“In the end, we will remember not the words of our enemies, but the silence of our friends.”

—Martin Luther King, Jr.

"Code Blue, Emergency Department Code Team to PACU.” A female senior resident dons her personal protective equipment and assembles her team. An enthusiastic male junior resident asks if he can accompany her, and off they go. They encounter a frantic scene in the post-anesthesia care unit (PACU). Before the senior resident can lead the rapid response, a PACU nurse addresses the junior resident: “You are leading the code, correct? What medications would you like?”

“Microaggressions” are subtle, commonplace exchanges that—whether intentional or unintentional—communicate disparaging messages to members of marginalized groups.¹ These groups often include women, members of racial/ethnic groups that are underrepresented in medicine, and lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) individuals. Although an individual may not intend to cause harm, their words may still negatively impact the receiving party, who regularly experiences differential treatment based on sex, race, ethnicity, or other social identities. The effects of microaggressions extend beyond personal offense to include anxiety, depression, and even hypertension.^1,2

Addressing microaggressions can be challenging. Given that the recipients of microaggressions are often burdened with responding to them, it is important for bystanders to be empowered to respond as well. A bystander witnesses and recognizes the microaggression and can address it. Based on the work of Sue et al,³ we suggest that bystanders adopt the following strategies:

• Make the “invisible” visible. Many people do not perceive their actions as biased or prejudiced. It is therefore important to bring the implicit bias to the forefront by asking for clarification, naming the implication, or challenging the stereotype.
• Disarm the microaggression. Don’t be afraid to stop, deflect, disagree, or challenge what was said or done, thereby highlighting its potentially harmful impact. Another option is to interrupt the comment as it’s being said and redirect the conversation.
• Educate the speaker. Create a nonpunitive discussion by appealing to common values, promoting empathy, and increasing awareness of societal benefits. The speaker may become defensive and emphasize that their intent was not to cause harm. You must emphasize that, regardless of intent, the impact was hurtful. You may refocus the discussion with a simple statement such as, “I know you meant well, and…”
• Seek external support when needed. Addressing microaggressions can be emotionally taxing. Don’t be afraid to utilize community services, find a support group, or seek advice from professionals.

By virtue of being a neutral third party, bystanders who intervene may have greater success at explaining the impact of the microaggression. In doing so, the bystander also relieves the recipient of the microaggression of a burdensome response. In the above example, another provider in the PACU might pull the nurse aside later and say, “When you asked the junior resident if he was leading the code, you unintentionally indicated that he was the most experienced, which made it more challenging for the female senior resident to lead the response.” In this way, the “invisible” implication of the nurse’s words—that the male resident was the most knowledgeable physician in the room—is made visible, and the female resident is relieved of responding.

Microaggressions do not occur in a vacuum; context matters. Before employing these strategies, consider when, where, and how you address microaggressions. These strategies validate and support those on the receiving end of microaggressions, and thus counteract their deleterious effects. The onus is on us: we must not be silent.

The authors have nothing to disclose.

“In the end, we will remember not the words of our enemies, but the silence of our friends.”

—Martin Luther King, Jr.

"Code Blue, Emergency Department Code Team to PACU.” A female senior resident dons her personal protective equipment and assembles her team. An enthusiastic male junior resident asks if he can accompany her, and off they go. They encounter a frantic scene in the post-anesthesia care unit (PACU). Before the senior resident can lead the rapid response, a PACU nurse addresses the junior resident: “You are leading the code, correct? What medications would you like?”

“Microaggressions” are subtle, commonplace exchanges that—whether intentional or unintentional—communicate disparaging messages to members of marginalized groups.¹ These groups often include women, members of racial/ethnic groups that are underrepresented in medicine, and lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) individuals. Although an individual may not intend to cause harm, their words may still negatively impact the receiving party, who regularly experiences differential treatment based on sex, race, ethnicity, or other social identities. The effects of microaggressions extend beyond personal offense to include anxiety, depression, and even hypertension.^1,2

Addressing microaggressions can be challenging. Given that the recipients of microaggressions are often burdened with responding to them, it is important for bystanders to be empowered to respond as well. A bystander witnesses and recognizes the microaggression and can address it. Based on the work of Sue et al,³ we suggest that bystanders adopt the following strategies:

• Make the “invisible” visible. Many people do not perceive their actions as biased or prejudiced. It is therefore important to bring the implicit bias to the forefront by asking for clarification, naming the implication, or challenging the stereotype.
• Disarm the microaggression. Don’t be afraid to stop, deflect, disagree, or challenge what was said or done, thereby highlighting its potentially harmful impact. Another option is to interrupt the comment as it’s being said and redirect the conversation.
• Educate the speaker. Create a nonpunitive discussion by appealing to common values, promoting empathy, and increasing awareness of societal benefits. The speaker may become defensive and emphasize that their intent was not to cause harm. You must emphasize that, regardless of intent, the impact was hurtful. You may refocus the discussion with a simple statement such as, “I know you meant well, and…”
• Seek external support when needed. Addressing microaggressions can be emotionally taxing. Don’t be afraid to utilize community services, find a support group, or seek advice from professionals.

By virtue of being a neutral third party, bystanders who intervene may have greater success at explaining the impact of the microaggression. In doing so, the bystander also relieves the recipient of the microaggression of a burdensome response. In the above example, another provider in the PACU might pull the nurse aside later and say, “When you asked the junior resident if he was leading the code, you unintentionally indicated that he was the most experienced, which made it more challenging for the female senior resident to lead the response.” In this way, the “invisible” implication of the nurse’s words—that the male resident was the most knowledgeable physician in the room—is made visible, and the female resident is relieved of responding.

Microaggressions do not occur in a vacuum; context matters. Before employing these strategies, consider when, where, and how you address microaggressions. These strategies validate and support those on the receiving end of microaggressions, and thus counteract their deleterious effects. The onus is on us: we must not be silent.

The authors have nothing to disclose.

“In the end, we will remember not the words of our enemies, but the silence of our friends.”

—Martin Luther King, Jr.

"Code Blue, Emergency Department Code Team to PACU.” A female senior resident dons her personal protective equipment and assembles her team. An enthusiastic male junior resident asks if he can accompany her, and off they go. They encounter a frantic scene in the post-anesthesia care unit (PACU). Before the senior resident can lead the rapid response, a PACU nurse addresses the junior resident: “You are leading the code, correct? What medications would you like?”

“Microaggressions” are subtle, commonplace exchanges that—whether intentional or unintentional—communicate disparaging messages to members of marginalized groups.¹ These groups often include women, members of racial/ethnic groups that are underrepresented in medicine, and lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) individuals. Although an individual may not intend to cause harm, their words may still negatively impact the receiving party, who regularly experiences differential treatment based on sex, race, ethnicity, or other social identities. The effects of microaggressions extend beyond personal offense to include anxiety, depression, and even hypertension.^1,2

Addressing microaggressions can be challenging. Given that the recipients of microaggressions are often burdened with responding to them, it is important for bystanders to be empowered to respond as well. A bystander witnesses and recognizes the microaggression and can address it. Based on the work of Sue et al,³ we suggest that bystanders adopt the following strategies:

• Make the “invisible” visible. Many people do not perceive their actions as biased or prejudiced. It is therefore important to bring the implicit bias to the forefront by asking for clarification, naming the implication, or challenging the stereotype.
• Disarm the microaggression. Don’t be afraid to stop, deflect, disagree, or challenge what was said or done, thereby highlighting its potentially harmful impact. Another option is to interrupt the comment as it’s being said and redirect the conversation.
• Educate the speaker. Create a nonpunitive discussion by appealing to common values, promoting empathy, and increasing awareness of societal benefits. The speaker may become defensive and emphasize that their intent was not to cause harm. You must emphasize that, regardless of intent, the impact was hurtful. You may refocus the discussion with a simple statement such as, “I know you meant well, and…”
• Seek external support when needed. Addressing microaggressions can be emotionally taxing. Don’t be afraid to utilize community services, find a support group, or seek advice from professionals.

By virtue of being a neutral third party, bystanders who intervene may have greater success at explaining the impact of the microaggression. In doing so, the bystander also relieves the recipient of the microaggression of a burdensome response. In the above example, another provider in the PACU might pull the nurse aside later and say, “When you asked the junior resident if he was leading the code, you unintentionally indicated that he was the most experienced, which made it more challenging for the female senior resident to lead the response.” In this way, the “invisible” implication of the nurse’s words—that the male resident was the most knowledgeable physician in the room—is made visible, and the female resident is relieved of responding.

Microaggressions do not occur in a vacuum; context matters. Before employing these strategies, consider when, where, and how you address microaggressions. These strategies validate and support those on the receiving end of microaggressions, and thus counteract their deleterious effects. The onus is on us: we must not be silent.

The authors have nothing to disclose.

The negative symptoms of schizophrenia have been recognized for 100 years. Characterized by a loss of a function that should be present, negative symptoms include anhedonia, asociality, amotivation, and affective blunting. Individuals with schizophrenia who have a preponderance of negative symptoms (“deficit syndrome”) may comprise a special subset of patients. Compared with positive symptoms, negative symptoms are associated with worse global functioning and worse response to antipsychotic medication. Treatment of negative symptoms is challenging. Secondary negative symptoms—those that simulate or resemble primary negative symptoms but are attributable to another cause, such as major depressive disorder or the adverse effects of antipsychotic medication—need to be ruled out. Emerging evidence suggests that newer antipsychotics with novel mechanisms might be effective in treating negative symptoms. Antidepressants might also play a role.

This article describes types of negative symptoms, their clinical relevance, neuroanatomical and neurotransmission factors associated with negative symptoms, and current and future treatment options.

Modest improvements with antipsychotics

Schizophrenia affects an estimated 1% of the population.¹ Antipsychotic medication has been the mainstay of schizophrenia treatment since chlorpromazine was introduced in the 1950s; it was soon followed by many other antipsychotics. These first-generation antipsychotics (FGAs) were joined by second-generation antipsychotics (SGAs) in the 1990s. While SGAs are better tolerated and less likely to induce extrapyramidal side effects (EPS) than FGAs, they also are associated with troubling metabolic adverse effects (eg, impaired glucose tolerance).¹

All antipsychotics are believed to exert their therapeutic effects by blocking dopamine (D2) receptors and are effective in ameliorating the positive symptoms of schizophrenia, including hallucinations, delusions, bizarre behavior, disordered thinking, and agitation.¹ Early research had suggested that SGAs might also reduce the negative symptoms of schizophrenia, perhaps because they also block serotonin 2A receptors, a property thought to broaden their therapeutic profile. Over time, it became clear that neither FGAs nor SGAs conferred an advantage in treating negative symptoms, and that the observed improvements were modest.^2-5 However, recent research suggests that several newer antipsychotics might be effective in targeting negative symptoms.^2,6,7

History of negative symptoms

In the early 20th century, Swiss psychiatrist Eugen Bleuler coined the term schizophrenia to emphasize the cognitive impairment that occurs in patients with this illness, and which he conceptualized as a fragmenting of the psychic process.⁸ He believed that certain symptoms were fundamental to the illness, and described affective blunting, disturbance of association (ie, distorted thinking) autism (ie, impaired relationships), and ambivalence (ie, fragmented emotional responses). He viewed hallucinations and delusions as accessory symptoms because they were not unique to schizophrenia but were also found in other disorders (eg, mood disorders). Bleuler’s ideas took root, and generations of psychiatrists were taught his fundamental symptoms (“the 4 A’s”), the forerunner of today’s negative symptoms. Later, other experts chose to emphasize psychotic symptoms as most characteristic of schizophrenia, including Schneider’s “first-rank symptoms,” such as voices conversing or delusions of passivity.⁹

Negative symptoms were rediscovered in the 1970s and 1980s by psychiatric researchers interested in descriptive phenomenology.^10,11 Research confirmed the presence of a positive dimension in schizophrenia characterized by the loss of boundaries between the patient and the real world (eg, hallucinations, delusions), and a negative dimension characterized by the loss of a function that should be present, such as alogia and asociality. These experts carefully described negative symptoms and created scales to measure them, including the Scale for the Assessment of Negative Symptoms (SANS),¹² the Positive and Negative Syndrome Scale (PANSS),¹³ the Brief Negative Symptom Scale (BNSS),¹⁴ and the 16-item Negative Symptom Assessment (NSA-16).¹⁵ Contemporaneous to this work, a “deficit syndrome” was identified among patients with schizophrenia with prominent negative symptoms. The deficit syndrome is found in 25% to 30% of chronic cases.¹⁶ Negative symptoms are very common in patients with schizophrenia (Table 1⁹).^8,17

Early editions of the DSM defined schizophrenia mainly on the basis of disturbance of cognition, mood, and behavior, and a retreat from reality. With the publication of DSM-III in 1980, and in subsequent editions, schizophrenia was redefined as a relatively severe psychotic illness in which positive and negative symptoms were present, thereby acknowledging the importance of Bleuler’s fundamental symptoms. In DSM-5, negative symptoms are described as accounting for “a substantial portion of the morbidity associated with schizophrenia but are less prominent in other psychotic disorders.”¹⁸

Continue to: Types of negative symptoms

Types of negative symptoms

The following symptoms fall within the negative dimension¹⁹:

Alogia refers to the impoverished thinking and cognition that often occur in patients with schizophrenia. The patient’s thinking processes seem empty, turgid, or slow, as inferred from the patient’s speech. The 2 major manifestations of alogia are poverty of speech (nonfluent empty speech) and poverty of content of speech (fluent but empty speech). Examples of each appear in Table 2.¹⁹

Affective flattening or blunting manifests as a general impoverishment of emotional expression, reactivity, and feeling. Affective flattening can be assessed through observing a patient’s behavior and responsiveness during the interview.

Avolition-apathy manifests itself as a lack of energy and drive. Patients become inert and are unable to mobilize themselves to initiate or persist in completing many kinds of tasks.

Anhedonia-asociality encompasses the patient’s difficulties in experiencing interest or pleasure. It may express itself as a loss of interest in pleasurable activities, an inability to experience pleasure when participating in activities normally considered pleasurable, or a lack of involvement in social relationships.

Continue to: Attention

Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”¹⁸ Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.^1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.²⁰

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.³ What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.³

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.³ Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.^21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.^21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.²³ There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.²⁴ The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.²⁵ More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.² Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.^6,7

Continue to: Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶ The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³ A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹ The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

Continue to: Related Resources

• Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophr Res. 2017;186:1-2.
• Rabinowitz J. Treating negative symptoms of schizophrenia. Current Psychiatry. 2018;17(12):19-23.

Drug Brand Names

Benztropine • Cogentin
Cariprazine • Vraylar
Chlorpromazine • Promapar, Thorazine
Risperidone • Risperdal

The negative symptoms of schizophrenia have been recognized for 100 years. Characterized by a loss of a function that should be present, negative symptoms include anhedonia, asociality, amotivation, and affective blunting. Individuals with schizophrenia who have a preponderance of negative symptoms (“deficit syndrome”) may comprise a special subset of patients. Compared with positive symptoms, negative symptoms are associated with worse global functioning and worse response to antipsychotic medication. Treatment of negative symptoms is challenging. Secondary negative symptoms—those that simulate or resemble primary negative symptoms but are attributable to another cause, such as major depressive disorder or the adverse effects of antipsychotic medication—need to be ruled out. Emerging evidence suggests that newer antipsychotics with novel mechanisms might be effective in treating negative symptoms. Antidepressants might also play a role.

This article describes types of negative symptoms, their clinical relevance, neuroanatomical and neurotransmission factors associated with negative symptoms, and current and future treatment options.

Modest improvements with antipsychotics

Schizophrenia affects an estimated 1% of the population.¹ Antipsychotic medication has been the mainstay of schizophrenia treatment since chlorpromazine was introduced in the 1950s; it was soon followed by many other antipsychotics. These first-generation antipsychotics (FGAs) were joined by second-generation antipsychotics (SGAs) in the 1990s. While SGAs are better tolerated and less likely to induce extrapyramidal side effects (EPS) than FGAs, they also are associated with troubling metabolic adverse effects (eg, impaired glucose tolerance).¹

All antipsychotics are believed to exert their therapeutic effects by blocking dopamine (D2) receptors and are effective in ameliorating the positive symptoms of schizophrenia, including hallucinations, delusions, bizarre behavior, disordered thinking, and agitation.¹ Early research had suggested that SGAs might also reduce the negative symptoms of schizophrenia, perhaps because they also block serotonin 2A receptors, a property thought to broaden their therapeutic profile. Over time, it became clear that neither FGAs nor SGAs conferred an advantage in treating negative symptoms, and that the observed improvements were modest.^2-5 However, recent research suggests that several newer antipsychotics might be effective in targeting negative symptoms.^2,6,7

History of negative symptoms

In the early 20th century, Swiss psychiatrist Eugen Bleuler coined the term schizophrenia to emphasize the cognitive impairment that occurs in patients with this illness, and which he conceptualized as a fragmenting of the psychic process.⁸ He believed that certain symptoms were fundamental to the illness, and described affective blunting, disturbance of association (ie, distorted thinking) autism (ie, impaired relationships), and ambivalence (ie, fragmented emotional responses). He viewed hallucinations and delusions as accessory symptoms because they were not unique to schizophrenia but were also found in other disorders (eg, mood disorders). Bleuler’s ideas took root, and generations of psychiatrists were taught his fundamental symptoms (“the 4 A’s”), the forerunner of today’s negative symptoms. Later, other experts chose to emphasize psychotic symptoms as most characteristic of schizophrenia, including Schneider’s “first-rank symptoms,” such as voices conversing or delusions of passivity.⁹

Negative symptoms were rediscovered in the 1970s and 1980s by psychiatric researchers interested in descriptive phenomenology.^10,11 Research confirmed the presence of a positive dimension in schizophrenia characterized by the loss of boundaries between the patient and the real world (eg, hallucinations, delusions), and a negative dimension characterized by the loss of a function that should be present, such as alogia and asociality. These experts carefully described negative symptoms and created scales to measure them, including the Scale for the Assessment of Negative Symptoms (SANS),¹² the Positive and Negative Syndrome Scale (PANSS),¹³ the Brief Negative Symptom Scale (BNSS),¹⁴ and the 16-item Negative Symptom Assessment (NSA-16).¹⁵ Contemporaneous to this work, a “deficit syndrome” was identified among patients with schizophrenia with prominent negative symptoms. The deficit syndrome is found in 25% to 30% of chronic cases.¹⁶ Negative symptoms are very common in patients with schizophrenia (Table 1⁹).^8,17

Early editions of the DSM defined schizophrenia mainly on the basis of disturbance of cognition, mood, and behavior, and a retreat from reality. With the publication of DSM-III in 1980, and in subsequent editions, schizophrenia was redefined as a relatively severe psychotic illness in which positive and negative symptoms were present, thereby acknowledging the importance of Bleuler’s fundamental symptoms. In DSM-5, negative symptoms are described as accounting for “a substantial portion of the morbidity associated with schizophrenia but are less prominent in other psychotic disorders.”¹⁸

Continue to: Types of negative symptoms

Types of negative symptoms

The following symptoms fall within the negative dimension¹⁹:

Alogia refers to the impoverished thinking and cognition that often occur in patients with schizophrenia. The patient’s thinking processes seem empty, turgid, or slow, as inferred from the patient’s speech. The 2 major manifestations of alogia are poverty of speech (nonfluent empty speech) and poverty of content of speech (fluent but empty speech). Examples of each appear in Table 2.¹⁹

Affective flattening or blunting manifests as a general impoverishment of emotional expression, reactivity, and feeling. Affective flattening can be assessed through observing a patient’s behavior and responsiveness during the interview.

Avolition-apathy manifests itself as a lack of energy and drive. Patients become inert and are unable to mobilize themselves to initiate or persist in completing many kinds of tasks.

Anhedonia-asociality encompasses the patient’s difficulties in experiencing interest or pleasure. It may express itself as a loss of interest in pleasurable activities, an inability to experience pleasure when participating in activities normally considered pleasurable, or a lack of involvement in social relationships.

Continue to: Attention

Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”¹⁸ Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.^1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.²⁰

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.³ What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.³

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.³ Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.^21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.^21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.²³ There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.²⁴ The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.²⁵ More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.² Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.^6,7

Continue to: Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶ The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³ A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹ The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

Continue to: Related Resources

• Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophr Res. 2017;186:1-2.
• Rabinowitz J. Treating negative symptoms of schizophrenia. Current Psychiatry. 2018;17(12):19-23.

Drug Brand Names

Benztropine • Cogentin
Cariprazine • Vraylar
Chlorpromazine • Promapar, Thorazine
Risperidone • Risperdal

The negative symptoms of schizophrenia have been recognized for 100 years. Characterized by a loss of a function that should be present, negative symptoms include anhedonia, asociality, amotivation, and affective blunting. Individuals with schizophrenia who have a preponderance of negative symptoms (“deficit syndrome”) may comprise a special subset of patients. Compared with positive symptoms, negative symptoms are associated with worse global functioning and worse response to antipsychotic medication. Treatment of negative symptoms is challenging. Secondary negative symptoms—those that simulate or resemble primary negative symptoms but are attributable to another cause, such as major depressive disorder or the adverse effects of antipsychotic medication—need to be ruled out. Emerging evidence suggests that newer antipsychotics with novel mechanisms might be effective in treating negative symptoms. Antidepressants might also play a role.

This article describes types of negative symptoms, their clinical relevance, neuroanatomical and neurotransmission factors associated with negative symptoms, and current and future treatment options.

Modest improvements with antipsychotics

Schizophrenia affects an estimated 1% of the population.¹ Antipsychotic medication has been the mainstay of schizophrenia treatment since chlorpromazine was introduced in the 1950s; it was soon followed by many other antipsychotics. These first-generation antipsychotics (FGAs) were joined by second-generation antipsychotics (SGAs) in the 1990s. While SGAs are better tolerated and less likely to induce extrapyramidal side effects (EPS) than FGAs, they also are associated with troubling metabolic adverse effects (eg, impaired glucose tolerance).¹

All antipsychotics are believed to exert their therapeutic effects by blocking dopamine (D2) receptors and are effective in ameliorating the positive symptoms of schizophrenia, including hallucinations, delusions, bizarre behavior, disordered thinking, and agitation.¹ Early research had suggested that SGAs might also reduce the negative symptoms of schizophrenia, perhaps because they also block serotonin 2A receptors, a property thought to broaden their therapeutic profile. Over time, it became clear that neither FGAs nor SGAs conferred an advantage in treating negative symptoms, and that the observed improvements were modest.^2-5 However, recent research suggests that several newer antipsychotics might be effective in targeting negative symptoms.^2,6,7

History of negative symptoms

In the early 20th century, Swiss psychiatrist Eugen Bleuler coined the term schizophrenia to emphasize the cognitive impairment that occurs in patients with this illness, and which he conceptualized as a fragmenting of the psychic process.⁸ He believed that certain symptoms were fundamental to the illness, and described affective blunting, disturbance of association (ie, distorted thinking) autism (ie, impaired relationships), and ambivalence (ie, fragmented emotional responses). He viewed hallucinations and delusions as accessory symptoms because they were not unique to schizophrenia but were also found in other disorders (eg, mood disorders). Bleuler’s ideas took root, and generations of psychiatrists were taught his fundamental symptoms (“the 4 A’s”), the forerunner of today’s negative symptoms. Later, other experts chose to emphasize psychotic symptoms as most characteristic of schizophrenia, including Schneider’s “first-rank symptoms,” such as voices conversing or delusions of passivity.⁹

Negative symptoms were rediscovered in the 1970s and 1980s by psychiatric researchers interested in descriptive phenomenology.^10,11 Research confirmed the presence of a positive dimension in schizophrenia characterized by the loss of boundaries between the patient and the real world (eg, hallucinations, delusions), and a negative dimension characterized by the loss of a function that should be present, such as alogia and asociality. These experts carefully described negative symptoms and created scales to measure them, including the Scale for the Assessment of Negative Symptoms (SANS),¹² the Positive and Negative Syndrome Scale (PANSS),¹³ the Brief Negative Symptom Scale (BNSS),¹⁴ and the 16-item Negative Symptom Assessment (NSA-16).¹⁵ Contemporaneous to this work, a “deficit syndrome” was identified among patients with schizophrenia with prominent negative symptoms. The deficit syndrome is found in 25% to 30% of chronic cases.¹⁶ Negative symptoms are very common in patients with schizophrenia (Table 1⁹).^8,17

Early editions of the DSM defined schizophrenia mainly on the basis of disturbance of cognition, mood, and behavior, and a retreat from reality. With the publication of DSM-III in 1980, and in subsequent editions, schizophrenia was redefined as a relatively severe psychotic illness in which positive and negative symptoms were present, thereby acknowledging the importance of Bleuler’s fundamental symptoms. In DSM-5, negative symptoms are described as accounting for “a substantial portion of the morbidity associated with schizophrenia but are less prominent in other psychotic disorders.”¹⁸

Continue to: Types of negative symptoms

Types of negative symptoms

The following symptoms fall within the negative dimension¹⁹:

Alogia refers to the impoverished thinking and cognition that often occur in patients with schizophrenia. The patient’s thinking processes seem empty, turgid, or slow, as inferred from the patient’s speech. The 2 major manifestations of alogia are poverty of speech (nonfluent empty speech) and poverty of content of speech (fluent but empty speech). Examples of each appear in Table 2.¹⁹

Affective flattening or blunting manifests as a general impoverishment of emotional expression, reactivity, and feeling. Affective flattening can be assessed through observing a patient’s behavior and responsiveness during the interview.

Avolition-apathy manifests itself as a lack of energy and drive. Patients become inert and are unable to mobilize themselves to initiate or persist in completing many kinds of tasks.

Anhedonia-asociality encompasses the patient’s difficulties in experiencing interest or pleasure. It may express itself as a loss of interest in pleasurable activities, an inability to experience pleasure when participating in activities normally considered pleasurable, or a lack of involvement in social relationships.

Continue to: Attention

Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”¹⁸ Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.^1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.²⁰

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.³ What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.³

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.³ Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.^21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.^21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.²³ There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.²⁴ The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.²⁵ More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.² Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.^6,7

Continue to: Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶ The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³ A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹ The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

Continue to: Related Resources

• Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophr Res. 2017;186:1-2.
• Rabinowitz J. Treating negative symptoms of schizophrenia. Current Psychiatry. 2018;17(12):19-23.

Drug Brand Names

Benztropine • Cogentin
Cariprazine • Vraylar
Chlorpromazine • Promapar, Thorazine
Risperidone • Risperdal

The coronavirus disease 2019 (COVID-19) pandemic has introduced many new clinical challenges. Consider the patient with fever and dyspnea who tests positive for COVID-19 but does not believe in COVID-19 and wants to leave the hospital against medical advice (AMA). Or the patient with numerous cardiovascular risk factors and crushing substernal chest pain who is too afraid of contracting COVID-19 to come to the emergency department. These challenging clinical scenarios can be addressed in the context of decision-making capacity (DMC), for which our medical colleagues often call upon psychiatrists to assist. This article reviews the framework for DMC assessment, describes how COVID-19 affects DMC assessment, and discusses approaches to these scenarios using the DMC framework.

Review of decision-making capacity

Assessment of DMC is a fundamental clinical skill. It allows a physician to balance autonomy with beneficence and non-maleficence. An autonomous decision is a decision that is made intentionally, with understanding, and without controlling influences (these are the elements of informed consent).¹ However, if a patient cannot make a decision with intention and understanding, then beneficence and non-maleficence must prevail in order to protect the patient. Capacity assessments evaluate a patient’s ability to make an intentional and understood choice.

In order to prove capacity, a patient must demonstrate 4 functional abilities:

• choice refers to the ability to communicate a relatively stable choice^2,3
• understanding refers to the ability to convey information about the illness, risks/benefits of the chosen intervention, and risks/benefits of alternative options.^2,3 Understanding measures objective information about the medical situation
• appreciation refers to the patient’s ability to apply that information to his/her own life.^2,3 Appreciation requires insight into having the illness and the ability to anticipate how one’s life would be impacted by one’s condition and choice. This is where life experiences and values come into play
• reasoning is intimately tied to appreciation. It refers to the ability to explain how the decision was made and which factors were most important.^2,3

Most clinicians and ethicists endorse a “threshold” approach to decisional capacity, which specifies that the level of evidence required to prove capacity depends on the gravity of the medical situation (Figure 1A).^1,4,5 The gravity of the situation is based on the risk/benefit analysis. Consider two treatments with equal benefit: one has minimal adverse effects (gastrointestinal upset) and the second has significant adverse effects (myelosuppression). Accepting the first treatment requires less intentionality and understanding than accepting the second because the risk is much lower and thus has a lower capacity threshold (Figure 1B). The capacity to refuse these treatments results in the opposite ranking (Figure 1C).

Establishing a threshold helps guide the physician in determining how robust the patient’s responses must be to have decisional capacity. For a high-threshold decision, the patient must have a well-developed and highly detailed level of understanding, appreciation, and reasoning.

How COVID-19 affects assessment of decision-making capacity

Three characteristics of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 illness impact decision-making assessment:

• high level of contagiousness
• high health-care utilization
• the uncertainty about its clinical course and outcomes.

The high level of contagiousness stems from this virus’s estimated basic reproduction number (R₀) of 2.2 to 5.7 (which indicates the expected number of cases from any single case), its long incubation period, and the potential for asymptomatic and pre-symptomatic shedding.^6-9 Decision-making capacity assessments must therefore consider community-level effects in the risk/benefit analysis. Because SARS-CoV-2 is a new virus affecting humans, it can easily overwhelm existing hospital systems. This happened in Wuhan, China; Lombardy, Italy; and New York. In a stressed system, physicians will have to factor health-care utilization into the risk/benefit analysis. Finally, because this is a novel virus, there is still considerable uncertainty about the epidemiology, clinical course, and outcomes.¹⁰ The minimal dose of virus needed to cause illness is unknown. Patients can deteriorate quickly and unpredictably into needing ventilator support.¹¹ Treatment options are limited, and many candidates are being investigated.¹² This uncertainty hinders physicians’ ability to accurately estimate risks and benefits for an individual patient when discussing various medical decisions. As our understanding of SARS-CoV-2 improves, this uncertainty will lessen.

Continue to: Effects of the sociopolitical climate

In the United States, the COVID-19 pandemic emerged during a time of deep sociopolitical divide. Accordingly, beliefs about viral infectivity, severity of illness, and precautionary measures have varied. Some politicians, media outlets, and physicians have shared information that contradicts guidelines and recommendations from mainstream national and international medical and scientific organizations. Patients who subscribe to these reports and beliefs may not meet the threshold for understanding, appreciation, or reasoning. For example, if a patient’s beliefs about the virus depart from well-established medical evidence, they would technically lack understanding. The usual remedy for addressing misunderstanding is education and time. However, because of the divisiveness of the sociopolitical climate, the limited time physicians have with patients, and the fact that many DMC assessments will occur in acute-care settings, it may be difficult or near impossible to correct the misunderstanding.

The sociopolitical climate and its accompanying potentially erroneous or imbalanced narrative may thus directly impact patients’ understanding, appreciation, and reasoning. However, it can be problematic to declare incapacity in a patient whose understanding, appreciation, and reasoning arise from widely shared and relatively fixed sociopolitical values. Additionally, some clinicians and ethicists might object to declaring incapacity in a patient with no underlying mental or neurologic dysfunction. The United States has a functional approach to capacity, based solely on meeting criteria for the 4 functional abilities.^3,13 Mental or neurologic dysfunction is not legally required in the United States, but in practice, the consideration of incapacity is often closely linked to some form of cognitive impairment.¹⁴ Other countries do make dysfunction a specific criterion; for example, the United Kingdom dictates that mental incapacity can only occur in someone with “impairment of, or a disturbance in the functioning of, the mind or brain.”¹⁵

Leaving against medical advice

In the case of a patient who is COVID-19–positive, symptomatic, and wants to leave AMA, the threshold is automatically elevated because of societal-level risks (the risk of potential exposure or infection of others if a patient who is COVID-19–positive is not properly isolated). Further­more, the individual risk of the patient leaving AMA depends on his/her age, comorbidities, and current clinical status; because of the uncertainty and rapid deterioration seen with COVID-19 illness, the calculated risk may actually be higher than for a non-COVID-19–related illness. Thus, in order to leave AMA, the patient’s responses must be fairly robust (Figure 2). Table 1 describes the information needed for robust understanding, appreciation, and reasoning.

For patients who do not meet this threshold, it is important to determine why. If a patient has a psychiatric condition that not only impacts DMC but also meets criteria for a psychiatric hold (ie, an imminent risk of harm to self or others), a psychiatric hold should be placed. If the patient does not meet the threshold because of altered mental status or some other neurologic or cognitive comorbidity, a medical hold should be placed. Most states do not have an explicit legal basis for a medical hold, although it does fall under the incapacity laws in the United States; in the absence of a surrogate, declaration of medical emergency can also be used if applicable.^16,17 As a caveat, it can be difficult to detain someone on a medical hold because security officers may be afraid to physically detain someone without explicit legal paperwork.¹⁷

If a patient does not meet the capacity threshold but there does not seem to be a psychiatric, neurologic, or cognitive explanation, several options are possible. The first step would be to assess whether the patient is amenable to further discussion and compromise. A nonjudgmental and nonconfrontational approach that aims to further clarify the patient’s perspective and identify shared goals is key. Any plan that lowers the risks sufficiently would allow the patient to leave by lowering the capacity threshold. Enlisting the support of family and friends can be helpful. If this does not work, theoretically the patient should be detained in the hospital. Practically speaking, this may be difficult or unadvised. First, as described above, security officers may refuse to physically detain the patient.¹⁷ Second, the patient’s legally mandated surrogate may espouse similar COVID-related views as the patient; thus, this approach may not help keep the patient in the hospital. If the physician has serious concern about the risk of the patient leaving, he/she would have to consult the facility’s Ethics and Legal staff to determine capacity of the surrogate. Third, it can be problematic to declare incapacity in a patient whose understanding, appreciation, and reasoning arise from widely shared and relatively fixed sociopolitical values. In the current sociopolitical climate, involuntary detention may elicit a political backlash. Using medical detention for impending deterioration of clinical status would be more acceptable than using medical detention for isolation. Presently, there are no such laws for patients with COVID-19 (although this is not without precedent, as with active tuberculosis or Ebola^18,19), but individual jurisdictions may have isolation or quarantine orders; the local health department could be contacted and may evaluate on a case-by-case basis.

Continue to: Refusing to seek medical care

Refusing to seek medical care

Anecdotally, many physicians have reported an increase in patients who are refusing clinic- or hospital-based treatment for a medical condition because they fear they may catch the virus. Although this is not strictly a capacity case—there is little recourse for action if a patient is refusing treatment from home (unless the patient requires a psychiatric hold or already has a guardian for medical decisions)—the same elements of thresholds apply and can be helpful in guiding conversations with the patient.

For the patient, the benefits of staying at home are to avoid potentially exposing themselves and the members of their household to the virus and COVID-19 illness. The risks of staying home include progression of the patient’s primary illness, which could lead to increased morbidity and mortality. Staying home has an ancillary benefit to the community of reducing health-care utilization, but at the risk of increasing utilization in the future.

The risk/benefit profile is shown on the thresholds graph in Figure 3. There is considerable variability. It is helpful to stratify the risk of progression of the primary condition as low (can be postponed indefinitely with minimal risk), medium (can be postponed for a short amount of time; risk of increased morbidity with ongoing delay and possibly increased mortality), or high (cannot be postponed; will have greater morbidity and/or higher risk of mortality). Because of the uncertainty about COVID-19, it is harder to quantify the benefits of refusing care and staying at home, although older patients and patients with underlying health issues are at higher risk of severe illness and death.²⁰ However, by taking appropriate precautions when seeking care, viral exposure and risk of infection can be mitigated.

This risk/benefit analysis will help set the threshold for whether staying at home is reasonable or whether it would incur more risk of harm. If the latter, then the physician must elicit the patient’s understanding, appreciation, and reasoning related to their current medical condition and COVID-19. It is likely they are undervaluing the former and overvaluing the latter. Table 2 lists important points to cover during these discussions.

Although there is no legal recourse to force patients at home to come to the clinic or hospital for medical treatment, there are several possible strategies to motivate them to do so. One is to ask patients how likely (on a scale of 0 to 100) they think they are to contract COVID-19 if they came for evaluation/treatment, and how likely they feel they are to experience a bad outcome from their primary condition. Then, after providing psychoeducation about their primary medical condition and COVID-19–related precautions and risk, repeat this question. Another strategy is to empathize with the patient’s fears while also expressing concern about the primary medical condition and connecting with the patient on the shared desire to protect his/her health. A third is to draw a risk/benefit diagram (similar to Figure 3) or reassure the patient by describing the ways in which the clinic or hospital is minimizing exposure and infection risk. A final strategy is to enlist the help of the patient’s family or friends.

Continue to: Bottom Line

In order to have decision-making capacity, a patient must demonstrate choice, understanding, appreciation, and reasoning. The degree of understanding, appreciation, and reasoning required depends on the capacity threshold, which is determined by a risk/benefit analysis. Conducting a risk/benefit analysis during the coronavirus disease 2019 (COVID-19) pandemic requires consideration of societallevel factors (such as contagiousness to others and health-care utilization) and is complicated by a wide range of uncertainties and divisive sociopolitical views regarding COVID-19.

Related Resources

• Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840.
• Ryznar E, Hamaoka D, Lloyd RB. Capacity evaluations. https://admsep.org/csi-emodules.php?c=capacity&v=y. Accessed March 30, 2020.

Acknowledgments

The author thanks Drs. Awais Aftab, Zackary D. Berger, and R. Brett Lloyd for their helpful discussions on the topic.

The coronavirus disease 2019 (COVID-19) pandemic has introduced many new clinical challenges. Consider the patient with fever and dyspnea who tests positive for COVID-19 but does not believe in COVID-19 and wants to leave the hospital against medical advice (AMA). Or the patient with numerous cardiovascular risk factors and crushing substernal chest pain who is too afraid of contracting COVID-19 to come to the emergency department. These challenging clinical scenarios can be addressed in the context of decision-making capacity (DMC), for which our medical colleagues often call upon psychiatrists to assist. This article reviews the framework for DMC assessment, describes how COVID-19 affects DMC assessment, and discusses approaches to these scenarios using the DMC framework.

Review of decision-making capacity

Assessment of DMC is a fundamental clinical skill. It allows a physician to balance autonomy with beneficence and non-maleficence. An autonomous decision is a decision that is made intentionally, with understanding, and without controlling influences (these are the elements of informed consent).¹ However, if a patient cannot make a decision with intention and understanding, then beneficence and non-maleficence must prevail in order to protect the patient. Capacity assessments evaluate a patient’s ability to make an intentional and understood choice.

In order to prove capacity, a patient must demonstrate 4 functional abilities:

• choice refers to the ability to communicate a relatively stable choice^2,3
• understanding refers to the ability to convey information about the illness, risks/benefits of the chosen intervention, and risks/benefits of alternative options.^2,3 Understanding measures objective information about the medical situation
• appreciation refers to the patient’s ability to apply that information to his/her own life.^2,3 Appreciation requires insight into having the illness and the ability to anticipate how one’s life would be impacted by one’s condition and choice. This is where life experiences and values come into play
• reasoning is intimately tied to appreciation. It refers to the ability to explain how the decision was made and which factors were most important.^2,3

Most clinicians and ethicists endorse a “threshold” approach to decisional capacity, which specifies that the level of evidence required to prove capacity depends on the gravity of the medical situation (Figure 1A).^1,4,5 The gravity of the situation is based on the risk/benefit analysis. Consider two treatments with equal benefit: one has minimal adverse effects (gastrointestinal upset) and the second has significant adverse effects (myelosuppression). Accepting the first treatment requires less intentionality and understanding than accepting the second because the risk is much lower and thus has a lower capacity threshold (Figure 1B). The capacity to refuse these treatments results in the opposite ranking (Figure 1C).

Establishing a threshold helps guide the physician in determining how robust the patient’s responses must be to have decisional capacity. For a high-threshold decision, the patient must have a well-developed and highly detailed level of understanding, appreciation, and reasoning.

How COVID-19 affects assessment of decision-making capacity

Three characteristics of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 illness impact decision-making assessment:

• high level of contagiousness
• high health-care utilization
• the uncertainty about its clinical course and outcomes.

The high level of contagiousness stems from this virus’s estimated basic reproduction number (R₀) of 2.2 to 5.7 (which indicates the expected number of cases from any single case), its long incubation period, and the potential for asymptomatic and pre-symptomatic shedding.^6-9 Decision-making capacity assessments must therefore consider community-level effects in the risk/benefit analysis. Because SARS-CoV-2 is a new virus affecting humans, it can easily overwhelm existing hospital systems. This happened in Wuhan, China; Lombardy, Italy; and New York. In a stressed system, physicians will have to factor health-care utilization into the risk/benefit analysis. Finally, because this is a novel virus, there is still considerable uncertainty about the epidemiology, clinical course, and outcomes.¹⁰ The minimal dose of virus needed to cause illness is unknown. Patients can deteriorate quickly and unpredictably into needing ventilator support.¹¹ Treatment options are limited, and many candidates are being investigated.¹² This uncertainty hinders physicians’ ability to accurately estimate risks and benefits for an individual patient when discussing various medical decisions. As our understanding of SARS-CoV-2 improves, this uncertainty will lessen.

Continue to: Effects of the sociopolitical climate

In the United States, the COVID-19 pandemic emerged during a time of deep sociopolitical divide. Accordingly, beliefs about viral infectivity, severity of illness, and precautionary measures have varied. Some politicians, media outlets, and physicians have shared information that contradicts guidelines and recommendations from mainstream national and international medical and scientific organizations. Patients who subscribe to these reports and beliefs may not meet the threshold for understanding, appreciation, or reasoning. For example, if a patient’s beliefs about the virus depart from well-established medical evidence, they would technically lack understanding. The usual remedy for addressing misunderstanding is education and time. However, because of the divisiveness of the sociopolitical climate, the limited time physicians have with patients, and the fact that many DMC assessments will occur in acute-care settings, it may be difficult or near impossible to correct the misunderstanding.

The sociopolitical climate and its accompanying potentially erroneous or imbalanced narrative may thus directly impact patients’ understanding, appreciation, and reasoning. However, it can be problematic to declare incapacity in a patient whose understanding, appreciation, and reasoning arise from widely shared and relatively fixed sociopolitical values. Additionally, some clinicians and ethicists might object to declaring incapacity in a patient with no underlying mental or neurologic dysfunction. The United States has a functional approach to capacity, based solely on meeting criteria for the 4 functional abilities.^3,13 Mental or neurologic dysfunction is not legally required in the United States, but in practice, the consideration of incapacity is often closely linked to some form of cognitive impairment.¹⁴ Other countries do make dysfunction a specific criterion; for example, the United Kingdom dictates that mental incapacity can only occur in someone with “impairment of, or a disturbance in the functioning of, the mind or brain.”¹⁵

Leaving against medical advice

In the case of a patient who is COVID-19–positive, symptomatic, and wants to leave AMA, the threshold is automatically elevated because of societal-level risks (the risk of potential exposure or infection of others if a patient who is COVID-19–positive is not properly isolated). Further­more, the individual risk of the patient leaving AMA depends on his/her age, comorbidities, and current clinical status; because of the uncertainty and rapid deterioration seen with COVID-19 illness, the calculated risk may actually be higher than for a non-COVID-19–related illness. Thus, in order to leave AMA, the patient’s responses must be fairly robust (Figure 2). Table 1 describes the information needed for robust understanding, appreciation, and reasoning.

For patients who do not meet this threshold, it is important to determine why. If a patient has a psychiatric condition that not only impacts DMC but also meets criteria for a psychiatric hold (ie, an imminent risk of harm to self or others), a psychiatric hold should be placed. If the patient does not meet the threshold because of altered mental status or some other neurologic or cognitive comorbidity, a medical hold should be placed. Most states do not have an explicit legal basis for a medical hold, although it does fall under the incapacity laws in the United States; in the absence of a surrogate, declaration of medical emergency can also be used if applicable.^16,17 As a caveat, it can be difficult to detain someone on a medical hold because security officers may be afraid to physically detain someone without explicit legal paperwork.¹⁷

If a patient does not meet the capacity threshold but there does not seem to be a psychiatric, neurologic, or cognitive explanation, several options are possible. The first step would be to assess whether the patient is amenable to further discussion and compromise. A nonjudgmental and nonconfrontational approach that aims to further clarify the patient’s perspective and identify shared goals is key. Any plan that lowers the risks sufficiently would allow the patient to leave by lowering the capacity threshold. Enlisting the support of family and friends can be helpful. If this does not work, theoretically the patient should be detained in the hospital. Practically speaking, this may be difficult or unadvised. First, as described above, security officers may refuse to physically detain the patient.¹⁷ Second, the patient’s legally mandated surrogate may espouse similar COVID-related views as the patient; thus, this approach may not help keep the patient in the hospital. If the physician has serious concern about the risk of the patient leaving, he/she would have to consult the facility’s Ethics and Legal staff to determine capacity of the surrogate. Third, it can be problematic to declare incapacity in a patient whose understanding, appreciation, and reasoning arise from widely shared and relatively fixed sociopolitical values. In the current sociopolitical climate, involuntary detention may elicit a political backlash. Using medical detention for impending deterioration of clinical status would be more acceptable than using medical detention for isolation. Presently, there are no such laws for patients with COVID-19 (although this is not without precedent, as with active tuberculosis or Ebola^18,19), but individual jurisdictions may have isolation or quarantine orders; the local health department could be contacted and may evaluate on a case-by-case basis.

Continue to: Refusing to seek medical care

Refusing to seek medical care

Anecdotally, many physicians have reported an increase in patients who are refusing clinic- or hospital-based treatment for a medical condition because they fear they may catch the virus. Although this is not strictly a capacity case—there is little recourse for action if a patient is refusing treatment from home (unless the patient requires a psychiatric hold or already has a guardian for medical decisions)—the same elements of thresholds apply and can be helpful in guiding conversations with the patient.

For the patient, the benefits of staying at home are to avoid potentially exposing themselves and the members of their household to the virus and COVID-19 illness. The risks of staying home include progression of the patient’s primary illness, which could lead to increased morbidity and mortality. Staying home has an ancillary benefit to the community of reducing health-care utilization, but at the risk of increasing utilization in the future.

The risk/benefit profile is shown on the thresholds graph in Figure 3. There is considerable variability. It is helpful to stratify the risk of progression of the primary condition as low (can be postponed indefinitely with minimal risk), medium (can be postponed for a short amount of time; risk of increased morbidity with ongoing delay and possibly increased mortality), or high (cannot be postponed; will have greater morbidity and/or higher risk of mortality). Because of the uncertainty about COVID-19, it is harder to quantify the benefits of refusing care and staying at home, although older patients and patients with underlying health issues are at higher risk of severe illness and death.²⁰ However, by taking appropriate precautions when seeking care, viral exposure and risk of infection can be mitigated.

This risk/benefit analysis will help set the threshold for whether staying at home is reasonable or whether it would incur more risk of harm. If the latter, then the physician must elicit the patient’s understanding, appreciation, and reasoning related to their current medical condition and COVID-19. It is likely they are undervaluing the former and overvaluing the latter. Table 2 lists important points to cover during these discussions.

Although there is no legal recourse to force patients at home to come to the clinic or hospital for medical treatment, there are several possible strategies to motivate them to do so. One is to ask patients how likely (on a scale of 0 to 100) they think they are to contract COVID-19 if they came for evaluation/treatment, and how likely they feel they are to experience a bad outcome from their primary condition. Then, after providing psychoeducation about their primary medical condition and COVID-19–related precautions and risk, repeat this question. Another strategy is to empathize with the patient’s fears while also expressing concern about the primary medical condition and connecting with the patient on the shared desire to protect his/her health. A third is to draw a risk/benefit diagram (similar to Figure 3) or reassure the patient by describing the ways in which the clinic or hospital is minimizing exposure and infection risk. A final strategy is to enlist the help of the patient’s family or friends.

Continue to: Bottom Line

In order to have decision-making capacity, a patient must demonstrate choice, understanding, appreciation, and reasoning. The degree of understanding, appreciation, and reasoning required depends on the capacity threshold, which is determined by a risk/benefit analysis. Conducting a risk/benefit analysis during the coronavirus disease 2019 (COVID-19) pandemic requires consideration of societallevel factors (such as contagiousness to others and health-care utilization) and is complicated by a wide range of uncertainties and divisive sociopolitical views regarding COVID-19.

Related Resources

• Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840.
• Ryznar E, Hamaoka D, Lloyd RB. Capacity evaluations. https://admsep.org/csi-emodules.php?c=capacity&v=y. Accessed March 30, 2020.

Acknowledgments

The author thanks Drs. Awais Aftab, Zackary D. Berger, and R. Brett Lloyd for their helpful discussions on the topic.

The coronavirus disease 2019 (COVID-19) pandemic has introduced many new clinical challenges. Consider the patient with fever and dyspnea who tests positive for COVID-19 but does not believe in COVID-19 and wants to leave the hospital against medical advice (AMA). Or the patient with numerous cardiovascular risk factors and crushing substernal chest pain who is too afraid of contracting COVID-19 to come to the emergency department. These challenging clinical scenarios can be addressed in the context of decision-making capacity (DMC), for which our medical colleagues often call upon psychiatrists to assist. This article reviews the framework for DMC assessment, describes how COVID-19 affects DMC assessment, and discusses approaches to these scenarios using the DMC framework.

Review of decision-making capacity

Assessment of DMC is a fundamental clinical skill. It allows a physician to balance autonomy with beneficence and non-maleficence. An autonomous decision is a decision that is made intentionally, with understanding, and without controlling influences (these are the elements of informed consent).¹ However, if a patient cannot make a decision with intention and understanding, then beneficence and non-maleficence must prevail in order to protect the patient. Capacity assessments evaluate a patient’s ability to make an intentional and understood choice.

In order to prove capacity, a patient must demonstrate 4 functional abilities:

• choice refers to the ability to communicate a relatively stable choice^2,3
• understanding refers to the ability to convey information about the illness, risks/benefits of the chosen intervention, and risks/benefits of alternative options.^2,3 Understanding measures objective information about the medical situation
• appreciation refers to the patient’s ability to apply that information to his/her own life.^2,3 Appreciation requires insight into having the illness and the ability to anticipate how one’s life would be impacted by one’s condition and choice. This is where life experiences and values come into play
• reasoning is intimately tied to appreciation. It refers to the ability to explain how the decision was made and which factors were most important.^2,3

Most clinicians and ethicists endorse a “threshold” approach to decisional capacity, which specifies that the level of evidence required to prove capacity depends on the gravity of the medical situation (Figure 1A).^1,4,5 The gravity of the situation is based on the risk/benefit analysis. Consider two treatments with equal benefit: one has minimal adverse effects (gastrointestinal upset) and the second has significant adverse effects (myelosuppression). Accepting the first treatment requires less intentionality and understanding than accepting the second because the risk is much lower and thus has a lower capacity threshold (Figure 1B). The capacity to refuse these treatments results in the opposite ranking (Figure 1C).

Establishing a threshold helps guide the physician in determining how robust the patient’s responses must be to have decisional capacity. For a high-threshold decision, the patient must have a well-developed and highly detailed level of understanding, appreciation, and reasoning.

How COVID-19 affects assessment of decision-making capacity

Three characteristics of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 illness impact decision-making assessment:

• high level of contagiousness
• high health-care utilization
• the uncertainty about its clinical course and outcomes.

The high level of contagiousness stems from this virus’s estimated basic reproduction number (R₀) of 2.2 to 5.7 (which indicates the expected number of cases from any single case), its long incubation period, and the potential for asymptomatic and pre-symptomatic shedding.^6-9 Decision-making capacity assessments must therefore consider community-level effects in the risk/benefit analysis. Because SARS-CoV-2 is a new virus affecting humans, it can easily overwhelm existing hospital systems. This happened in Wuhan, China; Lombardy, Italy; and New York. In a stressed system, physicians will have to factor health-care utilization into the risk/benefit analysis. Finally, because this is a novel virus, there is still considerable uncertainty about the epidemiology, clinical course, and outcomes.¹⁰ The minimal dose of virus needed to cause illness is unknown. Patients can deteriorate quickly and unpredictably into needing ventilator support.¹¹ Treatment options are limited, and many candidates are being investigated.¹² This uncertainty hinders physicians’ ability to accurately estimate risks and benefits for an individual patient when discussing various medical decisions. As our understanding of SARS-CoV-2 improves, this uncertainty will lessen.

Continue to: Effects of the sociopolitical climate

In the United States, the COVID-19 pandemic emerged during a time of deep sociopolitical divide. Accordingly, beliefs about viral infectivity, severity of illness, and precautionary measures have varied. Some politicians, media outlets, and physicians have shared information that contradicts guidelines and recommendations from mainstream national and international medical and scientific organizations. Patients who subscribe to these reports and beliefs may not meet the threshold for understanding, appreciation, or reasoning. For example, if a patient’s beliefs about the virus depart from well-established medical evidence, they would technically lack understanding. The usual remedy for addressing misunderstanding is education and time. However, because of the divisiveness of the sociopolitical climate, the limited time physicians have with patients, and the fact that many DMC assessments will occur in acute-care settings, it may be difficult or near impossible to correct the misunderstanding.

The sociopolitical climate and its accompanying potentially erroneous or imbalanced narrative may thus directly impact patients’ understanding, appreciation, and reasoning. However, it can be problematic to declare incapacity in a patient whose understanding, appreciation, and reasoning arise from widely shared and relatively fixed sociopolitical values. Additionally, some clinicians and ethicists might object to declaring incapacity in a patient with no underlying mental or neurologic dysfunction. The United States has a functional approach to capacity, based solely on meeting criteria for the 4 functional abilities.^3,13 Mental or neurologic dysfunction is not legally required in the United States, but in practice, the consideration of incapacity is often closely linked to some form of cognitive impairment.¹⁴ Other countries do make dysfunction a specific criterion; for example, the United Kingdom dictates that mental incapacity can only occur in someone with “impairment of, or a disturbance in the functioning of, the mind or brain.”¹⁵

Leaving against medical advice

In the case of a patient who is COVID-19–positive, symptomatic, and wants to leave AMA, the threshold is automatically elevated because of societal-level risks (the risk of potential exposure or infection of others if a patient who is COVID-19–positive is not properly isolated). Further­more, the individual risk of the patient leaving AMA depends on his/her age, comorbidities, and current clinical status; because of the uncertainty and rapid deterioration seen with COVID-19 illness, the calculated risk may actually be higher than for a non-COVID-19–related illness. Thus, in order to leave AMA, the patient’s responses must be fairly robust (Figure 2). Table 1 describes the information needed for robust understanding, appreciation, and reasoning.

For patients who do not meet this threshold, it is important to determine why. If a patient has a psychiatric condition that not only impacts DMC but also meets criteria for a psychiatric hold (ie, an imminent risk of harm to self or others), a psychiatric hold should be placed. If the patient does not meet the threshold because of altered mental status or some other neurologic or cognitive comorbidity, a medical hold should be placed. Most states do not have an explicit legal basis for a medical hold, although it does fall under the incapacity laws in the United States; in the absence of a surrogate, declaration of medical emergency can also be used if applicable.^16,17 As a caveat, it can be difficult to detain someone on a medical hold because security officers may be afraid to physically detain someone without explicit legal paperwork.¹⁷

If a patient does not meet the capacity threshold but there does not seem to be a psychiatric, neurologic, or cognitive explanation, several options are possible. The first step would be to assess whether the patient is amenable to further discussion and compromise. A nonjudgmental and nonconfrontational approach that aims to further clarify the patient’s perspective and identify shared goals is key. Any plan that lowers the risks sufficiently would allow the patient to leave by lowering the capacity threshold. Enlisting the support of family and friends can be helpful. If this does not work, theoretically the patient should be detained in the hospital. Practically speaking, this may be difficult or unadvised. First, as described above, security officers may refuse to physically detain the patient.¹⁷ Second, the patient’s legally mandated surrogate may espouse similar COVID-related views as the patient; thus, this approach may not help keep the patient in the hospital. If the physician has serious concern about the risk of the patient leaving, he/she would have to consult the facility’s Ethics and Legal staff to determine capacity of the surrogate. Third, it can be problematic to declare incapacity in a patient whose understanding, appreciation, and reasoning arise from widely shared and relatively fixed sociopolitical values. In the current sociopolitical climate, involuntary detention may elicit a political backlash. Using medical detention for impending deterioration of clinical status would be more acceptable than using medical detention for isolation. Presently, there are no such laws for patients with COVID-19 (although this is not without precedent, as with active tuberculosis or Ebola^18,19), but individual jurisdictions may have isolation or quarantine orders; the local health department could be contacted and may evaluate on a case-by-case basis.

Continue to: Refusing to seek medical care

Refusing to seek medical care

Anecdotally, many physicians have reported an increase in patients who are refusing clinic- or hospital-based treatment for a medical condition because they fear they may catch the virus. Although this is not strictly a capacity case—there is little recourse for action if a patient is refusing treatment from home (unless the patient requires a psychiatric hold or already has a guardian for medical decisions)—the same elements of thresholds apply and can be helpful in guiding conversations with the patient.

For the patient, the benefits of staying at home are to avoid potentially exposing themselves and the members of their household to the virus and COVID-19 illness. The risks of staying home include progression of the patient’s primary illness, which could lead to increased morbidity and mortality. Staying home has an ancillary benefit to the community of reducing health-care utilization, but at the risk of increasing utilization in the future.

The risk/benefit profile is shown on the thresholds graph in Figure 3. There is considerable variability. It is helpful to stratify the risk of progression of the primary condition as low (can be postponed indefinitely with minimal risk), medium (can be postponed for a short amount of time; risk of increased morbidity with ongoing delay and possibly increased mortality), or high (cannot be postponed; will have greater morbidity and/or higher risk of mortality). Because of the uncertainty about COVID-19, it is harder to quantify the benefits of refusing care and staying at home, although older patients and patients with underlying health issues are at higher risk of severe illness and death.²⁰ However, by taking appropriate precautions when seeking care, viral exposure and risk of infection can be mitigated.

This risk/benefit analysis will help set the threshold for whether staying at home is reasonable or whether it would incur more risk of harm. If the latter, then the physician must elicit the patient’s understanding, appreciation, and reasoning related to their current medical condition and COVID-19. It is likely they are undervaluing the former and overvaluing the latter. Table 2 lists important points to cover during these discussions.

Although there is no legal recourse to force patients at home to come to the clinic or hospital for medical treatment, there are several possible strategies to motivate them to do so. One is to ask patients how likely (on a scale of 0 to 100) they think they are to contract COVID-19 if they came for evaluation/treatment, and how likely they feel they are to experience a bad outcome from their primary condition. Then, after providing psychoeducation about their primary medical condition and COVID-19–related precautions and risk, repeat this question. Another strategy is to empathize with the patient’s fears while also expressing concern about the primary medical condition and connecting with the patient on the shared desire to protect his/her health. A third is to draw a risk/benefit diagram (similar to Figure 3) or reassure the patient by describing the ways in which the clinic or hospital is minimizing exposure and infection risk. A final strategy is to enlist the help of the patient’s family or friends.

Continue to: Bottom Line

In order to have decision-making capacity, a patient must demonstrate choice, understanding, appreciation, and reasoning. The degree of understanding, appreciation, and reasoning required depends on the capacity threshold, which is determined by a risk/benefit analysis. Conducting a risk/benefit analysis during the coronavirus disease 2019 (COVID-19) pandemic requires consideration of societallevel factors (such as contagiousness to others and health-care utilization) and is complicated by a wide range of uncertainties and divisive sociopolitical views regarding COVID-19.

Related Resources

• Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840.
• Ryznar E, Hamaoka D, Lloyd RB. Capacity evaluations. https://admsep.org/csi-emodules.php?c=capacity&v=y. Accessed March 30, 2020.

Acknowledgments

The author thanks Drs. Awais Aftab, Zackary D. Berger, and R. Brett Lloyd for their helpful discussions on the topic.

Since beginning my psychiatry residency, I have come to dread situations in which I feel like the antagonist in my patient’s life. These are moments when, due to psychiatric illness or intoxication, my patient does not want my help. In these situations, the patient’s condition may prevent shared decision-making to determine the best care for them. I experienced such a situation on my first day of residency, and that encounter taught me several valuable lessons.

An anxiety-filled first day

While working with my attending physician in a psychiatric emergency department, we met with a patient who had become agitated and was threatening staff members. The patient was also loudly protesting any use of medications. As a medical student, I had encountered patients who were agitated, but this moment felt vastly different because I was now tasked with addressing the problem. I still remember how my muscles tensed out of anxiety. As the attending took the lead in talking with the patient, the situation continued to escalate. The patient’s agitation was preventing them from being able to safely cooperate with staff despite our efforts at verbal de-escalation. As several staff members stayed with the patient, my attending and I went back to the workroom, where she instructed me to place orders for emergent medications. I sat there, an anxious intern with the solemn power and responsibility to order medications that might need to be administered against the will of an agitated patient. The moment was surreal.

A harsh reality

I had envisioned my first day of residency to be quite different. I had expected to sit with patients, healing them by listening to their stories and giving them the attention they deserved. But instead, I found myself nervously inputting medication orders, checking and rechecking that the doses and administration routes were accurate—all the while knowing that the patient would likely refuse the medications. If that occurred, the patient would need to be held by staff so the medications could be administered. Although I knew that administering emergent medications was the appropriate clinical decision to prevent harm to the patient and others, I felt conflicted by acting in opposition to the patient’s wishes. In that moment, intoxication or illness compromised patient autonomy for the sake of beneficence. I struggled with a creeping sense of guilt.

Although I did not have the chance to interact with this specific patient again, I often reflect on that encounter. I have learned that at times, the use of emergent medications or court commitments for medication administration or hospitalizations is necessary. Since that first shift, I have cared for many other patients who have received emergent medications under similar circumstances. I have observed that such treatment often stabilizes patients and enables me to engage them in meaningful conversation to optimize their care.

Lessons learned

While some of what I have experienced during my training has made me uncomfortable, I have taken with me several valuable lessons. When a patient’s intoxication or illness prevents shared decision-making, our focus as physicians should remain on the patient’s safety, health, and well-being. It is necessary to engage patients in conversations to enable us to understand what ails them and promptly determine the right treatment, tailored to their specific needs and goals.

Moving forward, I know that I will encounter many more similar situations. I hope to position myself quickly and safely alongside agitated patients to engage them in shared decision-making. As a physician, I will approach every encounter with my patients as an opportunity to understand their goals for care, and empower them to make informed decisions regarding their treatment.

Since beginning my psychiatry residency, I have come to dread situations in which I feel like the antagonist in my patient’s life. These are moments when, due to psychiatric illness or intoxication, my patient does not want my help. In these situations, the patient’s condition may prevent shared decision-making to determine the best care for them. I experienced such a situation on my first day of residency, and that encounter taught me several valuable lessons.

An anxiety-filled first day

While working with my attending physician in a psychiatric emergency department, we met with a patient who had become agitated and was threatening staff members. The patient was also loudly protesting any use of medications. As a medical student, I had encountered patients who were agitated, but this moment felt vastly different because I was now tasked with addressing the problem. I still remember how my muscles tensed out of anxiety. As the attending took the lead in talking with the patient, the situation continued to escalate. The patient’s agitation was preventing them from being able to safely cooperate with staff despite our efforts at verbal de-escalation. As several staff members stayed with the patient, my attending and I went back to the workroom, where she instructed me to place orders for emergent medications. I sat there, an anxious intern with the solemn power and responsibility to order medications that might need to be administered against the will of an agitated patient. The moment was surreal.

A harsh reality

I had envisioned my first day of residency to be quite different. I had expected to sit with patients, healing them by listening to their stories and giving them the attention they deserved. But instead, I found myself nervously inputting medication orders, checking and rechecking that the doses and administration routes were accurate—all the while knowing that the patient would likely refuse the medications. If that occurred, the patient would need to be held by staff so the medications could be administered. Although I knew that administering emergent medications was the appropriate clinical decision to prevent harm to the patient and others, I felt conflicted by acting in opposition to the patient’s wishes. In that moment, intoxication or illness compromised patient autonomy for the sake of beneficence. I struggled with a creeping sense of guilt.

Although I did not have the chance to interact with this specific patient again, I often reflect on that encounter. I have learned that at times, the use of emergent medications or court commitments for medication administration or hospitalizations is necessary. Since that first shift, I have cared for many other patients who have received emergent medications under similar circumstances. I have observed that such treatment often stabilizes patients and enables me to engage them in meaningful conversation to optimize their care.

Lessons learned

While some of what I have experienced during my training has made me uncomfortable, I have taken with me several valuable lessons. When a patient’s intoxication or illness prevents shared decision-making, our focus as physicians should remain on the patient’s safety, health, and well-being. It is necessary to engage patients in conversations to enable us to understand what ails them and promptly determine the right treatment, tailored to their specific needs and goals.

Moving forward, I know that I will encounter many more similar situations. I hope to position myself quickly and safely alongside agitated patients to engage them in shared decision-making. As a physician, I will approach every encounter with my patients as an opportunity to understand their goals for care, and empower them to make informed decisions regarding their treatment.

Since beginning my psychiatry residency, I have come to dread situations in which I feel like the antagonist in my patient’s life. These are moments when, due to psychiatric illness or intoxication, my patient does not want my help. In these situations, the patient’s condition may prevent shared decision-making to determine the best care for them. I experienced such a situation on my first day of residency, and that encounter taught me several valuable lessons.

An anxiety-filled first day

While working with my attending physician in a psychiatric emergency department, we met with a patient who had become agitated and was threatening staff members. The patient was also loudly protesting any use of medications. As a medical student, I had encountered patients who were agitated, but this moment felt vastly different because I was now tasked with addressing the problem. I still remember how my muscles tensed out of anxiety. As the attending took the lead in talking with the patient, the situation continued to escalate. The patient’s agitation was preventing them from being able to safely cooperate with staff despite our efforts at verbal de-escalation. As several staff members stayed with the patient, my attending and I went back to the workroom, where she instructed me to place orders for emergent medications. I sat there, an anxious intern with the solemn power and responsibility to order medications that might need to be administered against the will of an agitated patient. The moment was surreal.

A harsh reality

I had envisioned my first day of residency to be quite different. I had expected to sit with patients, healing them by listening to their stories and giving them the attention they deserved. But instead, I found myself nervously inputting medication orders, checking and rechecking that the doses and administration routes were accurate—all the while knowing that the patient would likely refuse the medications. If that occurred, the patient would need to be held by staff so the medications could be administered. Although I knew that administering emergent medications was the appropriate clinical decision to prevent harm to the patient and others, I felt conflicted by acting in opposition to the patient’s wishes. In that moment, intoxication or illness compromised patient autonomy for the sake of beneficence. I struggled with a creeping sense of guilt.

Although I did not have the chance to interact with this specific patient again, I often reflect on that encounter. I have learned that at times, the use of emergent medications or court commitments for medication administration or hospitalizations is necessary. Since that first shift, I have cared for many other patients who have received emergent medications under similar circumstances. I have observed that such treatment often stabilizes patients and enables me to engage them in meaningful conversation to optimize their care.

Lessons learned

While some of what I have experienced during my training has made me uncomfortable, I have taken with me several valuable lessons. When a patient’s intoxication or illness prevents shared decision-making, our focus as physicians should remain on the patient’s safety, health, and well-being. It is necessary to engage patients in conversations to enable us to understand what ails them and promptly determine the right treatment, tailored to their specific needs and goals.

Moving forward, I know that I will encounter many more similar situations. I hope to position myself quickly and safely alongside agitated patients to engage them in shared decision-making. As a physician, I will approach every encounter with my patients as an opportunity to understand their goals for care, and empower them to make informed decisions regarding their treatment.

My role as a mother expands and contracts in hard-won harmony with my role as a psychiatry resident. The magnitude of this responsibility compounded on itself when, seemingly overnight, the world we once trusted suddenly became unsafe. Coronavirus disease 2019 (COVID-19), deadly to immunocompromised individuals and the harbinger of a lethal autoimmune syndrome in children, was at our doorstep.

COVID-19 and parents who work in health care

After COVID-19 reached the United States, my fellow residents and I began to exchange nervous text messages, wondering what we could expect. Not only did the biological threat of the virus loom at the limited hospital entry points, but news alerts about infected front-line health care professionals and supply shortages jammed our cellphones. We quickly learned that some front-line physicians and nurses in New York had decided to live separately from their families. One article reported that a resident who was 5 months postpartum had chosen to live separately from her infant to protect her from exposure. “What a fundamental conflict of identity,” I thought as I read the article. Looking at my own young family, I felt our vulnerability overcome me. Would I have to do the same?

Difficult choices that exemplify both excitement and fear seem to define parenthood. Only months ago, I was selecting a car seat. As I scoured consumer reports, I became aware of a harrowing irony: in the excitement of nesting, I was also preparing for a collision. In March, when the quarantine began, I found myself evaluating my options for how to protect my family during a pandemic that often feels like a car crash in slow motion.

Health care professionals began to separate from their families to reduce the risk of transmission. Whether children went to live with relatives or health care workers stopped snuggling their young children, a structural boundary was formed just as the roots of attachment were taking shape. When asked about the loss inherent in this separation, these young parents expressed sadness but also said the choice was clear: their need to protect their families was absolute.

Meanwhile, some residents found themselves in a crash course on telemedicine. Safe from coronavirus exposure at work and liberated from a daily commute, these parents saw their young children more than ever before. Young child­ren saw their parents who were residents more than ever before. Perhaps the isolation of a front-line resident was sadly not a new experience.

Reassessing priorities

Now that the first wave of infections has broken over our coastal cities, residents from the front lines of COVID-19 are reuniting with their families. The sacrifices they made are re-evaluated as they begin to recognize anew the value of physical closeness with their loved ones in a dangerous world. One family that separated during the first wave said they would plan an alternate strategy, perhaps invest in a babysitter, rather than divide the household a second time.

While COVID-19 hit us hard, it has also forced a rare opportunity for self-assessment of priorities that we as trainees rarely take. We don’t have a consumer report on the safety ratings of COVID-19 plans. There is no formula for success. Instead, we each balance work and personal life with individual strategies to cope with elements outside of our control. This coping strategy may look different for each family. I hope all training departments take this plurality into account when considering the new demands on residents that have emerged during COVID-19.

My role as a mother expands and contracts in hard-won harmony with my role as a psychiatry resident. The magnitude of this responsibility compounded on itself when, seemingly overnight, the world we once trusted suddenly became unsafe. Coronavirus disease 2019 (COVID-19), deadly to immunocompromised individuals and the harbinger of a lethal autoimmune syndrome in children, was at our doorstep.

COVID-19 and parents who work in health care

After COVID-19 reached the United States, my fellow residents and I began to exchange nervous text messages, wondering what we could expect. Not only did the biological threat of the virus loom at the limited hospital entry points, but news alerts about infected front-line health care professionals and supply shortages jammed our cellphones. We quickly learned that some front-line physicians and nurses in New York had decided to live separately from their families. One article reported that a resident who was 5 months postpartum had chosen to live separately from her infant to protect her from exposure. “What a fundamental conflict of identity,” I thought as I read the article. Looking at my own young family, I felt our vulnerability overcome me. Would I have to do the same?

Difficult choices that exemplify both excitement and fear seem to define parenthood. Only months ago, I was selecting a car seat. As I scoured consumer reports, I became aware of a harrowing irony: in the excitement of nesting, I was also preparing for a collision. In March, when the quarantine began, I found myself evaluating my options for how to protect my family during a pandemic that often feels like a car crash in slow motion.

Health care professionals began to separate from their families to reduce the risk of transmission. Whether children went to live with relatives or health care workers stopped snuggling their young children, a structural boundary was formed just as the roots of attachment were taking shape. When asked about the loss inherent in this separation, these young parents expressed sadness but also said the choice was clear: their need to protect their families was absolute.

Meanwhile, some residents found themselves in a crash course on telemedicine. Safe from coronavirus exposure at work and liberated from a daily commute, these parents saw their young children more than ever before. Young child­ren saw their parents who were residents more than ever before. Perhaps the isolation of a front-line resident was sadly not a new experience.

Reassessing priorities

Now that the first wave of infections has broken over our coastal cities, residents from the front lines of COVID-19 are reuniting with their families. The sacrifices they made are re-evaluated as they begin to recognize anew the value of physical closeness with their loved ones in a dangerous world. One family that separated during the first wave said they would plan an alternate strategy, perhaps invest in a babysitter, rather than divide the household a second time.

While COVID-19 hit us hard, it has also forced a rare opportunity for self-assessment of priorities that we as trainees rarely take. We don’t have a consumer report on the safety ratings of COVID-19 plans. There is no formula for success. Instead, we each balance work and personal life with individual strategies to cope with elements outside of our control. This coping strategy may look different for each family. I hope all training departments take this plurality into account when considering the new demands on residents that have emerged during COVID-19.

My role as a mother expands and contracts in hard-won harmony with my role as a psychiatry resident. The magnitude of this responsibility compounded on itself when, seemingly overnight, the world we once trusted suddenly became unsafe. Coronavirus disease 2019 (COVID-19), deadly to immunocompromised individuals and the harbinger of a lethal autoimmune syndrome in children, was at our doorstep.

COVID-19 and parents who work in health care

After COVID-19 reached the United States, my fellow residents and I began to exchange nervous text messages, wondering what we could expect. Not only did the biological threat of the virus loom at the limited hospital entry points, but news alerts about infected front-line health care professionals and supply shortages jammed our cellphones. We quickly learned that some front-line physicians and nurses in New York had decided to live separately from their families. One article reported that a resident who was 5 months postpartum had chosen to live separately from her infant to protect her from exposure. “What a fundamental conflict of identity,” I thought as I read the article. Looking at my own young family, I felt our vulnerability overcome me. Would I have to do the same?

Difficult choices that exemplify both excitement and fear seem to define parenthood. Only months ago, I was selecting a car seat. As I scoured consumer reports, I became aware of a harrowing irony: in the excitement of nesting, I was also preparing for a collision. In March, when the quarantine began, I found myself evaluating my options for how to protect my family during a pandemic that often feels like a car crash in slow motion.

Health care professionals began to separate from their families to reduce the risk of transmission. Whether children went to live with relatives or health care workers stopped snuggling their young children, a structural boundary was formed just as the roots of attachment were taking shape. When asked about the loss inherent in this separation, these young parents expressed sadness but also said the choice was clear: their need to protect their families was absolute.

Meanwhile, some residents found themselves in a crash course on telemedicine. Safe from coronavirus exposure at work and liberated from a daily commute, these parents saw their young children more than ever before. Young child­ren saw their parents who were residents more than ever before. Perhaps the isolation of a front-line resident was sadly not a new experience.

Reassessing priorities

Now that the first wave of infections has broken over our coastal cities, residents from the front lines of COVID-19 are reuniting with their families. The sacrifices they made are re-evaluated as they begin to recognize anew the value of physical closeness with their loved ones in a dangerous world. One family that separated during the first wave said they would plan an alternate strategy, perhaps invest in a babysitter, rather than divide the household a second time.

While COVID-19 hit us hard, it has also forced a rare opportunity for self-assessment of priorities that we as trainees rarely take. We don’t have a consumer report on the safety ratings of COVID-19 plans. There is no formula for success. Instead, we each balance work and personal life with individual strategies to cope with elements outside of our control. This coping strategy may look different for each family. I hope all training departments take this plurality into account when considering the new demands on residents that have emerged during COVID-19.

I am a psychiatrist at a community mental health center located close to a large city. I want to report on our experience treating 100 consecutive, non-duplicative patients during the coronavirus disease 2019 (COVID-19) pandemic. Most of these patients had medical assistance or Medicare. Fifty-one were white, 46 were black, and 3 were Asian; 50 were men, and their ages ranged from 16 to 83 (mean: 54; median: 56). Using each patient as his/her own control (pre- and post–COVID-19), here I report 6 observations I made while treating these patients.

1. Telehealth worked for most patients. Of the 100 patients, 18 were seen in-person. Of the 18 seen in person, 14 received long-acting IM injections, and 2 patients presented with urgent matters that I felt required in-person evaluations. One patient needed to fill out several forms and provide consents, and 1 patient with chronic illness was treated at the clinic because he mistakenly arrived in person for his appointment.

The remaining 82 patients had telehealth sessions. Only 9 patients said they were able to use video conferencing, so the remaining 73 patients were treated by phone. These patients were mostly poor and/or older and had no access to smartphones or computers. This is especially important because the current emergency telehealth rules allow phone-only sessions, while regular telehealth rules do not. Our clinic strongly advocates for the extension of emergency telehealth rules. I have e-mailed many elected officials about this, but I have received few replies and no substantive responses. Our clinic also needs to help our patients obtain increased audiovisual capabilities.

2. Female patients fared better in their treatment than males.

3. Older patients did better than younger patients. Older patients’ experiences of living through past crises were helpful because they were able to compare how they persevered in the past with the current pandemic.

4. White patients showed more improvements compared with black patients. White patients generally had greater access to resources and support.

5. Patients with psychotic diagnoses/symptoms improved more than those with neurotic/anxiety/depressive diagnoses or symptoms. Most of our patients with psychotic diagnoses were already in a supportive, structured living environment, so the new “COVID-19 world” may be less disruptive for them. Additionally, it was more difficult for our patients to get substances of abuse because they had less mobility and access during the pandemic.

Continue to: Support

6. Support, especially from family but also institutional support, trumped other factors. The more support and structure our patients had, the better they did.

My observations may not be generalizable because I am reporting on a relatively small population size, most patients were older, and most were established patients who were likely more stable. I plan to follow up with these patients to see how the new COVID-19 world continues to affect them, and us.

Daniel D. Storch, MD
Key Point Health Services
Catonsville, Maryland

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

I am a psychiatrist at a community mental health center located close to a large city. I want to report on our experience treating 100 consecutive, non-duplicative patients during the coronavirus disease 2019 (COVID-19) pandemic. Most of these patients had medical assistance or Medicare. Fifty-one were white, 46 were black, and 3 were Asian; 50 were men, and their ages ranged from 16 to 83 (mean: 54; median: 56). Using each patient as his/her own control (pre- and post–COVID-19), here I report 6 observations I made while treating these patients.

1. Telehealth worked for most patients. Of the 100 patients, 18 were seen in-person. Of the 18 seen in person, 14 received long-acting IM injections, and 2 patients presented with urgent matters that I felt required in-person evaluations. One patient needed to fill out several forms and provide consents, and 1 patient with chronic illness was treated at the clinic because he mistakenly arrived in person for his appointment.

The remaining 82 patients had telehealth sessions. Only 9 patients said they were able to use video conferencing, so the remaining 73 patients were treated by phone. These patients were mostly poor and/or older and had no access to smartphones or computers. This is especially important because the current emergency telehealth rules allow phone-only sessions, while regular telehealth rules do not. Our clinic strongly advocates for the extension of emergency telehealth rules. I have e-mailed many elected officials about this, but I have received few replies and no substantive responses. Our clinic also needs to help our patients obtain increased audiovisual capabilities.

2. Female patients fared better in their treatment than males.

3. Older patients did better than younger patients. Older patients’ experiences of living through past crises were helpful because they were able to compare how they persevered in the past with the current pandemic.

4. White patients showed more improvements compared with black patients. White patients generally had greater access to resources and support.

5. Patients with psychotic diagnoses/symptoms improved more than those with neurotic/anxiety/depressive diagnoses or symptoms. Most of our patients with psychotic diagnoses were already in a supportive, structured living environment, so the new “COVID-19 world” may be less disruptive for them. Additionally, it was more difficult for our patients to get substances of abuse because they had less mobility and access during the pandemic.

Continue to: Support

6. Support, especially from family but also institutional support, trumped other factors. The more support and structure our patients had, the better they did.

My observations may not be generalizable because I am reporting on a relatively small population size, most patients were older, and most were established patients who were likely more stable. I plan to follow up with these patients to see how the new COVID-19 world continues to affect them, and us.

Daniel D. Storch, MD
Key Point Health Services
Catonsville, Maryland

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

I am a psychiatrist at a community mental health center located close to a large city. I want to report on our experience treating 100 consecutive, non-duplicative patients during the coronavirus disease 2019 (COVID-19) pandemic. Most of these patients had medical assistance or Medicare. Fifty-one were white, 46 were black, and 3 were Asian; 50 were men, and their ages ranged from 16 to 83 (mean: 54; median: 56). Using each patient as his/her own control (pre- and post–COVID-19), here I report 6 observations I made while treating these patients.

1. Telehealth worked for most patients. Of the 100 patients, 18 were seen in-person. Of the 18 seen in person, 14 received long-acting IM injections, and 2 patients presented with urgent matters that I felt required in-person evaluations. One patient needed to fill out several forms and provide consents, and 1 patient with chronic illness was treated at the clinic because he mistakenly arrived in person for his appointment.

The remaining 82 patients had telehealth sessions. Only 9 patients said they were able to use video conferencing, so the remaining 73 patients were treated by phone. These patients were mostly poor and/or older and had no access to smartphones or computers. This is especially important because the current emergency telehealth rules allow phone-only sessions, while regular telehealth rules do not. Our clinic strongly advocates for the extension of emergency telehealth rules. I have e-mailed many elected officials about this, but I have received few replies and no substantive responses. Our clinic also needs to help our patients obtain increased audiovisual capabilities.

2. Female patients fared better in their treatment than males.

3. Older patients did better than younger patients. Older patients’ experiences of living through past crises were helpful because they were able to compare how they persevered in the past with the current pandemic.

4. White patients showed more improvements compared with black patients. White patients generally had greater access to resources and support.

5. Patients with psychotic diagnoses/symptoms improved more than those with neurotic/anxiety/depressive diagnoses or symptoms. Most of our patients with psychotic diagnoses were already in a supportive, structured living environment, so the new “COVID-19 world” may be less disruptive for them. Additionally, it was more difficult for our patients to get substances of abuse because they had less mobility and access during the pandemic.

Continue to: Support

6. Support, especially from family but also institutional support, trumped other factors. The more support and structure our patients had, the better they did.

My observations may not be generalizable because I am reporting on a relatively small population size, most patients were older, and most were established patients who were likely more stable. I plan to follow up with these patients to see how the new COVID-19 world continues to affect them, and us.

Daniel D. Storch, MD
Key Point Health Services
Catonsville, Maryland

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

It’s election season again. Every 4 years, October becomes the purgatory month of politics. But this year, it’s even more complicated, being juxtaposed against a chaotic mosaic of a viral pandemic, economic travails, social upheaval, and exceptionally toxic political hyperpartisanship.

The widespread expectation is that citizens will vote for their party’s candidates, but there is now a body of evidence suggesting that our brains may be pre-wired to be liberal or conservative.

Enter neuro-politics. This discipline is younger than neuro-economics, neuro-law, neuro-ethics, neuro-marketing, neuro-art, neuro-culture, or neuro-esthetics. Neuro-politics focuses on the intersection of politics with neuroscience.¹ However, there are many antecedents to neuro-politics reflected in the writings of Plato, Aristotle, Niccolò Machiavelli, John Locke, Baruch Spinoza, Henri Bergson, William James, and others.

Neuro-politics attempts to generate data to answer a variety of questions about political behavior, such as:

• Is political orientation associated with differences in certain brain regions?
• Are there reliable neural biomarkers of political orientation?
• Is political orientation modifiable, and if so, why are some individuals ferociously entrenched to one political dogma while others are able to untether themselves and adopt another political doctrine?
• What are the brain characteristics of “swing voters” who may align themselves with different parties in different election cycles?
• Is there a “religification” of politics among the ardent fanatics who regard the tenets of their political beliefs as “articles of faith?”
• Is the brain modified by certain attributes (such as educational level, age, sex, marital status, race, ethnicity, and religious affiliation) that translate to political decision-making?
• Can neuro-politics explain the sprouting of psychiatric symptoms such as obsessions, anxiety, irritability, anger, hatred, and conspiracy theories?
• Is political extremism driven by cortical structures, limbic structures, or both?

Politics and the brain

Here is a brief review of some studies that examined the relationship of political orientation or voting behavior with brain structure and function:

1. Roger Sperry, the 1981 Nobel Laureate (for his studies on split-brain patients) reported that in patients who underwent callosotomy, both cerebral hemispheres gave the same ratings of politicians when their photos were shown to each hemisphere separately.²

2. A functional magnetic resonance imaging (fMRI) study found that the faces of candidates activated participants’ ventromedial and anterior prefrontal cortices. Amygdala activation was associated with the intensity of the emotion.³

Continue to: A skin conductance...

3. A skin conductance study reported that politically liberal individuals had low reactivity to sudden noises and threatening stimuli, while conservative counterparts demonstrated high physiological reactions to noises and stimuli.⁴

4. Images of a losing candidate elicited greater activation on fMRI in the insula and ventral anterior cingulate compared to no activation by exposure to an image of the winning candidate.⁵

5. Another fMRI study found that “individualism” was associated with activation of the medial prefrontal cortex and temporo-parietal junction when participants listened to a set of political statements. On the other hand, “conservatism” activated the dorsolateral prefrontal cortex, while “radicalism” activated the ventral striatum and posterior cingulate.⁶

6. An EEG activity study of healthy individuals revealed desynchronization in the alpha band related to the politicians who lost simulated elections and were judged as “less trustworthy” when the participant watched their faces.⁷

7. A structural MRI study of young adults reported that liberalism was associated with increased gray matter volume in the anterior cingulate, while conservatism was associated with increased volume of the right amygdala. The authors replicated their findings and concluded there is a possible link between brain structure and psychological mechanisms that mediate political attitudes.⁸

Continue to: To examine the effect of...

8. To examine the effect of a “first impression” based on the physical appearance of candidates, researchers compared individuals with damage to the lateral orbitofrontal cortex (OFC) with a group that had frontal damage that spared the lateral OFC and another group of matched healthy volunteers. They used a simulated elections paradigm in which participants voted based solely on photographs of the candidates’ faces. Only the group with OFC damage was influenced by attractiveness, while those with an intact frontal lobe or non-OFC frontal damage relied on other data, such as competence.⁹ These researchers concluded that an intact OFC is necessary for political decision-making.

9. A study using cognitive tasks reported that liberals are more adept at dealing with novel information than conservatives.¹⁰

What part of your brain will you use?

Regardless of the data generated by the neuro-politics studies, the bottom line is: What part of your brain do you use when you cast your vote for an issue, a representative, a senator, or a president? Is it a purely intellectual decision (ie, cortical), or is it driven by visceral emotions (ie, limbic)? Do you believe that every single item in your party’s platform is right and virtuous, while every item in the other party’s platform is wrong and evil? Can you think of any redeeming feature of the candidate you hate or the party you despise?

One attribute that we psychiatrists possess by virtue of our training and clinical work is that we are able to transcend dichotomies and to perceive nuances and shades of gray about controversial issues. So I hope we employ the circuits of our brain where wisdom putatively resides¹¹ and which may develop further (via neuroplasticity) with the conduct of psychotherapy.¹² Those brain circuits include:

• prefrontal cortex (for emotional regulation, decision-making, and value relativism)
• lateral prefrontal cortex (to facilitate calculated, reason-based decision-making)
• medial prefrontal cortex (for emotional valence and pro-social attitudes and behaviors).

However, being human, it is quite likely that our amygdala may “seep through” and color our judgment and decisions. But let us try to cast a vote that is not only good for the country but also good for our patients, many of whom may not even be able to vote. Election season is a time to make a positive difference in our patients’ lives, not just ours. Let’s hope our brains exploit this unique opportunity.

It’s election season again. Every 4 years, October becomes the purgatory month of politics. But this year, it’s even more complicated, being juxtaposed against a chaotic mosaic of a viral pandemic, economic travails, social upheaval, and exceptionally toxic political hyperpartisanship.

The widespread expectation is that citizens will vote for their party’s candidates, but there is now a body of evidence suggesting that our brains may be pre-wired to be liberal or conservative.

Enter neuro-politics. This discipline is younger than neuro-economics, neuro-law, neuro-ethics, neuro-marketing, neuro-art, neuro-culture, or neuro-esthetics. Neuro-politics focuses on the intersection of politics with neuroscience.¹ However, there are many antecedents to neuro-politics reflected in the writings of Plato, Aristotle, Niccolò Machiavelli, John Locke, Baruch Spinoza, Henri Bergson, William James, and others.

Neuro-politics attempts to generate data to answer a variety of questions about political behavior, such as:

• Is political orientation associated with differences in certain brain regions?
• Are there reliable neural biomarkers of political orientation?
• Is political orientation modifiable, and if so, why are some individuals ferociously entrenched to one political dogma while others are able to untether themselves and adopt another political doctrine?
• What are the brain characteristics of “swing voters” who may align themselves with different parties in different election cycles?
• Is there a “religification” of politics among the ardent fanatics who regard the tenets of their political beliefs as “articles of faith?”
• Is the brain modified by certain attributes (such as educational level, age, sex, marital status, race, ethnicity, and religious affiliation) that translate to political decision-making?
• Can neuro-politics explain the sprouting of psychiatric symptoms such as obsessions, anxiety, irritability, anger, hatred, and conspiracy theories?
• Is political extremism driven by cortical structures, limbic structures, or both?

Politics and the brain

Here is a brief review of some studies that examined the relationship of political orientation or voting behavior with brain structure and function:

1. Roger Sperry, the 1981 Nobel Laureate (for his studies on split-brain patients) reported that in patients who underwent callosotomy, both cerebral hemispheres gave the same ratings of politicians when their photos were shown to each hemisphere separately.²

2. A functional magnetic resonance imaging (fMRI) study found that the faces of candidates activated participants’ ventromedial and anterior prefrontal cortices. Amygdala activation was associated with the intensity of the emotion.³

Continue to: A skin conductance...

3. A skin conductance study reported that politically liberal individuals had low reactivity to sudden noises and threatening stimuli, while conservative counterparts demonstrated high physiological reactions to noises and stimuli.⁴

4. Images of a losing candidate elicited greater activation on fMRI in the insula and ventral anterior cingulate compared to no activation by exposure to an image of the winning candidate.⁵

5. Another fMRI study found that “individualism” was associated with activation of the medial prefrontal cortex and temporo-parietal junction when participants listened to a set of political statements. On the other hand, “conservatism” activated the dorsolateral prefrontal cortex, while “radicalism” activated the ventral striatum and posterior cingulate.⁶

6. An EEG activity study of healthy individuals revealed desynchronization in the alpha band related to the politicians who lost simulated elections and were judged as “less trustworthy” when the participant watched their faces.⁷

7. A structural MRI study of young adults reported that liberalism was associated with increased gray matter volume in the anterior cingulate, while conservatism was associated with increased volume of the right amygdala. The authors replicated their findings and concluded there is a possible link between brain structure and psychological mechanisms that mediate political attitudes.⁸

Continue to: To examine the effect of...

8. To examine the effect of a “first impression” based on the physical appearance of candidates, researchers compared individuals with damage to the lateral orbitofrontal cortex (OFC) with a group that had frontal damage that spared the lateral OFC and another group of matched healthy volunteers. They used a simulated elections paradigm in which participants voted based solely on photographs of the candidates’ faces. Only the group with OFC damage was influenced by attractiveness, while those with an intact frontal lobe or non-OFC frontal damage relied on other data, such as competence.⁹ These researchers concluded that an intact OFC is necessary for political decision-making.

9. A study using cognitive tasks reported that liberals are more adept at dealing with novel information than conservatives.¹⁰

What part of your brain will you use?

Regardless of the data generated by the neuro-politics studies, the bottom line is: What part of your brain do you use when you cast your vote for an issue, a representative, a senator, or a president? Is it a purely intellectual decision (ie, cortical), or is it driven by visceral emotions (ie, limbic)? Do you believe that every single item in your party’s platform is right and virtuous, while every item in the other party’s platform is wrong and evil? Can you think of any redeeming feature of the candidate you hate or the party you despise?

One attribute that we psychiatrists possess by virtue of our training and clinical work is that we are able to transcend dichotomies and to perceive nuances and shades of gray about controversial issues. So I hope we employ the circuits of our brain where wisdom putatively resides¹¹ and which may develop further (via neuroplasticity) with the conduct of psychotherapy.¹² Those brain circuits include:

• prefrontal cortex (for emotional regulation, decision-making, and value relativism)
• lateral prefrontal cortex (to facilitate calculated, reason-based decision-making)
• medial prefrontal cortex (for emotional valence and pro-social attitudes and behaviors).

However, being human, it is quite likely that our amygdala may “seep through” and color our judgment and decisions. But let us try to cast a vote that is not only good for the country but also good for our patients, many of whom may not even be able to vote. Election season is a time to make a positive difference in our patients’ lives, not just ours. Let’s hope our brains exploit this unique opportunity.

It’s election season again. Every 4 years, October becomes the purgatory month of politics. But this year, it’s even more complicated, being juxtaposed against a chaotic mosaic of a viral pandemic, economic travails, social upheaval, and exceptionally toxic political hyperpartisanship.

The widespread expectation is that citizens will vote for their party’s candidates, but there is now a body of evidence suggesting that our brains may be pre-wired to be liberal or conservative.

Enter neuro-politics. This discipline is younger than neuro-economics, neuro-law, neuro-ethics, neuro-marketing, neuro-art, neuro-culture, or neuro-esthetics. Neuro-politics focuses on the intersection of politics with neuroscience.¹ However, there are many antecedents to neuro-politics reflected in the writings of Plato, Aristotle, Niccolò Machiavelli, John Locke, Baruch Spinoza, Henri Bergson, William James, and others.

Neuro-politics attempts to generate data to answer a variety of questions about political behavior, such as:

• Is political orientation associated with differences in certain brain regions?
• Are there reliable neural biomarkers of political orientation?
• Is political orientation modifiable, and if so, why are some individuals ferociously entrenched to one political dogma while others are able to untether themselves and adopt another political doctrine?
• What are the brain characteristics of “swing voters” who may align themselves with different parties in different election cycles?
• Is there a “religification” of politics among the ardent fanatics who regard the tenets of their political beliefs as “articles of faith?”
• Is the brain modified by certain attributes (such as educational level, age, sex, marital status, race, ethnicity, and religious affiliation) that translate to political decision-making?
• Can neuro-politics explain the sprouting of psychiatric symptoms such as obsessions, anxiety, irritability, anger, hatred, and conspiracy theories?
• Is political extremism driven by cortical structures, limbic structures, or both?

Politics and the brain

Here is a brief review of some studies that examined the relationship of political orientation or voting behavior with brain structure and function:

1. Roger Sperry, the 1981 Nobel Laureate (for his studies on split-brain patients) reported that in patients who underwent callosotomy, both cerebral hemispheres gave the same ratings of politicians when their photos were shown to each hemisphere separately.²

2. A functional magnetic resonance imaging (fMRI) study found that the faces of candidates activated participants’ ventromedial and anterior prefrontal cortices. Amygdala activation was associated with the intensity of the emotion.³

Continue to: A skin conductance...

3. A skin conductance study reported that politically liberal individuals had low reactivity to sudden noises and threatening stimuli, while conservative counterparts demonstrated high physiological reactions to noises and stimuli.⁴

4. Images of a losing candidate elicited greater activation on fMRI in the insula and ventral anterior cingulate compared to no activation by exposure to an image of the winning candidate.⁵

5. Another fMRI study found that “individualism” was associated with activation of the medial prefrontal cortex and temporo-parietal junction when participants listened to a set of political statements. On the other hand, “conservatism” activated the dorsolateral prefrontal cortex, while “radicalism” activated the ventral striatum and posterior cingulate.⁶

6. An EEG activity study of healthy individuals revealed desynchronization in the alpha band related to the politicians who lost simulated elections and were judged as “less trustworthy” when the participant watched their faces.⁷

7. A structural MRI study of young adults reported that liberalism was associated with increased gray matter volume in the anterior cingulate, while conservatism was associated with increased volume of the right amygdala. The authors replicated their findings and concluded there is a possible link between brain structure and psychological mechanisms that mediate political attitudes.⁸

Continue to: To examine the effect of...

8. To examine the effect of a “first impression” based on the physical appearance of candidates, researchers compared individuals with damage to the lateral orbitofrontal cortex (OFC) with a group that had frontal damage that spared the lateral OFC and another group of matched healthy volunteers. They used a simulated elections paradigm in which participants voted based solely on photographs of the candidates’ faces. Only the group with OFC damage was influenced by attractiveness, while those with an intact frontal lobe or non-OFC frontal damage relied on other data, such as competence.⁹ These researchers concluded that an intact OFC is necessary for political decision-making.

9. A study using cognitive tasks reported that liberals are more adept at dealing with novel information than conservatives.¹⁰

What part of your brain will you use?

Regardless of the data generated by the neuro-politics studies, the bottom line is: What part of your brain do you use when you cast your vote for an issue, a representative, a senator, or a president? Is it a purely intellectual decision (ie, cortical), or is it driven by visceral emotions (ie, limbic)? Do you believe that every single item in your party’s platform is right and virtuous, while every item in the other party’s platform is wrong and evil? Can you think of any redeeming feature of the candidate you hate or the party you despise?

One attribute that we psychiatrists possess by virtue of our training and clinical work is that we are able to transcend dichotomies and to perceive nuances and shades of gray about controversial issues. So I hope we employ the circuits of our brain where wisdom putatively resides¹¹ and which may develop further (via neuroplasticity) with the conduct of psychotherapy.¹² Those brain circuits include:

• prefrontal cortex (for emotional regulation, decision-making, and value relativism)
• lateral prefrontal cortex (to facilitate calculated, reason-based decision-making)
• medial prefrontal cortex (for emotional valence and pro-social attitudes and behaviors).

However, being human, it is quite likely that our amygdala may “seep through” and color our judgment and decisions. But let us try to cast a vote that is not only good for the country but also good for our patients, many of whom may not even be able to vote. Election season is a time to make a positive difference in our patients’ lives, not just ours. Let’s hope our brains exploit this unique opportunity.

Ms. T, age 55, presents to her psychiatrist’s clinic with a chief complaint of ongoing symptoms of anhedonia and lethargy related to her diagnosis of major depressive disorder (MDD). She also has a history of peripheral arterial disease, hypothyroidism, and generalized anxiety disorder. Her current antidepressant regimen is duloxetine, 60 mg/d, and mirtazapine, 15 mg at night. She recently elected to undergo pharmacogenetic testing, which showed that she is heterozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (MTHFR C677T CT carrier). Her test report states that she may have impaired folate metabolism. Her psychiatrist adds L-methylfolate, 15 mg/d, to her current antidepressant regimen.

What is the relationship between folic acid and MTHFR?

Methylenetetrahydrofolate reductase is an intracellular enzyme responsible for one of several steps involved in converting dietary folic acid to its physiologically active form, L-methylfolate.¹ Once active, L-methylfolate can be transported into the CNS, where it participates in one-carbon transfer reactions.^2,3 Mutations in the MTHFR gene have been associated with decreased activity of the enzyme, which has been shown to result in accumulation of homocysteine and may lead to decreased synthesis of neurotransmitters.^2,4Commercial pharmacogenetic testing panels may offer MTHFR genetic testing to assist with prescribing decisions for patients with mental illness. The most well-characterized mutation currently is C677T (rsID1801133), which is a single amino acid base pair change (cytosine [C] to thymine [T]) that leads to increased thermolability and instability of the enzyme.⁵ Carrying 1 or 2 T alleles can lead to a 35% or 70% reduction in enzyme activity, respectively. The T variant allele is most frequent in Hispanics (20% to 25%), Asians (up to 63%), and Caucasians (8% to 20%); however, it is relatively uncommon in African Americans (<2%).^5,6 Another variant, A1289C (rs1801131), has also been associated with decreased enzyme function, particularly when analyzed in combination with C677T. However, carrying the 1289C variant allele does not appear to result in as large of a reduction of enzyme function as the 677T variant.⁷

What is the relationship between MTHFR C677T and depression?

Some researchers have proposed that the C677T mutation in MTHFR may be associated with depression as a result of decreased neurotransmitter synthesis, but studies have not consistently supported this hypothesis. Several studies suggest an association between MTHFR mutations and MDD^8-10:

Jiang et al⁸ performed a meta-analysis of 13 studies including 1,295 Chinese patients and found that having at least 1 C677T variant allele was significantly associated with an increased risk of depression (for T vs C odds ratio 1.52, 95% confidence interval 1.24 to 1.85). The authors noted a stronger association identified in the Northern Chinese population compared with the Southern Chinese population.⁸

Bousman et al⁹ found that American patients with MDD and the 677CC genotype had greater Patient Health Questionnaire-9 (PHQ-9) scores at assessments at 24, 36, and 48 months post-baseline compared with those with the 677TT genotype (P = .024), which was unexpected based on previously reported associations.⁹

Schiepers et al¹⁰ also assessed the association between the MTHFR genotype in a Dutch ambulatory care population over 12 years. There was no association identified between scores on the depression subscale of the Symptom Checklist 90 and C677T diplotype.¹⁰

Table 1^6,8-12 provides summaries of these and other selected studies on MTHFR and MDD. Overall, although a pathophysiological basis for depression and decreased MTHFR function has been proposed, the current body of literature does not indicate a consistent link between MTHFR C677T genetic variants alone and depression.

Continue to: Medication changes based on MTHFR: What is the evidence?

Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³ conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

Continue to: Mech and Farah...

Mech and Farah¹⁵ performed a random­ized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16 contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

Continue to: Related Resources

• Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007;165(1):1-13.
• Trimmer E. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current Pharmaceutical Design. 2013;19(4):2574-3595.

Drug Brand Names

Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
L-methylfolate • Deplin
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft

Ms. T, age 55, presents to her psychiatrist’s clinic with a chief complaint of ongoing symptoms of anhedonia and lethargy related to her diagnosis of major depressive disorder (MDD). She also has a history of peripheral arterial disease, hypothyroidism, and generalized anxiety disorder. Her current antidepressant regimen is duloxetine, 60 mg/d, and mirtazapine, 15 mg at night. She recently elected to undergo pharmacogenetic testing, which showed that she is heterozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (MTHFR C677T CT carrier). Her test report states that she may have impaired folate metabolism. Her psychiatrist adds L-methylfolate, 15 mg/d, to her current antidepressant regimen.

What is the relationship between folic acid and MTHFR?

Methylenetetrahydrofolate reductase is an intracellular enzyme responsible for one of several steps involved in converting dietary folic acid to its physiologically active form, L-methylfolate.¹ Once active, L-methylfolate can be transported into the CNS, where it participates in one-carbon transfer reactions.^2,3 Mutations in the MTHFR gene have been associated with decreased activity of the enzyme, which has been shown to result in accumulation of homocysteine and may lead to decreased synthesis of neurotransmitters.^2,4Commercial pharmacogenetic testing panels may offer MTHFR genetic testing to assist with prescribing decisions for patients with mental illness. The most well-characterized mutation currently is C677T (rsID1801133), which is a single amino acid base pair change (cytosine [C] to thymine [T]) that leads to increased thermolability and instability of the enzyme.⁵ Carrying 1 or 2 T alleles can lead to a 35% or 70% reduction in enzyme activity, respectively. The T variant allele is most frequent in Hispanics (20% to 25%), Asians (up to 63%), and Caucasians (8% to 20%); however, it is relatively uncommon in African Americans (<2%).^5,6 Another variant, A1289C (rs1801131), has also been associated with decreased enzyme function, particularly when analyzed in combination with C677T. However, carrying the 1289C variant allele does not appear to result in as large of a reduction of enzyme function as the 677T variant.⁷

What is the relationship between MTHFR C677T and depression?

Some researchers have proposed that the C677T mutation in MTHFR may be associated with depression as a result of decreased neurotransmitter synthesis, but studies have not consistently supported this hypothesis. Several studies suggest an association between MTHFR mutations and MDD^8-10:

Jiang et al⁸ performed a meta-analysis of 13 studies including 1,295 Chinese patients and found that having at least 1 C677T variant allele was significantly associated with an increased risk of depression (for T vs C odds ratio 1.52, 95% confidence interval 1.24 to 1.85). The authors noted a stronger association identified in the Northern Chinese population compared with the Southern Chinese population.⁸

Bousman et al⁹ found that American patients with MDD and the 677CC genotype had greater Patient Health Questionnaire-9 (PHQ-9) scores at assessments at 24, 36, and 48 months post-baseline compared with those with the 677TT genotype (P = .024), which was unexpected based on previously reported associations.⁹

Schiepers et al¹⁰ also assessed the association between the MTHFR genotype in a Dutch ambulatory care population over 12 years. There was no association identified between scores on the depression subscale of the Symptom Checklist 90 and C677T diplotype.¹⁰

Table 1^6,8-12 provides summaries of these and other selected studies on MTHFR and MDD. Overall, although a pathophysiological basis for depression and decreased MTHFR function has been proposed, the current body of literature does not indicate a consistent link between MTHFR C677T genetic variants alone and depression.

Continue to: Medication changes based on MTHFR: What is the evidence?

Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³ conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

Continue to: Mech and Farah...

Mech and Farah¹⁵ performed a random­ized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16 contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

Continue to: Related Resources

• Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007;165(1):1-13.
• Trimmer E. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current Pharmaceutical Design. 2013;19(4):2574-3595.

Drug Brand Names

Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
L-methylfolate • Deplin
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft

Ms. T, age 55, presents to her psychiatrist’s clinic with a chief complaint of ongoing symptoms of anhedonia and lethargy related to her diagnosis of major depressive disorder (MDD). She also has a history of peripheral arterial disease, hypothyroidism, and generalized anxiety disorder. Her current antidepressant regimen is duloxetine, 60 mg/d, and mirtazapine, 15 mg at night. She recently elected to undergo pharmacogenetic testing, which showed that she is heterozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (MTHFR C677T CT carrier). Her test report states that she may have impaired folate metabolism. Her psychiatrist adds L-methylfolate, 15 mg/d, to her current antidepressant regimen.

What is the relationship between folic acid and MTHFR?

Methylenetetrahydrofolate reductase is an intracellular enzyme responsible for one of several steps involved in converting dietary folic acid to its physiologically active form, L-methylfolate.¹ Once active, L-methylfolate can be transported into the CNS, where it participates in one-carbon transfer reactions.^2,3 Mutations in the MTHFR gene have been associated with decreased activity of the enzyme, which has been shown to result in accumulation of homocysteine and may lead to decreased synthesis of neurotransmitters.^2,4Commercial pharmacogenetic testing panels may offer MTHFR genetic testing to assist with prescribing decisions for patients with mental illness. The most well-characterized mutation currently is C677T (rsID1801133), which is a single amino acid base pair change (cytosine [C] to thymine [T]) that leads to increased thermolability and instability of the enzyme.⁵ Carrying 1 or 2 T alleles can lead to a 35% or 70% reduction in enzyme activity, respectively. The T variant allele is most frequent in Hispanics (20% to 25%), Asians (up to 63%), and Caucasians (8% to 20%); however, it is relatively uncommon in African Americans (<2%).^5,6 Another variant, A1289C (rs1801131), has also been associated with decreased enzyme function, particularly when analyzed in combination with C677T. However, carrying the 1289C variant allele does not appear to result in as large of a reduction of enzyme function as the 677T variant.⁷

What is the relationship between MTHFR C677T and depression?

Some researchers have proposed that the C677T mutation in MTHFR may be associated with depression as a result of decreased neurotransmitter synthesis, but studies have not consistently supported this hypothesis. Several studies suggest an association between MTHFR mutations and MDD^8-10:

Jiang et al⁸ performed a meta-analysis of 13 studies including 1,295 Chinese patients and found that having at least 1 C677T variant allele was significantly associated with an increased risk of depression (for T vs C odds ratio 1.52, 95% confidence interval 1.24 to 1.85). The authors noted a stronger association identified in the Northern Chinese population compared with the Southern Chinese population.⁸

Bousman et al⁹ found that American patients with MDD and the 677CC genotype had greater Patient Health Questionnaire-9 (PHQ-9) scores at assessments at 24, 36, and 48 months post-baseline compared with those with the 677TT genotype (P = .024), which was unexpected based on previously reported associations.⁹

Schiepers et al¹⁰ also assessed the association between the MTHFR genotype in a Dutch ambulatory care population over 12 years. There was no association identified between scores on the depression subscale of the Symptom Checklist 90 and C677T diplotype.¹⁰

Table 1^6,8-12 provides summaries of these and other selected studies on MTHFR and MDD. Overall, although a pathophysiological basis for depression and decreased MTHFR function has been proposed, the current body of literature does not indicate a consistent link between MTHFR C677T genetic variants alone and depression.

Continue to: Medication changes based on MTHFR: What is the evidence?

Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³ conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

Continue to: Mech and Farah...

Mech and Farah¹⁵ performed a random­ized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16 contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

Continue to: Related Resources

• Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007;165(1):1-13.
• Trimmer E. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Current Pharmaceutical Design. 2013;19(4):2574-3595.

Drug Brand Names

Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
L-methylfolate • Deplin
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft

CASE Drooling, unsteady, and not himself

B, age 10, who is left handed and has autism spectrum disorder, is brought to the emergency department (ED) with a 1-day history of drooling, unsteady gait, and left wrist in sustained flexion. His parents report that for the past week, B has had cold symptoms, including rhinorrhea, a low-grade fever (100.0°F), and cough. Earlier in the day, he was seen at his pediatrician’s office, where he was diagnosed with an acute respiratory infection and started on amoxicillin, 500 mg twice daily for 7 days.

At baseline, B is nonverbal. He requires some assistance with his activities of daily living. He usually is able to walk without assistance and dress himself, but he is not toilet trained. His parents report that in the past day, he has had significant difficulties with tasks involving his left hand. Normally, B is able to feed himself “finger foods” but has been unable to do so today. His parents say that he has been unsteady on his feet, and has been “falling forward” when he tries to walk.

Two years ago, B was started on risperidone, 0.5 mg nightly, for behavioral aggression and self-mutilation. Over the next 12 months, the dosage was steadily increased to 1 mg twice daily, with good response. He has been taking his current dosage, 1 mg twice daily, for the past 12 months without adjustment. His parents report there have been no other medication changes, other than starting amoxicillin earlier that day.

As part of his initial ED evaluation, B is found to be mildly dehydrated, with an elevated sedimentation rate on urinalysis. His complete blood count (CBC) with differential is within normal limits. A comprehensive metabolic panel shows a slight increase in his creatinine level, indicating dehydration. B is administered IV fluid replacement because he is having difficulty drinking due to excessive drooling.

The ED physician is concerned that B may be experiencing an acute dystonic reaction from risperidone, so the team holds this medication, and gives B a one-time dose of IV diphenhydramine, 25 mg, for presumptive acute dystonic reaction. After several minutes, there is no improvement in the sustained flexion of his left wrist.

[polldaddy:10615848]

The authors’ observations

B presented with new-onset neurologic findings after a recently diagnosed upper respiratory viral illness. His symptoms appeared to be confined to his left upper extremity, specifically demonstrating left arm extension at the elbow with flexion of the left wrist. He also had new-onset unsteady gait with a stooped forward posture and required assistance with walking. Interestingly, despite B’s history of antipsychotic use, administering an anticholinergic agent did not lessen the dystonic posturing at his wrist and elbow.

EVALUATION Laboratory results reveal new clues

While in the ED, B undergoes MRI of the brain and spinal cord to rule out any mass lesions that could be impinging upon the motor pathways. Both brain and spinal cord imaging appear to be essentially normal, without evidence of impingement of the spinal nerves or lesions involving the brainstem or cerebellum.

Continue to: Due to concerns...

Due to concerns of possible airway obstruction, a CT scan of the neck is obtained to rule out any acute pathology, such as epiglottitis compromising his airway. The scan shows some inflammation and edema in the soft tissues that is thought to be secondary to his acute viral illness. B is able to maintain his airway and oxygenation, so intubation is not necessary.

A CPK test is ordered because there are concerns of sustained muscle contraction of B’s left wrist and elbow. The CPK level is 884 U/L (reference range 26 to 192 U/L). The elevation in CPK is consistent with prior laboratory findings of dehydration and indicating skeletal muscle breakdown from sustained muscle contraction. All other laboratory results, including a comprehensive metabolic panel, urine drug screen, and thyroid screening panel, are within normal limits.

[polldaddy:10615850]

EVALUATION No variation in facial expression

B is admitted to the general pediatrics service. Maintenance IV fluids are started due to concerns of dehydration and possible rhabdomyolysis due to his elevated CPK level. Risperidone is held throughout the hospital course due to concerns for an acute dystonic reaction. B is monitored for several days without clinical improvement and eventually discharged home with a diagnosis of inflammatory mononeuropathy due to viral infection. The patient is told to discontinue risperidone as part of discharge instructions.

Five days later, B returns to the hospital because there was no improvement in his left extremity or walking. His left elbow remains extended with left wrist in flexion. Psychiatry is consulted for further diagnostic clarity and evaluation.

On physical examination, B’s left arm remains unchanged. Despite discontinuing risperidone, there is evidence of cogwheel rigidity of the left wrist joint. Reflexes in the upper and lower extremities are 2+ and symmetrical bilaterally, suggesting intact upper and lower motor pathways. Babinski sign is absent bilaterally, which is a normal finding in B’s age group. B continues to have difficulty with ambulating and appears to “fall forward” while trying to walk with assistance. His parents also say that B is not laughing, smiling, or showing any variation in facial expression.

Continue to: Additional family history...

Additional family history is gathered from B’s parents for possible hereditary movement disorders such as Wilson’s disease. They report that no family members have developed involuntary movements or other neurologic syndromes. Additional considerations on the differential diagnosis for B include juvenile ALS or mononeuropathy involving the C5 and C6 nerve roots. B’s parents deny any recent shoulder trauma, and radiographic studies did not demonstrate any involvement of the nerve roots.

TREATMENT A trial of bromocriptine

At this point, B’s neurologic workup is essentially normal, and he is given a provisional diagnosis of antipsychotic-induced tardive dystonia vs tardive parkinsonism. Risperidone continues to be held, and B is monitored for clinical improvement. B is administered a one-time dose of diphenhydramine, 25 mg, for dystonia with no improvement in symptoms. He is then started on bromocriptine, 1.25 mg twice daily with meals, for parkinsonian symptoms secondary to antipsychotic medication use. After 1 day of treatment, B shows less sustained flexion of his left wrist. He is able to relax his left arm, shows improvements in ambulation, and requires less assistance. B continues to be observed closely and continues to improve toward his baseline.

At Day 4, he is discharged. B is able to walk mostly without assistance and demonstrates improvement in left wrist flexion. He is scheduled to see a movement disorders specialist a week after discharge. The initial diagnosis given by the movement disorder specialist is tardive dystonia.

The authors’ observations

Tardive dyskinesia is a well-known iatrogenic effect of antipsychotic medications that are commonly used to manage conditions such as schizophrenia or behavioral agitation associated with autism spectrum disorder. Symptoms of tardive dyskinesia typically emerge after 1 to 2 years of continuous exposure to dopamine receptor blocking agents (DRBAs). Tardive dyskinesia symptoms include involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, and upper and lower extremities, with significant functional impairment.¹

Tardive syndromes refer to a diverse array of hyperkinetic, hypokinetic, and sensory movement disorders resulting from at least 3 months of continuous DRBA therapy.² Tardive dyskinesia is perhaps the most well-known of the tardive syndromes, but is not the only one to consider when assessing for antipsychotic-induced movement disorders. A key feature differentiating a tardive syndrome is the persistence of the movement disorder after the DRBA is discontinued. In this case, B had been receiving a stable dose of risperidone for >1 year. He developed dystonic posturing of his left wrist and elbow that was both unresponsive to anticholinergic medication and persisted after risperidone was discontinued. The term “tardive” emphasizes the delay in development of abnormal involuntary movement symptoms after initiating antipsychotic medications.³ Table 1² shows a comparison of tardive dystonia vs an acute dystonic reaction.

Continue to: Other tardive syndromes include...

Other tardive syndromes include:

• tardive tics
• tardive parkinsonism
• tardive pain
• tardive myoclonus
• tardive akathisia
• tardive tremors.

The incidence of tardive syndromes increases 5% annually for the first 5 years of treatment. At 10 years of treatment, the annual incidence is thought to be 49%, and at 25 years of treatment, 68%.⁴ The predominant theory of the pathophysiology of tardive syndromes is that the chronic use of DRBAs causes a gradual hypersensitization of dopamine receptors.⁴ The diagnosis of a tardive syndrome is based on history of exposure to a DRBA as well as clinical observation of symptoms.

Compared with classic tardive dyskinesia, tardive dystonia is more common among younger patients. The mean age of onset of tardive dystonia is 40, and it typically affects young males.⁵ Typical posturing observed in cases of tardive dystonia include extension of the arms and flexion at the wrists.⁶ In contrast to cases of primary dystonia, tardive dystonia is typically associated with stereotypies, akathisia, or other movement disorders. Anticholinergic agents, such as benztropine or trihexyphenidyl, may or may not alleviate symptoms of tardive dystonia but can worsen tardive dyskinesia, so careful delineation between the 2 syndromes is important.⁶

The American Psychiatric Association has issued guidelines on screening for involuntary movement syndromes by using the Abnormal Involuntary Movement Scale (AIMS).⁷ The current recommendations include assessment every 6 months for patients receiving first-generation antipsychotics, and every 12 months for those receiving second-generation antipsychotics.⁷ Prescribers should also carefully assess for any pre-existing involuntary movements before prescribing a DRBA.⁷

[polldaddy:10615855]

The authors’ observations

In 2013, the American Academy of Neurology (AAN) published guidelines on the treatment of tardive dyskinesia. According to these guidelines, at that time, the treatments with the most evidence supporting their use were clonazepam, ginkgo biloba, amantadine, and tetrabenazine.⁸ Other medications, including bromocriptine, baclofen, botulinum toxin, and vitamin E, did not show sufficient evidence to be recommended or refuted as treatment options.⁸ Botulinum toxin has long been utilized to treat focal and cervical dystonias, although there is no clear consensus on its role in treating tardive syndromes because of the conflicting results of prior studies.⁸Table 2⁸ outlines the AAN guidelines for treating tardive dyskinesia.

Continue to: In 2017, valbenazine and deutetrabenazine...

In 2017, valbenazine and deutetrabenazine became the first FDA-approved treatments for tardive dyskinesia in adults. Both medications block the vesicular monoamine transporter 2 (VMAT2) system, which results in decreased synaptic dopamine and dopamine receptor stimulation. Both VMAT2 inhibitor medications have a category level A supporting their use for treating tardive dyskinesia.^8-10

Currently, there are no published treatment guidelines on pharmacologic management of tardive dystonia. In B’s case, bromocriptine, a dopamine agonist, was used to counter the dopamine-blocking effects of risperidone on the nigrostriatal pathway and improve parkinsonian features of B’s presentation, including bradykinesia, stooped forward posture, and masked facies. Bromocriptine was found to be effective in alleviating parkinsonian features; however, to date there is no evidence demonstrating its effectiveness in countering delayed dystonic effects of DRBAs.

OUTCOME Improvement of dystonia symptoms

One week after discharge, B is seen for a follow-up visit. He continues taking bromocriptine, 1.25 mg twice daily, with meals after discharge. On examination, he has some evidence of tardive dystonia, including flexion of left wrist and posturing while ambulating. B’s parkinsonian features, including stooped forward posture, masked facies, and cogwheel rigidity of the left wrist muscle, have resolved. B is now able to walk on his own without unsteadiness. Bromocriptine is discontinued after 1 month, and his symptoms of dystonia continue to improve.

Two months after hospitalization, B is started on quetiapine, 25 mg twice daily, for behavioral aggression. Quetiapine is chosen because it has a lower dopamine receptor affinity compared with risperidone, and theoretically, quetiapine is associated with a lower risk of developing tardive symptoms. During the next 6 months, B is monitored closely for recurrence of tardive symptoms. Quetiapine is slowly titrated to 25 mg in the morning, and 50 mg at bedtime. His behavioral agitation improves significantly and he does not have a recurrence of tardive symptoms.

Bottom Line

Tardive dystonia is a possible iatrogenic adverse effect for patients receiving long-term dopamine receptor blocking agent (DRBA) therapy. Tardive syndromes encompass delayed-onset movement disorders caused by long-term blockade of the dopamine receptor by antipsychotic agents. Tardive dystonia can be contrasted from acute dystonic reaction based on the time course of development as well as by the persistence of symptoms after DRBAs are withheld.

Continue to: Related Resources

• American Academy of Neurology. Summary of evidence-based guideline for clinicians: treatment of tardive syndromes. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Published 2013.
• Dystonia Medical Research Foundation. https://dystonia-foundation.org/.

Drug Brand Names

Amantadine • Gocovri, Symmetrel
Amoxicillin • Amoxil
Baclofen • Kemstro, Liroesal
Benztropine • Cogentin
Bromocriptine • Parlodel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Galantamine • Razadyne
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trihexyphenidyl • Artane, Tremin
Valbenazine • Ingrezza

CASE Drooling, unsteady, and not himself

B, age 10, who is left handed and has autism spectrum disorder, is brought to the emergency department (ED) with a 1-day history of drooling, unsteady gait, and left wrist in sustained flexion. His parents report that for the past week, B has had cold symptoms, including rhinorrhea, a low-grade fever (100.0°F), and cough. Earlier in the day, he was seen at his pediatrician’s office, where he was diagnosed with an acute respiratory infection and started on amoxicillin, 500 mg twice daily for 7 days.

At baseline, B is nonverbal. He requires some assistance with his activities of daily living. He usually is able to walk without assistance and dress himself, but he is not toilet trained. His parents report that in the past day, he has had significant difficulties with tasks involving his left hand. Normally, B is able to feed himself “finger foods” but has been unable to do so today. His parents say that he has been unsteady on his feet, and has been “falling forward” when he tries to walk.

Two years ago, B was started on risperidone, 0.5 mg nightly, for behavioral aggression and self-mutilation. Over the next 12 months, the dosage was steadily increased to 1 mg twice daily, with good response. He has been taking his current dosage, 1 mg twice daily, for the past 12 months without adjustment. His parents report there have been no other medication changes, other than starting amoxicillin earlier that day.

As part of his initial ED evaluation, B is found to be mildly dehydrated, with an elevated sedimentation rate on urinalysis. His complete blood count (CBC) with differential is within normal limits. A comprehensive metabolic panel shows a slight increase in his creatinine level, indicating dehydration. B is administered IV fluid replacement because he is having difficulty drinking due to excessive drooling.

The ED physician is concerned that B may be experiencing an acute dystonic reaction from risperidone, so the team holds this medication, and gives B a one-time dose of IV diphenhydramine, 25 mg, for presumptive acute dystonic reaction. After several minutes, there is no improvement in the sustained flexion of his left wrist.

[polldaddy:10615848]

The authors’ observations

B presented with new-onset neurologic findings after a recently diagnosed upper respiratory viral illness. His symptoms appeared to be confined to his left upper extremity, specifically demonstrating left arm extension at the elbow with flexion of the left wrist. He also had new-onset unsteady gait with a stooped forward posture and required assistance with walking. Interestingly, despite B’s history of antipsychotic use, administering an anticholinergic agent did not lessen the dystonic posturing at his wrist and elbow.

EVALUATION Laboratory results reveal new clues

While in the ED, B undergoes MRI of the brain and spinal cord to rule out any mass lesions that could be impinging upon the motor pathways. Both brain and spinal cord imaging appear to be essentially normal, without evidence of impingement of the spinal nerves or lesions involving the brainstem or cerebellum.

Continue to: Due to concerns...

Due to concerns of possible airway obstruction, a CT scan of the neck is obtained to rule out any acute pathology, such as epiglottitis compromising his airway. The scan shows some inflammation and edema in the soft tissues that is thought to be secondary to his acute viral illness. B is able to maintain his airway and oxygenation, so intubation is not necessary.

A CPK test is ordered because there are concerns of sustained muscle contraction of B’s left wrist and elbow. The CPK level is 884 U/L (reference range 26 to 192 U/L). The elevation in CPK is consistent with prior laboratory findings of dehydration and indicating skeletal muscle breakdown from sustained muscle contraction. All other laboratory results, including a comprehensive metabolic panel, urine drug screen, and thyroid screening panel, are within normal limits.

[polldaddy:10615850]

EVALUATION No variation in facial expression

B is admitted to the general pediatrics service. Maintenance IV fluids are started due to concerns of dehydration and possible rhabdomyolysis due to his elevated CPK level. Risperidone is held throughout the hospital course due to concerns for an acute dystonic reaction. B is monitored for several days without clinical improvement and eventually discharged home with a diagnosis of inflammatory mononeuropathy due to viral infection. The patient is told to discontinue risperidone as part of discharge instructions.

Five days later, B returns to the hospital because there was no improvement in his left extremity or walking. His left elbow remains extended with left wrist in flexion. Psychiatry is consulted for further diagnostic clarity and evaluation.

On physical examination, B’s left arm remains unchanged. Despite discontinuing risperidone, there is evidence of cogwheel rigidity of the left wrist joint. Reflexes in the upper and lower extremities are 2+ and symmetrical bilaterally, suggesting intact upper and lower motor pathways. Babinski sign is absent bilaterally, which is a normal finding in B’s age group. B continues to have difficulty with ambulating and appears to “fall forward” while trying to walk with assistance. His parents also say that B is not laughing, smiling, or showing any variation in facial expression.

Continue to: Additional family history...

Additional family history is gathered from B’s parents for possible hereditary movement disorders such as Wilson’s disease. They report that no family members have developed involuntary movements or other neurologic syndromes. Additional considerations on the differential diagnosis for B include juvenile ALS or mononeuropathy involving the C5 and C6 nerve roots. B’s parents deny any recent shoulder trauma, and radiographic studies did not demonstrate any involvement of the nerve roots.

TREATMENT A trial of bromocriptine

At this point, B’s neurologic workup is essentially normal, and he is given a provisional diagnosis of antipsychotic-induced tardive dystonia vs tardive parkinsonism. Risperidone continues to be held, and B is monitored for clinical improvement. B is administered a one-time dose of diphenhydramine, 25 mg, for dystonia with no improvement in symptoms. He is then started on bromocriptine, 1.25 mg twice daily with meals, for parkinsonian symptoms secondary to antipsychotic medication use. After 1 day of treatment, B shows less sustained flexion of his left wrist. He is able to relax his left arm, shows improvements in ambulation, and requires less assistance. B continues to be observed closely and continues to improve toward his baseline.

At Day 4, he is discharged. B is able to walk mostly without assistance and demonstrates improvement in left wrist flexion. He is scheduled to see a movement disorders specialist a week after discharge. The initial diagnosis given by the movement disorder specialist is tardive dystonia.

The authors’ observations

Tardive dyskinesia is a well-known iatrogenic effect of antipsychotic medications that are commonly used to manage conditions such as schizophrenia or behavioral agitation associated with autism spectrum disorder. Symptoms of tardive dyskinesia typically emerge after 1 to 2 years of continuous exposure to dopamine receptor blocking agents (DRBAs). Tardive dyskinesia symptoms include involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, and upper and lower extremities, with significant functional impairment.¹

Tardive syndromes refer to a diverse array of hyperkinetic, hypokinetic, and sensory movement disorders resulting from at least 3 months of continuous DRBA therapy.² Tardive dyskinesia is perhaps the most well-known of the tardive syndromes, but is not the only one to consider when assessing for antipsychotic-induced movement disorders. A key feature differentiating a tardive syndrome is the persistence of the movement disorder after the DRBA is discontinued. In this case, B had been receiving a stable dose of risperidone for >1 year. He developed dystonic posturing of his left wrist and elbow that was both unresponsive to anticholinergic medication and persisted after risperidone was discontinued. The term “tardive” emphasizes the delay in development of abnormal involuntary movement symptoms after initiating antipsychotic medications.³ Table 1² shows a comparison of tardive dystonia vs an acute dystonic reaction.

Continue to: Other tardive syndromes include...

Other tardive syndromes include:

• tardive tics
• tardive parkinsonism
• tardive pain
• tardive myoclonus
• tardive akathisia
• tardive tremors.

The incidence of tardive syndromes increases 5% annually for the first 5 years of treatment. At 10 years of treatment, the annual incidence is thought to be 49%, and at 25 years of treatment, 68%.⁴ The predominant theory of the pathophysiology of tardive syndromes is that the chronic use of DRBAs causes a gradual hypersensitization of dopamine receptors.⁴ The diagnosis of a tardive syndrome is based on history of exposure to a DRBA as well as clinical observation of symptoms.

Compared with classic tardive dyskinesia, tardive dystonia is more common among younger patients. The mean age of onset of tardive dystonia is 40, and it typically affects young males.⁵ Typical posturing observed in cases of tardive dystonia include extension of the arms and flexion at the wrists.⁶ In contrast to cases of primary dystonia, tardive dystonia is typically associated with stereotypies, akathisia, or other movement disorders. Anticholinergic agents, such as benztropine or trihexyphenidyl, may or may not alleviate symptoms of tardive dystonia but can worsen tardive dyskinesia, so careful delineation between the 2 syndromes is important.⁶

The American Psychiatric Association has issued guidelines on screening for involuntary movement syndromes by using the Abnormal Involuntary Movement Scale (AIMS).⁷ The current recommendations include assessment every 6 months for patients receiving first-generation antipsychotics, and every 12 months for those receiving second-generation antipsychotics.⁷ Prescribers should also carefully assess for any pre-existing involuntary movements before prescribing a DRBA.⁷

[polldaddy:10615855]

The authors’ observations

In 2013, the American Academy of Neurology (AAN) published guidelines on the treatment of tardive dyskinesia. According to these guidelines, at that time, the treatments with the most evidence supporting their use were clonazepam, ginkgo biloba, amantadine, and tetrabenazine.⁸ Other medications, including bromocriptine, baclofen, botulinum toxin, and vitamin E, did not show sufficient evidence to be recommended or refuted as treatment options.⁸ Botulinum toxin has long been utilized to treat focal and cervical dystonias, although there is no clear consensus on its role in treating tardive syndromes because of the conflicting results of prior studies.⁸Table 2⁸ outlines the AAN guidelines for treating tardive dyskinesia.

Continue to: In 2017, valbenazine and deutetrabenazine...

In 2017, valbenazine and deutetrabenazine became the first FDA-approved treatments for tardive dyskinesia in adults. Both medications block the vesicular monoamine transporter 2 (VMAT2) system, which results in decreased synaptic dopamine and dopamine receptor stimulation. Both VMAT2 inhibitor medications have a category level A supporting their use for treating tardive dyskinesia.^8-10

Currently, there are no published treatment guidelines on pharmacologic management of tardive dystonia. In B’s case, bromocriptine, a dopamine agonist, was used to counter the dopamine-blocking effects of risperidone on the nigrostriatal pathway and improve parkinsonian features of B’s presentation, including bradykinesia, stooped forward posture, and masked facies. Bromocriptine was found to be effective in alleviating parkinsonian features; however, to date there is no evidence demonstrating its effectiveness in countering delayed dystonic effects of DRBAs.

OUTCOME Improvement of dystonia symptoms

One week after discharge, B is seen for a follow-up visit. He continues taking bromocriptine, 1.25 mg twice daily, with meals after discharge. On examination, he has some evidence of tardive dystonia, including flexion of left wrist and posturing while ambulating. B’s parkinsonian features, including stooped forward posture, masked facies, and cogwheel rigidity of the left wrist muscle, have resolved. B is now able to walk on his own without unsteadiness. Bromocriptine is discontinued after 1 month, and his symptoms of dystonia continue to improve.

Two months after hospitalization, B is started on quetiapine, 25 mg twice daily, for behavioral aggression. Quetiapine is chosen because it has a lower dopamine receptor affinity compared with risperidone, and theoretically, quetiapine is associated with a lower risk of developing tardive symptoms. During the next 6 months, B is monitored closely for recurrence of tardive symptoms. Quetiapine is slowly titrated to 25 mg in the morning, and 50 mg at bedtime. His behavioral agitation improves significantly and he does not have a recurrence of tardive symptoms.

Bottom Line

Tardive dystonia is a possible iatrogenic adverse effect for patients receiving long-term dopamine receptor blocking agent (DRBA) therapy. Tardive syndromes encompass delayed-onset movement disorders caused by long-term blockade of the dopamine receptor by antipsychotic agents. Tardive dystonia can be contrasted from acute dystonic reaction based on the time course of development as well as by the persistence of symptoms after DRBAs are withheld.

Continue to: Related Resources

• American Academy of Neurology. Summary of evidence-based guideline for clinicians: treatment of tardive syndromes. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Published 2013.
• Dystonia Medical Research Foundation. https://dystonia-foundation.org/.

Drug Brand Names

Amantadine • Gocovri, Symmetrel
Amoxicillin • Amoxil
Baclofen • Kemstro, Liroesal
Benztropine • Cogentin
Bromocriptine • Parlodel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Galantamine • Razadyne
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trihexyphenidyl • Artane, Tremin
Valbenazine • Ingrezza

CASE Drooling, unsteady, and not himself

B, age 10, who is left handed and has autism spectrum disorder, is brought to the emergency department (ED) with a 1-day history of drooling, unsteady gait, and left wrist in sustained flexion. His parents report that for the past week, B has had cold symptoms, including rhinorrhea, a low-grade fever (100.0°F), and cough. Earlier in the day, he was seen at his pediatrician’s office, where he was diagnosed with an acute respiratory infection and started on amoxicillin, 500 mg twice daily for 7 days.

At baseline, B is nonverbal. He requires some assistance with his activities of daily living. He usually is able to walk without assistance and dress himself, but he is not toilet trained. His parents report that in the past day, he has had significant difficulties with tasks involving his left hand. Normally, B is able to feed himself “finger foods” but has been unable to do so today. His parents say that he has been unsteady on his feet, and has been “falling forward” when he tries to walk.

Two years ago, B was started on risperidone, 0.5 mg nightly, for behavioral aggression and self-mutilation. Over the next 12 months, the dosage was steadily increased to 1 mg twice daily, with good response. He has been taking his current dosage, 1 mg twice daily, for the past 12 months without adjustment. His parents report there have been no other medication changes, other than starting amoxicillin earlier that day.

As part of his initial ED evaluation, B is found to be mildly dehydrated, with an elevated sedimentation rate on urinalysis. His complete blood count (CBC) with differential is within normal limits. A comprehensive metabolic panel shows a slight increase in his creatinine level, indicating dehydration. B is administered IV fluid replacement because he is having difficulty drinking due to excessive drooling.

The ED physician is concerned that B may be experiencing an acute dystonic reaction from risperidone, so the team holds this medication, and gives B a one-time dose of IV diphenhydramine, 25 mg, for presumptive acute dystonic reaction. After several minutes, there is no improvement in the sustained flexion of his left wrist.

[polldaddy:10615848]

The authors’ observations

B presented with new-onset neurologic findings after a recently diagnosed upper respiratory viral illness. His symptoms appeared to be confined to his left upper extremity, specifically demonstrating left arm extension at the elbow with flexion of the left wrist. He also had new-onset unsteady gait with a stooped forward posture and required assistance with walking. Interestingly, despite B’s history of antipsychotic use, administering an anticholinergic agent did not lessen the dystonic posturing at his wrist and elbow.

EVALUATION Laboratory results reveal new clues

While in the ED, B undergoes MRI of the brain and spinal cord to rule out any mass lesions that could be impinging upon the motor pathways. Both brain and spinal cord imaging appear to be essentially normal, without evidence of impingement of the spinal nerves or lesions involving the brainstem or cerebellum.

Continue to: Due to concerns...

Due to concerns of possible airway obstruction, a CT scan of the neck is obtained to rule out any acute pathology, such as epiglottitis compromising his airway. The scan shows some inflammation and edema in the soft tissues that is thought to be secondary to his acute viral illness. B is able to maintain his airway and oxygenation, so intubation is not necessary.

A CPK test is ordered because there are concerns of sustained muscle contraction of B’s left wrist and elbow. The CPK level is 884 U/L (reference range 26 to 192 U/L). The elevation in CPK is consistent with prior laboratory findings of dehydration and indicating skeletal muscle breakdown from sustained muscle contraction. All other laboratory results, including a comprehensive metabolic panel, urine drug screen, and thyroid screening panel, are within normal limits.

[polldaddy:10615850]

EVALUATION No variation in facial expression

B is admitted to the general pediatrics service. Maintenance IV fluids are started due to concerns of dehydration and possible rhabdomyolysis due to his elevated CPK level. Risperidone is held throughout the hospital course due to concerns for an acute dystonic reaction. B is monitored for several days without clinical improvement and eventually discharged home with a diagnosis of inflammatory mononeuropathy due to viral infection. The patient is told to discontinue risperidone as part of discharge instructions.

Five days later, B returns to the hospital because there was no improvement in his left extremity or walking. His left elbow remains extended with left wrist in flexion. Psychiatry is consulted for further diagnostic clarity and evaluation.

On physical examination, B’s left arm remains unchanged. Despite discontinuing risperidone, there is evidence of cogwheel rigidity of the left wrist joint. Reflexes in the upper and lower extremities are 2+ and symmetrical bilaterally, suggesting intact upper and lower motor pathways. Babinski sign is absent bilaterally, which is a normal finding in B’s age group. B continues to have difficulty with ambulating and appears to “fall forward” while trying to walk with assistance. His parents also say that B is not laughing, smiling, or showing any variation in facial expression.

Continue to: Additional family history...

Additional family history is gathered from B’s parents for possible hereditary movement disorders such as Wilson’s disease. They report that no family members have developed involuntary movements or other neurologic syndromes. Additional considerations on the differential diagnosis for B include juvenile ALS or mononeuropathy involving the C5 and C6 nerve roots. B’s parents deny any recent shoulder trauma, and radiographic studies did not demonstrate any involvement of the nerve roots.

TREATMENT A trial of bromocriptine

At this point, B’s neurologic workup is essentially normal, and he is given a provisional diagnosis of antipsychotic-induced tardive dystonia vs tardive parkinsonism. Risperidone continues to be held, and B is monitored for clinical improvement. B is administered a one-time dose of diphenhydramine, 25 mg, for dystonia with no improvement in symptoms. He is then started on bromocriptine, 1.25 mg twice daily with meals, for parkinsonian symptoms secondary to antipsychotic medication use. After 1 day of treatment, B shows less sustained flexion of his left wrist. He is able to relax his left arm, shows improvements in ambulation, and requires less assistance. B continues to be observed closely and continues to improve toward his baseline.

At Day 4, he is discharged. B is able to walk mostly without assistance and demonstrates improvement in left wrist flexion. He is scheduled to see a movement disorders specialist a week after discharge. The initial diagnosis given by the movement disorder specialist is tardive dystonia.

The authors’ observations

Tardive dyskinesia is a well-known iatrogenic effect of antipsychotic medications that are commonly used to manage conditions such as schizophrenia or behavioral agitation associated with autism spectrum disorder. Symptoms of tardive dyskinesia typically emerge after 1 to 2 years of continuous exposure to dopamine receptor blocking agents (DRBAs). Tardive dyskinesia symptoms include involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, and upper and lower extremities, with significant functional impairment.¹

Tardive syndromes refer to a diverse array of hyperkinetic, hypokinetic, and sensory movement disorders resulting from at least 3 months of continuous DRBA therapy.² Tardive dyskinesia is perhaps the most well-known of the tardive syndromes, but is not the only one to consider when assessing for antipsychotic-induced movement disorders. A key feature differentiating a tardive syndrome is the persistence of the movement disorder after the DRBA is discontinued. In this case, B had been receiving a stable dose of risperidone for >1 year. He developed dystonic posturing of his left wrist and elbow that was both unresponsive to anticholinergic medication and persisted after risperidone was discontinued. The term “tardive” emphasizes the delay in development of abnormal involuntary movement symptoms after initiating antipsychotic medications.³ Table 1² shows a comparison of tardive dystonia vs an acute dystonic reaction.

Continue to: Other tardive syndromes include...

Other tardive syndromes include:

• tardive tics
• tardive parkinsonism
• tardive pain
• tardive myoclonus
• tardive akathisia
• tardive tremors.

The incidence of tardive syndromes increases 5% annually for the first 5 years of treatment. At 10 years of treatment, the annual incidence is thought to be 49%, and at 25 years of treatment, 68%.⁴ The predominant theory of the pathophysiology of tardive syndromes is that the chronic use of DRBAs causes a gradual hypersensitization of dopamine receptors.⁴ The diagnosis of a tardive syndrome is based on history of exposure to a DRBA as well as clinical observation of symptoms.

Compared with classic tardive dyskinesia, tardive dystonia is more common among younger patients. The mean age of onset of tardive dystonia is 40, and it typically affects young males.⁵ Typical posturing observed in cases of tardive dystonia include extension of the arms and flexion at the wrists.⁶ In contrast to cases of primary dystonia, tardive dystonia is typically associated with stereotypies, akathisia, or other movement disorders. Anticholinergic agents, such as benztropine or trihexyphenidyl, may or may not alleviate symptoms of tardive dystonia but can worsen tardive dyskinesia, so careful delineation between the 2 syndromes is important.⁶

The American Psychiatric Association has issued guidelines on screening for involuntary movement syndromes by using the Abnormal Involuntary Movement Scale (AIMS).⁷ The current recommendations include assessment every 6 months for patients receiving first-generation antipsychotics, and every 12 months for those receiving second-generation antipsychotics.⁷ Prescribers should also carefully assess for any pre-existing involuntary movements before prescribing a DRBA.⁷

[polldaddy:10615855]

The authors’ observations

In 2013, the American Academy of Neurology (AAN) published guidelines on the treatment of tardive dyskinesia. According to these guidelines, at that time, the treatments with the most evidence supporting their use were clonazepam, ginkgo biloba, amantadine, and tetrabenazine.⁸ Other medications, including bromocriptine, baclofen, botulinum toxin, and vitamin E, did not show sufficient evidence to be recommended or refuted as treatment options.⁸ Botulinum toxin has long been utilized to treat focal and cervical dystonias, although there is no clear consensus on its role in treating tardive syndromes because of the conflicting results of prior studies.⁸Table 2⁸ outlines the AAN guidelines for treating tardive dyskinesia.

Continue to: In 2017, valbenazine and deutetrabenazine...

In 2017, valbenazine and deutetrabenazine became the first FDA-approved treatments for tardive dyskinesia in adults. Both medications block the vesicular monoamine transporter 2 (VMAT2) system, which results in decreased synaptic dopamine and dopamine receptor stimulation. Both VMAT2 inhibitor medications have a category level A supporting their use for treating tardive dyskinesia.^8-10

Currently, there are no published treatment guidelines on pharmacologic management of tardive dystonia. In B’s case, bromocriptine, a dopamine agonist, was used to counter the dopamine-blocking effects of risperidone on the nigrostriatal pathway and improve parkinsonian features of B’s presentation, including bradykinesia, stooped forward posture, and masked facies. Bromocriptine was found to be effective in alleviating parkinsonian features; however, to date there is no evidence demonstrating its effectiveness in countering delayed dystonic effects of DRBAs.

OUTCOME Improvement of dystonia symptoms

One week after discharge, B is seen for a follow-up visit. He continues taking bromocriptine, 1.25 mg twice daily, with meals after discharge. On examination, he has some evidence of tardive dystonia, including flexion of left wrist and posturing while ambulating. B’s parkinsonian features, including stooped forward posture, masked facies, and cogwheel rigidity of the left wrist muscle, have resolved. B is now able to walk on his own without unsteadiness. Bromocriptine is discontinued after 1 month, and his symptoms of dystonia continue to improve.

Two months after hospitalization, B is started on quetiapine, 25 mg twice daily, for behavioral aggression. Quetiapine is chosen because it has a lower dopamine receptor affinity compared with risperidone, and theoretically, quetiapine is associated with a lower risk of developing tardive symptoms. During the next 6 months, B is monitored closely for recurrence of tardive symptoms. Quetiapine is slowly titrated to 25 mg in the morning, and 50 mg at bedtime. His behavioral agitation improves significantly and he does not have a recurrence of tardive symptoms.

Bottom Line

Tardive dystonia is a possible iatrogenic adverse effect for patients receiving long-term dopamine receptor blocking agent (DRBA) therapy. Tardive syndromes encompass delayed-onset movement disorders caused by long-term blockade of the dopamine receptor by antipsychotic agents. Tardive dystonia can be contrasted from acute dystonic reaction based on the time course of development as well as by the persistence of symptoms after DRBAs are withheld.

Continue to: Related Resources

• American Academy of Neurology. Summary of evidence-based guideline for clinicians: treatment of tardive syndromes. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Published 2013.
• Dystonia Medical Research Foundation. https://dystonia-foundation.org/.

Drug Brand Names

Amantadine • Gocovri, Symmetrel
Amoxicillin • Amoxil
Baclofen • Kemstro, Liroesal
Benztropine • Cogentin
Bromocriptine • Parlodel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Galantamine • Razadyne
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trihexyphenidyl • Artane, Tremin
Valbenazine • Ingrezza

Most psychiatrists will care for at least one patient who dies by suicide. Many clinicians consider this to be one of the most stressful and formative events of their careers, prompting strong emotions, logistical questions, and legal concerns. Because the aftermath of a patient suicide can be difficult, we offer guidance on how to cope with such events, and specifically how to address the legal concerns. 

Attend to self-care. “At a cardiac arrest, the first procedure is to take your own pulse.” This advice, from Samuel Shem’s The House of God, highlights the importance of self-awareness during highly stressful events.¹ When facing the aftermath of a patient suicide, be sure to attend to your own needs, such as eating, staying hydrated, and getting enough sleep. Identify and reach out to your support systems, such as friends and family. Your colleagues can be a source of support, both formally or informally. Reaching out to other psychiatrists, who likely have their own experience with patient suicide, can help process the event. A support group consisting of other psychiatrists also may be beneficial. Finally, avoid blaming yourself. Although you might perceive your patient’s suicide as a personal failing, suicide is notoriously difficult to predict and an unfortunate reality of working in this specialty.

Report the event. Follow your institution’s guidelines for reporting adverse events. You may be required to inform your supervisor, the risk management department, legal services, your malpractice provider, and/or the police. Your risk management department and malpractice provider may have their own regulations and recommendations.

Review the case. Institutions often have established processes for reviewing adverse events and, if applicable, suggesting constructive feedback or general quality improvements. A review process may provide an opportunity to look for potential negligence that could be an issue if there is a malpractice suit. Ideally, such processes are constructive and a time for reflection, rather than punitive or blaming. Trainees may find their supervisors’ presence and guidance to be particularly helpful during this review process. 

Assess malpractice risk. Although psychiatrists have a relatively low risk of being sued for malpractice, many lawsuits against psychiatrists occur after a completed patient suicide.² In a successful malpractice suit, the plaintiff needs to establish all 4 “Ds” of medical malpractice:

1) Duty, or an established physician–patient relationship

2) Damages from an adverse event

3) Dereliction of duty (negligence) 

4) Direct causality between the deviation and the damages.

In the event of a patient suicide, both a doctor–patient relationship (duty) and an adverse outcome (damages) exist.³ Establishing dereliction of duty and direct causality rests on the plaintiff to prove. Good documentation can serve as evidence against accusations of negligence.³ 

Typically, a patient’s medical record will be used as evidence in a malpractice suit. After a suicide, do not alter this record, such as by editing your past assessments of the patient. If an addendum must be made, such as to document a conversation with suicide survivors (family and friends of the deceased), be sure to label it as such with the current date. An addendum should contain only facts; avoid adding information that attempts to explain your patient’s suicide, justifying or apologizing for past treatment decisions, or otherwise editorializing. 

Continue to: Consider reaching out to suicide survivors

Consider reaching out to suicide survivors. The Health Insurance Portability and Accountability Act permits clinicians to use their best judgment when identifying individuals to contact and deciding what information to share after a patient’s death.⁴ Some states and practice settings have stricter confidentiality laws. Consider seeking legal counsel before interacting with suicide survivors.

Suicide survivors may experience feelings such as guilt, shame, and anger, and these feelings may lead suicide survivors to file a malpractice suit.³ Speaking with suicide survivors can help to address these feelings and potentially decrease the likelihood of them pursuing a malpractice suit. In addition, suicide survivors are at high risk for developing mental health issues, including suicidality. Contacting them can be an opportunity to encourage them to seek mental health treatment. It is important to clarify that any recommendations you provide in such situations do not constitute a doctor–patient relationship. 

Should you offer an apology? Consider seeking legal counsel if you wish to apologize. Some states have “apology laws” that render a clinician’s apologetic statements inadmissible if a malpractice suit should occur.⁵ These laws might include empathic statements (“I’m sorry for your loss”) or disclosures of error (“I’m sorry for causing your loss”).⁵ It is unclear whether these laws affect the likelihood and/or outcome of malpractice suits.⁵

Focus on empathy. Experiencing a patient suicide can be one of the most challenging events in a psychiatrist’s career. Empathy is crucial, both towards the suicide survivors and to oneself.  

Most psychiatrists will care for at least one patient who dies by suicide. Many clinicians consider this to be one of the most stressful and formative events of their careers, prompting strong emotions, logistical questions, and legal concerns. Because the aftermath of a patient suicide can be difficult, we offer guidance on how to cope with such events, and specifically how to address the legal concerns. 

Attend to self-care. “At a cardiac arrest, the first procedure is to take your own pulse.” This advice, from Samuel Shem’s The House of God, highlights the importance of self-awareness during highly stressful events.¹ When facing the aftermath of a patient suicide, be sure to attend to your own needs, such as eating, staying hydrated, and getting enough sleep. Identify and reach out to your support systems, such as friends and family. Your colleagues can be a source of support, both formally or informally. Reaching out to other psychiatrists, who likely have their own experience with patient suicide, can help process the event. A support group consisting of other psychiatrists also may be beneficial. Finally, avoid blaming yourself. Although you might perceive your patient’s suicide as a personal failing, suicide is notoriously difficult to predict and an unfortunate reality of working in this specialty.

Report the event. Follow your institution’s guidelines for reporting adverse events. You may be required to inform your supervisor, the risk management department, legal services, your malpractice provider, and/or the police. Your risk management department and malpractice provider may have their own regulations and recommendations.

Review the case. Institutions often have established processes for reviewing adverse events and, if applicable, suggesting constructive feedback or general quality improvements. A review process may provide an opportunity to look for potential negligence that could be an issue if there is a malpractice suit. Ideally, such processes are constructive and a time for reflection, rather than punitive or blaming. Trainees may find their supervisors’ presence and guidance to be particularly helpful during this review process. 

Assess malpractice risk. Although psychiatrists have a relatively low risk of being sued for malpractice, many lawsuits against psychiatrists occur after a completed patient suicide.² In a successful malpractice suit, the plaintiff needs to establish all 4 “Ds” of medical malpractice:

1) Duty, or an established physician–patient relationship

2) Damages from an adverse event

3) Dereliction of duty (negligence) 

4) Direct causality between the deviation and the damages.

In the event of a patient suicide, both a doctor–patient relationship (duty) and an adverse outcome (damages) exist.³ Establishing dereliction of duty and direct causality rests on the plaintiff to prove. Good documentation can serve as evidence against accusations of negligence.³ 

Typically, a patient’s medical record will be used as evidence in a malpractice suit. After a suicide, do not alter this record, such as by editing your past assessments of the patient. If an addendum must be made, such as to document a conversation with suicide survivors (family and friends of the deceased), be sure to label it as such with the current date. An addendum should contain only facts; avoid adding information that attempts to explain your patient’s suicide, justifying or apologizing for past treatment decisions, or otherwise editorializing. 

Continue to: Consider reaching out to suicide survivors

Consider reaching out to suicide survivors. The Health Insurance Portability and Accountability Act permits clinicians to use their best judgment when identifying individuals to contact and deciding what information to share after a patient’s death.⁴ Some states and practice settings have stricter confidentiality laws. Consider seeking legal counsel before interacting with suicide survivors.

Suicide survivors may experience feelings such as guilt, shame, and anger, and these feelings may lead suicide survivors to file a malpractice suit.³ Speaking with suicide survivors can help to address these feelings and potentially decrease the likelihood of them pursuing a malpractice suit. In addition, suicide survivors are at high risk for developing mental health issues, including suicidality. Contacting them can be an opportunity to encourage them to seek mental health treatment. It is important to clarify that any recommendations you provide in such situations do not constitute a doctor–patient relationship. 

Should you offer an apology? Consider seeking legal counsel if you wish to apologize. Some states have “apology laws” that render a clinician’s apologetic statements inadmissible if a malpractice suit should occur.⁵ These laws might include empathic statements (“I’m sorry for your loss”) or disclosures of error (“I’m sorry for causing your loss”).⁵ It is unclear whether these laws affect the likelihood and/or outcome of malpractice suits.⁵

Focus on empathy. Experiencing a patient suicide can be one of the most challenging events in a psychiatrist’s career. Empathy is crucial, both towards the suicide survivors and to oneself.  

Most psychiatrists will care for at least one patient who dies by suicide. Many clinicians consider this to be one of the most stressful and formative events of their careers, prompting strong emotions, logistical questions, and legal concerns. Because the aftermath of a patient suicide can be difficult, we offer guidance on how to cope with such events, and specifically how to address the legal concerns. 

Attend to self-care. “At a cardiac arrest, the first procedure is to take your own pulse.” This advice, from Samuel Shem’s The House of God, highlights the importance of self-awareness during highly stressful events.¹ When facing the aftermath of a patient suicide, be sure to attend to your own needs, such as eating, staying hydrated, and getting enough sleep. Identify and reach out to your support systems, such as friends and family. Your colleagues can be a source of support, both formally or informally. Reaching out to other psychiatrists, who likely have their own experience with patient suicide, can help process the event. A support group consisting of other psychiatrists also may be beneficial. Finally, avoid blaming yourself. Although you might perceive your patient’s suicide as a personal failing, suicide is notoriously difficult to predict and an unfortunate reality of working in this specialty.

Report the event. Follow your institution’s guidelines for reporting adverse events. You may be required to inform your supervisor, the risk management department, legal services, your malpractice provider, and/or the police. Your risk management department and malpractice provider may have their own regulations and recommendations.

Review the case. Institutions often have established processes for reviewing adverse events and, if applicable, suggesting constructive feedback or general quality improvements. A review process may provide an opportunity to look for potential negligence that could be an issue if there is a malpractice suit. Ideally, such processes are constructive and a time for reflection, rather than punitive or blaming. Trainees may find their supervisors’ presence and guidance to be particularly helpful during this review process. 

Assess malpractice risk. Although psychiatrists have a relatively low risk of being sued for malpractice, many lawsuits against psychiatrists occur after a completed patient suicide.² In a successful malpractice suit, the plaintiff needs to establish all 4 “Ds” of medical malpractice:

1) Duty, or an established physician–patient relationship

2) Damages from an adverse event

3) Dereliction of duty (negligence) 

4) Direct causality between the deviation and the damages.

In the event of a patient suicide, both a doctor–patient relationship (duty) and an adverse outcome (damages) exist.³ Establishing dereliction of duty and direct causality rests on the plaintiff to prove. Good documentation can serve as evidence against accusations of negligence.³ 

Typically, a patient’s medical record will be used as evidence in a malpractice suit. After a suicide, do not alter this record, such as by editing your past assessments of the patient. If an addendum must be made, such as to document a conversation with suicide survivors (family and friends of the deceased), be sure to label it as such with the current date. An addendum should contain only facts; avoid adding information that attempts to explain your patient’s suicide, justifying or apologizing for past treatment decisions, or otherwise editorializing. 

Continue to: Consider reaching out to suicide survivors

Consider reaching out to suicide survivors. The Health Insurance Portability and Accountability Act permits clinicians to use their best judgment when identifying individuals to contact and deciding what information to share after a patient’s death.⁴ Some states and practice settings have stricter confidentiality laws. Consider seeking legal counsel before interacting with suicide survivors.

Suicide survivors may experience feelings such as guilt, shame, and anger, and these feelings may lead suicide survivors to file a malpractice suit.³ Speaking with suicide survivors can help to address these feelings and potentially decrease the likelihood of them pursuing a malpractice suit. In addition, suicide survivors are at high risk for developing mental health issues, including suicidality. Contacting them can be an opportunity to encourage them to seek mental health treatment. It is important to clarify that any recommendations you provide in such situations do not constitute a doctor–patient relationship. 

Should you offer an apology? Consider seeking legal counsel if you wish to apologize. Some states have “apology laws” that render a clinician’s apologetic statements inadmissible if a malpractice suit should occur.⁵ These laws might include empathic statements (“I’m sorry for your loss”) or disclosures of error (“I’m sorry for causing your loss”).⁵ It is unclear whether these laws affect the likelihood and/or outcome of malpractice suits.⁵

Focus on empathy. Experiencing a patient suicide can be one of the most challenging events in a psychiatrist’s career. Empathy is crucial, both towards the suicide survivors and to oneself.