Mr. L, age 31, presents to the emergency department (ED) with somnolence after sustaining an arm laceration at work. While in the ED, Mr. L explains he has opioid use disorder (OUD) and last week received an initial 300 mg injection of extended-release buprenorphine (BUP-XR). Due to ongoing opioid cravings, he took nonprescribed fentanyl and alprazolam before work.

The ED clinicians address Mr. L’s arm injury and transfer him to the hospital’s low-threshold outpatient addiction clinic for further assessment and management. There, he is prescribed sublingual buprenorphine/naloxone (SL-BUP) 8 mg/2 mg daily as needed for 1 week to address ongoing opioid cravings, and is encouraged to return for another visit the following week.

The United States continues to struggle with the overdose crisis, largely fueled by illicitly manufactured opioids such as fentanyl.¹ Opioid agonist and partial agonist treatments such as methadone and buprenorphine decrease the risk of death in individuals with OUD by up to 50%.² While methadone has a history of proven effectiveness for OUD, accessibility is fraught with barriers (eg, patients must attend an opioid treatment program daily to receive a dose, pharmacies are unable to dispense methadone for OUD).

Buprenorphine has been shown to decrease opioid cravings while limiting euphoria due to its partial—as opposed to full—agonist activity.³ Several buprenorphine formulations are available (Table). Buprenorphine presents an opportunity to treat OUD like other chronic illnesses. In accordance with the US Department of Health and Human Services Practice Guideline (2021), any clinician can obtain a waiver to prescribe buprenorphine in any treatment setting, and patients can receive the medication at a pharmacy.⁴

However, many patients have barriers to consistent daily dosing of buprenorphine due to strict clinic/prescriber requirements, transportation difficulties, continued cravings, and other factors. BUP-XR, a buprenorphine injection administered once a month, may address several of these concerns, most notably the potential for better suppression of cravings by delivering a consistent level of buprenorphine over the course of 28 days.⁵ Since BUP-XR was FDA-approved in 2017, questions remain whether it can adequately quell opioid cravings in early treatment months prior to steady-state concentration.

This article addresses whether clinicians should consider supplemental SL-BUP in addition to BUP-XR during early treatment months and/or prior to steady-state.

Pharmacokinetics of BUP-XR

BUP-XR is administered by subcutaneous injection via an ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, Massachusetts).⁶ Upon injection, approximately 7% of the buprenorphine dose dissipates with the solvent, leading to maximum concentration approximately 24 hours post-dose. The remaining dose hardens to create a depot that elutes buprenorphine gradually over 28 days.⁷

Continue to: Buprenorphine requires...

Buprenorphine requires ≥70% mu-opioid receptor (MOR) occupancy to effectively suppress symptoms of craving and withdrawal in patients with OUD. Buprenorphine serum concentration correlates significantly with MOR occupancy, such that concentrations of 2 to 3 ng/mL are acknowledged as baseline minimums for clinical efficacy.⁸

BUP-XR is administered in 1 of 2 dosing regimens. In both, 2 separate 300 mg doses are administered 28 days apart during Month 1 and Month 2, followed by maintenance doses of either 300 mg (300/300 mg dosing regimen) or 100 mg (300/100 mg dosing regimen) every 28 days thereafter. Combined Phase II and Phase III data analyzing serum concentrations of BUP-XR across both dosing regimens revealed that, for most patients, there is a noticeable period during Month 1 and Month 2 when serum concentrations fall below 2 ng/mL.⁷ Steady-state concentrations of both regimens develop after 4 to 6 appropriately timed injections, providing average steady-state serum concentrations in Phase II and Phase III trials of 6.54 ng/mL for the 300/300 mg dosing regimen and 3.00 ng/mL for 300/100 mg dosing regimen.⁷

Real-world experiences with BUP-XR

The theoretical need for supplementation has been voiced in practice. A case series by Peckham et al⁹ noted that 55% (n = 22) of patients required SL-BUP supplementation for up to 120 days after the first BUP-XR injection to quell cravings and reduce nonprescribed opioid use.

The RECOVER trial by Ling et al¹⁰ demonstrated the importance of the first 2 months of BUP-XR therapy in the overall treatment success for patients with OUD. In this analysis, patients maintained on BUP-XR for 12 months reported a 75% likelihood of abstinence, compared to 24% for patients receiving 0 to 2 months of BUP-XR treatment. Other benefits included improved employment status and reduced depression rates. This trial did not specifically discuss supplemental SL-BUP or subthreshold concentrations of buprenorphine during early months.¹⁰

Individualized treatment should be based on OUD symptoms

While BUP-XR was designed to continuously deliver at least 2 ng/mL of buprenorphine, serum concentrations are labile during the first 2 months of treatment. This may result in breakthrough OUD symptoms, particularly withdrawal or opioid cravings. Additionally, due to individual variability, some patients may still experience serum concentrations below 2 ng/mL after Month 2 and until steady-state is achieved between Month 4 and Month 6.⁷

Continue to: Beyond a theoretical...

Beyond a theoretical need for supplementation with SL-BUP, there is limited information regarding optimal dosing, dosage intervals, or length of supplementation. Therefore, clear guidance is not available at this time, and treatment should be individualized based on subjective and objective OUD symptoms.

What also remains unknown are potential barriers patients may face in receiving 2 concurrent buprenorphine prescriptions. BUP-XR, administered in a health care setting, can be obtained 2 ways. A clinician can directly order the medication from the distributor to be administered via buy-and-bill. An alternate option requires the clinician to send a prescription to an appropriately credentialed pharmacy that will ship patient-specific orders directly to the clinic. Despite this, most SL-BUP prescriptions are billed and dispensed from community pharmacies. At the insurance level, there is risk the prescription claim will be rejected for duplication of therapy, which may require additional collaboration between the prescribing clinician, pharmacist, and insurance representative to ensure patients have access to the medication.

Pending studies and approvals may also provide greater guidance and flexibility in decision-making for patients with OUD. The CoLAB study currently underway in Australia is examining the efficacy and outcomes of an intermediate dose (200 mg) of BUP-XR and will also allow for supplemental SL-BUP doses.¹¹ Additionally, an alternative BUP-XR formulation, Brixadi, currently in use in the European Union as Buvidal, has submitted an application for FDA approval in the United States. The application indicates that Brixadi will be available with a wider range of doses and at both weekly and monthly intervals. Approval has been delayed due to deficiencies in the United States–based third-party production facilities. It is unclear how the FDA and manufacturer plan to proceed.¹²

Short-term supplementation with SL-BUP during early the months of treatment with BUP-XR should be considered to control OUD symptoms and assist with patient retention. Once steady-state is achieved, trough concentrations of buprenorphine are not expected to drop below 2 ng/mL with continued on-time maintenance doses and thus, supplementation can likely cease.

CASE CONTINUED

Mr. L is seen in the low-threshold outpatient clinic 1 week after his ED visit. His arm laceration is healing well, and he is noticeably more alert and engaged. Each morning this week, he awakes with cravings, sweating, and anxiety. These symptoms alleviate after he takes SL-BUP. Mr. L’s clinician gives him a copy of the Subjective Opioid Withdrawal Scale so he can assess his withdrawal symptoms each morning and provide this data at follow-up appointments. Mr. L and his clinician decide to meet weekly until his next injection to continue assessing his current supplemental dose, symptoms, and whether there should be additional adjustments to his treatment plan.

Related Resources

• Cho J, Bhimani J, Patel M, et al. Substance abuse among older adults: a growing problem. Current Psychiatry. 2018;17(3):14-20.
• Verma S. Opioid use disorder in adolescents: an overview. Current Psychiatry. 2020;19(2):12-14,16-21.

Drug Brand Names

Alprazolam • Xanax
Buprenorphine • Sublocade, Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Methadone • Methadose

Mr. L, age 31, presents to the emergency department (ED) with somnolence after sustaining an arm laceration at work. While in the ED, Mr. L explains he has opioid use disorder (OUD) and last week received an initial 300 mg injection of extended-release buprenorphine (BUP-XR). Due to ongoing opioid cravings, he took nonprescribed fentanyl and alprazolam before work.

The ED clinicians address Mr. L’s arm injury and transfer him to the hospital’s low-threshold outpatient addiction clinic for further assessment and management. There, he is prescribed sublingual buprenorphine/naloxone (SL-BUP) 8 mg/2 mg daily as needed for 1 week to address ongoing opioid cravings, and is encouraged to return for another visit the following week.

The United States continues to struggle with the overdose crisis, largely fueled by illicitly manufactured opioids such as fentanyl.¹ Opioid agonist and partial agonist treatments such as methadone and buprenorphine decrease the risk of death in individuals with OUD by up to 50%.² While methadone has a history of proven effectiveness for OUD, accessibility is fraught with barriers (eg, patients must attend an opioid treatment program daily to receive a dose, pharmacies are unable to dispense methadone for OUD).

Buprenorphine has been shown to decrease opioid cravings while limiting euphoria due to its partial—as opposed to full—agonist activity.³ Several buprenorphine formulations are available (Table). Buprenorphine presents an opportunity to treat OUD like other chronic illnesses. In accordance with the US Department of Health and Human Services Practice Guideline (2021), any clinician can obtain a waiver to prescribe buprenorphine in any treatment setting, and patients can receive the medication at a pharmacy.⁴

However, many patients have barriers to consistent daily dosing of buprenorphine due to strict clinic/prescriber requirements, transportation difficulties, continued cravings, and other factors. BUP-XR, a buprenorphine injection administered once a month, may address several of these concerns, most notably the potential for better suppression of cravings by delivering a consistent level of buprenorphine over the course of 28 days.⁵ Since BUP-XR was FDA-approved in 2017, questions remain whether it can adequately quell opioid cravings in early treatment months prior to steady-state concentration.

This article addresses whether clinicians should consider supplemental SL-BUP in addition to BUP-XR during early treatment months and/or prior to steady-state.

Pharmacokinetics of BUP-XR

BUP-XR is administered by subcutaneous injection via an ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, Massachusetts).⁶ Upon injection, approximately 7% of the buprenorphine dose dissipates with the solvent, leading to maximum concentration approximately 24 hours post-dose. The remaining dose hardens to create a depot that elutes buprenorphine gradually over 28 days.⁷

Continue to: Buprenorphine requires...

Buprenorphine requires ≥70% mu-opioid receptor (MOR) occupancy to effectively suppress symptoms of craving and withdrawal in patients with OUD. Buprenorphine serum concentration correlates significantly with MOR occupancy, such that concentrations of 2 to 3 ng/mL are acknowledged as baseline minimums for clinical efficacy.⁸

BUP-XR is administered in 1 of 2 dosing regimens. In both, 2 separate 300 mg doses are administered 28 days apart during Month 1 and Month 2, followed by maintenance doses of either 300 mg (300/300 mg dosing regimen) or 100 mg (300/100 mg dosing regimen) every 28 days thereafter. Combined Phase II and Phase III data analyzing serum concentrations of BUP-XR across both dosing regimens revealed that, for most patients, there is a noticeable period during Month 1 and Month 2 when serum concentrations fall below 2 ng/mL.⁷ Steady-state concentrations of both regimens develop after 4 to 6 appropriately timed injections, providing average steady-state serum concentrations in Phase II and Phase III trials of 6.54 ng/mL for the 300/300 mg dosing regimen and 3.00 ng/mL for 300/100 mg dosing regimen.⁷

Real-world experiences with BUP-XR

The theoretical need for supplementation has been voiced in practice. A case series by Peckham et al⁹ noted that 55% (n = 22) of patients required SL-BUP supplementation for up to 120 days after the first BUP-XR injection to quell cravings and reduce nonprescribed opioid use.

The RECOVER trial by Ling et al¹⁰ demonstrated the importance of the first 2 months of BUP-XR therapy in the overall treatment success for patients with OUD. In this analysis, patients maintained on BUP-XR for 12 months reported a 75% likelihood of abstinence, compared to 24% for patients receiving 0 to 2 months of BUP-XR treatment. Other benefits included improved employment status and reduced depression rates. This trial did not specifically discuss supplemental SL-BUP or subthreshold concentrations of buprenorphine during early months.¹⁰

Individualized treatment should be based on OUD symptoms

While BUP-XR was designed to continuously deliver at least 2 ng/mL of buprenorphine, serum concentrations are labile during the first 2 months of treatment. This may result in breakthrough OUD symptoms, particularly withdrawal or opioid cravings. Additionally, due to individual variability, some patients may still experience serum concentrations below 2 ng/mL after Month 2 and until steady-state is achieved between Month 4 and Month 6.⁷

Continue to: Beyond a theoretical...

Beyond a theoretical need for supplementation with SL-BUP, there is limited information regarding optimal dosing, dosage intervals, or length of supplementation. Therefore, clear guidance is not available at this time, and treatment should be individualized based on subjective and objective OUD symptoms.

What also remains unknown are potential barriers patients may face in receiving 2 concurrent buprenorphine prescriptions. BUP-XR, administered in a health care setting, can be obtained 2 ways. A clinician can directly order the medication from the distributor to be administered via buy-and-bill. An alternate option requires the clinician to send a prescription to an appropriately credentialed pharmacy that will ship patient-specific orders directly to the clinic. Despite this, most SL-BUP prescriptions are billed and dispensed from community pharmacies. At the insurance level, there is risk the prescription claim will be rejected for duplication of therapy, which may require additional collaboration between the prescribing clinician, pharmacist, and insurance representative to ensure patients have access to the medication.

Pending studies and approvals may also provide greater guidance and flexibility in decision-making for patients with OUD. The CoLAB study currently underway in Australia is examining the efficacy and outcomes of an intermediate dose (200 mg) of BUP-XR and will also allow for supplemental SL-BUP doses.¹¹ Additionally, an alternative BUP-XR formulation, Brixadi, currently in use in the European Union as Buvidal, has submitted an application for FDA approval in the United States. The application indicates that Brixadi will be available with a wider range of doses and at both weekly and monthly intervals. Approval has been delayed due to deficiencies in the United States–based third-party production facilities. It is unclear how the FDA and manufacturer plan to proceed.¹²

Short-term supplementation with SL-BUP during early the months of treatment with BUP-XR should be considered to control OUD symptoms and assist with patient retention. Once steady-state is achieved, trough concentrations of buprenorphine are not expected to drop below 2 ng/mL with continued on-time maintenance doses and thus, supplementation can likely cease.

CASE CONTINUED

Mr. L is seen in the low-threshold outpatient clinic 1 week after his ED visit. His arm laceration is healing well, and he is noticeably more alert and engaged. Each morning this week, he awakes with cravings, sweating, and anxiety. These symptoms alleviate after he takes SL-BUP. Mr. L’s clinician gives him a copy of the Subjective Opioid Withdrawal Scale so he can assess his withdrawal symptoms each morning and provide this data at follow-up appointments. Mr. L and his clinician decide to meet weekly until his next injection to continue assessing his current supplemental dose, symptoms, and whether there should be additional adjustments to his treatment plan.

Related Resources

• Cho J, Bhimani J, Patel M, et al. Substance abuse among older adults: a growing problem. Current Psychiatry. 2018;17(3):14-20.
• Verma S. Opioid use disorder in adolescents: an overview. Current Psychiatry. 2020;19(2):12-14,16-21.

Drug Brand Names

Alprazolam • Xanax
Buprenorphine • Sublocade, Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Methadone • Methadose

Mr. L, age 31, presents to the emergency department (ED) with somnolence after sustaining an arm laceration at work. While in the ED, Mr. L explains he has opioid use disorder (OUD) and last week received an initial 300 mg injection of extended-release buprenorphine (BUP-XR). Due to ongoing opioid cravings, he took nonprescribed fentanyl and alprazolam before work.

The ED clinicians address Mr. L’s arm injury and transfer him to the hospital’s low-threshold outpatient addiction clinic for further assessment and management. There, he is prescribed sublingual buprenorphine/naloxone (SL-BUP) 8 mg/2 mg daily as needed for 1 week to address ongoing opioid cravings, and is encouraged to return for another visit the following week.

The United States continues to struggle with the overdose crisis, largely fueled by illicitly manufactured opioids such as fentanyl.¹ Opioid agonist and partial agonist treatments such as methadone and buprenorphine decrease the risk of death in individuals with OUD by up to 50%.² While methadone has a history of proven effectiveness for OUD, accessibility is fraught with barriers (eg, patients must attend an opioid treatment program daily to receive a dose, pharmacies are unable to dispense methadone for OUD).

Buprenorphine has been shown to decrease opioid cravings while limiting euphoria due to its partial—as opposed to full—agonist activity.³ Several buprenorphine formulations are available (Table). Buprenorphine presents an opportunity to treat OUD like other chronic illnesses. In accordance with the US Department of Health and Human Services Practice Guideline (2021), any clinician can obtain a waiver to prescribe buprenorphine in any treatment setting, and patients can receive the medication at a pharmacy.⁴

However, many patients have barriers to consistent daily dosing of buprenorphine due to strict clinic/prescriber requirements, transportation difficulties, continued cravings, and other factors. BUP-XR, a buprenorphine injection administered once a month, may address several of these concerns, most notably the potential for better suppression of cravings by delivering a consistent level of buprenorphine over the course of 28 days.⁵ Since BUP-XR was FDA-approved in 2017, questions remain whether it can adequately quell opioid cravings in early treatment months prior to steady-state concentration.

This article addresses whether clinicians should consider supplemental SL-BUP in addition to BUP-XR during early treatment months and/or prior to steady-state.

Pharmacokinetics of BUP-XR

BUP-XR is administered by subcutaneous injection via an ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, Massachusetts).⁶ Upon injection, approximately 7% of the buprenorphine dose dissipates with the solvent, leading to maximum concentration approximately 24 hours post-dose. The remaining dose hardens to create a depot that elutes buprenorphine gradually over 28 days.⁷

Continue to: Buprenorphine requires...

Buprenorphine requires ≥70% mu-opioid receptor (MOR) occupancy to effectively suppress symptoms of craving and withdrawal in patients with OUD. Buprenorphine serum concentration correlates significantly with MOR occupancy, such that concentrations of 2 to 3 ng/mL are acknowledged as baseline minimums for clinical efficacy.⁸

BUP-XR is administered in 1 of 2 dosing regimens. In both, 2 separate 300 mg doses are administered 28 days apart during Month 1 and Month 2, followed by maintenance doses of either 300 mg (300/300 mg dosing regimen) or 100 mg (300/100 mg dosing regimen) every 28 days thereafter. Combined Phase II and Phase III data analyzing serum concentrations of BUP-XR across both dosing regimens revealed that, for most patients, there is a noticeable period during Month 1 and Month 2 when serum concentrations fall below 2 ng/mL.⁷ Steady-state concentrations of both regimens develop after 4 to 6 appropriately timed injections, providing average steady-state serum concentrations in Phase II and Phase III trials of 6.54 ng/mL for the 300/300 mg dosing regimen and 3.00 ng/mL for 300/100 mg dosing regimen.⁷

Real-world experiences with BUP-XR

The theoretical need for supplementation has been voiced in practice. A case series by Peckham et al⁹ noted that 55% (n = 22) of patients required SL-BUP supplementation for up to 120 days after the first BUP-XR injection to quell cravings and reduce nonprescribed opioid use.

The RECOVER trial by Ling et al¹⁰ demonstrated the importance of the first 2 months of BUP-XR therapy in the overall treatment success for patients with OUD. In this analysis, patients maintained on BUP-XR for 12 months reported a 75% likelihood of abstinence, compared to 24% for patients receiving 0 to 2 months of BUP-XR treatment. Other benefits included improved employment status and reduced depression rates. This trial did not specifically discuss supplemental SL-BUP or subthreshold concentrations of buprenorphine during early months.¹⁰

Individualized treatment should be based on OUD symptoms

While BUP-XR was designed to continuously deliver at least 2 ng/mL of buprenorphine, serum concentrations are labile during the first 2 months of treatment. This may result in breakthrough OUD symptoms, particularly withdrawal or opioid cravings. Additionally, due to individual variability, some patients may still experience serum concentrations below 2 ng/mL after Month 2 and until steady-state is achieved between Month 4 and Month 6.⁷

Continue to: Beyond a theoretical...

Beyond a theoretical need for supplementation with SL-BUP, there is limited information regarding optimal dosing, dosage intervals, or length of supplementation. Therefore, clear guidance is not available at this time, and treatment should be individualized based on subjective and objective OUD symptoms.

What also remains unknown are potential barriers patients may face in receiving 2 concurrent buprenorphine prescriptions. BUP-XR, administered in a health care setting, can be obtained 2 ways. A clinician can directly order the medication from the distributor to be administered via buy-and-bill. An alternate option requires the clinician to send a prescription to an appropriately credentialed pharmacy that will ship patient-specific orders directly to the clinic. Despite this, most SL-BUP prescriptions are billed and dispensed from community pharmacies. At the insurance level, there is risk the prescription claim will be rejected for duplication of therapy, which may require additional collaboration between the prescribing clinician, pharmacist, and insurance representative to ensure patients have access to the medication.

Pending studies and approvals may also provide greater guidance and flexibility in decision-making for patients with OUD. The CoLAB study currently underway in Australia is examining the efficacy and outcomes of an intermediate dose (200 mg) of BUP-XR and will also allow for supplemental SL-BUP doses.¹¹ Additionally, an alternative BUP-XR formulation, Brixadi, currently in use in the European Union as Buvidal, has submitted an application for FDA approval in the United States. The application indicates that Brixadi will be available with a wider range of doses and at both weekly and monthly intervals. Approval has been delayed due to deficiencies in the United States–based third-party production facilities. It is unclear how the FDA and manufacturer plan to proceed.¹²

Short-term supplementation with SL-BUP during early the months of treatment with BUP-XR should be considered to control OUD symptoms and assist with patient retention. Once steady-state is achieved, trough concentrations of buprenorphine are not expected to drop below 2 ng/mL with continued on-time maintenance doses and thus, supplementation can likely cease.

CASE CONTINUED

Mr. L is seen in the low-threshold outpatient clinic 1 week after his ED visit. His arm laceration is healing well, and he is noticeably more alert and engaged. Each morning this week, he awakes with cravings, sweating, and anxiety. These symptoms alleviate after he takes SL-BUP. Mr. L’s clinician gives him a copy of the Subjective Opioid Withdrawal Scale so he can assess his withdrawal symptoms each morning and provide this data at follow-up appointments. Mr. L and his clinician decide to meet weekly until his next injection to continue assessing his current supplemental dose, symptoms, and whether there should be additional adjustments to his treatment plan.

Related Resources

• Cho J, Bhimani J, Patel M, et al. Substance abuse among older adults: a growing problem. Current Psychiatry. 2018;17(3):14-20.
• Verma S. Opioid use disorder in adolescents: an overview. Current Psychiatry. 2020;19(2):12-14,16-21.

Drug Brand Names

Alprazolam • Xanax
Buprenorphine • Sublocade, Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Methadone • Methadose

CASE Schizophrenia, leukemia, and chemotherapy

Mr. A, age 30, has schizophrenia but has been stable on clozapine 600 mg/d. He presents to the emergency department with generalized pain that started in his right scapula, arm, elbow, and back. Laboratory tests and a diagnostic examination reveal severe leukocytosis, thrombocytopenia, and anemia, and clinicians diagnose Mr. A with B-cell acute lymphocytic leukemia (B-ALL). Upon admission, Mr. A is neutropenic with an absolute neutrophil count (ANC) of 1,420 µL (reference range 2,500 to 6,000 µL). The hematology team recommends chemotherapy. The treating clinicians also consult the psychiatry team for recommendations on how to best manage Mr. A’s schizophrenia during chemotherapy, including whether clozapine should be discontinued.

HISTORY Stable on clozapine for >10 years

Mr. A was diagnosed with schizophrenia at age 15 after developing paranoia and auditory hallucinations of people talking to him and to each other. He had been hospitalized multiple times for worsened auditory hallucinations and paranoia that led to significant agitation and violence. Previous treatment with multiple antipsychotics, including haloperidol, quetiapine, aripiprazole, olanzapine, risperidone, and ziprasidone, was not successful. Mr. A began clozapine >10 years ago, and his symptoms have been stable since, without any further psychiatric hospitalizations. Mr. A takes clozapine 600 mg/d and divalproex sodium 1,500 mg/d, which he tolerates well and without significant adverse effects. Though he continues to have intermittent auditory hallucinations, they are mild and manageable. Mr. A lives with his mother, who reports he occasionally talks to himself but when he does not take clozapine, the auditory hallucinations worsen and cause him to become paranoid and aggressive. His ANC is monitored monthly and had been normal for several years until he was diagnosed with B-ALL.

[polldaddy:11125941]

The authors’ observations

The decision to continue clozapine during chemotherapy is challenging and should weigh the risk of agranulocytosis against that of psychiatric destabilization. Because clozapine and chemotherapy are both associated with agranulocytosis, there is concern that concurrent treatment could increase this risk in an additive or synergistic manner. To the best of our knowledge, there are currently no controlled studies investigating the interactions between clozapine and chemotherapeutic agents. Evidence on the hematopoietic consequences of concurrent clozapine and chemotherapy treatment has been limited to case reports because the topic does not lend itself well to randomized controlled trials.

A recent systematic review found no adverse outcomes among the 27 published cases in which clozapine was continued during myelosuppressive chemotherapy.¹ The most notable finding was an association between clozapine discontinuation and psychiatric decompensation, which was reported in 12 of 13 cases in which clozapine was prophylactically discontinued to minimize the risk of agranulocytosis.

Patient-specific factors must also be considered, such as the likelihood that psychotic symptoms will recur or worsen if clozapine is discontinued, as well as the extent to which symptom recurrence would interfere with cancer treatment. Clinicians should evaluate the feasibility of switching to another antipsychotic by obtaining a thorough history of the patient’s previous antipsychotics, doses, treatment duration, and response. However, many patients are treated with clozapine because their psychotic symptoms did not improve with other treatments. The character and severity of the patient’s psychotic symptoms when untreated or prior to clozapine treatment can provide a clearer understanding of how a recurrence of symptoms may interfere with cancer treatment. To formulate an accurate assessment of risks and benefits, it is necessary to consider both available evidence and patient-specific factors. The significant agitation and paranoia that Mr. A experienced when not taking clozapine was likely to disrupt chemotherapy. Thus, the adverse consequences of discontinuing clozapine were both severe and likely.

TREATMENT Continuing clozapine

After an extensive discussion of risks, benefits, and alternative treatments with the hematology and psychiatry teams, Mr. A and his family decide to continue clozapine with increased ANC monitoring during chemotherapy. Concurrent treatment was pursued with close collaboration among the patient, the patient’s family, and the hematology and pharmacy teams, and in careful consideration of the clozapine risk evaluation and mitigation strategy. Mr. A’s ANC was monitored daily during chemotherapy treatments and weekly in the intervals between treatments.

As expected, chemotherapy resulted in bone marrow suppression and pancytopenia. Mr. A’s ANC steadily decreased during the next 10 days until it reached 0 µL. This was consistent with the predicted ANC nadir between Day 10 and Day 14, after which recovery was expected. However, Mr. A’s ANC remained at 0 µL on Day 15.

[polldaddy:11125947]

Continue to: The authors' observations

Temporary decreases in ANC are expected during chemotherapy, and the timing of onset and recovery is often well characterized. Prior to Day 15, the observed progressive marrow suppression was solely due to chemotherapy. However, because Mr. A’s ANC remained 0 µL longer than anticipated, reevaluation of clozapine’s effects was warranted.

Timing, clinical course, and comprehensive hematologic monitoring can provide important clues as to whether clozapine may be responsible for prolonged neutropenia. Though a prolonged ANC of 0 µL raised concern for clozapine-induced agranulocytosis (CIAG), comprehensive monitoring of hematologic cell lines was reassuring because CIAG selectively targets granulocytic cells (neutrophils).² In contrast, chemo­therapy can affect other cell lineages, including lymphocytes, red blood cells, and platelets, which causes pancytopenia.³ For Mr. A, though the clinical presentation of pancytopenia was significant and concerning, it was inconsistent with CIAG.

Additionally, the patient’s baseline risk of CIAG should be considered. After 18 weeks of clozapine treatment, the risk of CIAG decreases to a level similar to that associated with other antipsychotics.^4,5 Therefore, CIAG would be unlikely in a patient treated with clozapine for more than 1 year and who did not have a history of neutropenia, as was the case with Mr. A.

While bone marrow biopsy can help differentiate between the causes of agranulocytosis,⁶ it is highly invasive and may not be necessary if laboratory evidence is sufficient. However, if a treatment team is strongly considering discontinuing clozapine and there are no suitable alternatives, a biopsy may provide additional clarification.

TREATMENT CAR T-cell therapy and cancer remission

Clozapine is continued with daily monitoring. On Day 19, Mr. A’s ANC increases, reaching 2,600 µL by discharge on Day 40. Mr. A remains psychiatrically stable throughout his hospitalization and does not experience any complications associated with neutropenia, despite its prolonged duration.

Continue to: Unfortunately, multiple cycles of...

Unfortunately, multiple cycles of chemo­therapy fail to induce remission. Mr. A is referred for CD19/CD22 chimeric antigen receptor (CAR) T-cell therapy, which helps achieve remission. Allogeneic hematopoietic stem cell transplant (HSCT) is recommended to maximize the likelihood of sustained remission.⁷ As with chemotherapy, Mr. A and his family agree with the multidisciplinary treatment recommendation to continue clozapine during both CAR T-cell therapy and HSCT, because the risks associated with psychiatric decompensation were greater than a potential increased risk of agranulocytosis. Clozapine treatment is continued throughout both therapies without issue.

Four months after HSCT, Mr. A is admitted for neutropenic fever and left face cellulitis. Upon admission, his ANC is 30 µL and subsequently decreases to 0 µL. In addition to neutropenia, Mr. A is also anemic and thrombocytopenic. He undergoes a bone marrow biopsy.

[polldaddy:11125950]

The authors’ observations

While no published cases have examined the bone marrow of patients experiencing CIAG, 2 retrospective studies have characterized 2 classes of bone marrow findings associated with drug-induced agranulocytosis resulting from nonchemotherapeutic agents (Table).^8,9 Type I marrow appears hypercellular with adequate neutrophil precursors but an arrested neutrophil maturation, with few or no mature forms of neutrophils beyond myelocytes.^8,9 Type II demonstrates a severe reduction or complete absence of granulocytic precursors with normal or increased erythropoiesis and megakaryocytes.^8,9 These findings have been used to accurately differentiate between chemotherapy and nonchemotherapy drug-induced agranulocytosis,⁶ resulting in successful identification and discontinuation of the responsible agent.

Mr. A’s bone marrow biopsy showed severe pancytopenia with profound neutropenia and normocytic anemia, without evidence of residual leukemia, inconsistent with Type I or Type II. Findings were suggestive of a myelodysplastic syndrome, consistent with secondary graft failure. Symptoms resolved after treatment with antibiotics, granulocyte colony-stimulating factor, epoetin alfa, and thrombopoietin. Mr. A’s ANC remained 0 µL for 22 days before returning to normal (>1,500 µL) by Day 29. He had no secondary complications resulting from neutropenia. As the clinical evidence suggested, Mr. A’s neutropenia was unlikely to be due to clozapine. Clozapine was continued throughout his cancer treatment, and he remained psychiatrically stable.

Clozapine, cancer treatments, and agranulocytosis

This case demonstrates that clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even with the development of agranulocytosis and prolonged neutropenia. Evidence to guide psychiatric clinicians to evaluate the likelihood that agranulocytosis is clozapine-induced is limited.

Continue to: We offer an algorithm...

We offer an algorithm to assist clinicians faced with this challenging clinical dilemma (Figure). Based on our experience and limited current evidence, we recommend continuing clozapine during cancer treatment unless there is clear evidence to suggest otherwise. Presently, no evidence in published literature suggests worsened outcomes in patients treated concurrently with clozapine and cancer therapies.

OUTCOME Cancer-free and psychiatrically stable

Mr. A continues clozapine therapy throughout all phases of treatment, without interruption. No adverse effects are determined to be secondary to clozapine. He remains psychiatrically stable throughout treatment, and able to participate and engage in his oncologic therapy. Mr. A is now more than 1 year in remission with no recurrence of graft failure, and his psychiatric symptoms continue to be well controlled with clozapine.

Bottom Line

Clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even in patients who develop agranulocytosis and prolonged neutropenia. Based on our experience and limited evidence, we offer an algorithm to assist clinicians faced with this challenging clinical dilemma.

Related Resources

• Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: a systematic review of the literature. Eur J Haematol. 2019;103(4):277-286. doi:10.1111/ejh.13285
• Daniel JS, Gross T. Managing clozapine-induced neutropenia and agranulocytosis. Current Psychiatry. 2016;15(12):51-53.

Drug Brand Names

Aripiprazole • Abilify
Clozapine • Clozaril
Divalproex sodium • Depakote
Epoetin alfa • Epogen
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

CASE Schizophrenia, leukemia, and chemotherapy

Mr. A, age 30, has schizophrenia but has been stable on clozapine 600 mg/d. He presents to the emergency department with generalized pain that started in his right scapula, arm, elbow, and back. Laboratory tests and a diagnostic examination reveal severe leukocytosis, thrombocytopenia, and anemia, and clinicians diagnose Mr. A with B-cell acute lymphocytic leukemia (B-ALL). Upon admission, Mr. A is neutropenic with an absolute neutrophil count (ANC) of 1,420 µL (reference range 2,500 to 6,000 µL). The hematology team recommends chemotherapy. The treating clinicians also consult the psychiatry team for recommendations on how to best manage Mr. A’s schizophrenia during chemotherapy, including whether clozapine should be discontinued.

HISTORY Stable on clozapine for >10 years

Mr. A was diagnosed with schizophrenia at age 15 after developing paranoia and auditory hallucinations of people talking to him and to each other. He had been hospitalized multiple times for worsened auditory hallucinations and paranoia that led to significant agitation and violence. Previous treatment with multiple antipsychotics, including haloperidol, quetiapine, aripiprazole, olanzapine, risperidone, and ziprasidone, was not successful. Mr. A began clozapine >10 years ago, and his symptoms have been stable since, without any further psychiatric hospitalizations. Mr. A takes clozapine 600 mg/d and divalproex sodium 1,500 mg/d, which he tolerates well and without significant adverse effects. Though he continues to have intermittent auditory hallucinations, they are mild and manageable. Mr. A lives with his mother, who reports he occasionally talks to himself but when he does not take clozapine, the auditory hallucinations worsen and cause him to become paranoid and aggressive. His ANC is monitored monthly and had been normal for several years until he was diagnosed with B-ALL.

[polldaddy:11125941]

The authors’ observations

The decision to continue clozapine during chemotherapy is challenging and should weigh the risk of agranulocytosis against that of psychiatric destabilization. Because clozapine and chemotherapy are both associated with agranulocytosis, there is concern that concurrent treatment could increase this risk in an additive or synergistic manner. To the best of our knowledge, there are currently no controlled studies investigating the interactions between clozapine and chemotherapeutic agents. Evidence on the hematopoietic consequences of concurrent clozapine and chemotherapy treatment has been limited to case reports because the topic does not lend itself well to randomized controlled trials.

A recent systematic review found no adverse outcomes among the 27 published cases in which clozapine was continued during myelosuppressive chemotherapy.¹ The most notable finding was an association between clozapine discontinuation and psychiatric decompensation, which was reported in 12 of 13 cases in which clozapine was prophylactically discontinued to minimize the risk of agranulocytosis.

Patient-specific factors must also be considered, such as the likelihood that psychotic symptoms will recur or worsen if clozapine is discontinued, as well as the extent to which symptom recurrence would interfere with cancer treatment. Clinicians should evaluate the feasibility of switching to another antipsychotic by obtaining a thorough history of the patient’s previous antipsychotics, doses, treatment duration, and response. However, many patients are treated with clozapine because their psychotic symptoms did not improve with other treatments. The character and severity of the patient’s psychotic symptoms when untreated or prior to clozapine treatment can provide a clearer understanding of how a recurrence of symptoms may interfere with cancer treatment. To formulate an accurate assessment of risks and benefits, it is necessary to consider both available evidence and patient-specific factors. The significant agitation and paranoia that Mr. A experienced when not taking clozapine was likely to disrupt chemotherapy. Thus, the adverse consequences of discontinuing clozapine were both severe and likely.

TREATMENT Continuing clozapine

After an extensive discussion of risks, benefits, and alternative treatments with the hematology and psychiatry teams, Mr. A and his family decide to continue clozapine with increased ANC monitoring during chemotherapy. Concurrent treatment was pursued with close collaboration among the patient, the patient’s family, and the hematology and pharmacy teams, and in careful consideration of the clozapine risk evaluation and mitigation strategy. Mr. A’s ANC was monitored daily during chemotherapy treatments and weekly in the intervals between treatments.

As expected, chemotherapy resulted in bone marrow suppression and pancytopenia. Mr. A’s ANC steadily decreased during the next 10 days until it reached 0 µL. This was consistent with the predicted ANC nadir between Day 10 and Day 14, after which recovery was expected. However, Mr. A’s ANC remained at 0 µL on Day 15.

[polldaddy:11125947]

Continue to: The authors' observations

Temporary decreases in ANC are expected during chemotherapy, and the timing of onset and recovery is often well characterized. Prior to Day 15, the observed progressive marrow suppression was solely due to chemotherapy. However, because Mr. A’s ANC remained 0 µL longer than anticipated, reevaluation of clozapine’s effects was warranted.

Timing, clinical course, and comprehensive hematologic monitoring can provide important clues as to whether clozapine may be responsible for prolonged neutropenia. Though a prolonged ANC of 0 µL raised concern for clozapine-induced agranulocytosis (CIAG), comprehensive monitoring of hematologic cell lines was reassuring because CIAG selectively targets granulocytic cells (neutrophils).² In contrast, chemo­therapy can affect other cell lineages, including lymphocytes, red blood cells, and platelets, which causes pancytopenia.³ For Mr. A, though the clinical presentation of pancytopenia was significant and concerning, it was inconsistent with CIAG.

Additionally, the patient’s baseline risk of CIAG should be considered. After 18 weeks of clozapine treatment, the risk of CIAG decreases to a level similar to that associated with other antipsychotics.^4,5 Therefore, CIAG would be unlikely in a patient treated with clozapine for more than 1 year and who did not have a history of neutropenia, as was the case with Mr. A.

While bone marrow biopsy can help differentiate between the causes of agranulocytosis,⁶ it is highly invasive and may not be necessary if laboratory evidence is sufficient. However, if a treatment team is strongly considering discontinuing clozapine and there are no suitable alternatives, a biopsy may provide additional clarification.

TREATMENT CAR T-cell therapy and cancer remission

Clozapine is continued with daily monitoring. On Day 19, Mr. A’s ANC increases, reaching 2,600 µL by discharge on Day 40. Mr. A remains psychiatrically stable throughout his hospitalization and does not experience any complications associated with neutropenia, despite its prolonged duration.

Continue to: Unfortunately, multiple cycles of...

Unfortunately, multiple cycles of chemo­therapy fail to induce remission. Mr. A is referred for CD19/CD22 chimeric antigen receptor (CAR) T-cell therapy, which helps achieve remission. Allogeneic hematopoietic stem cell transplant (HSCT) is recommended to maximize the likelihood of sustained remission.⁷ As with chemotherapy, Mr. A and his family agree with the multidisciplinary treatment recommendation to continue clozapine during both CAR T-cell therapy and HSCT, because the risks associated with psychiatric decompensation were greater than a potential increased risk of agranulocytosis. Clozapine treatment is continued throughout both therapies without issue.

Four months after HSCT, Mr. A is admitted for neutropenic fever and left face cellulitis. Upon admission, his ANC is 30 µL and subsequently decreases to 0 µL. In addition to neutropenia, Mr. A is also anemic and thrombocytopenic. He undergoes a bone marrow biopsy.

[polldaddy:11125950]

The authors’ observations

While no published cases have examined the bone marrow of patients experiencing CIAG, 2 retrospective studies have characterized 2 classes of bone marrow findings associated with drug-induced agranulocytosis resulting from nonchemotherapeutic agents (Table).^8,9 Type I marrow appears hypercellular with adequate neutrophil precursors but an arrested neutrophil maturation, with few or no mature forms of neutrophils beyond myelocytes.^8,9 Type II demonstrates a severe reduction or complete absence of granulocytic precursors with normal or increased erythropoiesis and megakaryocytes.^8,9 These findings have been used to accurately differentiate between chemotherapy and nonchemotherapy drug-induced agranulocytosis,⁶ resulting in successful identification and discontinuation of the responsible agent.

Mr. A’s bone marrow biopsy showed severe pancytopenia with profound neutropenia and normocytic anemia, without evidence of residual leukemia, inconsistent with Type I or Type II. Findings were suggestive of a myelodysplastic syndrome, consistent with secondary graft failure. Symptoms resolved after treatment with antibiotics, granulocyte colony-stimulating factor, epoetin alfa, and thrombopoietin. Mr. A’s ANC remained 0 µL for 22 days before returning to normal (>1,500 µL) by Day 29. He had no secondary complications resulting from neutropenia. As the clinical evidence suggested, Mr. A’s neutropenia was unlikely to be due to clozapine. Clozapine was continued throughout his cancer treatment, and he remained psychiatrically stable.

Clozapine, cancer treatments, and agranulocytosis

This case demonstrates that clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even with the development of agranulocytosis and prolonged neutropenia. Evidence to guide psychiatric clinicians to evaluate the likelihood that agranulocytosis is clozapine-induced is limited.

Continue to: We offer an algorithm...

We offer an algorithm to assist clinicians faced with this challenging clinical dilemma (Figure). Based on our experience and limited current evidence, we recommend continuing clozapine during cancer treatment unless there is clear evidence to suggest otherwise. Presently, no evidence in published literature suggests worsened outcomes in patients treated concurrently with clozapine and cancer therapies.

OUTCOME Cancer-free and psychiatrically stable

Mr. A continues clozapine therapy throughout all phases of treatment, without interruption. No adverse effects are determined to be secondary to clozapine. He remains psychiatrically stable throughout treatment, and able to participate and engage in his oncologic therapy. Mr. A is now more than 1 year in remission with no recurrence of graft failure, and his psychiatric symptoms continue to be well controlled with clozapine.

Bottom Line

Clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even in patients who develop agranulocytosis and prolonged neutropenia. Based on our experience and limited evidence, we offer an algorithm to assist clinicians faced with this challenging clinical dilemma.

Related Resources

• Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: a systematic review of the literature. Eur J Haematol. 2019;103(4):277-286. doi:10.1111/ejh.13285
• Daniel JS, Gross T. Managing clozapine-induced neutropenia and agranulocytosis. Current Psychiatry. 2016;15(12):51-53.

Drug Brand Names

Aripiprazole • Abilify
Clozapine • Clozaril
Divalproex sodium • Depakote
Epoetin alfa • Epogen
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

CASE Schizophrenia, leukemia, and chemotherapy

Mr. A, age 30, has schizophrenia but has been stable on clozapine 600 mg/d. He presents to the emergency department with generalized pain that started in his right scapula, arm, elbow, and back. Laboratory tests and a diagnostic examination reveal severe leukocytosis, thrombocytopenia, and anemia, and clinicians diagnose Mr. A with B-cell acute lymphocytic leukemia (B-ALL). Upon admission, Mr. A is neutropenic with an absolute neutrophil count (ANC) of 1,420 µL (reference range 2,500 to 6,000 µL). The hematology team recommends chemotherapy. The treating clinicians also consult the psychiatry team for recommendations on how to best manage Mr. A’s schizophrenia during chemotherapy, including whether clozapine should be discontinued.

HISTORY Stable on clozapine for >10 years

Mr. A was diagnosed with schizophrenia at age 15 after developing paranoia and auditory hallucinations of people talking to him and to each other. He had been hospitalized multiple times for worsened auditory hallucinations and paranoia that led to significant agitation and violence. Previous treatment with multiple antipsychotics, including haloperidol, quetiapine, aripiprazole, olanzapine, risperidone, and ziprasidone, was not successful. Mr. A began clozapine >10 years ago, and his symptoms have been stable since, without any further psychiatric hospitalizations. Mr. A takes clozapine 600 mg/d and divalproex sodium 1,500 mg/d, which he tolerates well and without significant adverse effects. Though he continues to have intermittent auditory hallucinations, they are mild and manageable. Mr. A lives with his mother, who reports he occasionally talks to himself but when he does not take clozapine, the auditory hallucinations worsen and cause him to become paranoid and aggressive. His ANC is monitored monthly and had been normal for several years until he was diagnosed with B-ALL.

[polldaddy:11125941]

The authors’ observations

The decision to continue clozapine during chemotherapy is challenging and should weigh the risk of agranulocytosis against that of psychiatric destabilization. Because clozapine and chemotherapy are both associated with agranulocytosis, there is concern that concurrent treatment could increase this risk in an additive or synergistic manner. To the best of our knowledge, there are currently no controlled studies investigating the interactions between clozapine and chemotherapeutic agents. Evidence on the hematopoietic consequences of concurrent clozapine and chemotherapy treatment has been limited to case reports because the topic does not lend itself well to randomized controlled trials.

A recent systematic review found no adverse outcomes among the 27 published cases in which clozapine was continued during myelosuppressive chemotherapy.¹ The most notable finding was an association between clozapine discontinuation and psychiatric decompensation, which was reported in 12 of 13 cases in which clozapine was prophylactically discontinued to minimize the risk of agranulocytosis.

Patient-specific factors must also be considered, such as the likelihood that psychotic symptoms will recur or worsen if clozapine is discontinued, as well as the extent to which symptom recurrence would interfere with cancer treatment. Clinicians should evaluate the feasibility of switching to another antipsychotic by obtaining a thorough history of the patient’s previous antipsychotics, doses, treatment duration, and response. However, many patients are treated with clozapine because their psychotic symptoms did not improve with other treatments. The character and severity of the patient’s psychotic symptoms when untreated or prior to clozapine treatment can provide a clearer understanding of how a recurrence of symptoms may interfere with cancer treatment. To formulate an accurate assessment of risks and benefits, it is necessary to consider both available evidence and patient-specific factors. The significant agitation and paranoia that Mr. A experienced when not taking clozapine was likely to disrupt chemotherapy. Thus, the adverse consequences of discontinuing clozapine were both severe and likely.

TREATMENT Continuing clozapine

After an extensive discussion of risks, benefits, and alternative treatments with the hematology and psychiatry teams, Mr. A and his family decide to continue clozapine with increased ANC monitoring during chemotherapy. Concurrent treatment was pursued with close collaboration among the patient, the patient’s family, and the hematology and pharmacy teams, and in careful consideration of the clozapine risk evaluation and mitigation strategy. Mr. A’s ANC was monitored daily during chemotherapy treatments and weekly in the intervals between treatments.

As expected, chemotherapy resulted in bone marrow suppression and pancytopenia. Mr. A’s ANC steadily decreased during the next 10 days until it reached 0 µL. This was consistent with the predicted ANC nadir between Day 10 and Day 14, after which recovery was expected. However, Mr. A’s ANC remained at 0 µL on Day 15.

[polldaddy:11125947]

Continue to: The authors' observations

Temporary decreases in ANC are expected during chemotherapy, and the timing of onset and recovery is often well characterized. Prior to Day 15, the observed progressive marrow suppression was solely due to chemotherapy. However, because Mr. A’s ANC remained 0 µL longer than anticipated, reevaluation of clozapine’s effects was warranted.

Timing, clinical course, and comprehensive hematologic monitoring can provide important clues as to whether clozapine may be responsible for prolonged neutropenia. Though a prolonged ANC of 0 µL raised concern for clozapine-induced agranulocytosis (CIAG), comprehensive monitoring of hematologic cell lines was reassuring because CIAG selectively targets granulocytic cells (neutrophils).² In contrast, chemo­therapy can affect other cell lineages, including lymphocytes, red blood cells, and platelets, which causes pancytopenia.³ For Mr. A, though the clinical presentation of pancytopenia was significant and concerning, it was inconsistent with CIAG.

Additionally, the patient’s baseline risk of CIAG should be considered. After 18 weeks of clozapine treatment, the risk of CIAG decreases to a level similar to that associated with other antipsychotics.^4,5 Therefore, CIAG would be unlikely in a patient treated with clozapine for more than 1 year and who did not have a history of neutropenia, as was the case with Mr. A.

While bone marrow biopsy can help differentiate between the causes of agranulocytosis,⁶ it is highly invasive and may not be necessary if laboratory evidence is sufficient. However, if a treatment team is strongly considering discontinuing clozapine and there are no suitable alternatives, a biopsy may provide additional clarification.

TREATMENT CAR T-cell therapy and cancer remission

Clozapine is continued with daily monitoring. On Day 19, Mr. A’s ANC increases, reaching 2,600 µL by discharge on Day 40. Mr. A remains psychiatrically stable throughout his hospitalization and does not experience any complications associated with neutropenia, despite its prolonged duration.

Continue to: Unfortunately, multiple cycles of...

Unfortunately, multiple cycles of chemo­therapy fail to induce remission. Mr. A is referred for CD19/CD22 chimeric antigen receptor (CAR) T-cell therapy, which helps achieve remission. Allogeneic hematopoietic stem cell transplant (HSCT) is recommended to maximize the likelihood of sustained remission.⁷ As with chemotherapy, Mr. A and his family agree with the multidisciplinary treatment recommendation to continue clozapine during both CAR T-cell therapy and HSCT, because the risks associated with psychiatric decompensation were greater than a potential increased risk of agranulocytosis. Clozapine treatment is continued throughout both therapies without issue.

Four months after HSCT, Mr. A is admitted for neutropenic fever and left face cellulitis. Upon admission, his ANC is 30 µL and subsequently decreases to 0 µL. In addition to neutropenia, Mr. A is also anemic and thrombocytopenic. He undergoes a bone marrow biopsy.

[polldaddy:11125950]

The authors’ observations

While no published cases have examined the bone marrow of patients experiencing CIAG, 2 retrospective studies have characterized 2 classes of bone marrow findings associated with drug-induced agranulocytosis resulting from nonchemotherapeutic agents (Table).^8,9 Type I marrow appears hypercellular with adequate neutrophil precursors but an arrested neutrophil maturation, with few or no mature forms of neutrophils beyond myelocytes.^8,9 Type II demonstrates a severe reduction or complete absence of granulocytic precursors with normal or increased erythropoiesis and megakaryocytes.^8,9 These findings have been used to accurately differentiate between chemotherapy and nonchemotherapy drug-induced agranulocytosis,⁶ resulting in successful identification and discontinuation of the responsible agent.

Mr. A’s bone marrow biopsy showed severe pancytopenia with profound neutropenia and normocytic anemia, without evidence of residual leukemia, inconsistent with Type I or Type II. Findings were suggestive of a myelodysplastic syndrome, consistent with secondary graft failure. Symptoms resolved after treatment with antibiotics, granulocyte colony-stimulating factor, epoetin alfa, and thrombopoietin. Mr. A’s ANC remained 0 µL for 22 days before returning to normal (>1,500 µL) by Day 29. He had no secondary complications resulting from neutropenia. As the clinical evidence suggested, Mr. A’s neutropenia was unlikely to be due to clozapine. Clozapine was continued throughout his cancer treatment, and he remained psychiatrically stable.

Clozapine, cancer treatments, and agranulocytosis

This case demonstrates that clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even with the development of agranulocytosis and prolonged neutropenia. Evidence to guide psychiatric clinicians to evaluate the likelihood that agranulocytosis is clozapine-induced is limited.

Continue to: We offer an algorithm...

We offer an algorithm to assist clinicians faced with this challenging clinical dilemma (Figure). Based on our experience and limited current evidence, we recommend continuing clozapine during cancer treatment unless there is clear evidence to suggest otherwise. Presently, no evidence in published literature suggests worsened outcomes in patients treated concurrently with clozapine and cancer therapies.

OUTCOME Cancer-free and psychiatrically stable

Mr. A continues clozapine therapy throughout all phases of treatment, without interruption. No adverse effects are determined to be secondary to clozapine. He remains psychiatrically stable throughout treatment, and able to participate and engage in his oncologic therapy. Mr. A is now more than 1 year in remission with no recurrence of graft failure, and his psychiatric symptoms continue to be well controlled with clozapine.

Bottom Line

Clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even in patients who develop agranulocytosis and prolonged neutropenia. Based on our experience and limited evidence, we offer an algorithm to assist clinicians faced with this challenging clinical dilemma.

Related Resources

• Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: a systematic review of the literature. Eur J Haematol. 2019;103(4):277-286. doi:10.1111/ejh.13285
• Daniel JS, Gross T. Managing clozapine-induced neutropenia and agranulocytosis. Current Psychiatry. 2016;15(12):51-53.

Drug Brand Names

Aripiprazole • Abilify
Clozapine • Clozaril
Divalproex sodium • Depakote
Epoetin alfa • Epogen
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Boarding of psychiatric patients in the emergency department (ED) has been well documented.¹ Numerous researchers have discussed ways to address this public health crisis. In this Pearl, I use the acronym BOARDING to provide key strategies for psychiatric clinicians managing psychiatric patients who are boarding in an ED.

Be vigilant. As a patient’s time waiting in the ED increases, watch for clinical blind spots. New medical problems,² psychiatric issues, or medication errors³ may unexpectedly arise since the patient was originally stabilized by emergency medicine clinicians.

Orders. Since the patient could be waiting in the ED for 24 hours or longer, consider starting orders (eg, precautions, medications, diet, vital sign checks, labs, etc) as you would for a patient in an inpatient psychiatric unit or a dedicated psychiatric ED.

AWOL. Unlike inpatient psychiatric units, EDs generally are not locked. Extra resources (eg, sitter, safety alarm bracelet) may be needed to help prevent patients from leaving this setting unnoticed, especially those on involuntary psychiatric holds.

Re-evaluate. Ideally, re-evaluate the patient every shift. Does the patient still need an inpatient psychiatric setting? Can the involuntary psychiatric hold be discontinued?

Disposition. Is there a family member or reliable caregiver to whom the patient can be discharged? Can the patient go to a shelter or be stabilized in a short-term residential program, instead of an inpatient psychiatric unit?

Inpatient. If the patient waits 24 hours or longer, begin thinking like an inpatient psychiatric clinician. Are there any interventions you can reasonably begin in the ED that you would otherwise begin on an inpatient psychiatric unit?

Nursing. Work with ED nursing staff to familiarize them with the patient’s specific needs.

Guidelines. With the input of clinical and administrative leadership, establish local hospital-based guidelines for managing psychiatric patients who are boarding in the ED.

Boarding of psychiatric patients in the emergency department (ED) has been well documented.¹ Numerous researchers have discussed ways to address this public health crisis. In this Pearl, I use the acronym BOARDING to provide key strategies for psychiatric clinicians managing psychiatric patients who are boarding in an ED.

Be vigilant. As a patient’s time waiting in the ED increases, watch for clinical blind spots. New medical problems,² psychiatric issues, or medication errors³ may unexpectedly arise since the patient was originally stabilized by emergency medicine clinicians.

Orders. Since the patient could be waiting in the ED for 24 hours or longer, consider starting orders (eg, precautions, medications, diet, vital sign checks, labs, etc) as you would for a patient in an inpatient psychiatric unit or a dedicated psychiatric ED.

AWOL. Unlike inpatient psychiatric units, EDs generally are not locked. Extra resources (eg, sitter, safety alarm bracelet) may be needed to help prevent patients from leaving this setting unnoticed, especially those on involuntary psychiatric holds.

Re-evaluate. Ideally, re-evaluate the patient every shift. Does the patient still need an inpatient psychiatric setting? Can the involuntary psychiatric hold be discontinued?

Disposition. Is there a family member or reliable caregiver to whom the patient can be discharged? Can the patient go to a shelter or be stabilized in a short-term residential program, instead of an inpatient psychiatric unit?

Inpatient. If the patient waits 24 hours or longer, begin thinking like an inpatient psychiatric clinician. Are there any interventions you can reasonably begin in the ED that you would otherwise begin on an inpatient psychiatric unit?

Nursing. Work with ED nursing staff to familiarize them with the patient’s specific needs.

Guidelines. With the input of clinical and administrative leadership, establish local hospital-based guidelines for managing psychiatric patients who are boarding in the ED.

Boarding of psychiatric patients in the emergency department (ED) has been well documented.¹ Numerous researchers have discussed ways to address this public health crisis. In this Pearl, I use the acronym BOARDING to provide key strategies for psychiatric clinicians managing psychiatric patients who are boarding in an ED.

Be vigilant. As a patient’s time waiting in the ED increases, watch for clinical blind spots. New medical problems,² psychiatric issues, or medication errors³ may unexpectedly arise since the patient was originally stabilized by emergency medicine clinicians.

Orders. Since the patient could be waiting in the ED for 24 hours or longer, consider starting orders (eg, precautions, medications, diet, vital sign checks, labs, etc) as you would for a patient in an inpatient psychiatric unit or a dedicated psychiatric ED.

AWOL. Unlike inpatient psychiatric units, EDs generally are not locked. Extra resources (eg, sitter, safety alarm bracelet) may be needed to help prevent patients from leaving this setting unnoticed, especially those on involuntary psychiatric holds.

Re-evaluate. Ideally, re-evaluate the patient every shift. Does the patient still need an inpatient psychiatric setting? Can the involuntary psychiatric hold be discontinued?

Disposition. Is there a family member or reliable caregiver to whom the patient can be discharged? Can the patient go to a shelter or be stabilized in a short-term residential program, instead of an inpatient psychiatric unit?

Inpatient. If the patient waits 24 hours or longer, begin thinking like an inpatient psychiatric clinician. Are there any interventions you can reasonably begin in the ED that you would otherwise begin on an inpatient psychiatric unit?

Nursing. Work with ED nursing staff to familiarize them with the patient’s specific needs.

Guidelines. With the input of clinical and administrative leadership, establish local hospital-based guidelines for managing psychiatric patients who are boarding in the ED.

Ramadan is one of the obligatory pillars in Islam during which healthy Muslims are required to fast from dawn until sunset every day for 1 month. There are an estimated 3.45 million Muslims in the United States, and this population will continue to grow by 100,000 per year.¹ With the increased growth of the Muslim population, it is important for clinicians to be aware of how patients of Muslim faith are affected during Ramadan. In this article, we explore the potential risks, as well as the benefits, the month of Ramadan brings to patients. We will also explain how being religiously aware is necessary to provide optimal care for these individuals.

For some patients, fasting may pose risks

Similar to other communities in the United States, individuals who are Muslim experience mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, substance use disorders, and other psychiatric illnesses.² During the month of Ramadan, Muslims are to abstain completely from eating and drinking from dawn until sunset. This includes medications as well as food and drink.

Due to these circumstances, patients will often change the timing, frequency, and dosing of their medications to allow them to fast. One study found 60% of Muslims made medication adjustments during Ramadan without seeking medical advice.³ It is possible that such alterations may be detrimental. During Ramadan, some Muslims wake up early in the morning to eat a pre-dawn meal, and often go back to sleep. This has been reported to cause a delay in sleep-wake times and to reduce rapid eye movement sleep.⁴ These circadian rhythm changes can be detrimental to patients with bipolar disorder. One study found higher rates of relapse to depression and mania in patients with bipolar disorder who were fasting during Ramadan.⁵ Circadian rhythm disturbances also may worsen depression.⁶ Another point of concern is patients with eating disorders. One small case series (N = 6) found that fasting during Ramadan exacerbated symptoms in patients with eating disorders.⁷

Another concern is that dehydration while fasting can lead to lithium toxicity. However, one study found lithium levels remained stable while fasting for 10 to 12 hours.⁵ Another showed that changing lithium dosing from twice a day to once a day allowed for easier administration without causing a subtherapeutic change in blood lithium levels.⁸

The practice also may have benefits for mental health

For many Muslims, Ramadan is the best time of the year, where they reconnect with their religion and experience the utmost spiritual growth. Studies have shown that the incidence of suicide is lowest during Ramadan compared to other months.⁹ A study of older men found that intermittent fasting and calorie restriction (not during Ramadan) resulted in decreases in tension, confusion, anger, and mood disturbance.¹⁰ Another study found that fasting during Ramadan had a positive impact on depression, anxiety, stress, and cognitive function.¹¹

Clinical considerations

To provide the best care for Muslim patients during Ramadan, clinicians should take a holistic approach and take all factors into consideration. It is common for circadian rhythm disruptions to exacerbate mood disorders, so encourage patients to maintain healthy sleep hygiene to their best ability during this month. Another important consideration is medication timing and dosing.¹² For patients prescribed a medication that typically is taken twice a day, determine if this dosing can be changed to once a day, or if both doses can be taken when it is permissible to eat (sunset to dawn). For medications that are absorbed with food, consider how these medications might be adjusted and maintained while a patient is fasting. Some medications may be sedating or activating, so the timing of administration may need to be adjusted to meet the patient’s needs. Lastly, keep in mind that certain medications can have withdrawal effects, and the likelihood of this occurring while a patient is fasting.

One vital point is that if a patient is at high risk of clinically decompensating due to fasting or medication adjustments or discontinuation, advise them to not fast. Muslims with physical or mental illnesses are excused from fasting. Bear in mind that because Ramadan is meant to be a month of heightened spirituality, many Muslims will prefer to fast.

Ramadan is one of the obligatory pillars in Islam during which healthy Muslims are required to fast from dawn until sunset every day for 1 month. There are an estimated 3.45 million Muslims in the United States, and this population will continue to grow by 100,000 per year.¹ With the increased growth of the Muslim population, it is important for clinicians to be aware of how patients of Muslim faith are affected during Ramadan. In this article, we explore the potential risks, as well as the benefits, the month of Ramadan brings to patients. We will also explain how being religiously aware is necessary to provide optimal care for these individuals.

For some patients, fasting may pose risks

Similar to other communities in the United States, individuals who are Muslim experience mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, substance use disorders, and other psychiatric illnesses.² During the month of Ramadan, Muslims are to abstain completely from eating and drinking from dawn until sunset. This includes medications as well as food and drink.

Due to these circumstances, patients will often change the timing, frequency, and dosing of their medications to allow them to fast. One study found 60% of Muslims made medication adjustments during Ramadan without seeking medical advice.³ It is possible that such alterations may be detrimental. During Ramadan, some Muslims wake up early in the morning to eat a pre-dawn meal, and often go back to sleep. This has been reported to cause a delay in sleep-wake times and to reduce rapid eye movement sleep.⁴ These circadian rhythm changes can be detrimental to patients with bipolar disorder. One study found higher rates of relapse to depression and mania in patients with bipolar disorder who were fasting during Ramadan.⁵ Circadian rhythm disturbances also may worsen depression.⁶ Another point of concern is patients with eating disorders. One small case series (N = 6) found that fasting during Ramadan exacerbated symptoms in patients with eating disorders.⁷

Another concern is that dehydration while fasting can lead to lithium toxicity. However, one study found lithium levels remained stable while fasting for 10 to 12 hours.⁵ Another showed that changing lithium dosing from twice a day to once a day allowed for easier administration without causing a subtherapeutic change in blood lithium levels.⁸

The practice also may have benefits for mental health

For many Muslims, Ramadan is the best time of the year, where they reconnect with their religion and experience the utmost spiritual growth. Studies have shown that the incidence of suicide is lowest during Ramadan compared to other months.⁹ A study of older men found that intermittent fasting and calorie restriction (not during Ramadan) resulted in decreases in tension, confusion, anger, and mood disturbance.¹⁰ Another study found that fasting during Ramadan had a positive impact on depression, anxiety, stress, and cognitive function.¹¹

Clinical considerations

To provide the best care for Muslim patients during Ramadan, clinicians should take a holistic approach and take all factors into consideration. It is common for circadian rhythm disruptions to exacerbate mood disorders, so encourage patients to maintain healthy sleep hygiene to their best ability during this month. Another important consideration is medication timing and dosing.¹² For patients prescribed a medication that typically is taken twice a day, determine if this dosing can be changed to once a day, or if both doses can be taken when it is permissible to eat (sunset to dawn). For medications that are absorbed with food, consider how these medications might be adjusted and maintained while a patient is fasting. Some medications may be sedating or activating, so the timing of administration may need to be adjusted to meet the patient’s needs. Lastly, keep in mind that certain medications can have withdrawal effects, and the likelihood of this occurring while a patient is fasting.

One vital point is that if a patient is at high risk of clinically decompensating due to fasting or medication adjustments or discontinuation, advise them to not fast. Muslims with physical or mental illnesses are excused from fasting. Bear in mind that because Ramadan is meant to be a month of heightened spirituality, many Muslims will prefer to fast.

Ramadan is one of the obligatory pillars in Islam during which healthy Muslims are required to fast from dawn until sunset every day for 1 month. There are an estimated 3.45 million Muslims in the United States, and this population will continue to grow by 100,000 per year.¹ With the increased growth of the Muslim population, it is important for clinicians to be aware of how patients of Muslim faith are affected during Ramadan. In this article, we explore the potential risks, as well as the benefits, the month of Ramadan brings to patients. We will also explain how being religiously aware is necessary to provide optimal care for these individuals.

For some patients, fasting may pose risks

Similar to other communities in the United States, individuals who are Muslim experience mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, substance use disorders, and other psychiatric illnesses.² During the month of Ramadan, Muslims are to abstain completely from eating and drinking from dawn until sunset. This includes medications as well as food and drink.

Due to these circumstances, patients will often change the timing, frequency, and dosing of their medications to allow them to fast. One study found 60% of Muslims made medication adjustments during Ramadan without seeking medical advice.³ It is possible that such alterations may be detrimental. During Ramadan, some Muslims wake up early in the morning to eat a pre-dawn meal, and often go back to sleep. This has been reported to cause a delay in sleep-wake times and to reduce rapid eye movement sleep.⁴ These circadian rhythm changes can be detrimental to patients with bipolar disorder. One study found higher rates of relapse to depression and mania in patients with bipolar disorder who were fasting during Ramadan.⁵ Circadian rhythm disturbances also may worsen depression.⁶ Another point of concern is patients with eating disorders. One small case series (N = 6) found that fasting during Ramadan exacerbated symptoms in patients with eating disorders.⁷

Another concern is that dehydration while fasting can lead to lithium toxicity. However, one study found lithium levels remained stable while fasting for 10 to 12 hours.⁵ Another showed that changing lithium dosing from twice a day to once a day allowed for easier administration without causing a subtherapeutic change in blood lithium levels.⁸

The practice also may have benefits for mental health

For many Muslims, Ramadan is the best time of the year, where they reconnect with their religion and experience the utmost spiritual growth. Studies have shown that the incidence of suicide is lowest during Ramadan compared to other months.⁹ A study of older men found that intermittent fasting and calorie restriction (not during Ramadan) resulted in decreases in tension, confusion, anger, and mood disturbance.¹⁰ Another study found that fasting during Ramadan had a positive impact on depression, anxiety, stress, and cognitive function.¹¹

Clinical considerations

To provide the best care for Muslim patients during Ramadan, clinicians should take a holistic approach and take all factors into consideration. It is common for circadian rhythm disruptions to exacerbate mood disorders, so encourage patients to maintain healthy sleep hygiene to their best ability during this month. Another important consideration is medication timing and dosing.¹² For patients prescribed a medication that typically is taken twice a day, determine if this dosing can be changed to once a day, or if both doses can be taken when it is permissible to eat (sunset to dawn). For medications that are absorbed with food, consider how these medications might be adjusted and maintained while a patient is fasting. Some medications may be sedating or activating, so the timing of administration may need to be adjusted to meet the patient’s needs. Lastly, keep in mind that certain medications can have withdrawal effects, and the likelihood of this occurring while a patient is fasting.

One vital point is that if a patient is at high risk of clinically decompensating due to fasting or medication adjustments or discontinuation, advise them to not fast. Muslims with physical or mental illnesses are excused from fasting. Bear in mind that because Ramadan is meant to be a month of heightened spirituality, many Muslims will prefer to fast.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

The inaugural issue of GI & Hepatology News was published in January 2007, and the newspaper has gone on to become part of the fabric of the AGA. This year, we celebrate the newspaper’s 15th year with a special 15th Anniversary Series that will run from June through December 2022. We will feature reflections from GIHN’s three former editors-in-chief, Dr. Charles J. Lightdale, Dr. Colin Howden, and Dr. John Allen, on the evolution of the newspaper (and the field of GI) over the past 15 years. We also will present a series of Then and Now columns, highlighting high-impact areas of GI and hepatology covered in past GIHN issues, and reflecting on how the field has changed since that time.

In this month’s issue, we are pleased to kick off the 15th Anniversary Series with reflections by Dr. Lightdale, GIHN’s inaugural editor-in-chief, as well as a Then and Now column written by Dr. Kimberly M. Persley (GIHN associate editor and longstanding AGA member) reflecting on how the demographics of gastroenterology and of the AGA as an organization have changed over the past 15 years. I hope you will find these special contributions to be engaging and thought-provoking. Other issue highlights include a lead article describing impacts of social determinants of health in driving disparities in IBD care and offering recommendations for achieving IBD health equity, a new AGA Clinical Practice Update on dietary options for our many patients with irritable bowel syndrome, and new data on the safety of anti-TNF medications prior to surgery in patients with inflammatory bowel disease.

As summer vacation season commences, I hope you will join me in taking some well-deserved time away from work demands, spending some quality time with friends and family, and seizing the opportunity to rest and recharge.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

The inaugural issue of GI & Hepatology News was published in January 2007, and the newspaper has gone on to become part of the fabric of the AGA. This year, we celebrate the newspaper’s 15th year with a special 15th Anniversary Series that will run from June through December 2022. We will feature reflections from GIHN’s three former editors-in-chief, Dr. Charles J. Lightdale, Dr. Colin Howden, and Dr. John Allen, on the evolution of the newspaper (and the field of GI) over the past 15 years. We also will present a series of Then and Now columns, highlighting high-impact areas of GI and hepatology covered in past GIHN issues, and reflecting on how the field has changed since that time.

In this month’s issue, we are pleased to kick off the 15th Anniversary Series with reflections by Dr. Lightdale, GIHN’s inaugural editor-in-chief, as well as a Then and Now column written by Dr. Kimberly M. Persley (GIHN associate editor and longstanding AGA member) reflecting on how the demographics of gastroenterology and of the AGA as an organization have changed over the past 15 years. I hope you will find these special contributions to be engaging and thought-provoking. Other issue highlights include a lead article describing impacts of social determinants of health in driving disparities in IBD care and offering recommendations for achieving IBD health equity, a new AGA Clinical Practice Update on dietary options for our many patients with irritable bowel syndrome, and new data on the safety of anti-TNF medications prior to surgery in patients with inflammatory bowel disease.

As summer vacation season commences, I hope you will join me in taking some well-deserved time away from work demands, spending some quality time with friends and family, and seizing the opportunity to rest and recharge.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

The inaugural issue of GI & Hepatology News was published in January 2007, and the newspaper has gone on to become part of the fabric of the AGA. This year, we celebrate the newspaper’s 15th year with a special 15th Anniversary Series that will run from June through December 2022. We will feature reflections from GIHN’s three former editors-in-chief, Dr. Charles J. Lightdale, Dr. Colin Howden, and Dr. John Allen, on the evolution of the newspaper (and the field of GI) over the past 15 years. We also will present a series of Then and Now columns, highlighting high-impact areas of GI and hepatology covered in past GIHN issues, and reflecting on how the field has changed since that time.

In this month’s issue, we are pleased to kick off the 15th Anniversary Series with reflections by Dr. Lightdale, GIHN’s inaugural editor-in-chief, as well as a Then and Now column written by Dr. Kimberly M. Persley (GIHN associate editor and longstanding AGA member) reflecting on how the demographics of gastroenterology and of the AGA as an organization have changed over the past 15 years. I hope you will find these special contributions to be engaging and thought-provoking. Other issue highlights include a lead article describing impacts of social determinants of health in driving disparities in IBD care and offering recommendations for achieving IBD health equity, a new AGA Clinical Practice Update on dietary options for our many patients with irritable bowel syndrome, and new data on the safety of anti-TNF medications prior to surgery in patients with inflammatory bowel disease.

As summer vacation season commences, I hope you will join me in taking some well-deserved time away from work demands, spending some quality time with friends and family, and seizing the opportunity to rest and recharge.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

The expanding range of therapies and interventions available for treatment of non–small cell lung cancer (NSCLC) has brought medical oncologists and interventional pulmonologists into closer partnership.

Oncologist Dr. Joy Feliciano and interventional pulmonologist Dr. A. Christine Argento, both colleagues at Johns Hopkins University, comment on their evolving relationship as a team.

Pulmonologists now often serve as the "gatekeepers into thoracic oncology," says Dr. Argento. Recent advances in technology, including endobronchial ultrasound, navigational bronchoscopy, and robotic-assisted bronchoscopy, allow for diagnosis, staging, and collection of sufficient tissue for advanced studies into molecular markers and genetic studies necessary to guide treatment decisions for metastatic NSCLC.

In resectable disease, patients who might have gone straight to surgery in the past now can be considered for neoadjuvant treatments. Here again, says Dr. Feliciano, it is critical for oncologists to understand the biomarkers and molecular profile of the tumor before considering an intervention, and the role of bronchoscopy is key.

A multidisciplinary practice of NSCLC specialists, who have access to on-site or virtual tumor boards, sometimes on an international scale, helps ensure optimal treatment for patients in the increasingly complex NSCLC arena.

--

A. Christine Argento, MD, Associate Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Johns Hopkins University; Director of Bronchoscopy, Department of Interventional Pulmonary Medicine, Johns Hopkins Hospital, Baltimore, Maryland

A. Christine Argento, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Biodesix; Olympus; Cook; Intuitive; Boston Scientific

Josephine L. Feliciano, MD, Associate Professor, Clinical Director, Sidney Kimmel Cancer Center, Johns Hopkins University Hospital, Baltimore, Maryland

Josephine L. Feliciano, MD, has disclosed the following relevant financial relationships:

Received research grant from: Bristol-Myers; Pfizer; AstraZeneca.

Received income in an amount equal to or greater than $250 from: Genentech; AstraZeneca; Eli Lilly; Merck; Regeneron; Coherus; Takeda; Bristol-Myers

The expanding range of therapies and interventions available for treatment of non–small cell lung cancer (NSCLC) has brought medical oncologists and interventional pulmonologists into closer partnership.

Oncologist Dr. Joy Feliciano and interventional pulmonologist Dr. A. Christine Argento, both colleagues at Johns Hopkins University, comment on their evolving relationship as a team.

Pulmonologists now often serve as the "gatekeepers into thoracic oncology," says Dr. Argento. Recent advances in technology, including endobronchial ultrasound, navigational bronchoscopy, and robotic-assisted bronchoscopy, allow for diagnosis, staging, and collection of sufficient tissue for advanced studies into molecular markers and genetic studies necessary to guide treatment decisions for metastatic NSCLC.

In resectable disease, patients who might have gone straight to surgery in the past now can be considered for neoadjuvant treatments. Here again, says Dr. Feliciano, it is critical for oncologists to understand the biomarkers and molecular profile of the tumor before considering an intervention, and the role of bronchoscopy is key.

A multidisciplinary practice of NSCLC specialists, who have access to on-site or virtual tumor boards, sometimes on an international scale, helps ensure optimal treatment for patients in the increasingly complex NSCLC arena.

--

A. Christine Argento, MD, Associate Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Johns Hopkins University; Director of Bronchoscopy, Department of Interventional Pulmonary Medicine, Johns Hopkins Hospital, Baltimore, Maryland

A. Christine Argento, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Biodesix; Olympus; Cook; Intuitive; Boston Scientific

Josephine L. Feliciano, MD, Associate Professor, Clinical Director, Sidney Kimmel Cancer Center, Johns Hopkins University Hospital, Baltimore, Maryland

Josephine L. Feliciano, MD, has disclosed the following relevant financial relationships:

Received research grant from: Bristol-Myers; Pfizer; AstraZeneca.

Received income in an amount equal to or greater than $250 from: Genentech; AstraZeneca; Eli Lilly; Merck; Regeneron; Coherus; Takeda; Bristol-Myers

The expanding range of therapies and interventions available for treatment of non–small cell lung cancer (NSCLC) has brought medical oncologists and interventional pulmonologists into closer partnership.

Oncologist Dr. Joy Feliciano and interventional pulmonologist Dr. A. Christine Argento, both colleagues at Johns Hopkins University, comment on their evolving relationship as a team.

Pulmonologists now often serve as the "gatekeepers into thoracic oncology," says Dr. Argento. Recent advances in technology, including endobronchial ultrasound, navigational bronchoscopy, and robotic-assisted bronchoscopy, allow for diagnosis, staging, and collection of sufficient tissue for advanced studies into molecular markers and genetic studies necessary to guide treatment decisions for metastatic NSCLC.

In resectable disease, patients who might have gone straight to surgery in the past now can be considered for neoadjuvant treatments. Here again, says Dr. Feliciano, it is critical for oncologists to understand the biomarkers and molecular profile of the tumor before considering an intervention, and the role of bronchoscopy is key.

A multidisciplinary practice of NSCLC specialists, who have access to on-site or virtual tumor boards, sometimes on an international scale, helps ensure optimal treatment for patients in the increasingly complex NSCLC arena.

--

A. Christine Argento, MD, Associate Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Johns Hopkins University; Director of Bronchoscopy, Department of Interventional Pulmonary Medicine, Johns Hopkins Hospital, Baltimore, Maryland

A. Christine Argento, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Biodesix; Olympus; Cook; Intuitive; Boston Scientific

Josephine L. Feliciano, MD, Associate Professor, Clinical Director, Sidney Kimmel Cancer Center, Johns Hopkins University Hospital, Baltimore, Maryland

Josephine L. Feliciano, MD, has disclosed the following relevant financial relationships:

Received research grant from: Bristol-Myers; Pfizer; AstraZeneca.

Received income in an amount equal to or greater than $250 from: Genentech; AstraZeneca; Eli Lilly; Merck; Regeneron; Coherus; Takeda; Bristol-Myers

A study published in May in The Lancet journal eClinicalMedicine reports that breathomics testing is one step closer to becoming a reality as a lung cancer screening tool.

The tool was successfully used to identify, in 84 patients, 16 lung cancer–related carcinogenic volatile compounds (VOCs), such as aldehydes, hydrocarbons, ketones, carboxylic acids, and furan – some of which are compounds used in the production of common household goods, such as furniture, carpeting, and wood floors.

“The test is anticipated to be highlighted for primary screening of lung cancer but not the final diagnosis,” according to study authors who were led by Peiyu Wang, MD, PhD, chair of social medicine and health at Peking (China) University.

While early diagnosis and treatment are critical for improving lung cancer survival, early detection of lung cancer is challenging because of the lack of clinical manifestations and specific biomarkers. Annual CT scans are costly and include radiation exposure, Dr. Wang and his associates wrote.

Breathomics testing is considered a promising method for detection and screening for lung cancer. It has been under study for years and in 2014, researchers from Belgium published a review in Cancer Epidemiology Biomarkers and Prevention documenting the use of VOCs as early diagnostic or prognostic biomarkers for mesothelioma.

Lung cancer breath biomarkers identified in various studies have been highly heterogeneous because of differing sample collection methods, varying patient conditions, testing environments, and analysis methods. As a result, there currently is no breathomics test for lung cancer screening, Dr. Wang said in an interview.

In terms of its potential as a lung cancer screening tool, “Clinicians may introduce this test for people with high risk for lung cancer, such as elderly smokers, or people with suspected symptoms. It may also be introduced for young populations with subjective or objective needs to screen for lung cancer. As the proportion of lung adenocarcinoma in nonsmoking young women is increasing, the test may be a good method for lung cancer screening in this population,” Dr. Wang said.

After adjusting for age, sex, smoking, and comorbidities, researchers found elevated levels for 16 VOCs in patients with lung cancer. A diagnostic model including the 16 VOCs achieved an area under the curve of 0.952, sensitivity of 89.2%, specificity of 89.1%, and accuracy of 89.1% in lung cancer diagnosis. A model including the top eight VOCs achieved an area under the curve of 0.931, sensitivity of 86.0%, specificity of 87.2%, and accuracy of 86.9%.

After selecting 28 VOCs as candidates through a literature review, Dr. Wang and associates conducted a prospective discovery study from Sept. 1 to Dec. 31, 2020, using high-pressure photon ionization time-of-flight mass spectrometry to evaluate their performance for lung cancer diagnosis. The validation study included 157 lung cancer patients (mean age 57.0 years; 54.1 percent female) and 368 volunteers (mean age 44.5 years; 31.3% female).

“The external validation confirmed good performance of these biomarkers in lung cancer detection,” the researchers stated. It helped, they added, to solve the heterogeneity among published studies, establishing both 16 VOCs and 8 VOCS for lung cancer screening.

The authors stated that a large gap exists between breathomics research and clinical practices in lung cancer detection and screening. While the validated 16 VOCs, mainly aldehydes and hydrocarbon, showed potential for promoting this lung cancer screening strategy, more scientific studies are warranted to investigate the underlying mechanisms of identified lung cancer VOCs.

Dr. Wang declared no competing interests.

A study published in May in The Lancet journal eClinicalMedicine reports that breathomics testing is one step closer to becoming a reality as a lung cancer screening tool.

The tool was successfully used to identify, in 84 patients, 16 lung cancer–related carcinogenic volatile compounds (VOCs), such as aldehydes, hydrocarbons, ketones, carboxylic acids, and furan – some of which are compounds used in the production of common household goods, such as furniture, carpeting, and wood floors.

“The test is anticipated to be highlighted for primary screening of lung cancer but not the final diagnosis,” according to study authors who were led by Peiyu Wang, MD, PhD, chair of social medicine and health at Peking (China) University.

While early diagnosis and treatment are critical for improving lung cancer survival, early detection of lung cancer is challenging because of the lack of clinical manifestations and specific biomarkers. Annual CT scans are costly and include radiation exposure, Dr. Wang and his associates wrote.

Breathomics testing is considered a promising method for detection and screening for lung cancer. It has been under study for years and in 2014, researchers from Belgium published a review in Cancer Epidemiology Biomarkers and Prevention documenting the use of VOCs as early diagnostic or prognostic biomarkers for mesothelioma.

Lung cancer breath biomarkers identified in various studies have been highly heterogeneous because of differing sample collection methods, varying patient conditions, testing environments, and analysis methods. As a result, there currently is no breathomics test for lung cancer screening, Dr. Wang said in an interview.

In terms of its potential as a lung cancer screening tool, “Clinicians may introduce this test for people with high risk for lung cancer, such as elderly smokers, or people with suspected symptoms. It may also be introduced for young populations with subjective or objective needs to screen for lung cancer. As the proportion of lung adenocarcinoma in nonsmoking young women is increasing, the test may be a good method for lung cancer screening in this population,” Dr. Wang said.

After adjusting for age, sex, smoking, and comorbidities, researchers found elevated levels for 16 VOCs in patients with lung cancer. A diagnostic model including the 16 VOCs achieved an area under the curve of 0.952, sensitivity of 89.2%, specificity of 89.1%, and accuracy of 89.1% in lung cancer diagnosis. A model including the top eight VOCs achieved an area under the curve of 0.931, sensitivity of 86.0%, specificity of 87.2%, and accuracy of 86.9%.

After selecting 28 VOCs as candidates through a literature review, Dr. Wang and associates conducted a prospective discovery study from Sept. 1 to Dec. 31, 2020, using high-pressure photon ionization time-of-flight mass spectrometry to evaluate their performance for lung cancer diagnosis. The validation study included 157 lung cancer patients (mean age 57.0 years; 54.1 percent female) and 368 volunteers (mean age 44.5 years; 31.3% female).

“The external validation confirmed good performance of these biomarkers in lung cancer detection,” the researchers stated. It helped, they added, to solve the heterogeneity among published studies, establishing both 16 VOCs and 8 VOCS for lung cancer screening.

The authors stated that a large gap exists between breathomics research and clinical practices in lung cancer detection and screening. While the validated 16 VOCs, mainly aldehydes and hydrocarbon, showed potential for promoting this lung cancer screening strategy, more scientific studies are warranted to investigate the underlying mechanisms of identified lung cancer VOCs.

Dr. Wang declared no competing interests.

A study published in May in The Lancet journal eClinicalMedicine reports that breathomics testing is one step closer to becoming a reality as a lung cancer screening tool.

The tool was successfully used to identify, in 84 patients, 16 lung cancer–related carcinogenic volatile compounds (VOCs), such as aldehydes, hydrocarbons, ketones, carboxylic acids, and furan – some of which are compounds used in the production of common household goods, such as furniture, carpeting, and wood floors.

“The test is anticipated to be highlighted for primary screening of lung cancer but not the final diagnosis,” according to study authors who were led by Peiyu Wang, MD, PhD, chair of social medicine and health at Peking (China) University.

While early diagnosis and treatment are critical for improving lung cancer survival, early detection of lung cancer is challenging because of the lack of clinical manifestations and specific biomarkers. Annual CT scans are costly and include radiation exposure, Dr. Wang and his associates wrote.

Breathomics testing is considered a promising method for detection and screening for lung cancer. It has been under study for years and in 2014, researchers from Belgium published a review in Cancer Epidemiology Biomarkers and Prevention documenting the use of VOCs as early diagnostic or prognostic biomarkers for mesothelioma.

Lung cancer breath biomarkers identified in various studies have been highly heterogeneous because of differing sample collection methods, varying patient conditions, testing environments, and analysis methods. As a result, there currently is no breathomics test for lung cancer screening, Dr. Wang said in an interview.

In terms of its potential as a lung cancer screening tool, “Clinicians may introduce this test for people with high risk for lung cancer, such as elderly smokers, or people with suspected symptoms. It may also be introduced for young populations with subjective or objective needs to screen for lung cancer. As the proportion of lung adenocarcinoma in nonsmoking young women is increasing, the test may be a good method for lung cancer screening in this population,” Dr. Wang said.

After adjusting for age, sex, smoking, and comorbidities, researchers found elevated levels for 16 VOCs in patients with lung cancer. A diagnostic model including the 16 VOCs achieved an area under the curve of 0.952, sensitivity of 89.2%, specificity of 89.1%, and accuracy of 89.1% in lung cancer diagnosis. A model including the top eight VOCs achieved an area under the curve of 0.931, sensitivity of 86.0%, specificity of 87.2%, and accuracy of 86.9%.

After selecting 28 VOCs as candidates through a literature review, Dr. Wang and associates conducted a prospective discovery study from Sept. 1 to Dec. 31, 2020, using high-pressure photon ionization time-of-flight mass spectrometry to evaluate their performance for lung cancer diagnosis. The validation study included 157 lung cancer patients (mean age 57.0 years; 54.1 percent female) and 368 volunteers (mean age 44.5 years; 31.3% female).

“The external validation confirmed good performance of these biomarkers in lung cancer detection,” the researchers stated. It helped, they added, to solve the heterogeneity among published studies, establishing both 16 VOCs and 8 VOCS for lung cancer screening.

The authors stated that a large gap exists between breathomics research and clinical practices in lung cancer detection and screening. While the validated 16 VOCs, mainly aldehydes and hydrocarbon, showed potential for promoting this lung cancer screening strategy, more scientific studies are warranted to investigate the underlying mechanisms of identified lung cancer VOCs.

Dr. Wang declared no competing interests.

A new study suggests that, at least for certain male patients, the answer to infertility might lie with epigenetics.

According to the study, a commercially available test of epigenetic anomalies – factors that affect how genes express themselves – can grade the likelihood that sperm are viable for conception.

“The uniqueness of epigenetics is that some of the abnormalities detected have the potential to be modified with lifestyle,” said Larry I. Lipshultz, MD, head of the Division of Male Reproductive Medicine and Surgery at Baylor College of Medicine, Houston, who presented the new findings at the 2022 annual meeting of the American Urological Association.

For decades, semen analysis has been based on motility, morphology, and concentration. But these measures, while useful, are limited. Semen can still have low capacity for producing a pregnancy even when all three parameters are normal, Dr. Lipshultz told this news organization.

The test, called Path SpermQT (Inherent Biosciences) detects unstable gene promotors, which are the epigenetic markers for gene expression. In previous work with more than 1,300 gene samples, expression of the specific genes regulated by these promoters were linked to a wide variety of functions relevant to fertilization, such as spermatogenesis.

The test does not attempt to look for expression of specific unstable promoters but rather quantifies them to characterize sperm quality as excellent (≤ 10 unstable promoters), average (11-42), or poor (≥ 43).

In the studies that led to development of the SpermQT test, the number of unstable promoters correlated with pregnancy success. Pregnancy was achieved even among those in the group with poor sperm quality – but at very low rates.

Of the 172 semen samples collected so far in the ongoing analysis, sperm quality was characterized as excellent in 31%, average in 59%, and poor in 10%.

The stratifications for sperm quality were not significantly correlated with common measures of sperm viability, such as concentration, Dr. Lipshultz reported.

Certain patient characteristics were associated with greater sperm quality. These included use of antioxidant supplementation and low estrogen levels, as seen in men who had taken aromatase inhibitors.

So far, only one natural conception has occurred in the group with poor sperm versus eight in those with average or excellent quality.

The prognostic role of the test is only part of the picture.

“The exciting thing about this area of research is that epigenetics can be changed,” Dr. Lipshultz said in an interview. Based on the data so far, he said he is already starting to consider antioxidant supplementation and hormone modifications when sperm quality is poor.

The value of the Path SpermQT test for identifying treatment targets might eventually revolutionize the management of male infertility, Dr. Lipshultz said, but it has more immediate potential in helping couples decide whether to proceed with in vitro fertilization (IVF).

“We often see patients at an impasse when they are trying to decide to move to IVF,” he said. “A test like this could provide some direction. If sperm quality is good, the advice might be to keep trying. If poor, then a couple might want to move to IVF more quickly.”

A test of sperm quality on the basis of epigenetics “could change how we look at couples attempting to conceive,” agreed Peter N. Schlegel, MD, professor of urology and reproductive medicine, Weill Cornell Medicine, New York.

Dr. Schlegel praised several characteristics of the epigenetics test, including that 70%-80% of men with poor quality with SpermQT have normal results on standard assessments of semen. This finding suggests the tool is providing unique information about patients. He also noted that the studies so far indicate that sperm of poor quality for natural conception is still viable for IVF fertilization – which could be useful for couples weighing their options.

However, while the test is already available, Dr. Schlegel cautioned that much of the promise has yet to be documented.

“The results to date, despite being statistically significant, have only been gleaned from a small group of patients,” he said. “Much larger studies are needed before a change in practice is warranted.”

The value of SpermQT for identifying modifiable risks might be even further away.

“It is well recognized that environmental and lifestyle changes can affect methylation, but it is not known if the abnormalities seen so far could be influenced by lifestyle changes,” Dr. Schlegel said. Among the numerous steps needed to answer this question, he suggested that it might first be important “to evaluate why such changes in methylation occur.”

Dr. Lipshultz has financial relationships with several pharmaceutical companies, including Inherent Biosciences, which is marketing the SpermQT test. Dr. Schlegel has financial relationships with Theralogix, Posterity Health, and Roman Health.

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

A new study suggests that, at least for certain male patients, the answer to infertility might lie with epigenetics.

According to the study, a commercially available test of epigenetic anomalies – factors that affect how genes express themselves – can grade the likelihood that sperm are viable for conception.

“The uniqueness of epigenetics is that some of the abnormalities detected have the potential to be modified with lifestyle,” said Larry I. Lipshultz, MD, head of the Division of Male Reproductive Medicine and Surgery at Baylor College of Medicine, Houston, who presented the new findings at the 2022 annual meeting of the American Urological Association.

For decades, semen analysis has been based on motility, morphology, and concentration. But these measures, while useful, are limited. Semen can still have low capacity for producing a pregnancy even when all three parameters are normal, Dr. Lipshultz told this news organization.

The test, called Path SpermQT (Inherent Biosciences) detects unstable gene promotors, which are the epigenetic markers for gene expression. In previous work with more than 1,300 gene samples, expression of the specific genes regulated by these promoters were linked to a wide variety of functions relevant to fertilization, such as spermatogenesis.

The test does not attempt to look for expression of specific unstable promoters but rather quantifies them to characterize sperm quality as excellent (≤ 10 unstable promoters), average (11-42), or poor (≥ 43).

In the studies that led to development of the SpermQT test, the number of unstable promoters correlated with pregnancy success. Pregnancy was achieved even among those in the group with poor sperm quality – but at very low rates.

Of the 172 semen samples collected so far in the ongoing analysis, sperm quality was characterized as excellent in 31%, average in 59%, and poor in 10%.

The stratifications for sperm quality were not significantly correlated with common measures of sperm viability, such as concentration, Dr. Lipshultz reported.

Certain patient characteristics were associated with greater sperm quality. These included use of antioxidant supplementation and low estrogen levels, as seen in men who had taken aromatase inhibitors.

So far, only one natural conception has occurred in the group with poor sperm versus eight in those with average or excellent quality.

The prognostic role of the test is only part of the picture.

“The exciting thing about this area of research is that epigenetics can be changed,” Dr. Lipshultz said in an interview. Based on the data so far, he said he is already starting to consider antioxidant supplementation and hormone modifications when sperm quality is poor.

The value of the Path SpermQT test for identifying treatment targets might eventually revolutionize the management of male infertility, Dr. Lipshultz said, but it has more immediate potential in helping couples decide whether to proceed with in vitro fertilization (IVF).

“We often see patients at an impasse when they are trying to decide to move to IVF,” he said. “A test like this could provide some direction. If sperm quality is good, the advice might be to keep trying. If poor, then a couple might want to move to IVF more quickly.”

A test of sperm quality on the basis of epigenetics “could change how we look at couples attempting to conceive,” agreed Peter N. Schlegel, MD, professor of urology and reproductive medicine, Weill Cornell Medicine, New York.

Dr. Schlegel praised several characteristics of the epigenetics test, including that 70%-80% of men with poor quality with SpermQT have normal results on standard assessments of semen. This finding suggests the tool is providing unique information about patients. He also noted that the studies so far indicate that sperm of poor quality for natural conception is still viable for IVF fertilization – which could be useful for couples weighing their options.

However, while the test is already available, Dr. Schlegel cautioned that much of the promise has yet to be documented.

“The results to date, despite being statistically significant, have only been gleaned from a small group of patients,” he said. “Much larger studies are needed before a change in practice is warranted.”

The value of SpermQT for identifying modifiable risks might be even further away.

“It is well recognized that environmental and lifestyle changes can affect methylation, but it is not known if the abnormalities seen so far could be influenced by lifestyle changes,” Dr. Schlegel said. Among the numerous steps needed to answer this question, he suggested that it might first be important “to evaluate why such changes in methylation occur.”

Dr. Lipshultz has financial relationships with several pharmaceutical companies, including Inherent Biosciences, which is marketing the SpermQT test. Dr. Schlegel has financial relationships with Theralogix, Posterity Health, and Roman Health.

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

A new study suggests that, at least for certain male patients, the answer to infertility might lie with epigenetics.

According to the study, a commercially available test of epigenetic anomalies – factors that affect how genes express themselves – can grade the likelihood that sperm are viable for conception.

“The uniqueness of epigenetics is that some of the abnormalities detected have the potential to be modified with lifestyle,” said Larry I. Lipshultz, MD, head of the Division of Male Reproductive Medicine and Surgery at Baylor College of Medicine, Houston, who presented the new findings at the 2022 annual meeting of the American Urological Association.

For decades, semen analysis has been based on motility, morphology, and concentration. But these measures, while useful, are limited. Semen can still have low capacity for producing a pregnancy even when all three parameters are normal, Dr. Lipshultz told this news organization.

The test, called Path SpermQT (Inherent Biosciences) detects unstable gene promotors, which are the epigenetic markers for gene expression. In previous work with more than 1,300 gene samples, expression of the specific genes regulated by these promoters were linked to a wide variety of functions relevant to fertilization, such as spermatogenesis.

The test does not attempt to look for expression of specific unstable promoters but rather quantifies them to characterize sperm quality as excellent (≤ 10 unstable promoters), average (11-42), or poor (≥ 43).

In the studies that led to development of the SpermQT test, the number of unstable promoters correlated with pregnancy success. Pregnancy was achieved even among those in the group with poor sperm quality – but at very low rates.

Of the 172 semen samples collected so far in the ongoing analysis, sperm quality was characterized as excellent in 31%, average in 59%, and poor in 10%.

The stratifications for sperm quality were not significantly correlated with common measures of sperm viability, such as concentration, Dr. Lipshultz reported.

Certain patient characteristics were associated with greater sperm quality. These included use of antioxidant supplementation and low estrogen levels, as seen in men who had taken aromatase inhibitors.

So far, only one natural conception has occurred in the group with poor sperm versus eight in those with average or excellent quality.

The prognostic role of the test is only part of the picture.

“The exciting thing about this area of research is that epigenetics can be changed,” Dr. Lipshultz said in an interview. Based on the data so far, he said he is already starting to consider antioxidant supplementation and hormone modifications when sperm quality is poor.

The value of the Path SpermQT test for identifying treatment targets might eventually revolutionize the management of male infertility, Dr. Lipshultz said, but it has more immediate potential in helping couples decide whether to proceed with in vitro fertilization (IVF).

“We often see patients at an impasse when they are trying to decide to move to IVF,” he said. “A test like this could provide some direction. If sperm quality is good, the advice might be to keep trying. If poor, then a couple might want to move to IVF more quickly.”

A test of sperm quality on the basis of epigenetics “could change how we look at couples attempting to conceive,” agreed Peter N. Schlegel, MD, professor of urology and reproductive medicine, Weill Cornell Medicine, New York.

Dr. Schlegel praised several characteristics of the epigenetics test, including that 70%-80% of men with poor quality with SpermQT have normal results on standard assessments of semen. This finding suggests the tool is providing unique information about patients. He also noted that the studies so far indicate that sperm of poor quality for natural conception is still viable for IVF fertilization – which could be useful for couples weighing their options.

However, while the test is already available, Dr. Schlegel cautioned that much of the promise has yet to be documented.

“The results to date, despite being statistically significant, have only been gleaned from a small group of patients,” he said. “Much larger studies are needed before a change in practice is warranted.”

The value of SpermQT for identifying modifiable risks might be even further away.

“It is well recognized that environmental and lifestyle changes can affect methylation, but it is not known if the abnormalities seen so far could be influenced by lifestyle changes,” Dr. Schlegel said. Among the numerous steps needed to answer this question, he suggested that it might first be important “to evaluate why such changes in methylation occur.”

Dr. Lipshultz has financial relationships with several pharmaceutical companies, including Inherent Biosciences, which is marketing the SpermQT test. Dr. Schlegel has financial relationships with Theralogix, Posterity Health, and Roman Health.

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

Mrs. Stevens has migraines. Fortunately, they’re well controlled on nortriptyline, and she’s never had side effects from it. She’s taken it for more than 20 years now.

In that time she and I have had a strange, slow-motion, waltz.

In spite of the medicine helping her, she stops it on her own roughly twice a year, never calling my office in advance. Sometimes it’s to see if the headaches come back (they always do). Other times it’s because of something she read online, or a friend told her, or she overheard in the grocery checkout line.

Whatever the reason, her migraines always come back within a week, and then she calls my office for an urgent appointment.

I’ve never really understood this, as I know her history and am happy to just tell her to restart the medication and call it in. But, for whatever reason, the return of her migraines is something that she wants to discuss with me in person. Since it’s usually a pretty brief visit, my secretary puts her on the schedule and I get paid to tell her what could have been handled by phone. I’m not complaining. I have to make a living, too.

But still, it makes me wonder. She can’t be the only patient out there who does this. Multiply that by the number of doctors, the cost of visits, the time she takes off from work to come in ... it adds up.

The consequences of noncompliance in migraineurs certainly aren’t as bad – or as expensive – as those for seizure patients, but they aren’t minor either.

So why does this happen?

Believe me, for the past 20 years I’ve spent these occasional visits reminding Mrs. Stevens about the importance of sticking with her medication and calling my office if she has questions. She agrees to, but when she’s thinking about stopping nortriptyline ... she still does it and only tells me after the fact.

I can’t change human nature, or at least not hers. And when multiplied by many like her, it creates entirely unnecessary costs on our health care system. I wish there were a way to stop it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mrs. Stevens has migraines. Fortunately, they’re well controlled on nortriptyline, and she’s never had side effects from it. She’s taken it for more than 20 years now.

In that time she and I have had a strange, slow-motion, waltz.

In spite of the medicine helping her, she stops it on her own roughly twice a year, never calling my office in advance. Sometimes it’s to see if the headaches come back (they always do). Other times it’s because of something she read online, or a friend told her, or she overheard in the grocery checkout line.

Whatever the reason, her migraines always come back within a week, and then she calls my office for an urgent appointment.

I’ve never really understood this, as I know her history and am happy to just tell her to restart the medication and call it in. But, for whatever reason, the return of her migraines is something that she wants to discuss with me in person. Since it’s usually a pretty brief visit, my secretary puts her on the schedule and I get paid to tell her what could have been handled by phone. I’m not complaining. I have to make a living, too.

But still, it makes me wonder. She can’t be the only patient out there who does this. Multiply that by the number of doctors, the cost of visits, the time she takes off from work to come in ... it adds up.

The consequences of noncompliance in migraineurs certainly aren’t as bad – or as expensive – as those for seizure patients, but they aren’t minor either.

So why does this happen?

Believe me, for the past 20 years I’ve spent these occasional visits reminding Mrs. Stevens about the importance of sticking with her medication and calling my office if she has questions. She agrees to, but when she’s thinking about stopping nortriptyline ... she still does it and only tells me after the fact.

I can’t change human nature, or at least not hers. And when multiplied by many like her, it creates entirely unnecessary costs on our health care system. I wish there were a way to stop it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mrs. Stevens has migraines. Fortunately, they’re well controlled on nortriptyline, and she’s never had side effects from it. She’s taken it for more than 20 years now.

In that time she and I have had a strange, slow-motion, waltz.

In spite of the medicine helping her, she stops it on her own roughly twice a year, never calling my office in advance. Sometimes it’s to see if the headaches come back (they always do). Other times it’s because of something she read online, or a friend told her, or she overheard in the grocery checkout line.

Whatever the reason, her migraines always come back within a week, and then she calls my office for an urgent appointment.

I’ve never really understood this, as I know her history and am happy to just tell her to restart the medication and call it in. But, for whatever reason, the return of her migraines is something that she wants to discuss with me in person. Since it’s usually a pretty brief visit, my secretary puts her on the schedule and I get paid to tell her what could have been handled by phone. I’m not complaining. I have to make a living, too.

But still, it makes me wonder. She can’t be the only patient out there who does this. Multiply that by the number of doctors, the cost of visits, the time she takes off from work to come in ... it adds up.

The consequences of noncompliance in migraineurs certainly aren’t as bad – or as expensive – as those for seizure patients, but they aren’t minor either.

So why does this happen?

Believe me, for the past 20 years I’ve spent these occasional visits reminding Mrs. Stevens about the importance of sticking with her medication and calling my office if she has questions. She agrees to, but when she’s thinking about stopping nortriptyline ... she still does it and only tells me after the fact.

I can’t change human nature, or at least not hers. And when multiplied by many like her, it creates entirely unnecessary costs on our health care system. I wish there were a way to stop it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.