The Journal of Family Practice

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; [email protected].

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; [email protected].

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; [email protected].

Almost 8% of Americans ages ≥ 12 years have depression and 19.1% of Americans ages ≥ 18 years have experienced an anxiety disorder in the past year.^1,2 Furthermore, suicide, which can result from depression and anxiety, is the 10th leading cause of death in the United States, claiming about 40,000 to 49,000 lives per year since 2012, with increasing yearly rates.³ While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and alternative medicine (CAM) options. According to the National Center for Complementary and Integrative Health, more than 30% of American adults use CAM treatments.⁴

This article provides an overview of the evidence for commonly used CAM treatments for unipolar depression and anxiety in adults. It is designed to serve as a useful resource when patients are interested in looking beyond conventional medications.

St. John’s wort: ‘Yes’ for depression; ‘no’ for anxiety

Hypericum perforatum, more commonly known as St. John’s wort, is a widely used antidepressant, especially in Europe where it is prescribed, rather than offered over the counter as it is here. Its mechanism of action is not completely understood because its various constituents have different neuropharmacologic activities.^5,6

A 2008 Cochrane review evaluated 29 randomized, double-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of depression.⁷ St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar findings.⁸ In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate.

Mood disorders other than depression. Studies do not support a role for St. John’s wort in the treatment of anxiety disorders. There are no trials that assess the efficacy of St. John’s wort for the reduction of symptoms of general anxiety disorder as a primary outcome of treatment. Some small clinical trials have investigated the efficacy of St. John’s wort in obsessive-compulsive disorder and social anxiety disorder. In those studies, St. John’s wort performed no better than placebo.^9,10

A few words of caution. Preparations of St. John’s wort in the United States are not standardized, so St. John’s wort should be used in America with caution. Furthermore, long-term use of St. John’s wort for depression is questionable given that most studies have evaluated only up to 12 weeks of use.⁸

In patients with mildto-moderate depression, St. John’s wort produced rates of remission that were comparable to those produced by SSRIs— with a lower discontinuation rate.

If used, studies indicate that the St. John’s wort extract that should be used is 0.3% hypericin or 5% hyperforin administered in a dosage of 300 to 400 mg tid.^7,8,11 Physicians and patients can use www.consumerlabs.com to find St. John’s wort brands that have met specified quality criteria based on independent laboratory studies. This Web site can also be used to investigate the quality of the brands available for the other supplements discussed in this article.

Continue to: Adverse effects

Adverse effects. St. John’s wort and an SSRI can lead to serotonin syndrome, which is a constellation of symptoms involving mental status changes and autonomic and neuromuscular hyperactivity caused by serotonin overactivity.¹² Furthermore, treatment failures with anticoagulants, digoxin, hormonal contraceptives, immunosuppressants, and narcotics due to concomitant use with St. John’s wort have been reported.¹³

The most common adverse reactions to St. John’s wort include gastrointestinal symptoms, dizziness, sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling.¹⁴ However, multiple studies have supported St. John’s wort to be equally or better tolerated than conventional antidepressants.^7,8

Certain forms of folate can be adjunctive treatment for depression

Methylfolate is the form of folate that crosses the blood–brain barrier. A prospective observational study evaluated the cerebral spinal fluid of 33 patients with refractory depression. The authors found metabolic abnormalities in the cerebrospinal fluid of most of those patients, the most common of which was folate deficiency in 12 patients despite normal serum folate levels.¹⁵

Additionally, current understanding of the role of the Methylenetetrahydrofolate reductase (MTHFR) gene and the folate cycle in depression supports a potential role of methylfolate in depression treatment.¹⁶ The MTHFR gene encodes for an enzyme called MTHFR. The MTHFR enzyme converts 5,10-MTHF to 5-MTHF, which then crosses the blood–brain barrier and donates a methyl group for the conversion of homocysteine to methionine. Methionine is a precursor to monoamine neurotransmitters. Thus, decreased expression of the MTHFR gene leads to decreased methylfolate levels, which, in turn, potentially leads to insufficient neurotransmitter synthesis and homocysteine excess.

MTHFR gene polymorphisms and increased homocysteine levels have been found to be associated with the occurrence of depression. One thought is that methylfolate supplementation compensates for an underlying MTHFR enzyme deficiency in patients with depression. Further studies are needed to determine if screening depressed patients for MTHFR gene polymorphisms is of benefit.¹⁶

Continue to: A 2012 randomized controlled trial...

A 2012 randomized controlled trial (RCT) (N = 75) compared L-methylfolate 15 mg/d plus an SSRI with placebo plus an SSRI in patients with SSRI-resistant major depression.¹⁷ The trial found that a reduction of baseline symptoms by ≥ 50% occurred in more patients who received adjunctive L-methylfolate than placebo (32% vs 15%) and tolerability was comparable. These findings were again supported in 2016 with a 12-month study showing L-methylfolate to have long-term tolerability comparable to placebo,¹⁸ and in 2017 with a randomized trial (N = 260) that found escitalopram 10 mg/d plus L-methylfolate 15 mg/d to be significantly more effective at treating depression than escitalopram 10 mg/d alone.¹⁹ Thus, methylfolate may be an effective adjunctive treatment for depression at a dosage of 15 mg/d.

S-adenosyl methionine (SAMe) is a metabolite of folate derived from methionine that facilitates the synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. In Europe, as is the case with St. John’s wort, it is a prescription medication.

A randomized trial (N = 73) compared adjunctive SAMe 800 mg bid with placebo in the treatment of patients with unipolar major depression who did not experience improvement with SSRI treatment alone.²⁰ The investigators found that more patients who received SAMe than who received placebo had improvement in their depression (36.1% vs 17.6%), and more patients who received SAMe compared to placebo went into depression remission (25.8% vs 11.7%).

Adverse effects were comparable in both groups. Thus, SAMe at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.^20,21 The findings of 1 study (N = 65) suggest that patients could experience further improvement in their depression symptoms with SAMe at doses of as much as 3200 mg/d; however, 3200 mg/d increased the occurrence of gastrointestinal adverse effects (31.3% in the SAMe arm vs 3.8% in the placebo group).²¹

Folate. With regard to folate itself, randomized trials have not supported its efficacy in the treatment of depression in the general population.²²

Continue to: VItamin D may improve anxiety/depression in those with low levels

Vitamin D may improve anxiety/depression in those with low levels

Vitamin D supplementation is also being used more frequently in the treatment of depression. Case-control, cross-sectional, and cohort studies have linked low vitamin D levels to the occurrence of depression. A 2013 systematic review of 14 such studies (N = 31,424) found lower vitamin D levels in people with depression compared with controls.²³ Further studies are needed to determine if this relationship is causal, and quality RCTs investigating the effect of vitamin D supplementation on depression are lacking.

S-adenosyl methionine (SAMe) at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.

A 2019 study (N = 30) evaluated the ­impact of vitamin D supplementation on generalized anxiety disorder in patients with co-occurring vitamin D deficiency. Half received standard-of-care general anxiety disorder treatment plus 50,000 IU of vitamin D weekly for 3 months, while the other half received standard of care alone. Significant improvements in anxiety scores, increases in serum serotonin, and decreases in serum neopterin (an inflammatory marker) were observed in the vitamin D–treated group compared to the group that did not receive vitamin D.²⁴

It is not currently standard of care to check vitamin D levels in all patients presenting with mood disorders. However, if screening is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/or depressive symptoms. Despite this, no evidence exists to support vitamin D supplementation for depression or anxiety in patients with normal vitamin D levels.^24,25

The effects of omega-3 fatty acids are largely unclear

Research has shown that omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in fish oil, protect glutamatergic neurotransmission from glucocorticoids, which are released in the body during a stress response.²⁶ Small clinical trials have found n-3 PUFAs to reduce the symptoms of anxiety compared with placebo, but the acids have not been studied directly for anxiety disorders.^27,28

With regard to depression, evidence is conflicting as to whether n-3 PUFAs are of any benefit in treatment.²⁹ Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are hypothesized to be the components in omega-3 fatty acid preparations that could lead to a reduction in depressive symptoms. However, randomized trials have shown that EPA-predominant omega-3 fatty acid formulations have only a moderate or no clinically significant effect on depression over placebo, and that DHA-predominant omega-3 fatty acid formulations are only comparable or inferior to placebo.³⁰

Continue to: Response to EPA...

Response to EPA may be greater in patients with depression who have high levels of inflammatory biomarkers, such as interleuken (IL)-1 receptor antagonist (1Ra), IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin, and adiponectin, than in patients with low levels. An 8-week trial randomly assigned patients with unipolar major depression (N = 155) to receive either EPA, DHA, or placebo and found that improvement for the 3 groups was comparable; however, in the subgroup of patients with high levels of inflammatory markers, improvement in depressive symptoms was significantly greater with EPA than with either DHA or placebo.³¹

If screening for vitamin D levels is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/ or depression symptoms.

It is unclear whether different sources of n-3 PUFA, such as whole fish vs fish oil vs prescription omega-3 acid ethyl esters (Lovaza), are more or less efficacious in the treatment of anxiety or depression. Furthermore, there is no standard dosing for n-3 PUFA in the treatment of mood disorders. Given that the US Food and Drug Administration recommends no more than 2 g/d of combined EPA and DHA supplementation, we recommend using 2 g/d if one decides to treat depression/anxiety with n-3 PUFA.³²

N-3 PUFA supplementation is fairly benign. There have been previous concerns about n-3 PUFA supplementation increasing patients’ risk for gastrointestinal bleeding, but a 2006 systematic review that included 9 trials (N = 2612) that looked at clinically significant bleeding episodes found that even patients at high risk for bleeding (ie, those taking aspirin or warfarin) had no increased bleeding risk from taking n-3 PUFA supplementation at up to 4 g/d.³³

Don’t underestimate exercise and meditation; consider acupuncture

Exercise. Multiple practice guidelines, including the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” and meta-analyses have supported the use of exercise to treat unipolar major depression and anxiety.^34-37 However, only about 26% of American men and 19% of American women met the US Department of Health and Human Services’ “Federal Physical Activity Guidelines for Americans” in 2016.³⁸

Exercise alone is a reasonable monotherapy, as long as patients are monitored closely for worsening symptoms. Additionally, exercise as an add-on treatment can be helpful for more severe depression or anxiety.³⁹ The best type, duration, and frequency of exercise specifically for the treatment of depression or anxiety has yet to be determined, but physicians may base their exercise recommendations on the “Federal Physical Activity Guidelines for Americans” for general good health (TABLE).³⁸

Continue to: Meditation

Meditation, especially mindfulness meditation, is another strategy that has gained popularity in the treatment of anxiety and depression. Mindfulness has been defined as “the practice of maintaining a nonjudgmental state of heightened or complete awareness of one’s thoughts, emotions, or experiences on a moment-to-moment basis.”⁴⁰ A 2014 systematic review and meta-analysis of 47 trials with 3515 participants found that mindfulness meditation programs led to clinically significant moderate reductions in anxiety.⁴¹ Smaller effects were found for depression.

Nevertheless, meditation may be beneficial as an adjunctive treatment for depression. A small randomized trial (N = 25) compared an adjunctive breathing-based meditation intervention with a waitlist control (delayed yoga) in patients with unipolar major depression who failed to respond to at least 8 weeks of antidepressant treatment.⁴² The meditation intervention consisted of a group program with sitting meditation, breathing exercises, and yoga postures. Participants engaged in the meditation intervention for 2 to 3.5 hours per day for 8 weeks and demonstrated significant improvement in depression symptoms compared with the control group.⁴²

Acupuncture. A 2018 meta-analysis of 64 studies (N = 7104) suggests that acupuncture results in a small-to-moderate reduction in depressive symptoms when compared to no treatment, control/sham acupuncture, or medication.⁴³ Furthermore, acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.⁴³

Additionally, a 2019 analysis of 10 systematic reviews found acupuncture to be more effective than control/sham acupuncture in the treatment of general anxiety.⁴⁴ It should be noted, however, that a lot of heterogeneity and potential for bias existed across all of the studies. The studies analyzed were very low to low in quality. Thus, the evidence is insufficient to strongly recommend the use of acupuncture for depression or anxiety, although acupuncture is a safe intervention with low rates of adverse events.

Emotional support animals: Beneficial, but evidence is weak

Emotional support animals are gaining in popularity with Americans who have mood disorders. An important distinction must be made, however, between service animals and emotional support animals. A service animal is one “that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability.”⁴⁵ Under the Americans with Disabilities Act (ADA), service animals are limited to dogs, and, in some cases, specially trained miniature horses. Psychiatric service dogs can be trained to do anything from reminding their owner to take medicine to stopping self-mutilation activities.

Continue to: Emotional support animals...

Emotional support animals are not specially trained to perform tasks to help with disabilities. It’s their companionship that helps relieve symptoms of depression and/or anxiety.⁴⁵ Thus, emotional support animals are not covered under federal laws that apply to service animals. However, the Air Carrier Access Act does require airlines to allow emotional support animals to fly in the cabin for free. Furthermore, the Fair Housing Act allows emotional support animals to circumvent no-pet rules in housing and dorms. Airplanes and housing are the only places legally required to allow the unrestricted presence of emotional support animals.⁴⁶

Also, there are important distinctions between emotional support animals and pets. While anyone can own a pet, an emotional support animal is prescribed by a licensed mental health professional as a treatment for a mood disorder. Housing facilities and airlines will usually require an emotional support animal “prescription” or letter from a physician to recognize animals as such.

Exercise alone is a reasonable monotherapy for depression or anxiety as long as patients are monitored closely for worsening symptoms.

A 2018 systematic review evaluated the evidence behind emotional support animals, which included 17 peer-reviewed journal articles, conference papers, and research dissertations (N = 1727) mostly containing qualitative evidence.⁴⁷ Unfortunately, there are no RCTs, and there are limited case-control and cohort studies evaluating the effect of an emotional support animal on mood disorders. Based on the available evidence, there does seem to be a psychological benefit to owning an animal for both those with a diagnosable mental health disorder and the general population. This benefit seems to stem from a perceived reduction in social isolation and an increase in emotional support. Factors that determine the psychological benefit of emotional support animals include the type of pet, the number of pets, the attachment to the pet, and the perceived friendliness of the pet.⁴⁷

Animal-assisted therapy. A 2014 systematic review evaluated higher-level evidence behind animal-assisted therapy (AAT).⁴⁸ Although participating in therapy that involves interaction with animals is not the same as owning an emotional support animal, the concept—using an animal to improve mental health—is the same. The systematic review looked at 11 RCTs (N = 411) that studied the effect of AAT on mental health. Animals studied included dogs, cats, dolphins, birds, cows, rabbits, ferrets, and guinea pigs. Mental health disorders studied included schizophrenia, depression, anxiety, alcohol/drug abuse, and other addictive behaviors.

Acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.

Therapeutic animal exposure led to reported improvements in mood, quality of life, and social behavior. These improvements were attributed to the animals buffering people’s reactions to mental stressors. The animals provided a sense of comfort and safety and diverted attention away from immediate stressors. Furthermore, the memory of the animals brought participants a sense of comfort/happiness when they were later without the animal. However, the majority of participants were people who liked animals at baseline.⁴⁸

CORRESPONDENCE
Amanda E. Olagunju, DO, Operational Medicine Clinic, Langley AFB Hospital, 77 Nealy Avenue, Langley AFB, VA 23665; [email protected].

Almost 8% of Americans ages ≥ 12 years have depression and 19.1% of Americans ages ≥ 18 years have experienced an anxiety disorder in the past year.^1,2 Furthermore, suicide, which can result from depression and anxiety, is the 10th leading cause of death in the United States, claiming about 40,000 to 49,000 lives per year since 2012, with increasing yearly rates.³ While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and alternative medicine (CAM) options. According to the National Center for Complementary and Integrative Health, more than 30% of American adults use CAM treatments.⁴

This article provides an overview of the evidence for commonly used CAM treatments for unipolar depression and anxiety in adults. It is designed to serve as a useful resource when patients are interested in looking beyond conventional medications.

St. John’s wort: ‘Yes’ for depression; ‘no’ for anxiety

Hypericum perforatum, more commonly known as St. John’s wort, is a widely used antidepressant, especially in Europe where it is prescribed, rather than offered over the counter as it is here. Its mechanism of action is not completely understood because its various constituents have different neuropharmacologic activities.^5,6

A 2008 Cochrane review evaluated 29 randomized, double-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of depression.⁷ St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar findings.⁸ In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate.

Mood disorders other than depression. Studies do not support a role for St. John’s wort in the treatment of anxiety disorders. There are no trials that assess the efficacy of St. John’s wort for the reduction of symptoms of general anxiety disorder as a primary outcome of treatment. Some small clinical trials have investigated the efficacy of St. John’s wort in obsessive-compulsive disorder and social anxiety disorder. In those studies, St. John’s wort performed no better than placebo.^9,10

A few words of caution. Preparations of St. John’s wort in the United States are not standardized, so St. John’s wort should be used in America with caution. Furthermore, long-term use of St. John’s wort for depression is questionable given that most studies have evaluated only up to 12 weeks of use.⁸

In patients with mildto-moderate depression, St. John’s wort produced rates of remission that were comparable to those produced by SSRIs— with a lower discontinuation rate.

If used, studies indicate that the St. John’s wort extract that should be used is 0.3% hypericin or 5% hyperforin administered in a dosage of 300 to 400 mg tid.^7,8,11 Physicians and patients can use www.consumerlabs.com to find St. John’s wort brands that have met specified quality criteria based on independent laboratory studies. This Web site can also be used to investigate the quality of the brands available for the other supplements discussed in this article.

Continue to: Adverse effects

Adverse effects. St. John’s wort and an SSRI can lead to serotonin syndrome, which is a constellation of symptoms involving mental status changes and autonomic and neuromuscular hyperactivity caused by serotonin overactivity.¹² Furthermore, treatment failures with anticoagulants, digoxin, hormonal contraceptives, immunosuppressants, and narcotics due to concomitant use with St. John’s wort have been reported.¹³

The most common adverse reactions to St. John’s wort include gastrointestinal symptoms, dizziness, sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling.¹⁴ However, multiple studies have supported St. John’s wort to be equally or better tolerated than conventional antidepressants.^7,8

Certain forms of folate can be adjunctive treatment for depression

Methylfolate is the form of folate that crosses the blood–brain barrier. A prospective observational study evaluated the cerebral spinal fluid of 33 patients with refractory depression. The authors found metabolic abnormalities in the cerebrospinal fluid of most of those patients, the most common of which was folate deficiency in 12 patients despite normal serum folate levels.¹⁵

Additionally, current understanding of the role of the Methylenetetrahydrofolate reductase (MTHFR) gene and the folate cycle in depression supports a potential role of methylfolate in depression treatment.¹⁶ The MTHFR gene encodes for an enzyme called MTHFR. The MTHFR enzyme converts 5,10-MTHF to 5-MTHF, which then crosses the blood–brain barrier and donates a methyl group for the conversion of homocysteine to methionine. Methionine is a precursor to monoamine neurotransmitters. Thus, decreased expression of the MTHFR gene leads to decreased methylfolate levels, which, in turn, potentially leads to insufficient neurotransmitter synthesis and homocysteine excess.

MTHFR gene polymorphisms and increased homocysteine levels have been found to be associated with the occurrence of depression. One thought is that methylfolate supplementation compensates for an underlying MTHFR enzyme deficiency in patients with depression. Further studies are needed to determine if screening depressed patients for MTHFR gene polymorphisms is of benefit.¹⁶

Continue to: A 2012 randomized controlled trial...

A 2012 randomized controlled trial (RCT) (N = 75) compared L-methylfolate 15 mg/d plus an SSRI with placebo plus an SSRI in patients with SSRI-resistant major depression.¹⁷ The trial found that a reduction of baseline symptoms by ≥ 50% occurred in more patients who received adjunctive L-methylfolate than placebo (32% vs 15%) and tolerability was comparable. These findings were again supported in 2016 with a 12-month study showing L-methylfolate to have long-term tolerability comparable to placebo,¹⁸ and in 2017 with a randomized trial (N = 260) that found escitalopram 10 mg/d plus L-methylfolate 15 mg/d to be significantly more effective at treating depression than escitalopram 10 mg/d alone.¹⁹ Thus, methylfolate may be an effective adjunctive treatment for depression at a dosage of 15 mg/d.

S-adenosyl methionine (SAMe) is a metabolite of folate derived from methionine that facilitates the synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. In Europe, as is the case with St. John’s wort, it is a prescription medication.

A randomized trial (N = 73) compared adjunctive SAMe 800 mg bid with placebo in the treatment of patients with unipolar major depression who did not experience improvement with SSRI treatment alone.²⁰ The investigators found that more patients who received SAMe than who received placebo had improvement in their depression (36.1% vs 17.6%), and more patients who received SAMe compared to placebo went into depression remission (25.8% vs 11.7%).

Adverse effects were comparable in both groups. Thus, SAMe at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.^20,21 The findings of 1 study (N = 65) suggest that patients could experience further improvement in their depression symptoms with SAMe at doses of as much as 3200 mg/d; however, 3200 mg/d increased the occurrence of gastrointestinal adverse effects (31.3% in the SAMe arm vs 3.8% in the placebo group).²¹

Folate. With regard to folate itself, randomized trials have not supported its efficacy in the treatment of depression in the general population.²²

Continue to: VItamin D may improve anxiety/depression in those with low levels

Vitamin D may improve anxiety/depression in those with low levels

Vitamin D supplementation is also being used more frequently in the treatment of depression. Case-control, cross-sectional, and cohort studies have linked low vitamin D levels to the occurrence of depression. A 2013 systematic review of 14 such studies (N = 31,424) found lower vitamin D levels in people with depression compared with controls.²³ Further studies are needed to determine if this relationship is causal, and quality RCTs investigating the effect of vitamin D supplementation on depression are lacking.

S-adenosyl methionine (SAMe) at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.

A 2019 study (N = 30) evaluated the ­impact of vitamin D supplementation on generalized anxiety disorder in patients with co-occurring vitamin D deficiency. Half received standard-of-care general anxiety disorder treatment plus 50,000 IU of vitamin D weekly for 3 months, while the other half received standard of care alone. Significant improvements in anxiety scores, increases in serum serotonin, and decreases in serum neopterin (an inflammatory marker) were observed in the vitamin D–treated group compared to the group that did not receive vitamin D.²⁴

It is not currently standard of care to check vitamin D levels in all patients presenting with mood disorders. However, if screening is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/or depressive symptoms. Despite this, no evidence exists to support vitamin D supplementation for depression or anxiety in patients with normal vitamin D levels.^24,25

The effects of omega-3 fatty acids are largely unclear

Research has shown that omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in fish oil, protect glutamatergic neurotransmission from glucocorticoids, which are released in the body during a stress response.²⁶ Small clinical trials have found n-3 PUFAs to reduce the symptoms of anxiety compared with placebo, but the acids have not been studied directly for anxiety disorders.^27,28

With regard to depression, evidence is conflicting as to whether n-3 PUFAs are of any benefit in treatment.²⁹ Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are hypothesized to be the components in omega-3 fatty acid preparations that could lead to a reduction in depressive symptoms. However, randomized trials have shown that EPA-predominant omega-3 fatty acid formulations have only a moderate or no clinically significant effect on depression over placebo, and that DHA-predominant omega-3 fatty acid formulations are only comparable or inferior to placebo.³⁰

Continue to: Response to EPA...

Response to EPA may be greater in patients with depression who have high levels of inflammatory biomarkers, such as interleuken (IL)-1 receptor antagonist (1Ra), IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin, and adiponectin, than in patients with low levels. An 8-week trial randomly assigned patients with unipolar major depression (N = 155) to receive either EPA, DHA, or placebo and found that improvement for the 3 groups was comparable; however, in the subgroup of patients with high levels of inflammatory markers, improvement in depressive symptoms was significantly greater with EPA than with either DHA or placebo.³¹

If screening for vitamin D levels is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/ or depression symptoms.

It is unclear whether different sources of n-3 PUFA, such as whole fish vs fish oil vs prescription omega-3 acid ethyl esters (Lovaza), are more or less efficacious in the treatment of anxiety or depression. Furthermore, there is no standard dosing for n-3 PUFA in the treatment of mood disorders. Given that the US Food and Drug Administration recommends no more than 2 g/d of combined EPA and DHA supplementation, we recommend using 2 g/d if one decides to treat depression/anxiety with n-3 PUFA.³²

N-3 PUFA supplementation is fairly benign. There have been previous concerns about n-3 PUFA supplementation increasing patients’ risk for gastrointestinal bleeding, but a 2006 systematic review that included 9 trials (N = 2612) that looked at clinically significant bleeding episodes found that even patients at high risk for bleeding (ie, those taking aspirin or warfarin) had no increased bleeding risk from taking n-3 PUFA supplementation at up to 4 g/d.³³

Don’t underestimate exercise and meditation; consider acupuncture

Exercise. Multiple practice guidelines, including the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” and meta-analyses have supported the use of exercise to treat unipolar major depression and anxiety.^34-37 However, only about 26% of American men and 19% of American women met the US Department of Health and Human Services’ “Federal Physical Activity Guidelines for Americans” in 2016.³⁸

Exercise alone is a reasonable monotherapy, as long as patients are monitored closely for worsening symptoms. Additionally, exercise as an add-on treatment can be helpful for more severe depression or anxiety.³⁹ The best type, duration, and frequency of exercise specifically for the treatment of depression or anxiety has yet to be determined, but physicians may base their exercise recommendations on the “Federal Physical Activity Guidelines for Americans” for general good health (TABLE).³⁸

Continue to: Meditation

Meditation, especially mindfulness meditation, is another strategy that has gained popularity in the treatment of anxiety and depression. Mindfulness has been defined as “the practice of maintaining a nonjudgmental state of heightened or complete awareness of one’s thoughts, emotions, or experiences on a moment-to-moment basis.”⁴⁰ A 2014 systematic review and meta-analysis of 47 trials with 3515 participants found that mindfulness meditation programs led to clinically significant moderate reductions in anxiety.⁴¹ Smaller effects were found for depression.

Nevertheless, meditation may be beneficial as an adjunctive treatment for depression. A small randomized trial (N = 25) compared an adjunctive breathing-based meditation intervention with a waitlist control (delayed yoga) in patients with unipolar major depression who failed to respond to at least 8 weeks of antidepressant treatment.⁴² The meditation intervention consisted of a group program with sitting meditation, breathing exercises, and yoga postures. Participants engaged in the meditation intervention for 2 to 3.5 hours per day for 8 weeks and demonstrated significant improvement in depression symptoms compared with the control group.⁴²

Acupuncture. A 2018 meta-analysis of 64 studies (N = 7104) suggests that acupuncture results in a small-to-moderate reduction in depressive symptoms when compared to no treatment, control/sham acupuncture, or medication.⁴³ Furthermore, acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.⁴³

Additionally, a 2019 analysis of 10 systematic reviews found acupuncture to be more effective than control/sham acupuncture in the treatment of general anxiety.⁴⁴ It should be noted, however, that a lot of heterogeneity and potential for bias existed across all of the studies. The studies analyzed were very low to low in quality. Thus, the evidence is insufficient to strongly recommend the use of acupuncture for depression or anxiety, although acupuncture is a safe intervention with low rates of adverse events.

Emotional support animals: Beneficial, but evidence is weak

Emotional support animals are gaining in popularity with Americans who have mood disorders. An important distinction must be made, however, between service animals and emotional support animals. A service animal is one “that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability.”⁴⁵ Under the Americans with Disabilities Act (ADA), service animals are limited to dogs, and, in some cases, specially trained miniature horses. Psychiatric service dogs can be trained to do anything from reminding their owner to take medicine to stopping self-mutilation activities.

Continue to: Emotional support animals...

Emotional support animals are not specially trained to perform tasks to help with disabilities. It’s their companionship that helps relieve symptoms of depression and/or anxiety.⁴⁵ Thus, emotional support animals are not covered under federal laws that apply to service animals. However, the Air Carrier Access Act does require airlines to allow emotional support animals to fly in the cabin for free. Furthermore, the Fair Housing Act allows emotional support animals to circumvent no-pet rules in housing and dorms. Airplanes and housing are the only places legally required to allow the unrestricted presence of emotional support animals.⁴⁶

Also, there are important distinctions between emotional support animals and pets. While anyone can own a pet, an emotional support animal is prescribed by a licensed mental health professional as a treatment for a mood disorder. Housing facilities and airlines will usually require an emotional support animal “prescription” or letter from a physician to recognize animals as such.

Exercise alone is a reasonable monotherapy for depression or anxiety as long as patients are monitored closely for worsening symptoms.

A 2018 systematic review evaluated the evidence behind emotional support animals, which included 17 peer-reviewed journal articles, conference papers, and research dissertations (N = 1727) mostly containing qualitative evidence.⁴⁷ Unfortunately, there are no RCTs, and there are limited case-control and cohort studies evaluating the effect of an emotional support animal on mood disorders. Based on the available evidence, there does seem to be a psychological benefit to owning an animal for both those with a diagnosable mental health disorder and the general population. This benefit seems to stem from a perceived reduction in social isolation and an increase in emotional support. Factors that determine the psychological benefit of emotional support animals include the type of pet, the number of pets, the attachment to the pet, and the perceived friendliness of the pet.⁴⁷

Animal-assisted therapy. A 2014 systematic review evaluated higher-level evidence behind animal-assisted therapy (AAT).⁴⁸ Although participating in therapy that involves interaction with animals is not the same as owning an emotional support animal, the concept—using an animal to improve mental health—is the same. The systematic review looked at 11 RCTs (N = 411) that studied the effect of AAT on mental health. Animals studied included dogs, cats, dolphins, birds, cows, rabbits, ferrets, and guinea pigs. Mental health disorders studied included schizophrenia, depression, anxiety, alcohol/drug abuse, and other addictive behaviors.

Acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.

Therapeutic animal exposure led to reported improvements in mood, quality of life, and social behavior. These improvements were attributed to the animals buffering people’s reactions to mental stressors. The animals provided a sense of comfort and safety and diverted attention away from immediate stressors. Furthermore, the memory of the animals brought participants a sense of comfort/happiness when they were later without the animal. However, the majority of participants were people who liked animals at baseline.⁴⁸

CORRESPONDENCE
Amanda E. Olagunju, DO, Operational Medicine Clinic, Langley AFB Hospital, 77 Nealy Avenue, Langley AFB, VA 23665; [email protected].

Almost 8% of Americans ages ≥ 12 years have depression and 19.1% of Americans ages ≥ 18 years have experienced an anxiety disorder in the past year.^1,2 Furthermore, suicide, which can result from depression and anxiety, is the 10th leading cause of death in the United States, claiming about 40,000 to 49,000 lives per year since 2012, with increasing yearly rates.³ While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and alternative medicine (CAM) options. According to the National Center for Complementary and Integrative Health, more than 30% of American adults use CAM treatments.⁴

This article provides an overview of the evidence for commonly used CAM treatments for unipolar depression and anxiety in adults. It is designed to serve as a useful resource when patients are interested in looking beyond conventional medications.

St. John’s wort: ‘Yes’ for depression; ‘no’ for anxiety

Hypericum perforatum, more commonly known as St. John’s wort, is a widely used antidepressant, especially in Europe where it is prescribed, rather than offered over the counter as it is here. Its mechanism of action is not completely understood because its various constituents have different neuropharmacologic activities.^5,6

A 2008 Cochrane review evaluated 29 randomized, double-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of depression.⁷ St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar findings.⁸ In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate.

Mood disorders other than depression. Studies do not support a role for St. John’s wort in the treatment of anxiety disorders. There are no trials that assess the efficacy of St. John’s wort for the reduction of symptoms of general anxiety disorder as a primary outcome of treatment. Some small clinical trials have investigated the efficacy of St. John’s wort in obsessive-compulsive disorder and social anxiety disorder. In those studies, St. John’s wort performed no better than placebo.^9,10

A few words of caution. Preparations of St. John’s wort in the United States are not standardized, so St. John’s wort should be used in America with caution. Furthermore, long-term use of St. John’s wort for depression is questionable given that most studies have evaluated only up to 12 weeks of use.⁸

In patients with mildto-moderate depression, St. John’s wort produced rates of remission that were comparable to those produced by SSRIs— with a lower discontinuation rate.

If used, studies indicate that the St. John’s wort extract that should be used is 0.3% hypericin or 5% hyperforin administered in a dosage of 300 to 400 mg tid.^7,8,11 Physicians and patients can use www.consumerlabs.com to find St. John’s wort brands that have met specified quality criteria based on independent laboratory studies. This Web site can also be used to investigate the quality of the brands available for the other supplements discussed in this article.

Continue to: Adverse effects

Adverse effects. St. John’s wort and an SSRI can lead to serotonin syndrome, which is a constellation of symptoms involving mental status changes and autonomic and neuromuscular hyperactivity caused by serotonin overactivity.¹² Furthermore, treatment failures with anticoagulants, digoxin, hormonal contraceptives, immunosuppressants, and narcotics due to concomitant use with St. John’s wort have been reported.¹³

The most common adverse reactions to St. John’s wort include gastrointestinal symptoms, dizziness, sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling.¹⁴ However, multiple studies have supported St. John’s wort to be equally or better tolerated than conventional antidepressants.^7,8

Certain forms of folate can be adjunctive treatment for depression

Methylfolate is the form of folate that crosses the blood–brain barrier. A prospective observational study evaluated the cerebral spinal fluid of 33 patients with refractory depression. The authors found metabolic abnormalities in the cerebrospinal fluid of most of those patients, the most common of which was folate deficiency in 12 patients despite normal serum folate levels.¹⁵

Additionally, current understanding of the role of the Methylenetetrahydrofolate reductase (MTHFR) gene and the folate cycle in depression supports a potential role of methylfolate in depression treatment.¹⁶ The MTHFR gene encodes for an enzyme called MTHFR. The MTHFR enzyme converts 5,10-MTHF to 5-MTHF, which then crosses the blood–brain barrier and donates a methyl group for the conversion of homocysteine to methionine. Methionine is a precursor to monoamine neurotransmitters. Thus, decreased expression of the MTHFR gene leads to decreased methylfolate levels, which, in turn, potentially leads to insufficient neurotransmitter synthesis and homocysteine excess.

MTHFR gene polymorphisms and increased homocysteine levels have been found to be associated with the occurrence of depression. One thought is that methylfolate supplementation compensates for an underlying MTHFR enzyme deficiency in patients with depression. Further studies are needed to determine if screening depressed patients for MTHFR gene polymorphisms is of benefit.¹⁶

Continue to: A 2012 randomized controlled trial...

A 2012 randomized controlled trial (RCT) (N = 75) compared L-methylfolate 15 mg/d plus an SSRI with placebo plus an SSRI in patients with SSRI-resistant major depression.¹⁷ The trial found that a reduction of baseline symptoms by ≥ 50% occurred in more patients who received adjunctive L-methylfolate than placebo (32% vs 15%) and tolerability was comparable. These findings were again supported in 2016 with a 12-month study showing L-methylfolate to have long-term tolerability comparable to placebo,¹⁸ and in 2017 with a randomized trial (N = 260) that found escitalopram 10 mg/d plus L-methylfolate 15 mg/d to be significantly more effective at treating depression than escitalopram 10 mg/d alone.¹⁹ Thus, methylfolate may be an effective adjunctive treatment for depression at a dosage of 15 mg/d.

S-adenosyl methionine (SAMe) is a metabolite of folate derived from methionine that facilitates the synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. In Europe, as is the case with St. John’s wort, it is a prescription medication.

A randomized trial (N = 73) compared adjunctive SAMe 800 mg bid with placebo in the treatment of patients with unipolar major depression who did not experience improvement with SSRI treatment alone.²⁰ The investigators found that more patients who received SAMe than who received placebo had improvement in their depression (36.1% vs 17.6%), and more patients who received SAMe compared to placebo went into depression remission (25.8% vs 11.7%).

Adverse effects were comparable in both groups. Thus, SAMe at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.^20,21 The findings of 1 study (N = 65) suggest that patients could experience further improvement in their depression symptoms with SAMe at doses of as much as 3200 mg/d; however, 3200 mg/d increased the occurrence of gastrointestinal adverse effects (31.3% in the SAMe arm vs 3.8% in the placebo group).²¹

Folate. With regard to folate itself, randomized trials have not supported its efficacy in the treatment of depression in the general population.²²

Continue to: VItamin D may improve anxiety/depression in those with low levels

Vitamin D may improve anxiety/depression in those with low levels

Vitamin D supplementation is also being used more frequently in the treatment of depression. Case-control, cross-sectional, and cohort studies have linked low vitamin D levels to the occurrence of depression. A 2013 systematic review of 14 such studies (N = 31,424) found lower vitamin D levels in people with depression compared with controls.²³ Further studies are needed to determine if this relationship is causal, and quality RCTs investigating the effect of vitamin D supplementation on depression are lacking.

S-adenosyl methionine (SAMe) at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.

A 2019 study (N = 30) evaluated the ­impact of vitamin D supplementation on generalized anxiety disorder in patients with co-occurring vitamin D deficiency. Half received standard-of-care general anxiety disorder treatment plus 50,000 IU of vitamin D weekly for 3 months, while the other half received standard of care alone. Significant improvements in anxiety scores, increases in serum serotonin, and decreases in serum neopterin (an inflammatory marker) were observed in the vitamin D–treated group compared to the group that did not receive vitamin D.²⁴

It is not currently standard of care to check vitamin D levels in all patients presenting with mood disorders. However, if screening is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/or depressive symptoms. Despite this, no evidence exists to support vitamin D supplementation for depression or anxiety in patients with normal vitamin D levels.^24,25

The effects of omega-3 fatty acids are largely unclear

Research has shown that omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in fish oil, protect glutamatergic neurotransmission from glucocorticoids, which are released in the body during a stress response.²⁶ Small clinical trials have found n-3 PUFAs to reduce the symptoms of anxiety compared with placebo, but the acids have not been studied directly for anxiety disorders.^27,28

With regard to depression, evidence is conflicting as to whether n-3 PUFAs are of any benefit in treatment.²⁹ Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are hypothesized to be the components in omega-3 fatty acid preparations that could lead to a reduction in depressive symptoms. However, randomized trials have shown that EPA-predominant omega-3 fatty acid formulations have only a moderate or no clinically significant effect on depression over placebo, and that DHA-predominant omega-3 fatty acid formulations are only comparable or inferior to placebo.³⁰

Continue to: Response to EPA...

Response to EPA may be greater in patients with depression who have high levels of inflammatory biomarkers, such as interleuken (IL)-1 receptor antagonist (1Ra), IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin, and adiponectin, than in patients with low levels. An 8-week trial randomly assigned patients with unipolar major depression (N = 155) to receive either EPA, DHA, or placebo and found that improvement for the 3 groups was comparable; however, in the subgroup of patients with high levels of inflammatory markers, improvement in depressive symptoms was significantly greater with EPA than with either DHA or placebo.³¹

If screening for vitamin D levels is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/ or depression symptoms.

It is unclear whether different sources of n-3 PUFA, such as whole fish vs fish oil vs prescription omega-3 acid ethyl esters (Lovaza), are more or less efficacious in the treatment of anxiety or depression. Furthermore, there is no standard dosing for n-3 PUFA in the treatment of mood disorders. Given that the US Food and Drug Administration recommends no more than 2 g/d of combined EPA and DHA supplementation, we recommend using 2 g/d if one decides to treat depression/anxiety with n-3 PUFA.³²

N-3 PUFA supplementation is fairly benign. There have been previous concerns about n-3 PUFA supplementation increasing patients’ risk for gastrointestinal bleeding, but a 2006 systematic review that included 9 trials (N = 2612) that looked at clinically significant bleeding episodes found that even patients at high risk for bleeding (ie, those taking aspirin or warfarin) had no increased bleeding risk from taking n-3 PUFA supplementation at up to 4 g/d.³³

Don’t underestimate exercise and meditation; consider acupuncture

Exercise. Multiple practice guidelines, including the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” and meta-analyses have supported the use of exercise to treat unipolar major depression and anxiety.^34-37 However, only about 26% of American men and 19% of American women met the US Department of Health and Human Services’ “Federal Physical Activity Guidelines for Americans” in 2016.³⁸

Exercise alone is a reasonable monotherapy, as long as patients are monitored closely for worsening symptoms. Additionally, exercise as an add-on treatment can be helpful for more severe depression or anxiety.³⁹ The best type, duration, and frequency of exercise specifically for the treatment of depression or anxiety has yet to be determined, but physicians may base their exercise recommendations on the “Federal Physical Activity Guidelines for Americans” for general good health (TABLE).³⁸

Continue to: Meditation

Meditation, especially mindfulness meditation, is another strategy that has gained popularity in the treatment of anxiety and depression. Mindfulness has been defined as “the practice of maintaining a nonjudgmental state of heightened or complete awareness of one’s thoughts, emotions, or experiences on a moment-to-moment basis.”⁴⁰ A 2014 systematic review and meta-analysis of 47 trials with 3515 participants found that mindfulness meditation programs led to clinically significant moderate reductions in anxiety.⁴¹ Smaller effects were found for depression.

Nevertheless, meditation may be beneficial as an adjunctive treatment for depression. A small randomized trial (N = 25) compared an adjunctive breathing-based meditation intervention with a waitlist control (delayed yoga) in patients with unipolar major depression who failed to respond to at least 8 weeks of antidepressant treatment.⁴² The meditation intervention consisted of a group program with sitting meditation, breathing exercises, and yoga postures. Participants engaged in the meditation intervention for 2 to 3.5 hours per day for 8 weeks and demonstrated significant improvement in depression symptoms compared with the control group.⁴²

Acupuncture. A 2018 meta-analysis of 64 studies (N = 7104) suggests that acupuncture results in a small-to-moderate reduction in depressive symptoms when compared to no treatment, control/sham acupuncture, or medication.⁴³ Furthermore, acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.⁴³

Additionally, a 2019 analysis of 10 systematic reviews found acupuncture to be more effective than control/sham acupuncture in the treatment of general anxiety.⁴⁴ It should be noted, however, that a lot of heterogeneity and potential for bias existed across all of the studies. The studies analyzed were very low to low in quality. Thus, the evidence is insufficient to strongly recommend the use of acupuncture for depression or anxiety, although acupuncture is a safe intervention with low rates of adverse events.

Emotional support animals: Beneficial, but evidence is weak

Emotional support animals are gaining in popularity with Americans who have mood disorders. An important distinction must be made, however, between service animals and emotional support animals. A service animal is one “that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability.”⁴⁵ Under the Americans with Disabilities Act (ADA), service animals are limited to dogs, and, in some cases, specially trained miniature horses. Psychiatric service dogs can be trained to do anything from reminding their owner to take medicine to stopping self-mutilation activities.

Continue to: Emotional support animals...

Emotional support animals are not specially trained to perform tasks to help with disabilities. It’s their companionship that helps relieve symptoms of depression and/or anxiety.⁴⁵ Thus, emotional support animals are not covered under federal laws that apply to service animals. However, the Air Carrier Access Act does require airlines to allow emotional support animals to fly in the cabin for free. Furthermore, the Fair Housing Act allows emotional support animals to circumvent no-pet rules in housing and dorms. Airplanes and housing are the only places legally required to allow the unrestricted presence of emotional support animals.⁴⁶

Also, there are important distinctions between emotional support animals and pets. While anyone can own a pet, an emotional support animal is prescribed by a licensed mental health professional as a treatment for a mood disorder. Housing facilities and airlines will usually require an emotional support animal “prescription” or letter from a physician to recognize animals as such.

Exercise alone is a reasonable monotherapy for depression or anxiety as long as patients are monitored closely for worsening symptoms.

A 2018 systematic review evaluated the evidence behind emotional support animals, which included 17 peer-reviewed journal articles, conference papers, and research dissertations (N = 1727) mostly containing qualitative evidence.⁴⁷ Unfortunately, there are no RCTs, and there are limited case-control and cohort studies evaluating the effect of an emotional support animal on mood disorders. Based on the available evidence, there does seem to be a psychological benefit to owning an animal for both those with a diagnosable mental health disorder and the general population. This benefit seems to stem from a perceived reduction in social isolation and an increase in emotional support. Factors that determine the psychological benefit of emotional support animals include the type of pet, the number of pets, the attachment to the pet, and the perceived friendliness of the pet.⁴⁷

Animal-assisted therapy. A 2014 systematic review evaluated higher-level evidence behind animal-assisted therapy (AAT).⁴⁸ Although participating in therapy that involves interaction with animals is not the same as owning an emotional support animal, the concept—using an animal to improve mental health—is the same. The systematic review looked at 11 RCTs (N = 411) that studied the effect of AAT on mental health. Animals studied included dogs, cats, dolphins, birds, cows, rabbits, ferrets, and guinea pigs. Mental health disorders studied included schizophrenia, depression, anxiety, alcohol/drug abuse, and other addictive behaviors.

Acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.

Therapeutic animal exposure led to reported improvements in mood, quality of life, and social behavior. These improvements were attributed to the animals buffering people’s reactions to mental stressors. The animals provided a sense of comfort and safety and diverted attention away from immediate stressors. Furthermore, the memory of the animals brought participants a sense of comfort/happiness when they were later without the animal. However, the majority of participants were people who liked animals at baseline.⁴⁸

CORRESPONDENCE
Amanda E. Olagunju, DO, Operational Medicine Clinic, Langley AFB Hospital, 77 Nealy Avenue, Langley AFB, VA 23665; [email protected].

Foot and ankle injuries are among the most common conditions evaluated at primary care visits; the differential diagnosis of such injury is broad.¹ Although many of these injuries are easily identified on imaging studies, a number of subtle, yet important, conditions can be easily missed, especially if you do not routinely encounter them. Given that broad differential, a high degree of suspicion is required to make an accurate diagnosis, which allows appropriate treatment within a reasonable time frame and minimizes the risk of long-term morbidity.

This article outlines the diagnosis and initial management of 5 important, yet often elusive, types of foot and ankle conditions: Achilles tendon rupture, injury to the syndesmosis, ankle fracture, Lisfranc injury, and proximal fracture of the fifth metatarsal.

© Ken Jacobsen

Achilles tendon rupture

The Achilles tendon is the most frequently ruptured tendon in the body (approximately 20% of all large-tendon injuries)²; as many as 25% of cases are initially misdiagnosed.³

Presentation. Patients frequently present with pain at the Achilles tendon—2 to 6 cm above the insertion into the calcaneus—and an inability to fully bear weight.^4,5 A small percentage of patients are able to ambulate on the affected side, albeit with minor pain, which likely contributes to the rate of missed diagnosis. Absence of difficulty bearing weight is due to the presence of secondary plantar flexors, which can compensate for loss of chief plantar flexor function by the Achilles tendon.²

Although many of these injuries are easily identified on imaging studies, a number of subtle conditions can be easily missed, especially if you do not routinely encounter them.

Examination of a patient with an Achilles tendon rupture typically reveals edema, bruising, and a palpable gap within the tendon, 2 to 6 cm proximal to insertion.^3,4 The Thompson test—squeezing the calf with the patient prone and the knee on the affected side flexed—can aid in diagnosis. When the Achilles tendon is intact, plantar flexion occurs at the ankle; when the tendon is ruptured, plantar flexion is absent.⁵ The test can be modified when examining a patient who is unable to lie prone by having them rest the flexed knee on a chair while standing on the unaffected leg.

A diagnosis of Achilles tendon rupture is supported when at least 2 of the following conditions are met^4,5:

• positive Thompson test
• decreased strength during plantar flexion of the ankle
• palpable gap or pain at the typical location (2-6 cm above insertion)
• increased passive ankle dorsiflexion upon gentle ranging of the ankle joint.

Imaging has a limited role in the diagnosis of Achilles tendon rupture; because the findings of the physical examination are reliable, reserve x-rays for cases in which the diagnosis remains uncertain after examination.² Consider ordering plain x-rays to rule out an avulsion fracture at the insertion of the Achilles tendon; ultrasonography or magnetic resonance imaging (MRI) might assist you in detecting the rupture proper, along with the location of the tear for surgical planning, if surgery is deemed necessary by an orthopedic surgeon.^3-5

Continue to: Management

Management. Some degree of controversy surrounds preferred treatment of Achilles tendon rupture, although available evidence demonstrates that these injuries can be effectively managed by surgical repair or nonoperative treatment, as outcomes are comparable.^3,5 Operative management tends to reduce the risk of repeat rupture, compared to nonoperative treatment; however, the potential for surgical complications, including wound infection, sensory disturbance, and adhesions favors nonoperative treatment.^3,4,6

Nonoperative treatment consists of referral to a functional rehabilitation program, without which outcomes are, on the whole, less favorable than with surgery.^3,6 Surgery is preferred if functional rehabilitation is unavailable, 6 months of conservative management fails, or there is avulsion injury.^3,4,6

Injury to the syndesmosis

A complex of ligaments that provide dynamic stability to the ankle joint, the tibiofibular syndesmosis comprises:

• the anterior inferior tibiofibular ligament
• the posterior inferior tibiofibular ligament
• the inferior transverse tibiofibular ligament
• the interosseous membrane.

These structures are further supported by the deltoid ligament.^7,8

Some patients with Achilles tendon rupture can walk on the affected side, even with minor pain; the diagnosis might be missed without further in-depth evaluation.

Commonly referred to as a “high ankle sprain,” a syndesmotic injury is present in as many as 20% of ankle fractures and 5% to 10% of ankle sprains. Injury typically results from external rotation with hyperdorsiflexion of the ankle. Recovery is typically prolonged (ie, twice as long as recovery from a lateral ankle sprain). The diagnosis is missed in as many as 20% of patients; failure to recognize and treat syndesmotic instability appropriately can lead to posttraumatic arthritis.^7,9

Continue to: Presentation

Presentation. Patients generally present with ankle pain, swelling, instability, pain when walking on uneven terrain, and pain upon push-off.⁹

Examination reveals reduced passive ankle dorsiflexion and tenderness upon palpation of individual ligaments. Several clinical tests have been described to aid in detecting this often-elusive diagnosis^7,9,10,11:

• Squeeze test. The patient sits with the knee on the affected side bent at a 90° degree angle while the examiner applies compression, with one or both hands, to the tibia and fibula at midcalf. The test is positive when pain is elicited at the level of the syndesmosis just above the ankle joint.^9,11
• External rotation test. External rotation of the foot and ankle relative to the tibia reproduces pain.
• Crossed leg test. The affected ankle is crossed over the opposite knee in a figure-4 position. The test is positive when pain is elicited at the syndesmosis.¹⁰
• Cotton test. The proximal lower leg is steadied with 1 hand and the plantar heel grasped with the other hand. Pain when the heel is externally rotated (and radiographic widening of the syndesmosis under fluoroscopy) signal syndesmotic instability.
• Fibular translation test. When anterior or posterior drawer force is applied to the fibula, pain and increased translation of the fibula (compared to the contralateral side) suggest instability.

With the Cotton and fibular translation tests, interexaminer technique is more variable and findings are less reproducible.⁸ Taken alone, none of the above-listed tests are diagnostic; they can, however, assist in making a diagnosis of an injury to the syndesmosis.¹¹

Imaging typically involves anteroposterior [AP], lateral, and mortise plain films of the ankle and weight-bearing AP and lateral views of the tibia and fibula.⁹ Important measures on weight-bearing AP x-rays are the tibiofibular clear space (abnormal, > 6 mm) and the tibiofibular overlap (abnormal, < 6 mm) (both abnormalities shown in FIGURE 1). Comparing films of the affected ankle with views of the contralateral ankle is often useful.

Management of syndesmotic injuries depends on degree of disruption:

• Grade 1 injury is a sprain without diastasis on imaging. Management is conservative, with immobilization in a splint or boot for 1 to 3 weeks, followed by functional rehabilitation over 3 to 6 weeks.¹⁰
• Grade 2 injury is demonstrated by ­diastasis on a stress radiograph. Although evidence to guide successful identification of a grade 2 injury is lacking, it is clinically important to make that identification because these injuries might require surgical intervention, due to instability. Because the diagnosis of this injury can be challenging in primary care, high clinical suspicion of a grade 2 injury makes it appropriate to defer further evaluation to an orthopedic surgeon. On the other hand, if suspicion of a grade 2 injury is low, a trial of conservative management, with weekly clinical assessment, can be considered. A diagnosis of grade 2 injury can be inferred when a patient is unable to perform a single-leg hop after 3 weeks of immobilization; referral to an orthopedic surgeon is then indicated.¹²
• Grade 3 injury is frank separation at the distal tibiofibular joint that is detectable on a routine plain film. Management—surgical intervention to address instability—is often provided concurrently with the treatment for a Danis-Weber B or C fracture, which tends to coexist with grade 3 syndesmotic injury. (The Danis-Weber A–B–C classification of lateral ankle fracture will be discussed in a bit.)

Continue to: Ankle fracture

Ankle fracture

Fracture of the ankle joint is among the more common fractures in adults, comprising 10% of all fractures.^13,14 The ankle joint is defined as the junction of 3 bony structures: (1) the distal ends of the tibia and fibula and (2) the trochlea of the talus, all stabilized by (3) the collateral ligament complex. Appropriate diagnosis and timely intervention are needed to prevent long-term posttraumatic joint degeneration.

Presentation, examination, and imaging. In addition to difficulty bearing (or inability to bear) weight, patients with suspected ankle fracture can present with tenderness or pain, swelling (generally, the more severe the injury, the more severe the swelling, although this finding is time-dependent), and ecchymosis. However, distinguishing fracture from a ligamentous injury is often difficult by physical examination alone; the evidence-based Ottawa Ankle Rules can guide determination of the need for radiographic imaging, although this tool is less reliable in certain patient populations (TABLE^15-17).^13,15-17

Management. A widely used classification system for guiding ankle fracture management is the Danis-Weber classification (FIGURE 2). In this scheme, type A fractures (distal to the level of the tibial plafond) are managed with ankle stabilization bracing without immobilization. Nondisplaced type B and C fractures (at the level of the tibial plafond and proximal to it, respectively) should be treated with 6 weeks of immobilization in a walking boot; close follow-up within 1 week of injury is recommended to ensure that no displacement of fragments has occurred. Type B and C fractures need to be followed until bony union is achieved. If there is radiologic evidence of a fracture line after 3 months, referral to an orthopedic surgeon is indicated for management of delayed union.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Common indications for referral to Orthopedics for surgical intervention of ankle fracture include open fracture, bimalleolar and trimalleolar fracture, posterior malleolar fracture, medial malleolar displacement > 2 mm, and lateral malleolar displacement > 3 mm.¹⁸

Special concern: Talar fracture. Although talar fracture is rare, the injury is important to detect because a limited blood supply places fragments at risk of avascular necrosis.¹⁹ Talus fracture is frequently confused with ankle sprain because initial x-rays are not always revelatory.²⁰ A high index of suspicion is required to make the diagnosis, which should be suspected in high-energy injuries that result in pain and swelling of the ankle accompanied by difficulty weight-bearing, severely reduced range of motion, and tenderness to palpation at different areas of the talus.¹ Computed tomography (CT) or MRI might be necessary to detect a talar fracture if initial x-rays are negative. A low threshold for surgical management of talar fracture means that referral to Orthopedics is indicated once this injury is diagnosed.²¹

Continue to: Other frequently missed types of ankle fracture

Other frequently missed types of ankle fracture are shown in FIGURE 3.²² These are relatively uncommon injuries that can be missed for a number of reasons, alone or in combination, including their subtlety on radiography, their often vague clinical presentation, and providers’ lack of awareness of these types. Identification or strong suspicion of fracture at any of these sites (ie, in a patient who is persistently unable to bear weight) should prompt orthopedic referral.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Lisfranc injury

The tarsometatarsal joint comprises 3 cuneiforms, the cuboid, and 5 metatarsals. Stability is maintained by an intricate ligamentous complex. Lisfranc injury comprises a spectrum of midfoot injuries in which 1 or more metatarsals are displaced from the tarsus. These injuries are both rare and notoriously difficult to diagnose: As many as 20% of cases are missed on initial assessment. Without proper treatment, long-term disability and deformity, such as pes planus, can result.^22-24 Lisfranc injuries typically result from a direct blow to the midfoot or excessive pronation or supination in a plantarflexed foot.²³

Presentation. A historical clue to Lisfranc injury is a report of pain while walking down stairs. Patients can present with pain, swelling, and tenderness to palpation over the dorsal aspect of the Lisfranc joint. Weight-bearing on the injured foot frequently cannot be tolerated but is occasionally possible in some patients, especially those who have diabetes or other baseline neuropathy.²³

Examination. Physical examination can also reveal plantar ecchymosis, which is considered pathognomonic. Another highly supportive maneuver is passive abduction and pronation of the forefoot, which can elicit pain.^25,26

Imaging. Lisfranc injury can be diagnosed on weight-bearing x-rays; as many as one-half of cases are missed when only non-weight-bearing films are obtained. If initial weight-bearing cannot be tolerated by the patient, another attempt at imaging can be made after 1 week of rest.²⁴

Continue to: Distance > 2 mm between the base...

Distance > 2 mm between the base of the first and second metatarsals (FIGURE 4) or an avulsion fracture at the medial base of the second metatarsal or distal lateral corner of the medial cuneiform (the “fleck sign”) supports a disturbance of the Lisfranc joint complex.²⁴ Imaging of the contralateral foot might highlight the injury in subtle cases, followed by CT when diagnostic uncertainty persists.^24,25

IMAGE COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Management of Lisfranc injury depends on the stability of the joint complex. Stable injury without diastasis can be managed conservatively with immobilization in a short walker boot and limited weight-bearing for 2 weeks, followed by weight-bearing as tolerated in the boot if tenderness has improved.²⁴ After 6 to 8 weeks, if the patient is pain-free with abduction stress, weight-bearing without the boot (but with a rigid-sole shoe) is permissible for an additional 6 months. Sport-specific rehabilitation for an athlete can begin once the patient can walk down multiple flights of stairs without pain.²⁴

Orthopedic referral for surgical evaluation is recommended for all patients who have any radiographic evidence of dynamic instability, indicated by the fleck sign; displacement; or obvious diastasis between the metatarsals on imaging. A delay of 1 to 2 weeks from injury to fixation has not been associated with a negative outcome; delay as long as 6 weeks is permissible in some cases. Longer delay in surgical treatment (≥ 6 months) can be associated with posttraumatic arthritis and the need for Lisfranc fusion.^24-26

Whether a syndesmotic injury is managed conservatively (immobilization, rehabilitation) or surgically depends on the degree (grade 1, 2, or 3) of disruption.

Proximal fifth-metatarsal fractures

These common fractures are classified in 3 broad categories: tuberosity avulsion fracture, proximal diaphyseal (Jones) fracture, and stress fractures of the diaphysis (immediately distal to the site of the Jones fracture zone).^27-29 Differentiating an acute Jones fracture and other fracture types is clinically important because the watershed area at the metaphysis–diaphysis junction results in a higher risk of delayed union and nonunion of Jones fractures, compared to other fractures in this region (FIGURE 5).^28,29

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Presentation. Proximal fifth-metatarsal fractures generally present with lateral foot pain and tenderness at the base of the fifth metatarsal, made worse by inversion of the foot, and inability to bear weight on the lateral aspect of the foot. Acute pain can follow a more insidious course of lateral foot pain in stress fracture.

Continue to: Examination

Examination. On exam, there might be swelling and ecchymosis over the lateral foot, with sharp tenderness to palpation at the base of the fifth metatarsal.

Imaging. Most fractures are revealed on standing AP, oblique, and lateral x-rays. Plain films are often falsely negative early in stress fracture; MRI is the gold standard of diagnosis.^27,30

Management. Preferred treatment for a nondisplaced tuberosity avulsion fracture is typically 2-pronged: compressive dressings or casting for pain control and weight-bearing and range-of-motion exercises as tolerated.¹ Follow-up every 2 to 3 weeks is recommended to ensure appropriate healing—ie, pain nearly resolved by 3 weeks post-injury and radiographic union evident at 8 weeks. If displacement is > 3 mm, > 60% of the metatarsal–cuboid joint surface is affected, or there is a 1 to 2 mm step-off on the cuboid articular surface, consider referral to an orthopedist.^1,29

Jones fractures can be managed initially with posterior splinting, non-weight-bearing, and close follow-up. When radiographic healing has not been achieved by 6 to 8 weeks, non-weight-bearing status can be extended by another 4 weeks. When displacement is > 2 mm, or there is no healing after 12 weeks of immobilization and delayed union on x-rays, referral for surgical management is indicated.¹ In select cases, when earlier return to activity is desired, referral for early surgical fixation is appropriate.²⁷

Surgical referral is indicated in all cases of diaphysial stress fracture because of the high rate of nonunion and refracture. Conservative management, based on the orthopedic surgeon’s assessment, might be an option in a minority of patients.²⁹

CORRESPONDENCE
Aileen Roman, MD, Boston University Medical School, Department of Family Medicine, 11 Melnea Cass Boulevard, Boston MA, 02119; [email protected]