Watchman device

Photo courtesy of

Boston Scientific

Researchers have compared the cost-effectiveness of left atrial appendage closure (LAAC) with the Watchman device to treatment with warfarin or novel oral anticoagulants (NOACs) as stroke prophylaxis in patients with non-valvular atrial fibrillation.

The results showed that, in the long-term, both NOACs and LAAC were cost-effective relative to warfarin.

LAAC was cost-saving relative to warfarin by year 10 and relative to NOACs by year 5. NOACs were not cost-saving relative to warfarin over the 20-year period studied.

Vivek Reddy, MD, of the Mount Sinai Medical Center in New York, New York, and his colleagues reported these findings in the Journal of American College of Cardiology.

The researchers used a Markov model to evaluate the cost-effectiveness of warfarin, NOACs, and LAAC with the Watchman device from the perspective of the Centers for Medicare & Medicaid Services over a lifetime horizon, which was defined as 20 years.

The patients were 70 years of age and at moderate risk for stroke and bleeding. Clinical event rates, stroke outcomes, and quality of life information were drawn predominantly from 4-year data from the PROTECT AF trial and meta-analyses of warfarin and NOACs.

Costs were presented in 2015 US dollars. The researchers assessed cost-effectiveness annually to determine if there was an observable time horizon over which treatment options reached accepted levels of cost-effectiveness.

They found that LAAC was more expensive than warfarin in the first post-procedure year, and patients had fewer quality-adjusted life years (QALYs) with LAAC.

But by year 3, LAAC-treated patients had gained more QALYs than warfarin-treated patients. And LAAC became cost-effective relative to warfarin by year 7, with a cost per QALY gained of $42,994.

By year 10, LAAC was more effective and less costly than warfarin. This was true for the remainder of the 20-year time horizon. Over a lifetime, LAAC provided an additional 0.506 life-years and 0.638 QALYs relative to warfarin.

NOACs were more effective than warfarin in year 1 and achieved cost-effectiveness relative to warfarin at year 16, with a cost per QALY gained of $48,446.

NOACs were not cost-saving relative to warfarin over 20 years. However, the incremental cost-effectiveness ratio continued to decrease over time so the cost per QALY gained at 20 years was $40,602.

Compared to NOACs, LAAC was more expensive in the first year post-procedure. However, by year 5, LAAC was less expensive—$20,892 vs $20,924—and more effective—3.455 QALYs vs 3.448 QALYs. This remained true for the rest of the time horizon.

Over a patient’s lifetime, LAAC was estimated to provide an additional 0.298 life-years and 0.349 QALYs relative to NOACs.

Dr Reddy and other authors of this paper are paid consultants to Boston Scientific, manufacturer of the Watchman device. Another author is a full-time employee of Boston Scientific, and yet another author has a financial interest in the Watchman device. Dr Reddy is also a paid consultant for and has received grant support from Coherex and St. Jude Medical.

Watchman device

Photo courtesy of

Boston Scientific

Researchers have compared the cost-effectiveness of left atrial appendage closure (LAAC) with the Watchman device to treatment with warfarin or novel oral anticoagulants (NOACs) as stroke prophylaxis in patients with non-valvular atrial fibrillation.

The results showed that, in the long-term, both NOACs and LAAC were cost-effective relative to warfarin.

LAAC was cost-saving relative to warfarin by year 10 and relative to NOACs by year 5. NOACs were not cost-saving relative to warfarin over the 20-year period studied.

Vivek Reddy, MD, of the Mount Sinai Medical Center in New York, New York, and his colleagues reported these findings in the Journal of American College of Cardiology.

The researchers used a Markov model to evaluate the cost-effectiveness of warfarin, NOACs, and LAAC with the Watchman device from the perspective of the Centers for Medicare & Medicaid Services over a lifetime horizon, which was defined as 20 years.

The patients were 70 years of age and at moderate risk for stroke and bleeding. Clinical event rates, stroke outcomes, and quality of life information were drawn predominantly from 4-year data from the PROTECT AF trial and meta-analyses of warfarin and NOACs.

Costs were presented in 2015 US dollars. The researchers assessed cost-effectiveness annually to determine if there was an observable time horizon over which treatment options reached accepted levels of cost-effectiveness.

They found that LAAC was more expensive than warfarin in the first post-procedure year, and patients had fewer quality-adjusted life years (QALYs) with LAAC.

But by year 3, LAAC-treated patients had gained more QALYs than warfarin-treated patients. And LAAC became cost-effective relative to warfarin by year 7, with a cost per QALY gained of $42,994.

By year 10, LAAC was more effective and less costly than warfarin. This was true for the remainder of the 20-year time horizon. Over a lifetime, LAAC provided an additional 0.506 life-years and 0.638 QALYs relative to warfarin.

NOACs were more effective than warfarin in year 1 and achieved cost-effectiveness relative to warfarin at year 16, with a cost per QALY gained of $48,446.

NOACs were not cost-saving relative to warfarin over 20 years. However, the incremental cost-effectiveness ratio continued to decrease over time so the cost per QALY gained at 20 years was $40,602.

Compared to NOACs, LAAC was more expensive in the first year post-procedure. However, by year 5, LAAC was less expensive—$20,892 vs $20,924—and more effective—3.455 QALYs vs 3.448 QALYs. This remained true for the rest of the time horizon.

Over a patient’s lifetime, LAAC was estimated to provide an additional 0.298 life-years and 0.349 QALYs relative to NOACs.

Dr Reddy and other authors of this paper are paid consultants to Boston Scientific, manufacturer of the Watchman device. Another author is a full-time employee of Boston Scientific, and yet another author has a financial interest in the Watchman device. Dr Reddy is also a paid consultant for and has received grant support from Coherex and St. Jude Medical.

Watchman device

Photo courtesy of

Boston Scientific

Researchers have compared the cost-effectiveness of left atrial appendage closure (LAAC) with the Watchman device to treatment with warfarin or novel oral anticoagulants (NOACs) as stroke prophylaxis in patients with non-valvular atrial fibrillation.

The results showed that, in the long-term, both NOACs and LAAC were cost-effective relative to warfarin.

LAAC was cost-saving relative to warfarin by year 10 and relative to NOACs by year 5. NOACs were not cost-saving relative to warfarin over the 20-year period studied.

Vivek Reddy, MD, of the Mount Sinai Medical Center in New York, New York, and his colleagues reported these findings in the Journal of American College of Cardiology.

The researchers used a Markov model to evaluate the cost-effectiveness of warfarin, NOACs, and LAAC with the Watchman device from the perspective of the Centers for Medicare & Medicaid Services over a lifetime horizon, which was defined as 20 years.

The patients were 70 years of age and at moderate risk for stroke and bleeding. Clinical event rates, stroke outcomes, and quality of life information were drawn predominantly from 4-year data from the PROTECT AF trial and meta-analyses of warfarin and NOACs.

Costs were presented in 2015 US dollars. The researchers assessed cost-effectiveness annually to determine if there was an observable time horizon over which treatment options reached accepted levels of cost-effectiveness.

They found that LAAC was more expensive than warfarin in the first post-procedure year, and patients had fewer quality-adjusted life years (QALYs) with LAAC.

But by year 3, LAAC-treated patients had gained more QALYs than warfarin-treated patients. And LAAC became cost-effective relative to warfarin by year 7, with a cost per QALY gained of $42,994.

By year 10, LAAC was more effective and less costly than warfarin. This was true for the remainder of the 20-year time horizon. Over a lifetime, LAAC provided an additional 0.506 life-years and 0.638 QALYs relative to warfarin.

NOACs were more effective than warfarin in year 1 and achieved cost-effectiveness relative to warfarin at year 16, with a cost per QALY gained of $48,446.

NOACs were not cost-saving relative to warfarin over 20 years. However, the incremental cost-effectiveness ratio continued to decrease over time so the cost per QALY gained at 20 years was $40,602.

Compared to NOACs, LAAC was more expensive in the first year post-procedure. However, by year 5, LAAC was less expensive—$20,892 vs $20,924—and more effective—3.455 QALYs vs 3.448 QALYs. This remained true for the rest of the time horizon.

Over a patient’s lifetime, LAAC was estimated to provide an additional 0.298 life-years and 0.349 QALYs relative to NOACs.

Dr Reddy and other authors of this paper are paid consultants to Boston Scientific, manufacturer of the Watchman device. Another author is a full-time employee of Boston Scientific, and yet another author has a financial interest in the Watchman device. Dr Reddy is also a paid consultant for and has received grant support from Coherex and St. Jude Medical.

As physicians, we play a unique role in medicine. Drawing on research data, we provide a gateway of information to patients and families. Governing agencies use that data to make recommendations so that we can promote treatment with confidence. But we also have a responsibility if there is an ill outcome, so being well versed on vaccines and treatments is imperative.

Since the human papillomavirus (HPV) vaccines (Gardasil, Cervarix) were approved for the prevention of HPV, there has been controversy. Despite the ongoing reports of the vaccine’s success in lowering cervical cancer rates, many parents still feel that it puts their children at risk.

A 2012 study – a systematic review of parents’ knowledge of HPV – showed a decline from 2001 to 2011, with a rise in parents’ safety concerns, and fewer parents opting to have their children vaccinated (Obstet Gynecol Int. 2012. doi: 10.1155/2012/921236).

Several studies have shown the overwhelming decline in cervical cancer that is directly related to the implementation of the HPV vaccines. But there has been growing concern, as postural orthostatic hypotension (POTS), complex regional pain syndrome (CRPS), and sudden death have been cited as side effects of theses vaccines. POTS and CRPS have been in the headlines recently, since a report came out linking the vaccine to these syndromes. Although a review by the European Medicines Agency found that the evidence does not support the notion of the HPV vaccine causing POTS or CRPS, many groups still promote a ban of the vaccine.

In 2013, Japan withdrew its recommendation for administration of the HPV vaccine after reports that many girls had been seriously harmed by it, and now calls for follow-up for patients who believe they are having side effects. Researchers argue that the basis for this action is poorly founded, and that many young women are being deprived of a vaccine that would be protective. But just as many say that more investigation needs to be done before the recommendation can be reinstated, given the number of reports about women being seriously injured from the vaccine. The Japan Society of Obstetrics and Gynecology is pleading with the Japanese Health Ministry to commence recommending the HPV cancer-preventing vaccineonce again.

An Internet search of this topic shows there are several articles questioning the safety of the vaccine, and throughout the world, concerns are forcing more research to be done to ensure its safety. Although the research overwhelmingly shows that the risk-to-benefit ratio is in favor of the HPV vaccine, several sites are reporting injury.

In a study of 997,585 girls aged 10-17 years in Denmark and Sweden, among whom 296,826 received a total of 696,420 quadrivalent HPV vaccine doses, 1,043 (less than 1%) were found to have adverse reactions, compared with 11,944 (2%) of unvaccinated girls (BMJ 2013;347:f5906). Although some relationship between HPV vaccine and autoimmune disorders such as Behçet’s syndrome, Raynaud’s disease, and type 1 diabetes was apparent, no consistent evidence for a causal association was found.

“Analysis of data reported to the Vaccine Adverse Event Reporting System revealed disproportionate reporting of venous thromboembolism,” noted Dr. Lisen Arnheim-Dahlström of the Karolinska Institutet, Stockholm, lead author of the BMJ study, and associates. “A study by the Vaccine Safety Datalink, which involved eight outcomes, identified a nonsignificantly increased relative risk (1.98) of venous thromboembolism; medical record review could confirm five of the eight cases identified from databases using international classification of diseases codes, and all five had known risk factors for venous thromboembolism. In our analysis, based on 21 vaccine exposed cases, there was no significant association with venous thromboembolism within 90 days after exposure to [quadrivalent] HPV vaccine.”

These rising concerns are resulting in more parents declining the HPV vaccine, and more questions for the primary care physician to answer. Not only are parents alarmed, but so are the physicians who make the recommendations. Being aware of the most current research and reports for and against the vaccine’s use, and being able to discuss with the family the validity of this information, will help to dispel much of the anxiety.

Dr. Pearce is a pediatrician in Frankfort, Ill. To contact her, send email to [email protected].

As physicians, we play a unique role in medicine. Drawing on research data, we provide a gateway of information to patients and families. Governing agencies use that data to make recommendations so that we can promote treatment with confidence. But we also have a responsibility if there is an ill outcome, so being well versed on vaccines and treatments is imperative.

Since the human papillomavirus (HPV) vaccines (Gardasil, Cervarix) were approved for the prevention of HPV, there has been controversy. Despite the ongoing reports of the vaccine’s success in lowering cervical cancer rates, many parents still feel that it puts their children at risk.

A 2012 study – a systematic review of parents’ knowledge of HPV – showed a decline from 2001 to 2011, with a rise in parents’ safety concerns, and fewer parents opting to have their children vaccinated (Obstet Gynecol Int. 2012. doi: 10.1155/2012/921236).

Several studies have shown the overwhelming decline in cervical cancer that is directly related to the implementation of the HPV vaccines. But there has been growing concern, as postural orthostatic hypotension (POTS), complex regional pain syndrome (CRPS), and sudden death have been cited as side effects of theses vaccines. POTS and CRPS have been in the headlines recently, since a report came out linking the vaccine to these syndromes. Although a review by the European Medicines Agency found that the evidence does not support the notion of the HPV vaccine causing POTS or CRPS, many groups still promote a ban of the vaccine.

In 2013, Japan withdrew its recommendation for administration of the HPV vaccine after reports that many girls had been seriously harmed by it, and now calls for follow-up for patients who believe they are having side effects. Researchers argue that the basis for this action is poorly founded, and that many young women are being deprived of a vaccine that would be protective. But just as many say that more investigation needs to be done before the recommendation can be reinstated, given the number of reports about women being seriously injured from the vaccine. The Japan Society of Obstetrics and Gynecology is pleading with the Japanese Health Ministry to commence recommending the HPV cancer-preventing vaccineonce again.

An Internet search of this topic shows there are several articles questioning the safety of the vaccine, and throughout the world, concerns are forcing more research to be done to ensure its safety. Although the research overwhelmingly shows that the risk-to-benefit ratio is in favor of the HPV vaccine, several sites are reporting injury.

In a study of 997,585 girls aged 10-17 years in Denmark and Sweden, among whom 296,826 received a total of 696,420 quadrivalent HPV vaccine doses, 1,043 (less than 1%) were found to have adverse reactions, compared with 11,944 (2%) of unvaccinated girls (BMJ 2013;347:f5906). Although some relationship between HPV vaccine and autoimmune disorders such as Behçet’s syndrome, Raynaud’s disease, and type 1 diabetes was apparent, no consistent evidence for a causal association was found.

“Analysis of data reported to the Vaccine Adverse Event Reporting System revealed disproportionate reporting of venous thromboembolism,” noted Dr. Lisen Arnheim-Dahlström of the Karolinska Institutet, Stockholm, lead author of the BMJ study, and associates. “A study by the Vaccine Safety Datalink, which involved eight outcomes, identified a nonsignificantly increased relative risk (1.98) of venous thromboembolism; medical record review could confirm five of the eight cases identified from databases using international classification of diseases codes, and all five had known risk factors for venous thromboembolism. In our analysis, based on 21 vaccine exposed cases, there was no significant association with venous thromboembolism within 90 days after exposure to [quadrivalent] HPV vaccine.”

These rising concerns are resulting in more parents declining the HPV vaccine, and more questions for the primary care physician to answer. Not only are parents alarmed, but so are the physicians who make the recommendations. Being aware of the most current research and reports for and against the vaccine’s use, and being able to discuss with the family the validity of this information, will help to dispel much of the anxiety.

Dr. Pearce is a pediatrician in Frankfort, Ill. To contact her, send email to [email protected].

As physicians, we play a unique role in medicine. Drawing on research data, we provide a gateway of information to patients and families. Governing agencies use that data to make recommendations so that we can promote treatment with confidence. But we also have a responsibility if there is an ill outcome, so being well versed on vaccines and treatments is imperative.

Since the human papillomavirus (HPV) vaccines (Gardasil, Cervarix) were approved for the prevention of HPV, there has been controversy. Despite the ongoing reports of the vaccine’s success in lowering cervical cancer rates, many parents still feel that it puts their children at risk.

A 2012 study – a systematic review of parents’ knowledge of HPV – showed a decline from 2001 to 2011, with a rise in parents’ safety concerns, and fewer parents opting to have their children vaccinated (Obstet Gynecol Int. 2012. doi: 10.1155/2012/921236).

Several studies have shown the overwhelming decline in cervical cancer that is directly related to the implementation of the HPV vaccines. But there has been growing concern, as postural orthostatic hypotension (POTS), complex regional pain syndrome (CRPS), and sudden death have been cited as side effects of theses vaccines. POTS and CRPS have been in the headlines recently, since a report came out linking the vaccine to these syndromes. Although a review by the European Medicines Agency found that the evidence does not support the notion of the HPV vaccine causing POTS or CRPS, many groups still promote a ban of the vaccine.

In 2013, Japan withdrew its recommendation for administration of the HPV vaccine after reports that many girls had been seriously harmed by it, and now calls for follow-up for patients who believe they are having side effects. Researchers argue that the basis for this action is poorly founded, and that many young women are being deprived of a vaccine that would be protective. But just as many say that more investigation needs to be done before the recommendation can be reinstated, given the number of reports about women being seriously injured from the vaccine. The Japan Society of Obstetrics and Gynecology is pleading with the Japanese Health Ministry to commence recommending the HPV cancer-preventing vaccineonce again.

An Internet search of this topic shows there are several articles questioning the safety of the vaccine, and throughout the world, concerns are forcing more research to be done to ensure its safety. Although the research overwhelmingly shows that the risk-to-benefit ratio is in favor of the HPV vaccine, several sites are reporting injury.

In a study of 997,585 girls aged 10-17 years in Denmark and Sweden, among whom 296,826 received a total of 696,420 quadrivalent HPV vaccine doses, 1,043 (less than 1%) were found to have adverse reactions, compared with 11,944 (2%) of unvaccinated girls (BMJ 2013;347:f5906). Although some relationship between HPV vaccine and autoimmune disorders such as Behçet’s syndrome, Raynaud’s disease, and type 1 diabetes was apparent, no consistent evidence for a causal association was found.

“Analysis of data reported to the Vaccine Adverse Event Reporting System revealed disproportionate reporting of venous thromboembolism,” noted Dr. Lisen Arnheim-Dahlström of the Karolinska Institutet, Stockholm, lead author of the BMJ study, and associates. “A study by the Vaccine Safety Datalink, which involved eight outcomes, identified a nonsignificantly increased relative risk (1.98) of venous thromboembolism; medical record review could confirm five of the eight cases identified from databases using international classification of diseases codes, and all five had known risk factors for venous thromboembolism. In our analysis, based on 21 vaccine exposed cases, there was no significant association with venous thromboembolism within 90 days after exposure to [quadrivalent] HPV vaccine.”

These rising concerns are resulting in more parents declining the HPV vaccine, and more questions for the primary care physician to answer. Not only are parents alarmed, but so are the physicians who make the recommendations. Being aware of the most current research and reports for and against the vaccine’s use, and being able to discuss with the family the validity of this information, will help to dispel much of the anxiety.

Dr. Pearce is a pediatrician in Frankfort, Ill. To contact her, send email to [email protected].

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

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

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

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

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

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

CASE Psychotic, and nonadherent
Mr. K, a 42-year-old Fijian man, is brought to the emergency department by his older brother for evaluation of behavioral agitation. Mr. K is belligerent and threatens to kill his family members. Three years earlier, he was given a diagnosis of schizophrenia and treated at an inpatient psychiatric unit.

At that time, Mr. K was stabilized on risperidone, 4 mg/d. However, he did not follow-up with treatment after discharge and has not taken any psychotropic medications since that time.

His brother reports that Mr. K has been slowly deteriorating, talking to himself, staying up at night, and getting into arguments with his family over his delusional beliefs. Although Mr. K once worked as a security guard, he has not worked in 8 years. He has been living with his family, who are no longer willing to accept him into their home because they fear he might harm them.

In the emergency department, Mr. K reports that he has a throbbing headache. Blood pressure is 177/101 mm Hg; heart rate is 103 beats per minute; respiratory rate is 18 breaths per minute; weight is 185 lb; and body mass index (BMI) is 31.8. Physical examination is unremarkable.

Laboratory values show that sodium is 131 mEq/L; potassium, 3.7 mEq/L; bicarbonate, 26 mEq/L; glucose, 420 mg/dL; hemoglobin A_1c,12.7; and urine glucose, 3+. Mr. K denies being told he has diabetes.

What are Mr. K’s risk factors for diabetes?
   a) schizophrenia
   b) physical inactivity
   c) obesity
   d) Fijian ethnicity
   e) all of the above

The authors’ observations
The prevalence of type 2 diabetes mellitus (T2DM) in persons with schizophrenia or a schizoaffective disorder is twice that of the general population.^1-4 Multiple variables contribute to the increased prevalence of diabetes in this population, including genetic predisposition, environmental and cultural factors related to diet and physical activity, a high rate of smoking,^5,6 iatrogenic causes (metabolic dysregulation and weight gain from antipsychotic treatment), and socioeconomic factors (poverty, lack of access to health care). In addition, symptoms of psychosis such as thought disorder, delusions, hallucinations, and cognitive decline in persons with chronic schizophrenia and schizoaffective disorder can make basic health maintenance difficult.

In Mr. K’s case, premorbid risk of diabetes was elevated because of his Fijian ethnicity.⁷ With a BMI of 31.8, obesity further increased that risk.^5,6,8 In addition, his untreated chronic mental illness, lack of access to health care, low socioeconomic status, long-standing smoking habit, and previous exposure to antipsychotics also increased his risk of T2DM.

The interaction between diabetes and psychosis contributes to a vicious cycle that makes both conditions worse if either, or both, are untreated. In general, medical comorbidities are associated with depression and neurocognitive impairment in persons with schizophrenia.⁹ Specifically, diabetes is associated with lower global cognitive functioning among persons with schizophrenia.¹⁰ Poor cognitive functioning can, in turn, decrease the patient’s ability to manage his medical illness. Also, persons with schizophrenia are less likely to be treated for diabetes, dyslipidemia, and hypertension, as in Mr. K’s case.¹¹

How would you treat Mr. K’s newly diagnosed diabetes?
   a) refer him to a primary care physician
   b) start an oral agent
   c) start sliding-scale insulin
   d) start long-acting insulin
   e) recommend a carbohydrate-controlled diet=

TREATMENT Stabilization
Mr. K is admitted to the medical unit for treatment of hyperglycemia. The team starts him on amlodipine, 5 mg/d, for hypertension; aripiprazole, 10 mg/d, for psychosis; and sliding-scale insulin (lispro) and 20 units of insulin (glargine) nightly for diabetes. Mr. K’s blood glucose level is well regulated on this regimen; after being medically cleared, he is transferred to the inpatient psychiatric unit.

EVALUATION Denies symptoms
Mr. K appears older than his stated age, is poorly groomed, and is dressed in a hospital gown. He is isolated and appears to be internally preoccupied. He repeatedly denies hearing auditory hallucinations, but often is overheard responding to internal stimuli and mumbling indecipherably in a low tone. His speech is decreased and his affect is flat and guarded. He states that he is not “mental” but that he came to the hospital for “tooth pain.” Every day he asks when he can return home and he asks the staff to call his family to take him home. When informed that his family is not able to care for him, Mr. K states that he would live in a house he owns in Fiji, which his family members state is untrue.

How would you treat Mr. K’s psychosis?
   a) continue aripiprazole
   b) switch to risperidone, an agent to which he previously responded
   c) switch to olanzapine because he has not been sleeping well
   d) switch to haloperidol because of diabetes

The authors’ observations
Pharmacotherapy for patients with comorbid schizophrenia and diabetes requires consideration of clinical and psychosocial factors unique to this population.

Antipsychotic choice
Selection of an antipsychotic agent to address psychosis requires considering its efficacy, side-effect profile, and adherence rates, as well as its potential effects on metabolic regulation and weight (Table 1). Typical antipsychotics are less likely than atypical antipsychotics to cause metabolic dysregulation.¹² When treatment with atypical antipsychotics cannot be avoided—such as when side effects or an allergic reaction develop—consider selecting a relatively weight-neutral drug with a lower potential for metabolic dysregulation, such as aripiprazole. However, many times, using an agent with significant effects on metabolic regulation cannot be avoided, making treating and monitoring the resulting metabolic effects even more significant.

Glycemic control
Initiating an agent for glycemic control in persons with newly diagnosed diabetes requires weighing many factors, including mode of delivery (oral or subcutaneous), level of glycemic control required, comorbid medical illness (such as renal impairment and heart failure), cost, and potential long-term side effects of the medication (Table 2).¹³ Oral agents have a slower effect on lowering the blood glucose level, and each agent carries contraindications, but generally they are more affordable. Many present a low risk of hypoglycemia but sulfonylureas are an exception. In addition, metformin could lead to weight loss over the long term, which further lowers the risk of diabetes.

If, however, tight and immediate glycemic control is needed, subcutaneous insulin injections might be required, although this method is more costly, carries an increased risk of hypoglycemic episodes acutely, and leads to weight gain in the long run because of induced hunger and increased appetite.

Psychosocial factors
In addition to the clinical variables above, treating diabetes in patients with comorbid schizophrenia requires considering other psychosocial factors that might not be readily apparent (Table 3). For example, patients with schizophrenia might have decreased motivation, self-efficacy, and capacity for self-care when it comes to health maintenance and medication adherence.¹⁴ Chronically mentally ill persons might have reduced cognitive functioning that could affect their ability to maintain complicated medication regimens, such as administering insulin and monitoring blood glucose.

In addition, easy access to hypodermic needles and large amounts of insulin could become a safety concern in patients with ongoing hallucinations, delusions, and thought disorder, despite antipsychotic treatment. For example, a patient with schizophrenia and diabetes who has been maintained on insulin might begin hearing voices that tell her to inject her eyeballs with insulin. Similarly, although the risk of hypoglycemic episodes in patients treated with insulin is well known, patients with schizophrenia have a higher risk of acute complications of diabetes than other patients with diabetes.¹⁵Psychosocial factors, such as placement, support system, and follow-up care need to be considered. In some instances, the need to administer daily subcutaneous insulin could be a barrier to placement if the facility does not have the staff or expertise to monitor blood glucose and administer insulin.

If the patient is returning home, then the patient or a caretaker will need to be trained to monitor blood glucose and administer insulin. This might be difficult for persons with chronic mental illness who have lost the support and care of their family. Also, consider the issue of storing insulin, which requires refrigeration. Because of the potential complications involved in using insulin in patients with schizophrenia, practitioners should consider managing non-insulin dependent diabetes with an oral hypoglycemic agent, when possible, along with lifestyle modifications.

OUTCOME Weight loss, discharge
Mr. K is transitioned from aripiprazole to higher-potency oral risperidone, titrated to 6 mg/d. At this dosage, he continues to maintain a delusion about owning a house in Fiji, but was seen responding to internal stimuli less often. The treatment team places him on a diabetic and low-sodium diet of 1,800 kcal/d. His fasting blood glucose levels range in the 70s to 110s mg/dL during his first week of hospitalization.

The treatment team starts Mr. K on oral metformin, titrated to 1,000 mg twice daily, while tapering him off insulin lispro and glargine over the course of hospitalization. The transition from insulin to metformin also is considered because Mr. K’s daily insulin requirement is rather low (<0.5 units/kg).

Mr. K’s course is prolonged because his treatment team initiates the process of conservatorship and placement in the community. Approximately 6 months after his admission, Mr. K is discharged to an unlocked facility with support from an intensive outpatient mental health program. At 6 months follow-up with his outpatient provider, Mr. K’s hemoglobin A_1c is 7.0 and he weighs 155 lb with a BMI of 26.5.

The authors’ observations
Despite Mr. K’s initial elevated hemoglobin A_1c of 12.7 and weight of 185 lb, over approximately 6 months he experiences a 5.7-unit drop in hemoglobin A_1c and weight loss of 30 lb with dietary management and metformin—without the need for other agents. Other options for weight-neutral treatment of T2DM include exenatide, which also is available as a once weekly injectable formulation, canagliflozin, and the gliptins (sitagliptin, saxagliptin, and linagliptin) (Table 4).

Mr. K’s improved control of his diabetes occurred despite initiation of an atypical antipsychotic, which would have been expected to cause additional weight gain and make his diabetes worse secondary to metabolic effects.¹² Treatment with metformin in particular has been associated with weight loss in patients with¹⁶ and without¹⁷ comorbid schizophrenia, including those with antipsychotic-induced weight gain.^18-20

Bottom Line
Persons with schizophrenia are at higher risk of type 2 diabetes mellitus for many reasons, including metabolic effects of antipsychotics, reduced cognitive functioning, poor self-care, and limited access to health care. Typical antipsychotics are less likely to cause metabolic dysregulation but, if an atypical is needed, one that is relatively weight-neutral should be selected. When choosing an agent for glycemic control, consider a patient’s or a caretaker’s ability to administer medications, monitor blood glucose, and follow dietary recommendations.

Related Resources
• Cohn T. The link between schizophrenia and diabetes. Current Psychiatry. 2012;11(10):28-34,46.
• Annamalai A, Tek C. An overview of diabetes management in schizophrenia patients: office based strategies for primary care practitioners and endocrinologists [published online March 23, 2015]. Int J Endocrinol. 2015;2015:969182. doi: 10.1155/2015/969182.


Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Asenapine • Saphris
Canagliflozin • Invokana
Exenatide • Bydureon, Byetta
Glargine • Lantus
Linagliptin • Tradjenta
Lispro • Humalog
Lurasidone • Latuda
Metformin • Glucophage
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Saxagliptin • Onglyza
Sitagliptin • Januvia

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

CASE Psychotic, and nonadherent
Mr. K, a 42-year-old Fijian man, is brought to the emergency department by his older brother for evaluation of behavioral agitation. Mr. K is belligerent and threatens to kill his family members. Three years earlier, he was given a diagnosis of schizophrenia and treated at an inpatient psychiatric unit.

At that time, Mr. K was stabilized on risperidone, 4 mg/d. However, he did not follow-up with treatment after discharge and has not taken any psychotropic medications since that time.

His brother reports that Mr. K has been slowly deteriorating, talking to himself, staying up at night, and getting into arguments with his family over his delusional beliefs. Although Mr. K once worked as a security guard, he has not worked in 8 years. He has been living with his family, who are no longer willing to accept him into their home because they fear he might harm them.

In the emergency department, Mr. K reports that he has a throbbing headache. Blood pressure is 177/101 mm Hg; heart rate is 103 beats per minute; respiratory rate is 18 breaths per minute; weight is 185 lb; and body mass index (BMI) is 31.8. Physical examination is unremarkable.

Laboratory values show that sodium is 131 mEq/L; potassium, 3.7 mEq/L; bicarbonate, 26 mEq/L; glucose, 420 mg/dL; hemoglobin A_1c,12.7; and urine glucose, 3+. Mr. K denies being told he has diabetes.

What are Mr. K’s risk factors for diabetes?
   a) schizophrenia
   b) physical inactivity
   c) obesity
   d) Fijian ethnicity
   e) all of the above

The authors’ observations
The prevalence of type 2 diabetes mellitus (T2DM) in persons with schizophrenia or a schizoaffective disorder is twice that of the general population.^1-4 Multiple variables contribute to the increased prevalence of diabetes in this population, including genetic predisposition, environmental and cultural factors related to diet and physical activity, a high rate of smoking,^5,6 iatrogenic causes (metabolic dysregulation and weight gain from antipsychotic treatment), and socioeconomic factors (poverty, lack of access to health care). In addition, symptoms of psychosis such as thought disorder, delusions, hallucinations, and cognitive decline in persons with chronic schizophrenia and schizoaffective disorder can make basic health maintenance difficult.

In Mr. K’s case, premorbid risk of diabetes was elevated because of his Fijian ethnicity.⁷ With a BMI of 31.8, obesity further increased that risk.^5,6,8 In addition, his untreated chronic mental illness, lack of access to health care, low socioeconomic status, long-standing smoking habit, and previous exposure to antipsychotics also increased his risk of T2DM.

The interaction between diabetes and psychosis contributes to a vicious cycle that makes both conditions worse if either, or both, are untreated. In general, medical comorbidities are associated with depression and neurocognitive impairment in persons with schizophrenia.⁹ Specifically, diabetes is associated with lower global cognitive functioning among persons with schizophrenia.¹⁰ Poor cognitive functioning can, in turn, decrease the patient’s ability to manage his medical illness. Also, persons with schizophrenia are less likely to be treated for diabetes, dyslipidemia, and hypertension, as in Mr. K’s case.¹¹

How would you treat Mr. K’s newly diagnosed diabetes?
   a) refer him to a primary care physician
   b) start an oral agent
   c) start sliding-scale insulin
   d) start long-acting insulin
   e) recommend a carbohydrate-controlled diet=

TREATMENT Stabilization
Mr. K is admitted to the medical unit for treatment of hyperglycemia. The team starts him on amlodipine, 5 mg/d, for hypertension; aripiprazole, 10 mg/d, for psychosis; and sliding-scale insulin (lispro) and 20 units of insulin (glargine) nightly for diabetes. Mr. K’s blood glucose level is well regulated on this regimen; after being medically cleared, he is transferred to the inpatient psychiatric unit.

EVALUATION Denies symptoms
Mr. K appears older than his stated age, is poorly groomed, and is dressed in a hospital gown. He is isolated and appears to be internally preoccupied. He repeatedly denies hearing auditory hallucinations, but often is overheard responding to internal stimuli and mumbling indecipherably in a low tone. His speech is decreased and his affect is flat and guarded. He states that he is not “mental” but that he came to the hospital for “tooth pain.” Every day he asks when he can return home and he asks the staff to call his family to take him home. When informed that his family is not able to care for him, Mr. K states that he would live in a house he owns in Fiji, which his family members state is untrue.

How would you treat Mr. K’s psychosis?
   a) continue aripiprazole
   b) switch to risperidone, an agent to which he previously responded
   c) switch to olanzapine because he has not been sleeping well
   d) switch to haloperidol because of diabetes

The authors’ observations
Pharmacotherapy for patients with comorbid schizophrenia and diabetes requires consideration of clinical and psychosocial factors unique to this population.

Antipsychotic choice
Selection of an antipsychotic agent to address psychosis requires considering its efficacy, side-effect profile, and adherence rates, as well as its potential effects on metabolic regulation and weight (Table 1). Typical antipsychotics are less likely than atypical antipsychotics to cause metabolic dysregulation.¹² When treatment with atypical antipsychotics cannot be avoided—such as when side effects or an allergic reaction develop—consider selecting a relatively weight-neutral drug with a lower potential for metabolic dysregulation, such as aripiprazole. However, many times, using an agent with significant effects on metabolic regulation cannot be avoided, making treating and monitoring the resulting metabolic effects even more significant.

Glycemic control
Initiating an agent for glycemic control in persons with newly diagnosed diabetes requires weighing many factors, including mode of delivery (oral or subcutaneous), level of glycemic control required, comorbid medical illness (such as renal impairment and heart failure), cost, and potential long-term side effects of the medication (Table 2).¹³ Oral agents have a slower effect on lowering the blood glucose level, and each agent carries contraindications, but generally they are more affordable. Many present a low risk of hypoglycemia but sulfonylureas are an exception. In addition, metformin could lead to weight loss over the long term, which further lowers the risk of diabetes.

If, however, tight and immediate glycemic control is needed, subcutaneous insulin injections might be required, although this method is more costly, carries an increased risk of hypoglycemic episodes acutely, and leads to weight gain in the long run because of induced hunger and increased appetite.

Psychosocial factors
In addition to the clinical variables above, treating diabetes in patients with comorbid schizophrenia requires considering other psychosocial factors that might not be readily apparent (Table 3). For example, patients with schizophrenia might have decreased motivation, self-efficacy, and capacity for self-care when it comes to health maintenance and medication adherence.¹⁴ Chronically mentally ill persons might have reduced cognitive functioning that could affect their ability to maintain complicated medication regimens, such as administering insulin and monitoring blood glucose.

In addition, easy access to hypodermic needles and large amounts of insulin could become a safety concern in patients with ongoing hallucinations, delusions, and thought disorder, despite antipsychotic treatment. For example, a patient with schizophrenia and diabetes who has been maintained on insulin might begin hearing voices that tell her to inject her eyeballs with insulin. Similarly, although the risk of hypoglycemic episodes in patients treated with insulin is well known, patients with schizophrenia have a higher risk of acute complications of diabetes than other patients with diabetes.¹⁵Psychosocial factors, such as placement, support system, and follow-up care need to be considered. In some instances, the need to administer daily subcutaneous insulin could be a barrier to placement if the facility does not have the staff or expertise to monitor blood glucose and administer insulin.

If the patient is returning home, then the patient or a caretaker will need to be trained to monitor blood glucose and administer insulin. This might be difficult for persons with chronic mental illness who have lost the support and care of their family. Also, consider the issue of storing insulin, which requires refrigeration. Because of the potential complications involved in using insulin in patients with schizophrenia, practitioners should consider managing non-insulin dependent diabetes with an oral hypoglycemic agent, when possible, along with lifestyle modifications.

OUTCOME Weight loss, discharge
Mr. K is transitioned from aripiprazole to higher-potency oral risperidone, titrated to 6 mg/d. At this dosage, he continues to maintain a delusion about owning a house in Fiji, but was seen responding to internal stimuli less often. The treatment team places him on a diabetic and low-sodium diet of 1,800 kcal/d. His fasting blood glucose levels range in the 70s to 110s mg/dL during his first week of hospitalization.

The treatment team starts Mr. K on oral metformin, titrated to 1,000 mg twice daily, while tapering him off insulin lispro and glargine over the course of hospitalization. The transition from insulin to metformin also is considered because Mr. K’s daily insulin requirement is rather low (<0.5 units/kg).

Mr. K’s course is prolonged because his treatment team initiates the process of conservatorship and placement in the community. Approximately 6 months after his admission, Mr. K is discharged to an unlocked facility with support from an intensive outpatient mental health program. At 6 months follow-up with his outpatient provider, Mr. K’s hemoglobin A_1c is 7.0 and he weighs 155 lb with a BMI of 26.5.

The authors’ observations
Despite Mr. K’s initial elevated hemoglobin A_1c of 12.7 and weight of 185 lb, over approximately 6 months he experiences a 5.7-unit drop in hemoglobin A_1c and weight loss of 30 lb with dietary management and metformin—without the need for other agents. Other options for weight-neutral treatment of T2DM include exenatide, which also is available as a once weekly injectable formulation, canagliflozin, and the gliptins (sitagliptin, saxagliptin, and linagliptin) (Table 4).

Mr. K’s improved control of his diabetes occurred despite initiation of an atypical antipsychotic, which would have been expected to cause additional weight gain and make his diabetes worse secondary to metabolic effects.¹² Treatment with metformin in particular has been associated with weight loss in patients with¹⁶ and without¹⁷ comorbid schizophrenia, including those with antipsychotic-induced weight gain.^18-20

Bottom Line
Persons with schizophrenia are at higher risk of type 2 diabetes mellitus for many reasons, including metabolic effects of antipsychotics, reduced cognitive functioning, poor self-care, and limited access to health care. Typical antipsychotics are less likely to cause metabolic dysregulation but, if an atypical is needed, one that is relatively weight-neutral should be selected. When choosing an agent for glycemic control, consider a patient’s or a caretaker’s ability to administer medications, monitor blood glucose, and follow dietary recommendations.

Related Resources
• Cohn T. The link between schizophrenia and diabetes. Current Psychiatry. 2012;11(10):28-34,46.
• Annamalai A, Tek C. An overview of diabetes management in schizophrenia patients: office based strategies for primary care practitioners and endocrinologists [published online March 23, 2015]. Int J Endocrinol. 2015;2015:969182. doi: 10.1155/2015/969182.


Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Asenapine • Saphris
Canagliflozin • Invokana
Exenatide • Bydureon, Byetta
Glargine • Lantus
Linagliptin • Tradjenta
Lispro • Humalog
Lurasidone • Latuda
Metformin • Glucophage
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Saxagliptin • Onglyza
Sitagliptin • Januvia

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

CASE Psychotic, and nonadherent
Mr. K, a 42-year-old Fijian man, is brought to the emergency department by his older brother for evaluation of behavioral agitation. Mr. K is belligerent and threatens to kill his family members. Three years earlier, he was given a diagnosis of schizophrenia and treated at an inpatient psychiatric unit.

At that time, Mr. K was stabilized on risperidone, 4 mg/d. However, he did not follow-up with treatment after discharge and has not taken any psychotropic medications since that time.

His brother reports that Mr. K has been slowly deteriorating, talking to himself, staying up at night, and getting into arguments with his family over his delusional beliefs. Although Mr. K once worked as a security guard, he has not worked in 8 years. He has been living with his family, who are no longer willing to accept him into their home because they fear he might harm them.

In the emergency department, Mr. K reports that he has a throbbing headache. Blood pressure is 177/101 mm Hg; heart rate is 103 beats per minute; respiratory rate is 18 breaths per minute; weight is 185 lb; and body mass index (BMI) is 31.8. Physical examination is unremarkable.

Laboratory values show that sodium is 131 mEq/L; potassium, 3.7 mEq/L; bicarbonate, 26 mEq/L; glucose, 420 mg/dL; hemoglobin A_1c,12.7; and urine glucose, 3+. Mr. K denies being told he has diabetes.

What are Mr. K’s risk factors for diabetes?
   a) schizophrenia
   b) physical inactivity
   c) obesity
   d) Fijian ethnicity
   e) all of the above

The authors’ observations
The prevalence of type 2 diabetes mellitus (T2DM) in persons with schizophrenia or a schizoaffective disorder is twice that of the general population.^1-4 Multiple variables contribute to the increased prevalence of diabetes in this population, including genetic predisposition, environmental and cultural factors related to diet and physical activity, a high rate of smoking,^5,6 iatrogenic causes (metabolic dysregulation and weight gain from antipsychotic treatment), and socioeconomic factors (poverty, lack of access to health care). In addition, symptoms of psychosis such as thought disorder, delusions, hallucinations, and cognitive decline in persons with chronic schizophrenia and schizoaffective disorder can make basic health maintenance difficult.

In Mr. K’s case, premorbid risk of diabetes was elevated because of his Fijian ethnicity.⁷ With a BMI of 31.8, obesity further increased that risk.^5,6,8 In addition, his untreated chronic mental illness, lack of access to health care, low socioeconomic status, long-standing smoking habit, and previous exposure to antipsychotics also increased his risk of T2DM.

The interaction between diabetes and psychosis contributes to a vicious cycle that makes both conditions worse if either, or both, are untreated. In general, medical comorbidities are associated with depression and neurocognitive impairment in persons with schizophrenia.⁹ Specifically, diabetes is associated with lower global cognitive functioning among persons with schizophrenia.¹⁰ Poor cognitive functioning can, in turn, decrease the patient’s ability to manage his medical illness. Also, persons with schizophrenia are less likely to be treated for diabetes, dyslipidemia, and hypertension, as in Mr. K’s case.¹¹

How would you treat Mr. K’s newly diagnosed diabetes?
   a) refer him to a primary care physician
   b) start an oral agent
   c) start sliding-scale insulin
   d) start long-acting insulin
   e) recommend a carbohydrate-controlled diet=

TREATMENT Stabilization
Mr. K is admitted to the medical unit for treatment of hyperglycemia. The team starts him on amlodipine, 5 mg/d, for hypertension; aripiprazole, 10 mg/d, for psychosis; and sliding-scale insulin (lispro) and 20 units of insulin (glargine) nightly for diabetes. Mr. K’s blood glucose level is well regulated on this regimen; after being medically cleared, he is transferred to the inpatient psychiatric unit.

EVALUATION Denies symptoms
Mr. K appears older than his stated age, is poorly groomed, and is dressed in a hospital gown. He is isolated and appears to be internally preoccupied. He repeatedly denies hearing auditory hallucinations, but often is overheard responding to internal stimuli and mumbling indecipherably in a low tone. His speech is decreased and his affect is flat and guarded. He states that he is not “mental” but that he came to the hospital for “tooth pain.” Every day he asks when he can return home and he asks the staff to call his family to take him home. When informed that his family is not able to care for him, Mr. K states that he would live in a house he owns in Fiji, which his family members state is untrue.

How would you treat Mr. K’s psychosis?
   a) continue aripiprazole
   b) switch to risperidone, an agent to which he previously responded
   c) switch to olanzapine because he has not been sleeping well
   d) switch to haloperidol because of diabetes

The authors’ observations
Pharmacotherapy for patients with comorbid schizophrenia and diabetes requires consideration of clinical and psychosocial factors unique to this population.

Antipsychotic choice
Selection of an antipsychotic agent to address psychosis requires considering its efficacy, side-effect profile, and adherence rates, as well as its potential effects on metabolic regulation and weight (Table 1). Typical antipsychotics are less likely than atypical antipsychotics to cause metabolic dysregulation.¹² When treatment with atypical antipsychotics cannot be avoided—such as when side effects or an allergic reaction develop—consider selecting a relatively weight-neutral drug with a lower potential for metabolic dysregulation, such as aripiprazole. However, many times, using an agent with significant effects on metabolic regulation cannot be avoided, making treating and monitoring the resulting metabolic effects even more significant.

Glycemic control
Initiating an agent for glycemic control in persons with newly diagnosed diabetes requires weighing many factors, including mode of delivery (oral or subcutaneous), level of glycemic control required, comorbid medical illness (such as renal impairment and heart failure), cost, and potential long-term side effects of the medication (Table 2).¹³ Oral agents have a slower effect on lowering the blood glucose level, and each agent carries contraindications, but generally they are more affordable. Many present a low risk of hypoglycemia but sulfonylureas are an exception. In addition, metformin could lead to weight loss over the long term, which further lowers the risk of diabetes.

If, however, tight and immediate glycemic control is needed, subcutaneous insulin injections might be required, although this method is more costly, carries an increased risk of hypoglycemic episodes acutely, and leads to weight gain in the long run because of induced hunger and increased appetite.

Psychosocial factors
In addition to the clinical variables above, treating diabetes in patients with comorbid schizophrenia requires considering other psychosocial factors that might not be readily apparent (Table 3). For example, patients with schizophrenia might have decreased motivation, self-efficacy, and capacity for self-care when it comes to health maintenance and medication adherence.¹⁴ Chronically mentally ill persons might have reduced cognitive functioning that could affect their ability to maintain complicated medication regimens, such as administering insulin and monitoring blood glucose.

In addition, easy access to hypodermic needles and large amounts of insulin could become a safety concern in patients with ongoing hallucinations, delusions, and thought disorder, despite antipsychotic treatment. For example, a patient with schizophrenia and diabetes who has been maintained on insulin might begin hearing voices that tell her to inject her eyeballs with insulin. Similarly, although the risk of hypoglycemic episodes in patients treated with insulin is well known, patients with schizophrenia have a higher risk of acute complications of diabetes than other patients with diabetes.¹⁵Psychosocial factors, such as placement, support system, and follow-up care need to be considered. In some instances, the need to administer daily subcutaneous insulin could be a barrier to placement if the facility does not have the staff or expertise to monitor blood glucose and administer insulin.

If the patient is returning home, then the patient or a caretaker will need to be trained to monitor blood glucose and administer insulin. This might be difficult for persons with chronic mental illness who have lost the support and care of their family. Also, consider the issue of storing insulin, which requires refrigeration. Because of the potential complications involved in using insulin in patients with schizophrenia, practitioners should consider managing non-insulin dependent diabetes with an oral hypoglycemic agent, when possible, along with lifestyle modifications.

OUTCOME Weight loss, discharge
Mr. K is transitioned from aripiprazole to higher-potency oral risperidone, titrated to 6 mg/d. At this dosage, he continues to maintain a delusion about owning a house in Fiji, but was seen responding to internal stimuli less often. The treatment team places him on a diabetic and low-sodium diet of 1,800 kcal/d. His fasting blood glucose levels range in the 70s to 110s mg/dL during his first week of hospitalization.

The treatment team starts Mr. K on oral metformin, titrated to 1,000 mg twice daily, while tapering him off insulin lispro and glargine over the course of hospitalization. The transition from insulin to metformin also is considered because Mr. K’s daily insulin requirement is rather low (<0.5 units/kg).

Mr. K’s course is prolonged because his treatment team initiates the process of conservatorship and placement in the community. Approximately 6 months after his admission, Mr. K is discharged to an unlocked facility with support from an intensive outpatient mental health program. At 6 months follow-up with his outpatient provider, Mr. K’s hemoglobin A_1c is 7.0 and he weighs 155 lb with a BMI of 26.5.

The authors’ observations
Despite Mr. K’s initial elevated hemoglobin A_1c of 12.7 and weight of 185 lb, over approximately 6 months he experiences a 5.7-unit drop in hemoglobin A_1c and weight loss of 30 lb with dietary management and metformin—without the need for other agents. Other options for weight-neutral treatment of T2DM include exenatide, which also is available as a once weekly injectable formulation, canagliflozin, and the gliptins (sitagliptin, saxagliptin, and linagliptin) (Table 4).

Mr. K’s improved control of his diabetes occurred despite initiation of an atypical antipsychotic, which would have been expected to cause additional weight gain and make his diabetes worse secondary to metabolic effects.¹² Treatment with metformin in particular has been associated with weight loss in patients with¹⁶ and without¹⁷ comorbid schizophrenia, including those with antipsychotic-induced weight gain.^18-20

Bottom Line
Persons with schizophrenia are at higher risk of type 2 diabetes mellitus for many reasons, including metabolic effects of antipsychotics, reduced cognitive functioning, poor self-care, and limited access to health care. Typical antipsychotics are less likely to cause metabolic dysregulation but, if an atypical is needed, one that is relatively weight-neutral should be selected. When choosing an agent for glycemic control, consider a patient’s or a caretaker’s ability to administer medications, monitor blood glucose, and follow dietary recommendations.

Related Resources
• Cohn T. The link between schizophrenia and diabetes. Current Psychiatry. 2012;11(10):28-34,46.
• Annamalai A, Tek C. An overview of diabetes management in schizophrenia patients: office based strategies for primary care practitioners and endocrinologists [published online March 23, 2015]. Int J Endocrinol. 2015;2015:969182. doi: 10.1155/2015/969182.


Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Asenapine • Saphris
Canagliflozin • Invokana
Exenatide • Bydureon, Byetta
Glargine • Lantus
Linagliptin • Tradjenta
Lispro • Humalog
Lurasidone • Latuda
Metformin • Glucophage
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Saxagliptin • Onglyza
Sitagliptin • Januvia

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

SAN DIEGO – If you feel sleepy and out of sorts on a post-call day, compared with a normal work-day, you’re not alone.

Anesthesiology faculty reported significant increases in feeling irritable, jittery, and sleepy, along with significant decreases in feeling confident, energetic, and talkative following an on-call period, according to a study presented at the annual meeting of the American Society of Anesthesiologists.

To date, most studies of partial sleep deprivation in health care settings have focused on residents and interns, and less on medical faculty, said lead study author Dr. Haleh Saadat of the department of anesthesiology and pain medicine at Nationwide Children’s Hospital in Columbus, Ohio. “Our call is 17 hours, from 3 p.m. to 7 a.m.; but the call period at most hospitals is 24 hours, and even longer at some private practices,” she said in an interview.

To examine the effects of partial sleep deprivation on reaction time, simple cognitive skills, and mood status in 21 anesthesiologists, Dr. Saadat and her associates obtained verbal consent from the study participants and measured reaction time, mood states, and eight subjective behavioral characteristics at two different time points: between 6:30 a.m. and 8 a.m. on a regular noncall day of work, and between 6:30 a.m. and 8 a.m. after an overnight call (a shift that runs from 3 p.m. to 7 a.m.). The behavioral characteristics included feeling alert, energetic, anxious, confident, irritable, jittery/nervous, sleepy, and talkative, and the researchers used paired t-tests to compare variable means between regular sleep days and post-call days.

Reaction time decreased in all 21 subjects after night call, indicating worse performance (P = .047), while total mood disturbance was significantly higher on post-call days, relative to noncall days (P less than .001).

Of the 21 anesthesiologists, 19 completed all simple cognitive task questions at both time points and reported significant increases in several of these parameters on post-call days, compared with normal work-days.

Post-call observations found participants feeling more irritable, confident, energetic, sleepy (P less than .001), feeling more jittery (P = .003), and feeling less talkative (P less than .001) than on normal work–days.

Coping strategies used to address their sleep deprivation were measured as well, with “most of our subjects using problem solving, followed by seeking social support and avoidance,” Dr. Saadat noted. “People who used avoidance had greater declines in reaction time on post–call days, compared with the rest of the study participants. It didn’t matter whether you were male, female, younger, or older.”

Dr. Saadat called for additional studies to evaluate the neurocognitive impact of partial sleep deprivation on physicians’ on-call duties.

“I would like to see if we can replicate the results in bigger centers,” she said. “If this is what is happening, we may need to pay more attention to faculty’s work hours in both academic and private practice settings – not only among anesthesiologists, but also in other specialties. These observations require a closer look at the potential implications for patients’ and professionals’ safety.”

The researchers reported no financial disclosures.

[email protected]

SAN DIEGO – If you feel sleepy and out of sorts on a post-call day, compared with a normal work-day, you’re not alone.

Anesthesiology faculty reported significant increases in feeling irritable, jittery, and sleepy, along with significant decreases in feeling confident, energetic, and talkative following an on-call period, according to a study presented at the annual meeting of the American Society of Anesthesiologists.

To date, most studies of partial sleep deprivation in health care settings have focused on residents and interns, and less on medical faculty, said lead study author Dr. Haleh Saadat of the department of anesthesiology and pain medicine at Nationwide Children’s Hospital in Columbus, Ohio. “Our call is 17 hours, from 3 p.m. to 7 a.m.; but the call period at most hospitals is 24 hours, and even longer at some private practices,” she said in an interview.

To examine the effects of partial sleep deprivation on reaction time, simple cognitive skills, and mood status in 21 anesthesiologists, Dr. Saadat and her associates obtained verbal consent from the study participants and measured reaction time, mood states, and eight subjective behavioral characteristics at two different time points: between 6:30 a.m. and 8 a.m. on a regular noncall day of work, and between 6:30 a.m. and 8 a.m. after an overnight call (a shift that runs from 3 p.m. to 7 a.m.). The behavioral characteristics included feeling alert, energetic, anxious, confident, irritable, jittery/nervous, sleepy, and talkative, and the researchers used paired t-tests to compare variable means between regular sleep days and post-call days.

Reaction time decreased in all 21 subjects after night call, indicating worse performance (P = .047), while total mood disturbance was significantly higher on post-call days, relative to noncall days (P less than .001).

Of the 21 anesthesiologists, 19 completed all simple cognitive task questions at both time points and reported significant increases in several of these parameters on post-call days, compared with normal work-days.

Post-call observations found participants feeling more irritable, confident, energetic, sleepy (P less than .001), feeling more jittery (P = .003), and feeling less talkative (P less than .001) than on normal work–days.

Coping strategies used to address their sleep deprivation were measured as well, with “most of our subjects using problem solving, followed by seeking social support and avoidance,” Dr. Saadat noted. “People who used avoidance had greater declines in reaction time on post–call days, compared with the rest of the study participants. It didn’t matter whether you were male, female, younger, or older.”

Dr. Saadat called for additional studies to evaluate the neurocognitive impact of partial sleep deprivation on physicians’ on-call duties.

“I would like to see if we can replicate the results in bigger centers,” she said. “If this is what is happening, we may need to pay more attention to faculty’s work hours in both academic and private practice settings – not only among anesthesiologists, but also in other specialties. These observations require a closer look at the potential implications for patients’ and professionals’ safety.”

The researchers reported no financial disclosures.

[email protected]

SAN DIEGO – If you feel sleepy and out of sorts on a post-call day, compared with a normal work-day, you’re not alone.

Anesthesiology faculty reported significant increases in feeling irritable, jittery, and sleepy, along with significant decreases in feeling confident, energetic, and talkative following an on-call period, according to a study presented at the annual meeting of the American Society of Anesthesiologists.

To date, most studies of partial sleep deprivation in health care settings have focused on residents and interns, and less on medical faculty, said lead study author Dr. Haleh Saadat of the department of anesthesiology and pain medicine at Nationwide Children’s Hospital in Columbus, Ohio. “Our call is 17 hours, from 3 p.m. to 7 a.m.; but the call period at most hospitals is 24 hours, and even longer at some private practices,” she said in an interview.

To examine the effects of partial sleep deprivation on reaction time, simple cognitive skills, and mood status in 21 anesthesiologists, Dr. Saadat and her associates obtained verbal consent from the study participants and measured reaction time, mood states, and eight subjective behavioral characteristics at two different time points: between 6:30 a.m. and 8 a.m. on a regular noncall day of work, and between 6:30 a.m. and 8 a.m. after an overnight call (a shift that runs from 3 p.m. to 7 a.m.). The behavioral characteristics included feeling alert, energetic, anxious, confident, irritable, jittery/nervous, sleepy, and talkative, and the researchers used paired t-tests to compare variable means between regular sleep days and post-call days.

Reaction time decreased in all 21 subjects after night call, indicating worse performance (P = .047), while total mood disturbance was significantly higher on post-call days, relative to noncall days (P less than .001).

Of the 21 anesthesiologists, 19 completed all simple cognitive task questions at both time points and reported significant increases in several of these parameters on post-call days, compared with normal work-days.

Post-call observations found participants feeling more irritable, confident, energetic, sleepy (P less than .001), feeling more jittery (P = .003), and feeling less talkative (P less than .001) than on normal work–days.

Coping strategies used to address their sleep deprivation were measured as well, with “most of our subjects using problem solving, followed by seeking social support and avoidance,” Dr. Saadat noted. “People who used avoidance had greater declines in reaction time on post–call days, compared with the rest of the study participants. It didn’t matter whether you were male, female, younger, or older.”

Dr. Saadat called for additional studies to evaluate the neurocognitive impact of partial sleep deprivation on physicians’ on-call duties.

“I would like to see if we can replicate the results in bigger centers,” she said. “If this is what is happening, we may need to pay more attention to faculty’s work hours in both academic and private practice settings – not only among anesthesiologists, but also in other specialties. These observations require a closer look at the potential implications for patients’ and professionals’ safety.”

The researchers reported no financial disclosures.

[email protected]

Patients with unipolar depression who use antidepressants may increase their risk of subsequently being diagnosed with mania/bipolar disorder, a retrospective cohort study conducted in the United Kingdom showed.

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania. This association remained significant after adjusting for age and gender,” wrote Dr. Rashmi Patel of King’s College London and his colleagues.

The study comprised 21,012 adults who were diagnosed with depression and were receiving secondary mental health care for unipolar depression between April 1, 2006, and March 31, 2013. The researchers used electronic health records to determine which patients had used antidepressants prior to being diagnosed with depression and were subsequently diagnosed with mania or bipolar disorder, as well as the dates of the patients’ diagnoses. Patients were followed up to March 31, 2014.

Just under 1,000 (994) of the study participants were diagnosed with mania or bipolar disorder, representing 10.9 per 1,000 person-years. All types of antidepressants taken by the patients were associated with an increased incidence of mania/bipolar disorder (unadjusted hazard ratio greater than 1.0 for all antidepressants), with incidence rates ranging from 13.1 (tricyclic antidepressants) to 19.1 (trazodone) per 1,000 person-years.

“Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians of the risk of mania in people with depression prior to prescribing antidepressant therapy,” the investigators noted. They disclosed having received research funding from various sources.

Read the full study in BMJ Open (doi: 10.1136/bmjopen-2015-008341).

[email protected]

Patients with unipolar depression who use antidepressants may increase their risk of subsequently being diagnosed with mania/bipolar disorder, a retrospective cohort study conducted in the United Kingdom showed.

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania. This association remained significant after adjusting for age and gender,” wrote Dr. Rashmi Patel of King’s College London and his colleagues.

The study comprised 21,012 adults who were diagnosed with depression and were receiving secondary mental health care for unipolar depression between April 1, 2006, and March 31, 2013. The researchers used electronic health records to determine which patients had used antidepressants prior to being diagnosed with depression and were subsequently diagnosed with mania or bipolar disorder, as well as the dates of the patients’ diagnoses. Patients were followed up to March 31, 2014.

Just under 1,000 (994) of the study participants were diagnosed with mania or bipolar disorder, representing 10.9 per 1,000 person-years. All types of antidepressants taken by the patients were associated with an increased incidence of mania/bipolar disorder (unadjusted hazard ratio greater than 1.0 for all antidepressants), with incidence rates ranging from 13.1 (tricyclic antidepressants) to 19.1 (trazodone) per 1,000 person-years.

“Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians of the risk of mania in people with depression prior to prescribing antidepressant therapy,” the investigators noted. They disclosed having received research funding from various sources.

Read the full study in BMJ Open (doi: 10.1136/bmjopen-2015-008341).

[email protected]

Patients with unipolar depression who use antidepressants may increase their risk of subsequently being diagnosed with mania/bipolar disorder, a retrospective cohort study conducted in the United Kingdom showed.

“Our findings demonstrate a significant association between antidepressant therapy in patients with unipolar depression and an increased incidence of mania. This association remained significant after adjusting for age and gender,” wrote Dr. Rashmi Patel of King’s College London and his colleagues.

The study comprised 21,012 adults who were diagnosed with depression and were receiving secondary mental health care for unipolar depression between April 1, 2006, and March 31, 2013. The researchers used electronic health records to determine which patients had used antidepressants prior to being diagnosed with depression and were subsequently diagnosed with mania or bipolar disorder, as well as the dates of the patients’ diagnoses. Patients were followed up to March 31, 2014.

Just under 1,000 (994) of the study participants were diagnosed with mania or bipolar disorder, representing 10.9 per 1,000 person-years. All types of antidepressants taken by the patients were associated with an increased incidence of mania/bipolar disorder (unadjusted hazard ratio greater than 1.0 for all antidepressants), with incidence rates ranging from 13.1 (tricyclic antidepressants) to 19.1 (trazodone) per 1,000 person-years.

“Future research should not only focus on which classes of antidepressants are most associated with mania, but also on other associated factors in order to guide clinicians of the risk of mania in people with depression prior to prescribing antidepressant therapy,” the investigators noted. They disclosed having received research funding from various sources.

Read the full study in BMJ Open (doi: 10.1136/bmjopen-2015-008341).

[email protected]

Distal radius fracture is a common injury treated by orthopedic surgeons. Fifty percent or more of distal radius fractures (DRFs) occur with concomitant ulnar styloid fractures (USFs)^1-3 (Figure). The base of the ulnar styloid is the insertion site for portions of the triangular fibrocartilaginous complex (TFCC), which is a primary stabilizer of the distal radioulnar joint (DRUJ).^4,5

Although the topic has received significant attention in the literature, there remains a lack of consensus on the prognostic and clinical significance of USF occurring with DRF. In a series reported by May and colleagues,⁶ all patients with DRUJ instability after DRF also had an USF. Some authors have reported USF as a poor prognostic indicator for DRF, as the occurrence of USF was taken as a proxy for DRUJ instability.^7,8 Conversely, other authors have reported that USF nonunion has no effect on the outcome of volar plating of DRF.^9-11 In a retrospective cohort study of 182 patients, Li and colleagues¹² found no clinically significant difference in outcome between presence or absence of USF with DRF. They also reported that the quality of the DRF reduction was the main determinant of clinical outcome in patients with USF.

We examined a large cohort of patients treated for DRF to identify any possible effect of an associated USF on clinical outcome. All patients provided written informed consent for study inclusion.

Materials and Methods

We retrospectively evaluated 315 cases of DRFs treated (184 operatively, 131 nonoperatively) by members of the Trauma and Hand divisions at our institution over a 7-year period. All cases had sufficient follow-up. In each group, patients with concomitant USF were identified.

At presentation, all displaced fractures underwent closed reduction and immobilization with a sugar-tong splint. Baseline demographic data, injury information, and baseline functional scores on the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and the 36-Item Short Form Health Survey (SF-36) were recorded. Complete histories were taken and physical examinations performed. Standard radiographs of the injured and contralateral wrists were obtained at time of initial injury.¹³

Surgery was indicated in patients with an open fracture and in patients with an inherently unstable fracture pattern, using the instability criteria of Cooney and colleagues.¹⁴ According to these criteria, unstable fractures have lost alignment after closed reduction or have more than 20° of dorsal angulation, more than 10 mm of longitudinal shortening, or more than 2 mm of articular displacement.¹⁴ Patients were treated with either a volar locked plate or bridging external fixation with supplemental Kirschner-wire fixation (usually 2 or 3 wires). Patients in both groups (operative, nonoperative) participated in a formal outpatient therapy program that emphasized active and passive range of motion (ROM) of the finger, wrist motion (if clinically appropriate), and forearm motion. Mean clinical follow-up was 12 months (range, 8-18 months). At each clinic visit, we used a handheld dynamometer to measure ROM, grip strength, and other parameters and compared them with the same parameters on the uninjured side, along with functional outcome.

Differences in demographic characteristics were evaluated with 2 tests—the χ² test for categorical variables (eg, USF incidence, sex, hand dominance, fracture pattern) and the Student t test for continuous variables. Mann-Whitney U tests were used to assess differences between groups in DASH and SF-36 scores at long-term follow-up, as well as differences in ROM and radiographic measurements. Statistical significance was set at P < .05.

Results

DRFs occurred in the dominant-side wrist more commonly (P < .05) in the nonoperative group than in the operative group, though there was no difference in hand dominance and presence or absence of USF. There was a significant correlation of intra-articular fractures in the operative group (70%) compared with the nonoperative group (34%), though no association was found between presence of USF and intra-articular fracture location.

The percentage of concomitant USF was higher (P< .0002) in patients treated operatively (64.1%) than in those treated nonoperatively (38.9%). Mean (SD) pain score was higher (P = .0001) for patients with USF, 1.80 (2.43), than for patients without USF, 0.80 (1.55). This relationship held in both the operative group, 1.95 (2.48) versus 1.04 (1.58) (P = .027), and the nonoperative group, 1.29 (2.09) versus 0.66 (1.53) (P = .048). Similarly, at long-term follow-up for the entire patient cohort, mean (SD) DASH score was negatively affected by presence of USF, 17.03 (18.94) versus 9.21 (14.06) (P = .001), as was mean (SD) SF-36 score, 77.16 (17.69) versus 82.68 (16.10) (P = .022). This relationship also held in the operative and nonoperative groups with respect to pain and DASH scores, though there were only trends in this direction with respect to SF-36 scores. At final follow-up, there was no significant correlation of pain, SF-36, or DASH scores with presence of an intra-articular fracture as compared with an extra-articular fracture.

Time to radiographic healing was not influenced by presence of USF compared with absence of USF (11 vs 10.06 weeks; P > .05). Similarly, healing was no different in intra-articular fractures compared with extra-articular fractures (11 vs 10 weeks; P > .05).

Wrist ROM at final follow-up was not affected by presence of USF; there was no significant difference in wrist flexion, extension, or forearm rotation. In addition, mean (SD) grip strength was unaffected (P = .132) by presence or absence of USF with DRF overall, 45.45% (31.92) of contralateral versus 52.88% (30.03). However, grip strength was negatively affected (P = .035) by presence of USF in the nonoperative group, 37.79% (20.58) versus 54.52% (31.89) (Table).

Discussion

In this study, we determined that presence of USF was a negative predictor for clinical outcomes after DRF. Given the higher incidence of USF in operatively treated DRFs, USF likely represents a higher-energy mechanism of injury. We think these inferior clinical results are attributable to other wrist pathologies that commonly occur with these injuries. These pathologies, identified in the past, include stylocarpal impaction, extensor carpi ulnaris tendinitis, and pain at USF site.^6,10,15 In addition, intracarpal ligamentous injuries, including damage to scapholunate and lunotriquetral ligaments, have been shown to occur in roughly 80% of patients who sustain DRFs, with TFCC injuries occurring at a rate of 60%.¹⁶

Patient outcome is multifactorial and depends on initial injury characteristics, reduction quality, associated injuries, and patient demographics and lifestyle factors. Li and colleagues¹² showed that the quality of the DRF reduction influenced outcomes in these injuries, as the ulnar styloid and its associated TFCC are in turn reduced more anatomically with a restored DRF reduction. This concept applies to injuries treated both operatively and nonoperatively. Similarly, Xarchas and colleagues¹⁷ identified malunion of the ulnar styloid as causing chronic wrist pain because of triquetral impingement, which was treated successfully with ulnar styloidectomy. The poor results at final follow-up in their study may reflect severity of the initial injury, as reported by Frykman.¹⁸

Additional factors may compromise clinical outcomes after such injuries. For example, the effect of USF fragment size on outcome has been suggested and debated. In a retrospective series, May and colleagues⁶ identified fractures involving the base of the ulnar styloid or fovea as potentially destabilizing the DRUJ and in turn leading to chronic instability. This mechanism should be considered a potential contributor to protracted clinical recovery. Other studies have shown that, irrespective of USF fragment size, presence of USF with DRF is not a reliable predictor of DRUJ instability.^2,10,19 In the present study, we simply identified presence or absence of USF, irrespective of either stability or fragment size. In cases in which there was an USF without instability, we fixed the DRF in isolation, without surgically addressing the USF. Our data demonstrated that, even in the absence of DRUJ instability, presence of USF was a negative prognostic indicator for patient outcome.

This study had several limitations. First, its design was retrospective. A prospective study would have been ideal for eliminating certain inherent bias. Second, USF represents a higher association with DRUJ instability.⁶ As there are no validated tests for this clinical entity, identification is somewhat subjective. We did not separate patients by presence or absence of DRUJ instability and thus were not able to directly correlate the connection between USF, DRUJ instability, and poor outcomes in association with DRF. In addition, management of an unstable DRUJ after operative fixation of DRF is controversial, with techniques ranging from splinting in supination to pinning the DRUJ. This inconsistency likely contributed to some error between groups of patients in this study. Last, we did not stratify patients by USF fragment size, as previously discussed, which may have affected outcomes within patient groups.

Our data add to the evidence showing that USF in association with DRF portends poorer clinical outcomes. Concomitant USF should alert the treating physician to a higher-energy mechanism of injury and raise the index of suspicion for other associated injuries in the carpus.

Distal radius fracture is a common injury treated by orthopedic surgeons. Fifty percent or more of distal radius fractures (DRFs) occur with concomitant ulnar styloid fractures (USFs)^1-3 (Figure). The base of the ulnar styloid is the insertion site for portions of the triangular fibrocartilaginous complex (TFCC), which is a primary stabilizer of the distal radioulnar joint (DRUJ).^4,5

Although the topic has received significant attention in the literature, there remains a lack of consensus on the prognostic and clinical significance of USF occurring with DRF. In a series reported by May and colleagues,⁶ all patients with DRUJ instability after DRF also had an USF. Some authors have reported USF as a poor prognostic indicator for DRF, as the occurrence of USF was taken as a proxy for DRUJ instability.^7,8 Conversely, other authors have reported that USF nonunion has no effect on the outcome of volar plating of DRF.^9-11 In a retrospective cohort study of 182 patients, Li and colleagues¹² found no clinically significant difference in outcome between presence or absence of USF with DRF. They also reported that the quality of the DRF reduction was the main determinant of clinical outcome in patients with USF.

We examined a large cohort of patients treated for DRF to identify any possible effect of an associated USF on clinical outcome. All patients provided written informed consent for study inclusion.

Materials and Methods

We retrospectively evaluated 315 cases of DRFs treated (184 operatively, 131 nonoperatively) by members of the Trauma and Hand divisions at our institution over a 7-year period. All cases had sufficient follow-up. In each group, patients with concomitant USF were identified.

At presentation, all displaced fractures underwent closed reduction and immobilization with a sugar-tong splint. Baseline demographic data, injury information, and baseline functional scores on the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and the 36-Item Short Form Health Survey (SF-36) were recorded. Complete histories were taken and physical examinations performed. Standard radiographs of the injured and contralateral wrists were obtained at time of initial injury.¹³

Surgery was indicated in patients with an open fracture and in patients with an inherently unstable fracture pattern, using the instability criteria of Cooney and colleagues.¹⁴ According to these criteria, unstable fractures have lost alignment after closed reduction or have more than 20° of dorsal angulation, more than 10 mm of longitudinal shortening, or more than 2 mm of articular displacement.¹⁴ Patients were treated with either a volar locked plate or bridging external fixation with supplemental Kirschner-wire fixation (usually 2 or 3 wires). Patients in both groups (operative, nonoperative) participated in a formal outpatient therapy program that emphasized active and passive range of motion (ROM) of the finger, wrist motion (if clinically appropriate), and forearm motion. Mean clinical follow-up was 12 months (range, 8-18 months). At each clinic visit, we used a handheld dynamometer to measure ROM, grip strength, and other parameters and compared them with the same parameters on the uninjured side, along with functional outcome.

Differences in demographic characteristics were evaluated with 2 tests—the χ² test for categorical variables (eg, USF incidence, sex, hand dominance, fracture pattern) and the Student t test for continuous variables. Mann-Whitney U tests were used to assess differences between groups in DASH and SF-36 scores at long-term follow-up, as well as differences in ROM and radiographic measurements. Statistical significance was set at P < .05.

Results

DRFs occurred in the dominant-side wrist more commonly (P < .05) in the nonoperative group than in the operative group, though there was no difference in hand dominance and presence or absence of USF. There was a significant correlation of intra-articular fractures in the operative group (70%) compared with the nonoperative group (34%), though no association was found between presence of USF and intra-articular fracture location.

The percentage of concomitant USF was higher (P< .0002) in patients treated operatively (64.1%) than in those treated nonoperatively (38.9%). Mean (SD) pain score was higher (P = .0001) for patients with USF, 1.80 (2.43), than for patients without USF, 0.80 (1.55). This relationship held in both the operative group, 1.95 (2.48) versus 1.04 (1.58) (P = .027), and the nonoperative group, 1.29 (2.09) versus 0.66 (1.53) (P = .048). Similarly, at long-term follow-up for the entire patient cohort, mean (SD) DASH score was negatively affected by presence of USF, 17.03 (18.94) versus 9.21 (14.06) (P = .001), as was mean (SD) SF-36 score, 77.16 (17.69) versus 82.68 (16.10) (P = .022). This relationship also held in the operative and nonoperative groups with respect to pain and DASH scores, though there were only trends in this direction with respect to SF-36 scores. At final follow-up, there was no significant correlation of pain, SF-36, or DASH scores with presence of an intra-articular fracture as compared with an extra-articular fracture.

Time to radiographic healing was not influenced by presence of USF compared with absence of USF (11 vs 10.06 weeks; P > .05). Similarly, healing was no different in intra-articular fractures compared with extra-articular fractures (11 vs 10 weeks; P > .05).

Wrist ROM at final follow-up was not affected by presence of USF; there was no significant difference in wrist flexion, extension, or forearm rotation. In addition, mean (SD) grip strength was unaffected (P = .132) by presence or absence of USF with DRF overall, 45.45% (31.92) of contralateral versus 52.88% (30.03). However, grip strength was negatively affected (P = .035) by presence of USF in the nonoperative group, 37.79% (20.58) versus 54.52% (31.89) (Table).

Discussion

In this study, we determined that presence of USF was a negative predictor for clinical outcomes after DRF. Given the higher incidence of USF in operatively treated DRFs, USF likely represents a higher-energy mechanism of injury. We think these inferior clinical results are attributable to other wrist pathologies that commonly occur with these injuries. These pathologies, identified in the past, include stylocarpal impaction, extensor carpi ulnaris tendinitis, and pain at USF site.^6,10,15 In addition, intracarpal ligamentous injuries, including damage to scapholunate and lunotriquetral ligaments, have been shown to occur in roughly 80% of patients who sustain DRFs, with TFCC injuries occurring at a rate of 60%.¹⁶

Patient outcome is multifactorial and depends on initial injury characteristics, reduction quality, associated injuries, and patient demographics and lifestyle factors. Li and colleagues¹² showed that the quality of the DRF reduction influenced outcomes in these injuries, as the ulnar styloid and its associated TFCC are in turn reduced more anatomically with a restored DRF reduction. This concept applies to injuries treated both operatively and nonoperatively. Similarly, Xarchas and colleagues¹⁷ identified malunion of the ulnar styloid as causing chronic wrist pain because of triquetral impingement, which was treated successfully with ulnar styloidectomy. The poor results at final follow-up in their study may reflect severity of the initial injury, as reported by Frykman.¹⁸

Additional factors may compromise clinical outcomes after such injuries. For example, the effect of USF fragment size on outcome has been suggested and debated. In a retrospective series, May and colleagues⁶ identified fractures involving the base of the ulnar styloid or fovea as potentially destabilizing the DRUJ and in turn leading to chronic instability. This mechanism should be considered a potential contributor to protracted clinical recovery. Other studies have shown that, irrespective of USF fragment size, presence of USF with DRF is not a reliable predictor of DRUJ instability.^2,10,19 In the present study, we simply identified presence or absence of USF, irrespective of either stability or fragment size. In cases in which there was an USF without instability, we fixed the DRF in isolation, without surgically addressing the USF. Our data demonstrated that, even in the absence of DRUJ instability, presence of USF was a negative prognostic indicator for patient outcome.

This study had several limitations. First, its design was retrospective. A prospective study would have been ideal for eliminating certain inherent bias. Second, USF represents a higher association with DRUJ instability.⁶ As there are no validated tests for this clinical entity, identification is somewhat subjective. We did not separate patients by presence or absence of DRUJ instability and thus were not able to directly correlate the connection between USF, DRUJ instability, and poor outcomes in association with DRF. In addition, management of an unstable DRUJ after operative fixation of DRF is controversial, with techniques ranging from splinting in supination to pinning the DRUJ. This inconsistency likely contributed to some error between groups of patients in this study. Last, we did not stratify patients by USF fragment size, as previously discussed, which may have affected outcomes within patient groups.

Our data add to the evidence showing that USF in association with DRF portends poorer clinical outcomes. Concomitant USF should alert the treating physician to a higher-energy mechanism of injury and raise the index of suspicion for other associated injuries in the carpus.

Distal radius fracture is a common injury treated by orthopedic surgeons. Fifty percent or more of distal radius fractures (DRFs) occur with concomitant ulnar styloid fractures (USFs)^1-3 (Figure). The base of the ulnar styloid is the insertion site for portions of the triangular fibrocartilaginous complex (TFCC), which is a primary stabilizer of the distal radioulnar joint (DRUJ).^4,5

Although the topic has received significant attention in the literature, there remains a lack of consensus on the prognostic and clinical significance of USF occurring with DRF. In a series reported by May and colleagues,⁶ all patients with DRUJ instability after DRF also had an USF. Some authors have reported USF as a poor prognostic indicator for DRF, as the occurrence of USF was taken as a proxy for DRUJ instability.^7,8 Conversely, other authors have reported that USF nonunion has no effect on the outcome of volar plating of DRF.^9-11 In a retrospective cohort study of 182 patients, Li and colleagues¹² found no clinically significant difference in outcome between presence or absence of USF with DRF. They also reported that the quality of the DRF reduction was the main determinant of clinical outcome in patients with USF.

We examined a large cohort of patients treated for DRF to identify any possible effect of an associated USF on clinical outcome. All patients provided written informed consent for study inclusion.

Materials and Methods

We retrospectively evaluated 315 cases of DRFs treated (184 operatively, 131 nonoperatively) by members of the Trauma and Hand divisions at our institution over a 7-year period. All cases had sufficient follow-up. In each group, patients with concomitant USF were identified.

At presentation, all displaced fractures underwent closed reduction and immobilization with a sugar-tong splint. Baseline demographic data, injury information, and baseline functional scores on the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and the 36-Item Short Form Health Survey (SF-36) were recorded. Complete histories were taken and physical examinations performed. Standard radiographs of the injured and contralateral wrists were obtained at time of initial injury.¹³

Surgery was indicated in patients with an open fracture and in patients with an inherently unstable fracture pattern, using the instability criteria of Cooney and colleagues.¹⁴ According to these criteria, unstable fractures have lost alignment after closed reduction or have more than 20° of dorsal angulation, more than 10 mm of longitudinal shortening, or more than 2 mm of articular displacement.¹⁴ Patients were treated with either a volar locked plate or bridging external fixation with supplemental Kirschner-wire fixation (usually 2 or 3 wires). Patients in both groups (operative, nonoperative) participated in a formal outpatient therapy program that emphasized active and passive range of motion (ROM) of the finger, wrist motion (if clinically appropriate), and forearm motion. Mean clinical follow-up was 12 months (range, 8-18 months). At each clinic visit, we used a handheld dynamometer to measure ROM, grip strength, and other parameters and compared them with the same parameters on the uninjured side, along with functional outcome.

Differences in demographic characteristics were evaluated with 2 tests—the χ² test for categorical variables (eg, USF incidence, sex, hand dominance, fracture pattern) and the Student t test for continuous variables. Mann-Whitney U tests were used to assess differences between groups in DASH and SF-36 scores at long-term follow-up, as well as differences in ROM and radiographic measurements. Statistical significance was set at P < .05.

Results

DRFs occurred in the dominant-side wrist more commonly (P < .05) in the nonoperative group than in the operative group, though there was no difference in hand dominance and presence or absence of USF. There was a significant correlation of intra-articular fractures in the operative group (70%) compared with the nonoperative group (34%), though no association was found between presence of USF and intra-articular fracture location.

The percentage of concomitant USF was higher (P< .0002) in patients treated operatively (64.1%) than in those treated nonoperatively (38.9%). Mean (SD) pain score was higher (P = .0001) for patients with USF, 1.80 (2.43), than for patients without USF, 0.80 (1.55). This relationship held in both the operative group, 1.95 (2.48) versus 1.04 (1.58) (P = .027), and the nonoperative group, 1.29 (2.09) versus 0.66 (1.53) (P = .048). Similarly, at long-term follow-up for the entire patient cohort, mean (SD) DASH score was negatively affected by presence of USF, 17.03 (18.94) versus 9.21 (14.06) (P = .001), as was mean (SD) SF-36 score, 77.16 (17.69) versus 82.68 (16.10) (P = .022). This relationship also held in the operative and nonoperative groups with respect to pain and DASH scores, though there were only trends in this direction with respect to SF-36 scores. At final follow-up, there was no significant correlation of pain, SF-36, or DASH scores with presence of an intra-articular fracture as compared with an extra-articular fracture.

Time to radiographic healing was not influenced by presence of USF compared with absence of USF (11 vs 10.06 weeks; P > .05). Similarly, healing was no different in intra-articular fractures compared with extra-articular fractures (11 vs 10 weeks; P > .05).

Wrist ROM at final follow-up was not affected by presence of USF; there was no significant difference in wrist flexion, extension, or forearm rotation. In addition, mean (SD) grip strength was unaffected (P = .132) by presence or absence of USF with DRF overall, 45.45% (31.92) of contralateral versus 52.88% (30.03). However, grip strength was negatively affected (P = .035) by presence of USF in the nonoperative group, 37.79% (20.58) versus 54.52% (31.89) (Table).

Discussion

In this study, we determined that presence of USF was a negative predictor for clinical outcomes after DRF. Given the higher incidence of USF in operatively treated DRFs, USF likely represents a higher-energy mechanism of injury. We think these inferior clinical results are attributable to other wrist pathologies that commonly occur with these injuries. These pathologies, identified in the past, include stylocarpal impaction, extensor carpi ulnaris tendinitis, and pain at USF site.^6,10,15 In addition, intracarpal ligamentous injuries, including damage to scapholunate and lunotriquetral ligaments, have been shown to occur in roughly 80% of patients who sustain DRFs, with TFCC injuries occurring at a rate of 60%.¹⁶

Patient outcome is multifactorial and depends on initial injury characteristics, reduction quality, associated injuries, and patient demographics and lifestyle factors. Li and colleagues¹² showed that the quality of the DRF reduction influenced outcomes in these injuries, as the ulnar styloid and its associated TFCC are in turn reduced more anatomically with a restored DRF reduction. This concept applies to injuries treated both operatively and nonoperatively. Similarly, Xarchas and colleagues¹⁷ identified malunion of the ulnar styloid as causing chronic wrist pain because of triquetral impingement, which was treated successfully with ulnar styloidectomy. The poor results at final follow-up in their study may reflect severity of the initial injury, as reported by Frykman.¹⁸

Additional factors may compromise clinical outcomes after such injuries. For example, the effect of USF fragment size on outcome has been suggested and debated. In a retrospective series, May and colleagues⁶ identified fractures involving the base of the ulnar styloid or fovea as potentially destabilizing the DRUJ and in turn leading to chronic instability. This mechanism should be considered a potential contributor to protracted clinical recovery. Other studies have shown that, irrespective of USF fragment size, presence of USF with DRF is not a reliable predictor of DRUJ instability.^2,10,19 In the present study, we simply identified presence or absence of USF, irrespective of either stability or fragment size. In cases in which there was an USF without instability, we fixed the DRF in isolation, without surgically addressing the USF. Our data demonstrated that, even in the absence of DRUJ instability, presence of USF was a negative prognostic indicator for patient outcome.

This study had several limitations. First, its design was retrospective. A prospective study would have been ideal for eliminating certain inherent bias. Second, USF represents a higher association with DRUJ instability.⁶ As there are no validated tests for this clinical entity, identification is somewhat subjective. We did not separate patients by presence or absence of DRUJ instability and thus were not able to directly correlate the connection between USF, DRUJ instability, and poor outcomes in association with DRF. In addition, management of an unstable DRUJ after operative fixation of DRF is controversial, with techniques ranging from splinting in supination to pinning the DRUJ. This inconsistency likely contributed to some error between groups of patients in this study. Last, we did not stratify patients by USF fragment size, as previously discussed, which may have affected outcomes within patient groups.

Our data add to the evidence showing that USF in association with DRF portends poorer clinical outcomes. Concomitant USF should alert the treating physician to a higher-energy mechanism of injury and raise the index of suspicion for other associated injuries in the carpus.

The 3-month-old infant presents to the emergency department with a fever of 101° F. The emergency physician decides the infant looks ill enough to warrant some investigation. A urinalysis indicates a urinary tract infection. I am consulted to complete the admission to the hospital. The question arises, “Is a lumbar puncture indicated to rule out meningitis?”

I’ve been down this pathway many times. For years I have relied on a meta-analysis which corrected the bias of an old article from 1972.¹ Multiple studies in the 2000-2010 time frame have shown that the risk of concurrent meningitis in a young infant with a UTI is vanishingly small. It is much less than 2%, with many studies finding 0%. So on a typical day, my answer is no tap if there is no clinical suggestion of meningitis.

Hospital medicine has recently focused on reducing overdiagnosis and overtreatment. When you only occasionally admit patients to the hospital, untoward events appear random and uncommon. When you work there day in and day out, you appreciate that all medical interventions have risks and costs.

A recent editorial raised the question of stewardship in medicine.² It asked why physicians would choose a very expensive drug when there is little evidence of its superiority over a much cheaper predecessor. Physicians, whose actions influence a $3 trillion industry, have not embraced stewardship as a major component of their professional responsibilities. The physician does have a fiduciary duty toward the patient. The physician recommends the best care possible to achieve the patient’s goals of care. Dentistry is distinctly different in this regard. Dentists often have several ways of repairing decayed teeth. Various types of fillings are available. Gold fillings are more expensive. Newer implants are several times more expensive than crowns. Dentists routinely adjust their treatment plan based on what the patient can afford.

While most other industries have market competition and profitability as incentives to avoid extravagance, U.S. health care seems unbridled by fiscal responsibility. The news that a small pharmaceutical company had raised the price of an old generic antibiotic by 5000%³ exposed the irrationality and capriciousness⁴ of the pricing of medications in the United States. Many politicians decried the behavior but to little effect. Most consumer products, especially computers, become more powerful and cheaper with each decade. Health care does not follow this pattern

There are many factors that influence physician behavior. Concerns about malpractice may bias physicians toward expensive overtreatment. Modern medical research is usually published expounding on the benefits of a new technology over a previous therapy without any acknowledgment that the newer and more expensive treatment may have a downside. This biases people to use the latest and greatest treatment even though it may have only demonstrated noninferiority in its trials.

I try to use evidence-based medicine when it is available. In the clinical case described earlier, I indicate to the emergency doctor that unless there is a clinical impression of coexisting meningitis, the lumbar puncture is not indicated. I cite the meta-analysis as I have many times before. But this night is different. I am simultaneously admitting a teenager whose gastrostomy tube had become dislodged and couldn’t be replaced. This neurologically devastated child had had meningitis as an infant. He is a stark reminder of the consequences of a missed diagnosis.

The parents of that child have provided him wonderful care. His skin is in excellent condition. His moderate contractures are testimony to dedicated stretching regimens at home. It is evident that the parents love the child as he is. But I am sure they would give anything to have avoided this scenario and to reverse the consequences of that meningitis. And so, the best evidence we have, that the risk of meningitis in an infant is low, is not as reassuring to me on this night. At 3 a.m., the juxtaposition of the two patients is unsettling. Is the risk low enough? Would that new test⁵, serum procalcitonin, help me to make a better decision? How certain must I be that an intervention is unnecessary?

Health care policy, economics, and practice guidelines can be debated with detached objectivity around a conference table in the middle of the day. The trepidation in an emergency room at 3 a.m. is different. This is my patient. I am his doctor. That is the heart of medical ethics.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].

References

1. “How common is co-existing meningitis in infants with urinary tract infection?” on Bestbets.org.

2. “Why do doctors choose a $2,000 cure when a $50 one is just as good?” by Andrew Lam, Washington Post, Dec. 10, 2015.

3. “Drug Goes From $13.50 a Tablet to $750, Overnight” by Andrew Pollack, New York Times, Sept. 20, 2015.

4. “How an $84,000 drug got its price: ‘Let’s hold our position … whatever the headlines’ ” by Carolyn Y. Johnson and Brady Dennis, Washington Post, Dec. 1, 2015.

5. JAMA Pediatr. Published online, 2015 Nov 23. doi:10.1001/jamapediatrics.2015.3267.

The 3-month-old infant presents to the emergency department with a fever of 101° F. The emergency physician decides the infant looks ill enough to warrant some investigation. A urinalysis indicates a urinary tract infection. I am consulted to complete the admission to the hospital. The question arises, “Is a lumbar puncture indicated to rule out meningitis?”

I’ve been down this pathway many times. For years I have relied on a meta-analysis which corrected the bias of an old article from 1972.¹ Multiple studies in the 2000-2010 time frame have shown that the risk of concurrent meningitis in a young infant with a UTI is vanishingly small. It is much less than 2%, with many studies finding 0%. So on a typical day, my answer is no tap if there is no clinical suggestion of meningitis.

Hospital medicine has recently focused on reducing overdiagnosis and overtreatment. When you only occasionally admit patients to the hospital, untoward events appear random and uncommon. When you work there day in and day out, you appreciate that all medical interventions have risks and costs.

A recent editorial raised the question of stewardship in medicine.² It asked why physicians would choose a very expensive drug when there is little evidence of its superiority over a much cheaper predecessor. Physicians, whose actions influence a $3 trillion industry, have not embraced stewardship as a major component of their professional responsibilities. The physician does have a fiduciary duty toward the patient. The physician recommends the best care possible to achieve the patient’s goals of care. Dentistry is distinctly different in this regard. Dentists often have several ways of repairing decayed teeth. Various types of fillings are available. Gold fillings are more expensive. Newer implants are several times more expensive than crowns. Dentists routinely adjust their treatment plan based on what the patient can afford.

While most other industries have market competition and profitability as incentives to avoid extravagance, U.S. health care seems unbridled by fiscal responsibility. The news that a small pharmaceutical company had raised the price of an old generic antibiotic by 5000%³ exposed the irrationality and capriciousness⁴ of the pricing of medications in the United States. Many politicians decried the behavior but to little effect. Most consumer products, especially computers, become more powerful and cheaper with each decade. Health care does not follow this pattern

There are many factors that influence physician behavior. Concerns about malpractice may bias physicians toward expensive overtreatment. Modern medical research is usually published expounding on the benefits of a new technology over a previous therapy without any acknowledgment that the newer and more expensive treatment may have a downside. This biases people to use the latest and greatest treatment even though it may have only demonstrated noninferiority in its trials.

I try to use evidence-based medicine when it is available. In the clinical case described earlier, I indicate to the emergency doctor that unless there is a clinical impression of coexisting meningitis, the lumbar puncture is not indicated. I cite the meta-analysis as I have many times before. But this night is different. I am simultaneously admitting a teenager whose gastrostomy tube had become dislodged and couldn’t be replaced. This neurologically devastated child had had meningitis as an infant. He is a stark reminder of the consequences of a missed diagnosis.

The parents of that child have provided him wonderful care. His skin is in excellent condition. His moderate contractures are testimony to dedicated stretching regimens at home. It is evident that the parents love the child as he is. But I am sure they would give anything to have avoided this scenario and to reverse the consequences of that meningitis. And so, the best evidence we have, that the risk of meningitis in an infant is low, is not as reassuring to me on this night. At 3 a.m., the juxtaposition of the two patients is unsettling. Is the risk low enough? Would that new test⁵, serum procalcitonin, help me to make a better decision? How certain must I be that an intervention is unnecessary?

Health care policy, economics, and practice guidelines can be debated with detached objectivity around a conference table in the middle of the day. The trepidation in an emergency room at 3 a.m. is different. This is my patient. I am his doctor. That is the heart of medical ethics.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].

References

1. “How common is co-existing meningitis in infants with urinary tract infection?” on Bestbets.org.

2. “Why do doctors choose a $2,000 cure when a $50 one is just as good?” by Andrew Lam, Washington Post, Dec. 10, 2015.

3. “Drug Goes From $13.50 a Tablet to $750, Overnight” by Andrew Pollack, New York Times, Sept. 20, 2015.

4. “How an $84,000 drug got its price: ‘Let’s hold our position … whatever the headlines’ ” by Carolyn Y. Johnson and Brady Dennis, Washington Post, Dec. 1, 2015.

5. JAMA Pediatr. Published online, 2015 Nov 23. doi:10.1001/jamapediatrics.2015.3267.

The 3-month-old infant presents to the emergency department with a fever of 101° F. The emergency physician decides the infant looks ill enough to warrant some investigation. A urinalysis indicates a urinary tract infection. I am consulted to complete the admission to the hospital. The question arises, “Is a lumbar puncture indicated to rule out meningitis?”

I’ve been down this pathway many times. For years I have relied on a meta-analysis which corrected the bias of an old article from 1972.¹ Multiple studies in the 2000-2010 time frame have shown that the risk of concurrent meningitis in a young infant with a UTI is vanishingly small. It is much less than 2%, with many studies finding 0%. So on a typical day, my answer is no tap if there is no clinical suggestion of meningitis.

Hospital medicine has recently focused on reducing overdiagnosis and overtreatment. When you only occasionally admit patients to the hospital, untoward events appear random and uncommon. When you work there day in and day out, you appreciate that all medical interventions have risks and costs.

A recent editorial raised the question of stewardship in medicine.² It asked why physicians would choose a very expensive drug when there is little evidence of its superiority over a much cheaper predecessor. Physicians, whose actions influence a $3 trillion industry, have not embraced stewardship as a major component of their professional responsibilities. The physician does have a fiduciary duty toward the patient. The physician recommends the best care possible to achieve the patient’s goals of care. Dentistry is distinctly different in this regard. Dentists often have several ways of repairing decayed teeth. Various types of fillings are available. Gold fillings are more expensive. Newer implants are several times more expensive than crowns. Dentists routinely adjust their treatment plan based on what the patient can afford.

While most other industries have market competition and profitability as incentives to avoid extravagance, U.S. health care seems unbridled by fiscal responsibility. The news that a small pharmaceutical company had raised the price of an old generic antibiotic by 5000%³ exposed the irrationality and capriciousness⁴ of the pricing of medications in the United States. Many politicians decried the behavior but to little effect. Most consumer products, especially computers, become more powerful and cheaper with each decade. Health care does not follow this pattern

There are many factors that influence physician behavior. Concerns about malpractice may bias physicians toward expensive overtreatment. Modern medical research is usually published expounding on the benefits of a new technology over a previous therapy without any acknowledgment that the newer and more expensive treatment may have a downside. This biases people to use the latest and greatest treatment even though it may have only demonstrated noninferiority in its trials.

I try to use evidence-based medicine when it is available. In the clinical case described earlier, I indicate to the emergency doctor that unless there is a clinical impression of coexisting meningitis, the lumbar puncture is not indicated. I cite the meta-analysis as I have many times before. But this night is different. I am simultaneously admitting a teenager whose gastrostomy tube had become dislodged and couldn’t be replaced. This neurologically devastated child had had meningitis as an infant. He is a stark reminder of the consequences of a missed diagnosis.

The parents of that child have provided him wonderful care. His skin is in excellent condition. His moderate contractures are testimony to dedicated stretching regimens at home. It is evident that the parents love the child as he is. But I am sure they would give anything to have avoided this scenario and to reverse the consequences of that meningitis. And so, the best evidence we have, that the risk of meningitis in an infant is low, is not as reassuring to me on this night. At 3 a.m., the juxtaposition of the two patients is unsettling. Is the risk low enough? Would that new test⁵, serum procalcitonin, help me to make a better decision? How certain must I be that an intervention is unnecessary?

Health care policy, economics, and practice guidelines can be debated with detached objectivity around a conference table in the middle of the day. The trepidation in an emergency room at 3 a.m. is different. This is my patient. I am his doctor. That is the heart of medical ethics.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].

References

1. “How common is co-existing meningitis in infants with urinary tract infection?” on Bestbets.org.

2. “Why do doctors choose a $2,000 cure when a $50 one is just as good?” by Andrew Lam, Washington Post, Dec. 10, 2015.

3. “Drug Goes From $13.50 a Tablet to $750, Overnight” by Andrew Pollack, New York Times, Sept. 20, 2015.

4. “How an $84,000 drug got its price: ‘Let’s hold our position … whatever the headlines’ ” by Carolyn Y. Johnson and Brady Dennis, Washington Post, Dec. 1, 2015.

5. JAMA Pediatr. Published online, 2015 Nov 23. doi:10.1001/jamapediatrics.2015.3267.

Elbow epicondylitis is a painful condition caused by overuse and development of tendon degeneration. It is one of the most common elbow problems in adults, occurring both laterally and medially. “Tennis elbow” or lateral epicondylitis is diagnosed 7 to 10 times more often than the medial form, “golfer’s elbow.”¹ Although these injuries are often associated with racquet sports, activities such as bowling and weightlifting and the professions of carpentry, plumbing, and meat-cutting have been described as causes.^2,3

Elbow epicondylitis is thought to be the result of multiple microtraumatic events that cause disruption of the internal structure of the tendon and degeneration of the cells and matrix.⁴ Lesions caused by chronic overuse are now commonly called tendinosis and are not considered inflammatory in nature. Although the term tendinitis is used frequently and indiscriminately, histopathologic studies have shown that specimens of tendon obtained from areas of chronic overuse do not contain large numbers of macrophages, lymphocytes, or neutrophils.⁵ Rather, tendinosis appears to be a degenerative process that is characterized by the presence of dense populations of fibroblasts, vascular hyperplasia, and disorganized collagen. This constellation of findings has been termed by some authors as angiofibroblastic hyperplasia.⁶

Conservative care for the treatment of chronic tendinosis has been well described and is often successful. Treatment consists of rest, ice, compression, and elevation in the acute phase. This can be followed with bracing, activity modification, physical therapy, oral nonsteroidal anti-inflammatory drugs, topical applications, and injections of cortisone or platelet-rich plasma. When conservative treatment fails, surgical intervention may be considered. Procedures for the treatment of lateral epicondylitis include open débridement and release, arthroscopic débridement, percutaneous release, and radiofrequency (RF) coblation. The goals of operative treatment are to resect pathological material, to stimulate neovascularization by producing focused local bleeding, and to create a healthy scar while doing the least possible structural damage to surrounding tissues.⁴

The efficacy of a bipolar RF-based approach for using microtenotomy was first recognized when researchers studied the effects of transmyocardial revascularization for treating congestive heart failure.⁷ The use of RF- and laser-based transmyocardial revascularization initiated an angiogenic response in degenerated (ischemic) heart tissue. This success led to investigating the use of a RF-based approach for performing microtenotomy. Preclinical studies demonstrated that RF-based microtenotomy was effective for stimulating an angiogenic-healing response in tendon tissue.⁸ Histologic evaluation of treated tendons showed an early inflammatory response, with new blood-vessel formation by 28 days. In 2005, short-term results of this technique were published.⁹ This preliminary prospective case series showed that the treatment was safe and effectively improved or eliminated clinical symptoms.⁹ In the present midterm study, we hypothesized that pain scores would improve after RF microtenotomy and that these favorable results would continue to be observed over a longer term postoperatively.

Materials and Methods

Patients

This was a prospective, nonrandomized, single-center clinical study. After receiving institutional review board approval, patients who were 18 to 65 years of age with a diagnosis of tendinosis were approached for enrollment. For inclusion, patients had to be symptomatic for at least 6 months and had to have failed extensive conservative treatments. Nonoperative treatment included activity modification, enrollment in a facility- or home-based exercise program, bracing, oral nonsteroidal anti-inflammatory medication, and cortisone injection. Candidates with diabetes, confirmed or suspected pregnancy, surgery in the same tendon, implanted hardware adjacent to the target treatment region, or who were receiving care under workers’ compensation or had litigation-related injury were excluded. A single clinician performed a thorough medical history and clinical evaluation. The clinical follow-up and data collection were performed by an independent medical technician.

Clinical Outcomes

Pain status was assessed by using a visual analog scale (VAS). Postoperative clinical assessment was conducted within the first 2 days; at 7 to 10 days; at 4 to 6 weeks; and at 3, 6, 12, and 24 months, up to 9 years postoperatively. The VAS scales were completed annually up to 9 years after the procedure.

The percent improvement of VAS score was calculated. This value represented the difference between the patient’s preoperative and most recent VAS assessments. Failure of the procedure was defined as less than 50% improvement of the VAS score.

The RF-Based Microtenotomy Device

The Topaz Microdebrider (ArthroCare), connected to a System 2000 generator at setting 4 (175 V-RMS), was used to perform the RF-based microtenotomy. The device uses a controlled plasma-mediated RF-based process (coblation). Radiofrequency energy is used to excite the electrolytes in a conductive medium, such as a saline solution, to create precisely focused plasma. The energized particles in the plasma have sufficient energy to break molecular bonds,^10,11 excising or dissolving (ie, ablating) soft tissue at relatively low temperatures (typically, 40°-70° C).^12,13 The diameter of the active tip of the Topaz device is 0.8 mm.

Surgical Procedure

The senior author performed the majority of procedures in this study. Near the end of the series, the senior author’s associate also performed procedures. The symptomatic area of the tendon was identified and marked while the patient was alert. After the patient was positioned appropriately, light sedation was administered. A tourniquet was placed over the treatment limb and inflated to 250 mm Hg. A small incision, approximately 3 cm in length, was made over the marked treatment site to expose the involved tendon. After initiating sterile isotonic saline flow of 1 drop every 1 to 2 seconds from a line connected to the RF system, the tip of the device was placed on the tendon perpendicular to its surface (Figure 1). Using a light touch, it was activated for 500 milliseconds using a timer accessory for the control box. Five to 8 grams of pressure were applied with the device to penetrate the tendon and achieve successful ablation. The RF applications were performed at 5-mm intervals, to create a grid-like pattern on and throughout the symptomatic tendon area. The tendon was perforated to a depth of several millimeters on every second or third application throughout the treatment grid. After treatment of the symptomatic area, the wound was irrigated with copious amounts of normal saline solution and closed with interrupted nylon suture. Local anesthetic was injected only in the skin and in subcutaneous tissue. Standard wound dressings were applied. In the immediate postoperative period, the patient was advised to begin gentle active and passive range-of-motion exercises. Each patient was evaluated at 1 week postoperatively. At 6 weeks, patients were permitted to increase the intensity of their activities. Return to sports and heavy lifting was allowed once the patient was asymptomatic and had achieved full strength and range of motion; this typically occurred at 6 to 9 weeks after surgery.

Statistical Analysis

Normally distributed data were described using standard parametric statistics (ie, mean and standard deviation); non-normally distributed data were characterized using nonparametric descriptors (ie, median and quartiles). Statistical evaluation of improvement in pain status was performed by calculating 99% confidence intervals and using the Student t test for change between subsequent time points. Use of confidence intervals provides a descriptive analysis of the observed treatment effect, while permitting determination of statistical relevance. In all statistical testing, confidence bounds not including 0 were considered statistically significant. Probability of P ≤ .01 for committing type I experiment-wise error (rejecting a true null hypothesis) was selected for all statistical testing because of our lack of a control group, small sample size, and evaluation of multiple postoperative time points.

Results

Eighty consecutive patients with tendinosis of the elbow were included in this study. Sixty-nine patients were treated for lateral epicondylitis and 11 for medial epicondylitis. The average age of the patients (33 women, 47 men) was 50 years. The duration of follow-up evaluation ranged from 6 months to 9 years (mean, 2.5 years; median, 2 years). The Table presents the VAS improvement for these patients after the RF microtenotomy.

Within the lateral epicondylitis group, 91% (63/69) of the patients reported a successful outcome. The postoperative VAS improved to 1.3 from 6.9, which demonstrated an 81% improvement. Of the 6 patients that did not improve, 2 underwent repeat surgery.

Among the patients treated for medial epicondylitis, 91% (10/11) reported improvement in symptoms. The postoperative VAS improved to 1.3 from 6.1, a 79% improvement. One patient did not improve and did not undergo repeat surgery.

Discussion

For the treatment of medial and lateral elbow epicondylitis, RF microtenotomy is successful in 91% of patients. Symptomatic improvement was observed up to 9 years postoperatively. During this study, no complications were recorded; 7 treatment failures occurred. When compared with other techniques, the results with RF microtenotomy are equivalent or better.

In a retrospective study, Szabo and colleagues¹⁴ compared open, arthroscopic, and percutaneous release for lateral elbow tendinosis. They found the 3 methods to be highly effective for the treatment of tendinosis with no significant difference between them. Resection of the epicondyle and transfer of the anconeus muscle was found to be effective (94%) in a retrospective study by Almquist and colleagues.¹⁵ Dunn and coauthors¹⁶ reported a 97% success rate at 10 to 14 years postoperatively with a mini-open technique. Rubenthaler and colleagues¹⁷ showed 88% effectiveness for the open technique and 93% for the arthroscopic technique. With arthroscopic release of the extensor carpi radialis brevis tendon, Lattermann and coauthors¹⁸ reported clinical improvement in 94% of patients. In a study by Rose and colleagues,¹⁹ denervation of the lateral epicondyle was effective in relieving pain in 80% of patients who had had a positive response to a local anesthetic block. In a recently published study by Koh and coauthors,²⁰ 19 of 20 patients experienced a favorable outcome after treatment with ultrasonic microresection.

Regardless of surgical methods and their reported success rate, complications are associated with elbow surgery. Postoperative problems may include restricted function, elbow instability, persistent muscle weakness, and painful neuroma of the posterior cutaneous nerve.^10,21,22 The recent introduction of arthroscopic release offers the potential for less morbidity and enables visualization of the elbow joint. However, disadvantages of the arthroscopic approach include violation of the joint for extra-articular pathology, increased operative time and cost, and neurovascular complications. Additionally, it is possible that the entire spectrum of extra-articular tendinosis cannot be effectively identified arthroscopically.²³ In a prospective, randomized study, Meknas and colleagues²⁴ compared RF microtenotomy with extensor tendon release and repair. They showed that patients treated with RF-microtenotomy experienced earlier pain relief and improved grip strength over the release group.

Different proposed mechanisms of action have been described to explain the favorable effects of the RF-based microtenotomy procedure, such as induced healing by an angiogenic response in the tendon tissue. In an animal study, Harwood and colleagues⁸ showed that low-dose RF-based plasma microtenotomy has the ability to stimulate angiogenic growth factors in tendons, such as α_v integrin and vascular endothelial growth factor. These factors have been shown to be associated with healing.⁸ Early inflammatory response with new-vessel formation after 28 days was found in another animal study using the same method.²⁵ Evaluation of RF-based methods in a prospective controlled laboratory study using a rabbit-tendon model showed histologic evidence of early inflammation with development of neovasculature after treatment.⁸ A later histologic study using an aged Achilles rabbit tendon model was performed to evaluate the effect of RF-based plasma microtenotomy on collagen remodeling.²⁵ The degenerated tendon showed gaps, few normal crimpings, and a lack of reflectivity under polarized light. At 9 days after treatment, the treated tendon showed localized irregular crimpings, and, at 30 days, it showed regular crimping, tightly dense collagen fibers, and hypercellularity with good reflectivity. This was similar in appearance to a normal nondegenerated tendon (Figures 2A-2D). The RF-treated tendon also demonstrated an increase in production of insulin-like growth factor-1, β-fibroblast growth factor-1, α_v integrin, and vascular endothelial growth factor.

Pathologic nerve ingrowth or nerve irritation in the tendon substance has been considered a possible cause of the pain experienced with tendinosis. Radiofrequency treatment has been shown to induce acute degeneration and ablation of sensory nerve fibers.²⁶ These degenerated nerve fibers were observed to regenerate at 90 days after treatment.²⁷ These findings provide potential evidence for early pain relief that is maintained long term as the nerves regenerate.

This midterm follow-up of patients with elbow epicondylitis has shown that RF-based microtenotomy can produce successful, durable results. Microtenotomy is a technically simple procedure to perform and is associated with a rapid and uncomplicated recovery. It is safe and can effectively eliminate or markedly reduce clinical symptoms.

Limitations

Lateral epicondylitis has been described as a self-limited disease, with resolution of symptoms at 12 to 18 months with conservative treatment. This perspective challenges the indication of any proposed surgical treatment for the condition. Although the results of this research demonstrated the benefits of RF microtenotomy, there are inherent limitations of the study design. The study lacks a control group, and randomization would improve the strength of the study. Additional outcome measures, such as Disabilities of the Arm, Shoulder, and Hand score, and grip strength could complement pain scores to provide more data. These data were collected in a preliminary study.⁹ Postoperative histologic analysis of treated human tissue would be ideal, but ethical considerations limit study to animal models. An additional limitation is potential examiner bias. Data collection was performed by an independent medical technician; a third-party blinded evaluation could have been performed, but this was not feasible in a clinical setting.

Conclusion

Radiofrequency-based microtenotomy is a safe and effective procedure for elbow epicondylitis. The results are durable with successful outcomes observed 9 years after surgery.

Elbow epicondylitis is a painful condition caused by overuse and development of tendon degeneration. It is one of the most common elbow problems in adults, occurring both laterally and medially. “Tennis elbow” or lateral epicondylitis is diagnosed 7 to 10 times more often than the medial form, “golfer’s elbow.”¹ Although these injuries are often associated with racquet sports, activities such as bowling and weightlifting and the professions of carpentry, plumbing, and meat-cutting have been described as causes.^2,3

Elbow epicondylitis is thought to be the result of multiple microtraumatic events that cause disruption of the internal structure of the tendon and degeneration of the cells and matrix.⁴ Lesions caused by chronic overuse are now commonly called tendinosis and are not considered inflammatory in nature. Although the term tendinitis is used frequently and indiscriminately, histopathologic studies have shown that specimens of tendon obtained from areas of chronic overuse do not contain large numbers of macrophages, lymphocytes, or neutrophils.⁵ Rather, tendinosis appears to be a degenerative process that is characterized by the presence of dense populations of fibroblasts, vascular hyperplasia, and disorganized collagen. This constellation of findings has been termed by some authors as angiofibroblastic hyperplasia.⁶

Conservative care for the treatment of chronic tendinosis has been well described and is often successful. Treatment consists of rest, ice, compression, and elevation in the acute phase. This can be followed with bracing, activity modification, physical therapy, oral nonsteroidal anti-inflammatory drugs, topical applications, and injections of cortisone or platelet-rich plasma. When conservative treatment fails, surgical intervention may be considered. Procedures for the treatment of lateral epicondylitis include open débridement and release, arthroscopic débridement, percutaneous release, and radiofrequency (RF) coblation. The goals of operative treatment are to resect pathological material, to stimulate neovascularization by producing focused local bleeding, and to create a healthy scar while doing the least possible structural damage to surrounding tissues.⁴

The efficacy of a bipolar RF-based approach for using microtenotomy was first recognized when researchers studied the effects of transmyocardial revascularization for treating congestive heart failure.⁷ The use of RF- and laser-based transmyocardial revascularization initiated an angiogenic response in degenerated (ischemic) heart tissue. This success led to investigating the use of a RF-based approach for performing microtenotomy. Preclinical studies demonstrated that RF-based microtenotomy was effective for stimulating an angiogenic-healing response in tendon tissue.⁸ Histologic evaluation of treated tendons showed an early inflammatory response, with new blood-vessel formation by 28 days. In 2005, short-term results of this technique were published.⁹ This preliminary prospective case series showed that the treatment was safe and effectively improved or eliminated clinical symptoms.⁹ In the present midterm study, we hypothesized that pain scores would improve after RF microtenotomy and that these favorable results would continue to be observed over a longer term postoperatively.

Materials and Methods

Patients

This was a prospective, nonrandomized, single-center clinical study. After receiving institutional review board approval, patients who were 18 to 65 years of age with a diagnosis of tendinosis were approached for enrollment. For inclusion, patients had to be symptomatic for at least 6 months and had to have failed extensive conservative treatments. Nonoperative treatment included activity modification, enrollment in a facility- or home-based exercise program, bracing, oral nonsteroidal anti-inflammatory medication, and cortisone injection. Candidates with diabetes, confirmed or suspected pregnancy, surgery in the same tendon, implanted hardware adjacent to the target treatment region, or who were receiving care under workers’ compensation or had litigation-related injury were excluded. A single clinician performed a thorough medical history and clinical evaluation. The clinical follow-up and data collection were performed by an independent medical technician.

Clinical Outcomes

Pain status was assessed by using a visual analog scale (VAS). Postoperative clinical assessment was conducted within the first 2 days; at 7 to 10 days; at 4 to 6 weeks; and at 3, 6, 12, and 24 months, up to 9 years postoperatively. The VAS scales were completed annually up to 9 years after the procedure.

The percent improvement of VAS score was calculated. This value represented the difference between the patient’s preoperative and most recent VAS assessments. Failure of the procedure was defined as less than 50% improvement of the VAS score.

The RF-Based Microtenotomy Device

The Topaz Microdebrider (ArthroCare), connected to a System 2000 generator at setting 4 (175 V-RMS), was used to perform the RF-based microtenotomy. The device uses a controlled plasma-mediated RF-based process (coblation). Radiofrequency energy is used to excite the electrolytes in a conductive medium, such as a saline solution, to create precisely focused plasma. The energized particles in the plasma have sufficient energy to break molecular bonds,^10,11 excising or dissolving (ie, ablating) soft tissue at relatively low temperatures (typically, 40°-70° C).^12,13 The diameter of the active tip of the Topaz device is 0.8 mm.

Surgical Procedure

The senior author performed the majority of procedures in this study. Near the end of the series, the senior author’s associate also performed procedures. The symptomatic area of the tendon was identified and marked while the patient was alert. After the patient was positioned appropriately, light sedation was administered. A tourniquet was placed over the treatment limb and inflated to 250 mm Hg. A small incision, approximately 3 cm in length, was made over the marked treatment site to expose the involved tendon. After initiating sterile isotonic saline flow of 1 drop every 1 to 2 seconds from a line connected to the RF system, the tip of the device was placed on the tendon perpendicular to its surface (Figure 1). Using a light touch, it was activated for 500 milliseconds using a timer accessory for the control box. Five to 8 grams of pressure were applied with the device to penetrate the tendon and achieve successful ablation. The RF applications were performed at 5-mm intervals, to create a grid-like pattern on and throughout the symptomatic tendon area. The tendon was perforated to a depth of several millimeters on every second or third application throughout the treatment grid. After treatment of the symptomatic area, the wound was irrigated with copious amounts of normal saline solution and closed with interrupted nylon suture. Local anesthetic was injected only in the skin and in subcutaneous tissue. Standard wound dressings were applied. In the immediate postoperative period, the patient was advised to begin gentle active and passive range-of-motion exercises. Each patient was evaluated at 1 week postoperatively. At 6 weeks, patients were permitted to increase the intensity of their activities. Return to sports and heavy lifting was allowed once the patient was asymptomatic and had achieved full strength and range of motion; this typically occurred at 6 to 9 weeks after surgery.

Statistical Analysis

Normally distributed data were described using standard parametric statistics (ie, mean and standard deviation); non-normally distributed data were characterized using nonparametric descriptors (ie, median and quartiles). Statistical evaluation of improvement in pain status was performed by calculating 99% confidence intervals and using the Student t test for change between subsequent time points. Use of confidence intervals provides a descriptive analysis of the observed treatment effect, while permitting determination of statistical relevance. In all statistical testing, confidence bounds not including 0 were considered statistically significant. Probability of P ≤ .01 for committing type I experiment-wise error (rejecting a true null hypothesis) was selected for all statistical testing because of our lack of a control group, small sample size, and evaluation of multiple postoperative time points.

Results

Eighty consecutive patients with tendinosis of the elbow were included in this study. Sixty-nine patients were treated for lateral epicondylitis and 11 for medial epicondylitis. The average age of the patients (33 women, 47 men) was 50 years. The duration of follow-up evaluation ranged from 6 months to 9 years (mean, 2.5 years; median, 2 years). The Table presents the VAS improvement for these patients after the RF microtenotomy.

Within the lateral epicondylitis group, 91% (63/69) of the patients reported a successful outcome. The postoperative VAS improved to 1.3 from 6.9, which demonstrated an 81% improvement. Of the 6 patients that did not improve, 2 underwent repeat surgery.

Among the patients treated for medial epicondylitis, 91% (10/11) reported improvement in symptoms. The postoperative VAS improved to 1.3 from 6.1, a 79% improvement. One patient did not improve and did not undergo repeat surgery.

Discussion

For the treatment of medial and lateral elbow epicondylitis, RF microtenotomy is successful in 91% of patients. Symptomatic improvement was observed up to 9 years postoperatively. During this study, no complications were recorded; 7 treatment failures occurred. When compared with other techniques, the results with RF microtenotomy are equivalent or better.

In a retrospective study, Szabo and colleagues¹⁴ compared open, arthroscopic, and percutaneous release for lateral elbow tendinosis. They found the 3 methods to be highly effective for the treatment of tendinosis with no significant difference between them. Resection of the epicondyle and transfer of the anconeus muscle was found to be effective (94%) in a retrospective study by Almquist and colleagues.¹⁵ Dunn and coauthors¹⁶ reported a 97% success rate at 10 to 14 years postoperatively with a mini-open technique. Rubenthaler and colleagues¹⁷ showed 88% effectiveness for the open technique and 93% for the arthroscopic technique. With arthroscopic release of the extensor carpi radialis brevis tendon, Lattermann and coauthors¹⁸ reported clinical improvement in 94% of patients. In a study by Rose and colleagues,¹⁹ denervation of the lateral epicondyle was effective in relieving pain in 80% of patients who had had a positive response to a local anesthetic block. In a recently published study by Koh and coauthors,²⁰ 19 of 20 patients experienced a favorable outcome after treatment with ultrasonic microresection.

Regardless of surgical methods and their reported success rate, complications are associated with elbow surgery. Postoperative problems may include restricted function, elbow instability, persistent muscle weakness, and painful neuroma of the posterior cutaneous nerve.^10,21,22 The recent introduction of arthroscopic release offers the potential for less morbidity and enables visualization of the elbow joint. However, disadvantages of the arthroscopic approach include violation of the joint for extra-articular pathology, increased operative time and cost, and neurovascular complications. Additionally, it is possible that the entire spectrum of extra-articular tendinosis cannot be effectively identified arthroscopically.²³ In a prospective, randomized study, Meknas and colleagues²⁴ compared RF microtenotomy with extensor tendon release and repair. They showed that patients treated with RF-microtenotomy experienced earlier pain relief and improved grip strength over the release group.

Different proposed mechanisms of action have been described to explain the favorable effects of the RF-based microtenotomy procedure, such as induced healing by an angiogenic response in the tendon tissue. In an animal study, Harwood and colleagues⁸ showed that low-dose RF-based plasma microtenotomy has the ability to stimulate angiogenic growth factors in tendons, such as α_v integrin and vascular endothelial growth factor. These factors have been shown to be associated with healing.⁸ Early inflammatory response with new-vessel formation after 28 days was found in another animal study using the same method.²⁵ Evaluation of RF-based methods in a prospective controlled laboratory study using a rabbit-tendon model showed histologic evidence of early inflammation with development of neovasculature after treatment.⁸ A later histologic study using an aged Achilles rabbit tendon model was performed to evaluate the effect of RF-based plasma microtenotomy on collagen remodeling.²⁵ The degenerated tendon showed gaps, few normal crimpings, and a lack of reflectivity under polarized light. At 9 days after treatment, the treated tendon showed localized irregular crimpings, and, at 30 days, it showed regular crimping, tightly dense collagen fibers, and hypercellularity with good reflectivity. This was similar in appearance to a normal nondegenerated tendon (Figures 2A-2D). The RF-treated tendon also demonstrated an increase in production of insulin-like growth factor-1, β-fibroblast growth factor-1, α_v integrin, and vascular endothelial growth factor.

Pathologic nerve ingrowth or nerve irritation in the tendon substance has been considered a possible cause of the pain experienced with tendinosis. Radiofrequency treatment has been shown to induce acute degeneration and ablation of sensory nerve fibers.²⁶ These degenerated nerve fibers were observed to regenerate at 90 days after treatment.²⁷ These findings provide potential evidence for early pain relief that is maintained long term as the nerves regenerate.

This midterm follow-up of patients with elbow epicondylitis has shown that RF-based microtenotomy can produce successful, durable results. Microtenotomy is a technically simple procedure to perform and is associated with a rapid and uncomplicated recovery. It is safe and can effectively eliminate or markedly reduce clinical symptoms.

Limitations

Lateral epicondylitis has been described as a self-limited disease, with resolution of symptoms at 12 to 18 months with conservative treatment. This perspective challenges the indication of any proposed surgical treatment for the condition. Although the results of this research demonstrated the benefits of RF microtenotomy, there are inherent limitations of the study design. The study lacks a control group, and randomization would improve the strength of the study. Additional outcome measures, such as Disabilities of the Arm, Shoulder, and Hand score, and grip strength could complement pain scores to provide more data. These data were collected in a preliminary study.⁹ Postoperative histologic analysis of treated human tissue would be ideal, but ethical considerations limit study to animal models. An additional limitation is potential examiner bias. Data collection was performed by an independent medical technician; a third-party blinded evaluation could have been performed, but this was not feasible in a clinical setting.

Conclusion

Radiofrequency-based microtenotomy is a safe and effective procedure for elbow epicondylitis. The results are durable with successful outcomes observed 9 years after surgery.

Elbow epicondylitis is a painful condition caused by overuse and development of tendon degeneration. It is one of the most common elbow problems in adults, occurring both laterally and medially. “Tennis elbow” or lateral epicondylitis is diagnosed 7 to 10 times more often than the medial form, “golfer’s elbow.”¹ Although these injuries are often associated with racquet sports, activities such as bowling and weightlifting and the professions of carpentry, plumbing, and meat-cutting have been described as causes.^2,3

Elbow epicondylitis is thought to be the result of multiple microtraumatic events that cause disruption of the internal structure of the tendon and degeneration of the cells and matrix.⁴ Lesions caused by chronic overuse are now commonly called tendinosis and are not considered inflammatory in nature. Although the term tendinitis is used frequently and indiscriminately, histopathologic studies have shown that specimens of tendon obtained from areas of chronic overuse do not contain large numbers of macrophages, lymphocytes, or neutrophils.⁵ Rather, tendinosis appears to be a degenerative process that is characterized by the presence of dense populations of fibroblasts, vascular hyperplasia, and disorganized collagen. This constellation of findings has been termed by some authors as angiofibroblastic hyperplasia.⁶

Conservative care for the treatment of chronic tendinosis has been well described and is often successful. Treatment consists of rest, ice, compression, and elevation in the acute phase. This can be followed with bracing, activity modification, physical therapy, oral nonsteroidal anti-inflammatory drugs, topical applications, and injections of cortisone or platelet-rich plasma. When conservative treatment fails, surgical intervention may be considered. Procedures for the treatment of lateral epicondylitis include open débridement and release, arthroscopic débridement, percutaneous release, and radiofrequency (RF) coblation. The goals of operative treatment are to resect pathological material, to stimulate neovascularization by producing focused local bleeding, and to create a healthy scar while doing the least possible structural damage to surrounding tissues.⁴

The efficacy of a bipolar RF-based approach for using microtenotomy was first recognized when researchers studied the effects of transmyocardial revascularization for treating congestive heart failure.⁷ The use of RF- and laser-based transmyocardial revascularization initiated an angiogenic response in degenerated (ischemic) heart tissue. This success led to investigating the use of a RF-based approach for performing microtenotomy. Preclinical studies demonstrated that RF-based microtenotomy was effective for stimulating an angiogenic-healing response in tendon tissue.⁸ Histologic evaluation of treated tendons showed an early inflammatory response, with new blood-vessel formation by 28 days. In 2005, short-term results of this technique were published.⁹ This preliminary prospective case series showed that the treatment was safe and effectively improved or eliminated clinical symptoms.⁹ In the present midterm study, we hypothesized that pain scores would improve after RF microtenotomy and that these favorable results would continue to be observed over a longer term postoperatively.

Materials and Methods

Patients

This was a prospective, nonrandomized, single-center clinical study. After receiving institutional review board approval, patients who were 18 to 65 years of age with a diagnosis of tendinosis were approached for enrollment. For inclusion, patients had to be symptomatic for at least 6 months and had to have failed extensive conservative treatments. Nonoperative treatment included activity modification, enrollment in a facility- or home-based exercise program, bracing, oral nonsteroidal anti-inflammatory medication, and cortisone injection. Candidates with diabetes, confirmed or suspected pregnancy, surgery in the same tendon, implanted hardware adjacent to the target treatment region, or who were receiving care under workers’ compensation or had litigation-related injury were excluded. A single clinician performed a thorough medical history and clinical evaluation. The clinical follow-up and data collection were performed by an independent medical technician.

Clinical Outcomes

Pain status was assessed by using a visual analog scale (VAS). Postoperative clinical assessment was conducted within the first 2 days; at 7 to 10 days; at 4 to 6 weeks; and at 3, 6, 12, and 24 months, up to 9 years postoperatively. The VAS scales were completed annually up to 9 years after the procedure.

The percent improvement of VAS score was calculated. This value represented the difference between the patient’s preoperative and most recent VAS assessments. Failure of the procedure was defined as less than 50% improvement of the VAS score.

The RF-Based Microtenotomy Device

The Topaz Microdebrider (ArthroCare), connected to a System 2000 generator at setting 4 (175 V-RMS), was used to perform the RF-based microtenotomy. The device uses a controlled plasma-mediated RF-based process (coblation). Radiofrequency energy is used to excite the electrolytes in a conductive medium, such as a saline solution, to create precisely focused plasma. The energized particles in the plasma have sufficient energy to break molecular bonds,^10,11 excising or dissolving (ie, ablating) soft tissue at relatively low temperatures (typically, 40°-70° C).^12,13 The diameter of the active tip of the Topaz device is 0.8 mm.

Surgical Procedure

The senior author performed the majority of procedures in this study. Near the end of the series, the senior author’s associate also performed procedures. The symptomatic area of the tendon was identified and marked while the patient was alert. After the patient was positioned appropriately, light sedation was administered. A tourniquet was placed over the treatment limb and inflated to 250 mm Hg. A small incision, approximately 3 cm in length, was made over the marked treatment site to expose the involved tendon. After initiating sterile isotonic saline flow of 1 drop every 1 to 2 seconds from a line connected to the RF system, the tip of the device was placed on the tendon perpendicular to its surface (Figure 1). Using a light touch, it was activated for 500 milliseconds using a timer accessory for the control box. Five to 8 grams of pressure were applied with the device to penetrate the tendon and achieve successful ablation. The RF applications were performed at 5-mm intervals, to create a grid-like pattern on and throughout the symptomatic tendon area. The tendon was perforated to a depth of several millimeters on every second or third application throughout the treatment grid. After treatment of the symptomatic area, the wound was irrigated with copious amounts of normal saline solution and closed with interrupted nylon suture. Local anesthetic was injected only in the skin and in subcutaneous tissue. Standard wound dressings were applied. In the immediate postoperative period, the patient was advised to begin gentle active and passive range-of-motion exercises. Each patient was evaluated at 1 week postoperatively. At 6 weeks, patients were permitted to increase the intensity of their activities. Return to sports and heavy lifting was allowed once the patient was asymptomatic and had achieved full strength and range of motion; this typically occurred at 6 to 9 weeks after surgery.

Statistical Analysis

Normally distributed data were described using standard parametric statistics (ie, mean and standard deviation); non-normally distributed data were characterized using nonparametric descriptors (ie, median and quartiles). Statistical evaluation of improvement in pain status was performed by calculating 99% confidence intervals and using the Student t test for change between subsequent time points. Use of confidence intervals provides a descriptive analysis of the observed treatment effect, while permitting determination of statistical relevance. In all statistical testing, confidence bounds not including 0 were considered statistically significant. Probability of P ≤ .01 for committing type I experiment-wise error (rejecting a true null hypothesis) was selected for all statistical testing because of our lack of a control group, small sample size, and evaluation of multiple postoperative time points.

Results

Eighty consecutive patients with tendinosis of the elbow were included in this study. Sixty-nine patients were treated for lateral epicondylitis and 11 for medial epicondylitis. The average age of the patients (33 women, 47 men) was 50 years. The duration of follow-up evaluation ranged from 6 months to 9 years (mean, 2.5 years; median, 2 years). The Table presents the VAS improvement for these patients after the RF microtenotomy.

Within the lateral epicondylitis group, 91% (63/69) of the patients reported a successful outcome. The postoperative VAS improved to 1.3 from 6.9, which demonstrated an 81% improvement. Of the 6 patients that did not improve, 2 underwent repeat surgery.

Among the patients treated for medial epicondylitis, 91% (10/11) reported improvement in symptoms. The postoperative VAS improved to 1.3 from 6.1, a 79% improvement. One patient did not improve and did not undergo repeat surgery.

Discussion

For the treatment of medial and lateral elbow epicondylitis, RF microtenotomy is successful in 91% of patients. Symptomatic improvement was observed up to 9 years postoperatively. During this study, no complications were recorded; 7 treatment failures occurred. When compared with other techniques, the results with RF microtenotomy are equivalent or better.

In a retrospective study, Szabo and colleagues¹⁴ compared open, arthroscopic, and percutaneous release for lateral elbow tendinosis. They found the 3 methods to be highly effective for the treatment of tendinosis with no significant difference between them. Resection of the epicondyle and transfer of the anconeus muscle was found to be effective (94%) in a retrospective study by Almquist and colleagues.¹⁵ Dunn and coauthors¹⁶ reported a 97% success rate at 10 to 14 years postoperatively with a mini-open technique. Rubenthaler and colleagues¹⁷ showed 88% effectiveness for the open technique and 93% for the arthroscopic technique. With arthroscopic release of the extensor carpi radialis brevis tendon, Lattermann and coauthors¹⁸ reported clinical improvement in 94% of patients. In a study by Rose and colleagues,¹⁹ denervation of the lateral epicondyle was effective in relieving pain in 80% of patients who had had a positive response to a local anesthetic block. In a recently published study by Koh and coauthors,²⁰ 19 of 20 patients experienced a favorable outcome after treatment with ultrasonic microresection.

Regardless of surgical methods and their reported success rate, complications are associated with elbow surgery. Postoperative problems may include restricted function, elbow instability, persistent muscle weakness, and painful neuroma of the posterior cutaneous nerve.^10,21,22 The recent introduction of arthroscopic release offers the potential for less morbidity and enables visualization of the elbow joint. However, disadvantages of the arthroscopic approach include violation of the joint for extra-articular pathology, increased operative time and cost, and neurovascular complications. Additionally, it is possible that the entire spectrum of extra-articular tendinosis cannot be effectively identified arthroscopically.²³ In a prospective, randomized study, Meknas and colleagues²⁴ compared RF microtenotomy with extensor tendon release and repair. They showed that patients treated with RF-microtenotomy experienced earlier pain relief and improved grip strength over the release group.

Different proposed mechanisms of action have been described to explain the favorable effects of the RF-based microtenotomy procedure, such as induced healing by an angiogenic response in the tendon tissue. In an animal study, Harwood and colleagues⁸ showed that low-dose RF-based plasma microtenotomy has the ability to stimulate angiogenic growth factors in tendons, such as α_v integrin and vascular endothelial growth factor. These factors have been shown to be associated with healing.⁸ Early inflammatory response with new-vessel formation after 28 days was found in another animal study using the same method.²⁵ Evaluation of RF-based methods in a prospective controlled laboratory study using a rabbit-tendon model showed histologic evidence of early inflammation with development of neovasculature after treatment.⁸ A later histologic study using an aged Achilles rabbit tendon model was performed to evaluate the effect of RF-based plasma microtenotomy on collagen remodeling.²⁵ The degenerated tendon showed gaps, few normal crimpings, and a lack of reflectivity under polarized light. At 9 days after treatment, the treated tendon showed localized irregular crimpings, and, at 30 days, it showed regular crimping, tightly dense collagen fibers, and hypercellularity with good reflectivity. This was similar in appearance to a normal nondegenerated tendon (Figures 2A-2D). The RF-treated tendon also demonstrated an increase in production of insulin-like growth factor-1, β-fibroblast growth factor-1, α_v integrin, and vascular endothelial growth factor.

Pathologic nerve ingrowth or nerve irritation in the tendon substance has been considered a possible cause of the pain experienced with tendinosis. Radiofrequency treatment has been shown to induce acute degeneration and ablation of sensory nerve fibers.²⁶ These degenerated nerve fibers were observed to regenerate at 90 days after treatment.²⁷ These findings provide potential evidence for early pain relief that is maintained long term as the nerves regenerate.

This midterm follow-up of patients with elbow epicondylitis has shown that RF-based microtenotomy can produce successful, durable results. Microtenotomy is a technically simple procedure to perform and is associated with a rapid and uncomplicated recovery. It is safe and can effectively eliminate or markedly reduce clinical symptoms.

Limitations

Lateral epicondylitis has been described as a self-limited disease, with resolution of symptoms at 12 to 18 months with conservative treatment. This perspective challenges the indication of any proposed surgical treatment for the condition. Although the results of this research demonstrated the benefits of RF microtenotomy, there are inherent limitations of the study design. The study lacks a control group, and randomization would improve the strength of the study. Additional outcome measures, such as Disabilities of the Arm, Shoulder, and Hand score, and grip strength could complement pain scores to provide more data. These data were collected in a preliminary study.⁹ Postoperative histologic analysis of treated human tissue would be ideal, but ethical considerations limit study to animal models. An additional limitation is potential examiner bias. Data collection was performed by an independent medical technician; a third-party blinded evaluation could have been performed, but this was not feasible in a clinical setting.

Conclusion

Radiofrequency-based microtenotomy is a safe and effective procedure for elbow epicondylitis. The results are durable with successful outcomes observed 9 years after surgery.

AGA applauds the announcement by the American Board of Internal Medicine that it is extending the suspension of the practice improvement, patient safety, and patient voice requirements until at least December 2018.

Throughout 2015, AGA has pushed ABIM to reconsider the burdensome recertification process. Gastroenterologists need a recertification system that fosters active learning, not high-stakes testing.

Our campaign continues – AGA is communicating with other subspecialty societies to work together to secure the best approach to MOC consistent with the principles we previously published:

• MOC needs to be simpler, less intrusive, and less expensive.

• We support ending the high‐stakes, every-10‐year exam.

• We do not support closed‐book assessments as they do not represent the current realities of medicine in the digital age.

• We support the principles of lifelong learning as evidenced by ongoing CME activities, rather than lifelong testing.

• We support the concept that, for the many diplomates who specialize within certain areas of gastroenterology and hepatology, MOC should not need to include high‐stakes assessments of areas where the diplomate may not practice.

We hear you that MOC is a burden and we will continue to push for the principles of individualization, specialization, and dropping the high-stakes exam – sooner rather than later.

Practicalities for those up for recertification

While we advocate for a new MOC system, there are requirements that still stand. Make sure you are up to date before the end of 2015:

• If you need to complete MOC points by Dec. 31, 2015, AGA has activities you can complete to earn those points. Please visit the MOC section of the AGA website to see how we can help you.

• Each board certified physician’s requirements are slightly different based on the year of your certification or most recent recertification. For details specific to you, we urge you to log in to your ABIM Physician Portal.

For more information, read our paper, The Gastroenterologist-accountable Professionalism in Practice Pathway, and consensus principles for reform that AGA developed with ACG, ASGE, AASLD, ANMS and NASPGHAN.

AGA applauds the announcement by the American Board of Internal Medicine that it is extending the suspension of the practice improvement, patient safety, and patient voice requirements until at least December 2018.

Throughout 2015, AGA has pushed ABIM to reconsider the burdensome recertification process. Gastroenterologists need a recertification system that fosters active learning, not high-stakes testing.

Our campaign continues – AGA is communicating with other subspecialty societies to work together to secure the best approach to MOC consistent with the principles we previously published:

• MOC needs to be simpler, less intrusive, and less expensive.

• We support ending the high‐stakes, every-10‐year exam.

• We do not support closed‐book assessments as they do not represent the current realities of medicine in the digital age.

• We support the principles of lifelong learning as evidenced by ongoing CME activities, rather than lifelong testing.

• We support the concept that, for the many diplomates who specialize within certain areas of gastroenterology and hepatology, MOC should not need to include high‐stakes assessments of areas where the diplomate may not practice.

We hear you that MOC is a burden and we will continue to push for the principles of individualization, specialization, and dropping the high-stakes exam – sooner rather than later.

Practicalities for those up for recertification

While we advocate for a new MOC system, there are requirements that still stand. Make sure you are up to date before the end of 2015:

• If you need to complete MOC points by Dec. 31, 2015, AGA has activities you can complete to earn those points. Please visit the MOC section of the AGA website to see how we can help you.

• Each board certified physician’s requirements are slightly different based on the year of your certification or most recent recertification. For details specific to you, we urge you to log in to your ABIM Physician Portal.

For more information, read our paper, The Gastroenterologist-accountable Professionalism in Practice Pathway, and consensus principles for reform that AGA developed with ACG, ASGE, AASLD, ANMS and NASPGHAN.

AGA applauds the announcement by the American Board of Internal Medicine that it is extending the suspension of the practice improvement, patient safety, and patient voice requirements until at least December 2018.

Throughout 2015, AGA has pushed ABIM to reconsider the burdensome recertification process. Gastroenterologists need a recertification system that fosters active learning, not high-stakes testing.

Our campaign continues – AGA is communicating with other subspecialty societies to work together to secure the best approach to MOC consistent with the principles we previously published:

• MOC needs to be simpler, less intrusive, and less expensive.

• We support ending the high‐stakes, every-10‐year exam.

• We do not support closed‐book assessments as they do not represent the current realities of medicine in the digital age.

• We support the principles of lifelong learning as evidenced by ongoing CME activities, rather than lifelong testing.

• We support the concept that, for the many diplomates who specialize within certain areas of gastroenterology and hepatology, MOC should not need to include high‐stakes assessments of areas where the diplomate may not practice.

We hear you that MOC is a burden and we will continue to push for the principles of individualization, specialization, and dropping the high-stakes exam – sooner rather than later.

Practicalities for those up for recertification

While we advocate for a new MOC system, there are requirements that still stand. Make sure you are up to date before the end of 2015:

• If you need to complete MOC points by Dec. 31, 2015, AGA has activities you can complete to earn those points. Please visit the MOC section of the AGA website to see how we can help you.

• Each board certified physician’s requirements are slightly different based on the year of your certification or most recent recertification. For details specific to you, we urge you to log in to your ABIM Physician Portal.

For more information, read our paper, The Gastroenterologist-accountable Professionalism in Practice Pathway, and consensus principles for reform that AGA developed with ACG, ASGE, AASLD, ANMS and NASPGHAN.