Carfilzomib (Kyprolis)

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) in combination with lenalidomide and dexamethasone to treat patients with relapsed multiple myeloma (MM) who have received 1 to 3 prior lines of therapy.

Carfilzomib already has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last treatment.

The FDA’s expanded approval was based on results of the phase 3 ASPIRE trial.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive lenalidomide and dexamethasone with or without carfilzomib for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

There was a statistically significant prolongation of progression-free survival (PFS), as determined by an independent review committee, in the carfilzomib arm (hazard ratio=0.69, P=0.0001). The median PFS was 26.3 months in the 3-drug arm and 17.6 months in the 2-drug arm.

A treatment effect was observed across all subgroups tested, but the magnitude of the treatment effect was reduced in patients with higher tumor burden at baseline. The improvement in median PFS was 11 months for patients with International Staging System (ISS) Stage I disease, 8 months for ISS Stage II, and 2 months for ISS Stage III.

An interim analysis of overall survival, the key secondary endpoint, was conducted at the same time. The difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate (partial response or better) was 87% in the 3-drug arm and 67% in the 2-drug arm.

The safety profile of carfilzomib in the 3-drug combination was similar to that described on the current label.

Cardiovascular events, venous thromboembolic events (VTE), and thrombocytopenia occurred more frequently in the 3-drug arm than in the 2-drug arm. In cycles 1 to 12, the VTE rate was 13% and 6%, respectively, despite protocol-mandated use of thromboprophylaxis.

The revised labeling for carfilzomib includes new Warnings and Precautions for VTE, cardiac toxicities, acute renal failure, pulmonary toxicities, and hypertension. The increased safety risks, including mortality, for elderly patients is described. Detailed safety information in the prescribing information was also updated for the use of carfilzomib monotherapy.

The recommended dose schedule for carfilzomib has been revised for both monotherapy and combination treatment. For details, see the full prescribing information.

Carfilzomib is marketed as Kyprolis in the US by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Carfilzomib (Kyprolis)

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) in combination with lenalidomide and dexamethasone to treat patients with relapsed multiple myeloma (MM) who have received 1 to 3 prior lines of therapy.

Carfilzomib already has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last treatment.

The FDA’s expanded approval was based on results of the phase 3 ASPIRE trial.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive lenalidomide and dexamethasone with or without carfilzomib for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

There was a statistically significant prolongation of progression-free survival (PFS), as determined by an independent review committee, in the carfilzomib arm (hazard ratio=0.69, P=0.0001). The median PFS was 26.3 months in the 3-drug arm and 17.6 months in the 2-drug arm.

A treatment effect was observed across all subgroups tested, but the magnitude of the treatment effect was reduced in patients with higher tumor burden at baseline. The improvement in median PFS was 11 months for patients with International Staging System (ISS) Stage I disease, 8 months for ISS Stage II, and 2 months for ISS Stage III.

An interim analysis of overall survival, the key secondary endpoint, was conducted at the same time. The difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate (partial response or better) was 87% in the 3-drug arm and 67% in the 2-drug arm.

The safety profile of carfilzomib in the 3-drug combination was similar to that described on the current label.

Cardiovascular events, venous thromboembolic events (VTE), and thrombocytopenia occurred more frequently in the 3-drug arm than in the 2-drug arm. In cycles 1 to 12, the VTE rate was 13% and 6%, respectively, despite protocol-mandated use of thromboprophylaxis.

The revised labeling for carfilzomib includes new Warnings and Precautions for VTE, cardiac toxicities, acute renal failure, pulmonary toxicities, and hypertension. The increased safety risks, including mortality, for elderly patients is described. Detailed safety information in the prescribing information was also updated for the use of carfilzomib monotherapy.

The recommended dose schedule for carfilzomib has been revised for both monotherapy and combination treatment. For details, see the full prescribing information.

Carfilzomib is marketed as Kyprolis in the US by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Carfilzomib (Kyprolis)

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) in combination with lenalidomide and dexamethasone to treat patients with relapsed multiple myeloma (MM) who have received 1 to 3 prior lines of therapy.

Carfilzomib already has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last treatment.

The FDA’s expanded approval was based on results of the phase 3 ASPIRE trial.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive lenalidomide and dexamethasone with or without carfilzomib for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

There was a statistically significant prolongation of progression-free survival (PFS), as determined by an independent review committee, in the carfilzomib arm (hazard ratio=0.69, P=0.0001). The median PFS was 26.3 months in the 3-drug arm and 17.6 months in the 2-drug arm.

A treatment effect was observed across all subgroups tested, but the magnitude of the treatment effect was reduced in patients with higher tumor burden at baseline. The improvement in median PFS was 11 months for patients with International Staging System (ISS) Stage I disease, 8 months for ISS Stage II, and 2 months for ISS Stage III.

An interim analysis of overall survival, the key secondary endpoint, was conducted at the same time. The difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate (partial response or better) was 87% in the 3-drug arm and 67% in the 2-drug arm.

The safety profile of carfilzomib in the 3-drug combination was similar to that described on the current label.

Cardiovascular events, venous thromboembolic events (VTE), and thrombocytopenia occurred more frequently in the 3-drug arm than in the 2-drug arm. In cycles 1 to 12, the VTE rate was 13% and 6%, respectively, despite protocol-mandated use of thromboprophylaxis.

The revised labeling for carfilzomib includes new Warnings and Precautions for VTE, cardiac toxicities, acute renal failure, pulmonary toxicities, and hypertension. The increased safety risks, including mortality, for elderly patients is described. Detailed safety information in the prescribing information was also updated for the use of carfilzomib monotherapy.

The recommended dose schedule for carfilzomib has been revised for both monotherapy and combination treatment. For details, see the full prescribing information.

Carfilzomib is marketed as Kyprolis in the US by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Aromatase inhibitors and bisphosphonates can improve survival in postmenopausal early-stage breast cancer, and combining the two drug classes can help negate their individual adverse effects, according to two studies published online in The Lancet.

The research offers “the best evidence yet for the effects of aromatase inhibitors and bisphosphonates on postmenopausal women with early breast cancer,” according to a news release by The Lancet that accompanied the reports.

© Ingram Publishing/Thinkstock

Breast cancer typically occurs after menopause and is usually detected early enough to be operable, but can metastasize years later in bone or other sites if dormant malignant cells become activated, noted researchers from the Early Breast Cancer Trialists’ Collaborative Group, which conducted both meta-analyses.

For the aromatase inhibitor (AI) study, researchers analyzed data from almost 32,000 postmenopausal women with estrogen receptor–positive (ER-positive) early breast cancer who had participated in nine randomized, multiyear trials comparing AIs with standard tamoxifen-based endocrine therapy. Compared with tamoxifen, AI therapy cut the chances of breast cancer recurrence by about 30% during years 0-1 and 2-4 (P less than .001), they reported. “However, in the 2014 ASCO guidelines on endocrine treatment of postmenopausal women with ER-positive early breast cancer, three of the four recommended options start with tamoxifen; a review seems appropriate,” the investigators noted (Lancet 2015 July 24 [doi:10.1016/S0140-6736(15)61074-1]). Treatment with AIs also appeared to cut 10-year breast cancer mortality by about 15% compared with tamoxifen, and to lower the risk of dying of breast cancer by about 40% compared with no endocrine therapy, the researchers reported. “The impact of AIs is particularly remarkable given how specific these drugs are – removing only the tiny amount of estrogen that remains in the circulation of women after the menopause – and given the extraordinary molecular differences between ER-positive tumors,” Dr. Mitch Dowsett, the lead author, said in a statement.

“But AI treatment is not free of side effects, and it’s important to ensure that women with significant side effects are supported to try to continue to take treatment and fully benefit from it,” added Dr. Dowsett of The Royal Marsden and The Institute of Cancer Research, both in London.

Because AIs can increase fracture risk, clinicians need to monitor treated patients’ bone health and should consider using bisphosphonates when indicated, Dr. Dowsett and his associates added. The study also linked AIs to a slightly lower rate of endometrial cancer compared with tamoxifen therapy, helping offset the increased fracture risk, they said.

For the second study, investigators analyzed data from more than 18,700 women who had participated in 26 randomized controlled trials of bisphosphonates that assessed breast cancer recurrence, distant metastasis, and mortality. Bisphosphonate treatment did not seem to affect outcomes in premenopausal women, they found. But in postmenopausal patients, treatment led to “highly significant reductions” in local recurrence (risk ratio, 0.86, 95% confidence interval, 0.78 to 0.94; P = .002), distant recurrence (P = .0003), bone recurrence (P = .0002) and breast cancer mortality (P = .002), they reported (Lancet 2015 July 24 [doi:10.1016/S0140-6736(15)60908-4]).

Use of bisphosphonates also was tied to a small drop in fracture rates, which was probably real based on studies of other groups of patients, they noted. While bisphosphonates have been used primarily to help prevent bone loss and fractures in postmenopausal women with ER-positive disease who are receiving AIs, the findings show an additional oncological benefit “and suggest that adjuvant bisphosphonates should be considered in a broader range of postmenopausal women,” the researchers concluded. They were unable to assess rates of osteonecrosis of the jaw, but past reports point to rates of about 1% of patients on clodronate, ibandronate, or 6-monthly zoledronic acid therapy, and about 2% of those receiving more intensive zoledronic acid treatment, they noted.

Cancer Research UK and the UK Medical Research Council funded both studies. Ten authors from the AI study and eight authors from the bisphosphonate study reported financial relationships with a number of pharmaceutical companies.

Aromatase inhibitors and bisphosphonates can improve survival in postmenopausal early-stage breast cancer, and combining the two drug classes can help negate their individual adverse effects, according to two studies published online in The Lancet.

The research offers “the best evidence yet for the effects of aromatase inhibitors and bisphosphonates on postmenopausal women with early breast cancer,” according to a news release by The Lancet that accompanied the reports.

© Ingram Publishing/Thinkstock

Breast cancer typically occurs after menopause and is usually detected early enough to be operable, but can metastasize years later in bone or other sites if dormant malignant cells become activated, noted researchers from the Early Breast Cancer Trialists’ Collaborative Group, which conducted both meta-analyses.

For the aromatase inhibitor (AI) study, researchers analyzed data from almost 32,000 postmenopausal women with estrogen receptor–positive (ER-positive) early breast cancer who had participated in nine randomized, multiyear trials comparing AIs with standard tamoxifen-based endocrine therapy. Compared with tamoxifen, AI therapy cut the chances of breast cancer recurrence by about 30% during years 0-1 and 2-4 (P less than .001), they reported. “However, in the 2014 ASCO guidelines on endocrine treatment of postmenopausal women with ER-positive early breast cancer, three of the four recommended options start with tamoxifen; a review seems appropriate,” the investigators noted (Lancet 2015 July 24 [doi:10.1016/S0140-6736(15)61074-1]). Treatment with AIs also appeared to cut 10-year breast cancer mortality by about 15% compared with tamoxifen, and to lower the risk of dying of breast cancer by about 40% compared with no endocrine therapy, the researchers reported. “The impact of AIs is particularly remarkable given how specific these drugs are – removing only the tiny amount of estrogen that remains in the circulation of women after the menopause – and given the extraordinary molecular differences between ER-positive tumors,” Dr. Mitch Dowsett, the lead author, said in a statement.

“But AI treatment is not free of side effects, and it’s important to ensure that women with significant side effects are supported to try to continue to take treatment and fully benefit from it,” added Dr. Dowsett of The Royal Marsden and The Institute of Cancer Research, both in London.

Because AIs can increase fracture risk, clinicians need to monitor treated patients’ bone health and should consider using bisphosphonates when indicated, Dr. Dowsett and his associates added. The study also linked AIs to a slightly lower rate of endometrial cancer compared with tamoxifen therapy, helping offset the increased fracture risk, they said.

For the second study, investigators analyzed data from more than 18,700 women who had participated in 26 randomized controlled trials of bisphosphonates that assessed breast cancer recurrence, distant metastasis, and mortality. Bisphosphonate treatment did not seem to affect outcomes in premenopausal women, they found. But in postmenopausal patients, treatment led to “highly significant reductions” in local recurrence (risk ratio, 0.86, 95% confidence interval, 0.78 to 0.94; P = .002), distant recurrence (P = .0003), bone recurrence (P = .0002) and breast cancer mortality (P = .002), they reported (Lancet 2015 July 24 [doi:10.1016/S0140-6736(15)60908-4]).

Use of bisphosphonates also was tied to a small drop in fracture rates, which was probably real based on studies of other groups of patients, they noted. While bisphosphonates have been used primarily to help prevent bone loss and fractures in postmenopausal women with ER-positive disease who are receiving AIs, the findings show an additional oncological benefit “and suggest that adjuvant bisphosphonates should be considered in a broader range of postmenopausal women,” the researchers concluded. They were unable to assess rates of osteonecrosis of the jaw, but past reports point to rates of about 1% of patients on clodronate, ibandronate, or 6-monthly zoledronic acid therapy, and about 2% of those receiving more intensive zoledronic acid treatment, they noted.

Cancer Research UK and the UK Medical Research Council funded both studies. Ten authors from the AI study and eight authors from the bisphosphonate study reported financial relationships with a number of pharmaceutical companies.

Aromatase inhibitors and bisphosphonates can improve survival in postmenopausal early-stage breast cancer, and combining the two drug classes can help negate their individual adverse effects, according to two studies published online in The Lancet.

The research offers “the best evidence yet for the effects of aromatase inhibitors and bisphosphonates on postmenopausal women with early breast cancer,” according to a news release by The Lancet that accompanied the reports.

© Ingram Publishing/Thinkstock

Breast cancer typically occurs after menopause and is usually detected early enough to be operable, but can metastasize years later in bone or other sites if dormant malignant cells become activated, noted researchers from the Early Breast Cancer Trialists’ Collaborative Group, which conducted both meta-analyses.

For the aromatase inhibitor (AI) study, researchers analyzed data from almost 32,000 postmenopausal women with estrogen receptor–positive (ER-positive) early breast cancer who had participated in nine randomized, multiyear trials comparing AIs with standard tamoxifen-based endocrine therapy. Compared with tamoxifen, AI therapy cut the chances of breast cancer recurrence by about 30% during years 0-1 and 2-4 (P less than .001), they reported. “However, in the 2014 ASCO guidelines on endocrine treatment of postmenopausal women with ER-positive early breast cancer, three of the four recommended options start with tamoxifen; a review seems appropriate,” the investigators noted (Lancet 2015 July 24 [doi:10.1016/S0140-6736(15)61074-1]). Treatment with AIs also appeared to cut 10-year breast cancer mortality by about 15% compared with tamoxifen, and to lower the risk of dying of breast cancer by about 40% compared with no endocrine therapy, the researchers reported. “The impact of AIs is particularly remarkable given how specific these drugs are – removing only the tiny amount of estrogen that remains in the circulation of women after the menopause – and given the extraordinary molecular differences between ER-positive tumors,” Dr. Mitch Dowsett, the lead author, said in a statement.

“But AI treatment is not free of side effects, and it’s important to ensure that women with significant side effects are supported to try to continue to take treatment and fully benefit from it,” added Dr. Dowsett of The Royal Marsden and The Institute of Cancer Research, both in London.

Because AIs can increase fracture risk, clinicians need to monitor treated patients’ bone health and should consider using bisphosphonates when indicated, Dr. Dowsett and his associates added. The study also linked AIs to a slightly lower rate of endometrial cancer compared with tamoxifen therapy, helping offset the increased fracture risk, they said.

For the second study, investigators analyzed data from more than 18,700 women who had participated in 26 randomized controlled trials of bisphosphonates that assessed breast cancer recurrence, distant metastasis, and mortality. Bisphosphonate treatment did not seem to affect outcomes in premenopausal women, they found. But in postmenopausal patients, treatment led to “highly significant reductions” in local recurrence (risk ratio, 0.86, 95% confidence interval, 0.78 to 0.94; P = .002), distant recurrence (P = .0003), bone recurrence (P = .0002) and breast cancer mortality (P = .002), they reported (Lancet 2015 July 24 [doi:10.1016/S0140-6736(15)60908-4]).

Use of bisphosphonates also was tied to a small drop in fracture rates, which was probably real based on studies of other groups of patients, they noted. While bisphosphonates have been used primarily to help prevent bone loss and fractures in postmenopausal women with ER-positive disease who are receiving AIs, the findings show an additional oncological benefit “and suggest that adjuvant bisphosphonates should be considered in a broader range of postmenopausal women,” the researchers concluded. They were unable to assess rates of osteonecrosis of the jaw, but past reports point to rates of about 1% of patients on clodronate, ibandronate, or 6-monthly zoledronic acid therapy, and about 2% of those receiving more intensive zoledronic acid treatment, they noted.

Cancer Research UK and the UK Medical Research Council funded both studies. Ten authors from the AI study and eight authors from the bisphosphonate study reported financial relationships with a number of pharmaceutical companies.

Methadone maintenance therapy is widely used for helping patients recover from an opioid use disor­der. When these patients develop an acute medical problem that requires hospital­ization, there often is confusion among providers regarding methadone pharma­cology, regulations, and general safety issues. We have observed that the lack of awareness of these practices can lead to poor medical and surgical outcomes, increased length of stay, and diminished patient satisfaction.

Consider the following common pit­falls—all of which we have encountered on our psychiatry consult service—and ways to avoid them when treating methadone-maintained patients.

Don’t give a full methadone maintenance dosage without verifying the dosage and the date when it was last administered. Methadone typically has a long, but vari­able, half-life, with ranges of 4 to 130 hours being reported.¹ Do not rush to give the full dose without verification from the patient’s methadone maintenance treatment pro­gram (MMTP). Small doses—not to exceed 40 mg in 24 hours—can be administered until you verify the dosage. Multiple days of missed dosing result in decreased toler­ance and will require a dosage reduction.

Consult with the MMTP when restarting methadone in a patient who has missed any days of outpatient dosing. Because metha­done can take days to reach a serum steady state, it can cause oversedation or obtunda­tion after it’s restarted in a person who has lost tolerance due to multiple consecutive days of missed doses.

Don’t automatically give the full, veri­fied dose if the patient appears sedated. A variety of other substances (benzodiaz­epines, heroin, tricyclic antidepressants) can increase the effects of methadone. Even the verified methadone maintenance dos­age may need to be reduced or held until these other substances are cleared from the patient’s system.

Don’t be afraid to adjust the metha­done dosage if medically indicated. Medically hospitalized patients might be placed on medications that can alter metha­done metabolism. The primary enzyme responsible for methadone metabolism is cytochrome P450 3A4, which can cre­ate significant drug-drug interactions with rifampin, carbamazepine, phenytoin, and barbiturates, among others.²

Don’t taper methadone just because the patient does not want to be on it any longer. A patient’s methadone dosage should be adjusted in the hospital only if there is an acute medical indication to do so. Otherwise, all dosage changes must be made on an outpatient basis at the MMTP.

Don’t be afraid to give opioids to treat acute pain. Methadone maintenance does not treat acute pain. In fact, compared with the general population, these patients likely will need a higher-than-expected opioid dosage to treat acute pain.³

Don’t initiate methadone maintenance in the hospital. Methadone maintenance can be initiated only at an MMTP that has been certified by appropriate federal and state agencies.⁴ Small doses of methadone can be given to treat or prevent opioid withdrawal in patients admitted to the hospital for conditions other than an opi­oid use disorder. An exception: A pregnant woman with an opioid use disorder who seeks methadone initiation in the hospital.

Don’t forget to monitor the QTc interval. Methadone can prolong the QTc interval. Although the overall rate of cardiac toxicity is low, it is reasonable to obtain an electro­cardiogram in patients with heart disease, those predisposed to prolonged QTc, or those taking another QT-prolonging agent.5

Don’t let negative countertransference prevent you from giving quality care. Patients with a drug addiction can be challenging. They can elicit anger among members of their treatment team because of their character pathology or a provid­er’s discomfort and unfamiliarity. One might be tempted to spend less time with so-called “difficult” patients, but keep in mind that methadone-maintained patients often carry chaotic medical and social issues that require a thoughtful and thor­ough approach to treatment.

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

Methadone maintenance therapy is widely used for helping patients recover from an opioid use disor­der. When these patients develop an acute medical problem that requires hospital­ization, there often is confusion among providers regarding methadone pharma­cology, regulations, and general safety issues. We have observed that the lack of awareness of these practices can lead to poor medical and surgical outcomes, increased length of stay, and diminished patient satisfaction.

Consider the following common pit­falls—all of which we have encountered on our psychiatry consult service—and ways to avoid them when treating methadone-maintained patients.

Don’t give a full methadone maintenance dosage without verifying the dosage and the date when it was last administered. Methadone typically has a long, but vari­able, half-life, with ranges of 4 to 130 hours being reported.¹ Do not rush to give the full dose without verification from the patient’s methadone maintenance treatment pro­gram (MMTP). Small doses—not to exceed 40 mg in 24 hours—can be administered until you verify the dosage. Multiple days of missed dosing result in decreased toler­ance and will require a dosage reduction.

Consult with the MMTP when restarting methadone in a patient who has missed any days of outpatient dosing. Because metha­done can take days to reach a serum steady state, it can cause oversedation or obtunda­tion after it’s restarted in a person who has lost tolerance due to multiple consecutive days of missed doses.

Don’t automatically give the full, veri­fied dose if the patient appears sedated. A variety of other substances (benzodiaz­epines, heroin, tricyclic antidepressants) can increase the effects of methadone. Even the verified methadone maintenance dos­age may need to be reduced or held until these other substances are cleared from the patient’s system.

Don’t be afraid to adjust the metha­done dosage if medically indicated. Medically hospitalized patients might be placed on medications that can alter metha­done metabolism. The primary enzyme responsible for methadone metabolism is cytochrome P450 3A4, which can cre­ate significant drug-drug interactions with rifampin, carbamazepine, phenytoin, and barbiturates, among others.²

Don’t taper methadone just because the patient does not want to be on it any longer. A patient’s methadone dosage should be adjusted in the hospital only if there is an acute medical indication to do so. Otherwise, all dosage changes must be made on an outpatient basis at the MMTP.

Don’t be afraid to give opioids to treat acute pain. Methadone maintenance does not treat acute pain. In fact, compared with the general population, these patients likely will need a higher-than-expected opioid dosage to treat acute pain.³

Don’t initiate methadone maintenance in the hospital. Methadone maintenance can be initiated only at an MMTP that has been certified by appropriate federal and state agencies.⁴ Small doses of methadone can be given to treat or prevent opioid withdrawal in patients admitted to the hospital for conditions other than an opi­oid use disorder. An exception: A pregnant woman with an opioid use disorder who seeks methadone initiation in the hospital.

Don’t forget to monitor the QTc interval. Methadone can prolong the QTc interval. Although the overall rate of cardiac toxicity is low, it is reasonable to obtain an electro­cardiogram in patients with heart disease, those predisposed to prolonged QTc, or those taking another QT-prolonging agent.5

Don’t let negative countertransference prevent you from giving quality care. Patients with a drug addiction can be challenging. They can elicit anger among members of their treatment team because of their character pathology or a provid­er’s discomfort and unfamiliarity. One might be tempted to spend less time with so-called “difficult” patients, but keep in mind that methadone-maintained patients often carry chaotic medical and social issues that require a thoughtful and thor­ough approach to treatment.

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

Methadone maintenance therapy is widely used for helping patients recover from an opioid use disor­der. When these patients develop an acute medical problem that requires hospital­ization, there often is confusion among providers regarding methadone pharma­cology, regulations, and general safety issues. We have observed that the lack of awareness of these practices can lead to poor medical and surgical outcomes, increased length of stay, and diminished patient satisfaction.

Consider the following common pit­falls—all of which we have encountered on our psychiatry consult service—and ways to avoid them when treating methadone-maintained patients.

Don’t give a full methadone maintenance dosage without verifying the dosage and the date when it was last administered. Methadone typically has a long, but vari­able, half-life, with ranges of 4 to 130 hours being reported.¹ Do not rush to give the full dose without verification from the patient’s methadone maintenance treatment pro­gram (MMTP). Small doses—not to exceed 40 mg in 24 hours—can be administered until you verify the dosage. Multiple days of missed dosing result in decreased toler­ance and will require a dosage reduction.

Consult with the MMTP when restarting methadone in a patient who has missed any days of outpatient dosing. Because metha­done can take days to reach a serum steady state, it can cause oversedation or obtunda­tion after it’s restarted in a person who has lost tolerance due to multiple consecutive days of missed doses.

Don’t automatically give the full, veri­fied dose if the patient appears sedated. A variety of other substances (benzodiaz­epines, heroin, tricyclic antidepressants) can increase the effects of methadone. Even the verified methadone maintenance dos­age may need to be reduced or held until these other substances are cleared from the patient’s system.

Don’t be afraid to adjust the metha­done dosage if medically indicated. Medically hospitalized patients might be placed on medications that can alter metha­done metabolism. The primary enzyme responsible for methadone metabolism is cytochrome P450 3A4, which can cre­ate significant drug-drug interactions with rifampin, carbamazepine, phenytoin, and barbiturates, among others.²

Don’t taper methadone just because the patient does not want to be on it any longer. A patient’s methadone dosage should be adjusted in the hospital only if there is an acute medical indication to do so. Otherwise, all dosage changes must be made on an outpatient basis at the MMTP.

Don’t be afraid to give opioids to treat acute pain. Methadone maintenance does not treat acute pain. In fact, compared with the general population, these patients likely will need a higher-than-expected opioid dosage to treat acute pain.³

Don’t initiate methadone maintenance in the hospital. Methadone maintenance can be initiated only at an MMTP that has been certified by appropriate federal and state agencies.⁴ Small doses of methadone can be given to treat or prevent opioid withdrawal in patients admitted to the hospital for conditions other than an opi­oid use disorder. An exception: A pregnant woman with an opioid use disorder who seeks methadone initiation in the hospital.

Don’t forget to monitor the QTc interval. Methadone can prolong the QTc interval. Although the overall rate of cardiac toxicity is low, it is reasonable to obtain an electro­cardiogram in patients with heart disease, those predisposed to prolonged QTc, or those taking another QT-prolonging agent.5

Don’t let negative countertransference prevent you from giving quality care. Patients with a drug addiction can be challenging. They can elicit anger among members of their treatment team because of their character pathology or a provid­er’s discomfort and unfamiliarity. One might be tempted to spend less time with so-called “difficult” patients, but keep in mind that methadone-maintained patients often carry chaotic medical and social issues that require a thoughtful and thor­ough approach to treatment.

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

Mindfulness has become an impor­tant supportive psychotherapeutic intervention for a variety of psychi­atric conditions,^1-3 regardless of what other modalities the psychiatrist employs (eg, phar­macotherapy, other psychotherapeutic inter­ventions). In general, mindfulness involves engaging in meditation exercises, analogous to working out in the gym, to strengthen “mindfulness muscles.” These exercises increase the patient’s ability to remain in the moment, “as is,” and without judgment.

I think of mindfulness exercises as an “ego gym” for the patient as he (she) gets to exercise the ego functions of agency, atten­tion, awareness, acceptance, and empathy. Advising and helping patients to be present and exist with their thoughts is a psycho-educational approach and form of advice consistent with principles of supportive therapy. In this article, I provide a practical framework for doing and teaching mind­fulness using the mnemonic BREATHE.

Flow is more important than sequence
The 7 elements of mindfulness exercises contained in BREATHE do not need to be done in order. Rather, mindfulness gener­ally involves each of the following elements flowing, or tumbling, into each other, not standing as a distinct entity.

Being in the now, “as is,” without judg­ment (eg, being present/being vs doing; Buddhist origins; diaphragmatic breath­ing/body scans; “breathing-space” medi­tation exercises). In general, mindfulness meditation exercises focus on some sen­sory experience (eg, the physical sensa­tion of breathing or of a difficult emotion, or sounds and smells in the environment). Some mindfulness meditations are called “body scans.”

A patient can shift his (her) focus during mindfulness meditation to a sound or some other stimulus intruding on his original meditative focus, such as an intense emo­tion or pain, that might arise and become the new focus of mindfulness meditation. Ideally, mindfulness exercises are done without the intention of achieving anything (ie, there is no “striving” for anything when being mindful). Striving, after all, is doing; mindfulness is being.

R(AIN). Mindfulness, as operationalized by Kabat-Zinn,⁴ starts with a focus on breath­ing similar to many meditation practices in Buddhism. When the patient wanders into intense emotions, such as suffering, that become the focus of mindfulness, use the mnemonic-within-a-mnemonic RAIN as a guide; typically, this involves first anchoring with a few deep breaths, and then becoming mindful by:
   • Recognizing (and labeling, nam­ing, “tagging”) the emotion (eg, sad, hurt, angry, embarrassed); this engages frontal lobe processes that diminishes amygdaloid limbic system overactivity¹
   • Allowing (ie, accepting suffering)
   • Investigating, with an open and curious attitude, using one’s senses to experience, feel, and explore thoughts and emotions
   • Non-identifying with one’s thoughts, feelings, emotions, or suffering (expressed in the important mindfulness refrain: “You are not your thoughts or emotions. You are the entity that simply is aware of them.”).

Experiencing. The patient stops at the perceived experience or sensation and does not automatically react with thoughts, emo­tions, distress, or judgments. Mindfulness is a psychotherapeutic intervention that is “more experiential than cognitive.” Encourage the patient to stop at the “door of experience” and not enter the doors of thinking, emotion, and feeling.

Accepting without judgment—also called “awarenessing” or “avoid avoiding.” This involves being aware of the experi­ence regardless of what it entails, whether suffering, thoughts, emotions, or pain, and not trying to escape or avoid the difficult experience. Psychodynamic principles help us understand how psychological defenses designed to avoid the experience of the “unbearable affect” often lead to more problems for patients. In mindfulness, only avoiding is to be avoided.

Thoughts. People tend to over-identify with their thoughts and emotions. In mindfulness, you emphasize to the patient that (1) he is not his thoughts or emotions and (2) these cognitive processes do not represent facts.

Heartfulness—or, healthy, happy, free from harm. Mindfulness from the Buddhist tradition also includes “heartfulness” and “loving-kindness” and the development of compassion and kindness for one’s self and others. Mindfulness meditation there­fore also involves development of loving-kindness/compassion toward oneself and others—even one’s enemies (eg, “May I be healthy, happy, and free from harm.”). I have found this aspect of mindfulness useful for patients who feel angry or entitled, with characterological problems.

Empathy for others. As an extension of, or further emphasis on, loving-kindness, medi­tation focuses on understanding the suffer­ing of others. In certain monastic practices, this mindfulness meditation involves “tak­ing on” the suffering of another.

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

Mindfulness has become an impor­tant supportive psychotherapeutic intervention for a variety of psychi­atric conditions,^1-3 regardless of what other modalities the psychiatrist employs (eg, phar­macotherapy, other psychotherapeutic inter­ventions). In general, mindfulness involves engaging in meditation exercises, analogous to working out in the gym, to strengthen “mindfulness muscles.” These exercises increase the patient’s ability to remain in the moment, “as is,” and without judgment.

I think of mindfulness exercises as an “ego gym” for the patient as he (she) gets to exercise the ego functions of agency, atten­tion, awareness, acceptance, and empathy. Advising and helping patients to be present and exist with their thoughts is a psycho-educational approach and form of advice consistent with principles of supportive therapy. In this article, I provide a practical framework for doing and teaching mind­fulness using the mnemonic BREATHE.

Flow is more important than sequence
The 7 elements of mindfulness exercises contained in BREATHE do not need to be done in order. Rather, mindfulness gener­ally involves each of the following elements flowing, or tumbling, into each other, not standing as a distinct entity.

Being in the now, “as is,” without judg­ment (eg, being present/being vs doing; Buddhist origins; diaphragmatic breath­ing/body scans; “breathing-space” medi­tation exercises). In general, mindfulness meditation exercises focus on some sen­sory experience (eg, the physical sensa­tion of breathing or of a difficult emotion, or sounds and smells in the environment). Some mindfulness meditations are called “body scans.”

A patient can shift his (her) focus during mindfulness meditation to a sound or some other stimulus intruding on his original meditative focus, such as an intense emo­tion or pain, that might arise and become the new focus of mindfulness meditation. Ideally, mindfulness exercises are done without the intention of achieving anything (ie, there is no “striving” for anything when being mindful). Striving, after all, is doing; mindfulness is being.

R(AIN). Mindfulness, as operationalized by Kabat-Zinn,⁴ starts with a focus on breath­ing similar to many meditation practices in Buddhism. When the patient wanders into intense emotions, such as suffering, that become the focus of mindfulness, use the mnemonic-within-a-mnemonic RAIN as a guide; typically, this involves first anchoring with a few deep breaths, and then becoming mindful by:
   • Recognizing (and labeling, nam­ing, “tagging”) the emotion (eg, sad, hurt, angry, embarrassed); this engages frontal lobe processes that diminishes amygdaloid limbic system overactivity¹
   • Allowing (ie, accepting suffering)
   • Investigating, with an open and curious attitude, using one’s senses to experience, feel, and explore thoughts and emotions
   • Non-identifying with one’s thoughts, feelings, emotions, or suffering (expressed in the important mindfulness refrain: “You are not your thoughts or emotions. You are the entity that simply is aware of them.”).

Experiencing. The patient stops at the perceived experience or sensation and does not automatically react with thoughts, emo­tions, distress, or judgments. Mindfulness is a psychotherapeutic intervention that is “more experiential than cognitive.” Encourage the patient to stop at the “door of experience” and not enter the doors of thinking, emotion, and feeling.

Accepting without judgment—also called “awarenessing” or “avoid avoiding.” This involves being aware of the experi­ence regardless of what it entails, whether suffering, thoughts, emotions, or pain, and not trying to escape or avoid the difficult experience. Psychodynamic principles help us understand how psychological defenses designed to avoid the experience of the “unbearable affect” often lead to more problems for patients. In mindfulness, only avoiding is to be avoided.

Thoughts. People tend to over-identify with their thoughts and emotions. In mindfulness, you emphasize to the patient that (1) he is not his thoughts or emotions and (2) these cognitive processes do not represent facts.

Heartfulness—or, healthy, happy, free from harm. Mindfulness from the Buddhist tradition also includes “heartfulness” and “loving-kindness” and the development of compassion and kindness for one’s self and others. Mindfulness meditation there­fore also involves development of loving-kindness/compassion toward oneself and others—even one’s enemies (eg, “May I be healthy, happy, and free from harm.”). I have found this aspect of mindfulness useful for patients who feel angry or entitled, with characterological problems.

Empathy for others. As an extension of, or further emphasis on, loving-kindness, medi­tation focuses on understanding the suffer­ing of others. In certain monastic practices, this mindfulness meditation involves “tak­ing on” the suffering of another.

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

Mindfulness has become an impor­tant supportive psychotherapeutic intervention for a variety of psychi­atric conditions,^1-3 regardless of what other modalities the psychiatrist employs (eg, phar­macotherapy, other psychotherapeutic inter­ventions). In general, mindfulness involves engaging in meditation exercises, analogous to working out in the gym, to strengthen “mindfulness muscles.” These exercises increase the patient’s ability to remain in the moment, “as is,” and without judgment.

I think of mindfulness exercises as an “ego gym” for the patient as he (she) gets to exercise the ego functions of agency, atten­tion, awareness, acceptance, and empathy. Advising and helping patients to be present and exist with their thoughts is a psycho-educational approach and form of advice consistent with principles of supportive therapy. In this article, I provide a practical framework for doing and teaching mind­fulness using the mnemonic BREATHE.

Flow is more important than sequence
The 7 elements of mindfulness exercises contained in BREATHE do not need to be done in order. Rather, mindfulness gener­ally involves each of the following elements flowing, or tumbling, into each other, not standing as a distinct entity.

Being in the now, “as is,” without judg­ment (eg, being present/being vs doing; Buddhist origins; diaphragmatic breath­ing/body scans; “breathing-space” medi­tation exercises). In general, mindfulness meditation exercises focus on some sen­sory experience (eg, the physical sensa­tion of breathing or of a difficult emotion, or sounds and smells in the environment). Some mindfulness meditations are called “body scans.”

A patient can shift his (her) focus during mindfulness meditation to a sound or some other stimulus intruding on his original meditative focus, such as an intense emo­tion or pain, that might arise and become the new focus of mindfulness meditation. Ideally, mindfulness exercises are done without the intention of achieving anything (ie, there is no “striving” for anything when being mindful). Striving, after all, is doing; mindfulness is being.

R(AIN). Mindfulness, as operationalized by Kabat-Zinn,⁴ starts with a focus on breath­ing similar to many meditation practices in Buddhism. When the patient wanders into intense emotions, such as suffering, that become the focus of mindfulness, use the mnemonic-within-a-mnemonic RAIN as a guide; typically, this involves first anchoring with a few deep breaths, and then becoming mindful by:
   • Recognizing (and labeling, nam­ing, “tagging”) the emotion (eg, sad, hurt, angry, embarrassed); this engages frontal lobe processes that diminishes amygdaloid limbic system overactivity¹
   • Allowing (ie, accepting suffering)
   • Investigating, with an open and curious attitude, using one’s senses to experience, feel, and explore thoughts and emotions
   • Non-identifying with one’s thoughts, feelings, emotions, or suffering (expressed in the important mindfulness refrain: “You are not your thoughts or emotions. You are the entity that simply is aware of them.”).

Experiencing. The patient stops at the perceived experience or sensation and does not automatically react with thoughts, emo­tions, distress, or judgments. Mindfulness is a psychotherapeutic intervention that is “more experiential than cognitive.” Encourage the patient to stop at the “door of experience” and not enter the doors of thinking, emotion, and feeling.

Accepting without judgment—also called “awarenessing” or “avoid avoiding.” This involves being aware of the experi­ence regardless of what it entails, whether suffering, thoughts, emotions, or pain, and not trying to escape or avoid the difficult experience. Psychodynamic principles help us understand how psychological defenses designed to avoid the experience of the “unbearable affect” often lead to more problems for patients. In mindfulness, only avoiding is to be avoided.

Thoughts. People tend to over-identify with their thoughts and emotions. In mindfulness, you emphasize to the patient that (1) he is not his thoughts or emotions and (2) these cognitive processes do not represent facts.

Heartfulness—or, healthy, happy, free from harm. Mindfulness from the Buddhist tradition also includes “heartfulness” and “loving-kindness” and the development of compassion and kindness for one’s self and others. Mindfulness meditation there­fore also involves development of loving-kindness/compassion toward oneself and others—even one’s enemies (eg, “May I be healthy, happy, and free from harm.”). I have found this aspect of mindfulness useful for patients who feel angry or entitled, with characterological problems.

Empathy for others. As an extension of, or further emphasis on, loving-kindness, medi­tation focuses on understanding the suffer­ing of others. In certain monastic practices, this mindfulness meditation involves “tak­ing on” the suffering of another.

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

Asenapine an atypical antipsychotic sold under the brand name Saphris, was granted a second, pediatric indi­cation by the FDA in March 2015 as mono­therapy for acute treatment of manic or mixed episodes of bipolar I disorder in chil­dren and adolescents age 10 to 17 (Table 1).¹ (Asenapine was first approved in August 2009 as monotherapy or adjunctive therapy to lithium or valproate in adults for schizo­phrenia and bipolar I disorder.^1,2)

Dosage and administration
Asenapine is available as 2.5-, 5-, and 10-mg sublingual tablets, the only atypical anti­psychotic with this formulation.¹ The rec­ommended dosage for the new indication is 2.5 mg twice daily for 3 days, titrated to 5 mg twice daily, titrated again to 10 mg twice daily after 3 days.³ In a phase I study, pedi­atric patients appeared to be more sensitive to dystonia when the recommended dosage escalation schedule was not followed.³

In clinical trials, drinking water 2 to 5 minutes after taking asenapine decreased exposure to the drug. Instruct patients not to swallow the tablet and to avoid eating and drinking for 10 minutes after administration.³

For full prescribing information for pediat­ric and adult patients, see Reference 3.

Safety and efficacy
In a 3-week, placebo-controlled, double-blind trial of 403 patients, 302 children and adolescents age 10 to 17 received asenap­ine at fixed dosages of 2.5 to 10 mg twice daily; the remainder were given placebo. The Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions Severity of Illness scores of patients who received asenapine improved significantly compared with those who received placebo, as measured by change from baseline to week 3 (Table 2).¹

Asenapine was not shown to be effective in pediatric patients with schizophrenia in an 8-week, placebo-controlled, double-blind trial.

The pharmacokinetics of asenapine in pediatric patients are similar to those seen in adults.

Adverse effects
In pediatric patients, the most common reported adverse effects of asenapine are:
   • dizziness
   • dysgeusia
   • fatigue
   • increased appetite
   • increased weight
   • nausea
   • oral paresthesia
   • somnolence.

Similar adverse effects were reported in the pediatric bipolar disorder and adult bipolar disorder clinical trials (Table 3).³ A complete list of reported adverse effects is given in the package insert.³

When treating pediatric patients, moni­tor the child’s weight gain against expected normal weight gain.

Asenapine is contraindicated in patients with hepatic impairment and those who have a hypersensitivity to asenapine or any components in its formulation.³

Asenapine an atypical antipsychotic sold under the brand name Saphris, was granted a second, pediatric indi­cation by the FDA in March 2015 as mono­therapy for acute treatment of manic or mixed episodes of bipolar I disorder in chil­dren and adolescents age 10 to 17 (Table 1).¹ (Asenapine was first approved in August 2009 as monotherapy or adjunctive therapy to lithium or valproate in adults for schizo­phrenia and bipolar I disorder.^1,2)

Dosage and administration
Asenapine is available as 2.5-, 5-, and 10-mg sublingual tablets, the only atypical anti­psychotic with this formulation.¹ The rec­ommended dosage for the new indication is 2.5 mg twice daily for 3 days, titrated to 5 mg twice daily, titrated again to 10 mg twice daily after 3 days.³ In a phase I study, pedi­atric patients appeared to be more sensitive to dystonia when the recommended dosage escalation schedule was not followed.³

In clinical trials, drinking water 2 to 5 minutes after taking asenapine decreased exposure to the drug. Instruct patients not to swallow the tablet and to avoid eating and drinking for 10 minutes after administration.³

For full prescribing information for pediat­ric and adult patients, see Reference 3.

Safety and efficacy
In a 3-week, placebo-controlled, double-blind trial of 403 patients, 302 children and adolescents age 10 to 17 received asenap­ine at fixed dosages of 2.5 to 10 mg twice daily; the remainder were given placebo. The Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions Severity of Illness scores of patients who received asenapine improved significantly compared with those who received placebo, as measured by change from baseline to week 3 (Table 2).¹

Asenapine was not shown to be effective in pediatric patients with schizophrenia in an 8-week, placebo-controlled, double-blind trial.

The pharmacokinetics of asenapine in pediatric patients are similar to those seen in adults.

Adverse effects
In pediatric patients, the most common reported adverse effects of asenapine are:
   • dizziness
   • dysgeusia
   • fatigue
   • increased appetite
   • increased weight
   • nausea
   • oral paresthesia
   • somnolence.

Similar adverse effects were reported in the pediatric bipolar disorder and adult bipolar disorder clinical trials (Table 3).³ A complete list of reported adverse effects is given in the package insert.³

When treating pediatric patients, moni­tor the child’s weight gain against expected normal weight gain.

Asenapine is contraindicated in patients with hepatic impairment and those who have a hypersensitivity to asenapine or any components in its formulation.³

Asenapine an atypical antipsychotic sold under the brand name Saphris, was granted a second, pediatric indi­cation by the FDA in March 2015 as mono­therapy for acute treatment of manic or mixed episodes of bipolar I disorder in chil­dren and adolescents age 10 to 17 (Table 1).¹ (Asenapine was first approved in August 2009 as monotherapy or adjunctive therapy to lithium or valproate in adults for schizo­phrenia and bipolar I disorder.^1,2)

Dosage and administration
Asenapine is available as 2.5-, 5-, and 10-mg sublingual tablets, the only atypical anti­psychotic with this formulation.¹ The rec­ommended dosage for the new indication is 2.5 mg twice daily for 3 days, titrated to 5 mg twice daily, titrated again to 10 mg twice daily after 3 days.³ In a phase I study, pedi­atric patients appeared to be more sensitive to dystonia when the recommended dosage escalation schedule was not followed.³

In clinical trials, drinking water 2 to 5 minutes after taking asenapine decreased exposure to the drug. Instruct patients not to swallow the tablet and to avoid eating and drinking for 10 minutes after administration.³

For full prescribing information for pediat­ric and adult patients, see Reference 3.

Safety and efficacy
In a 3-week, placebo-controlled, double-blind trial of 403 patients, 302 children and adolescents age 10 to 17 received asenap­ine at fixed dosages of 2.5 to 10 mg twice daily; the remainder were given placebo. The Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions Severity of Illness scores of patients who received asenapine improved significantly compared with those who received placebo, as measured by change from baseline to week 3 (Table 2).¹

Asenapine was not shown to be effective in pediatric patients with schizophrenia in an 8-week, placebo-controlled, double-blind trial.

The pharmacokinetics of asenapine in pediatric patients are similar to those seen in adults.

Adverse effects
In pediatric patients, the most common reported adverse effects of asenapine are:
   • dizziness
   • dysgeusia
   • fatigue
   • increased appetite
   • increased weight
   • nausea
   • oral paresthesia
   • somnolence.

Similar adverse effects were reported in the pediatric bipolar disorder and adult bipolar disorder clinical trials (Table 3).³ A complete list of reported adverse effects is given in the package insert.³

When treating pediatric patients, moni­tor the child’s weight gain against expected normal weight gain.

Asenapine is contraindicated in patients with hepatic impairment and those who have a hypersensitivity to asenapine or any components in its formulation.³

Young adult cancer survivors will continue to have high hospitalization rates over time, a Canadian study shows.

In five-year cancer survivors diagnosed between ages 20 and 44, hospitalization rates were elevated for at least 20 years, compared to rates in age- and sex-matched controls, according to Dr. Nancy N. Baxter at St. Michael's Hospital in Toronto and colleagues.

For all malignancies except melanoma and testicular cancer, the adjusted relative rate (ARR) of hospitalizations was significantly higher among survivors than controls.

"Late effects and complications of cancer treatments are experienced by many survivors for the rest of their lives," Dr. Baxter told Reuters Health via e-mail. The patients in this population-based study were treated from 1992-1999. "Therapies have changed, she said. "In some cases there may be fewer late effects, but in others, they may be worse."

The study cohort included 20,275 survivors of young adult cancers who were recurrence-free for at least five years, and 101,344 controls. The authors observed survivors for a median of 9.93 years (range 0-16 years), according to their report online July 13 in the Journal of Clinical Oncology. During this period, 34.3% had at least one hospitalization,

vs. 27.3% for controls. The rate per 100 person-years was similar between male and female survivors.

Overall, the ARR of hospitalization in survivors compared with controls was 1.51. At all-time periods, survivors were more likely to be hospitalized than controls. The rate of hospitalization (per 100-person years) among survivors was 0.22 during years 5 to 8, 9 to11, and 12 to14. It decreased significantly during years 15 to 17 and 18 to 20, falling to 0.17 and 0.15, respectively (P<0.0001). Among controls, the hospitalization rate was relatively constant during all time periods, ranging from 0.13 at 5 to 8 years to 0.12 at years 18 to 20.

The ARR of hospitalizations in survivors compared with controls was also relatively constant during for the first three3 time periods: 1.67, 1.55, and 1.57 at years 5 to 8, 9 to

11, and 12 to 14, respectively. It decreased to 1.36 at 15 to 17 years and 1.22 at years 18 to 20. Those who survived gastrointestinal, urologic, colorectal, or brain cancers, or leukemia or lymphoma, had an ARR of hospitalization at least twice that of controls.

"We only looked at hospital admissions, not visits to the family doctor or medical conditions and disabilities that didn't require inpatient care," Dr. Baxter said, explaining that this likely underestimated the long-term impact of intense treatments that include surgery, chemotherapy, radiation, and hormonal therapy.

"Understanding the late effects of cancer treatment will help us design better treatments, counsel patients, and improve symptom management."

Young adult cancer survivors will continue to have high hospitalization rates over time, a Canadian study shows.

In five-year cancer survivors diagnosed between ages 20 and 44, hospitalization rates were elevated for at least 20 years, compared to rates in age- and sex-matched controls, according to Dr. Nancy N. Baxter at St. Michael's Hospital in Toronto and colleagues.

For all malignancies except melanoma and testicular cancer, the adjusted relative rate (ARR) of hospitalizations was significantly higher among survivors than controls.

"Late effects and complications of cancer treatments are experienced by many survivors for the rest of their lives," Dr. Baxter told Reuters Health via e-mail. The patients in this population-based study were treated from 1992-1999. "Therapies have changed, she said. "In some cases there may be fewer late effects, but in others, they may be worse."

The study cohort included 20,275 survivors of young adult cancers who were recurrence-free for at least five years, and 101,344 controls. The authors observed survivors for a median of 9.93 years (range 0-16 years), according to their report online July 13 in the Journal of Clinical Oncology. During this period, 34.3% had at least one hospitalization,

vs. 27.3% for controls. The rate per 100 person-years was similar between male and female survivors.

Overall, the ARR of hospitalization in survivors compared with controls was 1.51. At all-time periods, survivors were more likely to be hospitalized than controls. The rate of hospitalization (per 100-person years) among survivors was 0.22 during years 5 to 8, 9 to11, and 12 to14. It decreased significantly during years 15 to 17 and 18 to 20, falling to 0.17 and 0.15, respectively (P<0.0001). Among controls, the hospitalization rate was relatively constant during all time periods, ranging from 0.13 at 5 to 8 years to 0.12 at years 18 to 20.

The ARR of hospitalizations in survivors compared with controls was also relatively constant during for the first three3 time periods: 1.67, 1.55, and 1.57 at years 5 to 8, 9 to

11, and 12 to 14, respectively. It decreased to 1.36 at 15 to 17 years and 1.22 at years 18 to 20. Those who survived gastrointestinal, urologic, colorectal, or brain cancers, or leukemia or lymphoma, had an ARR of hospitalization at least twice that of controls.

"We only looked at hospital admissions, not visits to the family doctor or medical conditions and disabilities that didn't require inpatient care," Dr. Baxter said, explaining that this likely underestimated the long-term impact of intense treatments that include surgery, chemotherapy, radiation, and hormonal therapy.

"Understanding the late effects of cancer treatment will help us design better treatments, counsel patients, and improve symptom management."

Young adult cancer survivors will continue to have high hospitalization rates over time, a Canadian study shows.

In five-year cancer survivors diagnosed between ages 20 and 44, hospitalization rates were elevated for at least 20 years, compared to rates in age- and sex-matched controls, according to Dr. Nancy N. Baxter at St. Michael's Hospital in Toronto and colleagues.

For all malignancies except melanoma and testicular cancer, the adjusted relative rate (ARR) of hospitalizations was significantly higher among survivors than controls.

"Late effects and complications of cancer treatments are experienced by many survivors for the rest of their lives," Dr. Baxter told Reuters Health via e-mail. The patients in this population-based study were treated from 1992-1999. "Therapies have changed, she said. "In some cases there may be fewer late effects, but in others, they may be worse."

The study cohort included 20,275 survivors of young adult cancers who were recurrence-free for at least five years, and 101,344 controls. The authors observed survivors for a median of 9.93 years (range 0-16 years), according to their report online July 13 in the Journal of Clinical Oncology. During this period, 34.3% had at least one hospitalization,

vs. 27.3% for controls. The rate per 100 person-years was similar between male and female survivors.

Overall, the ARR of hospitalization in survivors compared with controls was 1.51. At all-time periods, survivors were more likely to be hospitalized than controls. The rate of hospitalization (per 100-person years) among survivors was 0.22 during years 5 to 8, 9 to11, and 12 to14. It decreased significantly during years 15 to 17 and 18 to 20, falling to 0.17 and 0.15, respectively (P<0.0001). Among controls, the hospitalization rate was relatively constant during all time periods, ranging from 0.13 at 5 to 8 years to 0.12 at years 18 to 20.

The ARR of hospitalizations in survivors compared with controls was also relatively constant during for the first three3 time periods: 1.67, 1.55, and 1.57 at years 5 to 8, 9 to

11, and 12 to 14, respectively. It decreased to 1.36 at 15 to 17 years and 1.22 at years 18 to 20. Those who survived gastrointestinal, urologic, colorectal, or brain cancers, or leukemia or lymphoma, had an ARR of hospitalization at least twice that of controls.

"We only looked at hospital admissions, not visits to the family doctor or medical conditions and disabilities that didn't require inpatient care," Dr. Baxter said, explaining that this likely underestimated the long-term impact of intense treatments that include surgery, chemotherapy, radiation, and hormonal therapy.

"Understanding the late effects of cancer treatment will help us design better treatments, counsel patients, and improve symptom management."

Session: Let’s Measure Our Own Performance: Propose and Evaluate Pediatric Hospital Medicine Quality Indicators

Summary: During this workshop, a staff of multiple, nationally-recognized quality leaders led a group to review, help develop, and help validate quality measures. The workshop was facilitated via the use of interactive survey tools, didactic sessions, and small groups.

Presenters discussed why quality measures are important and relevant. These included:

1. Improved quality of care,
2. Demonstration of value,
3. Third-party pay for performance indicators,
4. Determining our own indicators (versus being chosen for us), and
5. Performance incentives.

As part of the introduction to the workshop, the various quality measure validation methods were reviewed. These consisted of methods such as UCLA/RAND and Delphi Panel, as a means to determine validation and feasibility.

Validation was discussed in terms of what is being measured is the true outcome that was hoped to be achieved. The feasibility component used to make sure that the data used for quality measures, or process to be implemented for improvement, can easily be acquired to determine adherence, and that data is free of error. Facilitators reviewed various examples of validity and feasibility of quality measures with direct examples and discussions with attendees.

During the first breakout session, the groups were separated into teams focused on 1. care transitions, 2. safety, and 3. clinical care. The groups were asked to determine three quality indicators per individual, discuss the top five indicators voted on by the group, and than to review and discuss as a group the validity and feasibility of the measures using a scoring tool of 1-3: Not Valid/Feasible, 4-6: Equivocal, 7-9: Valid/Feasible. At the end, a delegated group speaker was asked to discuss either the pros/cons of one of their measures in regards to validity and feasibility to the total audience. Facilitators assisted on clarifying the reasons of why validity and feasibility metrics were appropriate.

During the final parts of workshop, positive and negatives of quality metrics determination methodology were discussed. The attendees reflected on the process of how quality measures are determined along with how these may be used within their settings.

Key Takeaways

Clearly determining the validity and feasibility of quality metrics for pediatrics has become an important topic. It not only has significant ramifications to the value we provide to our patients, but also the financial sustainability of programs and institutions, especially with the current changes in payment models. The workshop gave a clear and concise way of how to come up with quality metrics and the facilitators greatly added to the understanding of how we can “raise the floor” and “raise the ceiling” of pediatric care. TH

Dr. Alvarez is a pediatric hospitalist and medical director of community hospital services at Children’s National Health System in Washington, D.C.

Session: Let’s Measure Our Own Performance: Propose and Evaluate Pediatric Hospital Medicine Quality Indicators

Summary: During this workshop, a staff of multiple, nationally-recognized quality leaders led a group to review, help develop, and help validate quality measures. The workshop was facilitated via the use of interactive survey tools, didactic sessions, and small groups.

Presenters discussed why quality measures are important and relevant. These included:

1. Improved quality of care,
2. Demonstration of value,
3. Third-party pay for performance indicators,
4. Determining our own indicators (versus being chosen for us), and
5. Performance incentives.

As part of the introduction to the workshop, the various quality measure validation methods were reviewed. These consisted of methods such as UCLA/RAND and Delphi Panel, as a means to determine validation and feasibility.

Validation was discussed in terms of what is being measured is the true outcome that was hoped to be achieved. The feasibility component used to make sure that the data used for quality measures, or process to be implemented for improvement, can easily be acquired to determine adherence, and that data is free of error. Facilitators reviewed various examples of validity and feasibility of quality measures with direct examples and discussions with attendees.

During the first breakout session, the groups were separated into teams focused on 1. care transitions, 2. safety, and 3. clinical care. The groups were asked to determine three quality indicators per individual, discuss the top five indicators voted on by the group, and than to review and discuss as a group the validity and feasibility of the measures using a scoring tool of 1-3: Not Valid/Feasible, 4-6: Equivocal, 7-9: Valid/Feasible. At the end, a delegated group speaker was asked to discuss either the pros/cons of one of their measures in regards to validity and feasibility to the total audience. Facilitators assisted on clarifying the reasons of why validity and feasibility metrics were appropriate.

During the final parts of workshop, positive and negatives of quality metrics determination methodology were discussed. The attendees reflected on the process of how quality measures are determined along with how these may be used within their settings.

Key Takeaways

Clearly determining the validity and feasibility of quality metrics for pediatrics has become an important topic. It not only has significant ramifications to the value we provide to our patients, but also the financial sustainability of programs and institutions, especially with the current changes in payment models. The workshop gave a clear and concise way of how to come up with quality metrics and the facilitators greatly added to the understanding of how we can “raise the floor” and “raise the ceiling” of pediatric care. TH

Dr. Alvarez is a pediatric hospitalist and medical director of community hospital services at Children’s National Health System in Washington, D.C.

Session: Let’s Measure Our Own Performance: Propose and Evaluate Pediatric Hospital Medicine Quality Indicators

Summary: During this workshop, a staff of multiple, nationally-recognized quality leaders led a group to review, help develop, and help validate quality measures. The workshop was facilitated via the use of interactive survey tools, didactic sessions, and small groups.

Presenters discussed why quality measures are important and relevant. These included:

1. Improved quality of care,
2. Demonstration of value,
3. Third-party pay for performance indicators,
4. Determining our own indicators (versus being chosen for us), and
5. Performance incentives.

As part of the introduction to the workshop, the various quality measure validation methods were reviewed. These consisted of methods such as UCLA/RAND and Delphi Panel, as a means to determine validation and feasibility.

Validation was discussed in terms of what is being measured is the true outcome that was hoped to be achieved. The feasibility component used to make sure that the data used for quality measures, or process to be implemented for improvement, can easily be acquired to determine adherence, and that data is free of error. Facilitators reviewed various examples of validity and feasibility of quality measures with direct examples and discussions with attendees.

During the first breakout session, the groups were separated into teams focused on 1. care transitions, 2. safety, and 3. clinical care. The groups were asked to determine three quality indicators per individual, discuss the top five indicators voted on by the group, and than to review and discuss as a group the validity and feasibility of the measures using a scoring tool of 1-3: Not Valid/Feasible, 4-6: Equivocal, 7-9: Valid/Feasible. At the end, a delegated group speaker was asked to discuss either the pros/cons of one of their measures in regards to validity and feasibility to the total audience. Facilitators assisted on clarifying the reasons of why validity and feasibility metrics were appropriate.

During the final parts of workshop, positive and negatives of quality metrics determination methodology were discussed. The attendees reflected on the process of how quality measures are determined along with how these may be used within their settings.

Key Takeaways

Clearly determining the validity and feasibility of quality metrics for pediatrics has become an important topic. It not only has significant ramifications to the value we provide to our patients, but also the financial sustainability of programs and institutions, especially with the current changes in payment models. The workshop gave a clear and concise way of how to come up with quality metrics and the facilitators greatly added to the understanding of how we can “raise the floor” and “raise the ceiling” of pediatric care. TH

Dr. Alvarez is a pediatric hospitalist and medical director of community hospital services at Children’s National Health System in Washington, D.C.

“The Burden of Craft in Arthroscopic Rotator Cuff Repair” is a summary of the annual Neer Lecture that was delivered by Stephen S. Burkhart, MD, at the 2014 annual meeting of American Shoulder and Elbow Surgeons. It is a fascinating personal story of the 35-year evolution of arthroscopic rotator cuff surgery presented by one of the most respected arthroscopic innovators of our times. I especially enjoyed his apt citations of classic leaders—Churchill and Gandhi—but 3 points I believe deserve special comment.

First, Steve describes the challenges he faced bringing new products to market in the 1980s. How do we resolve the inherent conflict between innovation that introduces new technology and the “tried and true” standards of established practice? Do the hard work that Steve has done over the years: pose a hypothesis, design a study to answer the question, publish results in peer-reviewed journals, and embrace the techniques that demonstrate better outcomes for patients.

My second point relates to surgeon–device industry relationships, a subject of great interest to The American Journal of Orthopedics dating back to 2006.^1-3 Dr. Burkhart learned early on that he could not fashion new arthroscopic instruments in his garage. Nor could a company develop useful instruments without a knowledgeable surgeon’s input. Hence, a partnership between the innovator-surgeon and the device industry is essential to bring new and effective “tools” to market. Dr. Burkhart’s partnership with Arthrex has benefited many thousands of patients.

The agreements announced in 2007 between the US Department of Justice and 5 orthopedic device manufacturers (interestingly, current presidential candidate and Governor of New Jersey Chris Christie was the lead US Attorney on the case!) dramatically altered the surgeon–industry interaction and established strict guidelines that governed these relationships.⁴ These were needed reforms. However, the changes did not preclude an entrepreneurial surgeon with great ideas and a device manufacturer from profiting from excellent products that advanced patient care, provided, quoting from my editorial of 2006, “that these partnerships comply with legal and ethical standards” and are transparent as well as fully disclosed.¹

Finally, Steve’s last point focuses on the “burden of craft,” a topic dear to all orthopedic surgeons and our professional societies. All of us are committed to improving our surgical skills and, as a profession, we are consistently engaged in learning from our talented colleagues, who are only too willing to share their expertise. The burden of craft requires eager students and dedicated teachers, all committed to the same goal—better outcomes for our patients. We are indeed fortunate that, as orthopedic surgeons, we fundamentally support a culture of continued learning.

I thank Steve for his eloquent paper on this important principle.

“The Burden of Craft in Arthroscopic Rotator Cuff Repair” is a summary of the annual Neer Lecture that was delivered by Stephen S. Burkhart, MD, at the 2014 annual meeting of American Shoulder and Elbow Surgeons. It is a fascinating personal story of the 35-year evolution of arthroscopic rotator cuff surgery presented by one of the most respected arthroscopic innovators of our times. I especially enjoyed his apt citations of classic leaders—Churchill and Gandhi—but 3 points I believe deserve special comment.

First, Steve describes the challenges he faced bringing new products to market in the 1980s. How do we resolve the inherent conflict between innovation that introduces new technology and the “tried and true” standards of established practice? Do the hard work that Steve has done over the years: pose a hypothesis, design a study to answer the question, publish results in peer-reviewed journals, and embrace the techniques that demonstrate better outcomes for patients.

My second point relates to surgeon–device industry relationships, a subject of great interest to The American Journal of Orthopedics dating back to 2006.^1-3 Dr. Burkhart learned early on that he could not fashion new arthroscopic instruments in his garage. Nor could a company develop useful instruments without a knowledgeable surgeon’s input. Hence, a partnership between the innovator-surgeon and the device industry is essential to bring new and effective “tools” to market. Dr. Burkhart’s partnership with Arthrex has benefited many thousands of patients.

The agreements announced in 2007 between the US Department of Justice and 5 orthopedic device manufacturers (interestingly, current presidential candidate and Governor of New Jersey Chris Christie was the lead US Attorney on the case!) dramatically altered the surgeon–industry interaction and established strict guidelines that governed these relationships.⁴ These were needed reforms. However, the changes did not preclude an entrepreneurial surgeon with great ideas and a device manufacturer from profiting from excellent products that advanced patient care, provided, quoting from my editorial of 2006, “that these partnerships comply with legal and ethical standards” and are transparent as well as fully disclosed.¹

Finally, Steve’s last point focuses on the “burden of craft,” a topic dear to all orthopedic surgeons and our professional societies. All of us are committed to improving our surgical skills and, as a profession, we are consistently engaged in learning from our talented colleagues, who are only too willing to share their expertise. The burden of craft requires eager students and dedicated teachers, all committed to the same goal—better outcomes for our patients. We are indeed fortunate that, as orthopedic surgeons, we fundamentally support a culture of continued learning.

I thank Steve for his eloquent paper on this important principle.

“The Burden of Craft in Arthroscopic Rotator Cuff Repair” is a summary of the annual Neer Lecture that was delivered by Stephen S. Burkhart, MD, at the 2014 annual meeting of American Shoulder and Elbow Surgeons. It is a fascinating personal story of the 35-year evolution of arthroscopic rotator cuff surgery presented by one of the most respected arthroscopic innovators of our times. I especially enjoyed his apt citations of classic leaders—Churchill and Gandhi—but 3 points I believe deserve special comment.

First, Steve describes the challenges he faced bringing new products to market in the 1980s. How do we resolve the inherent conflict between innovation that introduces new technology and the “tried and true” standards of established practice? Do the hard work that Steve has done over the years: pose a hypothesis, design a study to answer the question, publish results in peer-reviewed journals, and embrace the techniques that demonstrate better outcomes for patients.

My second point relates to surgeon–device industry relationships, a subject of great interest to The American Journal of Orthopedics dating back to 2006.^1-3 Dr. Burkhart learned early on that he could not fashion new arthroscopic instruments in his garage. Nor could a company develop useful instruments without a knowledgeable surgeon’s input. Hence, a partnership between the innovator-surgeon and the device industry is essential to bring new and effective “tools” to market. Dr. Burkhart’s partnership with Arthrex has benefited many thousands of patients.

The agreements announced in 2007 between the US Department of Justice and 5 orthopedic device manufacturers (interestingly, current presidential candidate and Governor of New Jersey Chris Christie was the lead US Attorney on the case!) dramatically altered the surgeon–industry interaction and established strict guidelines that governed these relationships.⁴ These were needed reforms. However, the changes did not preclude an entrepreneurial surgeon with great ideas and a device manufacturer from profiting from excellent products that advanced patient care, provided, quoting from my editorial of 2006, “that these partnerships comply with legal and ethical standards” and are transparent as well as fully disclosed.¹

Finally, Steve’s last point focuses on the “burden of craft,” a topic dear to all orthopedic surgeons and our professional societies. All of us are committed to improving our surgical skills and, as a profession, we are consistently engaged in learning from our talented colleagues, who are only too willing to share their expertise. The burden of craft requires eager students and dedicated teachers, all committed to the same goal—better outcomes for our patients. We are indeed fortunate that, as orthopedic surgeons, we fundamentally support a culture of continued learning.

I thank Steve for his eloquent paper on this important principle.

For HIV-positive patients with Burkitt lymphoma, a modified intensive chemotherapy regimen produced overall and progression-free survival rates comparable with those seen in HIV-free patients with Burkitt, with manageable toxicities, reported researchers in a multicenter clinical trial.

The AIDS Malignancy Consortium (AMC) 048 study looked at the use of a modified version of the dose intensive CODOX-M/IVAC regimen, consisting of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine. Compared with the standard regimen, the investigators added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, limited the use of vincristine, and used combination intrathecal chemotherapy to prevent central nervous system involvement.

Courtesy Wikimedia Commons/Ed Uthman, MD/Creative Commons License

The study included 34 HIV-positive patients (30 men and 4 women) with Burkitt, 26 of whom were also receiving highly active antiretroviral therapy (HAART). The patients ranged in age from 19-55 (median 42) years. Of the 34 patients, 25 had Ann Arbor stage IV disease, 2 had stage III, 1 had stage IIE, 2 had stage II, and 4 had stage I. Median age was 42 years (range, 19-55 years).

The median CD4 count was 195 cells/mL; five patients had fewer than 100 cells/mL

Progression-free survival at 1 year was 69%, and 1- and 2-year overall survival were 72% and 69%, respectively.

The modified CODOX-M/IVAC regimen was associated with a grade 3 to 4 toxicity rate of 79%, with no grade 3 or 4 mucositis reported. In contrast, virtually all patients who receive the unmodified regimen develop at least one grade 3 or greater toxicity.

In total, there were 20 hematologic, 14 infectious, and 6 metabolic toxicities. Five patients did not complete treatment because of adverse events.

There were 11 deaths, including 1 treatment-related death of a patient with encephalopathy, hepatic failure, hepatitis B, and pneumonia cited as contributing causes. Of the remaining 10 patients, 8 died from systemic disease progression, and 2 died during follow-up, 1 during remission from a fungal infection and 1 from nonmalignant complications of HIV.

The investigators say that the addition of rituximab may have contributed to the favorable outcomes, and that rescheduling and limiting the amount of high-dose methotrexate delivered likely contributed to lower incidences of both severe mucositis and neutropenic fever.

Although a separate trial is evaluating a different regimen (EPOCH-R; etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in Burkitt lymphoma, “the modified AMC 048 version of CODOX-M/IVAC-R may better serve patients who present with CNS disease or are at high risk for CNS relapse (e.g., patients with bone marrow, testicular, or multiple extranodal sites), because it contains high-dose cytarabine and methotrexate, drugs that cross the blood-brain barrier. Consequently, AMC048 represents a reasonable treatment option in the appropriate setting, possibly irrespective of HIV status.”

The study by Dr. Ariela Noy from the Memorial Sloan Kettering Cancer Center in New York and her colleagues, is published in Blood.

For HIV-positive patients with Burkitt lymphoma, a modified intensive chemotherapy regimen produced overall and progression-free survival rates comparable with those seen in HIV-free patients with Burkitt, with manageable toxicities, reported researchers in a multicenter clinical trial.

The AIDS Malignancy Consortium (AMC) 048 study looked at the use of a modified version of the dose intensive CODOX-M/IVAC regimen, consisting of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine. Compared with the standard regimen, the investigators added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, limited the use of vincristine, and used combination intrathecal chemotherapy to prevent central nervous system involvement.

Courtesy Wikimedia Commons/Ed Uthman, MD/Creative Commons License

The study included 34 HIV-positive patients (30 men and 4 women) with Burkitt, 26 of whom were also receiving highly active antiretroviral therapy (HAART). The patients ranged in age from 19-55 (median 42) years. Of the 34 patients, 25 had Ann Arbor stage IV disease, 2 had stage III, 1 had stage IIE, 2 had stage II, and 4 had stage I. Median age was 42 years (range, 19-55 years).

The median CD4 count was 195 cells/mL; five patients had fewer than 100 cells/mL

Progression-free survival at 1 year was 69%, and 1- and 2-year overall survival were 72% and 69%, respectively.

The modified CODOX-M/IVAC regimen was associated with a grade 3 to 4 toxicity rate of 79%, with no grade 3 or 4 mucositis reported. In contrast, virtually all patients who receive the unmodified regimen develop at least one grade 3 or greater toxicity.

In total, there were 20 hematologic, 14 infectious, and 6 metabolic toxicities. Five patients did not complete treatment because of adverse events.

There were 11 deaths, including 1 treatment-related death of a patient with encephalopathy, hepatic failure, hepatitis B, and pneumonia cited as contributing causes. Of the remaining 10 patients, 8 died from systemic disease progression, and 2 died during follow-up, 1 during remission from a fungal infection and 1 from nonmalignant complications of HIV.

The investigators say that the addition of rituximab may have contributed to the favorable outcomes, and that rescheduling and limiting the amount of high-dose methotrexate delivered likely contributed to lower incidences of both severe mucositis and neutropenic fever.

Although a separate trial is evaluating a different regimen (EPOCH-R; etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in Burkitt lymphoma, “the modified AMC 048 version of CODOX-M/IVAC-R may better serve patients who present with CNS disease or are at high risk for CNS relapse (e.g., patients with bone marrow, testicular, or multiple extranodal sites), because it contains high-dose cytarabine and methotrexate, drugs that cross the blood-brain barrier. Consequently, AMC048 represents a reasonable treatment option in the appropriate setting, possibly irrespective of HIV status.”

The study by Dr. Ariela Noy from the Memorial Sloan Kettering Cancer Center in New York and her colleagues, is published in Blood.

For HIV-positive patients with Burkitt lymphoma, a modified intensive chemotherapy regimen produced overall and progression-free survival rates comparable with those seen in HIV-free patients with Burkitt, with manageable toxicities, reported researchers in a multicenter clinical trial.

The AIDS Malignancy Consortium (AMC) 048 study looked at the use of a modified version of the dose intensive CODOX-M/IVAC regimen, consisting of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine. Compared with the standard regimen, the investigators added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, limited the use of vincristine, and used combination intrathecal chemotherapy to prevent central nervous system involvement.

Courtesy Wikimedia Commons/Ed Uthman, MD/Creative Commons License

The study included 34 HIV-positive patients (30 men and 4 women) with Burkitt, 26 of whom were also receiving highly active antiretroviral therapy (HAART). The patients ranged in age from 19-55 (median 42) years. Of the 34 patients, 25 had Ann Arbor stage IV disease, 2 had stage III, 1 had stage IIE, 2 had stage II, and 4 had stage I. Median age was 42 years (range, 19-55 years).

The median CD4 count was 195 cells/mL; five patients had fewer than 100 cells/mL

Progression-free survival at 1 year was 69%, and 1- and 2-year overall survival were 72% and 69%, respectively.

The modified CODOX-M/IVAC regimen was associated with a grade 3 to 4 toxicity rate of 79%, with no grade 3 or 4 mucositis reported. In contrast, virtually all patients who receive the unmodified regimen develop at least one grade 3 or greater toxicity.

In total, there were 20 hematologic, 14 infectious, and 6 metabolic toxicities. Five patients did not complete treatment because of adverse events.

There were 11 deaths, including 1 treatment-related death of a patient with encephalopathy, hepatic failure, hepatitis B, and pneumonia cited as contributing causes. Of the remaining 10 patients, 8 died from systemic disease progression, and 2 died during follow-up, 1 during remission from a fungal infection and 1 from nonmalignant complications of HIV.

The investigators say that the addition of rituximab may have contributed to the favorable outcomes, and that rescheduling and limiting the amount of high-dose methotrexate delivered likely contributed to lower incidences of both severe mucositis and neutropenic fever.

Although a separate trial is evaluating a different regimen (EPOCH-R; etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in Burkitt lymphoma, “the modified AMC 048 version of CODOX-M/IVAC-R may better serve patients who present with CNS disease or are at high risk for CNS relapse (e.g., patients with bone marrow, testicular, or multiple extranodal sites), because it contains high-dose cytarabine and methotrexate, drugs that cross the blood-brain barrier. Consequently, AMC048 represents a reasonable treatment option in the appropriate setting, possibly irrespective of HIV status.”

The study by Dr. Ariela Noy from the Memorial Sloan Kettering Cancer Center in New York and her colleagues, is published in Blood.

CASE A fainting spell
Ms. A, age 13, is admitted to a pediatric unit after fainting and losing consciousness for 5 minutes in the shower, during which time she was non-responsive. She reports feeling nause­ated and having blurry vision before dropping to the floor.

Ms. A reports intentional self-restriction of calories, self-induced vomiting, and other purg­ing behaviors, such as laxative abuse and exces­sive exercising.

During the mental status examination, Ms. A is lying in bed wearing hospital clothes, legs flexed at the knee, hands on her side, and a fixed gaze at the ceiling with poor eye con­tact. She is of slender stature and tall, seems slightly older than her stated age, and is poorly groomed.

Throughout the interview, Ms. A has sig­nificant psychomotor retardation, reports her mood as tired, and has a blunted affect. She speaks at a low volume and has poverty of speech; she takes deep sighs before answer­ing questions. Her thought process is linear and she cooperates with the interview. She has poor recall, including delayed 3-minute recall and poor sustained attention. Her abstraction capacity is fair and her intellect is average and comparable with her age group. Ms. A is pre­occupied that eating will cause weight gain. She denies hallucinations but reports passive death wishes with self-harm by scratching.

What is the differential diagnosis to explain Ms. A’s presentation?
   a) syncope
   b) seizures
   c) dehydration
   d) hypotension

HISTORY Preoccupied with weight
Ms. A reports vomiting twice a day, while show­ering and at night when no one is around, every day for 2 months. She stopped eating and taking in fluids 3 days before admission to the medical unit. Also, she reports restricting her diet to 700 to 1,000 calories a day, skipping lunch at school, and eating minimally at night. Ms. A uses raspberry ketones and green coffee beans, which are adver­tised to aid weight loss, and laxative pills from her mother’s medicine cabinet once or twice a week when her throat is sore from vomiting. She reports exercising excessively, which includes running, crunches, and lifting weights. She has lost approximately 30 lb in the last 2 months.

Ms. A says she fears gaining weight and feels increased guilt after eating a meal. She said that looking at food induced “anxiety attack” symptoms of increased heart rate, sweaty palms, feeling of choking, nervousness, and shakiness. She adds that she does not want to be “bigger” than her classmates. Her under­standing of the consequences of not eating is, “It will get worse, I will shut down and die. I do not fear death, I only fear getting bigger than others.”

She reports that her fixation on avoiding food started when she realized that she was the tallest girl in her class and the only girl in her class running on the track team, after which she quit athletics. She reports that depression symptoms pre-dated her eating disorder symp­toms; onset of significant depression likely was precipitated by her grandfather’s death a year earlier, and then exacerbated by the recent death of a family pet.

Ms. A’s depressive symptoms are described as anhedonia (avoiding being outside and not enjoying drawing anymore), decreased energy, tearfulness, sadness, decreased con­centration, and passive suicidal thoughts. Her mother is supportive and motivates her daughter to “get better.” Ms. A denies any symptoms of psychosis, other anxiety symp­toms, other mood disorder symptoms, sub­stance abuse, or homicidality.

Ms. A’s mother says she felt that, recently, her daughter has been having some difficulty with confused thoughts and significantly delayed responses. However, the mother reports that her daughter always had some­what delayed responses from what she felt is typical. Her mother adds that Ms. A’s suicidal thoughts have worsened since her daughter started restricting her diet.

Which diagnosis likely accounts for Ms. A’s presentation?
   a) major depressive disorder (MDD)
   b) eating disorder, not otherwise specified (NOS)
   c) anorexia nervosa, purging type
   d) catatonia, unspecified
   e) anxiety disorder NOS
   f) cognitive disorder
   g) psychosis NOS

The authors’ observations
There are many reported causes of catatonia in children and adolescents, including those that are psychiatric, medical, or neurological, as well as drugs (Table 1).^1,2 Affective disor­ders have been associated with catatonia in adults, but has not been widely reported in children and adolescents.^1,3 Organic and neu­rologic causes, such as neurological tumors and cerebral hemorrhage, should be ruled out first because, although rare, they can be fatal (Table 2).² If the cause of catatonia is not recognized quickly (Figure,^1,2) effective treatment could be delayed.⁴

Presentation in adults and adolescents is similar.

An eating disorder could be comorbid with another psychiatric disorder, such as MDD, dysthymia, or panic disorder.⁵ Ms. A’s report of depression before she began restricting food favored a primary diagnosis of MDD. Her depressive symptoms of low appetite or low self-worth could have led to her preoccupation with body image.

There has been evidence that negative self-image and eating disorders are associ­ated, but data are limited and the connection remains unclear.⁶ Ms. A’s self-esteem was very low. Her fixation on restricting food could have been perpetuated by her self-criticism and by being excluded from her peer group in school. Her weight loss could have brought anxiety symptoms to the fore­front because of physiologic changes that accompany extreme weight loss.

The treatment team was concerned about her delayed responses, which could be explained by the catatonic features that reflected the severity of her depression. She had no obvious symptoms of psychosis, but her intrusive thoughts and obsessions with avoiding food did not completely rule out psychosis.

Childhood-onset schizophrenia, although rare, has been associated with catatonia; fol­lowing up with a catatonia rating scale, such as the Catatonia Rating Scale or the Bush- Francis Catatonia Rating Scale (BFCRS), would be useful for tracking symptom prog­ress. In Ms. A’s case, her mood disorder was primary, but did not rule out psychosis-like prodromal symptoms.⁷

Ms. A is diagnosed with MDD, single episode, severe, with catatonic features, and without psychosis, and eating disorder, NOS.

EVALUATION Mostly normal
Ms. A does not have a history of mental ill­ness and was not seeing a psychiatrist or therapist, nor did she have any prior psychi­atric admissions. She denies suicide attempts, but reports self-injurious behavior involving scratching her skin, which started during the current mood episode. She has never taken any psychotropic medications. Ms. A lives at home with her biological mother and father and 17-year-old brother. She attends middle school with average grades and has no his­tory of disciplinary actions. She has no his­tory of bullying or teasing, although she did report some previous difficulty with relational aggression toward her peers in the 5th grade. Her mother has a history of anorexia nervosa that began when she was a teenager, but these symptoms are stable and under control. There is additionally a family history of bipolar disorder.

Ms. A has a family history of coronary artery disease and diabetes in the mother and maternal relatives. Her grandfather died from liver cancer. She was allergic to sulfa drugs and was taking a multivitamin and minocycline for acne.

Physical examination reveals some super­ficial scratches but otherwise was within normal limits. Initial lab results reveal a nor­mal complete blood count and differential. Thyroid-stimulating hormone is 1.29 mIU/L and free T4 is 0.96 mg/dL, both within normal limits. Urinalysis is within normal limits and urine pregnancy test is negative. A compre­hensive metabolic panel shows mild elevation in aspartate aminotransferase (AST) at 60 U/L and alanine aminotransferase (ALT) at 92 U/L, respectively. Phosphorus level is within nor­mal limits. Prealbumin level is slightly low at 15.1 mg/dL.

Which treatment plan would you recommend for Ms. A?
   a) discharge with outpatient psychiatric treatment
   b) recommend medical stabilization with follow-up from the psychosomatic team and then outpatient psychiatric follow-up
   c) admit her to the psychiatric acute inpa­tient hospital with psychiatric outpatient discharge follow-up plan
   d) discharge her home with follow-up with her primary care physician
   e) recommend follow-up from the psycho­somatic team while on medical floor with acute inpatient admission and psychiatric outpatient follow-up at discharge

The authors’ observations
Scarcity of data and reporting of cases of ado­lescent catatonia limits guidance for diagno­sis and treatment.⁸ There are several rating scales with variability in definition, but that overall provide a guiding tool for detecting catatonia. The Brief Cognitive Rating Scale is considered the most versatile because it is more valid, reliable, and requires less time to complete than other rating scales.⁹

Ms. A’s symptoms were a combination of depressive symptoms with severity defined by catatonic features, eating disorder with worsening course, anxiety symptoms, and genetic loading of eating disorder in her mother. The challenge of this case was making an accurate diagnosis and treating Ms. A, which required continuous obser­vation following an eating disorder proto­col, resolution of her catatonia, resuming a normal diet, and decreasing her suicidality. Retrospectively, her scores on the BFCRS were high on screening items 1 to 14, which measure presence or absence and severity of symptoms.

The best option was to admit Ms. A to an inpatient psychiatric facility after she is cleared medically with outpatient services to follow up.

How would you treat Ms. A’s symptoms?
   a) aggressively treat catatonia
   b) address her eating disorder
   c) work to resolve her depression

The authors’ observations
The challenge was to choose the psycho­tropic medication that would target her depression, obsessive, rigid thoughts, and catatonia. Administering an antidepressant with an antipsychotic would have relieved her depressive and obsessive symptoms but would not have improved her catato­nia. The psychosomatic medicine team rec­ommended starting a selective serotonin reuptake inhibitor and a benzodiazepine to target both the depression and the cata­tonic symptoms. Ms. A received sertraline, 12.5 mg/d, which was increased to 25 mg/d on the third day. IV lorazepam, 1 mg, 3 times a day, was recommended but the pediatric team prescribed an oral formulation. The hospital’s eating disorder protocol was insti­tuted on the day of admission.

Treatment options for catatonia
Benzodiazepines are the first line of treat­ment for catatonia and other neurolep­tics, specifically antipsychotics, have been considered dangerous.¹⁰ Benzodiazepine-resistant catatonia, which is sometimes seen in patients with autism, might respond to electroconvulsive therapy (ECT),¹¹ although in some states it cannot be administered to children age <18.¹² Benzodiazepines have shown dramatic improvement within hours, as has ECT.^8,13 Additionally, if patients do not respond to a benzodiazepine or ECT, con­sider other options such as zolpidem, olan­zapine,¹⁴ or sensory integration system (in adolescents with autism).¹⁵

Ms. A did not need ECT or an alternative treatment because she responded well to 3 doses of oral lorazepam. Her amotivation, negativism, and rigidity with prolonged posturing improved. Her psychomotor retardation improved overall, although she reported some dizziness and had some pos­tural hypotension, which was attributed to her eating issues and dehydration.

OUTCOME Feeling motivated
Ms. A is transferred to psychiatric inpatient unit. She tolerates sertraline, which is titrated to 50 mg/d. She is placed on the hospital’s standard eating disorder protocol. She con­tinues to eat well with adequate intake of solids and liquid and exhibits only some anxi­ety associated with meals. During the course of hospitalization, she attends group therapy and her catatonic symptoms completely resolve. She says she thinks that her thoughts are improving and that she is not longer feel­ing confused. She reports being motivated to continue to improve her eating disorder symptoms.

The treatment team holds a family session during which family dynamic issues that are stressful to Ms. A are discussed, such as some conflict with her parents as well as some nega­tive interactions between Ms. A and her father. Repeat comprehensive metabolic panel on admission to the inpatient psychiatric hospital reveals persistent elevation of AST at 92 U/L and ALT at 143 U/L. Ms. A is discharged home with follow-up with a psychiatrist and a thera­pist. The treatment team also recommends that she follow up in a program that special­izes in eating disorders.

4-month follow-up. Ms. A returns to inpa­tient psychiatric hospital after overdose of ser­traline and aripiprazole, which were started by an outpatient psychiatrist. She reports severe depressive symptoms because of school stressors. She denies any problems eating and did not show any symptoms of catato­nia. In her chart, there is a mention of “cloudy thoughts” and quietness. At this admission, her ALT is 17 U/L and AST is 19 U/L. Sertraline is increased to 150 mg/d and aripiprazole is reduced to 2 mg/d and then later increased to 5 mg/d, after which she is discharged home with an outpatient psychiatric follow-up.

1-year follow-up. Ms. A has been follow­ing up with an outpatient psychiatrist and is receiving sertraline, 150 mg/d, aripiprazole, 2.5 mg/d, and extended-release methylphe­nidate, 36 mg/d, along with L-methylfolate, multivitamins, and omega-3 fish oil as adju­vants for her depressive symptoms. Ms. A does not show symptoms of an eating disorder or catatonia, and her depression and psychomo­tor activity have improved, with better overall functionality, after adding the stimulant and adjunctives to the antidepressant.

The authors’ observations
The importance of including catatonia NOS with its various specifiers, such as medi­cal, metabolic, toxic, affective, etc., has been discussed.^16,17 In Ms. A’s case, instead of treating the specific symptoms—affective or eating disorder or obsessive quality of thought content, mimicking psychotic-like symptoms—addressing the catatonia ini­tially had a better outcome. More studies related to chronic and acute catatonia in adolescents are needed because of the risk of increased morbidity and premature death.¹⁸ Early recognition of catatonia is needed¹⁹ because it often is underdiagnosed.²⁰

Eating disorders often become worse over the first 5 years, and close monitoring and assessment is needed for adolescents.²¹ Also, prodromal psychotic symptoms require follow-up because techniques for early detection and intervention for children and adolescents are still in their infancy.²²

Bottom Line
Catatonia in adolescents should be addressed early, when it is treatable and the outcome is favorable. It is important to recognize catatonia in an emergency department or inpatient medical unit setting in a hospital because it is often underdiagnosed or misdiagnosed. The presentation of catatonia is similar in adolescents and adults. Benzodiazepines are first-line treatment for catatonia; consider electroconvulsive therapy if patients do not respond to drug therapy.

Related Resources
• Roberto AJ, Pinnaka S, Mohan A, et al. Adolescent catatonia successfully treated with lorazepam and aripiprazole. Case Rep Psychiatry. 2014;2014:309517. doi: 10.1155/2014/309517.
• Raffin M, Zugaj-Bensaou L, Bodeau N, et al. Treatment use in a prospective naturalistic cohort of children and adolescents with catatonia. Eur Child Adolesc Psychiatry. 2015;24(4):441-449.

Drug Brand Names
Aripiprazole • Abilify                                  Minocycline • Minocin
L-methylfolate • Deplin                              Olanzapine • Zyprexa
Lorazepam • Ativan                                   Sertraline • Zoloft
Methylphenidate • Ritalin,  Concerta          Zolpidem • Ambien, Intermezzo

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

CASE A fainting spell
Ms. A, age 13, is admitted to a pediatric unit after fainting and losing consciousness for 5 minutes in the shower, during which time she was non-responsive. She reports feeling nause­ated and having blurry vision before dropping to the floor.

Ms. A reports intentional self-restriction of calories, self-induced vomiting, and other purg­ing behaviors, such as laxative abuse and exces­sive exercising.

During the mental status examination, Ms. A is lying in bed wearing hospital clothes, legs flexed at the knee, hands on her side, and a fixed gaze at the ceiling with poor eye con­tact. She is of slender stature and tall, seems slightly older than her stated age, and is poorly groomed.

Throughout the interview, Ms. A has sig­nificant psychomotor retardation, reports her mood as tired, and has a blunted affect. She speaks at a low volume and has poverty of speech; she takes deep sighs before answer­ing questions. Her thought process is linear and she cooperates with the interview. She has poor recall, including delayed 3-minute recall and poor sustained attention. Her abstraction capacity is fair and her intellect is average and comparable with her age group. Ms. A is pre­occupied that eating will cause weight gain. She denies hallucinations but reports passive death wishes with self-harm by scratching.

What is the differential diagnosis to explain Ms. A’s presentation?
   a) syncope
   b) seizures
   c) dehydration
   d) hypotension

HISTORY Preoccupied with weight
Ms. A reports vomiting twice a day, while show­ering and at night when no one is around, every day for 2 months. She stopped eating and taking in fluids 3 days before admission to the medical unit. Also, she reports restricting her diet to 700 to 1,000 calories a day, skipping lunch at school, and eating minimally at night. Ms. A uses raspberry ketones and green coffee beans, which are adver­tised to aid weight loss, and laxative pills from her mother’s medicine cabinet once or twice a week when her throat is sore from vomiting. She reports exercising excessively, which includes running, crunches, and lifting weights. She has lost approximately 30 lb in the last 2 months.

Ms. A says she fears gaining weight and feels increased guilt after eating a meal. She said that looking at food induced “anxiety attack” symptoms of increased heart rate, sweaty palms, feeling of choking, nervousness, and shakiness. She adds that she does not want to be “bigger” than her classmates. Her under­standing of the consequences of not eating is, “It will get worse, I will shut down and die. I do not fear death, I only fear getting bigger than others.”

She reports that her fixation on avoiding food started when she realized that she was the tallest girl in her class and the only girl in her class running on the track team, after which she quit athletics. She reports that depression symptoms pre-dated her eating disorder symp­toms; onset of significant depression likely was precipitated by her grandfather’s death a year earlier, and then exacerbated by the recent death of a family pet.

Ms. A’s depressive symptoms are described as anhedonia (avoiding being outside and not enjoying drawing anymore), decreased energy, tearfulness, sadness, decreased con­centration, and passive suicidal thoughts. Her mother is supportive and motivates her daughter to “get better.” Ms. A denies any symptoms of psychosis, other anxiety symp­toms, other mood disorder symptoms, sub­stance abuse, or homicidality.

Ms. A’s mother says she felt that, recently, her daughter has been having some difficulty with confused thoughts and significantly delayed responses. However, the mother reports that her daughter always had some­what delayed responses from what she felt is typical. Her mother adds that Ms. A’s suicidal thoughts have worsened since her daughter started restricting her diet.

Which diagnosis likely accounts for Ms. A’s presentation?
   a) major depressive disorder (MDD)
   b) eating disorder, not otherwise specified (NOS)
   c) anorexia nervosa, purging type
   d) catatonia, unspecified
   e) anxiety disorder NOS
   f) cognitive disorder
   g) psychosis NOS

The authors’ observations
There are many reported causes of catatonia in children and adolescents, including those that are psychiatric, medical, or neurological, as well as drugs (Table 1).^1,2 Affective disor­ders have been associated with catatonia in adults, but has not been widely reported in children and adolescents.^1,3 Organic and neu­rologic causes, such as neurological tumors and cerebral hemorrhage, should be ruled out first because, although rare, they can be fatal (Table 2).² If the cause of catatonia is not recognized quickly (Figure,^1,2) effective treatment could be delayed.⁴

Presentation in adults and adolescents is similar.

An eating disorder could be comorbid with another psychiatric disorder, such as MDD, dysthymia, or panic disorder.⁵ Ms. A’s report of depression before she began restricting food favored a primary diagnosis of MDD. Her depressive symptoms of low appetite or low self-worth could have led to her preoccupation with body image.

There has been evidence that negative self-image and eating disorders are associ­ated, but data are limited and the connection remains unclear.⁶ Ms. A’s self-esteem was very low. Her fixation on restricting food could have been perpetuated by her self-criticism and by being excluded from her peer group in school. Her weight loss could have brought anxiety symptoms to the fore­front because of physiologic changes that accompany extreme weight loss.

The treatment team was concerned about her delayed responses, which could be explained by the catatonic features that reflected the severity of her depression. She had no obvious symptoms of psychosis, but her intrusive thoughts and obsessions with avoiding food did not completely rule out psychosis.

Childhood-onset schizophrenia, although rare, has been associated with catatonia; fol­lowing up with a catatonia rating scale, such as the Catatonia Rating Scale or the Bush- Francis Catatonia Rating Scale (BFCRS), would be useful for tracking symptom prog­ress. In Ms. A’s case, her mood disorder was primary, but did not rule out psychosis-like prodromal symptoms.⁷

Ms. A is diagnosed with MDD, single episode, severe, with catatonic features, and without psychosis, and eating disorder, NOS.

EVALUATION Mostly normal
Ms. A does not have a history of mental ill­ness and was not seeing a psychiatrist or therapist, nor did she have any prior psychi­atric admissions. She denies suicide attempts, but reports self-injurious behavior involving scratching her skin, which started during the current mood episode. She has never taken any psychotropic medications. Ms. A lives at home with her biological mother and father and 17-year-old brother. She attends middle school with average grades and has no his­tory of disciplinary actions. She has no his­tory of bullying or teasing, although she did report some previous difficulty with relational aggression toward her peers in the 5th grade. Her mother has a history of anorexia nervosa that began when she was a teenager, but these symptoms are stable and under control. There is additionally a family history of bipolar disorder.

Ms. A has a family history of coronary artery disease and diabetes in the mother and maternal relatives. Her grandfather died from liver cancer. She was allergic to sulfa drugs and was taking a multivitamin and minocycline for acne.

Physical examination reveals some super­ficial scratches but otherwise was within normal limits. Initial lab results reveal a nor­mal complete blood count and differential. Thyroid-stimulating hormone is 1.29 mIU/L and free T4 is 0.96 mg/dL, both within normal limits. Urinalysis is within normal limits and urine pregnancy test is negative. A compre­hensive metabolic panel shows mild elevation in aspartate aminotransferase (AST) at 60 U/L and alanine aminotransferase (ALT) at 92 U/L, respectively. Phosphorus level is within nor­mal limits. Prealbumin level is slightly low at 15.1 mg/dL.

Which treatment plan would you recommend for Ms. A?
   a) discharge with outpatient psychiatric treatment
   b) recommend medical stabilization with follow-up from the psychosomatic team and then outpatient psychiatric follow-up
   c) admit her to the psychiatric acute inpa­tient hospital with psychiatric outpatient discharge follow-up plan
   d) discharge her home with follow-up with her primary care physician
   e) recommend follow-up from the psycho­somatic team while on medical floor with acute inpatient admission and psychiatric outpatient follow-up at discharge

The authors’ observations
Scarcity of data and reporting of cases of ado­lescent catatonia limits guidance for diagno­sis and treatment.⁸ There are several rating scales with variability in definition, but that overall provide a guiding tool for detecting catatonia. The Brief Cognitive Rating Scale is considered the most versatile because it is more valid, reliable, and requires less time to complete than other rating scales.⁹

Ms. A’s symptoms were a combination of depressive symptoms with severity defined by catatonic features, eating disorder with worsening course, anxiety symptoms, and genetic loading of eating disorder in her mother. The challenge of this case was making an accurate diagnosis and treating Ms. A, which required continuous obser­vation following an eating disorder proto­col, resolution of her catatonia, resuming a normal diet, and decreasing her suicidality. Retrospectively, her scores on the BFCRS were high on screening items 1 to 14, which measure presence or absence and severity of symptoms.

The best option was to admit Ms. A to an inpatient psychiatric facility after she is cleared medically with outpatient services to follow up.

How would you treat Ms. A’s symptoms?
   a) aggressively treat catatonia
   b) address her eating disorder
   c) work to resolve her depression

The authors’ observations
The challenge was to choose the psycho­tropic medication that would target her depression, obsessive, rigid thoughts, and catatonia. Administering an antidepressant with an antipsychotic would have relieved her depressive and obsessive symptoms but would not have improved her catato­nia. The psychosomatic medicine team rec­ommended starting a selective serotonin reuptake inhibitor and a benzodiazepine to target both the depression and the cata­tonic symptoms. Ms. A received sertraline, 12.5 mg/d, which was increased to 25 mg/d on the third day. IV lorazepam, 1 mg, 3 times a day, was recommended but the pediatric team prescribed an oral formulation. The hospital’s eating disorder protocol was insti­tuted on the day of admission.

Treatment options for catatonia
Benzodiazepines are the first line of treat­ment for catatonia and other neurolep­tics, specifically antipsychotics, have been considered dangerous.¹⁰ Benzodiazepine-resistant catatonia, which is sometimes seen in patients with autism, might respond to electroconvulsive therapy (ECT),¹¹ although in some states it cannot be administered to children age <18.¹² Benzodiazepines have shown dramatic improvement within hours, as has ECT.^8,13 Additionally, if patients do not respond to a benzodiazepine or ECT, con­sider other options such as zolpidem, olan­zapine,¹⁴ or sensory integration system (in adolescents with autism).¹⁵

Ms. A did not need ECT or an alternative treatment because she responded well to 3 doses of oral lorazepam. Her amotivation, negativism, and rigidity with prolonged posturing improved. Her psychomotor retardation improved overall, although she reported some dizziness and had some pos­tural hypotension, which was attributed to her eating issues and dehydration.

OUTCOME Feeling motivated
Ms. A is transferred to psychiatric inpatient unit. She tolerates sertraline, which is titrated to 50 mg/d. She is placed on the hospital’s standard eating disorder protocol. She con­tinues to eat well with adequate intake of solids and liquid and exhibits only some anxi­ety associated with meals. During the course of hospitalization, she attends group therapy and her catatonic symptoms completely resolve. She says she thinks that her thoughts are improving and that she is not longer feel­ing confused. She reports being motivated to continue to improve her eating disorder symptoms.

The treatment team holds a family session during which family dynamic issues that are stressful to Ms. A are discussed, such as some conflict with her parents as well as some nega­tive interactions between Ms. A and her father. Repeat comprehensive metabolic panel on admission to the inpatient psychiatric hospital reveals persistent elevation of AST at 92 U/L and ALT at 143 U/L. Ms. A is discharged home with follow-up with a psychiatrist and a thera­pist. The treatment team also recommends that she follow up in a program that special­izes in eating disorders.

4-month follow-up. Ms. A returns to inpa­tient psychiatric hospital after overdose of ser­traline and aripiprazole, which were started by an outpatient psychiatrist. She reports severe depressive symptoms because of school stressors. She denies any problems eating and did not show any symptoms of catato­nia. In her chart, there is a mention of “cloudy thoughts” and quietness. At this admission, her ALT is 17 U/L and AST is 19 U/L. Sertraline is increased to 150 mg/d and aripiprazole is reduced to 2 mg/d and then later increased to 5 mg/d, after which she is discharged home with an outpatient psychiatric follow-up.

1-year follow-up. Ms. A has been follow­ing up with an outpatient psychiatrist and is receiving sertraline, 150 mg/d, aripiprazole, 2.5 mg/d, and extended-release methylphe­nidate, 36 mg/d, along with L-methylfolate, multivitamins, and omega-3 fish oil as adju­vants for her depressive symptoms. Ms. A does not show symptoms of an eating disorder or catatonia, and her depression and psychomo­tor activity have improved, with better overall functionality, after adding the stimulant and adjunctives to the antidepressant.

The authors’ observations
The importance of including catatonia NOS with its various specifiers, such as medi­cal, metabolic, toxic, affective, etc., has been discussed.^16,17 In Ms. A’s case, instead of treating the specific symptoms—affective or eating disorder or obsessive quality of thought content, mimicking psychotic-like symptoms—addressing the catatonia ini­tially had a better outcome. More studies related to chronic and acute catatonia in adolescents are needed because of the risk of increased morbidity and premature death.¹⁸ Early recognition of catatonia is needed¹⁹ because it often is underdiagnosed.²⁰

Eating disorders often become worse over the first 5 years, and close monitoring and assessment is needed for adolescents.²¹ Also, prodromal psychotic symptoms require follow-up because techniques for early detection and intervention for children and adolescents are still in their infancy.²²

Bottom Line
Catatonia in adolescents should be addressed early, when it is treatable and the outcome is favorable. It is important to recognize catatonia in an emergency department or inpatient medical unit setting in a hospital because it is often underdiagnosed or misdiagnosed. The presentation of catatonia is similar in adolescents and adults. Benzodiazepines are first-line treatment for catatonia; consider electroconvulsive therapy if patients do not respond to drug therapy.

Related Resources
• Roberto AJ, Pinnaka S, Mohan A, et al. Adolescent catatonia successfully treated with lorazepam and aripiprazole. Case Rep Psychiatry. 2014;2014:309517. doi: 10.1155/2014/309517.
• Raffin M, Zugaj-Bensaou L, Bodeau N, et al. Treatment use in a prospective naturalistic cohort of children and adolescents with catatonia. Eur Child Adolesc Psychiatry. 2015;24(4):441-449.

Drug Brand Names
Aripiprazole • Abilify                                  Minocycline • Minocin
L-methylfolate • Deplin                              Olanzapine • Zyprexa
Lorazepam • Ativan                                   Sertraline • Zoloft
Methylphenidate • Ritalin,  Concerta          Zolpidem • Ambien, Intermezzo

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

CASE A fainting spell
Ms. A, age 13, is admitted to a pediatric unit after fainting and losing consciousness for 5 minutes in the shower, during which time she was non-responsive. She reports feeling nause­ated and having blurry vision before dropping to the floor.

Ms. A reports intentional self-restriction of calories, self-induced vomiting, and other purg­ing behaviors, such as laxative abuse and exces­sive exercising.

During the mental status examination, Ms. A is lying in bed wearing hospital clothes, legs flexed at the knee, hands on her side, and a fixed gaze at the ceiling with poor eye con­tact. She is of slender stature and tall, seems slightly older than her stated age, and is poorly groomed.

Throughout the interview, Ms. A has sig­nificant psychomotor retardation, reports her mood as tired, and has a blunted affect. She speaks at a low volume and has poverty of speech; she takes deep sighs before answer­ing questions. Her thought process is linear and she cooperates with the interview. She has poor recall, including delayed 3-minute recall and poor sustained attention. Her abstraction capacity is fair and her intellect is average and comparable with her age group. Ms. A is pre­occupied that eating will cause weight gain. She denies hallucinations but reports passive death wishes with self-harm by scratching.

What is the differential diagnosis to explain Ms. A’s presentation?
   a) syncope
   b) seizures
   c) dehydration
   d) hypotension

HISTORY Preoccupied with weight
Ms. A reports vomiting twice a day, while show­ering and at night when no one is around, every day for 2 months. She stopped eating and taking in fluids 3 days before admission to the medical unit. Also, she reports restricting her diet to 700 to 1,000 calories a day, skipping lunch at school, and eating minimally at night. Ms. A uses raspberry ketones and green coffee beans, which are adver­tised to aid weight loss, and laxative pills from her mother’s medicine cabinet once or twice a week when her throat is sore from vomiting. She reports exercising excessively, which includes running, crunches, and lifting weights. She has lost approximately 30 lb in the last 2 months.

Ms. A says she fears gaining weight and feels increased guilt after eating a meal. She said that looking at food induced “anxiety attack” symptoms of increased heart rate, sweaty palms, feeling of choking, nervousness, and shakiness. She adds that she does not want to be “bigger” than her classmates. Her under­standing of the consequences of not eating is, “It will get worse, I will shut down and die. I do not fear death, I only fear getting bigger than others.”

She reports that her fixation on avoiding food started when she realized that she was the tallest girl in her class and the only girl in her class running on the track team, after which she quit athletics. She reports that depression symptoms pre-dated her eating disorder symp­toms; onset of significant depression likely was precipitated by her grandfather’s death a year earlier, and then exacerbated by the recent death of a family pet.

Ms. A’s depressive symptoms are described as anhedonia (avoiding being outside and not enjoying drawing anymore), decreased energy, tearfulness, sadness, decreased con­centration, and passive suicidal thoughts. Her mother is supportive and motivates her daughter to “get better.” Ms. A denies any symptoms of psychosis, other anxiety symp­toms, other mood disorder symptoms, sub­stance abuse, or homicidality.

Ms. A’s mother says she felt that, recently, her daughter has been having some difficulty with confused thoughts and significantly delayed responses. However, the mother reports that her daughter always had some­what delayed responses from what she felt is typical. Her mother adds that Ms. A’s suicidal thoughts have worsened since her daughter started restricting her diet.

Which diagnosis likely accounts for Ms. A’s presentation?
   a) major depressive disorder (MDD)
   b) eating disorder, not otherwise specified (NOS)
   c) anorexia nervosa, purging type
   d) catatonia, unspecified
   e) anxiety disorder NOS
   f) cognitive disorder
   g) psychosis NOS

The authors’ observations
There are many reported causes of catatonia in children and adolescents, including those that are psychiatric, medical, or neurological, as well as drugs (Table 1).^1,2 Affective disor­ders have been associated with catatonia in adults, but has not been widely reported in children and adolescents.^1,3 Organic and neu­rologic causes, such as neurological tumors and cerebral hemorrhage, should be ruled out first because, although rare, they can be fatal (Table 2).² If the cause of catatonia is not recognized quickly (Figure,^1,2) effective treatment could be delayed.⁴

Presentation in adults and adolescents is similar.

An eating disorder could be comorbid with another psychiatric disorder, such as MDD, dysthymia, or panic disorder.⁵ Ms. A’s report of depression before she began restricting food favored a primary diagnosis of MDD. Her depressive symptoms of low appetite or low self-worth could have led to her preoccupation with body image.

There has been evidence that negative self-image and eating disorders are associ­ated, but data are limited and the connection remains unclear.⁶ Ms. A’s self-esteem was very low. Her fixation on restricting food could have been perpetuated by her self-criticism and by being excluded from her peer group in school. Her weight loss could have brought anxiety symptoms to the fore­front because of physiologic changes that accompany extreme weight loss.

The treatment team was concerned about her delayed responses, which could be explained by the catatonic features that reflected the severity of her depression. She had no obvious symptoms of psychosis, but her intrusive thoughts and obsessions with avoiding food did not completely rule out psychosis.

Childhood-onset schizophrenia, although rare, has been associated with catatonia; fol­lowing up with a catatonia rating scale, such as the Catatonia Rating Scale or the Bush- Francis Catatonia Rating Scale (BFCRS), would be useful for tracking symptom prog­ress. In Ms. A’s case, her mood disorder was primary, but did not rule out psychosis-like prodromal symptoms.⁷

Ms. A is diagnosed with MDD, single episode, severe, with catatonic features, and without psychosis, and eating disorder, NOS.

EVALUATION Mostly normal
Ms. A does not have a history of mental ill­ness and was not seeing a psychiatrist or therapist, nor did she have any prior psychi­atric admissions. She denies suicide attempts, but reports self-injurious behavior involving scratching her skin, which started during the current mood episode. She has never taken any psychotropic medications. Ms. A lives at home with her biological mother and father and 17-year-old brother. She attends middle school with average grades and has no his­tory of disciplinary actions. She has no his­tory of bullying or teasing, although she did report some previous difficulty with relational aggression toward her peers in the 5th grade. Her mother has a history of anorexia nervosa that began when she was a teenager, but these symptoms are stable and under control. There is additionally a family history of bipolar disorder.

Ms. A has a family history of coronary artery disease and diabetes in the mother and maternal relatives. Her grandfather died from liver cancer. She was allergic to sulfa drugs and was taking a multivitamin and minocycline for acne.

Physical examination reveals some super­ficial scratches but otherwise was within normal limits. Initial lab results reveal a nor­mal complete blood count and differential. Thyroid-stimulating hormone is 1.29 mIU/L and free T4 is 0.96 mg/dL, both within normal limits. Urinalysis is within normal limits and urine pregnancy test is negative. A compre­hensive metabolic panel shows mild elevation in aspartate aminotransferase (AST) at 60 U/L and alanine aminotransferase (ALT) at 92 U/L, respectively. Phosphorus level is within nor­mal limits. Prealbumin level is slightly low at 15.1 mg/dL.

Which treatment plan would you recommend for Ms. A?
   a) discharge with outpatient psychiatric treatment
   b) recommend medical stabilization with follow-up from the psychosomatic team and then outpatient psychiatric follow-up
   c) admit her to the psychiatric acute inpa­tient hospital with psychiatric outpatient discharge follow-up plan
   d) discharge her home with follow-up with her primary care physician
   e) recommend follow-up from the psycho­somatic team while on medical floor with acute inpatient admission and psychiatric outpatient follow-up at discharge

The authors’ observations
Scarcity of data and reporting of cases of ado­lescent catatonia limits guidance for diagno­sis and treatment.⁸ There are several rating scales with variability in definition, but that overall provide a guiding tool for detecting catatonia. The Brief Cognitive Rating Scale is considered the most versatile because it is more valid, reliable, and requires less time to complete than other rating scales.⁹

Ms. A’s symptoms were a combination of depressive symptoms with severity defined by catatonic features, eating disorder with worsening course, anxiety symptoms, and genetic loading of eating disorder in her mother. The challenge of this case was making an accurate diagnosis and treating Ms. A, which required continuous obser­vation following an eating disorder proto­col, resolution of her catatonia, resuming a normal diet, and decreasing her suicidality. Retrospectively, her scores on the BFCRS were high on screening items 1 to 14, which measure presence or absence and severity of symptoms.

The best option was to admit Ms. A to an inpatient psychiatric facility after she is cleared medically with outpatient services to follow up.

How would you treat Ms. A’s symptoms?
   a) aggressively treat catatonia
   b) address her eating disorder
   c) work to resolve her depression

The authors’ observations
The challenge was to choose the psycho­tropic medication that would target her depression, obsessive, rigid thoughts, and catatonia. Administering an antidepressant with an antipsychotic would have relieved her depressive and obsessive symptoms but would not have improved her catato­nia. The psychosomatic medicine team rec­ommended starting a selective serotonin reuptake inhibitor and a benzodiazepine to target both the depression and the cata­tonic symptoms. Ms. A received sertraline, 12.5 mg/d, which was increased to 25 mg/d on the third day. IV lorazepam, 1 mg, 3 times a day, was recommended but the pediatric team prescribed an oral formulation. The hospital’s eating disorder protocol was insti­tuted on the day of admission.

Treatment options for catatonia
Benzodiazepines are the first line of treat­ment for catatonia and other neurolep­tics, specifically antipsychotics, have been considered dangerous.¹⁰ Benzodiazepine-resistant catatonia, which is sometimes seen in patients with autism, might respond to electroconvulsive therapy (ECT),¹¹ although in some states it cannot be administered to children age <18.¹² Benzodiazepines have shown dramatic improvement within hours, as has ECT.^8,13 Additionally, if patients do not respond to a benzodiazepine or ECT, con­sider other options such as zolpidem, olan­zapine,¹⁴ or sensory integration system (in adolescents with autism).¹⁵

Ms. A did not need ECT or an alternative treatment because she responded well to 3 doses of oral lorazepam. Her amotivation, negativism, and rigidity with prolonged posturing improved. Her psychomotor retardation improved overall, although she reported some dizziness and had some pos­tural hypotension, which was attributed to her eating issues and dehydration.

OUTCOME Feeling motivated
Ms. A is transferred to psychiatric inpatient unit. She tolerates sertraline, which is titrated to 50 mg/d. She is placed on the hospital’s standard eating disorder protocol. She con­tinues to eat well with adequate intake of solids and liquid and exhibits only some anxi­ety associated with meals. During the course of hospitalization, she attends group therapy and her catatonic symptoms completely resolve. She says she thinks that her thoughts are improving and that she is not longer feel­ing confused. She reports being motivated to continue to improve her eating disorder symptoms.

The treatment team holds a family session during which family dynamic issues that are stressful to Ms. A are discussed, such as some conflict with her parents as well as some nega­tive interactions between Ms. A and her father. Repeat comprehensive metabolic panel on admission to the inpatient psychiatric hospital reveals persistent elevation of AST at 92 U/L and ALT at 143 U/L. Ms. A is discharged home with follow-up with a psychiatrist and a thera­pist. The treatment team also recommends that she follow up in a program that special­izes in eating disorders.

4-month follow-up. Ms. A returns to inpa­tient psychiatric hospital after overdose of ser­traline and aripiprazole, which were started by an outpatient psychiatrist. She reports severe depressive symptoms because of school stressors. She denies any problems eating and did not show any symptoms of catato­nia. In her chart, there is a mention of “cloudy thoughts” and quietness. At this admission, her ALT is 17 U/L and AST is 19 U/L. Sertraline is increased to 150 mg/d and aripiprazole is reduced to 2 mg/d and then later increased to 5 mg/d, after which she is discharged home with an outpatient psychiatric follow-up.

1-year follow-up. Ms. A has been follow­ing up with an outpatient psychiatrist and is receiving sertraline, 150 mg/d, aripiprazole, 2.5 mg/d, and extended-release methylphe­nidate, 36 mg/d, along with L-methylfolate, multivitamins, and omega-3 fish oil as adju­vants for her depressive symptoms. Ms. A does not show symptoms of an eating disorder or catatonia, and her depression and psychomo­tor activity have improved, with better overall functionality, after adding the stimulant and adjunctives to the antidepressant.

The authors’ observations
The importance of including catatonia NOS with its various specifiers, such as medi­cal, metabolic, toxic, affective, etc., has been discussed.^16,17 In Ms. A’s case, instead of treating the specific symptoms—affective or eating disorder or obsessive quality of thought content, mimicking psychotic-like symptoms—addressing the catatonia ini­tially had a better outcome. More studies related to chronic and acute catatonia in adolescents are needed because of the risk of increased morbidity and premature death.¹⁸ Early recognition of catatonia is needed¹⁹ because it often is underdiagnosed.²⁰

Eating disorders often become worse over the first 5 years, and close monitoring and assessment is needed for adolescents.²¹ Also, prodromal psychotic symptoms require follow-up because techniques for early detection and intervention for children and adolescents are still in their infancy.²²

Bottom Line
Catatonia in adolescents should be addressed early, when it is treatable and the outcome is favorable. It is important to recognize catatonia in an emergency department or inpatient medical unit setting in a hospital because it is often underdiagnosed or misdiagnosed. The presentation of catatonia is similar in adolescents and adults. Benzodiazepines are first-line treatment for catatonia; consider electroconvulsive therapy if patients do not respond to drug therapy.

Related Resources
• Roberto AJ, Pinnaka S, Mohan A, et al. Adolescent catatonia successfully treated with lorazepam and aripiprazole. Case Rep Psychiatry. 2014;2014:309517. doi: 10.1155/2014/309517.
• Raffin M, Zugaj-Bensaou L, Bodeau N, et al. Treatment use in a prospective naturalistic cohort of children and adolescents with catatonia. Eur Child Adolesc Psychiatry. 2015;24(4):441-449.

Drug Brand Names
Aripiprazole • Abilify                                  Minocycline • Minocin
L-methylfolate • Deplin                              Olanzapine • Zyprexa
Lorazepam • Ativan                                   Sertraline • Zoloft
Methylphenidate • Ritalin,  Concerta          Zolpidem • Ambien, Intermezzo

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