A mother had given birth to two children with thalamic abnormalities that resulted in seizures, developmental delays, and death. Before getting pregnant again, the parents sought genetic counseling and were told that identifying the specific defective gene would be impossible. The geneticist advised them that a child conceived with a donor egg and father’s sperm would have essentially the same risk as the general population. The parents asked in writing if it would be safer to
use both donor egg and donor sperm; the geneticist responded that the difference in risk was negligible.

The mother gave birth in June 2007 to a child conceived with a donated egg and the father’s sperm. After the child began to show the same symptoms as the others, an MRI of the child’s brain revealed a thalamic abnormality, and testing revealed Alpers syndrome caused by POLG gene mutations. The third child died in September 2008.

PARENTS’ CLAIM The chances of having a child with Alpers syndrome are
about 1:200,000 in the general population; if one parent is a known carrier, the chance is 1:1,000. If the parents had known this risk, they would have used donor egg and donor sperm to conceive or adopted. They were not told about Alpers syndrome and its relationship to the POLG gene until after their third child was born. The geneticist was negligent in failing to provide this information.

PHYSICIAN’S DEFENSE The parents received appropriate and accurate genetic counseling.

VERDICT A $1 million Florida verdict was returned.

What caused a delay in breast cancer diagnosis?
A 39-year-old woman underwent mammography in October 2004. After recommending a spotcompression film of a left-breast lesion, and then ultrasonography, the radiologist concluded that the lesion was benign, and suggested a 1-year follow-up. Reports were sent to the patient and her primary care physician.

In August 2006, when mammography was suspicious for breast cancer, a biopsy diagnosed infiltrating ductal carcinoma of the left breast. After undergoing a mastectomy, radiation therapy, and chemotherapy, the patient was cancer-free at the time of the trial.

patient’s CLAIM The radiologist failed to properly interpret the 2004 mammography.

physician’s DEFENSE The radiologist’s interpretations of the 2004 tests were correct. The patient failed to follow up in 1 year, as recommended, and this delayed the cancer diagnosis. The patient’s survival indicated that she had been cured of her breast cancer.

VERDICT A confidential settlement was reached with the hospital before the trial. An Illinois defense verdict was returned for the radiologist.


Heparin overdose for preemie
At 27 weeks' gestation, a woman went to a clinic with preeclampsia. After she was stabilized, the baby was born by emergency cesarean delivery.

At birth, the baby was thrombocytopenic (platelet count, 37,000/mL) with a heart rate of 60 bpm. The child’s cord blood pH was 7.27, indicating no significant hypoxia. At 1 minute of life, the child’s heart rate had not improved. After trying three times to place an endotracheal tube, chest compressions were begun at 10 minutes of life. An umbilical vein catheter (UVC) was placed at 22 minutes. Heparin was used to flush the UVC. After 40 minutes, the baby’s pH was 6.88, indicating severe acidosis. The infant was transferred to another hospital 3 hours after birth.

Head ultrasonography at 5 days of life revealed hemorrhagic and ischemic changes in the baby’s brain. The child suffered massive brain damage, is ventilator-dependent, and has a G-tube for feeding. She cannot sit up, walk, or speak, and will require specialized care for life.

Parent's claim Emergency resuscitation was not performed at birth: the low heart rate and thrombocytopenia were not treated; the UVC was not immediately placed. Twice, adult doses of heparin were used instead of normal saline to flush the UVC; heparin caused bleeding in the baby’s brain. 

Defendant's Defense The case was settled during trial.

Verdict A $3 million Maryland settlement was reached.

Uterine rupture: $130M verdict

After a woman's first child was born by cesarean delivery, vaginal birth after cesarean (VBAC) was planned for her second pregnancy. When a nurse recognized a ruptured uterus, the ObGyn ordered a cesarean delivery. The newborn suffered severe brain damage, with seizures. She has cerebral palsy with near-normal intelligence, but cannot talk or walk and continues to have seizures.

 Parents' claim The baby’s injuries occurred due to a failure to respond to fetal distress. When the intrauterine pressure catheter (IUPC) stopped working for 27 minutes, the nurse did not notify the ObGyn or apply an external monitor. Fetal heart decelerations occurred, including a prolonged deceleration for 3 minutes; the nurse did not notify the ObGyn, reposition the mother, provide oxygen and extra fluids, or discontinue oxytocin. A cesarean delivery should have occurred 30 to 60 minutes earlier.

Defendants' defense The fetal heart rates were what typically occur during the second stage of labor. The hospital’s accepted practices were followed. When the IUPC failed, the nurse measured contractions by hand and analyzed the fetal heartbeat from audible sounds; therefore, it was not necessary to notify the ObGyn. The physician was promptly called when uterine rupture was suspected. Uterine rupture and placental abruption caused the child’s injury. Uterine rupture cannot be predicted or prevented and is a known complication of VBAC.

Verdict After the parents declined an $8 million settlement, the matter was tried to a defense verdict. That decision was overturned on appeal, and, at a second trial, a $130 million New York verdict was returned against the hospital that employed the ObGyn and nurse.

Uterus, small bowel injured during D&C

A 65-year-old woman underwent dilation and curettage (D&C) to screen for uterine cancer performed by an ObGyn and a general surgeon. Her uterus and small intestine were perforated during the procedure, and a second operation was required to repair the damage.

Patient's claim Both physicians were negligent in performing D&C.

Physician's defense The ObGyn denied negligence and countered that the injuries are known complications of the procedure.

Verdict The surgeon settled for a confidential amount before trial. A New Jersey defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

A mother had given birth to two children with thalamic abnormalities that resulted in seizures, developmental delays, and death. Before getting pregnant again, the parents sought genetic counseling and were told that identifying the specific defective gene would be impossible. The geneticist advised them that a child conceived with a donor egg and father’s sperm would have essentially the same risk as the general population. The parents asked in writing if it would be safer to
use both donor egg and donor sperm; the geneticist responded that the difference in risk was negligible.

The mother gave birth in June 2007 to a child conceived with a donated egg and the father’s sperm. After the child began to show the same symptoms as the others, an MRI of the child’s brain revealed a thalamic abnormality, and testing revealed Alpers syndrome caused by POLG gene mutations. The third child died in September 2008.

PARENTS’ CLAIM The chances of having a child with Alpers syndrome are
about 1:200,000 in the general population; if one parent is a known carrier, the chance is 1:1,000. If the parents had known this risk, they would have used donor egg and donor sperm to conceive or adopted. They were not told about Alpers syndrome and its relationship to the POLG gene until after their third child was born. The geneticist was negligent in failing to provide this information.

PHYSICIAN’S DEFENSE The parents received appropriate and accurate genetic counseling.

VERDICT A $1 million Florida verdict was returned.

What caused a delay in breast cancer diagnosis?
A 39-year-old woman underwent mammography in October 2004. After recommending a spotcompression film of a left-breast lesion, and then ultrasonography, the radiologist concluded that the lesion was benign, and suggested a 1-year follow-up. Reports were sent to the patient and her primary care physician.

In August 2006, when mammography was suspicious for breast cancer, a biopsy diagnosed infiltrating ductal carcinoma of the left breast. After undergoing a mastectomy, radiation therapy, and chemotherapy, the patient was cancer-free at the time of the trial.

patient’s CLAIM The radiologist failed to properly interpret the 2004 mammography.

physician’s DEFENSE The radiologist’s interpretations of the 2004 tests were correct. The patient failed to follow up in 1 year, as recommended, and this delayed the cancer diagnosis. The patient’s survival indicated that she had been cured of her breast cancer.

VERDICT A confidential settlement was reached with the hospital before the trial. An Illinois defense verdict was returned for the radiologist.


Heparin overdose for preemie
At 27 weeks' gestation, a woman went to a clinic with preeclampsia. After she was stabilized, the baby was born by emergency cesarean delivery.

At birth, the baby was thrombocytopenic (platelet count, 37,000/mL) with a heart rate of 60 bpm. The child’s cord blood pH was 7.27, indicating no significant hypoxia. At 1 minute of life, the child’s heart rate had not improved. After trying three times to place an endotracheal tube, chest compressions were begun at 10 minutes of life. An umbilical vein catheter (UVC) was placed at 22 minutes. Heparin was used to flush the UVC. After 40 minutes, the baby’s pH was 6.88, indicating severe acidosis. The infant was transferred to another hospital 3 hours after birth.

Head ultrasonography at 5 days of life revealed hemorrhagic and ischemic changes in the baby’s brain. The child suffered massive brain damage, is ventilator-dependent, and has a G-tube for feeding. She cannot sit up, walk, or speak, and will require specialized care for life.

Parent's claim Emergency resuscitation was not performed at birth: the low heart rate and thrombocytopenia were not treated; the UVC was not immediately placed. Twice, adult doses of heparin were used instead of normal saline to flush the UVC; heparin caused bleeding in the baby’s brain. 

Defendant's Defense The case was settled during trial.

Verdict A $3 million Maryland settlement was reached.

Uterine rupture: $130M verdict

After a woman's first child was born by cesarean delivery, vaginal birth after cesarean (VBAC) was planned for her second pregnancy. When a nurse recognized a ruptured uterus, the ObGyn ordered a cesarean delivery. The newborn suffered severe brain damage, with seizures. She has cerebral palsy with near-normal intelligence, but cannot talk or walk and continues to have seizures.

 Parents' claim The baby’s injuries occurred due to a failure to respond to fetal distress. When the intrauterine pressure catheter (IUPC) stopped working for 27 minutes, the nurse did not notify the ObGyn or apply an external monitor. Fetal heart decelerations occurred, including a prolonged deceleration for 3 minutes; the nurse did not notify the ObGyn, reposition the mother, provide oxygen and extra fluids, or discontinue oxytocin. A cesarean delivery should have occurred 30 to 60 minutes earlier.

Defendants' defense The fetal heart rates were what typically occur during the second stage of labor. The hospital’s accepted practices were followed. When the IUPC failed, the nurse measured contractions by hand and analyzed the fetal heartbeat from audible sounds; therefore, it was not necessary to notify the ObGyn. The physician was promptly called when uterine rupture was suspected. Uterine rupture and placental abruption caused the child’s injury. Uterine rupture cannot be predicted or prevented and is a known complication of VBAC.

Verdict After the parents declined an $8 million settlement, the matter was tried to a defense verdict. That decision was overturned on appeal, and, at a second trial, a $130 million New York verdict was returned against the hospital that employed the ObGyn and nurse.

Uterus, small bowel injured during D&C

A 65-year-old woman underwent dilation and curettage (D&C) to screen for uterine cancer performed by an ObGyn and a general surgeon. Her uterus and small intestine were perforated during the procedure, and a second operation was required to repair the damage.

Patient's claim Both physicians were negligent in performing D&C.

Physician's defense The ObGyn denied negligence and countered that the injuries are known complications of the procedure.

Verdict The surgeon settled for a confidential amount before trial. A New Jersey defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

A mother had given birth to two children with thalamic abnormalities that resulted in seizures, developmental delays, and death. Before getting pregnant again, the parents sought genetic counseling and were told that identifying the specific defective gene would be impossible. The geneticist advised them that a child conceived with a donor egg and father’s sperm would have essentially the same risk as the general population. The parents asked in writing if it would be safer to
use both donor egg and donor sperm; the geneticist responded that the difference in risk was negligible.

The mother gave birth in June 2007 to a child conceived with a donated egg and the father’s sperm. After the child began to show the same symptoms as the others, an MRI of the child’s brain revealed a thalamic abnormality, and testing revealed Alpers syndrome caused by POLG gene mutations. The third child died in September 2008.

PARENTS’ CLAIM The chances of having a child with Alpers syndrome are
about 1:200,000 in the general population; if one parent is a known carrier, the chance is 1:1,000. If the parents had known this risk, they would have used donor egg and donor sperm to conceive or adopted. They were not told about Alpers syndrome and its relationship to the POLG gene until after their third child was born. The geneticist was negligent in failing to provide this information.

PHYSICIAN’S DEFENSE The parents received appropriate and accurate genetic counseling.

VERDICT A $1 million Florida verdict was returned.

What caused a delay in breast cancer diagnosis?
A 39-year-old woman underwent mammography in October 2004. After recommending a spotcompression film of a left-breast lesion, and then ultrasonography, the radiologist concluded that the lesion was benign, and suggested a 1-year follow-up. Reports were sent to the patient and her primary care physician.

In August 2006, when mammography was suspicious for breast cancer, a biopsy diagnosed infiltrating ductal carcinoma of the left breast. After undergoing a mastectomy, radiation therapy, and chemotherapy, the patient was cancer-free at the time of the trial.

patient’s CLAIM The radiologist failed to properly interpret the 2004 mammography.

physician’s DEFENSE The radiologist’s interpretations of the 2004 tests were correct. The patient failed to follow up in 1 year, as recommended, and this delayed the cancer diagnosis. The patient’s survival indicated that she had been cured of her breast cancer.

VERDICT A confidential settlement was reached with the hospital before the trial. An Illinois defense verdict was returned for the radiologist.


Heparin overdose for preemie
At 27 weeks' gestation, a woman went to a clinic with preeclampsia. After she was stabilized, the baby was born by emergency cesarean delivery.

At birth, the baby was thrombocytopenic (platelet count, 37,000/mL) with a heart rate of 60 bpm. The child’s cord blood pH was 7.27, indicating no significant hypoxia. At 1 minute of life, the child’s heart rate had not improved. After trying three times to place an endotracheal tube, chest compressions were begun at 10 minutes of life. An umbilical vein catheter (UVC) was placed at 22 minutes. Heparin was used to flush the UVC. After 40 minutes, the baby’s pH was 6.88, indicating severe acidosis. The infant was transferred to another hospital 3 hours after birth.

Head ultrasonography at 5 days of life revealed hemorrhagic and ischemic changes in the baby’s brain. The child suffered massive brain damage, is ventilator-dependent, and has a G-tube for feeding. She cannot sit up, walk, or speak, and will require specialized care for life.

Parent's claim Emergency resuscitation was not performed at birth: the low heart rate and thrombocytopenia were not treated; the UVC was not immediately placed. Twice, adult doses of heparin were used instead of normal saline to flush the UVC; heparin caused bleeding in the baby’s brain. 

Defendant's Defense The case was settled during trial.

Verdict A $3 million Maryland settlement was reached.

Uterine rupture: $130M verdict

After a woman's first child was born by cesarean delivery, vaginal birth after cesarean (VBAC) was planned for her second pregnancy. When a nurse recognized a ruptured uterus, the ObGyn ordered a cesarean delivery. The newborn suffered severe brain damage, with seizures. She has cerebral palsy with near-normal intelligence, but cannot talk or walk and continues to have seizures.

 Parents' claim The baby’s injuries occurred due to a failure to respond to fetal distress. When the intrauterine pressure catheter (IUPC) stopped working for 27 minutes, the nurse did not notify the ObGyn or apply an external monitor. Fetal heart decelerations occurred, including a prolonged deceleration for 3 minutes; the nurse did not notify the ObGyn, reposition the mother, provide oxygen and extra fluids, or discontinue oxytocin. A cesarean delivery should have occurred 30 to 60 minutes earlier.

Defendants' defense The fetal heart rates were what typically occur during the second stage of labor. The hospital’s accepted practices were followed. When the IUPC failed, the nurse measured contractions by hand and analyzed the fetal heartbeat from audible sounds; therefore, it was not necessary to notify the ObGyn. The physician was promptly called when uterine rupture was suspected. Uterine rupture and placental abruption caused the child’s injury. Uterine rupture cannot be predicted or prevented and is a known complication of VBAC.

Verdict After the parents declined an $8 million settlement, the matter was tried to a defense verdict. That decision was overturned on appeal, and, at a second trial, a $130 million New York verdict was returned against the hospital that employed the ObGyn and nurse.

Uterus, small bowel injured during D&C

A 65-year-old woman underwent dilation and curettage (D&C) to screen for uterine cancer performed by an ObGyn and a general surgeon. Her uterus and small intestine were perforated during the procedure, and a second operation was required to repair the damage.

Patient's claim Both physicians were negligent in performing D&C.

Physician's defense The ObGyn denied negligence and countered that the injuries are known complications of the procedure.

Verdict The surgeon settled for a confidential amount before trial. A New Jersey defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Ovarian cancer causes more deaths than any other cancer affecting the female reproductive system.¹ One reason it’s so deadly: It usually isn’t detected until it has reached an advanced stage. No clear-cut symptoms point definitively to ovarian malignancy, and no feasible screening strategy has been found to increase detection at an early stage.

Among the strategies that have been utilized to detect ovarian cancer are bimanual examination of the adnexae (primarily in postmenopausal women), measurement of cancer antigen (CA) 125, and transvaginal ultrasonography (TVUS) of the ovaries. The last two strategies sometimes are combined in high-risk women.

TVUS can highlight ovarian abnormalities and provide information about their structure. The question then becomes which abnormalities are likely to resolve without treatment, and which should be scrutinized more closely. In this study, Pavlik and colleagues reviewed TVUS findings from 39,337 women enrolled in the University of Kentucky Ovarian Cancer Screening Program, which involved 221,576 baseline and interval TVUS scans.

Details of the study
Women in this study were screened with annual TVUS scans between 1987 and 2002. The population included:

• asymptomatic women aged 50 or older
• asymptomatic women over age 25 who had a first- or second-degree relative with documented ovarian cancer.

The initial TVUS scan was normal in almost 90% of women, and only about 10% subsequently experienced an abnormal scan. About half (46.7%) of the ovarian abnormalities identified via TVUS were found on the very first scan. Of these, 63.2% resolved during follow-up with no treatment.

Approximately 80% of women had no abnormal TVUS findings at any time during the observation period. This is notable because participants had a high risk for ovarian cancer by virtue of advanced age or family history.

TVUS abnormalities had a higher prevalence in premenopausal women (35%) than in postmenopausal women (17%; P<.001). The incidence of ovarian cysts also was significantly higher among premenopausal women (15.3% vs 8.2%; P<.001). These differences are to be expected, owing to the functional nature of premenopausal ovaries in regard to folliculogenesis, ovulation, and endometriosis.

Positive predictive values ranged from 15.3% to 24.7%
Over the 25 years covered by this study, our understanding of the malignant potential of various ovarian masses has evolved considerably. We have long known that unilocular cysts are extremely unlikely to be malignant, but now we are aware that even septated cysts are unlikely to represent cancer.

As for the success of this ovarian cancer-screening program, which identified 85 true malignancies and 472 nonmalignancies in surgical specimens, it had an overall positive predictive value of 15.3%. After January 1, 2008, however, when serial observation expanded to include septated cysts (because published data confirmed these masses to have low malignant potential), positive predictive value improved to 24.7%.

Pavlik and colleagues also discussed findings from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which relied on a single TVUS abnormality to trigger a recommendation for surgery, with a positive predictive value of only 5.1%.²

Most cancers were diagnosed at an early stage
Of the invasive epithelial cancers identified in this study, the stage distribution at diagnosis was:

• Stage 1: 45%
• Stage 2: 23%
• Stage 3: 32%
• Stage 4: None.

This finding is notable, given statistics from the “real world,” where about 80% of ovarian cancers are diagnosed at Stage 3 or Stage 4.

Among benign findings that were managed surgically, 47% were serous cystadenomas, 13% were hemorrhagic cysts, 9% were fibromas, thecomas, or Brenner tumors, and the rest were fairly equally divided between hydrosalpinx or paratubal cysts; endometriomas; and mucinous cystadenomas, leiomyomas, and cystic teratomas.

What this evidence means for practice

In general, unilocular or septate cysts can be followed every 6 months by TVUS. Although more complex tumors may resolve spontaneously, they should be followed with serial TVUS, with caution, at intervals of 6 weeks to 3 months. The findings of each scan should determine the subsequent course of action, which could involve further monitoring or surgical extirpation.

Regrettably, this study did not utilize color flow Doppler imaging. Because malignant tumors are rich in neovascularity, and the vessels laid down by such tumors often lack a normal media layer, they often exhibit very low resistance to flow. Although neovascularity is not a perfect diagnostic indicator of malignancy, the presence of abundant blood flow and low resistance can raise the index of suspicion. In my opinion, color flow Doppler should be incorporated into ultrasonographic evaluation of potential ovarian malignancies.

—Steven R. Goldstein, MD

Tell us what you think, at [email protected]. Please include your name and city and state.

Ovarian cancer causes more deaths than any other cancer affecting the female reproductive system.¹ One reason it’s so deadly: It usually isn’t detected until it has reached an advanced stage. No clear-cut symptoms point definitively to ovarian malignancy, and no feasible screening strategy has been found to increase detection at an early stage.

Among the strategies that have been utilized to detect ovarian cancer are bimanual examination of the adnexae (primarily in postmenopausal women), measurement of cancer antigen (CA) 125, and transvaginal ultrasonography (TVUS) of the ovaries. The last two strategies sometimes are combined in high-risk women.

TVUS can highlight ovarian abnormalities and provide information about their structure. The question then becomes which abnormalities are likely to resolve without treatment, and which should be scrutinized more closely. In this study, Pavlik and colleagues reviewed TVUS findings from 39,337 women enrolled in the University of Kentucky Ovarian Cancer Screening Program, which involved 221,576 baseline and interval TVUS scans.

Details of the study
Women in this study were screened with annual TVUS scans between 1987 and 2002. The population included:

• asymptomatic women aged 50 or older
• asymptomatic women over age 25 who had a first- or second-degree relative with documented ovarian cancer.

The initial TVUS scan was normal in almost 90% of women, and only about 10% subsequently experienced an abnormal scan. About half (46.7%) of the ovarian abnormalities identified via TVUS were found on the very first scan. Of these, 63.2% resolved during follow-up with no treatment.

Approximately 80% of women had no abnormal TVUS findings at any time during the observation period. This is notable because participants had a high risk for ovarian cancer by virtue of advanced age or family history.

TVUS abnormalities had a higher prevalence in premenopausal women (35%) than in postmenopausal women (17%; P<.001). The incidence of ovarian cysts also was significantly higher among premenopausal women (15.3% vs 8.2%; P<.001). These differences are to be expected, owing to the functional nature of premenopausal ovaries in regard to folliculogenesis, ovulation, and endometriosis.

Positive predictive values ranged from 15.3% to 24.7%
Over the 25 years covered by this study, our understanding of the malignant potential of various ovarian masses has evolved considerably. We have long known that unilocular cysts are extremely unlikely to be malignant, but now we are aware that even septated cysts are unlikely to represent cancer.

As for the success of this ovarian cancer-screening program, which identified 85 true malignancies and 472 nonmalignancies in surgical specimens, it had an overall positive predictive value of 15.3%. After January 1, 2008, however, when serial observation expanded to include septated cysts (because published data confirmed these masses to have low malignant potential), positive predictive value improved to 24.7%.

Pavlik and colleagues also discussed findings from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which relied on a single TVUS abnormality to trigger a recommendation for surgery, with a positive predictive value of only 5.1%.²

Most cancers were diagnosed at an early stage
Of the invasive epithelial cancers identified in this study, the stage distribution at diagnosis was:

• Stage 1: 45%
• Stage 2: 23%
• Stage 3: 32%
• Stage 4: None.

This finding is notable, given statistics from the “real world,” where about 80% of ovarian cancers are diagnosed at Stage 3 or Stage 4.

Among benign findings that were managed surgically, 47% were serous cystadenomas, 13% were hemorrhagic cysts, 9% were fibromas, thecomas, or Brenner tumors, and the rest were fairly equally divided between hydrosalpinx or paratubal cysts; endometriomas; and mucinous cystadenomas, leiomyomas, and cystic teratomas.

What this evidence means for practice

In general, unilocular or septate cysts can be followed every 6 months by TVUS. Although more complex tumors may resolve spontaneously, they should be followed with serial TVUS, with caution, at intervals of 6 weeks to 3 months. The findings of each scan should determine the subsequent course of action, which could involve further monitoring or surgical extirpation.

Regrettably, this study did not utilize color flow Doppler imaging. Because malignant tumors are rich in neovascularity, and the vessels laid down by such tumors often lack a normal media layer, they often exhibit very low resistance to flow. Although neovascularity is not a perfect diagnostic indicator of malignancy, the presence of abundant blood flow and low resistance can raise the index of suspicion. In my opinion, color flow Doppler should be incorporated into ultrasonographic evaluation of potential ovarian malignancies.

—Steven R. Goldstein, MD

Tell us what you think, at [email protected]. Please include your name and city and state.

Ovarian cancer causes more deaths than any other cancer affecting the female reproductive system.¹ One reason it’s so deadly: It usually isn’t detected until it has reached an advanced stage. No clear-cut symptoms point definitively to ovarian malignancy, and no feasible screening strategy has been found to increase detection at an early stage.

Among the strategies that have been utilized to detect ovarian cancer are bimanual examination of the adnexae (primarily in postmenopausal women), measurement of cancer antigen (CA) 125, and transvaginal ultrasonography (TVUS) of the ovaries. The last two strategies sometimes are combined in high-risk women.

TVUS can highlight ovarian abnormalities and provide information about their structure. The question then becomes which abnormalities are likely to resolve without treatment, and which should be scrutinized more closely. In this study, Pavlik and colleagues reviewed TVUS findings from 39,337 women enrolled in the University of Kentucky Ovarian Cancer Screening Program, which involved 221,576 baseline and interval TVUS scans.

Details of the study
Women in this study were screened with annual TVUS scans between 1987 and 2002. The population included:

• asymptomatic women aged 50 or older
• asymptomatic women over age 25 who had a first- or second-degree relative with documented ovarian cancer.

The initial TVUS scan was normal in almost 90% of women, and only about 10% subsequently experienced an abnormal scan. About half (46.7%) of the ovarian abnormalities identified via TVUS were found on the very first scan. Of these, 63.2% resolved during follow-up with no treatment.

Approximately 80% of women had no abnormal TVUS findings at any time during the observation period. This is notable because participants had a high risk for ovarian cancer by virtue of advanced age or family history.

TVUS abnormalities had a higher prevalence in premenopausal women (35%) than in postmenopausal women (17%; P<.001). The incidence of ovarian cysts also was significantly higher among premenopausal women (15.3% vs 8.2%; P<.001). These differences are to be expected, owing to the functional nature of premenopausal ovaries in regard to folliculogenesis, ovulation, and endometriosis.

Positive predictive values ranged from 15.3% to 24.7%
Over the 25 years covered by this study, our understanding of the malignant potential of various ovarian masses has evolved considerably. We have long known that unilocular cysts are extremely unlikely to be malignant, but now we are aware that even septated cysts are unlikely to represent cancer.

As for the success of this ovarian cancer-screening program, which identified 85 true malignancies and 472 nonmalignancies in surgical specimens, it had an overall positive predictive value of 15.3%. After January 1, 2008, however, when serial observation expanded to include septated cysts (because published data confirmed these masses to have low malignant potential), positive predictive value improved to 24.7%.

Pavlik and colleagues also discussed findings from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which relied on a single TVUS abnormality to trigger a recommendation for surgery, with a positive predictive value of only 5.1%.²

Most cancers were diagnosed at an early stage
Of the invasive epithelial cancers identified in this study, the stage distribution at diagnosis was:

• Stage 1: 45%
• Stage 2: 23%
• Stage 3: 32%
• Stage 4: None.

This finding is notable, given statistics from the “real world,” where about 80% of ovarian cancers are diagnosed at Stage 3 or Stage 4.

Among benign findings that were managed surgically, 47% were serous cystadenomas, 13% were hemorrhagic cysts, 9% were fibromas, thecomas, or Brenner tumors, and the rest were fairly equally divided between hydrosalpinx or paratubal cysts; endometriomas; and mucinous cystadenomas, leiomyomas, and cystic teratomas.

What this evidence means for practice

In general, unilocular or septate cysts can be followed every 6 months by TVUS. Although more complex tumors may resolve spontaneously, they should be followed with serial TVUS, with caution, at intervals of 6 weeks to 3 months. The findings of each scan should determine the subsequent course of action, which could involve further monitoring or surgical extirpation.

Regrettably, this study did not utilize color flow Doppler imaging. Because malignant tumors are rich in neovascularity, and the vessels laid down by such tumors often lack a normal media layer, they often exhibit very low resistance to flow. Although neovascularity is not a perfect diagnostic indicator of malignancy, the presence of abundant blood flow and low resistance can raise the index of suspicion. In my opinion, color flow Doppler should be incorporated into ultrasonographic evaluation of potential ovarian malignancies.

—Steven R. Goldstein, MD

Tell us what you think, at [email protected]. Please include your name and city and state.

Available treatments for schizophrenia (eg, antipsychotics) are primarily effective on positive symptoms (hallucinations, delusions, etc.). It is, however, increasingly clear that schizophrenia also is a severe neuropsychiatric illness associated with deficits in cognitive function. These deficits represent a core feature of the disorder, and are a major determinant of long-term disability.¹ Cognitive dysfunction is among the earliest signs of illness that, typically, presents in the prodromal phase.

Since the formulation of the dopaminergic model of schizophrenia, cognitive studies of the disease primarily have examined dysfunction in dopaminergic-rich regions of the brain, such as the prefrontal cortex, and, therefore, have focused largely on executive functioning. But neurocognitive deficits in schizophrenia are not limited to executive functioning; comparable deficits have been observed across multiple areas of cognition.²

More recent formulations of cognitive dysfunction in schizophrenia divide deficits into multiple domains. These include verbal, visual, and working memory; attention and vigilance; speed of processing, reasoning, and problem solving; and social cognition (Table). Neurocognitive impairments often are closely associated with deficits in early sensory processing and basic neurophysiology.³

The prevalence of cognitive dysfunction also can be estimated using baseline data from the large-scale Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial.⁴ Although cognitive dysfunction was not one of the inclusion criteria in CATIE, most patients who were enrolled had profound cognitive deficits.⁵ Furthermore, meta-analyses⁶ suggest that composite neurocognitive measures can explain as much as 60% of the variance of overall functioning in schizophrenia.

Antipsychotics aren’t the answer

The cognitive-enhancing benefits of antipsychotic medications are minimal.⁷ As evidence of a direct relationship between cognitive dysfunction and long-term functional outcome in schizophrenia becomes established, the need for safe and effective treatment for these symptoms becomes more urgent. Given the mechanistic complexity of the potential cause of poor cognitive performance, the search for an effective treatment is ongoing—but that search has not been successful.

Despite mixed results for recent novel mechanism trials (http://newsroom.lilly.com/releasedetail.cfm?releaseid=703018) and a number of companies ceasing drug development, the work to develop safe and effective treatments for cognitive dysfunction in schizophrenia continues, as exemplified by National Institute of Mental Health-initiated programs to spur development of drugs that work by a novel mechanism. Rather than simply assessing novel compounds with paper-and-pencil cognitive scales, such programs seek to assess the ability of the compound to engage with the intended receptor (target),⁹ using imaging or electrophysiological tools. Without utilization of a target engagement biomarker, there is no way to know whether 1) the drug simply does not get into the brain in sufficient concentration to be effective in humans or 2) the overall mechanism is wrong.

In this article, we review several promising targets and techniques that are the subject of active research on the treatment of cognitive disorders in schizophrenia. This list isn’t exhaustive; our aim is to highlight a few of the promising treatments now being studied in clinical trials.

Acetylcholine receptors

Acetylcholine receptors comprise two major families, nicotinic and muscarinic receptors; evidence implicates deficits of both families in schizophrenia.¹⁰ Following up on epidemiological studies¹¹ of the high percentage of schizophrenia patients who smoke tobacco (60% to 90%), the role of alpha-7 nicotinic acetylcholine receptors (á7 nAchR) has been explored. Nicotine itself might normalize some disrupted auditory processes, as measured by electroencephalography.¹²

Several clinical trials of partial á7 nAchR agonists have been conducted, with EVP-6124 and TC-5619 furthest along in development.

EVP-6124. Information is unavailable publicly on EVP-6124, except for an abstract presented in 2011 at the 51st Annual Meeting of the American College of Neuropsychopharmacology.¹³ In that study, 319 patients with schizophrenia were randomized to EVP-6124 (0.3 mg/d or 1 mg/d [n = 213]) or placebo (n = 106) adjunctive to at least 4 weeks of non-clozapine antipsychotics. Efficacy was shown up to 1 mg, in a dose-responsive manner. Modest, but significant, improvements in cognition, clinical function, and negative symptoms were seen. The most commonly reported side effects were headache (3.8%), nausea (3.2%), and nasopharyngitis (2.5%). Phase III studies are underway.

TC-5619. This partial á7 nAchR also showed positive results recently in a Phase II trial. Significant (P < .05) improvement was demonstrated in executive function in the Groton Maze Learning Task of the CogState Schizophrenia Battery and the Scale for Assessment of Negative Symptoms.¹⁴

Strong anatomic links also exist between muscarinic acetylcholine receptors and the brain dopaminergic system, especially muscarinic type-1 and type-4 (M1 and M4) receptors. The potential utility of an M1, M4, or combined M/M4 agonist is also supported by studies of M1 and M4 knockout mice, with particular evidence of cognitive enhancement with the use of M1 agonists.¹⁵

GSK1034702. Administration of the M1 allosteric agonist GSK1034702 to healthy human smokers, using the nicotine abstinence model of cognitive dysfunction, resulted in improvements in immediate recall.¹⁶

Xanomeline. In a small pilot study of 20 schizophrenia patients, xanomeline, a mixed M1/M4 agonist, demonstrated significant improvements in verbal learning, short-term memory, and overall symptoms.¹⁷

Dopamine receptors

All marketed antipsychotics block the dopamine type-2 (D2) receptor¹⁸; they are primarily effective on positive symptoms.⁴ In contrast, a role for the dopamine type-1 (D1) receptor in cognition is suggested by studies that demonstrate reduced D1 and N-methyl-d-aspartate (NMDA) glutamate receptor function in the prefrontal cortex.^19-22

In a model of cognitive impairment in non-human primates, low-dose intermittent dosing of D1-receptor agonists produced improvements in cognitive function.²³ This strategy aims to sensitize, rather than induce tolerance, to the effects of the D1-receptor agonist. Benefits were primarily seen in working memory. Phase II trials of a potent D1-receptor agonist, DAR-100A, the active enantiomer of dihydrexidine²⁴ are ongoing (www.clinicaltrials.gov/ct2/show/NCT01519557).

Glutamatergic receptors

Intoxication with NMDA antagonists (such as phencyclidine and ketamine) yields a phenotype with similarity to schizophrenia.²⁵ More than 20 years of research has provided evidence for the role of glutamatergic NMDA receptors in the pathophysiology of schizophrenia.^26,27

NMDA receptors are distributed widely in the brain, but specific glutamatergic processes are localized to areas that are associated with cognition. This relative distribution provides a convenient framework from which to view the pattern of cognitive dysfunction associated with schizophrenia:

Previous reviews of ketamine administration have described cognitive deficits in healthy control subjects, comparable to what is seen in schizophrenia.²⁸ The deficits are noted primarily in measures of executive functioning, attention/vigilance, verbal fluency, and visual and verbal working memory. 

Most treatment studies of glutamatergic-based drugs have focused on positive and negative symptoms. Two recent comprehensive meta-analyses^29,30 of NMDA-based treatments support small-to-moderate effect size improvement in total symptoms and in negative symptoms, in patients with chronic schizophrenia, when the drugs are used in combination with non-clozapine antipsychotics.

Bitopertin. A novel glycine-transport inhibitor, bitopertin, showed significant improvement in negative symptoms as an adjunctive treatment in a large Phase II trial.^31,32 In the “per protocol” population (ie, patients who completed 8 weeks of treatment without any major protocol violations [n = 231]), negative symptoms diminished to a significantly (P < .05) greater degree from baseline in the 10 mg/d and 30 mg/d dosage groups, compared with placebo. Phase III studies of bitopertin are ongoing (www.clinicaltrials.gov/ct2/show/NCT01192906). 

Direct evidence of a cognitive benefit of glutamatergic-based drugs is limited. In a recent large, multicenter study, low dosage D-serine (~30 mg/kg/d) did not separate from placebo,³³ but an open-label study suggests increased efficacy with dosages >30 mg/kg/d.³⁴ In addition to symptomatic improvements, a highly significant, large effect-size improvement was seen for overall cognition for dosages ≥60 mg/kg/d, leading to a significant dose-by-time interaction (P < .01).

Combination approaches. The value of combining glutamatergic medication and a cognitive training program is supported by the role of NMDA receptors in learning. For example, D-cycloserine, a glycine-site partial agonist, has been shown in several studies to enhance learning and behavioral therapies in anxiety disorders.³⁵ Although an initial study in schizophrenia was negative for the effectiveness of D-serine (a glycine-site full agonist) and combined cognitive training,³⁶ further research is ongoing to evaluate a role for such combined therapy.^37,38

Brain stimulation

Two nonpharmacotherapeutic brain stimulation techniques, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been applied in the study of schizophrenia symptoms, particularly for enhancing cognition.³⁹ Both techniques use electric stimulation to influence activity of underlying brain regions: rTMS utilizes a magnetic coil and electromagnetic induction; tDCS, in contrast, utilizes constant low (<2 mA) direct current to specific regions of the scalp. 

Cortical neuronal excitability is increased by anodal tDCS and high-frequency rTMS and reduced by cathodal tDCS and low-frequency rTMS. Both tDCS and rTMS appear to be NMDA receptor-dependent. tDCS is relatively inexpensive and requires less expertise to administer than rTMS does.

Both techniques might be efficacious for treating resistant auditory hallucinations.^40,41 Applying rTMS over the left dorsolateral prefrontal cortex has led to improvement in verbal learning and visuomotor tracking in patients with schizophrenia.³⁹ Stimulation of both sides of the prefrontal cortex with rTMS has brought improvement in visual memory, executive function, spatial working memory, and attention. Few papers have been published so far regarding enhancement of cognition with tDCS in schizophrenia,⁴² but beneficial effects of this technique have been seen across several disorders.⁴³

Cognitive remediation techniques

A fundamental starting point for cognitive remediation is the idea that there is plasticity in the brain and that repetitive practice can lead to cognitive improvement. Cognitive remediation therapy often adopts computerized programs and exercises that attempt to improve psychosocial function by targeting structures of the brain that are involved in cognitive function, such as attention, working memory, executive functioning, planning, and cognitive flexibility.

In schizophrenia, cognitive remediation studies have traditionally targeted higher-order processes, such as attention and higher level processes, that might lead to improvement in overall cognition and function.⁴⁴ Cognitive remediation typically is utilized complementary to pharmacotherapy, with some studies supporting the use of combined use of cognition-enhancing drugs and remediation programs.

A 2007 meta-analysis showed a medium-size but significant improvement in cognition through the use of cognitive remediation therapy⁴⁵—especially when it is combined with psychiatric rehabilitation. More recent studies utilizing techniques that focus on bottom-up (auditory and visual processing) techniques has shown significant improvements.^46-48 Several multicenter studies utilizing Posit Science programs combined with antipsychotic medication are ongoing (www.clinicaltrials.gov/ct2/show/NCT01173874 and www.clinicaltrials.gov/ct2/show/NCT01422902).

Bottom Line

Although cognitive dysfunction is a leading cause of disability in schizophrenia, no treatments are approved for this condition. Numerous novel-mechanism and nonpharmaceutical modalities are actively being studied for this difficult-to-treat problem, however—offering hope to patients.

Related Resources

Javitt DC, Zukin SR, Heresco-Levy U, et al. Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Has an angel shown the way? Schizophr Bull. 2012; 38(5):958-966.

Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37.

Millan MJ, Agid Y, Brune M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012; 11(2):141-168.

Drug Brand Names

D-cycloserine • Seromycin               Ketamine • Ketalar
Xanomeline • Lumeron, Memcor

Disclosures

Dr. Kantrowitz receives grant or research support from EnVivo, the National Institute of Mental Health, Novartis, Pfizer, Roche-Genentech, the Stanley Foundation, and Sunovion; is a consultant to Health Advances, LLC, the Healthcare Advisory Board, Otsuka Pharmaceuticals, Strategic Edge Communications, and Vindico Medical Education; and owns a small number of shares of common stock in GlaxoSmithKline. Ms. Levy and Dr. Ballon report no financial relationships with manufacturers of any products mentioned in this article or with manufacturers of competing products.

Available treatments for schizophrenia (eg, antipsychotics) are primarily effective on positive symptoms (hallucinations, delusions, etc.). It is, however, increasingly clear that schizophrenia also is a severe neuropsychiatric illness associated with deficits in cognitive function. These deficits represent a core feature of the disorder, and are a major determinant of long-term disability.¹ Cognitive dysfunction is among the earliest signs of illness that, typically, presents in the prodromal phase.

Since the formulation of the dopaminergic model of schizophrenia, cognitive studies of the disease primarily have examined dysfunction in dopaminergic-rich regions of the brain, such as the prefrontal cortex, and, therefore, have focused largely on executive functioning. But neurocognitive deficits in schizophrenia are not limited to executive functioning; comparable deficits have been observed across multiple areas of cognition.²

More recent formulations of cognitive dysfunction in schizophrenia divide deficits into multiple domains. These include verbal, visual, and working memory; attention and vigilance; speed of processing, reasoning, and problem solving; and social cognition (Table). Neurocognitive impairments often are closely associated with deficits in early sensory processing and basic neurophysiology.³

The prevalence of cognitive dysfunction also can be estimated using baseline data from the large-scale Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial.⁴ Although cognitive dysfunction was not one of the inclusion criteria in CATIE, most patients who were enrolled had profound cognitive deficits.⁵ Furthermore, meta-analyses⁶ suggest that composite neurocognitive measures can explain as much as 60% of the variance of overall functioning in schizophrenia.

Antipsychotics aren’t the answer

The cognitive-enhancing benefits of antipsychotic medications are minimal.⁷ As evidence of a direct relationship between cognitive dysfunction and long-term functional outcome in schizophrenia becomes established, the need for safe and effective treatment for these symptoms becomes more urgent. Given the mechanistic complexity of the potential cause of poor cognitive performance, the search for an effective treatment is ongoing—but that search has not been successful.

Despite mixed results for recent novel mechanism trials (http://newsroom.lilly.com/releasedetail.cfm?releaseid=703018) and a number of companies ceasing drug development, the work to develop safe and effective treatments for cognitive dysfunction in schizophrenia continues, as exemplified by National Institute of Mental Health-initiated programs to spur development of drugs that work by a novel mechanism. Rather than simply assessing novel compounds with paper-and-pencil cognitive scales, such programs seek to assess the ability of the compound to engage with the intended receptor (target),⁹ using imaging or electrophysiological tools. Without utilization of a target engagement biomarker, there is no way to know whether 1) the drug simply does not get into the brain in sufficient concentration to be effective in humans or 2) the overall mechanism is wrong.

In this article, we review several promising targets and techniques that are the subject of active research on the treatment of cognitive disorders in schizophrenia. This list isn’t exhaustive; our aim is to highlight a few of the promising treatments now being studied in clinical trials.

Acetylcholine receptors

Acetylcholine receptors comprise two major families, nicotinic and muscarinic receptors; evidence implicates deficits of both families in schizophrenia.¹⁰ Following up on epidemiological studies¹¹ of the high percentage of schizophrenia patients who smoke tobacco (60% to 90%), the role of alpha-7 nicotinic acetylcholine receptors (á7 nAchR) has been explored. Nicotine itself might normalize some disrupted auditory processes, as measured by electroencephalography.¹²

Several clinical trials of partial á7 nAchR agonists have been conducted, with EVP-6124 and TC-5619 furthest along in development.

EVP-6124. Information is unavailable publicly on EVP-6124, except for an abstract presented in 2011 at the 51st Annual Meeting of the American College of Neuropsychopharmacology.¹³ In that study, 319 patients with schizophrenia were randomized to EVP-6124 (0.3 mg/d or 1 mg/d [n = 213]) or placebo (n = 106) adjunctive to at least 4 weeks of non-clozapine antipsychotics. Efficacy was shown up to 1 mg, in a dose-responsive manner. Modest, but significant, improvements in cognition, clinical function, and negative symptoms were seen. The most commonly reported side effects were headache (3.8%), nausea (3.2%), and nasopharyngitis (2.5%). Phase III studies are underway.

TC-5619. This partial á7 nAchR also showed positive results recently in a Phase II trial. Significant (P < .05) improvement was demonstrated in executive function in the Groton Maze Learning Task of the CogState Schizophrenia Battery and the Scale for Assessment of Negative Symptoms.¹⁴

Strong anatomic links also exist between muscarinic acetylcholine receptors and the brain dopaminergic system, especially muscarinic type-1 and type-4 (M1 and M4) receptors. The potential utility of an M1, M4, or combined M/M4 agonist is also supported by studies of M1 and M4 knockout mice, with particular evidence of cognitive enhancement with the use of M1 agonists.¹⁵

GSK1034702. Administration of the M1 allosteric agonist GSK1034702 to healthy human smokers, using the nicotine abstinence model of cognitive dysfunction, resulted in improvements in immediate recall.¹⁶

Xanomeline. In a small pilot study of 20 schizophrenia patients, xanomeline, a mixed M1/M4 agonist, demonstrated significant improvements in verbal learning, short-term memory, and overall symptoms.¹⁷

Dopamine receptors

All marketed antipsychotics block the dopamine type-2 (D2) receptor¹⁸; they are primarily effective on positive symptoms.⁴ In contrast, a role for the dopamine type-1 (D1) receptor in cognition is suggested by studies that demonstrate reduced D1 and N-methyl-d-aspartate (NMDA) glutamate receptor function in the prefrontal cortex.^19-22

In a model of cognitive impairment in non-human primates, low-dose intermittent dosing of D1-receptor agonists produced improvements in cognitive function.²³ This strategy aims to sensitize, rather than induce tolerance, to the effects of the D1-receptor agonist. Benefits were primarily seen in working memory. Phase II trials of a potent D1-receptor agonist, DAR-100A, the active enantiomer of dihydrexidine²⁴ are ongoing (www.clinicaltrials.gov/ct2/show/NCT01519557).

Glutamatergic receptors

Intoxication with NMDA antagonists (such as phencyclidine and ketamine) yields a phenotype with similarity to schizophrenia.²⁵ More than 20 years of research has provided evidence for the role of glutamatergic NMDA receptors in the pathophysiology of schizophrenia.^26,27

NMDA receptors are distributed widely in the brain, but specific glutamatergic processes are localized to areas that are associated with cognition. This relative distribution provides a convenient framework from which to view the pattern of cognitive dysfunction associated with schizophrenia:

Previous reviews of ketamine administration have described cognitive deficits in healthy control subjects, comparable to what is seen in schizophrenia.²⁸ The deficits are noted primarily in measures of executive functioning, attention/vigilance, verbal fluency, and visual and verbal working memory. 

Most treatment studies of glutamatergic-based drugs have focused on positive and negative symptoms. Two recent comprehensive meta-analyses^29,30 of NMDA-based treatments support small-to-moderate effect size improvement in total symptoms and in negative symptoms, in patients with chronic schizophrenia, when the drugs are used in combination with non-clozapine antipsychotics.

Bitopertin. A novel glycine-transport inhibitor, bitopertin, showed significant improvement in negative symptoms as an adjunctive treatment in a large Phase II trial.^31,32 In the “per protocol” population (ie, patients who completed 8 weeks of treatment without any major protocol violations [n = 231]), negative symptoms diminished to a significantly (P < .05) greater degree from baseline in the 10 mg/d and 30 mg/d dosage groups, compared with placebo. Phase III studies of bitopertin are ongoing (www.clinicaltrials.gov/ct2/show/NCT01192906). 

Direct evidence of a cognitive benefit of glutamatergic-based drugs is limited. In a recent large, multicenter study, low dosage D-serine (~30 mg/kg/d) did not separate from placebo,³³ but an open-label study suggests increased efficacy with dosages >30 mg/kg/d.³⁴ In addition to symptomatic improvements, a highly significant, large effect-size improvement was seen for overall cognition for dosages ≥60 mg/kg/d, leading to a significant dose-by-time interaction (P < .01).

Combination approaches. The value of combining glutamatergic medication and a cognitive training program is supported by the role of NMDA receptors in learning. For example, D-cycloserine, a glycine-site partial agonist, has been shown in several studies to enhance learning and behavioral therapies in anxiety disorders.³⁵ Although an initial study in schizophrenia was negative for the effectiveness of D-serine (a glycine-site full agonist) and combined cognitive training,³⁶ further research is ongoing to evaluate a role for such combined therapy.^37,38

Brain stimulation

Two nonpharmacotherapeutic brain stimulation techniques, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been applied in the study of schizophrenia symptoms, particularly for enhancing cognition.³⁹ Both techniques use electric stimulation to influence activity of underlying brain regions: rTMS utilizes a magnetic coil and electromagnetic induction; tDCS, in contrast, utilizes constant low (<2 mA) direct current to specific regions of the scalp. 

Cortical neuronal excitability is increased by anodal tDCS and high-frequency rTMS and reduced by cathodal tDCS and low-frequency rTMS. Both tDCS and rTMS appear to be NMDA receptor-dependent. tDCS is relatively inexpensive and requires less expertise to administer than rTMS does.

Both techniques might be efficacious for treating resistant auditory hallucinations.^40,41 Applying rTMS over the left dorsolateral prefrontal cortex has led to improvement in verbal learning and visuomotor tracking in patients with schizophrenia.³⁹ Stimulation of both sides of the prefrontal cortex with rTMS has brought improvement in visual memory, executive function, spatial working memory, and attention. Few papers have been published so far regarding enhancement of cognition with tDCS in schizophrenia,⁴² but beneficial effects of this technique have been seen across several disorders.⁴³

Cognitive remediation techniques

A fundamental starting point for cognitive remediation is the idea that there is plasticity in the brain and that repetitive practice can lead to cognitive improvement. Cognitive remediation therapy often adopts computerized programs and exercises that attempt to improve psychosocial function by targeting structures of the brain that are involved in cognitive function, such as attention, working memory, executive functioning, planning, and cognitive flexibility.

In schizophrenia, cognitive remediation studies have traditionally targeted higher-order processes, such as attention and higher level processes, that might lead to improvement in overall cognition and function.⁴⁴ Cognitive remediation typically is utilized complementary to pharmacotherapy, with some studies supporting the use of combined use of cognition-enhancing drugs and remediation programs.

A 2007 meta-analysis showed a medium-size but significant improvement in cognition through the use of cognitive remediation therapy⁴⁵—especially when it is combined with psychiatric rehabilitation. More recent studies utilizing techniques that focus on bottom-up (auditory and visual processing) techniques has shown significant improvements.^46-48 Several multicenter studies utilizing Posit Science programs combined with antipsychotic medication are ongoing (www.clinicaltrials.gov/ct2/show/NCT01173874 and www.clinicaltrials.gov/ct2/show/NCT01422902).

Bottom Line

Although cognitive dysfunction is a leading cause of disability in schizophrenia, no treatments are approved for this condition. Numerous novel-mechanism and nonpharmaceutical modalities are actively being studied for this difficult-to-treat problem, however—offering hope to patients.

Related Resources

Javitt DC, Zukin SR, Heresco-Levy U, et al. Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Has an angel shown the way? Schizophr Bull. 2012; 38(5):958-966.

Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37.

Millan MJ, Agid Y, Brune M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012; 11(2):141-168.

Drug Brand Names

D-cycloserine • Seromycin               Ketamine • Ketalar
Xanomeline • Lumeron, Memcor

Disclosures

Dr. Kantrowitz receives grant or research support from EnVivo, the National Institute of Mental Health, Novartis, Pfizer, Roche-Genentech, the Stanley Foundation, and Sunovion; is a consultant to Health Advances, LLC, the Healthcare Advisory Board, Otsuka Pharmaceuticals, Strategic Edge Communications, and Vindico Medical Education; and owns a small number of shares of common stock in GlaxoSmithKline. Ms. Levy and Dr. Ballon report no financial relationships with manufacturers of any products mentioned in this article or with manufacturers of competing products.

Available treatments for schizophrenia (eg, antipsychotics) are primarily effective on positive symptoms (hallucinations, delusions, etc.). It is, however, increasingly clear that schizophrenia also is a severe neuropsychiatric illness associated with deficits in cognitive function. These deficits represent a core feature of the disorder, and are a major determinant of long-term disability.¹ Cognitive dysfunction is among the earliest signs of illness that, typically, presents in the prodromal phase.

Since the formulation of the dopaminergic model of schizophrenia, cognitive studies of the disease primarily have examined dysfunction in dopaminergic-rich regions of the brain, such as the prefrontal cortex, and, therefore, have focused largely on executive functioning. But neurocognitive deficits in schizophrenia are not limited to executive functioning; comparable deficits have been observed across multiple areas of cognition.²

More recent formulations of cognitive dysfunction in schizophrenia divide deficits into multiple domains. These include verbal, visual, and working memory; attention and vigilance; speed of processing, reasoning, and problem solving; and social cognition (Table). Neurocognitive impairments often are closely associated with deficits in early sensory processing and basic neurophysiology.³

The prevalence of cognitive dysfunction also can be estimated using baseline data from the large-scale Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial.⁴ Although cognitive dysfunction was not one of the inclusion criteria in CATIE, most patients who were enrolled had profound cognitive deficits.⁵ Furthermore, meta-analyses⁶ suggest that composite neurocognitive measures can explain as much as 60% of the variance of overall functioning in schizophrenia.

Antipsychotics aren’t the answer

The cognitive-enhancing benefits of antipsychotic medications are minimal.⁷ As evidence of a direct relationship between cognitive dysfunction and long-term functional outcome in schizophrenia becomes established, the need for safe and effective treatment for these symptoms becomes more urgent. Given the mechanistic complexity of the potential cause of poor cognitive performance, the search for an effective treatment is ongoing—but that search has not been successful.

Despite mixed results for recent novel mechanism trials (http://newsroom.lilly.com/releasedetail.cfm?releaseid=703018) and a number of companies ceasing drug development, the work to develop safe and effective treatments for cognitive dysfunction in schizophrenia continues, as exemplified by National Institute of Mental Health-initiated programs to spur development of drugs that work by a novel mechanism. Rather than simply assessing novel compounds with paper-and-pencil cognitive scales, such programs seek to assess the ability of the compound to engage with the intended receptor (target),⁹ using imaging or electrophysiological tools. Without utilization of a target engagement biomarker, there is no way to know whether 1) the drug simply does not get into the brain in sufficient concentration to be effective in humans or 2) the overall mechanism is wrong.

In this article, we review several promising targets and techniques that are the subject of active research on the treatment of cognitive disorders in schizophrenia. This list isn’t exhaustive; our aim is to highlight a few of the promising treatments now being studied in clinical trials.

Acetylcholine receptors

Acetylcholine receptors comprise two major families, nicotinic and muscarinic receptors; evidence implicates deficits of both families in schizophrenia.¹⁰ Following up on epidemiological studies¹¹ of the high percentage of schizophrenia patients who smoke tobacco (60% to 90%), the role of alpha-7 nicotinic acetylcholine receptors (á7 nAchR) has been explored. Nicotine itself might normalize some disrupted auditory processes, as measured by electroencephalography.¹²

Several clinical trials of partial á7 nAchR agonists have been conducted, with EVP-6124 and TC-5619 furthest along in development.

EVP-6124. Information is unavailable publicly on EVP-6124, except for an abstract presented in 2011 at the 51st Annual Meeting of the American College of Neuropsychopharmacology.¹³ In that study, 319 patients with schizophrenia were randomized to EVP-6124 (0.3 mg/d or 1 mg/d [n = 213]) or placebo (n = 106) adjunctive to at least 4 weeks of non-clozapine antipsychotics. Efficacy was shown up to 1 mg, in a dose-responsive manner. Modest, but significant, improvements in cognition, clinical function, and negative symptoms were seen. The most commonly reported side effects were headache (3.8%), nausea (3.2%), and nasopharyngitis (2.5%). Phase III studies are underway.

TC-5619. This partial á7 nAchR also showed positive results recently in a Phase II trial. Significant (P < .05) improvement was demonstrated in executive function in the Groton Maze Learning Task of the CogState Schizophrenia Battery and the Scale for Assessment of Negative Symptoms.¹⁴

Strong anatomic links also exist between muscarinic acetylcholine receptors and the brain dopaminergic system, especially muscarinic type-1 and type-4 (M1 and M4) receptors. The potential utility of an M1, M4, or combined M/M4 agonist is also supported by studies of M1 and M4 knockout mice, with particular evidence of cognitive enhancement with the use of M1 agonists.¹⁵

GSK1034702. Administration of the M1 allosteric agonist GSK1034702 to healthy human smokers, using the nicotine abstinence model of cognitive dysfunction, resulted in improvements in immediate recall.¹⁶

Xanomeline. In a small pilot study of 20 schizophrenia patients, xanomeline, a mixed M1/M4 agonist, demonstrated significant improvements in verbal learning, short-term memory, and overall symptoms.¹⁷

Dopamine receptors

All marketed antipsychotics block the dopamine type-2 (D2) receptor¹⁸; they are primarily effective on positive symptoms.⁴ In contrast, a role for the dopamine type-1 (D1) receptor in cognition is suggested by studies that demonstrate reduced D1 and N-methyl-d-aspartate (NMDA) glutamate receptor function in the prefrontal cortex.^19-22

In a model of cognitive impairment in non-human primates, low-dose intermittent dosing of D1-receptor agonists produced improvements in cognitive function.²³ This strategy aims to sensitize, rather than induce tolerance, to the effects of the D1-receptor agonist. Benefits were primarily seen in working memory. Phase II trials of a potent D1-receptor agonist, DAR-100A, the active enantiomer of dihydrexidine²⁴ are ongoing (www.clinicaltrials.gov/ct2/show/NCT01519557).

Glutamatergic receptors

Intoxication with NMDA antagonists (such as phencyclidine and ketamine) yields a phenotype with similarity to schizophrenia.²⁵ More than 20 years of research has provided evidence for the role of glutamatergic NMDA receptors in the pathophysiology of schizophrenia.^26,27

NMDA receptors are distributed widely in the brain, but specific glutamatergic processes are localized to areas that are associated with cognition. This relative distribution provides a convenient framework from which to view the pattern of cognitive dysfunction associated with schizophrenia:

Previous reviews of ketamine administration have described cognitive deficits in healthy control subjects, comparable to what is seen in schizophrenia.²⁸ The deficits are noted primarily in measures of executive functioning, attention/vigilance, verbal fluency, and visual and verbal working memory. 

Most treatment studies of glutamatergic-based drugs have focused on positive and negative symptoms. Two recent comprehensive meta-analyses^29,30 of NMDA-based treatments support small-to-moderate effect size improvement in total symptoms and in negative symptoms, in patients with chronic schizophrenia, when the drugs are used in combination with non-clozapine antipsychotics.

Bitopertin. A novel glycine-transport inhibitor, bitopertin, showed significant improvement in negative symptoms as an adjunctive treatment in a large Phase II trial.^31,32 In the “per protocol” population (ie, patients who completed 8 weeks of treatment without any major protocol violations [n = 231]), negative symptoms diminished to a significantly (P < .05) greater degree from baseline in the 10 mg/d and 30 mg/d dosage groups, compared with placebo. Phase III studies of bitopertin are ongoing (www.clinicaltrials.gov/ct2/show/NCT01192906). 

Direct evidence of a cognitive benefit of glutamatergic-based drugs is limited. In a recent large, multicenter study, low dosage D-serine (~30 mg/kg/d) did not separate from placebo,³³ but an open-label study suggests increased efficacy with dosages >30 mg/kg/d.³⁴ In addition to symptomatic improvements, a highly significant, large effect-size improvement was seen for overall cognition for dosages ≥60 mg/kg/d, leading to a significant dose-by-time interaction (P < .01).

Combination approaches. The value of combining glutamatergic medication and a cognitive training program is supported by the role of NMDA receptors in learning. For example, D-cycloserine, a glycine-site partial agonist, has been shown in several studies to enhance learning and behavioral therapies in anxiety disorders.³⁵ Although an initial study in schizophrenia was negative for the effectiveness of D-serine (a glycine-site full agonist) and combined cognitive training,³⁶ further research is ongoing to evaluate a role for such combined therapy.^37,38

Brain stimulation

Two nonpharmacotherapeutic brain stimulation techniques, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been applied in the study of schizophrenia symptoms, particularly for enhancing cognition.³⁹ Both techniques use electric stimulation to influence activity of underlying brain regions: rTMS utilizes a magnetic coil and electromagnetic induction; tDCS, in contrast, utilizes constant low (<2 mA) direct current to specific regions of the scalp. 

Cortical neuronal excitability is increased by anodal tDCS and high-frequency rTMS and reduced by cathodal tDCS and low-frequency rTMS. Both tDCS and rTMS appear to be NMDA receptor-dependent. tDCS is relatively inexpensive and requires less expertise to administer than rTMS does.

Both techniques might be efficacious for treating resistant auditory hallucinations.^40,41 Applying rTMS over the left dorsolateral prefrontal cortex has led to improvement in verbal learning and visuomotor tracking in patients with schizophrenia.³⁹ Stimulation of both sides of the prefrontal cortex with rTMS has brought improvement in visual memory, executive function, spatial working memory, and attention. Few papers have been published so far regarding enhancement of cognition with tDCS in schizophrenia,⁴² but beneficial effects of this technique have been seen across several disorders.⁴³

Cognitive remediation techniques

A fundamental starting point for cognitive remediation is the idea that there is plasticity in the brain and that repetitive practice can lead to cognitive improvement. Cognitive remediation therapy often adopts computerized programs and exercises that attempt to improve psychosocial function by targeting structures of the brain that are involved in cognitive function, such as attention, working memory, executive functioning, planning, and cognitive flexibility.

In schizophrenia, cognitive remediation studies have traditionally targeted higher-order processes, such as attention and higher level processes, that might lead to improvement in overall cognition and function.⁴⁴ Cognitive remediation typically is utilized complementary to pharmacotherapy, with some studies supporting the use of combined use of cognition-enhancing drugs and remediation programs.

A 2007 meta-analysis showed a medium-size but significant improvement in cognition through the use of cognitive remediation therapy⁴⁵—especially when it is combined with psychiatric rehabilitation. More recent studies utilizing techniques that focus on bottom-up (auditory and visual processing) techniques has shown significant improvements.^46-48 Several multicenter studies utilizing Posit Science programs combined with antipsychotic medication are ongoing (www.clinicaltrials.gov/ct2/show/NCT01173874 and www.clinicaltrials.gov/ct2/show/NCT01422902).

Bottom Line

Although cognitive dysfunction is a leading cause of disability in schizophrenia, no treatments are approved for this condition. Numerous novel-mechanism and nonpharmaceutical modalities are actively being studied for this difficult-to-treat problem, however—offering hope to patients.

Related Resources

Javitt DC, Zukin SR, Heresco-Levy U, et al. Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Has an angel shown the way? Schizophr Bull. 2012; 38(5):958-966.

Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37.

Millan MJ, Agid Y, Brune M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012; 11(2):141-168.

Drug Brand Names

D-cycloserine • Seromycin               Ketamine • Ketalar
Xanomeline • Lumeron, Memcor

Disclosures

Dr. Kantrowitz receives grant or research support from EnVivo, the National Institute of Mental Health, Novartis, Pfizer, Roche-Genentech, the Stanley Foundation, and Sunovion; is a consultant to Health Advances, LLC, the Healthcare Advisory Board, Otsuka Pharmaceuticals, Strategic Edge Communications, and Vindico Medical Education; and owns a small number of shares of common stock in GlaxoSmithKline. Ms. Levy and Dr. Ballon report no financial relationships with manufacturers of any products mentioned in this article or with manufacturers of competing products.

CASE: Paranoid and online

Mr. M, age 22, is brought to the emergency department by family because they are concerned about his paranoia and increasing agitation related to Facebook posts by friends and siblings. At age 8, Mr. M was diagnosed with depression, attention-deficit/hyperactivity disorder (ADHD), and anger management problems, which were well controlled with fluoxetine until last year, when he discontinued psychiatric follow-up. Mr. M’s girlfriend ended their relationship 1 month ago, although it is unclear whether the break-up was caused by his depressive symptoms or exacerbated them. In the last 2 days, his parents have noticed an increase in his delusional thoughts and aggressive behavior.

Family psychiatric history is not significant. Five years ago, Mr. M suffered a head injury in a motor vehicle collision, but completed high school without evidence of cognitive impairment or behavioral changes.

Mr. M appears disheveled and irritable. He reports his mood as “depressed,” but denies suicidal or homicidal ideations. He has no history of violence or antisocial behavior.

Mr. M is alert and oriented with clear speech, intact language, and grossly intact memory and concentration—although, he admits, “I just obsess over certain thoughts.” He endorses feelings of anxiety, insomnia, low energy, lack of sleep secondary to his paranoia, and claims that “something was said on Facebook about a girl and everyone is in on it.” He explains that his Facebook friends talk in “analogies” about him, and reports that, “I can just tell that’s what they are talking about even if they don’t say it directly.”

The authors’ observations

The last decade has seen a rise in the creation and use of social networking sites such as Facebook, Myspace, and Twitter. Facebook has 1.15 billion monthly active users.¹ Seventy-five percent of teenagers own cell phones, and 25% report using their phones to access social media outlets.² More than 50% of teenagers visit a social networking site daily, with 22% logging in to their favorite social media network more than 10 times a day.³ The easy accessibility of social media outlets has prompted study of the association of that accessibility with anxiety, depression, and self-esteem.^3-7

Although not a DSM-5 or ICD-10 diagnosis, internet addiction has been correlated with depression.⁸ Similarly, O’Keefe and colleagues describe Facebook depression in teens who spend a large amount of time on social networking sites.⁴ The recently developed Bergen Facebook Addiction Scale (BFAS)⁹ evaluates the six core elements of addiction (salience, mood modification, tolerance, withdrawal, conflict, and relapse) in Facebook users.

Facebook certainly provides a valuable mechanism for friends to stay connected in an increasingly global society, and has acknowledged the potential it has to address mental illness. In 2011, Facebook partnered with the National Suicide Prevention Lifeline to allow users to report observed suicidal content, thereby utilizing the online community to facilitate delivery of mental health resources.^10,11

HISTORY: Sibling rivalry

Mr. M had a romantic relationship with “Ms. B” in high school that he describes as “on and off,” beginning during his sophomore year. He describes himself as a “quick learner” who is task-oriented. He says he was outgoing in high school but became more introverted during his last year there. After high school, Mr. M worked as an electrician and discontinued psychiatric follow-up because he “felt fine.” He lives at home with his parents, two older sisters, and twin brother, who he identifies as being a lifelong “rival.”

After Ms. B ended her relationship with Mr. M, he began to suspect that she had become romantically involved with his twin brother. After Mr. M observed his brother leaving the house one night, he confronted his twin, who denied any involvement with Ms. B. After his brother left, Mr. M became enraged and punched a wall, fracturing his hand.

Two weeks before admission, Mr. M became increasingly preoccupied with suspicions of his brother’s involvement with Ms. B and looked for evidence on Facebook. Mr. M intensely monitored his Facebook news feed, which constantly updates to show public posts made by a user’s Facebook friends. He interpreted his friends’ posts as either directly relating to him or to a new relationship between Ms. B and his twin brother, stating that his friends were “talking in analogies” rather than directly using names.

Mr. M’s Facebook use rapidly increased to 3 or more hours a day. He can access Facebook from his laptop or cell phone, and reports logging in more than 10 times throughout the day. He says that, on Facebook, “it’s easier to talk trash” because people can say things they would not normally say face to face. He also states that Facebook is “ruining personal relationships,” and that it is “so easy to be in touch with everyone without really being in touch.”

The authors’ observations

In Mr. M’s case, Facebook served as a vehicle through which he could pursue a non-bizarre delusion. Mr. M openly admitted to viewing his twin brother as a rival; it is not surprising, therefore, that his delusions targeted his brother and ex-girlfriend.

Before social networks, the perseveration of this delusion might have been limited to internal thinking, or gathering corroborative information by means of stalking. Social media outlets have provided a means to perseverate and implicate others remotely, however, and Mr. M soon expanded his delusions to include more peers.

After beginning to suspect that friends and family are commenting on or criticizing him through Facebook, Mr. M experienced an irresistible impulse to repeatedly check the social network, which may have provided short-term relief of anticipatory anxiety, but that perpetuated the cycle. Constant access to the internet facilitated and intensified Mr. M’s cycle of paranoia, anxiety, and dysphoria. He called this process an “addiction.” A conceptual framework of the development of Mr. M’s maladaptive use of Facebook is illustrated in Figure 1.

Risk factors

Insecurity with one’s self-worth also may be a warning sign. Online social networking circumvents the need for physical interaction. A Facebook profile allows a person to selectively portray himself (herself) to the world, which may not be congruous with how his peers see him in everyday life. Patients who fear criticism or judgment may be more prone to maladaptive Facebook use, because they might feel empowered by the control they have over how others see them—online, at least.

Limited or, in Mr. M’s case, singular romantic experience may have influenced the course of his illness. Mr. M described his romantic involvement as a single, tumultuous relationship that lasted several years. Young patients with limited romantic experience may struggle to develop healthy protective mechanisms and may become preoccupied with the details of the situation, such that it interferes with functioning.

Mr. M’s history of ADHD might be a risk factor for abnormal patterns of internet use. Patients with ADHD have increased attentiveness with visually stimulating tasks—specifically, computers and video games.¹²

Last, it is unclear how, or if, Mr. M’s history of head injury contributed to his symptoms. There were no clear, temporal changes in cognition or emotion associated with the head injury, and he did not receive regular follow-up. Significant cognitive impairment does not appear to be a factor.

TREATMENT: Observed use

Quetiapine is selected to target psychosis, agitation, and insomnia characterized by difficulty with sleep initiation. Risperidone is added as a short-term agent to boost antipsychotic effect during the day when Mr. M is not fully responsive to quetiapine alone. Valproic acid is added on admission as a mood stabilizer to target emotional lability, impulsiveness, and possible mania.

After several days of treatment, and without access to a computer, Mr. M is calmer. We begin to assess the challenges of self-limiting time spent on Facebook; Mr. M explains that, before hospitalization, he had deactivated his Facebook account several times to try to rid himself of what he describes as an “addiction to social media”; soon afterward, however, he experienced overwhelming anxiety that led him to reactivate his account.

We sit with Mr. M as he logs in to Facebook and discuss the range of alternative explanations that specific public messages on his news feed could have. Explicitly listing alternative explanations is a technique used in cognitive-behavioral therapy. Mr. M begins to demonstrate increased insight regarding his paranoia and possible misinterpretation of information gleaned via Facebook; however, he still believes that masked references to him had existed. During his hospital stay he begins to acknowledge the problems that online interactions pose compared with face-to-face interactions, stating that, “There’s no emotion in [Facebook], so you can easily misinterpret what someone says.”

The authors’ observations

Mr. M was discharged after 7 days of treatment and has been seen weekly as an outpatient for 3 months without need for further hospitalization.

Bottom Line

Pervasive access to social media represents a vehicle for relapse of many psychiatric conditions. Younger patients may be especially at risk because they are more likely to use social media and are in the age range for onset of psychiatric illness. Although some degree of dependence on online networks can be considered normal, patients suffering from mental illness represent a vulnerable population for maladaptive online interactions.

Related Resources

• Sandler EP. If you’re in crisis, go online. Psychology Today. www.psychologytoday.com/blog/promoting-hope-preventing-suicide/201110/if-you-re-in-crisis-go-online. Published October 26, 2011.

• Nitzan U, Shoshan E, Lev-Ran S, et al. Internet-related psychosis−a sign of the times. Isr J Psychiatry Relat Sci. 2011;48(3):207-211.

• Martin EA, Bailey DH, Cicero DC, et al. Social networking profile correlates of schizotypy. Psychiatry Res. 2012;200(2-3):641-646.

Drug Brand Names

Fluoxetine • Prozac               Quetiapine • Seroquel

Risperidone • Risperdal         Valproic acid • Depakote

Disclosure

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

CASE: Paranoid and online

Mr. M, age 22, is brought to the emergency department by family because they are concerned about his paranoia and increasing agitation related to Facebook posts by friends and siblings. At age 8, Mr. M was diagnosed with depression, attention-deficit/hyperactivity disorder (ADHD), and anger management problems, which were well controlled with fluoxetine until last year, when he discontinued psychiatric follow-up. Mr. M’s girlfriend ended their relationship 1 month ago, although it is unclear whether the break-up was caused by his depressive symptoms or exacerbated them. In the last 2 days, his parents have noticed an increase in his delusional thoughts and aggressive behavior.

Family psychiatric history is not significant. Five years ago, Mr. M suffered a head injury in a motor vehicle collision, but completed high school without evidence of cognitive impairment or behavioral changes.

Mr. M appears disheveled and irritable. He reports his mood as “depressed,” but denies suicidal or homicidal ideations. He has no history of violence or antisocial behavior.

Mr. M is alert and oriented with clear speech, intact language, and grossly intact memory and concentration—although, he admits, “I just obsess over certain thoughts.” He endorses feelings of anxiety, insomnia, low energy, lack of sleep secondary to his paranoia, and claims that “something was said on Facebook about a girl and everyone is in on it.” He explains that his Facebook friends talk in “analogies” about him, and reports that, “I can just tell that’s what they are talking about even if they don’t say it directly.”

The authors’ observations

The last decade has seen a rise in the creation and use of social networking sites such as Facebook, Myspace, and Twitter. Facebook has 1.15 billion monthly active users.¹ Seventy-five percent of teenagers own cell phones, and 25% report using their phones to access social media outlets.² More than 50% of teenagers visit a social networking site daily, with 22% logging in to their favorite social media network more than 10 times a day.³ The easy accessibility of social media outlets has prompted study of the association of that accessibility with anxiety, depression, and self-esteem.^3-7

Although not a DSM-5 or ICD-10 diagnosis, internet addiction has been correlated with depression.⁸ Similarly, O’Keefe and colleagues describe Facebook depression in teens who spend a large amount of time on social networking sites.⁴ The recently developed Bergen Facebook Addiction Scale (BFAS)⁹ evaluates the six core elements of addiction (salience, mood modification, tolerance, withdrawal, conflict, and relapse) in Facebook users.

Facebook certainly provides a valuable mechanism for friends to stay connected in an increasingly global society, and has acknowledged the potential it has to address mental illness. In 2011, Facebook partnered with the National Suicide Prevention Lifeline to allow users to report observed suicidal content, thereby utilizing the online community to facilitate delivery of mental health resources.^10,11

HISTORY: Sibling rivalry

Mr. M had a romantic relationship with “Ms. B” in high school that he describes as “on and off,” beginning during his sophomore year. He describes himself as a “quick learner” who is task-oriented. He says he was outgoing in high school but became more introverted during his last year there. After high school, Mr. M worked as an electrician and discontinued psychiatric follow-up because he “felt fine.” He lives at home with his parents, two older sisters, and twin brother, who he identifies as being a lifelong “rival.”

After Ms. B ended her relationship with Mr. M, he began to suspect that she had become romantically involved with his twin brother. After Mr. M observed his brother leaving the house one night, he confronted his twin, who denied any involvement with Ms. B. After his brother left, Mr. M became enraged and punched a wall, fracturing his hand.

Two weeks before admission, Mr. M became increasingly preoccupied with suspicions of his brother’s involvement with Ms. B and looked for evidence on Facebook. Mr. M intensely monitored his Facebook news feed, which constantly updates to show public posts made by a user’s Facebook friends. He interpreted his friends’ posts as either directly relating to him or to a new relationship between Ms. B and his twin brother, stating that his friends were “talking in analogies” rather than directly using names.

Mr. M’s Facebook use rapidly increased to 3 or more hours a day. He can access Facebook from his laptop or cell phone, and reports logging in more than 10 times throughout the day. He says that, on Facebook, “it’s easier to talk trash” because people can say things they would not normally say face to face. He also states that Facebook is “ruining personal relationships,” and that it is “so easy to be in touch with everyone without really being in touch.”

The authors’ observations

In Mr. M’s case, Facebook served as a vehicle through which he could pursue a non-bizarre delusion. Mr. M openly admitted to viewing his twin brother as a rival; it is not surprising, therefore, that his delusions targeted his brother and ex-girlfriend.

Before social networks, the perseveration of this delusion might have been limited to internal thinking, or gathering corroborative information by means of stalking. Social media outlets have provided a means to perseverate and implicate others remotely, however, and Mr. M soon expanded his delusions to include more peers.

After beginning to suspect that friends and family are commenting on or criticizing him through Facebook, Mr. M experienced an irresistible impulse to repeatedly check the social network, which may have provided short-term relief of anticipatory anxiety, but that perpetuated the cycle. Constant access to the internet facilitated and intensified Mr. M’s cycle of paranoia, anxiety, and dysphoria. He called this process an “addiction.” A conceptual framework of the development of Mr. M’s maladaptive use of Facebook is illustrated in Figure 1.

Risk factors

Insecurity with one’s self-worth also may be a warning sign. Online social networking circumvents the need for physical interaction. A Facebook profile allows a person to selectively portray himself (herself) to the world, which may not be congruous with how his peers see him in everyday life. Patients who fear criticism or judgment may be more prone to maladaptive Facebook use, because they might feel empowered by the control they have over how others see them—online, at least.

Limited or, in Mr. M’s case, singular romantic experience may have influenced the course of his illness. Mr. M described his romantic involvement as a single, tumultuous relationship that lasted several years. Young patients with limited romantic experience may struggle to develop healthy protective mechanisms and may become preoccupied with the details of the situation, such that it interferes with functioning.

Mr. M’s history of ADHD might be a risk factor for abnormal patterns of internet use. Patients with ADHD have increased attentiveness with visually stimulating tasks—specifically, computers and video games.¹²

Last, it is unclear how, or if, Mr. M’s history of head injury contributed to his symptoms. There were no clear, temporal changes in cognition or emotion associated with the head injury, and he did not receive regular follow-up. Significant cognitive impairment does not appear to be a factor.

TREATMENT: Observed use

Quetiapine is selected to target psychosis, agitation, and insomnia characterized by difficulty with sleep initiation. Risperidone is added as a short-term agent to boost antipsychotic effect during the day when Mr. M is not fully responsive to quetiapine alone. Valproic acid is added on admission as a mood stabilizer to target emotional lability, impulsiveness, and possible mania.

After several days of treatment, and without access to a computer, Mr. M is calmer. We begin to assess the challenges of self-limiting time spent on Facebook; Mr. M explains that, before hospitalization, he had deactivated his Facebook account several times to try to rid himself of what he describes as an “addiction to social media”; soon afterward, however, he experienced overwhelming anxiety that led him to reactivate his account.

We sit with Mr. M as he logs in to Facebook and discuss the range of alternative explanations that specific public messages on his news feed could have. Explicitly listing alternative explanations is a technique used in cognitive-behavioral therapy. Mr. M begins to demonstrate increased insight regarding his paranoia and possible misinterpretation of information gleaned via Facebook; however, he still believes that masked references to him had existed. During his hospital stay he begins to acknowledge the problems that online interactions pose compared with face-to-face interactions, stating that, “There’s no emotion in [Facebook], so you can easily misinterpret what someone says.”

The authors’ observations

Mr. M was discharged after 7 days of treatment and has been seen weekly as an outpatient for 3 months without need for further hospitalization.

Bottom Line

Pervasive access to social media represents a vehicle for relapse of many psychiatric conditions. Younger patients may be especially at risk because they are more likely to use social media and are in the age range for onset of psychiatric illness. Although some degree of dependence on online networks can be considered normal, patients suffering from mental illness represent a vulnerable population for maladaptive online interactions.

Related Resources

• Sandler EP. If you’re in crisis, go online. Psychology Today. www.psychologytoday.com/blog/promoting-hope-preventing-suicide/201110/if-you-re-in-crisis-go-online. Published October 26, 2011.

• Nitzan U, Shoshan E, Lev-Ran S, et al. Internet-related psychosis−a sign of the times. Isr J Psychiatry Relat Sci. 2011;48(3):207-211.

• Martin EA, Bailey DH, Cicero DC, et al. Social networking profile correlates of schizotypy. Psychiatry Res. 2012;200(2-3):641-646.

Drug Brand Names

Fluoxetine • Prozac               Quetiapine • Seroquel

Risperidone • Risperdal         Valproic acid • Depakote

Disclosure

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

CASE: Paranoid and online

Mr. M, age 22, is brought to the emergency department by family because they are concerned about his paranoia and increasing agitation related to Facebook posts by friends and siblings. At age 8, Mr. M was diagnosed with depression, attention-deficit/hyperactivity disorder (ADHD), and anger management problems, which were well controlled with fluoxetine until last year, when he discontinued psychiatric follow-up. Mr. M’s girlfriend ended their relationship 1 month ago, although it is unclear whether the break-up was caused by his depressive symptoms or exacerbated them. In the last 2 days, his parents have noticed an increase in his delusional thoughts and aggressive behavior.

Family psychiatric history is not significant. Five years ago, Mr. M suffered a head injury in a motor vehicle collision, but completed high school without evidence of cognitive impairment or behavioral changes.

Mr. M appears disheveled and irritable. He reports his mood as “depressed,” but denies suicidal or homicidal ideations. He has no history of violence or antisocial behavior.

Mr. M is alert and oriented with clear speech, intact language, and grossly intact memory and concentration—although, he admits, “I just obsess over certain thoughts.” He endorses feelings of anxiety, insomnia, low energy, lack of sleep secondary to his paranoia, and claims that “something was said on Facebook about a girl and everyone is in on it.” He explains that his Facebook friends talk in “analogies” about him, and reports that, “I can just tell that’s what they are talking about even if they don’t say it directly.”

The authors’ observations

The last decade has seen a rise in the creation and use of social networking sites such as Facebook, Myspace, and Twitter. Facebook has 1.15 billion monthly active users.¹ Seventy-five percent of teenagers own cell phones, and 25% report using their phones to access social media outlets.² More than 50% of teenagers visit a social networking site daily, with 22% logging in to their favorite social media network more than 10 times a day.³ The easy accessibility of social media outlets has prompted study of the association of that accessibility with anxiety, depression, and self-esteem.^3-7

Although not a DSM-5 or ICD-10 diagnosis, internet addiction has been correlated with depression.⁸ Similarly, O’Keefe and colleagues describe Facebook depression in teens who spend a large amount of time on social networking sites.⁴ The recently developed Bergen Facebook Addiction Scale (BFAS)⁹ evaluates the six core elements of addiction (salience, mood modification, tolerance, withdrawal, conflict, and relapse) in Facebook users.

Facebook certainly provides a valuable mechanism for friends to stay connected in an increasingly global society, and has acknowledged the potential it has to address mental illness. In 2011, Facebook partnered with the National Suicide Prevention Lifeline to allow users to report observed suicidal content, thereby utilizing the online community to facilitate delivery of mental health resources.^10,11

HISTORY: Sibling rivalry

Mr. M had a romantic relationship with “Ms. B” in high school that he describes as “on and off,” beginning during his sophomore year. He describes himself as a “quick learner” who is task-oriented. He says he was outgoing in high school but became more introverted during his last year there. After high school, Mr. M worked as an electrician and discontinued psychiatric follow-up because he “felt fine.” He lives at home with his parents, two older sisters, and twin brother, who he identifies as being a lifelong “rival.”

After Ms. B ended her relationship with Mr. M, he began to suspect that she had become romantically involved with his twin brother. After Mr. M observed his brother leaving the house one night, he confronted his twin, who denied any involvement with Ms. B. After his brother left, Mr. M became enraged and punched a wall, fracturing his hand.

Two weeks before admission, Mr. M became increasingly preoccupied with suspicions of his brother’s involvement with Ms. B and looked for evidence on Facebook. Mr. M intensely monitored his Facebook news feed, which constantly updates to show public posts made by a user’s Facebook friends. He interpreted his friends’ posts as either directly relating to him or to a new relationship between Ms. B and his twin brother, stating that his friends were “talking in analogies” rather than directly using names.

Mr. M’s Facebook use rapidly increased to 3 or more hours a day. He can access Facebook from his laptop or cell phone, and reports logging in more than 10 times throughout the day. He says that, on Facebook, “it’s easier to talk trash” because people can say things they would not normally say face to face. He also states that Facebook is “ruining personal relationships,” and that it is “so easy to be in touch with everyone without really being in touch.”

The authors’ observations

In Mr. M’s case, Facebook served as a vehicle through which he could pursue a non-bizarre delusion. Mr. M openly admitted to viewing his twin brother as a rival; it is not surprising, therefore, that his delusions targeted his brother and ex-girlfriend.

Before social networks, the perseveration of this delusion might have been limited to internal thinking, or gathering corroborative information by means of stalking. Social media outlets have provided a means to perseverate and implicate others remotely, however, and Mr. M soon expanded his delusions to include more peers.

After beginning to suspect that friends and family are commenting on or criticizing him through Facebook, Mr. M experienced an irresistible impulse to repeatedly check the social network, which may have provided short-term relief of anticipatory anxiety, but that perpetuated the cycle. Constant access to the internet facilitated and intensified Mr. M’s cycle of paranoia, anxiety, and dysphoria. He called this process an “addiction.” A conceptual framework of the development of Mr. M’s maladaptive use of Facebook is illustrated in Figure 1.

Risk factors

Insecurity with one’s self-worth also may be a warning sign. Online social networking circumvents the need for physical interaction. A Facebook profile allows a person to selectively portray himself (herself) to the world, which may not be congruous with how his peers see him in everyday life. Patients who fear criticism or judgment may be more prone to maladaptive Facebook use, because they might feel empowered by the control they have over how others see them—online, at least.

Limited or, in Mr. M’s case, singular romantic experience may have influenced the course of his illness. Mr. M described his romantic involvement as a single, tumultuous relationship that lasted several years. Young patients with limited romantic experience may struggle to develop healthy protective mechanisms and may become preoccupied with the details of the situation, such that it interferes with functioning.

Mr. M’s history of ADHD might be a risk factor for abnormal patterns of internet use. Patients with ADHD have increased attentiveness with visually stimulating tasks—specifically, computers and video games.¹²

Last, it is unclear how, or if, Mr. M’s history of head injury contributed to his symptoms. There were no clear, temporal changes in cognition or emotion associated with the head injury, and he did not receive regular follow-up. Significant cognitive impairment does not appear to be a factor.

TREATMENT: Observed use

Quetiapine is selected to target psychosis, agitation, and insomnia characterized by difficulty with sleep initiation. Risperidone is added as a short-term agent to boost antipsychotic effect during the day when Mr. M is not fully responsive to quetiapine alone. Valproic acid is added on admission as a mood stabilizer to target emotional lability, impulsiveness, and possible mania.

After several days of treatment, and without access to a computer, Mr. M is calmer. We begin to assess the challenges of self-limiting time spent on Facebook; Mr. M explains that, before hospitalization, he had deactivated his Facebook account several times to try to rid himself of what he describes as an “addiction to social media”; soon afterward, however, he experienced overwhelming anxiety that led him to reactivate his account.

We sit with Mr. M as he logs in to Facebook and discuss the range of alternative explanations that specific public messages on his news feed could have. Explicitly listing alternative explanations is a technique used in cognitive-behavioral therapy. Mr. M begins to demonstrate increased insight regarding his paranoia and possible misinterpretation of information gleaned via Facebook; however, he still believes that masked references to him had existed. During his hospital stay he begins to acknowledge the problems that online interactions pose compared with face-to-face interactions, stating that, “There’s no emotion in [Facebook], so you can easily misinterpret what someone says.”

The authors’ observations

Mr. M was discharged after 7 days of treatment and has been seen weekly as an outpatient for 3 months without need for further hospitalization.

Bottom Line

Pervasive access to social media represents a vehicle for relapse of many psychiatric conditions. Younger patients may be especially at risk because they are more likely to use social media and are in the age range for onset of psychiatric illness. Although some degree of dependence on online networks can be considered normal, patients suffering from mental illness represent a vulnerable population for maladaptive online interactions.

Related Resources

• Sandler EP. If you’re in crisis, go online. Psychology Today. www.psychologytoday.com/blog/promoting-hope-preventing-suicide/201110/if-you-re-in-crisis-go-online. Published October 26, 2011.

• Nitzan U, Shoshan E, Lev-Ran S, et al. Internet-related psychosis−a sign of the times. Isr J Psychiatry Relat Sci. 2011;48(3):207-211.

• Martin EA, Bailey DH, Cicero DC, et al. Social networking profile correlates of schizotypy. Psychiatry Res. 2012;200(2-3):641-646.

Drug Brand Names

Fluoxetine • Prozac               Quetiapine • Seroquel

Risperidone • Risperdal         Valproic acid • Depakote

Disclosure

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

As symptoms of posttraumatic stress disorder (PTSD) progress, the involved person’s physical and mental health deteriorates.¹ This sparks lifestyle changes that allow them to avoid re-exposure to triggering stimuli; however, it also increases their risk of social isolation. Early clinical investigation has found that patients who experience hyperarousal symptoms of overt PTSD—difficulty sleeping, emotional dyscontrol, hypervigilance, and an enhanced startle response—could benefit from the stress-reducing capacity of glucocorticoids.

Decreased glucocorticoids

After a distressing situation, norepinephrine levels rise acutely.^2,3 This contributes to a protective retention of potentially threatening memories, which is how people learn to avoid danger.

Glucocorticoid secretion enhances a patient’s coping mechanisms by helping them process information in a way that diminishes retrieval of fear-evoking memories.^2,3 Glucocorticoid, also called cortisol, is referred to as a “stress hormone.” Cortisol promotes emotional adaptability following a traumatic event; this action diminishes future, inappropriate retrieval of frightening memories as a physiologic mechanism to help people cope with upsetting situations.³

PTSD pathogenesis involves altered hypothalamic-pituitary-adrenal axis function; sustained stress results in decreased levels of circulating glucocorticoid. This is a consequence of enhanced negative feedback and increased glucocorticoid receptor sensitivity, which is evidenced by results of abnormal dexamethasone suppression tests.¹ Downregulation of corticotropin-releasing hormone (CRH) receptors in the pituitary glands and increased CRH levels have been documented in PTSD patients.^1,4 An association between high CRH levels and an increase in startle response explains the exaggerated startle response observed in patients with PTSD. Higher circulating glucocorticoid has the opposite effect⁴; there is an inverse relationship between the daily level of glucocorticoid and startle amplitude. A low level of circulating glucocorticoid promotes recall of frightening events that results in persistent re-experiencing of traumatic memories.^2,3

Glucocorticoids in PTSD

Glucocorticoid administration reduces psychological and physiological responses to stress.³ Exogenous glucocorticoid administration affects cognition by interacting with serotonin, dopamine, and ã-aminobutyric acid by actions on the amygdala, medial prefrontal cortex, and hippocampus.^2,3 Research among  veterans with and without PTSD recorded a decrease in startle response after administration of a single dose of 20 mg of hydrocortisone.⁴ Results of a large study documented that one dose of hydrocortisone administered at >35 mg can inhibit threatening memories and improve social function.³ Hydrocortisone is linked to anxiolytic effects in healthy persons and patients with social phobia or panic disorder.^3,4 Because treatment of PTSD with antidepressants and benzodiazepines often is ineffective,⁵ glucocorticoids may offer a new pharmacotherapy option. Glucocorticoids have been prescribed as prophylactic agents shortly after an acutely stressful event to prevent development of PTSD.⁴ Hydrocortisone is not FDA-approved to treat PTSD; informed consent, physician discretion, and close monitoring are emphasized.

Glucocorticoid use in mitigating PTSD symptom emergence is under investigation. Research suggests that just one acute dose of hydrocortisone might benefit patients prone to PTSD.^3,4 Further study is needed to establish whether prescribing hydrocortisone is efficacious.

Disclosure

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

As symptoms of posttraumatic stress disorder (PTSD) progress, the involved person’s physical and mental health deteriorates.¹ This sparks lifestyle changes that allow them to avoid re-exposure to triggering stimuli; however, it also increases their risk of social isolation. Early clinical investigation has found that patients who experience hyperarousal symptoms of overt PTSD—difficulty sleeping, emotional dyscontrol, hypervigilance, and an enhanced startle response—could benefit from the stress-reducing capacity of glucocorticoids.

Decreased glucocorticoids

After a distressing situation, norepinephrine levels rise acutely.^2,3 This contributes to a protective retention of potentially threatening memories, which is how people learn to avoid danger.

Glucocorticoid secretion enhances a patient’s coping mechanisms by helping them process information in a way that diminishes retrieval of fear-evoking memories.^2,3 Glucocorticoid, also called cortisol, is referred to as a “stress hormone.” Cortisol promotes emotional adaptability following a traumatic event; this action diminishes future, inappropriate retrieval of frightening memories as a physiologic mechanism to help people cope with upsetting situations.³

PTSD pathogenesis involves altered hypothalamic-pituitary-adrenal axis function; sustained stress results in decreased levels of circulating glucocorticoid. This is a consequence of enhanced negative feedback and increased glucocorticoid receptor sensitivity, which is evidenced by results of abnormal dexamethasone suppression tests.¹ Downregulation of corticotropin-releasing hormone (CRH) receptors in the pituitary glands and increased CRH levels have been documented in PTSD patients.^1,4 An association between high CRH levels and an increase in startle response explains the exaggerated startle response observed in patients with PTSD. Higher circulating glucocorticoid has the opposite effect⁴; there is an inverse relationship between the daily level of glucocorticoid and startle amplitude. A low level of circulating glucocorticoid promotes recall of frightening events that results in persistent re-experiencing of traumatic memories.^2,3

Glucocorticoids in PTSD

Glucocorticoid administration reduces psychological and physiological responses to stress.³ Exogenous glucocorticoid administration affects cognition by interacting with serotonin, dopamine, and ã-aminobutyric acid by actions on the amygdala, medial prefrontal cortex, and hippocampus.^2,3 Research among  veterans with and without PTSD recorded a decrease in startle response after administration of a single dose of 20 mg of hydrocortisone.⁴ Results of a large study documented that one dose of hydrocortisone administered at >35 mg can inhibit threatening memories and improve social function.³ Hydrocortisone is linked to anxiolytic effects in healthy persons and patients with social phobia or panic disorder.^3,4 Because treatment of PTSD with antidepressants and benzodiazepines often is ineffective,⁵ glucocorticoids may offer a new pharmacotherapy option. Glucocorticoids have been prescribed as prophylactic agents shortly after an acutely stressful event to prevent development of PTSD.⁴ Hydrocortisone is not FDA-approved to treat PTSD; informed consent, physician discretion, and close monitoring are emphasized.

Glucocorticoid use in mitigating PTSD symptom emergence is under investigation. Research suggests that just one acute dose of hydrocortisone might benefit patients prone to PTSD.^3,4 Further study is needed to establish whether prescribing hydrocortisone is efficacious.

Disclosure

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

As symptoms of posttraumatic stress disorder (PTSD) progress, the involved person’s physical and mental health deteriorates.¹ This sparks lifestyle changes that allow them to avoid re-exposure to triggering stimuli; however, it also increases their risk of social isolation. Early clinical investigation has found that patients who experience hyperarousal symptoms of overt PTSD—difficulty sleeping, emotional dyscontrol, hypervigilance, and an enhanced startle response—could benefit from the stress-reducing capacity of glucocorticoids.

Decreased glucocorticoids

After a distressing situation, norepinephrine levels rise acutely.^2,3 This contributes to a protective retention of potentially threatening memories, which is how people learn to avoid danger.

Glucocorticoid secretion enhances a patient’s coping mechanisms by helping them process information in a way that diminishes retrieval of fear-evoking memories.^2,3 Glucocorticoid, also called cortisol, is referred to as a “stress hormone.” Cortisol promotes emotional adaptability following a traumatic event; this action diminishes future, inappropriate retrieval of frightening memories as a physiologic mechanism to help people cope with upsetting situations.³

PTSD pathogenesis involves altered hypothalamic-pituitary-adrenal axis function; sustained stress results in decreased levels of circulating glucocorticoid. This is a consequence of enhanced negative feedback and increased glucocorticoid receptor sensitivity, which is evidenced by results of abnormal dexamethasone suppression tests.¹ Downregulation of corticotropin-releasing hormone (CRH) receptors in the pituitary glands and increased CRH levels have been documented in PTSD patients.^1,4 An association between high CRH levels and an increase in startle response explains the exaggerated startle response observed in patients with PTSD. Higher circulating glucocorticoid has the opposite effect⁴; there is an inverse relationship between the daily level of glucocorticoid and startle amplitude. A low level of circulating glucocorticoid promotes recall of frightening events that results in persistent re-experiencing of traumatic memories.^2,3

Glucocorticoids in PTSD

Glucocorticoid administration reduces psychological and physiological responses to stress.³ Exogenous glucocorticoid administration affects cognition by interacting with serotonin, dopamine, and ã-aminobutyric acid by actions on the amygdala, medial prefrontal cortex, and hippocampus.^2,3 Research among  veterans with and without PTSD recorded a decrease in startle response after administration of a single dose of 20 mg of hydrocortisone.⁴ Results of a large study documented that one dose of hydrocortisone administered at >35 mg can inhibit threatening memories and improve social function.³ Hydrocortisone is linked to anxiolytic effects in healthy persons and patients with social phobia or panic disorder.^3,4 Because treatment of PTSD with antidepressants and benzodiazepines often is ineffective,⁵ glucocorticoids may offer a new pharmacotherapy option. Glucocorticoids have been prescribed as prophylactic agents shortly after an acutely stressful event to prevent development of PTSD.⁴ Hydrocortisone is not FDA-approved to treat PTSD; informed consent, physician discretion, and close monitoring are emphasized.

Glucocorticoid use in mitigating PTSD symptom emergence is under investigation. Research suggests that just one acute dose of hydrocortisone might benefit patients prone to PTSD.^3,4 Further study is needed to establish whether prescribing hydrocortisone is efficacious.

Disclosure

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

A practice recommendation in “Travelers diarrhea: Prevention, treatment, and post-trip evaluation" (J Fam Pract. 2013;62:356-361) incorrectly called for self-treatment with a fluoroquinolone (or azithromycin) and loperamide for diarrhea that is bloody or accompanied by fever. In fact, both the Centers for Disease Control and Prevention and the Infectious Diseases Society of America advise against the use of loperamide by travelers with fever or bloody diarrhea. The practice recommendation should have read: “Advise travelers to initiate self-treatment for travelers’ diarrhea with a fluoroquinolone (or azithromycin if in South or Southeast Asia) at the onset of diarrhea if it is bloody or accompanied by fever.”

A practice recommendation in “Travelers diarrhea: Prevention, treatment, and post-trip evaluation" (J Fam Pract. 2013;62:356-361) incorrectly called for self-treatment with a fluoroquinolone (or azithromycin) and loperamide for diarrhea that is bloody or accompanied by fever. In fact, both the Centers for Disease Control and Prevention and the Infectious Diseases Society of America advise against the use of loperamide by travelers with fever or bloody diarrhea. The practice recommendation should have read: “Advise travelers to initiate self-treatment for travelers’ diarrhea with a fluoroquinolone (or azithromycin if in South or Southeast Asia) at the onset of diarrhea if it is bloody or accompanied by fever.”

A practice recommendation in “Travelers diarrhea: Prevention, treatment, and post-trip evaluation" (J Fam Pract. 2013;62:356-361) incorrectly called for self-treatment with a fluoroquinolone (or azithromycin) and loperamide for diarrhea that is bloody or accompanied by fever. In fact, both the Centers for Disease Control and Prevention and the Infectious Diseases Society of America advise against the use of loperamide by travelers with fever or bloody diarrhea. The practice recommendation should have read: “Advise travelers to initiate self-treatment for travelers’ diarrhea with a fluoroquinolone (or azithromycin if in South or Southeast Asia) at the onset of diarrhea if it is bloody or accompanied by fever.”

ANSWER
The radiograph demonstrates no evidence of an acute fracture or dislocation. Normal gas/stool pattern is present. Essentially, this radiograph is normal. 

The patient most likely has an acute strain of her hip quadriceps or flexor. On occasion, severe enough strain injuries can cause a slight avulsion fracture within the hip at the muscle origination point. These can sometimes be evident on plain films.

ANSWER
The radiograph demonstrates no evidence of an acute fracture or dislocation. Normal gas/stool pattern is present. Essentially, this radiograph is normal. 

The patient most likely has an acute strain of her hip quadriceps or flexor. On occasion, severe enough strain injuries can cause a slight avulsion fracture within the hip at the muscle origination point. These can sometimes be evident on plain films.

ANSWER
The radiograph demonstrates no evidence of an acute fracture or dislocation. Normal gas/stool pattern is present. Essentially, this radiograph is normal. 

The patient most likely has an acute strain of her hip quadriceps or flexor. On occasion, severe enough strain injuries can cause a slight avulsion fracture within the hip at the muscle origination point. These can sometimes be evident on plain films.

ANSWER

The correct interpretation is sinus rhythm with a first-degree atrioventricular (AV) block, right superior axis deviation, and low voltage QRS complexes. The measured PR interval of 360 ms is correct!

The P waves are best seen in precordial leads V₁ to V₃. Notice that the P waves fall between the QRS complex and the T wave. The P wave is upright and not inverted, so it is not occurring retrograde from the preceding QRS complex. The sinus node depolarizes, and a long delay occurs within the atria and AV node before conducting down the normal conduction system in the ventricles. This conduction delay is so long that the preceding beat (QRS complex) is still repolarizing (T wave) by the time the sinus node depolarizes again.  Thus, the P wave is responsible for the next QRS complex after duration of 360 ms.

A right superior axis deviation, also known as an extreme right axis deviation, is evidenced by an R-wave axis of 192°. Low-voltage QRS complexes are due to the patient’s body habitus. Morbid obesity significantly diminishes the electrical vectors measured by the surface ECG electrodes.

Finally, extra credit is due if you recognize the long QTc interval as well. The maximum normal QTc adjusted for a heart rate of 100 beats/min in men is 310 ms. This ECG barely meets that criteria; in this case, the prolonged QTc interval is of no significance.

ANSWER

The correct interpretation is sinus rhythm with a first-degree atrioventricular (AV) block, right superior axis deviation, and low voltage QRS complexes. The measured PR interval of 360 ms is correct!

The P waves are best seen in precordial leads V₁ to V₃. Notice that the P waves fall between the QRS complex and the T wave. The P wave is upright and not inverted, so it is not occurring retrograde from the preceding QRS complex. The sinus node depolarizes, and a long delay occurs within the atria and AV node before conducting down the normal conduction system in the ventricles. This conduction delay is so long that the preceding beat (QRS complex) is still repolarizing (T wave) by the time the sinus node depolarizes again.  Thus, the P wave is responsible for the next QRS complex after duration of 360 ms.

A right superior axis deviation, also known as an extreme right axis deviation, is evidenced by an R-wave axis of 192°. Low-voltage QRS complexes are due to the patient’s body habitus. Morbid obesity significantly diminishes the electrical vectors measured by the surface ECG electrodes.

Finally, extra credit is due if you recognize the long QTc interval as well. The maximum normal QTc adjusted for a heart rate of 100 beats/min in men is 310 ms. This ECG barely meets that criteria; in this case, the prolonged QTc interval is of no significance.

ANSWER

The correct interpretation is sinus rhythm with a first-degree atrioventricular (AV) block, right superior axis deviation, and low voltage QRS complexes. The measured PR interval of 360 ms is correct!

The P waves are best seen in precordial leads V₁ to V₃. Notice that the P waves fall between the QRS complex and the T wave. The P wave is upright and not inverted, so it is not occurring retrograde from the preceding QRS complex. The sinus node depolarizes, and a long delay occurs within the atria and AV node before conducting down the normal conduction system in the ventricles. This conduction delay is so long that the preceding beat (QRS complex) is still repolarizing (T wave) by the time the sinus node depolarizes again.  Thus, the P wave is responsible for the next QRS complex after duration of 360 ms.

A right superior axis deviation, also known as an extreme right axis deviation, is evidenced by an R-wave axis of 192°. Low-voltage QRS complexes are due to the patient’s body habitus. Morbid obesity significantly diminishes the electrical vectors measured by the surface ECG electrodes.

Finally, extra credit is due if you recognize the long QTc interval as well. The maximum normal QTc adjusted for a heart rate of 100 beats/min in men is 310 ms. This ECG barely meets that criteria; in this case, the prolonged QTc interval is of no significance.

One of the most common complications of pregnancy is gestational diabetes mellitus (GDM). It is defined as glucose intolerance with first onset during pregnancy.¹ In 2011, the incidence of GDM in the United States was between 2% and 10% of all pregnancies. Potential complications associated with GDM include macrosomia, pre-eclampsia, preterm birth, increased risk for cesarean section, neonatal hypoglycemia, shoulder dystocia, and polyhydramnios. Women with a history of gestational diabetes have a 35% to 60% likelihood of developing type 2 diabetes over the following 10 to 20 years.²

Q: When should screening for GDM occur?

According to the American Diabetes Association’s (ADA) 2012 Clinical Practice Recommendations, a pregnant woman should be screened for undiagnosed type 2 diabetes at her first prenatal visit if she has certain risk factors.³ These include, but are not limited to, family history of diabetes, overweight/obesity, sedentary life­style, elevated blood pressure and/or cholesterol, impaired fasting glucose or impaired glucose tolerance, or certain ethnic backgrounds (eg, Hispanic, Native American, and non-Hispanic black).⁴ In 2011, the ADA revised its recommendations for GDM screening and diagnosis to be in accordance with those from the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an interna­tional consensus group with representatives from multiple obstetric and diabetes organizations, including ADA.

Q: How is GDM diagnosed?

Current recommendations stipulate that women with no previous history of diabetes or prediabetes undergo one-step testing: a 75-g glucose tolerance test (GTT) at 24 to 28 weeks’ gestation.^5,6 For women with a prior history of GDM, screening is recommended earlier in the pregnancy. The GTT should be performed after an overnight fast of at least eight hours.³ An elevation of any one of the values above normal reference range is consistent with the diagnosis of GDM. (Previously, the diagnostic criteria required two abnormal values.) Multiple international studies using the new criteria have estimated an increased incidence of gestational diabetes in up to 18% of pregnancies.^5,6

Some organizations have not endorsed the IADPSG/ADA diagnostic criteria at this time; as a result, many practitioners continue to use two-step testing for diagnosing GDM. To do the two-step testing, a 50-g glucose load is given, followed by a blood glucose reading one hour later. If the one-hour reading is within normal range, no further testing is warranted and the patient does not have gestational diabetes. If the test is abnormal, she must undergo a fasting three-hour GTT using a 100-g glucose load.

Q: What advice should a woman get once she’s diagnosed with GDM? 

As soon as a woman is diagnosed with GDM, she should be referred for a gestational diabetes education class and nutrition counseling. Specifically, she should learn what it means for her to have GDM, implications for her and her baby, and the importance of eating a healthy diet (not the proverbial concept of “eating for two”), physical activity, self-monitoring blood glucose, and adherence to any prescribed medications.

Probably the most important aspect of education is nutrition counseling. It is known that smaller meals consumed more frequently throughout the day reduce spikes in blood glucose levels. One suggestion is to eat three small meals and three low-carbohydrate (15 g) snacks each day. Meals and snacks are generally established based on fixed carbohydrate amounts. A certified diabetes educator or registered dietitian (RD) can recommend healthy meal and snack ideas that are tasty, promote satiety, and minimize spikes in glucose levels.

Q: What are the current treatment options for GDM?

During the process of receiving GDM education, the patient should be prescribed a glucometer, along with specific glucose targets. Blood glucose should be checked multiple times a day, preferably fasting and postprandial measurements. Medical practices vary in their preferred glucose targets; some individuals require tighter control than others. The ADA suggests the following targets:

• Before a meal (preprandial):
95 mg/dL or less.

 • One hour after a meal (postprandial): 140 mg/dL or less.

• Two hours after a meal (postprandial): 120 mg/dL or less. ⁷ 

If blood glucose levels remain within normal range, it is possible to control gestational diabetes with dietary modification and physical activity. If readings are consistently elevated, then the patient must be started on medication. There are currently no FDA-approved oral medications to treat gestational diabetes. Glyburide is commonly used, although it is not FDA approved for this indication. More studies to establish its safety are likely needed for FDA approval.⁸

If pharmaceutical treatment is warranted, insulin is the safest and most effective agent. It is the only medication that is FDA approved for treatment of GDM.  Levemir (insulin detemir [rDNA origin] injection) gained FDA approval for use in pregnancy in 2012, so it has become more widespread than NPH for basal insulin usage.⁹

Although it is usually managed by an endocrinologist or perinatologist, an experienced obstetrician could also manage GDM. Often, the patient is referred to an endocrinologist. The endocrine provider, along with the diabetes educator and RD, focus on nutrition counseling and diabetes management so the obstetrician can focus on maternal and fetal health. 

Q: What is the recommended follow-up?

Since embryonic and fetal development occurs at such a rapid rate, time is of the essence for getting a patient’s blood glucose to goal. While treating diabetes in general can be challenging, this is usually not the case with GDM. Most women with GDM are motivated to take care of themselves for the well-being of their developing baby. The influence of a baby developing inside a mother is so strong that diabetic women who become pregnant often take better care of themselves than they do when they are not pregnant.

The patient’s daily responsibilities should include eating a healthy and diet checking her blood glucose levels throughout the day. These readings must be recorded. Clinic visits should occur often, with emailing of glucose readings between visits as needed. The frequency of visits varies among practices, depending on the patient’s level of glucose control and intensity of the treatment regimen.

Q: Why is postpartum testing important?

After delivery, most cases of GDM usually resolve. However, approximately 5% to 10% of women with gestational diabetes are found to have diabetes immediately after pregnancy.² To evaluate for persistent diabetes, a two-hour GTT should be done at six weeks’ postpartum. Although an A1C can now be used to diagnose diabetes, the ADA does not recommend checking it for this purpose.³

If the two-hour GTT result is normal, a woman should be screened for diabetes every three years for the rest of her life.³ If a diagnosis of impaired fasting glucose or impaired glucose tolerance is made, then she should be tested for diabetes on an annual basis or in the interim if she develops classic symptoms of hyperglycemia.³ If diabetes is diagnosed, she should be treated accordingly as a type 2 diabetic patient.

At this time, the patient should be counseled on lifestyle interventions and consider starting metformin therapy if appropriate. Diabetes education classes are available for prediabetes. To maintain good health and prevent/delay onset of type 2 diabetes, here are some tips to follow: 

 • The same diet as during pregnancy does not have to be followed, although healthy eating habits are always a good idea.

• Physical activity (approximately 30 min five times a week) will help shed weight gained during pregnancy.

• Breastfeeding promotes weight loss.¹⁰

• Patients should aim for weight loss of 7% of body weight.³

• Continue annual physical exams, keeping an eye on blood pressure, weight, and cholesterol levels.

It’s reasonable for the patient to check glucose levels occasionally after delivery. If elevated readings occur, the patient can make an appointment with her primary care provider or endocrinologist.

References
1.  American Association for Clinical Chemistry. A New Definition of Gestational Diabetes. www.aacc.org/publications/cln/2010/may/Pages/CoverStory2May2010.aspx. Accessed June 30, 2013.

2. National Diabetes Statistics, 2011. www.diabetes.niddk.nih.gov/dm/pubs/statistics/#Gestational. Accessed July 22, 2013.

3. American Diabetes Association. 2012 Clinical Practice Recommendations. Diabetes Care. 2012;35(suppl 1). http://professional.diabetes.org/SlideLibrary/media/4839/ADA%20Standards%20of%20Medical%20Care%202012%20FINAL.ppt. Accessed June 24, 2013.

4. American Diabetes Association. Diabetes basics: your risk. www.diabetes.org/diabetes-basics/prevention/risk-factors. Accessed August 13, 2013.

5. American Diabetes Association. Diabetes Basics: What is Gestational Diabetes? www.diabetes.org/diabetes-basics/gestational/what-is-gestational-diabetes.html. Accessed August 13, 2013.

 6. Johnson K. New criteria for gestational diabetes increase diagnoses (December 5, 2011). www.medscape.com/viewarticle/754733. Accessed August 13, 2013.

 7. American Diabetes Association. Diabetes basics: how to treat gestational diabetes. www.diabetes.org/diabetes-basics/gestational/how-to-treat-gestational.html. Accessed August 13, 2013.

8. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30(suppl 2). http://care.diabetesjournals.org/content/30/Supplement_2/S209.full. Accessed August 13, 2013.

9. Lowes R. Levemir assigned more reassuring pregnancy risk category (April 2, 2012). www.medscape.com/viewarticle/761349. Accessed August 13, 2013.

10. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol. 2012;8(11):639-649.

One of the most common complications of pregnancy is gestational diabetes mellitus (GDM). It is defined as glucose intolerance with first onset during pregnancy.¹ In 2011, the incidence of GDM in the United States was between 2% and 10% of all pregnancies. Potential complications associated with GDM include macrosomia, pre-eclampsia, preterm birth, increased risk for cesarean section, neonatal hypoglycemia, shoulder dystocia, and polyhydramnios. Women with a history of gestational diabetes have a 35% to 60% likelihood of developing type 2 diabetes over the following 10 to 20 years.²

Q: When should screening for GDM occur?

According to the American Diabetes Association’s (ADA) 2012 Clinical Practice Recommendations, a pregnant woman should be screened for undiagnosed type 2 diabetes at her first prenatal visit if she has certain risk factors.³ These include, but are not limited to, family history of diabetes, overweight/obesity, sedentary life­style, elevated blood pressure and/or cholesterol, impaired fasting glucose or impaired glucose tolerance, or certain ethnic backgrounds (eg, Hispanic, Native American, and non-Hispanic black).⁴ In 2011, the ADA revised its recommendations for GDM screening and diagnosis to be in accordance with those from the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an interna­tional consensus group with representatives from multiple obstetric and diabetes organizations, including ADA.

Q: How is GDM diagnosed?

Current recommendations stipulate that women with no previous history of diabetes or prediabetes undergo one-step testing: a 75-g glucose tolerance test (GTT) at 24 to 28 weeks’ gestation.^5,6 For women with a prior history of GDM, screening is recommended earlier in the pregnancy. The GTT should be performed after an overnight fast of at least eight hours.³ An elevation of any one of the values above normal reference range is consistent with the diagnosis of GDM. (Previously, the diagnostic criteria required two abnormal values.) Multiple international studies using the new criteria have estimated an increased incidence of gestational diabetes in up to 18% of pregnancies.^5,6

Some organizations have not endorsed the IADPSG/ADA diagnostic criteria at this time; as a result, many practitioners continue to use two-step testing for diagnosing GDM. To do the two-step testing, a 50-g glucose load is given, followed by a blood glucose reading one hour later. If the one-hour reading is within normal range, no further testing is warranted and the patient does not have gestational diabetes. If the test is abnormal, she must undergo a fasting three-hour GTT using a 100-g glucose load.

Q: What advice should a woman get once she’s diagnosed with GDM? 

As soon as a woman is diagnosed with GDM, she should be referred for a gestational diabetes education class and nutrition counseling. Specifically, she should learn what it means for her to have GDM, implications for her and her baby, and the importance of eating a healthy diet (not the proverbial concept of “eating for two”), physical activity, self-monitoring blood glucose, and adherence to any prescribed medications.

Probably the most important aspect of education is nutrition counseling. It is known that smaller meals consumed more frequently throughout the day reduce spikes in blood glucose levels. One suggestion is to eat three small meals and three low-carbohydrate (15 g) snacks each day. Meals and snacks are generally established based on fixed carbohydrate amounts. A certified diabetes educator or registered dietitian (RD) can recommend healthy meal and snack ideas that are tasty, promote satiety, and minimize spikes in glucose levels.

Q: What are the current treatment options for GDM?

During the process of receiving GDM education, the patient should be prescribed a glucometer, along with specific glucose targets. Blood glucose should be checked multiple times a day, preferably fasting and postprandial measurements. Medical practices vary in their preferred glucose targets; some individuals require tighter control than others. The ADA suggests the following targets:

• Before a meal (preprandial):
95 mg/dL or less.

 • One hour after a meal (postprandial): 140 mg/dL or less.

• Two hours after a meal (postprandial): 120 mg/dL or less. ⁷ 

If blood glucose levels remain within normal range, it is possible to control gestational diabetes with dietary modification and physical activity. If readings are consistently elevated, then the patient must be started on medication. There are currently no FDA-approved oral medications to treat gestational diabetes. Glyburide is commonly used, although it is not FDA approved for this indication. More studies to establish its safety are likely needed for FDA approval.⁸

If pharmaceutical treatment is warranted, insulin is the safest and most effective agent. It is the only medication that is FDA approved for treatment of GDM.  Levemir (insulin detemir [rDNA origin] injection) gained FDA approval for use in pregnancy in 2012, so it has become more widespread than NPH for basal insulin usage.⁹

Although it is usually managed by an endocrinologist or perinatologist, an experienced obstetrician could also manage GDM. Often, the patient is referred to an endocrinologist. The endocrine provider, along with the diabetes educator and RD, focus on nutrition counseling and diabetes management so the obstetrician can focus on maternal and fetal health. 

Q: What is the recommended follow-up?

Since embryonic and fetal development occurs at such a rapid rate, time is of the essence for getting a patient’s blood glucose to goal. While treating diabetes in general can be challenging, this is usually not the case with GDM. Most women with GDM are motivated to take care of themselves for the well-being of their developing baby. The influence of a baby developing inside a mother is so strong that diabetic women who become pregnant often take better care of themselves than they do when they are not pregnant.

The patient’s daily responsibilities should include eating a healthy and diet checking her blood glucose levels throughout the day. These readings must be recorded. Clinic visits should occur often, with emailing of glucose readings between visits as needed. The frequency of visits varies among practices, depending on the patient’s level of glucose control and intensity of the treatment regimen.

Q: Why is postpartum testing important?

After delivery, most cases of GDM usually resolve. However, approximately 5% to 10% of women with gestational diabetes are found to have diabetes immediately after pregnancy.² To evaluate for persistent diabetes, a two-hour GTT should be done at six weeks’ postpartum. Although an A1C can now be used to diagnose diabetes, the ADA does not recommend checking it for this purpose.³

If the two-hour GTT result is normal, a woman should be screened for diabetes every three years for the rest of her life.³ If a diagnosis of impaired fasting glucose or impaired glucose tolerance is made, then she should be tested for diabetes on an annual basis or in the interim if she develops classic symptoms of hyperglycemia.³ If diabetes is diagnosed, she should be treated accordingly as a type 2 diabetic patient.

At this time, the patient should be counseled on lifestyle interventions and consider starting metformin therapy if appropriate. Diabetes education classes are available for prediabetes. To maintain good health and prevent/delay onset of type 2 diabetes, here are some tips to follow: 

 • The same diet as during pregnancy does not have to be followed, although healthy eating habits are always a good idea.

• Physical activity (approximately 30 min five times a week) will help shed weight gained during pregnancy.

• Breastfeeding promotes weight loss.¹⁰

• Patients should aim for weight loss of 7% of body weight.³

• Continue annual physical exams, keeping an eye on blood pressure, weight, and cholesterol levels.

It’s reasonable for the patient to check glucose levels occasionally after delivery. If elevated readings occur, the patient can make an appointment with her primary care provider or endocrinologist.

References
1.  American Association for Clinical Chemistry. A New Definition of Gestational Diabetes. www.aacc.org/publications/cln/2010/may/Pages/CoverStory2May2010.aspx. Accessed June 30, 2013.

2. National Diabetes Statistics, 2011. www.diabetes.niddk.nih.gov/dm/pubs/statistics/#Gestational. Accessed July 22, 2013.

3. American Diabetes Association. 2012 Clinical Practice Recommendations. Diabetes Care. 2012;35(suppl 1). http://professional.diabetes.org/SlideLibrary/media/4839/ADA%20Standards%20of%20Medical%20Care%202012%20FINAL.ppt. Accessed June 24, 2013.

4. American Diabetes Association. Diabetes basics: your risk. www.diabetes.org/diabetes-basics/prevention/risk-factors. Accessed August 13, 2013.

5. American Diabetes Association. Diabetes Basics: What is Gestational Diabetes? www.diabetes.org/diabetes-basics/gestational/what-is-gestational-diabetes.html. Accessed August 13, 2013.

 6. Johnson K. New criteria for gestational diabetes increase diagnoses (December 5, 2011). www.medscape.com/viewarticle/754733. Accessed August 13, 2013.

 7. American Diabetes Association. Diabetes basics: how to treat gestational diabetes. www.diabetes.org/diabetes-basics/gestational/how-to-treat-gestational.html. Accessed August 13, 2013.

8. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30(suppl 2). http://care.diabetesjournals.org/content/30/Supplement_2/S209.full. Accessed August 13, 2013.

9. Lowes R. Levemir assigned more reassuring pregnancy risk category (April 2, 2012). www.medscape.com/viewarticle/761349. Accessed August 13, 2013.

10. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol. 2012;8(11):639-649.

One of the most common complications of pregnancy is gestational diabetes mellitus (GDM). It is defined as glucose intolerance with first onset during pregnancy.¹ In 2011, the incidence of GDM in the United States was between 2% and 10% of all pregnancies. Potential complications associated with GDM include macrosomia, pre-eclampsia, preterm birth, increased risk for cesarean section, neonatal hypoglycemia, shoulder dystocia, and polyhydramnios. Women with a history of gestational diabetes have a 35% to 60% likelihood of developing type 2 diabetes over the following 10 to 20 years.²

Q: When should screening for GDM occur?

According to the American Diabetes Association’s (ADA) 2012 Clinical Practice Recommendations, a pregnant woman should be screened for undiagnosed type 2 diabetes at her first prenatal visit if she has certain risk factors.³ These include, but are not limited to, family history of diabetes, overweight/obesity, sedentary life­style, elevated blood pressure and/or cholesterol, impaired fasting glucose or impaired glucose tolerance, or certain ethnic backgrounds (eg, Hispanic, Native American, and non-Hispanic black).⁴ In 2011, the ADA revised its recommendations for GDM screening and diagnosis to be in accordance with those from the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an interna­tional consensus group with representatives from multiple obstetric and diabetes organizations, including ADA.

Q: How is GDM diagnosed?

Current recommendations stipulate that women with no previous history of diabetes or prediabetes undergo one-step testing: a 75-g glucose tolerance test (GTT) at 24 to 28 weeks’ gestation.^5,6 For women with a prior history of GDM, screening is recommended earlier in the pregnancy. The GTT should be performed after an overnight fast of at least eight hours.³ An elevation of any one of the values above normal reference range is consistent with the diagnosis of GDM. (Previously, the diagnostic criteria required two abnormal values.) Multiple international studies using the new criteria have estimated an increased incidence of gestational diabetes in up to 18% of pregnancies.^5,6

Some organizations have not endorsed the IADPSG/ADA diagnostic criteria at this time; as a result, many practitioners continue to use two-step testing for diagnosing GDM. To do the two-step testing, a 50-g glucose load is given, followed by a blood glucose reading one hour later. If the one-hour reading is within normal range, no further testing is warranted and the patient does not have gestational diabetes. If the test is abnormal, she must undergo a fasting three-hour GTT using a 100-g glucose load.

Q: What advice should a woman get once she’s diagnosed with GDM? 

As soon as a woman is diagnosed with GDM, she should be referred for a gestational diabetes education class and nutrition counseling. Specifically, she should learn what it means for her to have GDM, implications for her and her baby, and the importance of eating a healthy diet (not the proverbial concept of “eating for two”), physical activity, self-monitoring blood glucose, and adherence to any prescribed medications.

Probably the most important aspect of education is nutrition counseling. It is known that smaller meals consumed more frequently throughout the day reduce spikes in blood glucose levels. One suggestion is to eat three small meals and three low-carbohydrate (15 g) snacks each day. Meals and snacks are generally established based on fixed carbohydrate amounts. A certified diabetes educator or registered dietitian (RD) can recommend healthy meal and snack ideas that are tasty, promote satiety, and minimize spikes in glucose levels.

Q: What are the current treatment options for GDM?

During the process of receiving GDM education, the patient should be prescribed a glucometer, along with specific glucose targets. Blood glucose should be checked multiple times a day, preferably fasting and postprandial measurements. Medical practices vary in their preferred glucose targets; some individuals require tighter control than others. The ADA suggests the following targets:

• Before a meal (preprandial):
95 mg/dL or less.

 • One hour after a meal (postprandial): 140 mg/dL or less.

• Two hours after a meal (postprandial): 120 mg/dL or less. ⁷ 

If blood glucose levels remain within normal range, it is possible to control gestational diabetes with dietary modification and physical activity. If readings are consistently elevated, then the patient must be started on medication. There are currently no FDA-approved oral medications to treat gestational diabetes. Glyburide is commonly used, although it is not FDA approved for this indication. More studies to establish its safety are likely needed for FDA approval.⁸

If pharmaceutical treatment is warranted, insulin is the safest and most effective agent. It is the only medication that is FDA approved for treatment of GDM.  Levemir (insulin detemir [rDNA origin] injection) gained FDA approval for use in pregnancy in 2012, so it has become more widespread than NPH for basal insulin usage.⁹

Although it is usually managed by an endocrinologist or perinatologist, an experienced obstetrician could also manage GDM. Often, the patient is referred to an endocrinologist. The endocrine provider, along with the diabetes educator and RD, focus on nutrition counseling and diabetes management so the obstetrician can focus on maternal and fetal health. 

Q: What is the recommended follow-up?

Since embryonic and fetal development occurs at such a rapid rate, time is of the essence for getting a patient’s blood glucose to goal. While treating diabetes in general can be challenging, this is usually not the case with GDM. Most women with GDM are motivated to take care of themselves for the well-being of their developing baby. The influence of a baby developing inside a mother is so strong that diabetic women who become pregnant often take better care of themselves than they do when they are not pregnant.

The patient’s daily responsibilities should include eating a healthy and diet checking her blood glucose levels throughout the day. These readings must be recorded. Clinic visits should occur often, with emailing of glucose readings between visits as needed. The frequency of visits varies among practices, depending on the patient’s level of glucose control and intensity of the treatment regimen.

Q: Why is postpartum testing important?

After delivery, most cases of GDM usually resolve. However, approximately 5% to 10% of women with gestational diabetes are found to have diabetes immediately after pregnancy.² To evaluate for persistent diabetes, a two-hour GTT should be done at six weeks’ postpartum. Although an A1C can now be used to diagnose diabetes, the ADA does not recommend checking it for this purpose.³

If the two-hour GTT result is normal, a woman should be screened for diabetes every three years for the rest of her life.³ If a diagnosis of impaired fasting glucose or impaired glucose tolerance is made, then she should be tested for diabetes on an annual basis or in the interim if she develops classic symptoms of hyperglycemia.³ If diabetes is diagnosed, she should be treated accordingly as a type 2 diabetic patient.

At this time, the patient should be counseled on lifestyle interventions and consider starting metformin therapy if appropriate. Diabetes education classes are available for prediabetes. To maintain good health and prevent/delay onset of type 2 diabetes, here are some tips to follow: 

 • The same diet as during pregnancy does not have to be followed, although healthy eating habits are always a good idea.

• Physical activity (approximately 30 min five times a week) will help shed weight gained during pregnancy.

• Breastfeeding promotes weight loss.¹⁰

• Patients should aim for weight loss of 7% of body weight.³

• Continue annual physical exams, keeping an eye on blood pressure, weight, and cholesterol levels.

It’s reasonable for the patient to check glucose levels occasionally after delivery. If elevated readings occur, the patient can make an appointment with her primary care provider or endocrinologist.

References
1.  American Association for Clinical Chemistry. A New Definition of Gestational Diabetes. www.aacc.org/publications/cln/2010/may/Pages/CoverStory2May2010.aspx. Accessed June 30, 2013.

2. National Diabetes Statistics, 2011. www.diabetes.niddk.nih.gov/dm/pubs/statistics/#Gestational. Accessed July 22, 2013.

3. American Diabetes Association. 2012 Clinical Practice Recommendations. Diabetes Care. 2012;35(suppl 1). http://professional.diabetes.org/SlideLibrary/media/4839/ADA%20Standards%20of%20Medical%20Care%202012%20FINAL.ppt. Accessed June 24, 2013.

4. American Diabetes Association. Diabetes basics: your risk. www.diabetes.org/diabetes-basics/prevention/risk-factors. Accessed August 13, 2013.

5. American Diabetes Association. Diabetes Basics: What is Gestational Diabetes? www.diabetes.org/diabetes-basics/gestational/what-is-gestational-diabetes.html. Accessed August 13, 2013.

 6. Johnson K. New criteria for gestational diabetes increase diagnoses (December 5, 2011). www.medscape.com/viewarticle/754733. Accessed August 13, 2013.

 7. American Diabetes Association. Diabetes basics: how to treat gestational diabetes. www.diabetes.org/diabetes-basics/gestational/how-to-treat-gestational.html. Accessed August 13, 2013.

8. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30(suppl 2). http://care.diabetesjournals.org/content/30/Supplement_2/S209.full. Accessed August 13, 2013.

9. Lowes R. Levemir assigned more reassuring pregnancy risk category (April 2, 2012). www.medscape.com/viewarticle/761349. Accessed August 13, 2013.

10. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol. 2012;8(11):639-649.

ANSWER

The correct answer is alopecia areata (choice “d”), the causes of which are discussed below. It typically manifests with sudden-onset complete hair loss in a well-defined area or areas.

Androgenetic alopecia (choice “a”) is incorrect, since its onset is remarkably gradual and the areas it affects are patterned differently from those seen with alopecia areata.

Kerion (choice “b”) is the name of an edematous, inflamed mass in the scalp triggered by fungal infection (tinea capitis) and is almost always accompanied by broken skin and palpable lymph nodes in the area.

Lichen planopilaris (choice “c”) is lichen planus of the scalp and hair follicles, an inflammatory condition that can involve hair loss of variable size and shape, but not in the same well-defined pattern seen here.

DISCUSSION

There are dermatologists who specialize in diseases of the scalp, especially those resulting in hair loss. In addition to the differential diagnoses mentioned, they see conditions such as lupus, trichotillomania, and reactions to hair care products.

Alopecia areata (AA) seldom needs the attention of these specialists, except in atypical cases. The total hair loss in these well-defined, oval-to-round areas presents fairly acutely, with obviously excessive hair loss noted not only in the scalp but also in the comb, brush, or sink. Although AA is quite common (and thus well known to barbers and hairdressers), it is still often a total and very distressing mystery to the patient. Stress is one of the factors theorized to trigger it—but unfortunately, the more stressed the patient is about the hair loss, the worse it gets.

In the vast majority of cases, the condition resolves, the hair returns, and the grateful patient breathes a sigh of relief. Recurrences, however, are not at all uncommon. A tiny percentage of AA patients go on to lose all the hair in their scalp (alopecia totalis), and an even smaller percentage of those patients go on to lose every hair on their body, permanently (alopecia universalis).

Much has been reported about the cause, which appears to be autoimmune in nature, with an apparent hereditary predisposition. About 10% to 20% of affected patients have a positive family history of AA, and those with severe AA have a positive family history about 16% to 18% of the time.

The theory of an autoimmune basis is also strongly supported by the significantly increased incidence of other autoimmune diseases (especially thyroid disease and vitiligo) in AA patients and their families. But T-cells almost certainly play a role too: Reductions in their number are usually followed by resolution of AA, while increases have the opposite effect. Increased antibodies to various portions of the hair shaft and related structures have now been tied to AA episodes, but these may be epiphenomenal and not causative.

One constant is the perifollicular lymphocytic infiltrate surrounding anagen phase follicles of AA patients. When corticosteroids are administered (eg, by intralesional injection, orally, or systemically), it is this infiltrate that is thereby dissipated, promoting at least temporary hair regrowth. Topically applied steroid preparations are not as helpful, and no known treatment has a positive effect on the ultimate outcome.

Fortunately, most cases of AA resolve satisfactorily with minimal or no treatment. Numerous treatments have been tried for AA, including minoxidil, topical sensitizers (eg, squaric acid, di­ntrochlorobenzene), and several types of phototherapy. Studies of the efficacy of the various treatments is complicated by the self-limiting nature of the problem.

Predictors of potentially poor outcomes include youth, atopy, extent of involvement, and the presence of ophiasis, a term used to describe extensive involvement of the periphery of the scalp.

ANSWER

The correct answer is alopecia areata (choice “d”), the causes of which are discussed below. It typically manifests with sudden-onset complete hair loss in a well-defined area or areas.

Androgenetic alopecia (choice “a”) is incorrect, since its onset is remarkably gradual and the areas it affects are patterned differently from those seen with alopecia areata.

Kerion (choice “b”) is the name of an edematous, inflamed mass in the scalp triggered by fungal infection (tinea capitis) and is almost always accompanied by broken skin and palpable lymph nodes in the area.

Lichen planopilaris (choice “c”) is lichen planus of the scalp and hair follicles, an inflammatory condition that can involve hair loss of variable size and shape, but not in the same well-defined pattern seen here.

DISCUSSION

There are dermatologists who specialize in diseases of the scalp, especially those resulting in hair loss. In addition to the differential diagnoses mentioned, they see conditions such as lupus, trichotillomania, and reactions to hair care products.

Alopecia areata (AA) seldom needs the attention of these specialists, except in atypical cases. The total hair loss in these well-defined, oval-to-round areas presents fairly acutely, with obviously excessive hair loss noted not only in the scalp but also in the comb, brush, or sink. Although AA is quite common (and thus well known to barbers and hairdressers), it is still often a total and very distressing mystery to the patient. Stress is one of the factors theorized to trigger it—but unfortunately, the more stressed the patient is about the hair loss, the worse it gets.

In the vast majority of cases, the condition resolves, the hair returns, and the grateful patient breathes a sigh of relief. Recurrences, however, are not at all uncommon. A tiny percentage of AA patients go on to lose all the hair in their scalp (alopecia totalis), and an even smaller percentage of those patients go on to lose every hair on their body, permanently (alopecia universalis).

Much has been reported about the cause, which appears to be autoimmune in nature, with an apparent hereditary predisposition. About 10% to 20% of affected patients have a positive family history of AA, and those with severe AA have a positive family history about 16% to 18% of the time.

The theory of an autoimmune basis is also strongly supported by the significantly increased incidence of other autoimmune diseases (especially thyroid disease and vitiligo) in AA patients and their families. But T-cells almost certainly play a role too: Reductions in their number are usually followed by resolution of AA, while increases have the opposite effect. Increased antibodies to various portions of the hair shaft and related structures have now been tied to AA episodes, but these may be epiphenomenal and not causative.

One constant is the perifollicular lymphocytic infiltrate surrounding anagen phase follicles of AA patients. When corticosteroids are administered (eg, by intralesional injection, orally, or systemically), it is this infiltrate that is thereby dissipated, promoting at least temporary hair regrowth. Topically applied steroid preparations are not as helpful, and no known treatment has a positive effect on the ultimate outcome.

Fortunately, most cases of AA resolve satisfactorily with minimal or no treatment. Numerous treatments have been tried for AA, including minoxidil, topical sensitizers (eg, squaric acid, di­ntrochlorobenzene), and several types of phototherapy. Studies of the efficacy of the various treatments is complicated by the self-limiting nature of the problem.

Predictors of potentially poor outcomes include youth, atopy, extent of involvement, and the presence of ophiasis, a term used to describe extensive involvement of the periphery of the scalp.

ANSWER

The correct answer is alopecia areata (choice “d”), the causes of which are discussed below. It typically manifests with sudden-onset complete hair loss in a well-defined area or areas.

Androgenetic alopecia (choice “a”) is incorrect, since its onset is remarkably gradual and the areas it affects are patterned differently from those seen with alopecia areata.

Kerion (choice “b”) is the name of an edematous, inflamed mass in the scalp triggered by fungal infection (tinea capitis) and is almost always accompanied by broken skin and palpable lymph nodes in the area.

Lichen planopilaris (choice “c”) is lichen planus of the scalp and hair follicles, an inflammatory condition that can involve hair loss of variable size and shape, but not in the same well-defined pattern seen here.

DISCUSSION

There are dermatologists who specialize in diseases of the scalp, especially those resulting in hair loss. In addition to the differential diagnoses mentioned, they see conditions such as lupus, trichotillomania, and reactions to hair care products.

Alopecia areata (AA) seldom needs the attention of these specialists, except in atypical cases. The total hair loss in these well-defined, oval-to-round areas presents fairly acutely, with obviously excessive hair loss noted not only in the scalp but also in the comb, brush, or sink. Although AA is quite common (and thus well known to barbers and hairdressers), it is still often a total and very distressing mystery to the patient. Stress is one of the factors theorized to trigger it—but unfortunately, the more stressed the patient is about the hair loss, the worse it gets.

In the vast majority of cases, the condition resolves, the hair returns, and the grateful patient breathes a sigh of relief. Recurrences, however, are not at all uncommon. A tiny percentage of AA patients go on to lose all the hair in their scalp (alopecia totalis), and an even smaller percentage of those patients go on to lose every hair on their body, permanently (alopecia universalis).

Much has been reported about the cause, which appears to be autoimmune in nature, with an apparent hereditary predisposition. About 10% to 20% of affected patients have a positive family history of AA, and those with severe AA have a positive family history about 16% to 18% of the time.

The theory of an autoimmune basis is also strongly supported by the significantly increased incidence of other autoimmune diseases (especially thyroid disease and vitiligo) in AA patients and their families. But T-cells almost certainly play a role too: Reductions in their number are usually followed by resolution of AA, while increases have the opposite effect. Increased antibodies to various portions of the hair shaft and related structures have now been tied to AA episodes, but these may be epiphenomenal and not causative.

One constant is the perifollicular lymphocytic infiltrate surrounding anagen phase follicles of AA patients. When corticosteroids are administered (eg, by intralesional injection, orally, or systemically), it is this infiltrate that is thereby dissipated, promoting at least temporary hair regrowth. Topically applied steroid preparations are not as helpful, and no known treatment has a positive effect on the ultimate outcome.

Fortunately, most cases of AA resolve satisfactorily with minimal or no treatment. Numerous treatments have been tried for AA, including minoxidil, topical sensitizers (eg, squaric acid, di­ntrochlorobenzene), and several types of phototherapy. Studies of the efficacy of the various treatments is complicated by the self-limiting nature of the problem.

Predictors of potentially poor outcomes include youth, atopy, extent of involvement, and the presence of ophiasis, a term used to describe extensive involvement of the periphery of the scalp.