the lowest effective dose because these medications are less likely to cause EPS.^1,29 The antipsychotic with the lowest rate of EPS is clozapine, followed by quetiapine, olanzapine, ziprasidone, and aripiprazole. Conversely, high-potency first-generation antipsychotics (FGAs) have the highest rates of EPS, followed by intermediate-potency FGAs and risperidone.³⁰

Metabolic disturbances are another concern with concomitant antipsychotic/antiretroviral therapy. Patients with HIV who are receiving NRTIs or PIs can present with drug-induced lipodystrophy syndrome, which is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, and ultimately may cause metabolic syndrome.²⁹ The prevalence of metabolic syndrome in patients receiving PI therapy has a vast range—2% to 84%—which can be attributed to inconsistent definitions, criteria, and assessment methodology.²⁹ Use of a PI is considered to be the most prominent risk factor for developing lipodystrophy.²⁹ Among the PIs, metabolic disturbances in regards to lipids are most often seen with lopinavir/ritonavir (LPV/r), saquinavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir.³¹ In comparison with LPV/r, darunavir showed improvement in lipids.³² Atazanavir (ATV) boosted with ritonavir has not shown clinically significant adverse effects on lipids.³¹ Additionally, amprenavir, LPV/r, and ritonavir demonstrated more glucose uptake inhibition via blockade of the glucose transporter type 4 than ATV.³¹ Of the NRTIs, lipodystrophy syndrome is most commonly seen with stavudine, which is used minimally in practice.²

The rates of metabolic disturbance with antipsychotic use range from 2% to 36%.² The American Psychiatric Association recommends selecting one of the SGAs least likely to affect metabolic parameters.²⁹ Aripiprazole and ziprasidone are associated with the lowest risk of weight gain, hyperglycemia, and hyperlipidemia. They are followed by risperidone and quetiapine, which are associated with moderate risk, and then clozapine and olanzapine, which are associated with high risk.^2,30,33

Continue to: Management of metabolic adverse effects involves...

Management of metabolic adverse effects involves switching the antiretroviral agent and/or antipsychotic agent to an alternative associated with lower metabolic risk. Antipsychotics with low metabolic risk include aripiprazole, lurasidone, and ziprasidone. Lifestyle modifications are encouraged. Additionally, medication interventions, such as metformin, are also recommended in patients meeting criteria for pre-diabetes or type 2 diabetes mellitus.² Lipid panels and metabolic parameters should be monitored periodically, according to guidelines.^25,34

Bone marrow toxicity and blood dyscrasias. Lastly, consider the risk of bone marrow suppression. Patients receiving clozapine for treatment-resistant schizophrenia should be closely monitored for neutropenia and agranulocytosis. Although zidovudine is rarely used, its use is associated with adverse myelosuppressive effects, and the combination of clozapine and zidovudine could pose danger to the patient.^2,35,36

CASE CONTINUED

Because Mr. S’s diagnosis of HIV puts him at a higher risk of developing EPS, and because he is already experiencing increased wrist rigidity, the treatment team decides to switch his antipsychotic therapy to an agent with a lower risk of EPS. His comorbidities, including type 2 diabetes mellitus, hypertension, and hyperlipidemia, are taken into account, and an SGA with a benign metabolic profile is considered. Aripiprazole and ziprasidone are favorable options. However, because efavirenz, ATZ, and ritonavir may cause QTc prolongation, ziprasidone, the SGA with the highest rate of QTc prolongation, is not the preferred option.

Mr. S’s SGA therapy is switched from risperidone to aripiprazole. Because potential CYP-related interactions between aripiprazole and Mr. S’s current antiretroviral therapy could lead to increased aripiprazole levels. Mr. S is started on a low dose (5 mg/d) with the goal to titrate based on response and tolerability. Increased levels of aripiprazole may increase the risk of akathisia, drowsiness, headaches, and fatigue. Mr. S is monitored closely for improvement of EPS, adverse effects of medication, and metabolic parameters. Furthermore, if the treatment team believes there is a more preferred antipsychotic for the patient that it did not prescribe because of the risk of DDIs, it may be worthwhile to consider discussing the HAART regimen with the patient’s infectious disease treatment team.

Continue to: Acknowledgements

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

Related Resources

• Cohen MA. HIV: How to provide compassionate care. Current Psychiatry. 2013;12(6):19-23,A,B.
• Khan AY, Zaidi SN. Reducing morbidity and mortality from common medical conditions in schizophrenia. Current Psychiatry. 2016;15(3):30-32,34-38,40.

Drug Brand Names

Abacavir • Ziagen
Amlodipine • Norvasc
Amprenavir • Agenerase
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz
Brexpiprazole • Rexulti
Bupropion ER • Wellbutrin SR
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Darunavir • Prezista
Delavirdine • Rescriptor
Didanosine • Videx EC
Efavirenz • Sustiva
Efavirenz/emtricitabine/tenofovir disoproxil fumarate • Atripla
Enfuvirtide • Fuzeon
Emtricitabine • Emtriva
Etravirine • Intelence
Fluphenazine • Prolixin
Fosamprenavir • Lexiva
Gabapentin • Neurontin
Glipizide • Glucotrol
Haloperidol • Haldol
Iloperidone • Fanapt
Indinavir • Crixivan
Lamivudine • Epivir
Lopinavir/ritonavir • Kaletra
Loxapine • Loxitane
Lurasidone • Latuda
Maraviroc • Selzentry
Metformin • Glucophage
Metoclopramide • Reglan
Molindone • Moban
Nelfinavir • Viracept
Nevirapine • Viramune
Olanzapine • Zyprexa
Paliperidone • Invega
Perphenazine • Trilafon
Pimozide • Orap
Pravastatin • Pravachol
Quetiapine • Seroquel
Raltegravir • Isentress
Rilpivirine • Edurant
Risperidone • Risperdal
Ritonavir • Norvir
Saquinavir • Invirase
Stavudine • Zerit
Tenofovir disoproxil • Viread
Thioridazine • Mellaril
Thiothixene • Navane
Tipranavir • Aptivus
Trifluoperazine • Stelazine
Zidovudine • Retrovir
Ziprasidone • Geodon

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm³, and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder.¹ The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS.² Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs).^1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART.³

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection.³ Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously.³ These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued.³

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6.⁴

Continue to: The DDIs arise because...

Table 1,^6-14,19-28 Table 2,^15-28 Table 3,^6-14,19-28 and Table 4^15-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.

These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.^19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.^6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.

Continue to: Consider adverse effect profiles

Consider adverse effect profiles

When selecting an antipsychotic agent for a patient receiving HIV therapy, also consider adverse effect profiles. The emergence of adverse effects can greatly impact patients’ quality of life, leading to consequences of medication nonadherence and exacerbation of mental illness.

Extrapyramidal symptoms. Patients with HIV have a higher sensitivity to treatment-emergent EPS from antipsychotics.² This sensitivity is generally thought to arise from the involvement of HIV on the basal ganglia. Historically, psychotic symptoms in HIV have been managed with second-generation antipsychotics (SGAs) at the lowest effective dose because these medications are less likely to cause EPS.^1,29 The antipsychotic with the lowest rate of EPS is clozapine, followed by quetiapine, olanzapine, ziprasidone, and aripiprazole. Conversely, high-potency first-generation antipsychotics (FGAs) have the highest rates of EPS, followed by intermediate-potency FGAs and risperidone.³⁰

Metabolic disturbances are another concern with concomitant antipsychotic/antiretroviral therapy. Patients with HIV who are receiving NRTIs or PIs can present with drug-induced lipodystrophy syndrome, which is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, and ultimately may cause metabolic syndrome.²⁹ The prevalence of metabolic syndrome in patients receiving PI therapy has a vast range—2% to 84%—which can be attributed to inconsistent definitions, criteria, and assessment methodology.²⁹ Use of a PI is considered to be the most prominent risk factor for developing lipodystrophy.²⁹ Among the PIs, metabolic disturbances in regards to lipids are most often seen with lopinavir/ritonavir (LPV/r), saquinavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir.³¹ In comparison with LPV/r, darunavir showed improvement in lipids.³² Atazanavir (ATV) boosted with ritonavir has not shown clinically significant adverse effects on lipids.³¹ Additionally, amprenavir, LPV/r, and ritonavir demonstrated more glucose uptake inhibition via blockade of the glucose transporter type 4 than ATV.³¹ Of the NRTIs, lipodystrophy syndrome is most commonly seen with stavudine, which is used minimally in practice.²

The rates of metabolic disturbance with antipsychotic use range from 2% to 36%.² The American Psychiatric Association recommends selecting one of the SGAs least likely to affect metabolic parameters.²⁹ Aripiprazole and ziprasidone are associated with the lowest risk of weight gain, hyperglycemia, and hyperlipidemia. They are followed by risperidone and quetiapine, which are associated with moderate risk, and then clozapine and olanzapine, which are associated with high risk.^2,30,33

Continue to: Management of metabolic adverse effects involves...

Management of metabolic adverse effects involves switching the antiretroviral agent and/or antipsychotic agent to an alternative associated with lower metabolic risk. Antipsychotics with low metabolic risk include aripiprazole, lurasidone, and ziprasidone. Lifestyle modifications are encouraged. Additionally, medication interventions, such as metformin, are also recommended in patients meeting criteria for pre-diabetes or type 2 diabetes mellitus.² Lipid panels and metabolic parameters should be monitored periodically, according to guidelines.^25,34

Bone marrow toxicity and blood dyscrasias. Lastly, consider the risk of bone marrow suppression. Patients receiving clozapine for treatment-resistant schizophrenia should be closely monitored for neutropenia and agranulocytosis. Although zidovudine is rarely used, its use is associated with adverse myelosuppressive effects, and the combination of clozapine and zidovudine could pose danger to the patient.^2,35,36

CASE CONTINUED

Because Mr. S’s diagnosis of HIV puts him at a higher risk of developing EPS, and because he is already experiencing increased wrist rigidity, the treatment team decides to switch his antipsychotic therapy to an agent with a lower risk of EPS. His comorbidities, including type 2 diabetes mellitus, hypertension, and hyperlipidemia, are taken into account, and an SGA with a benign metabolic profile is considered. Aripiprazole and ziprasidone are favorable options. However, because efavirenz, ATZ, and ritonavir may cause QTc prolongation, ziprasidone, the SGA with the highest rate of QTc prolongation, is not the preferred option.

Mr. S’s SGA therapy is switched from risperidone to aripiprazole. Because potential CYP-related interactions between aripiprazole and Mr. S’s current antiretroviral therapy could lead to increased aripiprazole levels. Mr. S is started on a low dose (5 mg/d) with the goal to titrate based on response and tolerability. Increased levels of aripiprazole may increase the risk of akathisia, drowsiness, headaches, and fatigue. Mr. S is monitored closely for improvement of EPS, adverse effects of medication, and metabolic parameters. Furthermore, if the treatment team believes there is a more preferred antipsychotic for the patient that it did not prescribe because of the risk of DDIs, it may be worthwhile to consider discussing the HAART regimen with the patient’s infectious disease treatment team.

Continue to: Acknowledgements

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

Related Resources

• Cohen MA. HIV: How to provide compassionate care. Current Psychiatry. 2013;12(6):19-23,A,B.
• Khan AY, Zaidi SN. Reducing morbidity and mortality from common medical conditions in schizophrenia. Current Psychiatry. 2016;15(3):30-32,34-38,40.

Drug Brand Names

Abacavir • Ziagen
Amlodipine • Norvasc
Amprenavir • Agenerase
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz
Brexpiprazole • Rexulti
Bupropion ER • Wellbutrin SR
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Darunavir • Prezista
Delavirdine • Rescriptor
Didanosine • Videx EC
Efavirenz • Sustiva
Efavirenz/emtricitabine/tenofovir disoproxil fumarate • Atripla
Enfuvirtide • Fuzeon
Emtricitabine • Emtriva
Etravirine • Intelence
Fluphenazine • Prolixin
Fosamprenavir • Lexiva
Gabapentin • Neurontin
Glipizide • Glucotrol
Haloperidol • Haldol
Iloperidone • Fanapt
Indinavir • Crixivan
Lamivudine • Epivir
Lopinavir/ritonavir • Kaletra
Loxapine • Loxitane
Lurasidone • Latuda
Maraviroc • Selzentry
Metformin • Glucophage
Metoclopramide • Reglan
Molindone • Moban
Nelfinavir • Viracept
Nevirapine • Viramune
Olanzapine • Zyprexa
Paliperidone • Invega
Perphenazine • Trilafon
Pimozide • Orap
Pravastatin • Pravachol
Quetiapine • Seroquel
Raltegravir • Isentress
Rilpivirine • Edurant
Risperidone • Risperdal
Ritonavir • Norvir
Saquinavir • Invirase
Stavudine • Zerit
Tenofovir disoproxil • Viread
Thioridazine • Mellaril
Thiothixene • Navane
Tipranavir • Aptivus
Trifluoperazine • Stelazine
Zidovudine • Retrovir
Ziprasidone • Geodon

As the end of the academic year approaches, I always think of one last message to send to the freshly minted psychiatrists who will complete their 4 years of post-MD training. This year, I thought of emphasizing the principles of psychiatric practice, which the graduates will deliver for the next 4 to 5 decades of their professional lives. Those essential principles are coded in the DNA of psychiatric practice, just as the construction of all organs in the human body is coded within the DNA of the 22,000 genes that comprise our 23 chromosomes.

So here are the principles of psych­iatry that I propose govern the relationship of psychiatrists with their patients, encrypted within the DNA of our esteemed medical specialty:

• Provide total dedication to helping psychiatric patients recover from their illness and regain their wellness.
• Maintain total and unimpeachable confidentiality.
• Demonstrate unconditional acceptance and respect to every patient.
• Adopt a nonjudgmental stance toward all patients.
• Establish a strong therapeutic alliance as early as possible. It is the center of the doctor–patient relationship.
• Provide the same standard of care to all patients—the same care you would want your family members to receive.
• Provide evidence-based treatments first, and if no response, use unapproved treatments judiciously, but above all, do no harm.
• Educate patients, and their families, about the illness, and discuss the benefits and risks of various treatments.
• Do not practice “naked psychopharmacology.” Psychotherapy must always be provided side-by-side with medications.
• Support the patient’s family. Their burden often is very heavy.
• Emphasize adherence as a key patient responsibility, and address it at every visit.
• Do not hesitate to consult a seasoned colleague about your complex clinical cases.
• Deal effectively with negative countertransference. Recognize it, and refer the patient to another colleague if you cannot resolve it.
• Always inquire about thoughts of harming self or others and act accordingly.
• Always ask about alcohol and substance use, and about over-the-counter drugs as well. They all can complicate your patient’s treatment course and outcome.
• Never breach boundaries with your patient, and firmly guide the patient about breaching boundaries with you.
• Uphold the medical tenet that all “mental” disorders of thought, mood, affect, behavior, and cognition are generated by disruptions of brain structure and/or function, whether molecular, cellular, or connectomic, caused by various combinations of genetic and/or environmental etiologies.
• Check your patients’ physical health status, including all treatments they received from other specialists, and always rule out iatrogenesis and disruptive pharmacokinetic interactions that may trigger or exacerbate psychiatric symptoms.
• Learn and use clinical rating scales to quantify symptom severity and adverse effects at baseline and at each visit. Measuring the severity of psychosis, depression, or anxiety in psychiatry is like measuring fasting glucose, triglycerides, or blood pressure in internal medicine.
• Use rational adjunctive and augmentation therapies when indicated, but avoid irrational and hazardous polypharmacy.
• Document your clinical findings, diagnosis, and treatment plan conscientiously and accurately. The medical record is a clinical, billing, legal, and research document.
• Advocate tirelessly for psychiatric patients to increase their access to care, and fight the unfair and hurtful stigma vigorously until it is completely erased. A psychiatric disorder should have no more stigma than a broken leg or peptic ulcer, and insurance parity must be identical as well.
• Establish collaborative care for each of your patients and link them to a primary care provider if they do not already have one. Disorders of the body and the brain are bidirectional in their effects and psychiatric patients often suffer from multiple organ diseases.
• Do some pro bono care for indigent or uninsured patients, and actively ask companies to provide free drugs to patients who cannot afford the medication you believe they need.
• Recognize that every treatment you use as the current standard of care was at one time a research project. Know that the research of today is the treatment of tomorrow. So support the creation of new medical knowledge by referring patients to FDA clinical trials or to National Institutes of Health–funded biologic investigations.
• No matter how busy you are, write a case report or a letter to the editor about an unusual response or adverse effect. This generates hypotheses that researchers can pursue and test.
• Volunteer to serve as a clinical supervisor for medical students and residents from your local medical school. Most academic departments of psychiatry appreciate their community-based volunteer faculty.

You, the readers of Current Psychiatry, include thousands of experienced psychiatrists with years of practice in the real world. I invite you to add to this list of principles by writing to me at [email protected]. Join me in providing the freshly minted psychiatrists words of wisdom about the DNA of psychiatry to guide them before they embark on their careers as psychiatric physicians.

As the end of the academic year approaches, I always think of one last message to send to the freshly minted psychiatrists who will complete their 4 years of post-MD training. This year, I thought of emphasizing the principles of psychiatric practice, which the graduates will deliver for the next 4 to 5 decades of their professional lives. Those essential principles are coded in the DNA of psychiatric practice, just as the construction of all organs in the human body is coded within the DNA of the 22,000 genes that comprise our 23 chromosomes.

So here are the principles of psych­iatry that I propose govern the relationship of psychiatrists with their patients, encrypted within the DNA of our esteemed medical specialty:

• Provide total dedication to helping psychiatric patients recover from their illness and regain their wellness.
• Maintain total and unimpeachable confidentiality.
• Demonstrate unconditional acceptance and respect to every patient.
• Adopt a nonjudgmental stance toward all patients.
• Establish a strong therapeutic alliance as early as possible. It is the center of the doctor–patient relationship.
• Provide the same standard of care to all patients—the same care you would want your family members to receive.
• Provide evidence-based treatments first, and if no response, use unapproved treatments judiciously, but above all, do no harm.
• Educate patients, and their families, about the illness, and discuss the benefits and risks of various treatments.
• Do not practice “naked psychopharmacology.” Psychotherapy must always be provided side-by-side with medications.
• Support the patient’s family. Their burden often is very heavy.
• Emphasize adherence as a key patient responsibility, and address it at every visit.
• Do not hesitate to consult a seasoned colleague about your complex clinical cases.
• Deal effectively with negative countertransference. Recognize it, and refer the patient to another colleague if you cannot resolve it.
• Always inquire about thoughts of harming self or others and act accordingly.
• Always ask about alcohol and substance use, and about over-the-counter drugs as well. They all can complicate your patient’s treatment course and outcome.
• Never breach boundaries with your patient, and firmly guide the patient about breaching boundaries with you.
• Uphold the medical tenet that all “mental” disorders of thought, mood, affect, behavior, and cognition are generated by disruptions of brain structure and/or function, whether molecular, cellular, or connectomic, caused by various combinations of genetic and/or environmental etiologies.
• Check your patients’ physical health status, including all treatments they received from other specialists, and always rule out iatrogenesis and disruptive pharmacokinetic interactions that may trigger or exacerbate psychiatric symptoms.
• Learn and use clinical rating scales to quantify symptom severity and adverse effects at baseline and at each visit. Measuring the severity of psychosis, depression, or anxiety in psychiatry is like measuring fasting glucose, triglycerides, or blood pressure in internal medicine.
• Use rational adjunctive and augmentation therapies when indicated, but avoid irrational and hazardous polypharmacy.
• Document your clinical findings, diagnosis, and treatment plan conscientiously and accurately. The medical record is a clinical, billing, legal, and research document.
• Advocate tirelessly for psychiatric patients to increase their access to care, and fight the unfair and hurtful stigma vigorously until it is completely erased. A psychiatric disorder should have no more stigma than a broken leg or peptic ulcer, and insurance parity must be identical as well.
• Establish collaborative care for each of your patients and link them to a primary care provider if they do not already have one. Disorders of the body and the brain are bidirectional in their effects and psychiatric patients often suffer from multiple organ diseases.
• Do some pro bono care for indigent or uninsured patients, and actively ask companies to provide free drugs to patients who cannot afford the medication you believe they need.
• Recognize that every treatment you use as the current standard of care was at one time a research project. Know that the research of today is the treatment of tomorrow. So support the creation of new medical knowledge by referring patients to FDA clinical trials or to National Institutes of Health–funded biologic investigations.
• No matter how busy you are, write a case report or a letter to the editor about an unusual response or adverse effect. This generates hypotheses that researchers can pursue and test.
• Volunteer to serve as a clinical supervisor for medical students and residents from your local medical school. Most academic departments of psychiatry appreciate their community-based volunteer faculty.

You, the readers of Current Psychiatry, include thousands of experienced psychiatrists with years of practice in the real world. I invite you to add to this list of principles by writing to me at [email protected]. Join me in providing the freshly minted psychiatrists words of wisdom about the DNA of psychiatry to guide them before they embark on their careers as psychiatric physicians.

As the end of the academic year approaches, I always think of one last message to send to the freshly minted psychiatrists who will complete their 4 years of post-MD training. This year, I thought of emphasizing the principles of psychiatric practice, which the graduates will deliver for the next 4 to 5 decades of their professional lives. Those essential principles are coded in the DNA of psychiatric practice, just as the construction of all organs in the human body is coded within the DNA of the 22,000 genes that comprise our 23 chromosomes.

So here are the principles of psych­iatry that I propose govern the relationship of psychiatrists with their patients, encrypted within the DNA of our esteemed medical specialty:

• Provide total dedication to helping psychiatric patients recover from their illness and regain their wellness.
• Maintain total and unimpeachable confidentiality.
• Demonstrate unconditional acceptance and respect to every patient.
• Adopt a nonjudgmental stance toward all patients.
• Establish a strong therapeutic alliance as early as possible. It is the center of the doctor–patient relationship.
• Provide the same standard of care to all patients—the same care you would want your family members to receive.
• Provide evidence-based treatments first, and if no response, use unapproved treatments judiciously, but above all, do no harm.
• Educate patients, and their families, about the illness, and discuss the benefits and risks of various treatments.
• Do not practice “naked psychopharmacology.” Psychotherapy must always be provided side-by-side with medications.
• Support the patient’s family. Their burden often is very heavy.
• Emphasize adherence as a key patient responsibility, and address it at every visit.
• Do not hesitate to consult a seasoned colleague about your complex clinical cases.
• Deal effectively with negative countertransference. Recognize it, and refer the patient to another colleague if you cannot resolve it.
• Always inquire about thoughts of harming self or others and act accordingly.
• Always ask about alcohol and substance use, and about over-the-counter drugs as well. They all can complicate your patient’s treatment course and outcome.
• Never breach boundaries with your patient, and firmly guide the patient about breaching boundaries with you.
• Uphold the medical tenet that all “mental” disorders of thought, mood, affect, behavior, and cognition are generated by disruptions of brain structure and/or function, whether molecular, cellular, or connectomic, caused by various combinations of genetic and/or environmental etiologies.
• Check your patients’ physical health status, including all treatments they received from other specialists, and always rule out iatrogenesis and disruptive pharmacokinetic interactions that may trigger or exacerbate psychiatric symptoms.
• Learn and use clinical rating scales to quantify symptom severity and adverse effects at baseline and at each visit. Measuring the severity of psychosis, depression, or anxiety in psychiatry is like measuring fasting glucose, triglycerides, or blood pressure in internal medicine.
• Use rational adjunctive and augmentation therapies when indicated, but avoid irrational and hazardous polypharmacy.
• Document your clinical findings, diagnosis, and treatment plan conscientiously and accurately. The medical record is a clinical, billing, legal, and research document.
• Advocate tirelessly for psychiatric patients to increase their access to care, and fight the unfair and hurtful stigma vigorously until it is completely erased. A psychiatric disorder should have no more stigma than a broken leg or peptic ulcer, and insurance parity must be identical as well.
• Establish collaborative care for each of your patients and link them to a primary care provider if they do not already have one. Disorders of the body and the brain are bidirectional in their effects and psychiatric patients often suffer from multiple organ diseases.
• Do some pro bono care for indigent or uninsured patients, and actively ask companies to provide free drugs to patients who cannot afford the medication you believe they need.
• Recognize that every treatment you use as the current standard of care was at one time a research project. Know that the research of today is the treatment of tomorrow. So support the creation of new medical knowledge by referring patients to FDA clinical trials or to National Institutes of Health–funded biologic investigations.
• No matter how busy you are, write a case report or a letter to the editor about an unusual response or adverse effect. This generates hypotheses that researchers can pursue and test.
• Volunteer to serve as a clinical supervisor for medical students and residents from your local medical school. Most academic departments of psychiatry appreciate their community-based volunteer faculty.

You, the readers of Current Psychiatry, include thousands of experienced psychiatrists with years of practice in the real world. I invite you to add to this list of principles by writing to me at [email protected]. Join me in providing the freshly minted psychiatrists words of wisdom about the DNA of psychiatry to guide them before they embark on their careers as psychiatric physicians.

The Goldwater Rule and free speech

In his editorial, “The toxic zeitgeist of hyper-partisanship: A psychiatric perspective” (From the Editor, Current Psychiatry, February 2018, p. 17-18), Dr. Nasrallah notes that he “adheres” to the APA’s Goldwater Rule. The Goldwater Rule and the reason for its creation and current implementation in the United States cannot be fully understood without appreciating the political circumstances that led to its creation in 1964. The conservative movement had been using the slogan “better dead than red” to criticize Democrats who they felt were soft on communism. Unfortunately, some psychiatrists took these words and the views of Arizona senator Barry Goldwater quite literally. They claimed they understood his psychological structure by listening to his political views, and feared that he would risk starting a nuclear war. Of course, no psychiatrist actually examined senator Goldwater. During the 1964 presidential campaign, a television commercial from President Lyndon B. Johnson’s campaign included a mushroom cloud of a nuclear explosion with an implicit reference to senator Goldwater and the “better dead than red” slogan. In the end, psychiatry, and particularly psychoanalysis, as well as President Johnson’s campaign, were embarrassed.

One’s political views do not inform us of his or her mental health status. This appreciation can be obtained only by a thorough psychological assessment. This is the basis of the Goldwater Rule, coupled with the ethical responsibility not to discuss patients’ private communications.

Today, this rule is tested by the behavior and actions of President Donald Trump. Proponents of the Goldwater Rule state that a psychiatrist cannot diagnose someone without performing a face-to-face diagnostic evaluation. This assumes psychiatrists diagnose patients only by interviewing them. However, any psychiatrist who has worked in an emergency room has signed involuntary commitment papers for a patient who refuses to talk to them. This clinical action typically is based on reports of the patient’s potential dangerousness from family, friends, or the police.

The diagnostic criteria for some personality disorders are based only on observed or reported behavior. They do not indicate a need for an interview.  The diagnosis of a personality disorder cannot be made solely by interviewing an individual without knowledge of his or her behavior. Interviewing Bernie Madoff would not have revealed his sociopathic behavior.

The critical question may not be whether one could ethically make a psychiatric diagnosis of the President (I believe you can), but rather would it indicate or imply that he is dangerous? History informs us that the existence of a psychiatric disorder does not determine a politician’s fitness for office or if they are dangerous. Behavioral accounts of President Abraham Lincoln and his self-reports seem to confirm that at times he was depressed, but he clearly served our country with distinction.

Finally, it is not clear whether the Goldwater Rule is legal. It arguably interferes with a psychiatrist’s right of free speech without the risk of being accused of unethical behavior. I wonder what would happen if it were tested in court. Does the First Amendment of the U.S. Constitution protect a psychiatrist’s right to speak freely?

Sidney Weissman, MD
Clinical Professor of Psychiatry and Behavioral Science
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

The current ‘political morass’

Thank you, Dr. Nasrallah, for the wonderful synopsis of the current political morass in your editorial (From the Editor, Current Psychiatry, February 2018, p. 17-18). You followed Descartes’ dictum: you thought about matters in a novel fashion. I will assertively share this with others. It is a good piece of teaching.

James Gallagher, MD
Private psychiatric practice
Des Moines, Iowa

Continue to: The biological etiology of compulsive sexual behavior

Dr. Grant’s article, “Compulsive sexual behavior: A nonjudgmental approach” (Evidence-Based Reviews, Current Psychiatry, February 2018, p. 34,38-40,45-46), puts a well-deserved spotlight on a relatively underrecognized problem that most psychiatrists will encounter at least once during clinical practice. While the article is overall helpful, it completely leaves out any possible biological etiology and underpinnings to the condition that may be important to address while evaluating someone with compulsive sexual behavior. Specifically, are there any endocrine issues that should be considered that may also impact our approach to its treatment?

Mukesh Sanghadia, MD, MRCPsych (UK), Diplomate ABPN
PsychiatristCommunity Research Foundation
San Diego, California

The author responds

Dr. Sanghadia highlights the lack of possible biological etiology of compulsive sexual behavior (CSB) in my article. This is a fair comment. The lack of agreed-upon diagnostic criteria, however, has resulted in a vast literature discussing sexual behaviors that may or may not be related to each other, and even suggest that what is currently referred to as CSB may in fact be quite heterogeneous. My article mentions the few neuroimaging and neurocognitive studies that address a more rigorously defined CSB. Other possible etiologies have been suggested for a range of out-of-control sexual behaviors, but have not been studied with a focus on this formal diagnostic category. For example, endocrine issues have been explored to some extent in individuals with paraphilic sexual behaviors (behaviors that appear to many to have no relationship to CSB as discussed in my article), and in those cases of paraphilic sexual behavior, a range of endocrine hormones have been examined—gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone. But these studies have yielded no conclusive outcomes in terms of findings or treatments.

In summary, the biology of CSB lags far behind that of other mental health disorders (and even other psychiatric disorders lack conclusive biological etiologies). Establishing this behavior as a legitimate diagnostic entity with agreed-upon criteria may be the first step in furthering our understanding of its possible biology.

Jon E. Grant, JD, MD, MPH
Professor
Department of Psychiatry and Behavioral Neuroscience
University of Chicago, Pritzker School of Medicine
Chicago, Illinois

Continue to: A different view of patients with schizophrenia

After treating patients with schizophrenia for more than 30 years, I’ve observed a continuous flood of information about them. This overload has been consistent since my residency back in the 1980s. Theories ranging from the psychoanalytic to the biologic are numerous and valuable additions to our understanding of those who suffer with this malady, yet they provide no summation or overview with which to understand it.

For instance, we know that schizophrenia usually begins in the late teens or early twenties. We know that antidopaminergic medications usually help to varying degrees. Psychosocial interventions may contribute greatly to the ultimate outcome. Substance use invariably makes it worse. Establishing a connection with the patient can often be helpful. Medication compliance is crucial.

It is more or less accepted that there is deterioration of higher brain functions, hypofrontality, as well as so-called dysconnectivity of white matter. There is a genetic vulnerability, and there seems to be an excess of inflammation and changes in mitochondria. Most patients have low functioning, poor compensation, and a lack of social adeptness. However, some patients can recover quite nicely. Although most of us would agree that this is not dementia, we’d also concede that these patients’ cognitive functioning is not what it used to be. Electroconvulsive therapy also can sometimes be helpful.

So, how are we to view our patients with schizophrenia in a way that can be illuminating and give us a deeper sense of understanding this quizzical disorder? It has been helpful to me to regard these individuals as a people whose brain function has been usurped by a more primitive organization that is characterized by:

• a reduction in mental development, where patients function in a more childlike way with magical thinking and impaired reality-testing
• atrophy of higher brain structures, leading to hallucinatory experiences
• a hyper-dominergic state
• a usually gradual onset with some evidence of struggle between the old and new brain organizations
• impaired prepulse inhibition that’s likely secondary to diffuseness of thought
• eventual demise of higher brain structures with an inability to respond to anti-dopaminergics. (Antipsychotics can push the brain organization closer to the adult structure attained before the onset of the disease, at least initially.)

The list goes on. Thinking about patients with schizophrenia in this way allows me to appreciate what I feel is a more encompassing view of who they are and how they got there. I have some theories about where this more primitive organization may have originated, but whatever its origin, in a small percentage of people it is there, ready to assume control of their thinking just as they are reaching reproductive age. Early intervention and medication compliance may minimize damage.

If a theory helps us gain a greater understanding of our patients, then it’s worth considering. This proposition fits much of what we know about schizophrenia. Reading patients’ firsthand accounts of the illness helps confirm, in my opinion, this point of view.

Steven Lesk, MD
Private psychiatric practice
Fridley, Minnesota

Continue to: Cognitive impairment in schizophrenia

The authors of “Suspicious, sleepless, and smoking” (Cases That Test Your Skills, Current Psychiatry, September 2017, p. 49-50,52-54) assert that “…the severity of cognitive impairment in schizophrenia has no association with the positive symptoms of schizophrenia” and they add, “Treatment of the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.” However, in the case they present, Mr. F appears to demonstrate just the opposite: He is given antipsychotics, and over the course of his hospital stay, both his positive symptoms and his cognition improve. His scores on the Montreal Cognitive Assessment increase from 9 (Day 11) to 15 (Day 16) to 21 (Day 24). Thus, in this particular case, treatment with antipsychotics is clearly associated with cognitive improvement.

During the past 15 years, I have routinely measured cognitive functioning in patients with schizophrenia. Some have no impairment, some have severe impairment, and some fall in between these extremes. Most often, impairment occurs in the area of executive function, which can lead to significant disability. Indeed, positive symptoms can clear up completely with treatment, but the deficits in executive functioning can remain.

I think it is fair to say that cognitive impairment is a common, although not nearly universal, feature of schizophrenia that sometimes improves with antipsychotic medication. I look forward to the advent of more clinicians paying attention to the issue of cognition in schizophrenia and, hopefully, better treatments for it.

John M. Mahoney, PhD
Shasta Psychiatric Hospital
Redding, California

The authors respond

We thank Dr. Mahoney for his thoughtful letter and queries into the case of Mr. F.

First, regarding the prevalence of cognitive impairment in schizophrenia, it is our opinion that cognitive impairment is a distinct, core, and nearly universal feature of schizophrenia. This also is the conclusion of many clinicians and researchers based on their significant work in the field; still, just as in our initial case study, we concede that these symptoms are not part of the DSM-5’s formal diagnostic criteria.

The core question Dr. Mahoney seems to pose is whether we contradicted ourselves. We assert that cognitive impairment in schizophrenia is not effectively treated with existing medications, and yet we described Mr. F’s cognitive improvement after he received risperidone, 2 mg/d, titrated up to 2 mg twice daily. We first pointed out that part of our treatment strategy was to target comorbid depression in this patient; nonetheless, Dr. Mahoney’s question remains valid, and we will attempt to answer.

Dr. Mahoney has observed that his patients with schizophrenia variably experience improved cognition, and notes that executive function is a particularly common lingering impairment. On this we wholly agree; this is a helpful point of clarification, and a useful distinction in light of the above question. Improvement in positive and negative symptoms of schizophrenia, as psychosis resolves, is a well-known and studied effect of antipsychotic therapy. As a result, the sensorium becomes more congruent with external reality, and one would expect the patient to display improved orientation. This then might be reasonably expected to produce mental status improvements; however, while some improvement is frequently observed, this is neither consistent nor complete improvement. In the case of Mr. F, we document improvement, but also significant continued impairment. Thus, we maintain that treating the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.

We do not see this as a slight distinction or an argument of minutiae. That patients frequently experience some degree of lingering impairment is a salient point. Neurocognitive impairment is a strong contributor to and predictor of disability in schizophrenia, and neurocognitive abilities most strongly predict functional outcomes. From a patient’s point of view, these symptoms have real-world consequences. Thus, we believe they should be evaluated and treated as aggressively and consistently as other schizophrenia symptoms.

In our case, we attempted to convey one primary message: Despite the challenges of treatment, there are viable options that should be pursued in the treatment of schizophrenia-related cognitive impairments. Nonpharmacologic modalities have shown encouraging results. Cognitive remediation therapy produces durable cognitive improvement—especially when combined with adjunctive therapies, such as small group therapy and vocational rehabilitation, and when comorbid conditions (major depressive disorder in Mr. F’s case) are treated.

In summary, we reiterate that cognitive impairments in schizophrenia represent a strong predictor of patient-oriented outcomes; we maintain our assertion regarding their inadequate treatment with existing medications; and we suggest that future trials attempt to find effective alternative strategies. We encourage psychiatric clinicians to approach treatment of this facet of pathology with an open mind, and to utilize alternative multi-modal therapies for the benefit of their patients with schizophrenia while waiting for new safe and effective pharmaceutical regimens.

Jarrett Dawson, MD
Family medicine resident
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

Catalina Belean, MD
Assistant Professor
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

The Goldwater Rule and free speech

In his editorial, “The toxic zeitgeist of hyper-partisanship: A psychiatric perspective” (From the Editor, Current Psychiatry, February 2018, p. 17-18), Dr. Nasrallah notes that he “adheres” to the APA’s Goldwater Rule. The Goldwater Rule and the reason for its creation and current implementation in the United States cannot be fully understood without appreciating the political circumstances that led to its creation in 1964. The conservative movement had been using the slogan “better dead than red” to criticize Democrats who they felt were soft on communism. Unfortunately, some psychiatrists took these words and the views of Arizona senator Barry Goldwater quite literally. They claimed they understood his psychological structure by listening to his political views, and feared that he would risk starting a nuclear war. Of course, no psychiatrist actually examined senator Goldwater. During the 1964 presidential campaign, a television commercial from President Lyndon B. Johnson’s campaign included a mushroom cloud of a nuclear explosion with an implicit reference to senator Goldwater and the “better dead than red” slogan. In the end, psychiatry, and particularly psychoanalysis, as well as President Johnson’s campaign, were embarrassed.

One’s political views do not inform us of his or her mental health status. This appreciation can be obtained only by a thorough psychological assessment. This is the basis of the Goldwater Rule, coupled with the ethical responsibility not to discuss patients’ private communications.

Today, this rule is tested by the behavior and actions of President Donald Trump. Proponents of the Goldwater Rule state that a psychiatrist cannot diagnose someone without performing a face-to-face diagnostic evaluation. This assumes psychiatrists diagnose patients only by interviewing them. However, any psychiatrist who has worked in an emergency room has signed involuntary commitment papers for a patient who refuses to talk to them. This clinical action typically is based on reports of the patient’s potential dangerousness from family, friends, or the police.

The diagnostic criteria for some personality disorders are based only on observed or reported behavior. They do not indicate a need for an interview.  The diagnosis of a personality disorder cannot be made solely by interviewing an individual without knowledge of his or her behavior. Interviewing Bernie Madoff would not have revealed his sociopathic behavior.

The critical question may not be whether one could ethically make a psychiatric diagnosis of the President (I believe you can), but rather would it indicate or imply that he is dangerous? History informs us that the existence of a psychiatric disorder does not determine a politician’s fitness for office or if they are dangerous. Behavioral accounts of President Abraham Lincoln and his self-reports seem to confirm that at times he was depressed, but he clearly served our country with distinction.

Finally, it is not clear whether the Goldwater Rule is legal. It arguably interferes with a psychiatrist’s right of free speech without the risk of being accused of unethical behavior. I wonder what would happen if it were tested in court. Does the First Amendment of the U.S. Constitution protect a psychiatrist’s right to speak freely?

Sidney Weissman, MD
Clinical Professor of Psychiatry and Behavioral Science
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

The current ‘political morass’

Thank you, Dr. Nasrallah, for the wonderful synopsis of the current political morass in your editorial (From the Editor, Current Psychiatry, February 2018, p. 17-18). You followed Descartes’ dictum: you thought about matters in a novel fashion. I will assertively share this with others. It is a good piece of teaching.

James Gallagher, MD
Private psychiatric practice
Des Moines, Iowa

Continue to: The biological etiology of compulsive sexual behavior

Dr. Grant’s article, “Compulsive sexual behavior: A nonjudgmental approach” (Evidence-Based Reviews, Current Psychiatry, February 2018, p. 34,38-40,45-46), puts a well-deserved spotlight on a relatively underrecognized problem that most psychiatrists will encounter at least once during clinical practice. While the article is overall helpful, it completely leaves out any possible biological etiology and underpinnings to the condition that may be important to address while evaluating someone with compulsive sexual behavior. Specifically, are there any endocrine issues that should be considered that may also impact our approach to its treatment?

Mukesh Sanghadia, MD, MRCPsych (UK), Diplomate ABPN
PsychiatristCommunity Research Foundation
San Diego, California

The author responds

Dr. Sanghadia highlights the lack of possible biological etiology of compulsive sexual behavior (CSB) in my article. This is a fair comment. The lack of agreed-upon diagnostic criteria, however, has resulted in a vast literature discussing sexual behaviors that may or may not be related to each other, and even suggest that what is currently referred to as CSB may in fact be quite heterogeneous. My article mentions the few neuroimaging and neurocognitive studies that address a more rigorously defined CSB. Other possible etiologies have been suggested for a range of out-of-control sexual behaviors, but have not been studied with a focus on this formal diagnostic category. For example, endocrine issues have been explored to some extent in individuals with paraphilic sexual behaviors (behaviors that appear to many to have no relationship to CSB as discussed in my article), and in those cases of paraphilic sexual behavior, a range of endocrine hormones have been examined—gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone. But these studies have yielded no conclusive outcomes in terms of findings or treatments.

In summary, the biology of CSB lags far behind that of other mental health disorders (and even other psychiatric disorders lack conclusive biological etiologies). Establishing this behavior as a legitimate diagnostic entity with agreed-upon criteria may be the first step in furthering our understanding of its possible biology.

Jon E. Grant, JD, MD, MPH
Professor
Department of Psychiatry and Behavioral Neuroscience
University of Chicago, Pritzker School of Medicine
Chicago, Illinois

Continue to: A different view of patients with schizophrenia

After treating patients with schizophrenia for more than 30 years, I’ve observed a continuous flood of information about them. This overload has been consistent since my residency back in the 1980s. Theories ranging from the psychoanalytic to the biologic are numerous and valuable additions to our understanding of those who suffer with this malady, yet they provide no summation or overview with which to understand it.

For instance, we know that schizophrenia usually begins in the late teens or early twenties. We know that antidopaminergic medications usually help to varying degrees. Psychosocial interventions may contribute greatly to the ultimate outcome. Substance use invariably makes it worse. Establishing a connection with the patient can often be helpful. Medication compliance is crucial.

It is more or less accepted that there is deterioration of higher brain functions, hypofrontality, as well as so-called dysconnectivity of white matter. There is a genetic vulnerability, and there seems to be an excess of inflammation and changes in mitochondria. Most patients have low functioning, poor compensation, and a lack of social adeptness. However, some patients can recover quite nicely. Although most of us would agree that this is not dementia, we’d also concede that these patients’ cognitive functioning is not what it used to be. Electroconvulsive therapy also can sometimes be helpful.

So, how are we to view our patients with schizophrenia in a way that can be illuminating and give us a deeper sense of understanding this quizzical disorder? It has been helpful to me to regard these individuals as a people whose brain function has been usurped by a more primitive organization that is characterized by:

• a reduction in mental development, where patients function in a more childlike way with magical thinking and impaired reality-testing
• atrophy of higher brain structures, leading to hallucinatory experiences
• a hyper-dominergic state
• a usually gradual onset with some evidence of struggle between the old and new brain organizations
• impaired prepulse inhibition that’s likely secondary to diffuseness of thought
• eventual demise of higher brain structures with an inability to respond to anti-dopaminergics. (Antipsychotics can push the brain organization closer to the adult structure attained before the onset of the disease, at least initially.)

The list goes on. Thinking about patients with schizophrenia in this way allows me to appreciate what I feel is a more encompassing view of who they are and how they got there. I have some theories about where this more primitive organization may have originated, but whatever its origin, in a small percentage of people it is there, ready to assume control of their thinking just as they are reaching reproductive age. Early intervention and medication compliance may minimize damage.

If a theory helps us gain a greater understanding of our patients, then it’s worth considering. This proposition fits much of what we know about schizophrenia. Reading patients’ firsthand accounts of the illness helps confirm, in my opinion, this point of view.

Steven Lesk, MD
Private psychiatric practice
Fridley, Minnesota

Continue to: Cognitive impairment in schizophrenia

The authors of “Suspicious, sleepless, and smoking” (Cases That Test Your Skills, Current Psychiatry, September 2017, p. 49-50,52-54) assert that “…the severity of cognitive impairment in schizophrenia has no association with the positive symptoms of schizophrenia” and they add, “Treatment of the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.” However, in the case they present, Mr. F appears to demonstrate just the opposite: He is given antipsychotics, and over the course of his hospital stay, both his positive symptoms and his cognition improve. His scores on the Montreal Cognitive Assessment increase from 9 (Day 11) to 15 (Day 16) to 21 (Day 24). Thus, in this particular case, treatment with antipsychotics is clearly associated with cognitive improvement.

During the past 15 years, I have routinely measured cognitive functioning in patients with schizophrenia. Some have no impairment, some have severe impairment, and some fall in between these extremes. Most often, impairment occurs in the area of executive function, which can lead to significant disability. Indeed, positive symptoms can clear up completely with treatment, but the deficits in executive functioning can remain.

I think it is fair to say that cognitive impairment is a common, although not nearly universal, feature of schizophrenia that sometimes improves with antipsychotic medication. I look forward to the advent of more clinicians paying attention to the issue of cognition in schizophrenia and, hopefully, better treatments for it.

John M. Mahoney, PhD
Shasta Psychiatric Hospital
Redding, California

The authors respond

We thank Dr. Mahoney for his thoughtful letter and queries into the case of Mr. F.

First, regarding the prevalence of cognitive impairment in schizophrenia, it is our opinion that cognitive impairment is a distinct, core, and nearly universal feature of schizophrenia. This also is the conclusion of many clinicians and researchers based on their significant work in the field; still, just as in our initial case study, we concede that these symptoms are not part of the DSM-5’s formal diagnostic criteria.

The core question Dr. Mahoney seems to pose is whether we contradicted ourselves. We assert that cognitive impairment in schizophrenia is not effectively treated with existing medications, and yet we described Mr. F’s cognitive improvement after he received risperidone, 2 mg/d, titrated up to 2 mg twice daily. We first pointed out that part of our treatment strategy was to target comorbid depression in this patient; nonetheless, Dr. Mahoney’s question remains valid, and we will attempt to answer.

Dr. Mahoney has observed that his patients with schizophrenia variably experience improved cognition, and notes that executive function is a particularly common lingering impairment. On this we wholly agree; this is a helpful point of clarification, and a useful distinction in light of the above question. Improvement in positive and negative symptoms of schizophrenia, as psychosis resolves, is a well-known and studied effect of antipsychotic therapy. As a result, the sensorium becomes more congruent with external reality, and one would expect the patient to display improved orientation. This then might be reasonably expected to produce mental status improvements; however, while some improvement is frequently observed, this is neither consistent nor complete improvement. In the case of Mr. F, we document improvement, but also significant continued impairment. Thus, we maintain that treating the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.

We do not see this as a slight distinction or an argument of minutiae. That patients frequently experience some degree of lingering impairment is a salient point. Neurocognitive impairment is a strong contributor to and predictor of disability in schizophrenia, and neurocognitive abilities most strongly predict functional outcomes. From a patient’s point of view, these symptoms have real-world consequences. Thus, we believe they should be evaluated and treated as aggressively and consistently as other schizophrenia symptoms.

In our case, we attempted to convey one primary message: Despite the challenges of treatment, there are viable options that should be pursued in the treatment of schizophrenia-related cognitive impairments. Nonpharmacologic modalities have shown encouraging results. Cognitive remediation therapy produces durable cognitive improvement—especially when combined with adjunctive therapies, such as small group therapy and vocational rehabilitation, and when comorbid conditions (major depressive disorder in Mr. F’s case) are treated.

In summary, we reiterate that cognitive impairments in schizophrenia represent a strong predictor of patient-oriented outcomes; we maintain our assertion regarding their inadequate treatment with existing medications; and we suggest that future trials attempt to find effective alternative strategies. We encourage psychiatric clinicians to approach treatment of this facet of pathology with an open mind, and to utilize alternative multi-modal therapies for the benefit of their patients with schizophrenia while waiting for new safe and effective pharmaceutical regimens.

Jarrett Dawson, MD
Family medicine resident
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

Catalina Belean, MD
Assistant Professor
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

The Goldwater Rule and free speech

In his editorial, “The toxic zeitgeist of hyper-partisanship: A psychiatric perspective” (From the Editor, Current Psychiatry, February 2018, p. 17-18), Dr. Nasrallah notes that he “adheres” to the APA’s Goldwater Rule. The Goldwater Rule and the reason for its creation and current implementation in the United States cannot be fully understood without appreciating the political circumstances that led to its creation in 1964. The conservative movement had been using the slogan “better dead than red” to criticize Democrats who they felt were soft on communism. Unfortunately, some psychiatrists took these words and the views of Arizona senator Barry Goldwater quite literally. They claimed they understood his psychological structure by listening to his political views, and feared that he would risk starting a nuclear war. Of course, no psychiatrist actually examined senator Goldwater. During the 1964 presidential campaign, a television commercial from President Lyndon B. Johnson’s campaign included a mushroom cloud of a nuclear explosion with an implicit reference to senator Goldwater and the “better dead than red” slogan. In the end, psychiatry, and particularly psychoanalysis, as well as President Johnson’s campaign, were embarrassed.

One’s political views do not inform us of his or her mental health status. This appreciation can be obtained only by a thorough psychological assessment. This is the basis of the Goldwater Rule, coupled with the ethical responsibility not to discuss patients’ private communications.

Today, this rule is tested by the behavior and actions of President Donald Trump. Proponents of the Goldwater Rule state that a psychiatrist cannot diagnose someone without performing a face-to-face diagnostic evaluation. This assumes psychiatrists diagnose patients only by interviewing them. However, any psychiatrist who has worked in an emergency room has signed involuntary commitment papers for a patient who refuses to talk to them. This clinical action typically is based on reports of the patient’s potential dangerousness from family, friends, or the police.

The diagnostic criteria for some personality disorders are based only on observed or reported behavior. They do not indicate a need for an interview.  The diagnosis of a personality disorder cannot be made solely by interviewing an individual without knowledge of his or her behavior. Interviewing Bernie Madoff would not have revealed his sociopathic behavior.

The critical question may not be whether one could ethically make a psychiatric diagnosis of the President (I believe you can), but rather would it indicate or imply that he is dangerous? History informs us that the existence of a psychiatric disorder does not determine a politician’s fitness for office or if they are dangerous. Behavioral accounts of President Abraham Lincoln and his self-reports seem to confirm that at times he was depressed, but he clearly served our country with distinction.

Finally, it is not clear whether the Goldwater Rule is legal. It arguably interferes with a psychiatrist’s right of free speech without the risk of being accused of unethical behavior. I wonder what would happen if it were tested in court. Does the First Amendment of the U.S. Constitution protect a psychiatrist’s right to speak freely?

Sidney Weissman, MD
Clinical Professor of Psychiatry and Behavioral Science
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

The current ‘political morass’

Thank you, Dr. Nasrallah, for the wonderful synopsis of the current political morass in your editorial (From the Editor, Current Psychiatry, February 2018, p. 17-18). You followed Descartes’ dictum: you thought about matters in a novel fashion. I will assertively share this with others. It is a good piece of teaching.

James Gallagher, MD
Private psychiatric practice
Des Moines, Iowa

Continue to: The biological etiology of compulsive sexual behavior

Dr. Grant’s article, “Compulsive sexual behavior: A nonjudgmental approach” (Evidence-Based Reviews, Current Psychiatry, February 2018, p. 34,38-40,45-46), puts a well-deserved spotlight on a relatively underrecognized problem that most psychiatrists will encounter at least once during clinical practice. While the article is overall helpful, it completely leaves out any possible biological etiology and underpinnings to the condition that may be important to address while evaluating someone with compulsive sexual behavior. Specifically, are there any endocrine issues that should be considered that may also impact our approach to its treatment?

Mukesh Sanghadia, MD, MRCPsych (UK), Diplomate ABPN
PsychiatristCommunity Research Foundation
San Diego, California

The author responds

Dr. Sanghadia highlights the lack of possible biological etiology of compulsive sexual behavior (CSB) in my article. This is a fair comment. The lack of agreed-upon diagnostic criteria, however, has resulted in a vast literature discussing sexual behaviors that may or may not be related to each other, and even suggest that what is currently referred to as CSB may in fact be quite heterogeneous. My article mentions the few neuroimaging and neurocognitive studies that address a more rigorously defined CSB. Other possible etiologies have been suggested for a range of out-of-control sexual behaviors, but have not been studied with a focus on this formal diagnostic category. For example, endocrine issues have been explored to some extent in individuals with paraphilic sexual behaviors (behaviors that appear to many to have no relationship to CSB as discussed in my article), and in those cases of paraphilic sexual behavior, a range of endocrine hormones have been examined—gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone. But these studies have yielded no conclusive outcomes in terms of findings or treatments.

In summary, the biology of CSB lags far behind that of other mental health disorders (and even other psychiatric disorders lack conclusive biological etiologies). Establishing this behavior as a legitimate diagnostic entity with agreed-upon criteria may be the first step in furthering our understanding of its possible biology.

Jon E. Grant, JD, MD, MPH
Professor
Department of Psychiatry and Behavioral Neuroscience
University of Chicago, Pritzker School of Medicine
Chicago, Illinois

Continue to: A different view of patients with schizophrenia

After treating patients with schizophrenia for more than 30 years, I’ve observed a continuous flood of information about them. This overload has been consistent since my residency back in the 1980s. Theories ranging from the psychoanalytic to the biologic are numerous and valuable additions to our understanding of those who suffer with this malady, yet they provide no summation or overview with which to understand it.

For instance, we know that schizophrenia usually begins in the late teens or early twenties. We know that antidopaminergic medications usually help to varying degrees. Psychosocial interventions may contribute greatly to the ultimate outcome. Substance use invariably makes it worse. Establishing a connection with the patient can often be helpful. Medication compliance is crucial.

It is more or less accepted that there is deterioration of higher brain functions, hypofrontality, as well as so-called dysconnectivity of white matter. There is a genetic vulnerability, and there seems to be an excess of inflammation and changes in mitochondria. Most patients have low functioning, poor compensation, and a lack of social adeptness. However, some patients can recover quite nicely. Although most of us would agree that this is not dementia, we’d also concede that these patients’ cognitive functioning is not what it used to be. Electroconvulsive therapy also can sometimes be helpful.

So, how are we to view our patients with schizophrenia in a way that can be illuminating and give us a deeper sense of understanding this quizzical disorder? It has been helpful to me to regard these individuals as a people whose brain function has been usurped by a more primitive organization that is characterized by:

• a reduction in mental development, where patients function in a more childlike way with magical thinking and impaired reality-testing
• atrophy of higher brain structures, leading to hallucinatory experiences
• a hyper-dominergic state
• a usually gradual onset with some evidence of struggle between the old and new brain organizations
• impaired prepulse inhibition that’s likely secondary to diffuseness of thought
• eventual demise of higher brain structures with an inability to respond to anti-dopaminergics. (Antipsychotics can push the brain organization closer to the adult structure attained before the onset of the disease, at least initially.)

The list goes on. Thinking about patients with schizophrenia in this way allows me to appreciate what I feel is a more encompassing view of who they are and how they got there. I have some theories about where this more primitive organization may have originated, but whatever its origin, in a small percentage of people it is there, ready to assume control of their thinking just as they are reaching reproductive age. Early intervention and medication compliance may minimize damage.

If a theory helps us gain a greater understanding of our patients, then it’s worth considering. This proposition fits much of what we know about schizophrenia. Reading patients’ firsthand accounts of the illness helps confirm, in my opinion, this point of view.

Steven Lesk, MD
Private psychiatric practice
Fridley, Minnesota

Continue to: Cognitive impairment in schizophrenia

The authors of “Suspicious, sleepless, and smoking” (Cases That Test Your Skills, Current Psychiatry, September 2017, p. 49-50,52-54) assert that “…the severity of cognitive impairment in schizophrenia has no association with the positive symptoms of schizophrenia” and they add, “Treatment of the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.” However, in the case they present, Mr. F appears to demonstrate just the opposite: He is given antipsychotics, and over the course of his hospital stay, both his positive symptoms and his cognition improve. His scores on the Montreal Cognitive Assessment increase from 9 (Day 11) to 15 (Day 16) to 21 (Day 24). Thus, in this particular case, treatment with antipsychotics is clearly associated with cognitive improvement.

During the past 15 years, I have routinely measured cognitive functioning in patients with schizophrenia. Some have no impairment, some have severe impairment, and some fall in between these extremes. Most often, impairment occurs in the area of executive function, which can lead to significant disability. Indeed, positive symptoms can clear up completely with treatment, but the deficits in executive functioning can remain.

I think it is fair to say that cognitive impairment is a common, although not nearly universal, feature of schizophrenia that sometimes improves with antipsychotic medication. I look forward to the advent of more clinicians paying attention to the issue of cognition in schizophrenia and, hopefully, better treatments for it.

John M. Mahoney, PhD
Shasta Psychiatric Hospital
Redding, California

The authors respond

We thank Dr. Mahoney for his thoughtful letter and queries into the case of Mr. F.

First, regarding the prevalence of cognitive impairment in schizophrenia, it is our opinion that cognitive impairment is a distinct, core, and nearly universal feature of schizophrenia. This also is the conclusion of many clinicians and researchers based on their significant work in the field; still, just as in our initial case study, we concede that these symptoms are not part of the DSM-5’s formal diagnostic criteria.

The core question Dr. Mahoney seems to pose is whether we contradicted ourselves. We assert that cognitive impairment in schizophrenia is not effectively treated with existing medications, and yet we described Mr. F’s cognitive improvement after he received risperidone, 2 mg/d, titrated up to 2 mg twice daily. We first pointed out that part of our treatment strategy was to target comorbid depression in this patient; nonetheless, Dr. Mahoney’s question remains valid, and we will attempt to answer.

Dr. Mahoney has observed that his patients with schizophrenia variably experience improved cognition, and notes that executive function is a particularly common lingering impairment. On this we wholly agree; this is a helpful point of clarification, and a useful distinction in light of the above question. Improvement in positive and negative symptoms of schizophrenia, as psychosis resolves, is a well-known and studied effect of antipsychotic therapy. As a result, the sensorium becomes more congruent with external reality, and one would expect the patient to display improved orientation. This then might be reasonably expected to produce mental status improvements; however, while some improvement is frequently observed, this is neither consistent nor complete improvement. In the case of Mr. F, we document improvement, but also significant continued impairment. Thus, we maintain that treating the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.

We do not see this as a slight distinction or an argument of minutiae. That patients frequently experience some degree of lingering impairment is a salient point. Neurocognitive impairment is a strong contributor to and predictor of disability in schizophrenia, and neurocognitive abilities most strongly predict functional outcomes. From a patient’s point of view, these symptoms have real-world consequences. Thus, we believe they should be evaluated and treated as aggressively and consistently as other schizophrenia symptoms.

In our case, we attempted to convey one primary message: Despite the challenges of treatment, there are viable options that should be pursued in the treatment of schizophrenia-related cognitive impairments. Nonpharmacologic modalities have shown encouraging results. Cognitive remediation therapy produces durable cognitive improvement—especially when combined with adjunctive therapies, such as small group therapy and vocational rehabilitation, and when comorbid conditions (major depressive disorder in Mr. F’s case) are treated.

In summary, we reiterate that cognitive impairments in schizophrenia represent a strong predictor of patient-oriented outcomes; we maintain our assertion regarding their inadequate treatment with existing medications; and we suggest that future trials attempt to find effective alternative strategies. We encourage psychiatric clinicians to approach treatment of this facet of pathology with an open mind, and to utilize alternative multi-modal therapies for the benefit of their patients with schizophrenia while waiting for new safe and effective pharmaceutical regimens.

Jarrett Dawson, MD
Family medicine resident
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

Catalina Belean, MD
Assistant Professor
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

CASE Worsening outbursts and emotional lability

Mr. X, age 16, has cerebral palsy (CP), idiopathic normal pressure hydrocephalus (iNPH), and a history of impulse control disorder and behavioral instability, including episodes of aggression or combativeness. Mr. X’s mother reports that these episodes are almost always preceded by inappropriate laughing or crying. His outbursts and emotional lability have gotten worse during the last 6 months. Due to his disruptive behaviors, Mr. X has been unable to attend school, and his parents are considering group home placement. Although they were previously able to control their son’s aggressive behaviors, they fear for his safety, and after one such episode, they call 911. Mr. X is transported by police in handcuffs to the comprehensive psychiatric emergency room (CPEP) for evaluation.

While in CPEP, Mr. X remains uncooperative and disruptive; subsequently, he is placed in 4-point restraints and given haloperidol, 10 mg IM, and lorazepam, 2 mg IM, to prevent harm to himself or others. After 2 hours, he is unable to maintain a reality-based conversation but has become semi-cooperative. Mr. X’s mother decides to take him home and immediately makes an appointment with his outpatient psychiatrist.

[polldaddy:9991896]

The authors’ observations

Pseudobulbar affect (PBA) is a disorder characterized by sporadic episodes of inappropriate laughing and/or crying that are incongruent with situational context and are frequently exaggerated in comparison with the actual feelings of the patient. The duration of PBA episodes can last seconds to minutes and arise unpredictably.

PBA typically develops secondary to a neurologic disorder, most commonly Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), stroke, or traumatic brain injury (TBI).¹ PBA symptoms are present in an estimated 29.3% of patients with AD, 44.8% of patients with ALS, 45.8% of patients with MS, 26% of patients with PD, 37.8% of patients with stroke, and 52.4% of patients with TBI.² Although PBA appears far more frequently in patients with MS or ALS compared with those with PD, PD represents an under-recognized and larger patient population. A small fraction of patients also develops PBA secondary to hyperthyroidism, hypothyroidism, Graves’ disease, Wilson’s disease, brain tumors, and a multitude of encephalopathies.³ These neurologic disorders cause dysregulation of the corticopontine-cerebellar circuitry, resulting in functional impediment to the normal affect modulator action of the cerebellum.⁴

The neurologic insults that can result in PBA may include CP or iNPH. Cerebellar injury is a frequent pathological finding in CP.⁵ In patients with iNPH, in addition to altered CSF flow, enlarged ventricles compress the corticospinal tracts in the lateral ventricles,⁶ which is theorized to induce PBA symptoms.

PBA is diagnosed by subjective clinical evaluation and by using the Center for Neurologic Study–Lability Scale (CNS-LS). The CNS-LS is a 7-question survey that addresses the severity of affect lability (Table 1⁷). It may be completed by the patient or caregiver. Each question ranges in score from 1 to 5, with the total score ranging from 7 to 35. The minimum score required for the diagnosis of PBA is 13.⁷

PBA is frequently misdiagnosed as depression, although the 2 disorders can occur simultaneously (Table 2^1,8). A crucial distinguishing factor between depression and PBA is the extent of symptoms. Depression presents as feelings of sadness associated with crying and disinterest that occur for weeks to months. In contrast, PBA presents as brief, uncontrollable episodes of laughing and/or crying that last seconds to minutes. Unlike depression, the behaviors associated with PBA are exaggerated or do not match the patient’s feelings. Furthermore, a neurologic disease or brain injury is always present in a patient with PBA, but is not imperative for the diagnosis of depression.

Continue to: Compared with individuals without PBA...

Compared with individuals without PBA, patients with PBA also experience more distress, embarrassment, and social disability, and are consequently more likely to suffer from other psychiatric conditions, including depression, anxiety/panic attacks, bipolar disorder, posttraumatic stress disorder, psychotic disorder, and schizophrenia.¹ The Patient Health Questionnaire (PHQ-9), a tool for measuring depression severity, can be used in addition to the CNS-LS to determine if the patient has both depression and PBA.

HISTORY Poor response to anxiolytics and antipsychotics

Mr. X previously received a ventriculoperitoneal shunt for treating iNPH. He was not taking any medications for CP. To address his impulse control disorder, he was prescribed olanzapine, 20 mg/d, risperidone, 2 mg/d, and diazepam, 5 mg three times a day. Mr. X is uncontrolled on these medications, experiencing frequent behavioral outbursts at home. His mother completes a CNS-LS for him. He receives a score of 20, which suggests a diagnosis of PBA. His PHQ-9 score is 8, indicating mild depression.

[polldaddy:9991899]

TREATMENT Introducing a new medication

Mr. X is started on dextromethorphan/quinidine, 20/10 mg twice a day. His diazepam is reduced from 5 mg three times a day to 5 mg twice a day, his risperidone is continued at 2 mg/d, olanzapine is maintained at 20 mg/d, and he is scheduled for a 1-month follow-up visit. At the 1-month follow-up visit, Mr. X’s parents report a drastic reduction in their son’s aggressive outbursts and mood swings within the first week of starting dextromethorphan/quinidine. His PHQ-9 scale score is reduced to 0, CNS-LS scale score is reduced to 5, and Mr. X reports “100% improvement.” Due to the robust response to dextromethorphan/quinidine, he is weaned off risperidone.

Continue to: The authors' observations

Decreasing the severity and frequency of episodes constitutes the mainstay of treating PBA. In the past, off-label treatments, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, were prescribed to reduce PBA symptoms.⁵ Currently, dextromethorphan/quinidine is the only FDA-approved medication for treating PBA; however, its use in patients younger than age 18 is considered investigational.

Dextromethorphan/quinidine contains 20 mg of dextromethorphan hydrobromide, the pharmacologically active component of the medication via cytochrome P450 (CYP) 2D6, and 10 mg of quinidine sulfate, which increases the systemic bioavailability of dextromethorphan via CYP2D6 inhibition. The most common adverse effects associated with dextromethorphan/quinidine are dizziness, nausea, and diarrhea.⁹

Atypical antipsychotics, such as olanzapine and risperidone, have more warnings and precautions than dextromethorphan/quinidine. Risperidone has a “black-box” warning for QT prolongation, in addition to death and stroke in elderly patients.¹⁰ Although dextromethorphan/quinidine does not have a black-box warning, it does increase the risk of QT prolongation, and patients with cardiac risk factors should undergo an electrocardiogram before starting this medication. Additionally, risperidone and olanzapine are known to cause significant weight gain, which can increase the risk of developing hyperlipidemia, metabolic syndrome, and type 2 diabetes mellitus.^10,11 Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of all antipsychotics. NMS is characterized by fever, rigidity, altered consciousness, and increased heart and respiratory rates.¹²

Quinidine increases the bioavailability of dextromethorphan by inhibiting CYP2D6. When dextromethorphan/quinidine is simultaneously used with an SSRI that also inhibits CYP2D6, such as paroxetine or fluoxetine, the patient may be at increased risk for developing adverse effects such as respiratory depression and serotonin syndrome.¹³

[polldaddy:9991902]

Continue to: The authors' observations

Although the exact pathophysiology of PBA is unknown, multiple theories may explain the principle elements of the condition. In the absence of a neurologic insult, the cerebellum acts as an affect regulator, inhibiting laughter and crying at times in which they are considered inappropriate. Parvizi et al⁴ have theorized that the lesions involved in PBA disrupt the corticopontine-cerebellar circuitry, which impedes the ability of the cerebellum to function as an affect modulator.³ In addition to the dysregulation of cerebellar circuitry, altered serotonin and glutamate levels are believed to contribute to the deficient affect regulation observed in PBA; therefore, adding dextromethorphan/quinidine potentiates serotonin and glutamate levels in the synaptic cleft, resulting in a reduction in PBA episodes.⁴

OUTCOME Affect stability

Seven months after beginning dextromethorphan/quinidine, Mr. X has experienced resolution of his PBA episodes. His PHQ-9 score was reduced to 0 (no clinical signs of depression) within 1 month of starting this medication and his PHQ-9 scores remain below 5, representing minimal depressive severity. The CNS-LS scale is not conducted at further visits because the patient’s mother reported no further PBA episodes. Mr. X no longer exhibits episodes of aggression. These episodes seemed to have been a manifestation of his frustration and difficulty in controlling his PBA episodes. Furthermore, his dosage of diazepam was reduced, and he was weaned off risperidone. Mr. X’s parents report that he has a drastically improved affect. He continues to tolerate his medication well and no longer demonstrates any exacerbations of his psychiatric symptoms.

Bottom Line

Pseudobulbar affect (PBA) may occur secondary to various neurologic insults, including cerebral palsy and idiopathic normal pressure hydrocephalus. The condition is diagnosed by a subjective clinical evaluation and use of the Center for Neurologic Study–Lability Scale. Dextromethorphan/quinidine can significantly reduce PBA symptoms.

Acknowledgements

The authors thank Anthony S. Graziano and Rachel M. Watt, both Physician Assistant students, Daemen College, Amherst, New York.

Related Resources

• Frock B, Williams A, Caplan JP. Pseudobulbar affect: when patients laugh or cry, but don’t know why. Current Psychiatry. 2016;15(9):56-60,63.
• Crumpacker DW. Enhancing approaches to the identification and management of pseudobulbar affect. J Clin Psychiatry. 2016;77(9):e1155.

Drug Brand Names

Dextromethorphan/quinidine • Nuedexta
Diazepam • Valium
Fluoxetine • Prozac
Haloperidol • Haldol
Lorazepam • Ativan
Olanzapine • Zyprexa
Paroxetine • Paxil
Risperidone • Risperdal

CASE Worsening outbursts and emotional lability

Mr. X, age 16, has cerebral palsy (CP), idiopathic normal pressure hydrocephalus (iNPH), and a history of impulse control disorder and behavioral instability, including episodes of aggression or combativeness. Mr. X’s mother reports that these episodes are almost always preceded by inappropriate laughing or crying. His outbursts and emotional lability have gotten worse during the last 6 months. Due to his disruptive behaviors, Mr. X has been unable to attend school, and his parents are considering group home placement. Although they were previously able to control their son’s aggressive behaviors, they fear for his safety, and after one such episode, they call 911. Mr. X is transported by police in handcuffs to the comprehensive psychiatric emergency room (CPEP) for evaluation.

While in CPEP, Mr. X remains uncooperative and disruptive; subsequently, he is placed in 4-point restraints and given haloperidol, 10 mg IM, and lorazepam, 2 mg IM, to prevent harm to himself or others. After 2 hours, he is unable to maintain a reality-based conversation but has become semi-cooperative. Mr. X’s mother decides to take him home and immediately makes an appointment with his outpatient psychiatrist.

[polldaddy:9991896]

The authors’ observations

Pseudobulbar affect (PBA) is a disorder characterized by sporadic episodes of inappropriate laughing and/or crying that are incongruent with situational context and are frequently exaggerated in comparison with the actual feelings of the patient. The duration of PBA episodes can last seconds to minutes and arise unpredictably.

PBA typically develops secondary to a neurologic disorder, most commonly Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), stroke, or traumatic brain injury (TBI).¹ PBA symptoms are present in an estimated 29.3% of patients with AD, 44.8% of patients with ALS, 45.8% of patients with MS, 26% of patients with PD, 37.8% of patients with stroke, and 52.4% of patients with TBI.² Although PBA appears far more frequently in patients with MS or ALS compared with those with PD, PD represents an under-recognized and larger patient population. A small fraction of patients also develops PBA secondary to hyperthyroidism, hypothyroidism, Graves’ disease, Wilson’s disease, brain tumors, and a multitude of encephalopathies.³ These neurologic disorders cause dysregulation of the corticopontine-cerebellar circuitry, resulting in functional impediment to the normal affect modulator action of the cerebellum.⁴

The neurologic insults that can result in PBA may include CP or iNPH. Cerebellar injury is a frequent pathological finding in CP.⁵ In patients with iNPH, in addition to altered CSF flow, enlarged ventricles compress the corticospinal tracts in the lateral ventricles,⁶ which is theorized to induce PBA symptoms.

PBA is diagnosed by subjective clinical evaluation and by using the Center for Neurologic Study–Lability Scale (CNS-LS). The CNS-LS is a 7-question survey that addresses the severity of affect lability (Table 1⁷). It may be completed by the patient or caregiver. Each question ranges in score from 1 to 5, with the total score ranging from 7 to 35. The minimum score required for the diagnosis of PBA is 13.⁷

PBA is frequently misdiagnosed as depression, although the 2 disorders can occur simultaneously (Table 2^1,8). A crucial distinguishing factor between depression and PBA is the extent of symptoms. Depression presents as feelings of sadness associated with crying and disinterest that occur for weeks to months. In contrast, PBA presents as brief, uncontrollable episodes of laughing and/or crying that last seconds to minutes. Unlike depression, the behaviors associated with PBA are exaggerated or do not match the patient’s feelings. Furthermore, a neurologic disease or brain injury is always present in a patient with PBA, but is not imperative for the diagnosis of depression.

Continue to: Compared with individuals without PBA...

Compared with individuals without PBA, patients with PBA also experience more distress, embarrassment, and social disability, and are consequently more likely to suffer from other psychiatric conditions, including depression, anxiety/panic attacks, bipolar disorder, posttraumatic stress disorder, psychotic disorder, and schizophrenia.¹ The Patient Health Questionnaire (PHQ-9), a tool for measuring depression severity, can be used in addition to the CNS-LS to determine if the patient has both depression and PBA.

HISTORY Poor response to anxiolytics and antipsychotics

Mr. X previously received a ventriculoperitoneal shunt for treating iNPH. He was not taking any medications for CP. To address his impulse control disorder, he was prescribed olanzapine, 20 mg/d, risperidone, 2 mg/d, and diazepam, 5 mg three times a day. Mr. X is uncontrolled on these medications, experiencing frequent behavioral outbursts at home. His mother completes a CNS-LS for him. He receives a score of 20, which suggests a diagnosis of PBA. His PHQ-9 score is 8, indicating mild depression.

[polldaddy:9991899]

TREATMENT Introducing a new medication

Mr. X is started on dextromethorphan/quinidine, 20/10 mg twice a day. His diazepam is reduced from 5 mg three times a day to 5 mg twice a day, his risperidone is continued at 2 mg/d, olanzapine is maintained at 20 mg/d, and he is scheduled for a 1-month follow-up visit. At the 1-month follow-up visit, Mr. X’s parents report a drastic reduction in their son’s aggressive outbursts and mood swings within the first week of starting dextromethorphan/quinidine. His PHQ-9 scale score is reduced to 0, CNS-LS scale score is reduced to 5, and Mr. X reports “100% improvement.” Due to the robust response to dextromethorphan/quinidine, he is weaned off risperidone.

Continue to: The authors' observations

Decreasing the severity and frequency of episodes constitutes the mainstay of treating PBA. In the past, off-label treatments, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, were prescribed to reduce PBA symptoms.⁵ Currently, dextromethorphan/quinidine is the only FDA-approved medication for treating PBA; however, its use in patients younger than age 18 is considered investigational.

Dextromethorphan/quinidine contains 20 mg of dextromethorphan hydrobromide, the pharmacologically active component of the medication via cytochrome P450 (CYP) 2D6, and 10 mg of quinidine sulfate, which increases the systemic bioavailability of dextromethorphan via CYP2D6 inhibition. The most common adverse effects associated with dextromethorphan/quinidine are dizziness, nausea, and diarrhea.⁹

Atypical antipsychotics, such as olanzapine and risperidone, have more warnings and precautions than dextromethorphan/quinidine. Risperidone has a “black-box” warning for QT prolongation, in addition to death and stroke in elderly patients.¹⁰ Although dextromethorphan/quinidine does not have a black-box warning, it does increase the risk of QT prolongation, and patients with cardiac risk factors should undergo an electrocardiogram before starting this medication. Additionally, risperidone and olanzapine are known to cause significant weight gain, which can increase the risk of developing hyperlipidemia, metabolic syndrome, and type 2 diabetes mellitus.^10,11 Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of all antipsychotics. NMS is characterized by fever, rigidity, altered consciousness, and increased heart and respiratory rates.¹²

Quinidine increases the bioavailability of dextromethorphan by inhibiting CYP2D6. When dextromethorphan/quinidine is simultaneously used with an SSRI that also inhibits CYP2D6, such as paroxetine or fluoxetine, the patient may be at increased risk for developing adverse effects such as respiratory depression and serotonin syndrome.¹³

[polldaddy:9991902]

Continue to: The authors' observations

Although the exact pathophysiology of PBA is unknown, multiple theories may explain the principle elements of the condition. In the absence of a neurologic insult, the cerebellum acts as an affect regulator, inhibiting laughter and crying at times in which they are considered inappropriate. Parvizi et al⁴ have theorized that the lesions involved in PBA disrupt the corticopontine-cerebellar circuitry, which impedes the ability of the cerebellum to function as an affect modulator.³ In addition to the dysregulation of cerebellar circuitry, altered serotonin and glutamate levels are believed to contribute to the deficient affect regulation observed in PBA; therefore, adding dextromethorphan/quinidine potentiates serotonin and glutamate levels in the synaptic cleft, resulting in a reduction in PBA episodes.⁴

OUTCOME Affect stability

Seven months after beginning dextromethorphan/quinidine, Mr. X has experienced resolution of his PBA episodes. His PHQ-9 score was reduced to 0 (no clinical signs of depression) within 1 month of starting this medication and his PHQ-9 scores remain below 5, representing minimal depressive severity. The CNS-LS scale is not conducted at further visits because the patient’s mother reported no further PBA episodes. Mr. X no longer exhibits episodes of aggression. These episodes seemed to have been a manifestation of his frustration and difficulty in controlling his PBA episodes. Furthermore, his dosage of diazepam was reduced, and he was weaned off risperidone. Mr. X’s parents report that he has a drastically improved affect. He continues to tolerate his medication well and no longer demonstrates any exacerbations of his psychiatric symptoms.

Bottom Line

Pseudobulbar affect (PBA) may occur secondary to various neurologic insults, including cerebral palsy and idiopathic normal pressure hydrocephalus. The condition is diagnosed by a subjective clinical evaluation and use of the Center for Neurologic Study–Lability Scale. Dextromethorphan/quinidine can significantly reduce PBA symptoms.

Acknowledgements

The authors thank Anthony S. Graziano and Rachel M. Watt, both Physician Assistant students, Daemen College, Amherst, New York.

Related Resources

• Frock B, Williams A, Caplan JP. Pseudobulbar affect: when patients laugh or cry, but don’t know why. Current Psychiatry. 2016;15(9):56-60,63.
• Crumpacker DW. Enhancing approaches to the identification and management of pseudobulbar affect. J Clin Psychiatry. 2016;77(9):e1155.

Drug Brand Names

Dextromethorphan/quinidine • Nuedexta
Diazepam • Valium
Fluoxetine • Prozac
Haloperidol • Haldol
Lorazepam • Ativan
Olanzapine • Zyprexa
Paroxetine • Paxil
Risperidone • Risperdal

CASE Worsening outbursts and emotional lability

Mr. X, age 16, has cerebral palsy (CP), idiopathic normal pressure hydrocephalus (iNPH), and a history of impulse control disorder and behavioral instability, including episodes of aggression or combativeness. Mr. X’s mother reports that these episodes are almost always preceded by inappropriate laughing or crying. His outbursts and emotional lability have gotten worse during the last 6 months. Due to his disruptive behaviors, Mr. X has been unable to attend school, and his parents are considering group home placement. Although they were previously able to control their son’s aggressive behaviors, they fear for his safety, and after one such episode, they call 911. Mr. X is transported by police in handcuffs to the comprehensive psychiatric emergency room (CPEP) for evaluation.

While in CPEP, Mr. X remains uncooperative and disruptive; subsequently, he is placed in 4-point restraints and given haloperidol, 10 mg IM, and lorazepam, 2 mg IM, to prevent harm to himself or others. After 2 hours, he is unable to maintain a reality-based conversation but has become semi-cooperative. Mr. X’s mother decides to take him home and immediately makes an appointment with his outpatient psychiatrist.

[polldaddy:9991896]

The authors’ observations

Pseudobulbar affect (PBA) is a disorder characterized by sporadic episodes of inappropriate laughing and/or crying that are incongruent with situational context and are frequently exaggerated in comparison with the actual feelings of the patient. The duration of PBA episodes can last seconds to minutes and arise unpredictably.

PBA typically develops secondary to a neurologic disorder, most commonly Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), stroke, or traumatic brain injury (TBI).¹ PBA symptoms are present in an estimated 29.3% of patients with AD, 44.8% of patients with ALS, 45.8% of patients with MS, 26% of patients with PD, 37.8% of patients with stroke, and 52.4% of patients with TBI.² Although PBA appears far more frequently in patients with MS or ALS compared with those with PD, PD represents an under-recognized and larger patient population. A small fraction of patients also develops PBA secondary to hyperthyroidism, hypothyroidism, Graves’ disease, Wilson’s disease, brain tumors, and a multitude of encephalopathies.³ These neurologic disorders cause dysregulation of the corticopontine-cerebellar circuitry, resulting in functional impediment to the normal affect modulator action of the cerebellum.⁴

The neurologic insults that can result in PBA may include CP or iNPH. Cerebellar injury is a frequent pathological finding in CP.⁵ In patients with iNPH, in addition to altered CSF flow, enlarged ventricles compress the corticospinal tracts in the lateral ventricles,⁶ which is theorized to induce PBA symptoms.

PBA is diagnosed by subjective clinical evaluation and by using the Center for Neurologic Study–Lability Scale (CNS-LS). The CNS-LS is a 7-question survey that addresses the severity of affect lability (Table 1⁷). It may be completed by the patient or caregiver. Each question ranges in score from 1 to 5, with the total score ranging from 7 to 35. The minimum score required for the diagnosis of PBA is 13.⁷

PBA is frequently misdiagnosed as depression, although the 2 disorders can occur simultaneously (Table 2^1,8). A crucial distinguishing factor between depression and PBA is the extent of symptoms. Depression presents as feelings of sadness associated with crying and disinterest that occur for weeks to months. In contrast, PBA presents as brief, uncontrollable episodes of laughing and/or crying that last seconds to minutes. Unlike depression, the behaviors associated with PBA are exaggerated or do not match the patient’s feelings. Furthermore, a neurologic disease or brain injury is always present in a patient with PBA, but is not imperative for the diagnosis of depression.

Continue to: Compared with individuals without PBA...

Compared with individuals without PBA, patients with PBA also experience more distress, embarrassment, and social disability, and are consequently more likely to suffer from other psychiatric conditions, including depression, anxiety/panic attacks, bipolar disorder, posttraumatic stress disorder, psychotic disorder, and schizophrenia.¹ The Patient Health Questionnaire (PHQ-9), a tool for measuring depression severity, can be used in addition to the CNS-LS to determine if the patient has both depression and PBA.

HISTORY Poor response to anxiolytics and antipsychotics

Mr. X previously received a ventriculoperitoneal shunt for treating iNPH. He was not taking any medications for CP. To address his impulse control disorder, he was prescribed olanzapine, 20 mg/d, risperidone, 2 mg/d, and diazepam, 5 mg three times a day. Mr. X is uncontrolled on these medications, experiencing frequent behavioral outbursts at home. His mother completes a CNS-LS for him. He receives a score of 20, which suggests a diagnosis of PBA. His PHQ-9 score is 8, indicating mild depression.

[polldaddy:9991899]

TREATMENT Introducing a new medication

Mr. X is started on dextromethorphan/quinidine, 20/10 mg twice a day. His diazepam is reduced from 5 mg three times a day to 5 mg twice a day, his risperidone is continued at 2 mg/d, olanzapine is maintained at 20 mg/d, and he is scheduled for a 1-month follow-up visit. At the 1-month follow-up visit, Mr. X’s parents report a drastic reduction in their son’s aggressive outbursts and mood swings within the first week of starting dextromethorphan/quinidine. His PHQ-9 scale score is reduced to 0, CNS-LS scale score is reduced to 5, and Mr. X reports “100% improvement.” Due to the robust response to dextromethorphan/quinidine, he is weaned off risperidone.

Continue to: The authors' observations

Decreasing the severity and frequency of episodes constitutes the mainstay of treating PBA. In the past, off-label treatments, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, were prescribed to reduce PBA symptoms.⁵ Currently, dextromethorphan/quinidine is the only FDA-approved medication for treating PBA; however, its use in patients younger than age 18 is considered investigational.

Dextromethorphan/quinidine contains 20 mg of dextromethorphan hydrobromide, the pharmacologically active component of the medication via cytochrome P450 (CYP) 2D6, and 10 mg of quinidine sulfate, which increases the systemic bioavailability of dextromethorphan via CYP2D6 inhibition. The most common adverse effects associated with dextromethorphan/quinidine are dizziness, nausea, and diarrhea.⁹

Atypical antipsychotics, such as olanzapine and risperidone, have more warnings and precautions than dextromethorphan/quinidine. Risperidone has a “black-box” warning for QT prolongation, in addition to death and stroke in elderly patients.¹⁰ Although dextromethorphan/quinidine does not have a black-box warning, it does increase the risk of QT prolongation, and patients with cardiac risk factors should undergo an electrocardiogram before starting this medication. Additionally, risperidone and olanzapine are known to cause significant weight gain, which can increase the risk of developing hyperlipidemia, metabolic syndrome, and type 2 diabetes mellitus.^10,11 Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of all antipsychotics. NMS is characterized by fever, rigidity, altered consciousness, and increased heart and respiratory rates.¹²

Quinidine increases the bioavailability of dextromethorphan by inhibiting CYP2D6. When dextromethorphan/quinidine is simultaneously used with an SSRI that also inhibits CYP2D6, such as paroxetine or fluoxetine, the patient may be at increased risk for developing adverse effects such as respiratory depression and serotonin syndrome.¹³

[polldaddy:9991902]

Continue to: The authors' observations

Although the exact pathophysiology of PBA is unknown, multiple theories may explain the principle elements of the condition. In the absence of a neurologic insult, the cerebellum acts as an affect regulator, inhibiting laughter and crying at times in which they are considered inappropriate. Parvizi et al⁴ have theorized that the lesions involved in PBA disrupt the corticopontine-cerebellar circuitry, which impedes the ability of the cerebellum to function as an affect modulator.³ In addition to the dysregulation of cerebellar circuitry, altered serotonin and glutamate levels are believed to contribute to the deficient affect regulation observed in PBA; therefore, adding dextromethorphan/quinidine potentiates serotonin and glutamate levels in the synaptic cleft, resulting in a reduction in PBA episodes.⁴

OUTCOME Affect stability

Seven months after beginning dextromethorphan/quinidine, Mr. X has experienced resolution of his PBA episodes. His PHQ-9 score was reduced to 0 (no clinical signs of depression) within 1 month of starting this medication and his PHQ-9 scores remain below 5, representing minimal depressive severity. The CNS-LS scale is not conducted at further visits because the patient’s mother reported no further PBA episodes. Mr. X no longer exhibits episodes of aggression. These episodes seemed to have been a manifestation of his frustration and difficulty in controlling his PBA episodes. Furthermore, his dosage of diazepam was reduced, and he was weaned off risperidone. Mr. X’s parents report that he has a drastically improved affect. He continues to tolerate his medication well and no longer demonstrates any exacerbations of his psychiatric symptoms.

Bottom Line

Pseudobulbar affect (PBA) may occur secondary to various neurologic insults, including cerebral palsy and idiopathic normal pressure hydrocephalus. The condition is diagnosed by a subjective clinical evaluation and use of the Center for Neurologic Study–Lability Scale. Dextromethorphan/quinidine can significantly reduce PBA symptoms.

Acknowledgements

The authors thank Anthony S. Graziano and Rachel M. Watt, both Physician Assistant students, Daemen College, Amherst, New York.

Related Resources

• Frock B, Williams A, Caplan JP. Pseudobulbar affect: when patients laugh or cry, but don’t know why. Current Psychiatry. 2016;15(9):56-60,63.
• Crumpacker DW. Enhancing approaches to the identification and management of pseudobulbar affect. J Clin Psychiatry. 2016;77(9):e1155.

Drug Brand Names

Dextromethorphan/quinidine • Nuedexta
Diazepam • Valium
Fluoxetine • Prozac
Haloperidol • Haldol
Lorazepam • Ativan
Olanzapine • Zyprexa
Paroxetine • Paxil
Risperidone • Risperdal