Mr. H, age 43, presents to your clinic for management of posttraumatic stress disorder (PTSD). At his last appointment 8 weeks ago, he was continued on fluoxetine, 60 mg/d; he had been stable on this medication for 6 months. Today, Mr. H reports an increase in the frequency and severity of nightmares. He states that he wakes at least 3 times every week with “disturbing dreams” about his time in the military and does not feel rested even when he sleeps through the night. His Clinician-Administered PTSD Scale (CAPS) score is 95 on this visit, suggesting extreme PTSD symptomatology. Mr. H asks if anything can be done to reduce the frequency and intensity of his nightmares.

PTSD is the development of characteristic symptoms following exposure to ≥1 traumatic events. According to DSM-5, PTSD symptoms include the presence of ≥1 intrusion symptoms (recurrent, intrusive memories of the traumatic event; recurrent distressing dreams; dissociative reactions), persistent avoidance of stimuli, negative alterations in cognition and mood, and marked alterations in arousal and reactivity associated with the traumatic event(s).¹ The symptoms must be present for >1 month, cause clinically significant distress or impairment in functioning, and not be attributable to the psychologic effects of a substance or medical conditions.¹ This article focuses specifically on the hyperarousal symptoms, and the clinical controversies surrounding the use of prazosin for PTSD.

Prazosin for PTSD treatment

Sleep disorders are extremely common in patients with PTSD. Up to 90% of patients report sleep disturbances, and up to 70% report nightmares.² Prazosin has been widely used in the treatment of PTSD-related sleep disorders and nightmares.The American Psychiatric Association³ and the British Association of Psychopharmacology⁴ guidelines in-­clude prazosin as a first-line recommendation for treatment of PTSD. However, updated 2017 guidelines from the Veterans Affairs/Department of Defense (VA/DoD)⁵ and data from the 2018 Prazosin and Combat Trauma PTSD (PACT) trial⁶ contradict these original recommendations. Previously, the 2010 VA/DoD guideline said prazosin had insufficient evidence for monotherapy, but recommended it as adjunctive treatment for sleep and nightmares.⁷ The updated 2017 VA/DoD guideline recommends “weak against” prazosin use for global symptoms of PTSD, and says there is insufficient evidence for its use in nightmares.⁵ Below we summarize the findings of studies that contributed to those original recommendations, along with results of the PACT trial.

Raskind et al^8,9 conducted 2 studies of prazosin use in combat veterans with PTSD. In both studies, prazosin had significant positive effects on the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression of Change (CGIC) scores.^8,9 The 2007 study also found significant effects of prazosin on Pittsburgh Sleep Quality Index (PSQI) scores.⁹

Raskind et al¹⁰ conducted another study in 2013 of prazosin use for active-duty soldiers who had combat trauma PTSD with nightmares. Prazosin had positive effects for nightmares, sleep quality, and CAPS scores.¹⁰

Germain et al¹¹ reviewed prazosin for treating sleep disturbances in US military veterans. Prazosin was associated with significant improvements in insomnia and daytime PTSD symptom severity as demonstrated by changes in PSQI and CAPS scores.¹¹

Taylor et al¹² examined the effects of prazosin on sleep measures and clinical symptoms in civilians with PTSD. Prazosin significantly increased total sleep time, rapid eye movement sleep time, and CGIC scores while significantly decreasing trauma-related nightmares.¹²

Continue to: Overall, these trials...

Overall, these trials found efficacy for the use of prazosin for patients diagnosed with PTSD; however, the population size in each of these studies was small.

Results of the PACT trial

The PACT trial was a 26-week, multicenter, double-blind, randomized, placebo-controlled trial conducted across 12 VA medical centers.⁶ During the first 5 weeks, participants were randomized to receive placebo or prazosin, which could be titrated up to 20 mg/d in men and 12 mg/d in women. Participants remained on that dose from the end of Week 5 through Week 10. At that time, other pharmacologic therapies and psychotherapy could be added, discontinued, or adjusted. The mean maintenance total daily dose of prazosin was 14.8 mg.

A total of 413 patients were screened, 304 were randomized (152 per group), and 271 completed the 10-week primary outcome assessment. The population was almost entirely male (96.1% in the prazosin group and 99.3% in the placebo group), and most participants were White (64.5% in the prazosin group and 69.1% in the placebo group), with an average age of approximately 50 years. Primary outcomes included change from baseline to Week 10 in both CAPS item B2 (“recurrent distressing dreams”) and PSQI scores. CGIC score was evaluated at Week 10.

At Week 10, none of the primary outcomes were found to be statistically significant. The mean difference in change from baseline to Week 10 in CAPS item B2 score and PSQI score were 0.2 (P = .38) and 0.1 (P = .80), respectively. There was no significant difference in mean CGIC scores (P = .96). Repeated measures of CAPS item B2, PSQI, and CGIC scores were conducted through Week 26 as secondary outcomes. No significant differences were found. This study concluded that prazosin did not alleviate distressing dreams, improve sleep quality, or improve overall clinical symptoms.⁶

The PACT trial: Strengths and weaknesses

The PACT trial is the largest placebo-controlled trial for prazosin use in PTSD to date. It failed to show efficacy of prazosin for PTSD-associated nightmares, which contradicts previous studies. Although the mean total daily dose of prazosin was adequate and primary outcomes were measured with appropriate scales, the study failed to enroll the desired number of patients, which increased the possibility of false-negative results. Furthermore, participant recruitment may have led to selection bias because all participants were clinically stable, which could explain the lack of efficacy. However, the average CAPS scores were 80.7 in the prazosin group and 81.9 in the placebo group, which indicates that these patients had significant symptomatology at baseline and before entering the study.

Continue to: A major theme...

A major theme of studies evaluating prazosin treatment for PTSD is a focus on a military population and military-related trauma. Other than Taylor et al¹² (N=13), none of these trials included patients who were diagnosed with PTSD due to other traumas, such as sexual trauma, which limits the generalizability of the results. Furthermore, apart from the PACT trial, none of these studies had >100 participants, which further reduces external validity. Current guidelines have not been updated to include the results of the PACT trial, and it is unclear if the results of this trial are strong enough to change clinical practice.

CASE CONTINUED

To ensure patient-centered care, the treating clinicians conduct a risk/benefit discussion with the patient regarding starting prazosin. Mr. H opts to try prazosin, so the clinicians initiate a low dose (1 mg/d) to mitigate adverse effects, and plan to titrate to clinical effect or intolerability. Per evidence from the trials discussed, it is likely Mr. H will need to be titrated to at least 5 to 6 mg/d to see a clinical effect.

Related Resource

North CS, Hong BA, Downs DL. PTSD: A systematic approach to diagnosis and treatment. Current Psychiatry 2018;17(4):35-43.

Drug Brand Names

Fluoxetine • Prozac
Prazosin • Minipress

Mr. H, age 43, presents to your clinic for management of posttraumatic stress disorder (PTSD). At his last appointment 8 weeks ago, he was continued on fluoxetine, 60 mg/d; he had been stable on this medication for 6 months. Today, Mr. H reports an increase in the frequency and severity of nightmares. He states that he wakes at least 3 times every week with “disturbing dreams” about his time in the military and does not feel rested even when he sleeps through the night. His Clinician-Administered PTSD Scale (CAPS) score is 95 on this visit, suggesting extreme PTSD symptomatology. Mr. H asks if anything can be done to reduce the frequency and intensity of his nightmares.

PTSD is the development of characteristic symptoms following exposure to ≥1 traumatic events. According to DSM-5, PTSD symptoms include the presence of ≥1 intrusion symptoms (recurrent, intrusive memories of the traumatic event; recurrent distressing dreams; dissociative reactions), persistent avoidance of stimuli, negative alterations in cognition and mood, and marked alterations in arousal and reactivity associated with the traumatic event(s).¹ The symptoms must be present for >1 month, cause clinically significant distress or impairment in functioning, and not be attributable to the psychologic effects of a substance or medical conditions.¹ This article focuses specifically on the hyperarousal symptoms, and the clinical controversies surrounding the use of prazosin for PTSD.

Prazosin for PTSD treatment

Sleep disorders are extremely common in patients with PTSD. Up to 90% of patients report sleep disturbances, and up to 70% report nightmares.² Prazosin has been widely used in the treatment of PTSD-related sleep disorders and nightmares.The American Psychiatric Association³ and the British Association of Psychopharmacology⁴ guidelines in-­clude prazosin as a first-line recommendation for treatment of PTSD. However, updated 2017 guidelines from the Veterans Affairs/Department of Defense (VA/DoD)⁵ and data from the 2018 Prazosin and Combat Trauma PTSD (PACT) trial⁶ contradict these original recommendations. Previously, the 2010 VA/DoD guideline said prazosin had insufficient evidence for monotherapy, but recommended it as adjunctive treatment for sleep and nightmares.⁷ The updated 2017 VA/DoD guideline recommends “weak against” prazosin use for global symptoms of PTSD, and says there is insufficient evidence for its use in nightmares.⁵ Below we summarize the findings of studies that contributed to those original recommendations, along with results of the PACT trial.

Raskind et al^8,9 conducted 2 studies of prazosin use in combat veterans with PTSD. In both studies, prazosin had significant positive effects on the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression of Change (CGIC) scores.^8,9 The 2007 study also found significant effects of prazosin on Pittsburgh Sleep Quality Index (PSQI) scores.⁹

Raskind et al¹⁰ conducted another study in 2013 of prazosin use for active-duty soldiers who had combat trauma PTSD with nightmares. Prazosin had positive effects for nightmares, sleep quality, and CAPS scores.¹⁰

Germain et al¹¹ reviewed prazosin for treating sleep disturbances in US military veterans. Prazosin was associated with significant improvements in insomnia and daytime PTSD symptom severity as demonstrated by changes in PSQI and CAPS scores.¹¹

Taylor et al¹² examined the effects of prazosin on sleep measures and clinical symptoms in civilians with PTSD. Prazosin significantly increased total sleep time, rapid eye movement sleep time, and CGIC scores while significantly decreasing trauma-related nightmares.¹²

Continue to: Overall, these trials...

Overall, these trials found efficacy for the use of prazosin for patients diagnosed with PTSD; however, the population size in each of these studies was small.

Results of the PACT trial

The PACT trial was a 26-week, multicenter, double-blind, randomized, placebo-controlled trial conducted across 12 VA medical centers.⁶ During the first 5 weeks, participants were randomized to receive placebo or prazosin, which could be titrated up to 20 mg/d in men and 12 mg/d in women. Participants remained on that dose from the end of Week 5 through Week 10. At that time, other pharmacologic therapies and psychotherapy could be added, discontinued, or adjusted. The mean maintenance total daily dose of prazosin was 14.8 mg.

A total of 413 patients were screened, 304 were randomized (152 per group), and 271 completed the 10-week primary outcome assessment. The population was almost entirely male (96.1% in the prazosin group and 99.3% in the placebo group), and most participants were White (64.5% in the prazosin group and 69.1% in the placebo group), with an average age of approximately 50 years. Primary outcomes included change from baseline to Week 10 in both CAPS item B2 (“recurrent distressing dreams”) and PSQI scores. CGIC score was evaluated at Week 10.

At Week 10, none of the primary outcomes were found to be statistically significant. The mean difference in change from baseline to Week 10 in CAPS item B2 score and PSQI score were 0.2 (P = .38) and 0.1 (P = .80), respectively. There was no significant difference in mean CGIC scores (P = .96). Repeated measures of CAPS item B2, PSQI, and CGIC scores were conducted through Week 26 as secondary outcomes. No significant differences were found. This study concluded that prazosin did not alleviate distressing dreams, improve sleep quality, or improve overall clinical symptoms.⁶

The PACT trial: Strengths and weaknesses

The PACT trial is the largest placebo-controlled trial for prazosin use in PTSD to date. It failed to show efficacy of prazosin for PTSD-associated nightmares, which contradicts previous studies. Although the mean total daily dose of prazosin was adequate and primary outcomes were measured with appropriate scales, the study failed to enroll the desired number of patients, which increased the possibility of false-negative results. Furthermore, participant recruitment may have led to selection bias because all participants were clinically stable, which could explain the lack of efficacy. However, the average CAPS scores were 80.7 in the prazosin group and 81.9 in the placebo group, which indicates that these patients had significant symptomatology at baseline and before entering the study.

Continue to: A major theme...

A major theme of studies evaluating prazosin treatment for PTSD is a focus on a military population and military-related trauma. Other than Taylor et al¹² (N=13), none of these trials included patients who were diagnosed with PTSD due to other traumas, such as sexual trauma, which limits the generalizability of the results. Furthermore, apart from the PACT trial, none of these studies had >100 participants, which further reduces external validity. Current guidelines have not been updated to include the results of the PACT trial, and it is unclear if the results of this trial are strong enough to change clinical practice.

CASE CONTINUED

To ensure patient-centered care, the treating clinicians conduct a risk/benefit discussion with the patient regarding starting prazosin. Mr. H opts to try prazosin, so the clinicians initiate a low dose (1 mg/d) to mitigate adverse effects, and plan to titrate to clinical effect or intolerability. Per evidence from the trials discussed, it is likely Mr. H will need to be titrated to at least 5 to 6 mg/d to see a clinical effect.

Related Resource

North CS, Hong BA, Downs DL. PTSD: A systematic approach to diagnosis and treatment. Current Psychiatry 2018;17(4):35-43.

Drug Brand Names

Fluoxetine • Prozac
Prazosin • Minipress

Mr. H, age 43, presents to your clinic for management of posttraumatic stress disorder (PTSD). At his last appointment 8 weeks ago, he was continued on fluoxetine, 60 mg/d; he had been stable on this medication for 6 months. Today, Mr. H reports an increase in the frequency and severity of nightmares. He states that he wakes at least 3 times every week with “disturbing dreams” about his time in the military and does not feel rested even when he sleeps through the night. His Clinician-Administered PTSD Scale (CAPS) score is 95 on this visit, suggesting extreme PTSD symptomatology. Mr. H asks if anything can be done to reduce the frequency and intensity of his nightmares.

PTSD is the development of characteristic symptoms following exposure to ≥1 traumatic events. According to DSM-5, PTSD symptoms include the presence of ≥1 intrusion symptoms (recurrent, intrusive memories of the traumatic event; recurrent distressing dreams; dissociative reactions), persistent avoidance of stimuli, negative alterations in cognition and mood, and marked alterations in arousal and reactivity associated with the traumatic event(s).¹ The symptoms must be present for >1 month, cause clinically significant distress or impairment in functioning, and not be attributable to the psychologic effects of a substance or medical conditions.¹ This article focuses specifically on the hyperarousal symptoms, and the clinical controversies surrounding the use of prazosin for PTSD.

Prazosin for PTSD treatment

Sleep disorders are extremely common in patients with PTSD. Up to 90% of patients report sleep disturbances, and up to 70% report nightmares.² Prazosin has been widely used in the treatment of PTSD-related sleep disorders and nightmares.The American Psychiatric Association³ and the British Association of Psychopharmacology⁴ guidelines in-­clude prazosin as a first-line recommendation for treatment of PTSD. However, updated 2017 guidelines from the Veterans Affairs/Department of Defense (VA/DoD)⁵ and data from the 2018 Prazosin and Combat Trauma PTSD (PACT) trial⁶ contradict these original recommendations. Previously, the 2010 VA/DoD guideline said prazosin had insufficient evidence for monotherapy, but recommended it as adjunctive treatment for sleep and nightmares.⁷ The updated 2017 VA/DoD guideline recommends “weak against” prazosin use for global symptoms of PTSD, and says there is insufficient evidence for its use in nightmares.⁵ Below we summarize the findings of studies that contributed to those original recommendations, along with results of the PACT trial.

Raskind et al^8,9 conducted 2 studies of prazosin use in combat veterans with PTSD. In both studies, prazosin had significant positive effects on the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression of Change (CGIC) scores.^8,9 The 2007 study also found significant effects of prazosin on Pittsburgh Sleep Quality Index (PSQI) scores.⁹

Raskind et al¹⁰ conducted another study in 2013 of prazosin use for active-duty soldiers who had combat trauma PTSD with nightmares. Prazosin had positive effects for nightmares, sleep quality, and CAPS scores.¹⁰

Germain et al¹¹ reviewed prazosin for treating sleep disturbances in US military veterans. Prazosin was associated with significant improvements in insomnia and daytime PTSD symptom severity as demonstrated by changes in PSQI and CAPS scores.¹¹

Taylor et al¹² examined the effects of prazosin on sleep measures and clinical symptoms in civilians with PTSD. Prazosin significantly increased total sleep time, rapid eye movement sleep time, and CGIC scores while significantly decreasing trauma-related nightmares.¹²

Continue to: Overall, these trials...

Overall, these trials found efficacy for the use of prazosin for patients diagnosed with PTSD; however, the population size in each of these studies was small.

Results of the PACT trial

The PACT trial was a 26-week, multicenter, double-blind, randomized, placebo-controlled trial conducted across 12 VA medical centers.⁶ During the first 5 weeks, participants were randomized to receive placebo or prazosin, which could be titrated up to 20 mg/d in men and 12 mg/d in women. Participants remained on that dose from the end of Week 5 through Week 10. At that time, other pharmacologic therapies and psychotherapy could be added, discontinued, or adjusted. The mean maintenance total daily dose of prazosin was 14.8 mg.

A total of 413 patients were screened, 304 were randomized (152 per group), and 271 completed the 10-week primary outcome assessment. The population was almost entirely male (96.1% in the prazosin group and 99.3% in the placebo group), and most participants were White (64.5% in the prazosin group and 69.1% in the placebo group), with an average age of approximately 50 years. Primary outcomes included change from baseline to Week 10 in both CAPS item B2 (“recurrent distressing dreams”) and PSQI scores. CGIC score was evaluated at Week 10.

At Week 10, none of the primary outcomes were found to be statistically significant. The mean difference in change from baseline to Week 10 in CAPS item B2 score and PSQI score were 0.2 (P = .38) and 0.1 (P = .80), respectively. There was no significant difference in mean CGIC scores (P = .96). Repeated measures of CAPS item B2, PSQI, and CGIC scores were conducted through Week 26 as secondary outcomes. No significant differences were found. This study concluded that prazosin did not alleviate distressing dreams, improve sleep quality, or improve overall clinical symptoms.⁶

The PACT trial: Strengths and weaknesses

The PACT trial is the largest placebo-controlled trial for prazosin use in PTSD to date. It failed to show efficacy of prazosin for PTSD-associated nightmares, which contradicts previous studies. Although the mean total daily dose of prazosin was adequate and primary outcomes were measured with appropriate scales, the study failed to enroll the desired number of patients, which increased the possibility of false-negative results. Furthermore, participant recruitment may have led to selection bias because all participants were clinically stable, which could explain the lack of efficacy. However, the average CAPS scores were 80.7 in the prazosin group and 81.9 in the placebo group, which indicates that these patients had significant symptomatology at baseline and before entering the study.

Continue to: A major theme...

A major theme of studies evaluating prazosin treatment for PTSD is a focus on a military population and military-related trauma. Other than Taylor et al¹² (N=13), none of these trials included patients who were diagnosed with PTSD due to other traumas, such as sexual trauma, which limits the generalizability of the results. Furthermore, apart from the PACT trial, none of these studies had >100 participants, which further reduces external validity. Current guidelines have not been updated to include the results of the PACT trial, and it is unclear if the results of this trial are strong enough to change clinical practice.

CASE CONTINUED

To ensure patient-centered care, the treating clinicians conduct a risk/benefit discussion with the patient regarding starting prazosin. Mr. H opts to try prazosin, so the clinicians initiate a low dose (1 mg/d) to mitigate adverse effects, and plan to titrate to clinical effect or intolerability. Per evidence from the trials discussed, it is likely Mr. H will need to be titrated to at least 5 to 6 mg/d to see a clinical effect.

Related Resource

North CS, Hong BA, Downs DL. PTSD: A systematic approach to diagnosis and treatment. Current Psychiatry 2018;17(4):35-43.

Drug Brand Names

Fluoxetine • Prozac
Prazosin • Minipress

Lumateperone is a novel antipsychotic that possesses a variety of unique receptor affinities. The recommended dose of lumateperone is 42 mg/d. In clinical trials, reductions in Positive and Negative Syndrome Scale scores observed with lumateperone, 28 mg/d and 84 mg/d, failed to separate from placebo.¹ However, in these trials, safety profiles were similar for all 3 doses.

Despite the popular understanding of lumateperone’s “unexplained narrow therapeutic window,”² we report the case of a patient with schizophrenia who responded well to lumateperone, 84 mg/d, without adverse effects or EKG changes.

Case report. Mr. W, age 26, has treatment-resistant schizophrenia (paranoid type). He failed to achieve remission on fluphenazine (10 to 25 mg/d), perphenazine (4 to 24 mg/d), risperidone (started at 4 mg/d and increased to 8 mg/d), and olanzapine (15, 20, and 25 mg/d). None of these medications eliminated his auditory or visual hallucinations. His response was most robust to perphenazine, as he reported a 50% reduction in the frequency of auditory hallucinations and a near-complete resolution of visual hallucinations (once or twice per week), but he never achieved full remission.

We started lumateperone, 42 mg/d, without a cross-taper. After 4 weeks of partial response, the patient escalated his dose to 84 mg/d on his own. At a follow-up visit 3.5 weeks after this self-directed dose increase, Mr. W reported a complete resolution of his auditory and visual hallucinations.  

Six months later, Mr. W continued to receive lumateperone, 84 mg/d, without extrapyramidal symptoms, tardive dyskinesia, or other adverse effects. His QTc showed no significant change (410 ms vs 412 ms).

Although some studies indicate a possible “therapeutic window” for lumateperone dosing, clinicians should not deprive patients who partially respond to the recommended 42 mg/d dose of the opportunity for additional benefit through dose escalation. Due to the vagaries of psychiatric pathology, and unique profiles of metabolism and receptor sensitivity, there will always be patients who may require higher-than-recommended doses of lumateperone, as with all other agents.

Lumateperone is a novel antipsychotic that possesses a variety of unique receptor affinities. The recommended dose of lumateperone is 42 mg/d. In clinical trials, reductions in Positive and Negative Syndrome Scale scores observed with lumateperone, 28 mg/d and 84 mg/d, failed to separate from placebo.¹ However, in these trials, safety profiles were similar for all 3 doses.

Despite the popular understanding of lumateperone’s “unexplained narrow therapeutic window,”² we report the case of a patient with schizophrenia who responded well to lumateperone, 84 mg/d, without adverse effects or EKG changes.

Case report. Mr. W, age 26, has treatment-resistant schizophrenia (paranoid type). He failed to achieve remission on fluphenazine (10 to 25 mg/d), perphenazine (4 to 24 mg/d), risperidone (started at 4 mg/d and increased to 8 mg/d), and olanzapine (15, 20, and 25 mg/d). None of these medications eliminated his auditory or visual hallucinations. His response was most robust to perphenazine, as he reported a 50% reduction in the frequency of auditory hallucinations and a near-complete resolution of visual hallucinations (once or twice per week), but he never achieved full remission.

We started lumateperone, 42 mg/d, without a cross-taper. After 4 weeks of partial response, the patient escalated his dose to 84 mg/d on his own. At a follow-up visit 3.5 weeks after this self-directed dose increase, Mr. W reported a complete resolution of his auditory and visual hallucinations.  

Six months later, Mr. W continued to receive lumateperone, 84 mg/d, without extrapyramidal symptoms, tardive dyskinesia, or other adverse effects. His QTc showed no significant change (410 ms vs 412 ms).

Although some studies indicate a possible “therapeutic window” for lumateperone dosing, clinicians should not deprive patients who partially respond to the recommended 42 mg/d dose of the opportunity for additional benefit through dose escalation. Due to the vagaries of psychiatric pathology, and unique profiles of metabolism and receptor sensitivity, there will always be patients who may require higher-than-recommended doses of lumateperone, as with all other agents.

Lumateperone is a novel antipsychotic that possesses a variety of unique receptor affinities. The recommended dose of lumateperone is 42 mg/d. In clinical trials, reductions in Positive and Negative Syndrome Scale scores observed with lumateperone, 28 mg/d and 84 mg/d, failed to separate from placebo.¹ However, in these trials, safety profiles were similar for all 3 doses.

Despite the popular understanding of lumateperone’s “unexplained narrow therapeutic window,”² we report the case of a patient with schizophrenia who responded well to lumateperone, 84 mg/d, without adverse effects or EKG changes.

Case report. Mr. W, age 26, has treatment-resistant schizophrenia (paranoid type). He failed to achieve remission on fluphenazine (10 to 25 mg/d), perphenazine (4 to 24 mg/d), risperidone (started at 4 mg/d and increased to 8 mg/d), and olanzapine (15, 20, and 25 mg/d). None of these medications eliminated his auditory or visual hallucinations. His response was most robust to perphenazine, as he reported a 50% reduction in the frequency of auditory hallucinations and a near-complete resolution of visual hallucinations (once or twice per week), but he never achieved full remission.

We started lumateperone, 42 mg/d, without a cross-taper. After 4 weeks of partial response, the patient escalated his dose to 84 mg/d on his own. At a follow-up visit 3.5 weeks after this self-directed dose increase, Mr. W reported a complete resolution of his auditory and visual hallucinations.  

Six months later, Mr. W continued to receive lumateperone, 84 mg/d, without extrapyramidal symptoms, tardive dyskinesia, or other adverse effects. His QTc showed no significant change (410 ms vs 412 ms).

Although some studies indicate a possible “therapeutic window” for lumateperone dosing, clinicians should not deprive patients who partially respond to the recommended 42 mg/d dose of the opportunity for additional benefit through dose escalation. Due to the vagaries of psychiatric pathology, and unique profiles of metabolism and receptor sensitivity, there will always be patients who may require higher-than-recommended doses of lumateperone, as with all other agents.

Chlorpromazine (CPZ), a low-potency first-generation antipsychotic (FGA), was the first medication approved for the management of schizophrenia. Since its approval, some psychiatrists have prescribed subsequent antipsychotics based on CPZ’s efficacy and dosing. Comparing dosages of newer antipsychotics using a CPZ equivalent as a baseline remains a relevant method of determining which agent to prescribe, and at what dose.^1,2

Psychiatrists frequently care for patients who are treatment-refractory or older adults with poor medication tolerance and age-related medical illness. Quick access to the comparative potency of different antipsychotics can help guide titration to the approximate equivalent dose of CPZ when initiating a medication, switching from 1 antipsychotic to another, or augmenting or combining antipsychotics. Fortunately, many authors, such as Woods²and Davis,³ have codified the dosing ratio equivalences of FGAs and second-generation antipsychotics (SGAs) using CPZ, 100 mg. To help psychiatrists use CPZ dosages as a point of comparison for prescribing other antipsychotics, the Table^1,2,4 (page 14) lists dose equivalents for oral FGAs and SGAs based on CPZ, 100 mg. (For information on dose equivalents for injectable antipsychotics, see “Second-generation long-acting injectable antipsychotics: A practical guide,” Current Psychiatry, March 2020, p. 24-32.)

While this information cannot replace a psychiatrist’s clinical judgment, it can serve as a clinically useful prescribing tool. In addition to providing this Table, we discuss what you should consider when using these equivalents to switch antipsychotics and estimate the ultimate dose target for effective management of psychotic disorders.

A few caveats

Bioactive equivalent dosages should be targeted as a rough guide when switching from one FGA or SGA to another. Common indications for switching antipsychotics include an inadequate therapeutic response after a medication trial of an adequate dose and duration; relapse of psychosis despite medication adherence; intolerable adverse effects; cost; a new-onset, contraindicating medical illness; and lapses in medication compliance that necessitate a change to IM formulations.⁵ Keep in mind that medication changes should be tailored to the patient’s specific clinical characteristics.

Several other clinical and pharmacologic variabilities should be kept in mind when switching antipsychotics using CPZ dosage equivalents^5,6:

• The therapeutic CPZ equivalent doses may be less precise for SGAs than for FGAs because the equivalents are largely based on dopaminergic blockade instead of cholinergic, serotonergic, or histaminergic systems
• For some antipsychotics, the relationship between dose and potency is nonlinear. For example, as the dosage of haloperidol increases, its relative antipsychotic potency decreases
• Differences in half-lives between 2 agents can add complexity to calculating the dosage equivalent
• Regardless of comparative dosing, before initiating a new antipsychotic, psychiatrists should read the dosing instructions in the FDA-approved package insert, and exercise caution before titrating a new medication to the maximum recommended dose.

Chlorpromazine (CPZ), a low-potency first-generation antipsychotic (FGA), was the first medication approved for the management of schizophrenia. Since its approval, some psychiatrists have prescribed subsequent antipsychotics based on CPZ’s efficacy and dosing. Comparing dosages of newer antipsychotics using a CPZ equivalent as a baseline remains a relevant method of determining which agent to prescribe, and at what dose.^1,2

Psychiatrists frequently care for patients who are treatment-refractory or older adults with poor medication tolerance and age-related medical illness. Quick access to the comparative potency of different antipsychotics can help guide titration to the approximate equivalent dose of CPZ when initiating a medication, switching from 1 antipsychotic to another, or augmenting or combining antipsychotics. Fortunately, many authors, such as Woods²and Davis,³ have codified the dosing ratio equivalences of FGAs and second-generation antipsychotics (SGAs) using CPZ, 100 mg. To help psychiatrists use CPZ dosages as a point of comparison for prescribing other antipsychotics, the Table^1,2,4 (page 14) lists dose equivalents for oral FGAs and SGAs based on CPZ, 100 mg. (For information on dose equivalents for injectable antipsychotics, see “Second-generation long-acting injectable antipsychotics: A practical guide,” Current Psychiatry, March 2020, p. 24-32.)

While this information cannot replace a psychiatrist’s clinical judgment, it can serve as a clinically useful prescribing tool. In addition to providing this Table, we discuss what you should consider when using these equivalents to switch antipsychotics and estimate the ultimate dose target for effective management of psychotic disorders.

A few caveats

Bioactive equivalent dosages should be targeted as a rough guide when switching from one FGA or SGA to another. Common indications for switching antipsychotics include an inadequate therapeutic response after a medication trial of an adequate dose and duration; relapse of psychosis despite medication adherence; intolerable adverse effects; cost; a new-onset, contraindicating medical illness; and lapses in medication compliance that necessitate a change to IM formulations.⁵ Keep in mind that medication changes should be tailored to the patient’s specific clinical characteristics.

Several other clinical and pharmacologic variabilities should be kept in mind when switching antipsychotics using CPZ dosage equivalents^5,6:

• The therapeutic CPZ equivalent doses may be less precise for SGAs than for FGAs because the equivalents are largely based on dopaminergic blockade instead of cholinergic, serotonergic, or histaminergic systems
• For some antipsychotics, the relationship between dose and potency is nonlinear. For example, as the dosage of haloperidol increases, its relative antipsychotic potency decreases
• Differences in half-lives between 2 agents can add complexity to calculating the dosage equivalent
• Regardless of comparative dosing, before initiating a new antipsychotic, psychiatrists should read the dosing instructions in the FDA-approved package insert, and exercise caution before titrating a new medication to the maximum recommended dose.

Chlorpromazine (CPZ), a low-potency first-generation antipsychotic (FGA), was the first medication approved for the management of schizophrenia. Since its approval, some psychiatrists have prescribed subsequent antipsychotics based on CPZ’s efficacy and dosing. Comparing dosages of newer antipsychotics using a CPZ equivalent as a baseline remains a relevant method of determining which agent to prescribe, and at what dose.^1,2

Psychiatrists frequently care for patients who are treatment-refractory or older adults with poor medication tolerance and age-related medical illness. Quick access to the comparative potency of different antipsychotics can help guide titration to the approximate equivalent dose of CPZ when initiating a medication, switching from 1 antipsychotic to another, or augmenting or combining antipsychotics. Fortunately, many authors, such as Woods²and Davis,³ have codified the dosing ratio equivalences of FGAs and second-generation antipsychotics (SGAs) using CPZ, 100 mg. To help psychiatrists use CPZ dosages as a point of comparison for prescribing other antipsychotics, the Table^1,2,4 (page 14) lists dose equivalents for oral FGAs and SGAs based on CPZ, 100 mg. (For information on dose equivalents for injectable antipsychotics, see “Second-generation long-acting injectable antipsychotics: A practical guide,” Current Psychiatry, March 2020, p. 24-32.)

While this information cannot replace a psychiatrist’s clinical judgment, it can serve as a clinically useful prescribing tool. In addition to providing this Table, we discuss what you should consider when using these equivalents to switch antipsychotics and estimate the ultimate dose target for effective management of psychotic disorders.

A few caveats

Bioactive equivalent dosages should be targeted as a rough guide when switching from one FGA or SGA to another. Common indications for switching antipsychotics include an inadequate therapeutic response after a medication trial of an adequate dose and duration; relapse of psychosis despite medication adherence; intolerable adverse effects; cost; a new-onset, contraindicating medical illness; and lapses in medication compliance that necessitate a change to IM formulations.⁵ Keep in mind that medication changes should be tailored to the patient’s specific clinical characteristics.

Several other clinical and pharmacologic variabilities should be kept in mind when switching antipsychotics using CPZ dosage equivalents^5,6:

• The therapeutic CPZ equivalent doses may be less precise for SGAs than for FGAs because the equivalents are largely based on dopaminergic blockade instead of cholinergic, serotonergic, or histaminergic systems
• For some antipsychotics, the relationship between dose and potency is nonlinear. For example, as the dosage of haloperidol increases, its relative antipsychotic potency decreases
• Differences in half-lives between 2 agents can add complexity to calculating the dosage equivalent
• Regardless of comparative dosing, before initiating a new antipsychotic, psychiatrists should read the dosing instructions in the FDA-approved package insert, and exercise caution before titrating a new medication to the maximum recommended dose.

On occasion, a patient may refuse to cooperate with a suicide risk assessment or is unable to participate due to the severity of a psychiatric or medical condition. In such situations, how can we conduct an assessment that meets our ethical, professional, and legal obligations?

First, skipping a suicide risk assessment is never an option. A patient’s refusal or inability to cooperate does not release us from our duty of care. We are obligated to gather information about suicide risk to anticipate the likelihood and severity of harm.¹ Furthermore, collecting information helps us evaluate what types of precautions are necessary to reduce or eliminate suicide risk.

Some clinicians may believe that a suicide risk assessment is only possible when they can ask patients about ideation, intent, plans, and past suicidal behavior. While the patient’s self-report is valuable, it is only one data point, and in some cases, it may not be reliable or credible.² So how should you handle such situations? Here I describe 3 steps to take to estimate a patient’s suicide risk without their participation.

1. Obtain information from other sources.

These can include:

• your recent contacts with the patient
• the patient’s responses to previous inquiries about suicidality
• collateral reports from staff
• the patient’s chart and past medical records
• past suicide attempts (including the precipitants, the patient’s reasons for the attempt, details of the actions taken and methods used, any medical outcome, and the patient’s reaction to surviving)³
• past nonsuicidal self-injury
• past episodes of suicidal thinking
• treatment progress to date
• mental status.

Documenting your sources of information will indicate that you made reasonable efforts to appreciate the risk despite imperfect circumstances. Furthermore, these sources of data can support your work to assess the severity of the patient’s current suicidality, to clinically formulate why the patient is susceptible to suicidal thoughts and behavior, and to anticipate circumstances that could constitute a high-risk period for your patient to attempt suicide.

2. Document the reasons you were unable to interview the patient. For patients who are competent to refuse services, document the efforts you made to gain the patient’s cooperation. If the patient’s psychiatric condition (eg, florid psychosis) was the main impediment, note this.

3. Explain the limitations of your assessment. This might include acknowledging that your estimation of the patient’s suicide risk is missing important information but is the best possible estimate at the time. Explain how you determined the level of risk with a statement such as, “Because the patient was unable to participate, I estimated risk based on….” If the patient’s lack of participation lowers your confidence in your risk estimate, this also should be documented. Reduced confidence may indicate the need for additional steps to assure the patient’s safety (eg, admission, delaying discharge, initiating continuous observation).

On occasion, a patient may refuse to cooperate with a suicide risk assessment or is unable to participate due to the severity of a psychiatric or medical condition. In such situations, how can we conduct an assessment that meets our ethical, professional, and legal obligations?

First, skipping a suicide risk assessment is never an option. A patient’s refusal or inability to cooperate does not release us from our duty of care. We are obligated to gather information about suicide risk to anticipate the likelihood and severity of harm.¹ Furthermore, collecting information helps us evaluate what types of precautions are necessary to reduce or eliminate suicide risk.

Some clinicians may believe that a suicide risk assessment is only possible when they can ask patients about ideation, intent, plans, and past suicidal behavior. While the patient’s self-report is valuable, it is only one data point, and in some cases, it may not be reliable or credible.² So how should you handle such situations? Here I describe 3 steps to take to estimate a patient’s suicide risk without their participation.

1. Obtain information from other sources.

These can include:

• your recent contacts with the patient
• the patient’s responses to previous inquiries about suicidality
• collateral reports from staff
• the patient’s chart and past medical records
• past suicide attempts (including the precipitants, the patient’s reasons for the attempt, details of the actions taken and methods used, any medical outcome, and the patient’s reaction to surviving)³
• past nonsuicidal self-injury
• past episodes of suicidal thinking
• treatment progress to date
• mental status.

Documenting your sources of information will indicate that you made reasonable efforts to appreciate the risk despite imperfect circumstances. Furthermore, these sources of data can support your work to assess the severity of the patient’s current suicidality, to clinically formulate why the patient is susceptible to suicidal thoughts and behavior, and to anticipate circumstances that could constitute a high-risk period for your patient to attempt suicide.

2. Document the reasons you were unable to interview the patient. For patients who are competent to refuse services, document the efforts you made to gain the patient’s cooperation. If the patient’s psychiatric condition (eg, florid psychosis) was the main impediment, note this.

3. Explain the limitations of your assessment. This might include acknowledging that your estimation of the patient’s suicide risk is missing important information but is the best possible estimate at the time. Explain how you determined the level of risk with a statement such as, “Because the patient was unable to participate, I estimated risk based on….” If the patient’s lack of participation lowers your confidence in your risk estimate, this also should be documented. Reduced confidence may indicate the need for additional steps to assure the patient’s safety (eg, admission, delaying discharge, initiating continuous observation).

On occasion, a patient may refuse to cooperate with a suicide risk assessment or is unable to participate due to the severity of a psychiatric or medical condition. In such situations, how can we conduct an assessment that meets our ethical, professional, and legal obligations?

First, skipping a suicide risk assessment is never an option. A patient’s refusal or inability to cooperate does not release us from our duty of care. We are obligated to gather information about suicide risk to anticipate the likelihood and severity of harm.¹ Furthermore, collecting information helps us evaluate what types of precautions are necessary to reduce or eliminate suicide risk.

Some clinicians may believe that a suicide risk assessment is only possible when they can ask patients about ideation, intent, plans, and past suicidal behavior. While the patient’s self-report is valuable, it is only one data point, and in some cases, it may not be reliable or credible.² So how should you handle such situations? Here I describe 3 steps to take to estimate a patient’s suicide risk without their participation.

1. Obtain information from other sources.

These can include:

• your recent contacts with the patient
• the patient’s responses to previous inquiries about suicidality
• collateral reports from staff
• the patient’s chart and past medical records
• past suicide attempts (including the precipitants, the patient’s reasons for the attempt, details of the actions taken and methods used, any medical outcome, and the patient’s reaction to surviving)³
• past nonsuicidal self-injury
• past episodes of suicidal thinking
• treatment progress to date
• mental status.

Documenting your sources of information will indicate that you made reasonable efforts to appreciate the risk despite imperfect circumstances. Furthermore, these sources of data can support your work to assess the severity of the patient’s current suicidality, to clinically formulate why the patient is susceptible to suicidal thoughts and behavior, and to anticipate circumstances that could constitute a high-risk period for your patient to attempt suicide.

2. Document the reasons you were unable to interview the patient. For patients who are competent to refuse services, document the efforts you made to gain the patient’s cooperation. If the patient’s psychiatric condition (eg, florid psychosis) was the main impediment, note this.

3. Explain the limitations of your assessment. This might include acknowledging that your estimation of the patient’s suicide risk is missing important information but is the best possible estimate at the time. Explain how you determined the level of risk with a statement such as, “Because the patient was unable to participate, I estimated risk based on….” If the patient’s lack of participation lowers your confidence in your risk estimate, this also should be documented. Reduced confidence may indicate the need for additional steps to assure the patient’s safety (eg, admission, delaying discharge, initiating continuous observation).

The Biden administration has passed and signed the $1.9 trillion American Rescue Plan, which contains a plethora of moneys targeted to people, businesses, and health systems impacted by the pandemic. According to the Economist, the bill would bring the amount of COVID-related spending since December 2020 to $3 trillion (14% of prepandemic GDP) and to $6 trillion since the start of the pandemic. This type of stimulus (regarded as income, not savings, by most people) will generate unprecedented consumer spending. The risk, of course, is inflation, rising interest rates, and long-term debt.

That said, there is substantial funding targeting scientific research, vaccine distribution, public health entities, global health initiatives, rural health care, and a variety of other health-related issues. By my rough estimation, the Centers for Disease Control and Prevention will see $12 billion in incremental funding, $10 billion for public health projects including $3 billion for community health centers and federally qualified health centers, and over $3 billion for mental and behavioral health. The Department of Health & Human Services will see substantial funding for a variety of projects. Teaching health centers will see $330 million additional funds (including a $10,000 per-resident increase and payments to establish new graduate residency training programs).

The impact on low-income families and childhood poverty will be substantial and reverses the philosophical underpinning of recent welfare reforms. U.S. welfare dates back to the early 1900s and the philosophical foundation has evolved over time. According to the Constitutional Rights Foundation (www.crf-usa.org), it began after food riots broke out during the Great Depression. The Great Depression affected children and the elderly most severely, so the nation’s willingness to implement federal welfare was high. Prior to the Depression, the only federal program providing money to low-income people was the “mothers pension” designed to support poor fatherless children, but it excluded divorced, deserted and minority mothers. President Roosevelt was able to pass the Social Security Act (1935), which supported the elderly and began Federal welfare. During the Clinton presidency, welfare “as we know it” changed to include work requirements. With the passage of the current Biden legislation, those requirements are rolled back and funds are targeted broadly to low income Americans and children.
 

John I. Allen, MD, MBA, AGAF
Editor in Chief

The Biden administration has passed and signed the $1.9 trillion American Rescue Plan, which contains a plethora of moneys targeted to people, businesses, and health systems impacted by the pandemic. According to the Economist, the bill would bring the amount of COVID-related spending since December 2020 to $3 trillion (14% of prepandemic GDP) and to $6 trillion since the start of the pandemic. This type of stimulus (regarded as income, not savings, by most people) will generate unprecedented consumer spending. The risk, of course, is inflation, rising interest rates, and long-term debt.

That said, there is substantial funding targeting scientific research, vaccine distribution, public health entities, global health initiatives, rural health care, and a variety of other health-related issues. By my rough estimation, the Centers for Disease Control and Prevention will see $12 billion in incremental funding, $10 billion for public health projects including $3 billion for community health centers and federally qualified health centers, and over $3 billion for mental and behavioral health. The Department of Health & Human Services will see substantial funding for a variety of projects. Teaching health centers will see $330 million additional funds (including a $10,000 per-resident increase and payments to establish new graduate residency training programs).

The impact on low-income families and childhood poverty will be substantial and reverses the philosophical underpinning of recent welfare reforms. U.S. welfare dates back to the early 1900s and the philosophical foundation has evolved over time. According to the Constitutional Rights Foundation (www.crf-usa.org), it began after food riots broke out during the Great Depression. The Great Depression affected children and the elderly most severely, so the nation’s willingness to implement federal welfare was high. Prior to the Depression, the only federal program providing money to low-income people was the “mothers pension” designed to support poor fatherless children, but it excluded divorced, deserted and minority mothers. President Roosevelt was able to pass the Social Security Act (1935), which supported the elderly and began Federal welfare. During the Clinton presidency, welfare “as we know it” changed to include work requirements. With the passage of the current Biden legislation, those requirements are rolled back and funds are targeted broadly to low income Americans and children.
 

John I. Allen, MD, MBA, AGAF
Editor in Chief

The Biden administration has passed and signed the $1.9 trillion American Rescue Plan, which contains a plethora of moneys targeted to people, businesses, and health systems impacted by the pandemic. According to the Economist, the bill would bring the amount of COVID-related spending since December 2020 to $3 trillion (14% of prepandemic GDP) and to $6 trillion since the start of the pandemic. This type of stimulus (regarded as income, not savings, by most people) will generate unprecedented consumer spending. The risk, of course, is inflation, rising interest rates, and long-term debt.

That said, there is substantial funding targeting scientific research, vaccine distribution, public health entities, global health initiatives, rural health care, and a variety of other health-related issues. By my rough estimation, the Centers for Disease Control and Prevention will see $12 billion in incremental funding, $10 billion for public health projects including $3 billion for community health centers and federally qualified health centers, and over $3 billion for mental and behavioral health. The Department of Health & Human Services will see substantial funding for a variety of projects. Teaching health centers will see $330 million additional funds (including a $10,000 per-resident increase and payments to establish new graduate residency training programs).

The impact on low-income families and childhood poverty will be substantial and reverses the philosophical underpinning of recent welfare reforms. U.S. welfare dates back to the early 1900s and the philosophical foundation has evolved over time. According to the Constitutional Rights Foundation (www.crf-usa.org), it began after food riots broke out during the Great Depression. The Great Depression affected children and the elderly most severely, so the nation’s willingness to implement federal welfare was high. Prior to the Depression, the only federal program providing money to low-income people was the “mothers pension” designed to support poor fatherless children, but it excluded divorced, deserted and minority mothers. President Roosevelt was able to pass the Social Security Act (1935), which supported the elderly and began Federal welfare. During the Clinton presidency, welfare “as we know it” changed to include work requirements. With the passage of the current Biden legislation, those requirements are rolled back and funds are targeted broadly to low income Americans and children.
 

John I. Allen, MD, MBA, AGAF
Editor in Chief

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

Medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP) typically has focused on controlling tissue inflammation. Approximately 85% of patients will exhibit a type 2 inflammatory pattern, and recent studies have examined the implications of this process for the treatment of CRSwNP.

As in other respiratory diseases, emerging CRSwNP endotypes are helping researchers identify actionable targets and develop targeted biologic treatments. In fact, therapies targeting cytokines IL-4 and IL-13, which contribute to type 2 inflammation in CRSwNP, recently have been approved by the FDA.

Dr Stella Lee from the University of Pittsburgh discusses the use of new biologic therapies in clinical practice as well as strategies to test for potential drivers of type 2 inflammation.

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP) typically has focused on controlling tissue inflammation. Approximately 85% of patients will exhibit a type 2 inflammatory pattern, and recent studies have examined the implications of this process for the treatment of CRSwNP.

As in other respiratory diseases, emerging CRSwNP endotypes are helping researchers identify actionable targets and develop targeted biologic treatments. In fact, therapies targeting cytokines IL-4 and IL-13, which contribute to type 2 inflammation in CRSwNP, recently have been approved by the FDA.

Dr Stella Lee from the University of Pittsburgh discusses the use of new biologic therapies in clinical practice as well as strategies to test for potential drivers of type 2 inflammation.

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP) typically has focused on controlling tissue inflammation. Approximately 85% of patients will exhibit a type 2 inflammatory pattern, and recent studies have examined the implications of this process for the treatment of CRSwNP.

As in other respiratory diseases, emerging CRSwNP endotypes are helping researchers identify actionable targets and develop targeted biologic treatments. In fact, therapies targeting cytokines IL-4 and IL-13, which contribute to type 2 inflammation in CRSwNP, recently have been approved by the FDA.

Dr Stella Lee from the University of Pittsburgh discusses the use of new biologic therapies in clinical practice as well as strategies to test for potential drivers of type 2 inflammation.

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Treatments in chronic rhinosinusitis with nasal polyps (CRSwNP) focus on reducing chronic type 2 inflammation. When intranasal corticosteroids, nasal saline irrigation, antibiotics, and oral steroids fail, patients move to surgery. Unfortunately, 40% of patients experience polyp regrowth following surgery. 
New research in biologic therapy is showing promise. Inflammatory mediators IL-4, IL-5, IL-13, and IgE play key roles in CRSwNP. Targeting these specific inflammatory pathways may provide effective treatment options for refractory CRSwNP patients.
Dr Anju Peters discusses dupilumab, a biologic currently approved for CRSwNP, as well as other targeted biologics in development.

---

Anju T. Peters, MD, MSci, Professor, Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine; Director of Clinical Research, Associate Chief of Research, Education, and Clinical Affairs, Division of Allergy-Immunology, Northwestern Medicine, Chicago, Illinois.

Anju T. Peters, MD, MSci, has disclosed the following relevant financial relationships: 
Serve(d) on the advisory board for: Sanofi Regeneron; Optinose; AstraZeneca. Received research grant from: AstraZeneca; Optinose.

Treatments in chronic rhinosinusitis with nasal polyps (CRSwNP) focus on reducing chronic type 2 inflammation. When intranasal corticosteroids, nasal saline irrigation, antibiotics, and oral steroids fail, patients move to surgery. Unfortunately, 40% of patients experience polyp regrowth following surgery. 
New research in biologic therapy is showing promise. Inflammatory mediators IL-4, IL-5, IL-13, and IgE play key roles in CRSwNP. Targeting these specific inflammatory pathways may provide effective treatment options for refractory CRSwNP patients.
Dr Anju Peters discusses dupilumab, a biologic currently approved for CRSwNP, as well as other targeted biologics in development.

---

Anju T. Peters, MD, MSci, Professor, Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine; Director of Clinical Research, Associate Chief of Research, Education, and Clinical Affairs, Division of Allergy-Immunology, Northwestern Medicine, Chicago, Illinois.

Anju T. Peters, MD, MSci, has disclosed the following relevant financial relationships: 
Serve(d) on the advisory board for: Sanofi Regeneron; Optinose; AstraZeneca. Received research grant from: AstraZeneca; Optinose.

Treatments in chronic rhinosinusitis with nasal polyps (CRSwNP) focus on reducing chronic type 2 inflammation. When intranasal corticosteroids, nasal saline irrigation, antibiotics, and oral steroids fail, patients move to surgery. Unfortunately, 40% of patients experience polyp regrowth following surgery. 
New research in biologic therapy is showing promise. Inflammatory mediators IL-4, IL-5, IL-13, and IgE play key roles in CRSwNP. Targeting these specific inflammatory pathways may provide effective treatment options for refractory CRSwNP patients.
Dr Anju Peters discusses dupilumab, a biologic currently approved for CRSwNP, as well as other targeted biologics in development.

---

Anju T. Peters, MD, MSci, Professor, Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine; Director of Clinical Research, Associate Chief of Research, Education, and Clinical Affairs, Division of Allergy-Immunology, Northwestern Medicine, Chicago, Illinois.

Anju T. Peters, MD, MSci, has disclosed the following relevant financial relationships: 
Serve(d) on the advisory board for: Sanofi Regeneron; Optinose; AstraZeneca. Received research grant from: AstraZeneca; Optinose.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a common condition that significantly affects quality of life and results in more than a million surgeries a year worldwide.

Symptoms of CRSwNP often mimic allergic rhinitis or bacterial rhinosinusitis, and patients frequently receive inappropriate prescriptions for allergy medications and even multiple courses of antibiotics. But appropriate therapeutic intervention can help to relieve CRSwNP symptoms, prevent unnecessary pain and suffering, reduce disease progression, and potentially prevent the need for nasal polypectomy.

Dr Stella Lee from the University of Pittsburgh discusses the importance of early and accurate diagnosis of CRSwNP, which is now viewed as a long-term, systemic inflammatory disorder, as well as strategies to assess symptom and disease severity.  

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a common condition that significantly affects quality of life and results in more than a million surgeries a year worldwide.

Symptoms of CRSwNP often mimic allergic rhinitis or bacterial rhinosinusitis, and patients frequently receive inappropriate prescriptions for allergy medications and even multiple courses of antibiotics. But appropriate therapeutic intervention can help to relieve CRSwNP symptoms, prevent unnecessary pain and suffering, reduce disease progression, and potentially prevent the need for nasal polypectomy.

Dr Stella Lee from the University of Pittsburgh discusses the importance of early and accurate diagnosis of CRSwNP, which is now viewed as a long-term, systemic inflammatory disorder, as well as strategies to assess symptom and disease severity.  

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a common condition that significantly affects quality of life and results in more than a million surgeries a year worldwide.

Symptoms of CRSwNP often mimic allergic rhinitis or bacterial rhinosinusitis, and patients frequently receive inappropriate prescriptions for allergy medications and even multiple courses of antibiotics. But appropriate therapeutic intervention can help to relieve CRSwNP symptoms, prevent unnecessary pain and suffering, reduce disease progression, and potentially prevent the need for nasal polypectomy.

Dr Stella Lee from the University of Pittsburgh discusses the importance of early and accurate diagnosis of CRSwNP, which is now viewed as a long-term, systemic inflammatory disorder, as well as strategies to assess symptom and disease severity.  

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

The evidence in favor of endovascular therapy for selected stroke patients who present in the late time window, from 6 to 24 hours after stroke onset, has been strengthened by the results of a new meta-analysis of data from six clinical trials.

Results of the AURORA analysis showed that for every 100 patients treated with thrombectomy, 33 patients will have less disability, and 27 patients will achieve an independent level of functioning compared with patients who receive only standard medical care.

The benefit of mechanical removal of the clot for selected patients who may have salvageable brain tissue, as identified through the use of various imaging modalities, was maintained whether the patient had a “wake-up stroke” or the onset of symptoms was witnessed, regardless of the point in time within the late window. In fact, the benefit of intervention was greater for patients who presented in the latter part of the late time window.

Never too late for urgent medical care

“While the findings of this analysis do not contradict the mantra that the earlier treatment is instituted, the higher the chance of a good outcome, they highlight the fact that it is never too late to seek urgent medical care,” said lead investigator Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey.

“The implications of the findings from AURORA are that they could lead to a change in guidelines from endorsement of thrombectomy as level 1a recommendation in eligible patients presenting in the 6- to 16-hour time window to a 6- to 24-hour time window,” said Dr. Jovin.

“Furthermore, there are strong signals of benefit of thrombectomy in patients who are not selected based on volumetric analysis of baseline infarct (core) or extent of tissue at risk (penumbra), such that when those imaging modalities are not available or contraindicated, selection based on noncontrast CT and clinical information only may be acceptable,” he added. “Finally, the possibility of benefit from thrombectomy performed beyond 24 hours from last seen well is real and should be explored in future studies.”

The AURORA findings were presented at the virtual International Stroke Conference (ISC) 2021.

The objective of the study was to provide a more precise estimate of the benefit of thrombectomy for patients with stroke when performed within 6-24 hours after the patient was last seen well, Dr. Jovin explained.

He said the 6-hour cutoff was chosen somewhat arbitrarily, but added, “It is highly consequential, as it marks the point of demarcation between the early and late time window, and virtually all guidelines recommend different approaches, dependent on whether patients present before or after 6 hours from symptom onset.”

The 6+ hour window

Dr. Jovin pointed out that for patients who present beyond 6 hours, treatment options are more restricted, because the data on thrombectomy in this later period come mainly from two North American trials (DEFUSE 3 and DAWN) that had very stringent imaging criteria for enrollment.

“We wanted to create a heterogeneous dataset with regard to geography and selection criteria by forming the AURORA collaboration,” he commented. Their study involved an individual-level pooled analysis of all patients who underwent randomization after 6 hours from the time that they were last seen well. Patients were randomly assigned to receive either best medical therapy alone or best medical therapy plus thrombectomy (either with stent retrievers or aspiration) for anterior circulation proximal large-vessel occlusion stroke.

The data came from six trials: DAWN (which enrolled patients 6-24 hours from stroke onset), DEFUSE 3 (6-16 hours), ESCAPE (0-12 hours), REVASCAT (0-8 hours), RESILIENT (0-8 hours), and POSITIVE (0-12 hours). In total, 505 patients were included in the meta-analysis, 266 in the intervention group, and 239 in the control group.

“By pooling data on patients presenting after 6 hours from all these trails, we achieve greater precision for treatment effect estimation and increased the power for subgroup analysis,” Dr. Jovin noted.

Although the majority of the patients were in the DAWN and DIFFUSE 3 trials (n = 388), “there are still a good number from the other four trials (n = 117),” Dr. Jovin reported.

Most of the trials used Modified Rankin Scale (mRS) ordinal or shift analysis as their primary endpoint, which was the also the endpoint chosen for this meta-analysis.

Imaging selection criteria ranged from fully automated software-generated quantitative volumetric analysis of baseline infarct (core) or tissue at risk to CT perfusion and plain CT/CTA. The minimum ASPECTS score was 5 or 6.

There were no imbalances in baseline characteristics. The median NIH Stroke Scale score was 16, and the median ASPECTS score was 8. The median time to randomization was 10.5 hours.

With regard to safety, there was no significant difference in rates of symptomatic intracerebral hemorrhage (5.3% in the intervention group vs. 3.3% in the control group; P = .23) or in mortality at 90 days (16.5% vs. 19.3%; P = .87). Jovin noted that these results are very similar to those from the HERMES meta-analysis of patients treated in the early time window.

The primary outcome – ordinal analysis of the mRS distribution – showed an adjusted odds ratio of 2.54 (P < .0001) for benefit in the intervention group. The number needed to treat to reduce disability was 3. “This is again very similar to the HERMES meta-analysis of patients in the early window,” Dr. Jovin said.

The P value for heterogeneity of treatment effect across the six studies was nonsignificant.

Secondary outcome analysis showed an “almost 27%” difference in good functional outcome (MRS, 0-2) between the two groups (45.9% in the intervention group vs. 19.3% in the control group), which translates into a number needed to treat of 3.8, Dr. Jovin reported.

Subgroup analysis showed a treatment effect favoring intervention across all prespecified subgroup factors, including age, sex, occlusion location, mode of presentation (wake-up vs. witnessed), and ASPECTS score, with the caveat that most of the patients were enrolled with ASPECTS scores of 7 or greater.

Early versus late

Surprisingly, although thrombectomy was found to be beneficial in both the 6- to 12-hour and 12- to 24-hour time window, the magnitude of benefit was significantly higher in the later rather than the earlier time window. The odds ratio of a better outcome with thrombectomy on the mRS shift analysis in those presenting in the 6- to 12-hour period was 1.78, compared with 5.86 in the 12- to 24-hour time window.

“This should not be interpreted as a higher chance of a good outcome if treated late. In fact, the rate of good outcomes were numerically higher in the earlier treated patients, but the difference comes from the control group, which did much worse in patients randomized in the later time period,” Dr. Jovin said.

“Aurora was the goddess of dawn [in ancient Roman mythology], so this is a very fitting name, as it reminds us that we are in the dawn of a new era where patients are selected based on physiological data rather than on time, and we certainly hope that this work has brought us closer to this reality,” Dr. Jovin concluded.

Commenting on the study, Michael Hill, MD, University of Calgary (Alta.), said: “The work provides pooled empiric data to support the concept that time to treatment is no longer the sole threshold variable to be used in treatment decision-making. Instead, time is now simply another variable to consider in the context of clinical and imaging factors.”

Dr. Hill, who headed up the ESCAPE trial and was also involved in the current meta-analysis, added: “This meta-analysis supports the concept of patient selection using the ‘good scan’ model, rather than using a time-based concept of patient eligibility for endovascular therapy. It will further push changes in care, because the implication is that all patients with more severe acute stroke presentations need emergency neurovascular imaging to decide if they are eligible for treatment.”

The AURORA meta-analysis was funded by Stryker Neurovascular. Dr. Jovin reports stock holdings in Anaconda, Route 92, VizAi, FreeOx, Blockade Medical, Methinks, and Corindus; personal fees from Cerenovus and Contego Medical; travel support from Fundacio Ictus; and grant support from Medtronic and Stryker Neurovascular.

A version of this article first appeared on Medscape.com.

The evidence in favor of endovascular therapy for selected stroke patients who present in the late time window, from 6 to 24 hours after stroke onset, has been strengthened by the results of a new meta-analysis of data from six clinical trials.

Results of the AURORA analysis showed that for every 100 patients treated with thrombectomy, 33 patients will have less disability, and 27 patients will achieve an independent level of functioning compared with patients who receive only standard medical care.

The benefit of mechanical removal of the clot for selected patients who may have salvageable brain tissue, as identified through the use of various imaging modalities, was maintained whether the patient had a “wake-up stroke” or the onset of symptoms was witnessed, regardless of the point in time within the late window. In fact, the benefit of intervention was greater for patients who presented in the latter part of the late time window.

Never too late for urgent medical care

“While the findings of this analysis do not contradict the mantra that the earlier treatment is instituted, the higher the chance of a good outcome, they highlight the fact that it is never too late to seek urgent medical care,” said lead investigator Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey.

“The implications of the findings from AURORA are that they could lead to a change in guidelines from endorsement of thrombectomy as level 1a recommendation in eligible patients presenting in the 6- to 16-hour time window to a 6- to 24-hour time window,” said Dr. Jovin.

“Furthermore, there are strong signals of benefit of thrombectomy in patients who are not selected based on volumetric analysis of baseline infarct (core) or extent of tissue at risk (penumbra), such that when those imaging modalities are not available or contraindicated, selection based on noncontrast CT and clinical information only may be acceptable,” he added. “Finally, the possibility of benefit from thrombectomy performed beyond 24 hours from last seen well is real and should be explored in future studies.”

The AURORA findings were presented at the virtual International Stroke Conference (ISC) 2021.

The objective of the study was to provide a more precise estimate of the benefit of thrombectomy for patients with stroke when performed within 6-24 hours after the patient was last seen well, Dr. Jovin explained.

He said the 6-hour cutoff was chosen somewhat arbitrarily, but added, “It is highly consequential, as it marks the point of demarcation between the early and late time window, and virtually all guidelines recommend different approaches, dependent on whether patients present before or after 6 hours from symptom onset.”

The 6+ hour window

Dr. Jovin pointed out that for patients who present beyond 6 hours, treatment options are more restricted, because the data on thrombectomy in this later period come mainly from two North American trials (DEFUSE 3 and DAWN) that had very stringent imaging criteria for enrollment.

“We wanted to create a heterogeneous dataset with regard to geography and selection criteria by forming the AURORA collaboration,” he commented. Their study involved an individual-level pooled analysis of all patients who underwent randomization after 6 hours from the time that they were last seen well. Patients were randomly assigned to receive either best medical therapy alone or best medical therapy plus thrombectomy (either with stent retrievers or aspiration) for anterior circulation proximal large-vessel occlusion stroke.

The data came from six trials: DAWN (which enrolled patients 6-24 hours from stroke onset), DEFUSE 3 (6-16 hours), ESCAPE (0-12 hours), REVASCAT (0-8 hours), RESILIENT (0-8 hours), and POSITIVE (0-12 hours). In total, 505 patients were included in the meta-analysis, 266 in the intervention group, and 239 in the control group.

“By pooling data on patients presenting after 6 hours from all these trails, we achieve greater precision for treatment effect estimation and increased the power for subgroup analysis,” Dr. Jovin noted.

Although the majority of the patients were in the DAWN and DIFFUSE 3 trials (n = 388), “there are still a good number from the other four trials (n = 117),” Dr. Jovin reported.

Most of the trials used Modified Rankin Scale (mRS) ordinal or shift analysis as their primary endpoint, which was the also the endpoint chosen for this meta-analysis.

Imaging selection criteria ranged from fully automated software-generated quantitative volumetric analysis of baseline infarct (core) or tissue at risk to CT perfusion and plain CT/CTA. The minimum ASPECTS score was 5 or 6.

There were no imbalances in baseline characteristics. The median NIH Stroke Scale score was 16, and the median ASPECTS score was 8. The median time to randomization was 10.5 hours.

With regard to safety, there was no significant difference in rates of symptomatic intracerebral hemorrhage (5.3% in the intervention group vs. 3.3% in the control group; P = .23) or in mortality at 90 days (16.5% vs. 19.3%; P = .87). Jovin noted that these results are very similar to those from the HERMES meta-analysis of patients treated in the early time window.

The primary outcome – ordinal analysis of the mRS distribution – showed an adjusted odds ratio of 2.54 (P < .0001) for benefit in the intervention group. The number needed to treat to reduce disability was 3. “This is again very similar to the HERMES meta-analysis of patients in the early window,” Dr. Jovin said.

The P value for heterogeneity of treatment effect across the six studies was nonsignificant.

Secondary outcome analysis showed an “almost 27%” difference in good functional outcome (MRS, 0-2) between the two groups (45.9% in the intervention group vs. 19.3% in the control group), which translates into a number needed to treat of 3.8, Dr. Jovin reported.

Subgroup analysis showed a treatment effect favoring intervention across all prespecified subgroup factors, including age, sex, occlusion location, mode of presentation (wake-up vs. witnessed), and ASPECTS score, with the caveat that most of the patients were enrolled with ASPECTS scores of 7 or greater.

Early versus late

Surprisingly, although thrombectomy was found to be beneficial in both the 6- to 12-hour and 12- to 24-hour time window, the magnitude of benefit was significantly higher in the later rather than the earlier time window. The odds ratio of a better outcome with thrombectomy on the mRS shift analysis in those presenting in the 6- to 12-hour period was 1.78, compared with 5.86 in the 12- to 24-hour time window.

“This should not be interpreted as a higher chance of a good outcome if treated late. In fact, the rate of good outcomes were numerically higher in the earlier treated patients, but the difference comes from the control group, which did much worse in patients randomized in the later time period,” Dr. Jovin said.

“Aurora was the goddess of dawn [in ancient Roman mythology], so this is a very fitting name, as it reminds us that we are in the dawn of a new era where patients are selected based on physiological data rather than on time, and we certainly hope that this work has brought us closer to this reality,” Dr. Jovin concluded.

Commenting on the study, Michael Hill, MD, University of Calgary (Alta.), said: “The work provides pooled empiric data to support the concept that time to treatment is no longer the sole threshold variable to be used in treatment decision-making. Instead, time is now simply another variable to consider in the context of clinical and imaging factors.”

Dr. Hill, who headed up the ESCAPE trial and was also involved in the current meta-analysis, added: “This meta-analysis supports the concept of patient selection using the ‘good scan’ model, rather than using a time-based concept of patient eligibility for endovascular therapy. It will further push changes in care, because the implication is that all patients with more severe acute stroke presentations need emergency neurovascular imaging to decide if they are eligible for treatment.”

The AURORA meta-analysis was funded by Stryker Neurovascular. Dr. Jovin reports stock holdings in Anaconda, Route 92, VizAi, FreeOx, Blockade Medical, Methinks, and Corindus; personal fees from Cerenovus and Contego Medical; travel support from Fundacio Ictus; and grant support from Medtronic and Stryker Neurovascular.

A version of this article first appeared on Medscape.com.

The evidence in favor of endovascular therapy for selected stroke patients who present in the late time window, from 6 to 24 hours after stroke onset, has been strengthened by the results of a new meta-analysis of data from six clinical trials.

Results of the AURORA analysis showed that for every 100 patients treated with thrombectomy, 33 patients will have less disability, and 27 patients will achieve an independent level of functioning compared with patients who receive only standard medical care.

The benefit of mechanical removal of the clot for selected patients who may have salvageable brain tissue, as identified through the use of various imaging modalities, was maintained whether the patient had a “wake-up stroke” or the onset of symptoms was witnessed, regardless of the point in time within the late window. In fact, the benefit of intervention was greater for patients who presented in the latter part of the late time window.

Never too late for urgent medical care

“While the findings of this analysis do not contradict the mantra that the earlier treatment is instituted, the higher the chance of a good outcome, they highlight the fact that it is never too late to seek urgent medical care,” said lead investigator Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey.

“The implications of the findings from AURORA are that they could lead to a change in guidelines from endorsement of thrombectomy as level 1a recommendation in eligible patients presenting in the 6- to 16-hour time window to a 6- to 24-hour time window,” said Dr. Jovin.

“Furthermore, there are strong signals of benefit of thrombectomy in patients who are not selected based on volumetric analysis of baseline infarct (core) or extent of tissue at risk (penumbra), such that when those imaging modalities are not available or contraindicated, selection based on noncontrast CT and clinical information only may be acceptable,” he added. “Finally, the possibility of benefit from thrombectomy performed beyond 24 hours from last seen well is real and should be explored in future studies.”

The AURORA findings were presented at the virtual International Stroke Conference (ISC) 2021.

The objective of the study was to provide a more precise estimate of the benefit of thrombectomy for patients with stroke when performed within 6-24 hours after the patient was last seen well, Dr. Jovin explained.

He said the 6-hour cutoff was chosen somewhat arbitrarily, but added, “It is highly consequential, as it marks the point of demarcation between the early and late time window, and virtually all guidelines recommend different approaches, dependent on whether patients present before or after 6 hours from symptom onset.”

The 6+ hour window

Dr. Jovin pointed out that for patients who present beyond 6 hours, treatment options are more restricted, because the data on thrombectomy in this later period come mainly from two North American trials (DEFUSE 3 and DAWN) that had very stringent imaging criteria for enrollment.

“We wanted to create a heterogeneous dataset with regard to geography and selection criteria by forming the AURORA collaboration,” he commented. Their study involved an individual-level pooled analysis of all patients who underwent randomization after 6 hours from the time that they were last seen well. Patients were randomly assigned to receive either best medical therapy alone or best medical therapy plus thrombectomy (either with stent retrievers or aspiration) for anterior circulation proximal large-vessel occlusion stroke.

The data came from six trials: DAWN (which enrolled patients 6-24 hours from stroke onset), DEFUSE 3 (6-16 hours), ESCAPE (0-12 hours), REVASCAT (0-8 hours), RESILIENT (0-8 hours), and POSITIVE (0-12 hours). In total, 505 patients were included in the meta-analysis, 266 in the intervention group, and 239 in the control group.

“By pooling data on patients presenting after 6 hours from all these trails, we achieve greater precision for treatment effect estimation and increased the power for subgroup analysis,” Dr. Jovin noted.

Although the majority of the patients were in the DAWN and DIFFUSE 3 trials (n = 388), “there are still a good number from the other four trials (n = 117),” Dr. Jovin reported.

Most of the trials used Modified Rankin Scale (mRS) ordinal or shift analysis as their primary endpoint, which was the also the endpoint chosen for this meta-analysis.

Imaging selection criteria ranged from fully automated software-generated quantitative volumetric analysis of baseline infarct (core) or tissue at risk to CT perfusion and plain CT/CTA. The minimum ASPECTS score was 5 or 6.

There were no imbalances in baseline characteristics. The median NIH Stroke Scale score was 16, and the median ASPECTS score was 8. The median time to randomization was 10.5 hours.

With regard to safety, there was no significant difference in rates of symptomatic intracerebral hemorrhage (5.3% in the intervention group vs. 3.3% in the control group; P = .23) or in mortality at 90 days (16.5% vs. 19.3%; P = .87). Jovin noted that these results are very similar to those from the HERMES meta-analysis of patients treated in the early time window.

The primary outcome – ordinal analysis of the mRS distribution – showed an adjusted odds ratio of 2.54 (P < .0001) for benefit in the intervention group. The number needed to treat to reduce disability was 3. “This is again very similar to the HERMES meta-analysis of patients in the early window,” Dr. Jovin said.

The P value for heterogeneity of treatment effect across the six studies was nonsignificant.

Secondary outcome analysis showed an “almost 27%” difference in good functional outcome (MRS, 0-2) between the two groups (45.9% in the intervention group vs. 19.3% in the control group), which translates into a number needed to treat of 3.8, Dr. Jovin reported.

Subgroup analysis showed a treatment effect favoring intervention across all prespecified subgroup factors, including age, sex, occlusion location, mode of presentation (wake-up vs. witnessed), and ASPECTS score, with the caveat that most of the patients were enrolled with ASPECTS scores of 7 or greater.

Early versus late

Surprisingly, although thrombectomy was found to be beneficial in both the 6- to 12-hour and 12- to 24-hour time window, the magnitude of benefit was significantly higher in the later rather than the earlier time window. The odds ratio of a better outcome with thrombectomy on the mRS shift analysis in those presenting in the 6- to 12-hour period was 1.78, compared with 5.86 in the 12- to 24-hour time window.

“This should not be interpreted as a higher chance of a good outcome if treated late. In fact, the rate of good outcomes were numerically higher in the earlier treated patients, but the difference comes from the control group, which did much worse in patients randomized in the later time period,” Dr. Jovin said.

“Aurora was the goddess of dawn [in ancient Roman mythology], so this is a very fitting name, as it reminds us that we are in the dawn of a new era where patients are selected based on physiological data rather than on time, and we certainly hope that this work has brought us closer to this reality,” Dr. Jovin concluded.

Commenting on the study, Michael Hill, MD, University of Calgary (Alta.), said: “The work provides pooled empiric data to support the concept that time to treatment is no longer the sole threshold variable to be used in treatment decision-making. Instead, time is now simply another variable to consider in the context of clinical and imaging factors.”

Dr. Hill, who headed up the ESCAPE trial and was also involved in the current meta-analysis, added: “This meta-analysis supports the concept of patient selection using the ‘good scan’ model, rather than using a time-based concept of patient eligibility for endovascular therapy. It will further push changes in care, because the implication is that all patients with more severe acute stroke presentations need emergency neurovascular imaging to decide if they are eligible for treatment.”

The AURORA meta-analysis was funded by Stryker Neurovascular. Dr. Jovin reports stock holdings in Anaconda, Route 92, VizAi, FreeOx, Blockade Medical, Methinks, and Corindus; personal fees from Cerenovus and Contego Medical; travel support from Fundacio Ictus; and grant support from Medtronic and Stryker Neurovascular.

A version of this article first appeared on Medscape.com.