Reprocessing guidelines currently in place for clinical gastrointestinal endoscopes need to be reevaluated and updated as soon as possible, according to a study published in the American Journal of Infection Control (doi: 10.1016/j.ajic.2015.03.003).

Procedures that follow current guidelines do not fully decontaminate the colonoscopes and gastroscopes after they’re used for procedures, leaving behind microbe levels that are well above the accepted benchmark standards.

“Previous studies show that cleaning endoscope channels is laborious and time consuming, and technicians often skip steps,” wrote the study’s authors – led by Cori L. Ofstead, MSPH, of Ofstead & Associates, St. Paul, Minn. “This is concerning, given that the procedure-related risk of endoscopy may be higher than previously thought [and] without objective verification, clinicians can unknowingly use contaminated endoscopes for procedures.”

The study, conducted at the Mayo Clinic in Rochester, Minn., examined the use of 15 endoscopes involved in 60 separate procedures over the period of Nov. 4-8, 2013, to determine how each endoscope was treated after an operation and whether these cleaning procedures followed guidelines and effectively decontaminated the devices.

“Endoscope testing was performed in a dedicated room adjacent to the procedure room, which allowed for rapid sampling and testing [and] barrier separation [minimized] potential for environmental cross-contamination.” the authors explained.

They maintained aseptic environmental conditions while gathering data, using disinfectant wipes on surfaces, using disposable absorbent pads, and restricting room access.

The researchers wore gloves, impervious gowns, face masks with splash protection, hair nets, and shoe covers; the gloves were changed between each sample collection, and gowns were changed between endoscope collections.

Microbial cultures and rapid indicator tests were conducted for ATP, protein, hemoglobin, and carbohydrate residue. Viable microbe samples were collected from 92% of bedside-cleaned endoscopes, 46% of manually cleaned endoscopes, 64% of “high-level disinfected” endoscopes, and 9% of stored endoscopes. Results from rapid indicator tests showed that some form of contamination was present on 100% of bedside-cleaned endoscopes, 92% of manually cleaned endoscopes, 73% of high-level disinfected endoscopes, and 82% of stored endoscopes which had viable microbes.

“Current guidelines rely on visual inspection to verify cleaning [but] visible contamination was never present, potentially because blood and feces may be difficult to discern from endoscopes’ black exteriors, and microscopic organisms cannot be seen by the naked eye,” the researchers wrote.

Consequently, Ms. Ofstead and colleagues called for a reexamination of current guidelines to move away from the eyeball test, saying that the results found here should pave the way for future studies to devise methods of more effectively cleaning and disinfecting endoscopes in a shorter amount of time.

“In the meantime, methods to ensure effectiveness of reprocessing practices are needed, including the potential use of routine monitoring with rapid indicators and microbiologic cultures,” they suggested.

Ms. Ofstead is president and CEO of Ofstead & Associates, which has received research funding and speaking honoraria related to endoscopic procedures from 3M, Advanced Sterilization Products, Medivators, Invendo Medical, Boston Scientific, and Steris. Three coauthors are employed by Ofstead & Associates, but have no other disclosures to report. The remaining coauthors had no disclosures to report. Funding was provided by 3M, Mayo Clinic, and Ofstead & Associates.

[email protected]

Reprocessing guidelines currently in place for clinical gastrointestinal endoscopes need to be reevaluated and updated as soon as possible, according to a study published in the American Journal of Infection Control (doi: 10.1016/j.ajic.2015.03.003).

Procedures that follow current guidelines do not fully decontaminate the colonoscopes and gastroscopes after they’re used for procedures, leaving behind microbe levels that are well above the accepted benchmark standards.

“Previous studies show that cleaning endoscope channels is laborious and time consuming, and technicians often skip steps,” wrote the study’s authors – led by Cori L. Ofstead, MSPH, of Ofstead & Associates, St. Paul, Minn. “This is concerning, given that the procedure-related risk of endoscopy may be higher than previously thought [and] without objective verification, clinicians can unknowingly use contaminated endoscopes for procedures.”

The study, conducted at the Mayo Clinic in Rochester, Minn., examined the use of 15 endoscopes involved in 60 separate procedures over the period of Nov. 4-8, 2013, to determine how each endoscope was treated after an operation and whether these cleaning procedures followed guidelines and effectively decontaminated the devices.

“Endoscope testing was performed in a dedicated room adjacent to the procedure room, which allowed for rapid sampling and testing [and] barrier separation [minimized] potential for environmental cross-contamination.” the authors explained.

They maintained aseptic environmental conditions while gathering data, using disinfectant wipes on surfaces, using disposable absorbent pads, and restricting room access.

The researchers wore gloves, impervious gowns, face masks with splash protection, hair nets, and shoe covers; the gloves were changed between each sample collection, and gowns were changed between endoscope collections.

Microbial cultures and rapid indicator tests were conducted for ATP, protein, hemoglobin, and carbohydrate residue. Viable microbe samples were collected from 92% of bedside-cleaned endoscopes, 46% of manually cleaned endoscopes, 64% of “high-level disinfected” endoscopes, and 9% of stored endoscopes. Results from rapid indicator tests showed that some form of contamination was present on 100% of bedside-cleaned endoscopes, 92% of manually cleaned endoscopes, 73% of high-level disinfected endoscopes, and 82% of stored endoscopes which had viable microbes.

“Current guidelines rely on visual inspection to verify cleaning [but] visible contamination was never present, potentially because blood and feces may be difficult to discern from endoscopes’ black exteriors, and microscopic organisms cannot be seen by the naked eye,” the researchers wrote.

Consequently, Ms. Ofstead and colleagues called for a reexamination of current guidelines to move away from the eyeball test, saying that the results found here should pave the way for future studies to devise methods of more effectively cleaning and disinfecting endoscopes in a shorter amount of time.

“In the meantime, methods to ensure effectiveness of reprocessing practices are needed, including the potential use of routine monitoring with rapid indicators and microbiologic cultures,” they suggested.

Ms. Ofstead is president and CEO of Ofstead & Associates, which has received research funding and speaking honoraria related to endoscopic procedures from 3M, Advanced Sterilization Products, Medivators, Invendo Medical, Boston Scientific, and Steris. Three coauthors are employed by Ofstead & Associates, but have no other disclosures to report. The remaining coauthors had no disclosures to report. Funding was provided by 3M, Mayo Clinic, and Ofstead & Associates.

[email protected]

Reprocessing guidelines currently in place for clinical gastrointestinal endoscopes need to be reevaluated and updated as soon as possible, according to a study published in the American Journal of Infection Control (doi: 10.1016/j.ajic.2015.03.003).

Procedures that follow current guidelines do not fully decontaminate the colonoscopes and gastroscopes after they’re used for procedures, leaving behind microbe levels that are well above the accepted benchmark standards.

“Previous studies show that cleaning endoscope channels is laborious and time consuming, and technicians often skip steps,” wrote the study’s authors – led by Cori L. Ofstead, MSPH, of Ofstead & Associates, St. Paul, Minn. “This is concerning, given that the procedure-related risk of endoscopy may be higher than previously thought [and] without objective verification, clinicians can unknowingly use contaminated endoscopes for procedures.”

The study, conducted at the Mayo Clinic in Rochester, Minn., examined the use of 15 endoscopes involved in 60 separate procedures over the period of Nov. 4-8, 2013, to determine how each endoscope was treated after an operation and whether these cleaning procedures followed guidelines and effectively decontaminated the devices.

“Endoscope testing was performed in a dedicated room adjacent to the procedure room, which allowed for rapid sampling and testing [and] barrier separation [minimized] potential for environmental cross-contamination.” the authors explained.

They maintained aseptic environmental conditions while gathering data, using disinfectant wipes on surfaces, using disposable absorbent pads, and restricting room access.

The researchers wore gloves, impervious gowns, face masks with splash protection, hair nets, and shoe covers; the gloves were changed between each sample collection, and gowns were changed between endoscope collections.

Microbial cultures and rapid indicator tests were conducted for ATP, protein, hemoglobin, and carbohydrate residue. Viable microbe samples were collected from 92% of bedside-cleaned endoscopes, 46% of manually cleaned endoscopes, 64% of “high-level disinfected” endoscopes, and 9% of stored endoscopes. Results from rapid indicator tests showed that some form of contamination was present on 100% of bedside-cleaned endoscopes, 92% of manually cleaned endoscopes, 73% of high-level disinfected endoscopes, and 82% of stored endoscopes which had viable microbes.

“Current guidelines rely on visual inspection to verify cleaning [but] visible contamination was never present, potentially because blood and feces may be difficult to discern from endoscopes’ black exteriors, and microscopic organisms cannot be seen by the naked eye,” the researchers wrote.

Consequently, Ms. Ofstead and colleagues called for a reexamination of current guidelines to move away from the eyeball test, saying that the results found here should pave the way for future studies to devise methods of more effectively cleaning and disinfecting endoscopes in a shorter amount of time.

“In the meantime, methods to ensure effectiveness of reprocessing practices are needed, including the potential use of routine monitoring with rapid indicators and microbiologic cultures,” they suggested.

Ms. Ofstead is president and CEO of Ofstead & Associates, which has received research funding and speaking honoraria related to endoscopic procedures from 3M, Advanced Sterilization Products, Medivators, Invendo Medical, Boston Scientific, and Steris. Three coauthors are employed by Ofstead & Associates, but have no other disclosures to report. The remaining coauthors had no disclosures to report. Funding was provided by 3M, Mayo Clinic, and Ofstead & Associates.

[email protected]

The first intragastric balloon–based device designed to help obese people lose weight has been approved by the Food and Drug Administration, providing a treatment option that is less invasive than bariatric surgery and gastric banding.

The FDA approved the ReShape Integrated Dual Balloon System on July 28, for “weight reduction when used in conjunction with diet and exercise, in obese patients with a body mass index (BMI) of 30-40 kg/m² and one or more obesity-related comorbid conditions,” in adults who have not been able to lose weight with diet and exercise alone, according to the agency’s approval letter. Laparoscopic gastric banding is indicated for patients with a BMI of at least 40 kg/m² (or at least 30 kg/m² in people with one or more obesity-related comorbidities) and bariatric surgery is usually recommended for patients with a BMI of at least 40 kg/m² (or at least 35 kg/m² in people with at least one obesity-related comorbidity).

Courtesy ReShape Medical

The ReShape device is made up of two attached balloons that are placed in the stomach through a minimally invasive endoscopic procedure, where they are filled with about 2 cups of saline and methylene blue dye, under mild sedation; the balloons are sealed with mineral oil and left in place for up to 6 months. If a balloon ruptures, the dye appears in the urine. When it is time to remove the balloons, they are deflated then removed using another endoscopic procedure.

The device was evaluated in a pivotal study at eight U.S. sites of over 300 mostly female obese patients whose mean age was about 44 years; their mean weight was about 209-213 pounds, and their mean BMI was about 35 kg/m²; 187 received the device and 139 had the endoscopy only. All participants were on a medically managed diet and exercise program. At 6 months, those in the device group had lost a mean of about 24% of their weight, vs. a mean of about 11% among controls, a statistically significant difference (P = .0041). Those who had lost weight at 6 months “maintained 60% of this weight loss through 48 weeks of follow-up,” according to the FDA.

After placement of the device, common adverse events were vomiting, nausea, and abdominal pain, but most symptoms resolved within 30 days, according to the FDA. The development of gastric ulcerations is described as the “most worrisome” device-related risk, but “there were no unanticipated adverse device effects, no deaths, no intestinal obstructions, and no gastric perforations” in the study.

Among the 265 patients who received the device (those initially enrolled in the pivotal trial plus 78 who were in the control group and opted to receive the device after the first 6 months), 20 (7.5%) experienced severe adverse events; vomiting was the most common, in 4.5%. Serious events included gastric ulcers in two patients (0.8%) at 19 and at 97 days after the device was placed; in both cases, the device was removed. Almost 15% of those who received the device had to have it removed because of an adverse event. The rate of gastric ulcers after a minor change was made to the device was 10%; and the rate of balloon deflations without migration was 6%.

The FDA summary of the approval refers to the “marginal benefit of weight loss” among those in the treatment group, compared with controls, but adds that the decision to approve the device “is based in part on the limited options available to patients with mild to moderate obesity who have failed other means for conservative weight loss.”

While the effectiveness of the device is better than what would be expected with diet and exercise or pharmacologic therapy,” it is “substantially less than what would be expected with gastric banding or other surgical interventions.” The list of contraindications includes previous gastrointestinal surgery “with sequelae,” such as an obstruction or adhesions; previous bariatric surgery; any GI inflammatory disease, severe coagulopathy; and women who are pregnant or breastfeeding.

“The company plans to make the ReShape procedure available to patients first in select markets, as physicians and allied health professionals are trained in the procedure and support program to optimize patient outcome,” according to the company’s statement announcing approval.

The ReShape device has been available in Europe since 2007.

Information posted by the FDA, including labeling for professionals, is available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/pma/pma.cfm?num=P140012.

The AGA Center for GI Innovation and Technology is committed to supporting the development of new devices and their introduction to the market in a safe and efficient manner. The center has been working with the FDA for the past several years to help the agency determine how to assess obesity devices.

“It is gratifying to see that the FDA continues to facilitate technologies to address significant public health concerns,” said chair of the center, Dr. Michael L. Kochman, FACP, AGAF. “The AGA Center for GI Innovation and Technology’s obesity-focused meeting, held in conjunction with the FDA, and the annual AGA Tech Summits have helped inform the discussion surrounding the new and novel devices in the obesity and metabolism space.”

[email protected]

The first intragastric balloon–based device designed to help obese people lose weight has been approved by the Food and Drug Administration, providing a treatment option that is less invasive than bariatric surgery and gastric banding.

The FDA approved the ReShape Integrated Dual Balloon System on July 28, for “weight reduction when used in conjunction with diet and exercise, in obese patients with a body mass index (BMI) of 30-40 kg/m² and one or more obesity-related comorbid conditions,” in adults who have not been able to lose weight with diet and exercise alone, according to the agency’s approval letter. Laparoscopic gastric banding is indicated for patients with a BMI of at least 40 kg/m² (or at least 30 kg/m² in people with one or more obesity-related comorbidities) and bariatric surgery is usually recommended for patients with a BMI of at least 40 kg/m² (or at least 35 kg/m² in people with at least one obesity-related comorbidity).

Courtesy ReShape Medical

The ReShape device is made up of two attached balloons that are placed in the stomach through a minimally invasive endoscopic procedure, where they are filled with about 2 cups of saline and methylene blue dye, under mild sedation; the balloons are sealed with mineral oil and left in place for up to 6 months. If a balloon ruptures, the dye appears in the urine. When it is time to remove the balloons, they are deflated then removed using another endoscopic procedure.

The device was evaluated in a pivotal study at eight U.S. sites of over 300 mostly female obese patients whose mean age was about 44 years; their mean weight was about 209-213 pounds, and their mean BMI was about 35 kg/m²; 187 received the device and 139 had the endoscopy only. All participants were on a medically managed diet and exercise program. At 6 months, those in the device group had lost a mean of about 24% of their weight, vs. a mean of about 11% among controls, a statistically significant difference (P = .0041). Those who had lost weight at 6 months “maintained 60% of this weight loss through 48 weeks of follow-up,” according to the FDA.

After placement of the device, common adverse events were vomiting, nausea, and abdominal pain, but most symptoms resolved within 30 days, according to the FDA. The development of gastric ulcerations is described as the “most worrisome” device-related risk, but “there were no unanticipated adverse device effects, no deaths, no intestinal obstructions, and no gastric perforations” in the study.

Among the 265 patients who received the device (those initially enrolled in the pivotal trial plus 78 who were in the control group and opted to receive the device after the first 6 months), 20 (7.5%) experienced severe adverse events; vomiting was the most common, in 4.5%. Serious events included gastric ulcers in two patients (0.8%) at 19 and at 97 days after the device was placed; in both cases, the device was removed. Almost 15% of those who received the device had to have it removed because of an adverse event. The rate of gastric ulcers after a minor change was made to the device was 10%; and the rate of balloon deflations without migration was 6%.

The FDA summary of the approval refers to the “marginal benefit of weight loss” among those in the treatment group, compared with controls, but adds that the decision to approve the device “is based in part on the limited options available to patients with mild to moderate obesity who have failed other means for conservative weight loss.”

While the effectiveness of the device is better than what would be expected with diet and exercise or pharmacologic therapy,” it is “substantially less than what would be expected with gastric banding or other surgical interventions.” The list of contraindications includes previous gastrointestinal surgery “with sequelae,” such as an obstruction or adhesions; previous bariatric surgery; any GI inflammatory disease, severe coagulopathy; and women who are pregnant or breastfeeding.

“The company plans to make the ReShape procedure available to patients first in select markets, as physicians and allied health professionals are trained in the procedure and support program to optimize patient outcome,” according to the company’s statement announcing approval.

The ReShape device has been available in Europe since 2007.

Information posted by the FDA, including labeling for professionals, is available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/pma/pma.cfm?num=P140012.

The AGA Center for GI Innovation and Technology is committed to supporting the development of new devices and their introduction to the market in a safe and efficient manner. The center has been working with the FDA for the past several years to help the agency determine how to assess obesity devices.

“It is gratifying to see that the FDA continues to facilitate technologies to address significant public health concerns,” said chair of the center, Dr. Michael L. Kochman, FACP, AGAF. “The AGA Center for GI Innovation and Technology’s obesity-focused meeting, held in conjunction with the FDA, and the annual AGA Tech Summits have helped inform the discussion surrounding the new and novel devices in the obesity and metabolism space.”

[email protected]

The first intragastric balloon–based device designed to help obese people lose weight has been approved by the Food and Drug Administration, providing a treatment option that is less invasive than bariatric surgery and gastric banding.

The FDA approved the ReShape Integrated Dual Balloon System on July 28, for “weight reduction when used in conjunction with diet and exercise, in obese patients with a body mass index (BMI) of 30-40 kg/m² and one or more obesity-related comorbid conditions,” in adults who have not been able to lose weight with diet and exercise alone, according to the agency’s approval letter. Laparoscopic gastric banding is indicated for patients with a BMI of at least 40 kg/m² (or at least 30 kg/m² in people with one or more obesity-related comorbidities) and bariatric surgery is usually recommended for patients with a BMI of at least 40 kg/m² (or at least 35 kg/m² in people with at least one obesity-related comorbidity).

Courtesy ReShape Medical

The ReShape device is made up of two attached balloons that are placed in the stomach through a minimally invasive endoscopic procedure, where they are filled with about 2 cups of saline and methylene blue dye, under mild sedation; the balloons are sealed with mineral oil and left in place for up to 6 months. If a balloon ruptures, the dye appears in the urine. When it is time to remove the balloons, they are deflated then removed using another endoscopic procedure.

The device was evaluated in a pivotal study at eight U.S. sites of over 300 mostly female obese patients whose mean age was about 44 years; their mean weight was about 209-213 pounds, and their mean BMI was about 35 kg/m²; 187 received the device and 139 had the endoscopy only. All participants were on a medically managed diet and exercise program. At 6 months, those in the device group had lost a mean of about 24% of their weight, vs. a mean of about 11% among controls, a statistically significant difference (P = .0041). Those who had lost weight at 6 months “maintained 60% of this weight loss through 48 weeks of follow-up,” according to the FDA.

After placement of the device, common adverse events were vomiting, nausea, and abdominal pain, but most symptoms resolved within 30 days, according to the FDA. The development of gastric ulcerations is described as the “most worrisome” device-related risk, but “there were no unanticipated adverse device effects, no deaths, no intestinal obstructions, and no gastric perforations” in the study.

Among the 265 patients who received the device (those initially enrolled in the pivotal trial plus 78 who were in the control group and opted to receive the device after the first 6 months), 20 (7.5%) experienced severe adverse events; vomiting was the most common, in 4.5%. Serious events included gastric ulcers in two patients (0.8%) at 19 and at 97 days after the device was placed; in both cases, the device was removed. Almost 15% of those who received the device had to have it removed because of an adverse event. The rate of gastric ulcers after a minor change was made to the device was 10%; and the rate of balloon deflations without migration was 6%.

The FDA summary of the approval refers to the “marginal benefit of weight loss” among those in the treatment group, compared with controls, but adds that the decision to approve the device “is based in part on the limited options available to patients with mild to moderate obesity who have failed other means for conservative weight loss.”

While the effectiveness of the device is better than what would be expected with diet and exercise or pharmacologic therapy,” it is “substantially less than what would be expected with gastric banding or other surgical interventions.” The list of contraindications includes previous gastrointestinal surgery “with sequelae,” such as an obstruction or adhesions; previous bariatric surgery; any GI inflammatory disease, severe coagulopathy; and women who are pregnant or breastfeeding.

“The company plans to make the ReShape procedure available to patients first in select markets, as physicians and allied health professionals are trained in the procedure and support program to optimize patient outcome,” according to the company’s statement announcing approval.

The ReShape device has been available in Europe since 2007.

Information posted by the FDA, including labeling for professionals, is available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/pma/pma.cfm?num=P140012.

The AGA Center for GI Innovation and Technology is committed to supporting the development of new devices and their introduction to the market in a safe and efficient manner. The center has been working with the FDA for the past several years to help the agency determine how to assess obesity devices.

“It is gratifying to see that the FDA continues to facilitate technologies to address significant public health concerns,” said chair of the center, Dr. Michael L. Kochman, FACP, AGAF. “The AGA Center for GI Innovation and Technology’s obesity-focused meeting, held in conjunction with the FDA, and the annual AGA Tech Summits have helped inform the discussion surrounding the new and novel devices in the obesity and metabolism space.”

[email protected]

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

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

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

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

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

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

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

Bone marrow harvest

Photo by Chad McNeeley

Asking bone marrow donors about their grandparents’ ancestry may help match donors to the appropriate recipients, according to research published in PLOS ONE.

Investigators found that when donors were self-reporting their race/ethnicity and included information on their grandparents’ ancestry, their responses often matched their genetics better than when they simply selected from standard race/ethnicity categories.

The investigators said these results show that more research is needed to refine methods for collecting and interpreting information on race/ethnicity for medical purposes.

“In medicine, we’ve been under the assumption that it’s just a matter of presenting people with the right check boxes,” said Jill Hollenbach, PhD, of the University of California, San Francisco. “It turns out that it’s much more complex than that.”

She and her colleagues noted that identifying a 10/10 human leukocyte antigen (HLA) match in the National Marrow Donor Program’s Be The Match Registry can be difficult because most of the donors submitted samples at a time when genotyping was much less advanced than it is today.

To find likely matches to pursue, the registry uses bioinformatics to weed out the donors unlikely to have matching HLA genes. Although HLA genes are highly variable, certain variations are found at higher frequencies in some regions of the world than others.

A patient with geographic ancestry in East Asia, for example, is more likely to have the same HLA variation as someone with origins in East Asia, rather than someone with European ancestry.

To obtain such information, most medical facilities use the patients’ race/ethnicity self-identification as a proxy. This can be challenging for people who trace their ancestry to multiple origins.

“The United States census uses a “check all that apply” technique, which is OK, but we want to try to get a little more refined to improve our matching efficiency,” said study author Martin Maiers, director of Bioinformatics Research at the Be The Match Registry.

To assess the extent to which different means of self-identification correspond to genetic ancestry, the investigators recruited 1752 potential donors from the Be The Match Registry.

The team sent participants a questionnaire with multiple measures of self-identification, including race/ethnicity and geographic ancestry, and asked participants to assign geographic ancestry to their grandparents. Participants also submitted cheek swabs as DNA samples.

By analyzing the cheek swabs, the investigators genotyped 93 ancestry informative markers to identify the participants’ genetic ancestry. This revealed a strong correlation between the ancestry markers and HLA genes.

Unfortunately, no measure of self-identification showed complete correspondence with a donor’s genetic ancestry. However, information about the geographic origins of the donors’ grandparents corresponded most closely with genetics, particularly for participants with ancestry from multiple continents.

“The conventional wisdom of the last decade or two has been that race is a social construct,” Dr Hollenbach said. “That’s true, but race is also part of the language of self-identification in [the US]. Let’s understand how these different forms of self-identification and genetic ancestry intersect to improve transplant matching for people of all ancestral backgrounds.”

Bone marrow harvest

Photo by Chad McNeeley

Asking bone marrow donors about their grandparents’ ancestry may help match donors to the appropriate recipients, according to research published in PLOS ONE.

Investigators found that when donors were self-reporting their race/ethnicity and included information on their grandparents’ ancestry, their responses often matched their genetics better than when they simply selected from standard race/ethnicity categories.

The investigators said these results show that more research is needed to refine methods for collecting and interpreting information on race/ethnicity for medical purposes.

“In medicine, we’ve been under the assumption that it’s just a matter of presenting people with the right check boxes,” said Jill Hollenbach, PhD, of the University of California, San Francisco. “It turns out that it’s much more complex than that.”

She and her colleagues noted that identifying a 10/10 human leukocyte antigen (HLA) match in the National Marrow Donor Program’s Be The Match Registry can be difficult because most of the donors submitted samples at a time when genotyping was much less advanced than it is today.

To find likely matches to pursue, the registry uses bioinformatics to weed out the donors unlikely to have matching HLA genes. Although HLA genes are highly variable, certain variations are found at higher frequencies in some regions of the world than others.

A patient with geographic ancestry in East Asia, for example, is more likely to have the same HLA variation as someone with origins in East Asia, rather than someone with European ancestry.

To obtain such information, most medical facilities use the patients’ race/ethnicity self-identification as a proxy. This can be challenging for people who trace their ancestry to multiple origins.

“The United States census uses a “check all that apply” technique, which is OK, but we want to try to get a little more refined to improve our matching efficiency,” said study author Martin Maiers, director of Bioinformatics Research at the Be The Match Registry.

To assess the extent to which different means of self-identification correspond to genetic ancestry, the investigators recruited 1752 potential donors from the Be The Match Registry.

The team sent participants a questionnaire with multiple measures of self-identification, including race/ethnicity and geographic ancestry, and asked participants to assign geographic ancestry to their grandparents. Participants also submitted cheek swabs as DNA samples.

By analyzing the cheek swabs, the investigators genotyped 93 ancestry informative markers to identify the participants’ genetic ancestry. This revealed a strong correlation between the ancestry markers and HLA genes.

Unfortunately, no measure of self-identification showed complete correspondence with a donor’s genetic ancestry. However, information about the geographic origins of the donors’ grandparents corresponded most closely with genetics, particularly for participants with ancestry from multiple continents.

“The conventional wisdom of the last decade or two has been that race is a social construct,” Dr Hollenbach said. “That’s true, but race is also part of the language of self-identification in [the US]. Let’s understand how these different forms of self-identification and genetic ancestry intersect to improve transplant matching for people of all ancestral backgrounds.”

Bone marrow harvest

Photo by Chad McNeeley

Asking bone marrow donors about their grandparents’ ancestry may help match donors to the appropriate recipients, according to research published in PLOS ONE.

Investigators found that when donors were self-reporting their race/ethnicity and included information on their grandparents’ ancestry, their responses often matched their genetics better than when they simply selected from standard race/ethnicity categories.

The investigators said these results show that more research is needed to refine methods for collecting and interpreting information on race/ethnicity for medical purposes.

“In medicine, we’ve been under the assumption that it’s just a matter of presenting people with the right check boxes,” said Jill Hollenbach, PhD, of the University of California, San Francisco. “It turns out that it’s much more complex than that.”

She and her colleagues noted that identifying a 10/10 human leukocyte antigen (HLA) match in the National Marrow Donor Program’s Be The Match Registry can be difficult because most of the donors submitted samples at a time when genotyping was much less advanced than it is today.

To find likely matches to pursue, the registry uses bioinformatics to weed out the donors unlikely to have matching HLA genes. Although HLA genes are highly variable, certain variations are found at higher frequencies in some regions of the world than others.

A patient with geographic ancestry in East Asia, for example, is more likely to have the same HLA variation as someone with origins in East Asia, rather than someone with European ancestry.

To obtain such information, most medical facilities use the patients’ race/ethnicity self-identification as a proxy. This can be challenging for people who trace their ancestry to multiple origins.

“The United States census uses a “check all that apply” technique, which is OK, but we want to try to get a little more refined to improve our matching efficiency,” said study author Martin Maiers, director of Bioinformatics Research at the Be The Match Registry.

To assess the extent to which different means of self-identification correspond to genetic ancestry, the investigators recruited 1752 potential donors from the Be The Match Registry.

The team sent participants a questionnaire with multiple measures of self-identification, including race/ethnicity and geographic ancestry, and asked participants to assign geographic ancestry to their grandparents. Participants also submitted cheek swabs as DNA samples.

By analyzing the cheek swabs, the investigators genotyped 93 ancestry informative markers to identify the participants’ genetic ancestry. This revealed a strong correlation between the ancestry markers and HLA genes.

Unfortunately, no measure of self-identification showed complete correspondence with a donor’s genetic ancestry. However, information about the geographic origins of the donors’ grandparents corresponded most closely with genetics, particularly for participants with ancestry from multiple continents.

“The conventional wisdom of the last decade or two has been that race is a social construct,” Dr Hollenbach said. “That’s true, but race is also part of the language of self-identification in [the US]. Let’s understand how these different forms of self-identification and genetic ancestry intersect to improve transplant matching for people of all ancestral backgrounds.”

Red blood cells positive

for Staphylococcus infection

Photo by Bill Branson

Last year, researchers reported promising preclinical results with a device that can treat sepsis by mimicking the human spleen. The device filtered pathogens and toxins from the blood by passing it through a dialysis-like circuit.

Now, the researchers have developed a new, more streamlined device that, they believe, is more likely to translate to the clinic. The new device also synergizes with conventional antibiotic therapies.

The team described this device in Biomaterials.

“The inflammatory cascade that leads to sepsis is triggered by pathogens and, specifically, by the toxins they release,” said study author Donald Ingber, MD, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Cambridge, Massachusetts.

“Thus, the most effective strategy is to treat with the best antibiotics you can muster, while also removing the toxins and remaining pathogens from the patient’s blood as quickly as possible.”

How the device works

The researchers say their new blood-cleansing approach can be completed quickly, without even identifying the infectious agent. This is because the device uses a proprietary pathogen-capturing agent, known as FcMBL, that binds all types of live and dead infectious microbes, including bacteria, fungi, viruses, and the toxins they release.

FcMBL is a genetically engineered blood protein inspired by a naturally occurring human molecule called mannose binding lectin (MBL). MBL is found in the innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen.

The researchers’ original device concept was similar to how a dialysis machine works. Infected blood in an animal, or potentially one day in a patient, is flowed from one vein through catheters to the device.

There, FcMBL-coated magnetic beads are added to the blood, and the bead-bound pathogens are extracted from the circulating blood by magnets within the device before the cleansed blood is returned to the body through another vein.

The new device removes the complexity, regulatory challenges, and cost associated with the magnetic beads and microfluidic architecture of its predecessor. But it still uses the FcMBL protein to bind to pathogens and toxins.

The new system uses hollow fiber filters similar to those currently used in hemodialysis, but the inner walls of these filters are coated with FcMBL protein to remove pathogens from circulating blood.

Test results

In in vitro tests with human blood, the device reduced the number of Gram-negative bacteria (Escherichia coli), Gram-positive bacteria (Staphylococcus aureus), fungi (Candida albicans), and lipopolysaccharide-endotoxins by 90% to 99%.

In tests with rats, the device reduced levels of circulating pathogens and endotoxins by more than 99%, and it prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver, and kidney.

The researchers also tested the device in combination with bacteriocidal antibiotics in rats. The antibiotics prompted a “major increase” in the release of microbial fragments, or pathogen-associated molecular patterns (PAMPs).

The device could remove PAMPs from the blood within 2 hours, but high levels of PAMPs remained in rats treated with antibiotics alone.

The researchers said PAMP removal reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs.

“Using the device, alone or alongside antibiotics, we can quickly bring blood back to normal conditions, curtailing an inflammatory response rather than exacerbating it,” said Tohid Fatanat Didar, PhD, of the Wyss Institute.

“If all goes well, physicians will someday be able to use the device in tandem with standard antibiotic treatments to deliver a one-two punch to pathogens, synergistically killing and cleansing all live and dead invaders from the bloodstream.”

As the device has proven effective in small animal experiments, the researchers are planning to move to large animal studies. They must demonstrate proof-of-concept in these models before advancing to clinical trials.

“Our goal is to see this move out of the lab and into hospitals, as well as onto the battlefield,” Dr Ingber said, “where it can save lives within years rather than decades.”

Red blood cells positive

for Staphylococcus infection

Photo by Bill Branson

Last year, researchers reported promising preclinical results with a device that can treat sepsis by mimicking the human spleen. The device filtered pathogens and toxins from the blood by passing it through a dialysis-like circuit.

Now, the researchers have developed a new, more streamlined device that, they believe, is more likely to translate to the clinic. The new device also synergizes with conventional antibiotic therapies.

The team described this device in Biomaterials.

“The inflammatory cascade that leads to sepsis is triggered by pathogens and, specifically, by the toxins they release,” said study author Donald Ingber, MD, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Cambridge, Massachusetts.

“Thus, the most effective strategy is to treat with the best antibiotics you can muster, while also removing the toxins and remaining pathogens from the patient’s blood as quickly as possible.”

How the device works

The researchers say their new blood-cleansing approach can be completed quickly, without even identifying the infectious agent. This is because the device uses a proprietary pathogen-capturing agent, known as FcMBL, that binds all types of live and dead infectious microbes, including bacteria, fungi, viruses, and the toxins they release.

FcMBL is a genetically engineered blood protein inspired by a naturally occurring human molecule called mannose binding lectin (MBL). MBL is found in the innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen.

The researchers’ original device concept was similar to how a dialysis machine works. Infected blood in an animal, or potentially one day in a patient, is flowed from one vein through catheters to the device.

There, FcMBL-coated magnetic beads are added to the blood, and the bead-bound pathogens are extracted from the circulating blood by magnets within the device before the cleansed blood is returned to the body through another vein.

The new device removes the complexity, regulatory challenges, and cost associated with the magnetic beads and microfluidic architecture of its predecessor. But it still uses the FcMBL protein to bind to pathogens and toxins.

The new system uses hollow fiber filters similar to those currently used in hemodialysis, but the inner walls of these filters are coated with FcMBL protein to remove pathogens from circulating blood.

Test results

In in vitro tests with human blood, the device reduced the number of Gram-negative bacteria (Escherichia coli), Gram-positive bacteria (Staphylococcus aureus), fungi (Candida albicans), and lipopolysaccharide-endotoxins by 90% to 99%.

In tests with rats, the device reduced levels of circulating pathogens and endotoxins by more than 99%, and it prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver, and kidney.

The researchers also tested the device in combination with bacteriocidal antibiotics in rats. The antibiotics prompted a “major increase” in the release of microbial fragments, or pathogen-associated molecular patterns (PAMPs).

The device could remove PAMPs from the blood within 2 hours, but high levels of PAMPs remained in rats treated with antibiotics alone.

The researchers said PAMP removal reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs.

“Using the device, alone or alongside antibiotics, we can quickly bring blood back to normal conditions, curtailing an inflammatory response rather than exacerbating it,” said Tohid Fatanat Didar, PhD, of the Wyss Institute.

“If all goes well, physicians will someday be able to use the device in tandem with standard antibiotic treatments to deliver a one-two punch to pathogens, synergistically killing and cleansing all live and dead invaders from the bloodstream.”

As the device has proven effective in small animal experiments, the researchers are planning to move to large animal studies. They must demonstrate proof-of-concept in these models before advancing to clinical trials.

“Our goal is to see this move out of the lab and into hospitals, as well as onto the battlefield,” Dr Ingber said, “where it can save lives within years rather than decades.”

Red blood cells positive

for Staphylococcus infection

Photo by Bill Branson

Last year, researchers reported promising preclinical results with a device that can treat sepsis by mimicking the human spleen. The device filtered pathogens and toxins from the blood by passing it through a dialysis-like circuit.

Now, the researchers have developed a new, more streamlined device that, they believe, is more likely to translate to the clinic. The new device also synergizes with conventional antibiotic therapies.

The team described this device in Biomaterials.

“The inflammatory cascade that leads to sepsis is triggered by pathogens and, specifically, by the toxins they release,” said study author Donald Ingber, MD, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Cambridge, Massachusetts.

“Thus, the most effective strategy is to treat with the best antibiotics you can muster, while also removing the toxins and remaining pathogens from the patient’s blood as quickly as possible.”

How the device works

The researchers say their new blood-cleansing approach can be completed quickly, without even identifying the infectious agent. This is because the device uses a proprietary pathogen-capturing agent, known as FcMBL, that binds all types of live and dead infectious microbes, including bacteria, fungi, viruses, and the toxins they release.

FcMBL is a genetically engineered blood protein inspired by a naturally occurring human molecule called mannose binding lectin (MBL). MBL is found in the innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen.

The researchers’ original device concept was similar to how a dialysis machine works. Infected blood in an animal, or potentially one day in a patient, is flowed from one vein through catheters to the device.

There, FcMBL-coated magnetic beads are added to the blood, and the bead-bound pathogens are extracted from the circulating blood by magnets within the device before the cleansed blood is returned to the body through another vein.

The new device removes the complexity, regulatory challenges, and cost associated with the magnetic beads and microfluidic architecture of its predecessor. But it still uses the FcMBL protein to bind to pathogens and toxins.

The new system uses hollow fiber filters similar to those currently used in hemodialysis, but the inner walls of these filters are coated with FcMBL protein to remove pathogens from circulating blood.

Test results

In in vitro tests with human blood, the device reduced the number of Gram-negative bacteria (Escherichia coli), Gram-positive bacteria (Staphylococcus aureus), fungi (Candida albicans), and lipopolysaccharide-endotoxins by 90% to 99%.

In tests with rats, the device reduced levels of circulating pathogens and endotoxins by more than 99%, and it prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver, and kidney.

The researchers also tested the device in combination with bacteriocidal antibiotics in rats. The antibiotics prompted a “major increase” in the release of microbial fragments, or pathogen-associated molecular patterns (PAMPs).

The device could remove PAMPs from the blood within 2 hours, but high levels of PAMPs remained in rats treated with antibiotics alone.

The researchers said PAMP removal reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs.

“Using the device, alone or alongside antibiotics, we can quickly bring blood back to normal conditions, curtailing an inflammatory response rather than exacerbating it,” said Tohid Fatanat Didar, PhD, of the Wyss Institute.

“If all goes well, physicians will someday be able to use the device in tandem with standard antibiotic treatments to deliver a one-two punch to pathogens, synergistically killing and cleansing all live and dead invaders from the bloodstream.”

As the device has proven effective in small animal experiments, the researchers are planning to move to large animal studies. They must demonstrate proof-of-concept in these models before advancing to clinical trials.

“Our goal is to see this move out of the lab and into hospitals, as well as onto the battlefield,” Dr Ingber said, “where it can save lives within years rather than decades.”

T cells under a super-

resolution microscope

Image courtesy of UNSW

Early exposure to inflammatory cytokines can “paralyze” CD4 T cells, according to research published in Immunity.

The study suggests this mechanism may act as a firewall, shutting down the immune response before it gets out of hand.

According to researchers, this discovery could lead to more effective immunotherapies for cancer and reduce the need for immunosuppressants in transplant patients, among other applications.

“There’s a 3-signal process to activate T cells, of which each component is essential for proper activation,” said study author Gail Sckisel, PhD, of the University of California, Davis in Sacramento.

“But no one had really looked at what happens if they are delivered out of sequence. If the third signal—cytokines—is given prematurely, it basically paralyzes CD4 T cells.”

To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early—as is done with some immunotherapies—could actually hamper overall immunity.

“These stimulatory immunotherapies are designed to activate the immune system,” Dr Sckisel explained. “But considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.”

She and her colleagues demonstrated this principle in mice. After they received systemic immunotherapy, the animals had trouble mounting a primary T-cell response.

The researchers confirmed this finding in samples from patients receiving high-dose interleukin 2 to treat metastatic melanoma.

“We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss,” said study author William Murphy, PhD, also of the University of California, Davis.

“The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system.”

In addition to illuminating how T cells respond to cancer immunotherapy, the study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.

By shutting down CD4 T cells, immune stimulation prevented an autoimmune response. This provides the opportunity to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs.

“Transplant patients go on immunosuppressants for the rest of their lives, but if we could safely induce paralysis just prior to surgery, it’s possible that patients could develop tolerance,” Dr Sckisel said.

CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.

“This really highlights the importance of CD4 T cells,” Dr Murphy said. “The fact that they’re regulated and suppressed means they are definitely the orchestrators we need to take into account. It also shows how smart HIV is. The virus has been telling us CD4 T cells are critical because that’s what it attacks.”

The team’s next step is to continue this research in older mice. Age can bring a measurable loss in immune function, and inflammation may play a role in that process.

“For elderly people who have flu or pneumonia, their immune systems are activated, but maybe they can’t fight anything else,” Dr Murphy said. “This could change how we treat people who are very sick. If we can block pathways that suppress the immune response, we may be able to better fight infection.”

T cells under a super-

resolution microscope

Image courtesy of UNSW

Early exposure to inflammatory cytokines can “paralyze” CD4 T cells, according to research published in Immunity.

The study suggests this mechanism may act as a firewall, shutting down the immune response before it gets out of hand.

According to researchers, this discovery could lead to more effective immunotherapies for cancer and reduce the need for immunosuppressants in transplant patients, among other applications.

“There’s a 3-signal process to activate T cells, of which each component is essential for proper activation,” said study author Gail Sckisel, PhD, of the University of California, Davis in Sacramento.

“But no one had really looked at what happens if they are delivered out of sequence. If the third signal—cytokines—is given prematurely, it basically paralyzes CD4 T cells.”

To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early—as is done with some immunotherapies—could actually hamper overall immunity.

“These stimulatory immunotherapies are designed to activate the immune system,” Dr Sckisel explained. “But considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.”

She and her colleagues demonstrated this principle in mice. After they received systemic immunotherapy, the animals had trouble mounting a primary T-cell response.

The researchers confirmed this finding in samples from patients receiving high-dose interleukin 2 to treat metastatic melanoma.

“We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss,” said study author William Murphy, PhD, also of the University of California, Davis.

“The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system.”

In addition to illuminating how T cells respond to cancer immunotherapy, the study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.

By shutting down CD4 T cells, immune stimulation prevented an autoimmune response. This provides the opportunity to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs.

“Transplant patients go on immunosuppressants for the rest of their lives, but if we could safely induce paralysis just prior to surgery, it’s possible that patients could develop tolerance,” Dr Sckisel said.

CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.

“This really highlights the importance of CD4 T cells,” Dr Murphy said. “The fact that they’re regulated and suppressed means they are definitely the orchestrators we need to take into account. It also shows how smart HIV is. The virus has been telling us CD4 T cells are critical because that’s what it attacks.”

The team’s next step is to continue this research in older mice. Age can bring a measurable loss in immune function, and inflammation may play a role in that process.

“For elderly people who have flu or pneumonia, their immune systems are activated, but maybe they can’t fight anything else,” Dr Murphy said. “This could change how we treat people who are very sick. If we can block pathways that suppress the immune response, we may be able to better fight infection.”

T cells under a super-

resolution microscope

Image courtesy of UNSW

Early exposure to inflammatory cytokines can “paralyze” CD4 T cells, according to research published in Immunity.

The study suggests this mechanism may act as a firewall, shutting down the immune response before it gets out of hand.

According to researchers, this discovery could lead to more effective immunotherapies for cancer and reduce the need for immunosuppressants in transplant patients, among other applications.

“There’s a 3-signal process to activate T cells, of which each component is essential for proper activation,” said study author Gail Sckisel, PhD, of the University of California, Davis in Sacramento.

“But no one had really looked at what happens if they are delivered out of sequence. If the third signal—cytokines—is given prematurely, it basically paralyzes CD4 T cells.”

To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early—as is done with some immunotherapies—could actually hamper overall immunity.

“These stimulatory immunotherapies are designed to activate the immune system,” Dr Sckisel explained. “But considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.”

She and her colleagues demonstrated this principle in mice. After they received systemic immunotherapy, the animals had trouble mounting a primary T-cell response.

The researchers confirmed this finding in samples from patients receiving high-dose interleukin 2 to treat metastatic melanoma.

“We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss,” said study author William Murphy, PhD, also of the University of California, Davis.

“The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system.”

In addition to illuminating how T cells respond to cancer immunotherapy, the study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.

By shutting down CD4 T cells, immune stimulation prevented an autoimmune response. This provides the opportunity to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs.

“Transplant patients go on immunosuppressants for the rest of their lives, but if we could safely induce paralysis just prior to surgery, it’s possible that patients could develop tolerance,” Dr Sckisel said.

CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.

“This really highlights the importance of CD4 T cells,” Dr Murphy said. “The fact that they’re regulated and suppressed means they are definitely the orchestrators we need to take into account. It also shows how smart HIV is. The virus has been telling us CD4 T cells are critical because that’s what it attacks.”

The team’s next step is to continue this research in older mice. Age can bring a measurable loss in immune function, and inflammation may play a role in that process.

“For elderly people who have flu or pneumonia, their immune systems are activated, but maybe they can’t fight anything else,” Dr Murphy said. “This could change how we treat people who are very sick. If we can block pathways that suppress the immune response, we may be able to better fight infection.”

Doctor and patient

Photo courtesy of NIH

The National Institute for Health and Care Excellence (NICE) has developed a draft guideline detailing “best practices” in caring for patients with myeloma.

It is intended to help ensure “consistently excellent care” for myeloma patients over the age of 16 in England.

The guideline includes recommendations for diagnosing the disease, managing complications, communicating with patients, and ensuring access to appropriate care.

The draft guideline will remain open for public consultation until October 1, 2015.

“Advances in treatment over the last 15 years have seen more people with myeloma living longer, but there is still no cure,” said Mark Baker, clinical practice director for NICE.

“Our guideline, which is being developed by an independent group of experts, will set out best-practice care to ensure people live as normal a life as possible for as long as possible.”

The guideline’s provisional recommendations are as follows.

Communication and support: Offer prompt psychological assessment and support to myeloma patients at diagnosis and, as appropriate, at the beginning and end of each treatment, when the disease progresses, and when patients start to require end-of-life care.

Laboratory investigations to diagnose myeloma: For patients with suspected myeloma, healthcare professionals should use the same sample for all diagnostic and prognostic tests on bone marrow, so patients only have to have one biopsy.

Scans for patients with suspected myeloma: Offer imaging to all patients with a plasma cell disorder suspected to be myeloma. Doctors should consider whole-body MRI as the first imaging procedure.

Service delivery: Each hospital treating patients with myeloma who are over the age of 18 should ensure there is regional access to facilities for intensive inpatient chemotherapy or transplantation, renal support, spinal disease management, specialized pain management, therapeutic apheresis, radiotherapy, restorative dentistry and oral surgery, and clinical trials, particularly early phase trials.

Managing complications: Healthcare professionals should consider extending the pneumococcal vaccination to patients with myeloma who are under 65 in order to prevent infection.

This draft guideline also complements existing NICE guidance on the drug treatment of myeloma. It sets out which treatments—including stem cell transplants—should be used to manage the condition as well as those to prevent and treat bone disease and acute renal disease, which can be caused by myeloma.

Doctor and patient

Photo courtesy of NIH

The National Institute for Health and Care Excellence (NICE) has developed a draft guideline detailing “best practices” in caring for patients with myeloma.

It is intended to help ensure “consistently excellent care” for myeloma patients over the age of 16 in England.

The guideline includes recommendations for diagnosing the disease, managing complications, communicating with patients, and ensuring access to appropriate care.

The draft guideline will remain open for public consultation until October 1, 2015.

“Advances in treatment over the last 15 years have seen more people with myeloma living longer, but there is still no cure,” said Mark Baker, clinical practice director for NICE.

“Our guideline, which is being developed by an independent group of experts, will set out best-practice care to ensure people live as normal a life as possible for as long as possible.”

The guideline’s provisional recommendations are as follows.

Communication and support: Offer prompt psychological assessment and support to myeloma patients at diagnosis and, as appropriate, at the beginning and end of each treatment, when the disease progresses, and when patients start to require end-of-life care.

Laboratory investigations to diagnose myeloma: For patients with suspected myeloma, healthcare professionals should use the same sample for all diagnostic and prognostic tests on bone marrow, so patients only have to have one biopsy.

Scans for patients with suspected myeloma: Offer imaging to all patients with a plasma cell disorder suspected to be myeloma. Doctors should consider whole-body MRI as the first imaging procedure.

Service delivery: Each hospital treating patients with myeloma who are over the age of 18 should ensure there is regional access to facilities for intensive inpatient chemotherapy or transplantation, renal support, spinal disease management, specialized pain management, therapeutic apheresis, radiotherapy, restorative dentistry and oral surgery, and clinical trials, particularly early phase trials.

Managing complications: Healthcare professionals should consider extending the pneumococcal vaccination to patients with myeloma who are under 65 in order to prevent infection.

This draft guideline also complements existing NICE guidance on the drug treatment of myeloma. It sets out which treatments—including stem cell transplants—should be used to manage the condition as well as those to prevent and treat bone disease and acute renal disease, which can be caused by myeloma.

Doctor and patient

Photo courtesy of NIH

The National Institute for Health and Care Excellence (NICE) has developed a draft guideline detailing “best practices” in caring for patients with myeloma.

It is intended to help ensure “consistently excellent care” for myeloma patients over the age of 16 in England.

The guideline includes recommendations for diagnosing the disease, managing complications, communicating with patients, and ensuring access to appropriate care.

The draft guideline will remain open for public consultation until October 1, 2015.

“Advances in treatment over the last 15 years have seen more people with myeloma living longer, but there is still no cure,” said Mark Baker, clinical practice director for NICE.

“Our guideline, which is being developed by an independent group of experts, will set out best-practice care to ensure people live as normal a life as possible for as long as possible.”

The guideline’s provisional recommendations are as follows.

Communication and support: Offer prompt psychological assessment and support to myeloma patients at diagnosis and, as appropriate, at the beginning and end of each treatment, when the disease progresses, and when patients start to require end-of-life care.

Laboratory investigations to diagnose myeloma: For patients with suspected myeloma, healthcare professionals should use the same sample for all diagnostic and prognostic tests on bone marrow, so patients only have to have one biopsy.

Scans for patients with suspected myeloma: Offer imaging to all patients with a plasma cell disorder suspected to be myeloma. Doctors should consider whole-body MRI as the first imaging procedure.

Service delivery: Each hospital treating patients with myeloma who are over the age of 18 should ensure there is regional access to facilities for intensive inpatient chemotherapy or transplantation, renal support, spinal disease management, specialized pain management, therapeutic apheresis, radiotherapy, restorative dentistry and oral surgery, and clinical trials, particularly early phase trials.

Managing complications: Healthcare professionals should consider extending the pneumococcal vaccination to patients with myeloma who are under 65 in order to prevent infection.

This draft guideline also complements existing NICE guidance on the drug treatment of myeloma. It sets out which treatments—including stem cell transplants—should be used to manage the condition as well as those to prevent and treat bone disease and acute renal disease, which can be caused by myeloma.