Benjamin Samuel Young

Benjamin Young (2012), Senior Research Project – History of American Medicine, Prof. Martin Pernick

In the midst of the deepest economic recession since the Great Depression, a time when the foundations of capitalism were questioned, Barack Obama, newly elected and unwilling to forego the prerogative of his first 100 days, surveyed the state of the American health care system.  He found a patchwork of programs distributed between state and local governments.  Private interests had come to dominate the health care insurance system, costs regularly exceeded national inflation, and access to care was uneven.  Priorities were shaped by profits, not maximum health care provision. Democrats struggled to devise methods to reform the behemoth, knowing that previous administrations had failed in the same attempt. The bruising political process yielded the Patient Protection and Affordable Health Care Act of 2008, hybrid legislation that passed by a small margin and pleased few on the left or right.[1]

          To many progressive analysts, the Obama Administration should not have strained to synthesize a new program.  In the last seventy years, the Department of Veterans Affairs (VA) through its largest component, the Veterans Health Administration (VHA), has created a system of health care provision dedicated to wounded, poor and mentally ill veterans.  Concurrently, the VA’s affiliation with major medical schools has propelled important research and provided for the training of thousands of physicians and other healthcare professionals.[2]  The VA has also taken the lead in the adoption of electronic medical records and the articulation of ethical medical practice.

          Not all policy makers share this positive perspective. As budgets have grown, the VA has encountered fierce critics among small government enthusiasts. Michael F. Cannon of the libertarian Cato Institute argues that the VA is a duplicative system and that veterans, using government backed vouchers, would be better served in the private sector.  “Suppose that instead of providing benefits, the federal government increased military pay enough to enable new personnel to purchase private insurance to cover service-related injuries and illnesses.”[3]

          This paper does not endeavor to serve as a micro-economic comparator of competing health models.  It is rather, a brief history of the VA, both nationally and in Ann Arbor, and an exposition of the organization’s evolving mission.  The VA has worked to serve the needs of its core constituency, model progressive positions on patient care and access, teach young clinicians, and sponsor clinical research most relevant to veterans. These guiding principles differ markedly from the forces driving private health care and must be identified in order to counter destructive libertarian political forces and to propose the modern VA as a model of national reform.

.  ‘…let us strive onto finish the work we are in; to bind up the nation’s wounds; to care  for him who shall have borne the battle, and for his widow and his orphan; to do all which may achieve and cherish a just and lasting peace, among ourselves and with all nations.”[4]

          –President Abraham Lincoln, Second Inaugural Address, March 4, 1865

A Developing System

          The United States has always expressed an interest in caring for its veterans.  The first Federal hospital opened in Pittsburgh in 1778, but it was the magnitude of causalities from the American Civil War that forced the system to expand.  The tradition of the era was for individual states to contribute to their militia’s care and by 1933, 43 states managed 55 state homes.  The Michigan Soldiers’ Home in Grand Rapids exemplified this trend; State of Michigan Public Act 152 provided for the “establishment of a home for disabled soldiers, sailors and mariners” within the state of Michigan.[5]   The facility was dedicated in 1866 by former Major and Michigan Supreme Court Justice Allen B. Morse as a testament to Michigan’s “disabled and enfeebled veterans who lost their health and energies in defense of our homes. May it stand forever.”[6]  Applicant #4107 was Uriah Gress from the 6th Michigan Infantry.  Gress, suffering from “a broken hip and piles”, agreed to abide by the home’s rules which included completing daily chores and turning over seven dollars of his twelve dollar Federal pension.  He stayed in the home for 14 years but chose not to be buried in the adjacent Soldier’s Home Cemetery.[7]

Federal Care is Extended to Veterans

          Lincoln’s sentiments anticipated greater federal involvement, and in the decades following the Civil War, Washington assumed the administration of several state-run homes.  The National Asylum for Disabled Volunteer Soldiers opened in Maine in 1866, the first of 13 branches to address the needs of aging veterans.  This fusion of lightly funded state and federal programs survived through World War I.[8]      In 1921, brief correspondence about opening a veterans’ hospital in Ann Arbor transpired between an official at the US Veterans Bureau and the Brigadier General of the Michigan Reserves, but neither man followed through and the concept languished through the next decade.[9]  The creation the Veterans Administration in 1930 was intended to streamline decision making and consolidate the various governmental agencies involved in the care of the nation’s five-million veterans.  Between the war years, the need for expansion became evident and the many voices alerted central planners that Michigan had an inadequate number of beds.  The VA acknowledged the shortage and Grand Rapids and Saginaw were awarded 200-bed hospitals. The Veterans Hospital in Dearborn, built in 1939, added 300 beds to the system.  Ann Arbor was slated for a new 500-bed tubercular hospital.[10]

World War II

          The triumph of World War II was tempered by the responsibility of attending to the needs of the returning soldiers. President Roosevelt responded by creating the GI Bill of Rights which established an elaborate system of federal educational support.[11] The war had created 17 million new veterans and the crush on the existing care structure was severe.  The Saturday Evening Post foretold the crisis; VA hospitals were “short of doctors, nurses, beds, efficiency and the medical spirit that gives patients’ faith in their doctors.”  Veterans’ hospitals were called the “Backwater of Medicine” and “Third Rate Medicine for First Rate Men.”[12]  In1946, Harry S Truman appointed General Omar Bradley to lead the Veterans Administration and to repair the “vast dehumanized bureaucracy …prescribing medieval medicine.”[13] Congress was required to exempt the five-star general from the restriction forbidding active duty officers to lead civil agencies.[14]  Bradley leveraged his prestige to transform the “national scandal to a model establishment.”[15] Among his first appointments was General Paul Hawley, a WWII surgeon, to Chief Medical Director.  Hawley tapped Dr. Paul Magnusson from Northwestern University, an accomplished orthopedic surgeon with a reputation for combating inefficient bureaucracies.  Together they enlarged the VA’s treatment capacity, rebuilt the organization on a regional basis and transformed the agency’s relationship to physician training and education.[16]

          Federal veterans’ hospitals had loose affiliations with various medical schools since the 1880s, but few resources supported these relationships.[17]  The Civil Service Commission demanded that all VA personnel pass a civil service examination, a requirement that discouraged part time participation of medical school faculty.  Magnusson clashed with the Commission and prevailed by creating a separate medical personnel management system.  With this political victory, Magnusson implored colleagues at Northwestern University and the University of Minnesota to place attending staff at the local VA hospitals.  The Northwestern physicians moved quickly to analyze the existing system. Their report concluded that the VA management structure was insular and over-hospitalization of sub-acute patients blocked access to veterans with more dire need.[18] [19]

The VA Affiliates with Medical Schools

          The Northwestern report represented a synergy between the VA and academic medicine, and it spurred the development of Policy Memorandum No. 2 (1946).  This policy recognized the “necessity of understanding and cooperation” between the VA and leading medical schools.  The Department “is embarking on a program that is without precedent in the history of Federal hospitalization.”  The responsibilities of both parties were briefly outlined; the Department would maintain their mandate for veterans care and the cooperating medical schools would accept responsibility for graduate education and training.”[20]  The memo details little about additional funding to the medical schools; ostensibly the agreement offered the universities an expanded number of beds to train their house staff.  The opportunity for the Department to improve veterans care by increasing the supply of attending physicians was profound.  Prior to Memorandum 2, the one-thousand bed VA hospital in Palo Alto had only five doctors. “The outside of the hospital was beautiful… but what went on inside was beyond description.”[21]  Over the next generation, the hospital’s affiliation with Stanford Medical School transformed the facility into a world class hospital.[22]

          Memorandum 2 called for the formation of a Dean’s Committee’s at each affiliated site.  The governance structure, still in operation, was to be chaired by the head of the medical school, co-chaired by the VA chief of staff and comprised of officials from both institutions. The Dean’s Committee served to merge the interests of the medical schools and the VA and set the standards for hiring medical staff.[23]  With this partnership the VA underwrote undergraduate and graduate education and created joint resident training programs.  The first formal affiliation occurred in 1946 between Northwestern University, the University of Illinois and the Edward T. Hines Hospital outside Chicago.  The affiliation coincided with plans to increase the number of VA hospitals nationwide.  Heretofore, the Department’s belief was that wounded veterans should recuperate in relaxed and bucolic settings.  Memorandum 2 recognized that remote outposts were difficult to staff and to the chagrin of congressmen from rural areas; new hospitals were planned for urban areas with concentrations of well-trained physicians.[24]

Memorandum 2 and the University of Michigan

          The impact of Memorandum 2 resonated in Ann Arbor and factions emerged to influence Washington policies.  S.E. Jones asserts that the University of Michigan Vice President Marvin Niehus did not welcome the proposed tubercular hospital, owing to the perils of maintaining an infectious disease hospital in proximity to campus.  The University’s objective was to attract a general medical and surgical hospital although available records do not clarify whether the Medical School realized the full value of an affiliated program.  A battle ensued between Detroit and Ann Arbor and over the next two years, the proposed location of the new hospital shifted three times between the two areas.  Finally, the Federal Board of Hospitalization assigned the tuberculosis hospital to the Dearborn VA and awarded Ann Arbor the general hospital.  “Since the University of Michigan Medical School is located in Ann Arbor, it appears logical in accord with present thinking that (the hospital) be built in that city near the medical school.”[25]

           In 1947 the Federal Board acquired 16 acres of land outside the northeast city limits of Ann Arbor situated between Glacier Way, Geddes Road and Oakway.  After extended debate, the Ann Arbor City Council agreed to extend sewer and water lines outside previously defined city boundaries.  In the autumn of 1949, the J.D. Hedin Construction Company broke ground on the $7.1 million project.  The construction took four years to complete and was riddled by opposition from local neighborhoods, lawsuits, and labor and material shortages.  Construction on the land was surprisingly challenging, and the placement of the building’s deep foundation required significant engineering ingenuity.  The Korean War created labor shortages and this prompted the Hedin Company to offer salaries in excess of the war-time imposed wage freeze.  Hedin was successfully sued by the government for this practice; litigation that further slowed the construction schedule.[26] [27]*

          The Ann Arbor Veterans Administration Hospital opened in 1953 – thirty months behind schedule. It was dedicated by Vice Admiral Joel T. Boone who hailed the hospital’s affiliation with the University of Michigan Medical School.[28]  The Ann Arbor News published photographs of the opening ceremonies; the Ypsilanti High School Band performed as did the color guard from the American Legion Post in Dexter.[29]  The original information guide welcomed visitors to the multi-building hospital which featured  488 beds, a full operating room, diagnostic laboratories, comprehensive X-ray equipment and research space.  The hospital was built with a patient solarium and equipped with a state of art radio station and a pneumatic tube system to expedite inter-department communication.  The first Dean’s Committee was chaired by A.C. Furstenberg, Dean of the Medical School.  Other notable members of the original committee included the chairmen of surgery, internal medicine and psychiatry – Frederick A. Coller, Cyrus C. Sturgis and Raymond W. Waggoner, respectively.   Dr. Morley Beckett, the hospital’s long time manager, represented the Veterans Administration.[30]

Expanding Access to Care

          The U of M-VA affiliation exemplified similar partnerships that were replicated throughout the country.  The affiliations in Minneapolis, Boston, New York and San Francisco resulted in improved doctor-patient ratios.  Six months after Memorandum No. 2 was issued, four-thousand new doctors were involved in veteran care.  Within the decade, 63 of the nation’s 77 existing medical schools became affiliated with the Veterans Department. [31] [32]  Initially the infusion of physicians allowed hospitals to offer increasingly sophisticated inpatient hospital services.  By the 1990s, American medicine began to move away from inpatient admissions for low acuity conditions and started to emphasize outpatient care.[33]  The Ann Arbor VA followed this trend and slashed the number of inpatient beds to 104. Resources were transferred to geriatric care and primary care outpatient clinics.  In the mid-Nineties, Congress opened the door to low-income veterans and those without service-connected conditions.[34]  Recently, the VA mandated that its hospitals provide outreach to homeless veterans, many of whom have chronic mental illness.[35] Taken together, these policies dramatically expanded the pool of eligible patients. In 2011, the Ann Arbor VA, covering a fifteen-county region in Michigan and northern Ohio, had 455,000 outpatient visits.[36] [37]

Manpower and Teaching

          With their medical school affiliations,VA hospitals were recognized as desirable teaching arenas [38] Between 1960 and 1986 the number of trainees in the system increased from 16,000 to 105,000.  Twenty percent of the trainees received some form of VA training stipend.  Plans for expansion continued as the country entered Korea and Vietnam.  Congress foresaw a national shortage of physicians in the 1960s and provided federal funds to enlarge the class size of existing medical schools.  This did not satiate the demand and in 1972, the VA subsidized five new medical schools in underserved areas.[39]

          During this period, the Ann Arbor Veterans Health System (now VAAAHS) became integral to the educational mission of the University of Michigan.   The medical school benefited most directly; each decade saw an increase in the VA’s contribution to graduate medical training.  Monies from Washington also flowed freely to the schools of Nursing, Dentistry, Pharmacy and Social Work, enabling each school to broaden their reach.  VA training revenue came to fund many faculty positions and support the University’s mission to increase diversity among faculty and students.[40]  The University demanded that capable physicians train its medical residents and only VA staff with University appointment were allowed to participate formally in medical education. [41] The strong alliance with the medical school has a downside as well, according to former Ann Arbor VA clinical psychologist Lawrence Perlman.  “The prestige of the medical school attracts fine doctors, but the VA is often exploited and used as a place to train the most inexperienced residents.”[42]  Overall, the relationship outlined in Memorandum No. 2 has benefitted non-veterans as well.  A recent analysis reports that a large number of health care professionals practicing in the private sector spent a portion of their training in the VA and have transferred their knowledge to the general population.[43]

          Libertarians might argue that this training mission could exist within the private sector, but this argument is not persuasive.  In a profit-oriented system, the expense of training resident physicians would inevitably yield to cost-cutting.  The emphasis would shift from collaboration and teaching to the provision of reimbursed medical services.  Training of health care professionals requires full time faculty and modern facilities, elements already in place in the nation’s university-affiliated VA hospitals.

Key VA Clinical Programs:

          The VA-medical school collaboration has focused on specific clinical conditions commonly facing servicemen.  VAAAHS and its sister institutions have played leading roles in many areas of clinical investigation.  Research priorities have changed over the years, reflecting the VA’s central mission to meet the dynamic needs of the veteran population. It is unlikely that the private sector could respond as fluidly.  Among the key priorities have been programs for the blind and vision-impaired, physically injured and mentally ill.

Blind and Vision-Impaired

          Traditionally, the VA’s highest priority has been the care of veterans injured in combat.  A disproportionate number of returning World War II soldiers suffered service-connected blindness, and a concerned President Roosevelt responded to their needs. “No blinded serviceman from WWII would be returned to their homes without adequate training to meet the problems of necessity imposed on them by their blindness.” [44] General Bradley mandated that dedicated treatment programs be led, whenever possible, by veterans experiencing the same affliction.  In a strategy that has been maintained to the present, the VA has designated certain hospitals as centers of clinical excellence.  The Hines VA Medical Center west of Chicago established the first Blind Rehabilitation Center (BRC) in 1948.[45] 

          Like many innovative VA programs, at first the BRC was controversial.  Some within the blind community believed that residential treatment would promote self-pity and paternalism; they held that veterans should receive rehabilitation while living at home.  This issue intensified during the Korean conflict when 500 servicemen – nearly 5% of all casualties – were blinded. The focus of treatment during this era was mobility reorientation and psychosocial adjustment.  Critics maintained that veterans’ recovery be managed by established civilian organizations.[46]  The VA relentlessly pursued novel medical and surgical intervention, and in the 1960s this resolve paid dividends.  Combined VA and University research contributed to active technologies including micro-surgery for eye trauma and ophthalmologic disease.  The VA also advanced digital assistance technology for low vision. [47]  Since the Vietnam War, the Hines residential program has expanded to nine other facilities throughout the country.[48] This reflected the Department’s organization into Veterans Integrated Service Networks (VISN), a system premised on regional control and the equitable distribution of specialized services throughout the country.  VAAAHS, located in VISN 11, has been designated the Health Services Research and Development Center of Excellence.[49]  The Center researches ways to improve healthcare delivery in patients with chronic physical and mental illness.[50]
Rehabilitation Medicine

          The physical medicine challenges of veterans have evolved as advances in trauma care allowed more soldiers to survive their injuries.  In the Vietnam era, 60% of soldiers wounded on the battlefront survived; in Iraq and Afghanistan survival rates improved to 95%.[51] Those who survived were often severely wounded.  Spinal cord injuries became an unfortunate result of modern warfare and the VA addressed this need, again led by the collaboration of the Hines Veterans Hospital and University of Illinois.  Since the Civil War when the ubiquitous Minié ball splintered limbs, Army surgeons perfected amputation techniques.[52]  Post-operative rehabilitation of these veterans was of inconsistent quality until 1950 when the Vocational Rehabilitation Act developed systemized programs for injured veterans. During the reorganization of the VA in 1953, prosthetic research became a top priority and Public Act 729 ensured that veterans obtain high quality prosthetic devices.  The VA actively funded research in physical medicine and continues to publish the Journal of Rehabilitation Research and Development.[53] Recent VA contributions have included the Computer Leg, myoelectric hands and arms, and the use of composite materials for functional limbs. [54]  Since the opening of the hospital, VAAAHS has had a dedicated unit for physical medicine. The first patient admitted in 1953 was Elvio Rosati, a double amputee from Detroit who was among the honored invitees to the hospital’s 50^th anniversary in 2003.[55] [56]

Mental Health

The Greek historian Herodotus described the psychiatric casualties of war in the 6^th century BC.  His depiction of an Athenian soldier who, physically uninjured at the Battle of Marathon, became blind after witnessing the death of a fellow soldier, might be the earliest report of post-traumatic stress disorder.[57] One-tenth of mobilized American soldiers were psychiatrically hospitalized between 1942 and 1945; after prolonged combat, over 90% manifested psychiatric symptoms.[58] Bradley issued specific instructions to expand the supply of counselors to meet the many needs of returning veterans.[59]

Psychological trauma has long been identified by military medicine, albeit with different nomenclature. In World War I, military physicians diagnosed “shell shock.”  During World War II the afflicted were described as having “battle fatigue;” in Korea, the phenomenon was described as “traumatic war neurosis.” The term, Post-traumatic Stress Disorder (PTSD) was coined in the 1970s and codified in subsequent editions of the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM). [60]  In more recent years, the condition has expanded to include survivors of childhood abuse, but VA physicians have remained focused on the consequences of war trauma. Given the high prevalence of the condition, most VA mental health clinics including VAAAHS have designated PTSD programs.  Many of the academic leaders in PTSD research have VA affiliation and much of the academic literature emanates from VA funding.

Not all psychiatric casualties are service connected. Compared to the general population, veterans have higher rates of psychotic disorders, depression and substance use disorders.[61] According to Nicholas Kristof, for every one soldier killed on the battlefield in 2012, about 25 veterans die by suicide.[62] The outpatient substance abuse treatment program at the VAAAHS is full; the VA also provides residential treatments in Battle Creek and North Chicago.  This commitment contrasts with University Hospital, which has largely withdrawn from substance abuse treatment due to poor third party reimbursement.   Recently, the resources the VA has devoted to mental health has exceeded available manpower, particularly in remote areas or in hospitals unaffiliated with medical schools.  For example, a new 24- bed mental health facility in Helena, Montana has generous funding and a waiting list of patients but is unable to open because it cannot recruit attending psychiatrists.[63]

Electronic Medical Records

The VA has been at the forefront of information technology.  In the 1970s, the US Public Health Service began developing an electronic medical record (EMR).  The concept was heralded by VA leadership and several years later, Veterans Health Information Systems and Technology Architecture (VistA) was gradually introduced.  VistA was highly innovative; it demanded typed progress notes, eliminating communication errors that resulted from illegible handwriting.  Laboratory values were placed in a discrete part of the medical chart making it easier to track trends.  Radiology images could be viewed from any location.  VistA spelled the end of easily lost or misplaced paper charts. An unstable patient seen in the Toledo clinic could be admitted to the fully informed Ann Arbor VA that evening without the attending staff having to wait days for the physical chart to appear.  Medications and patient identification were bar-coded, a step that significantly reduced dispensing errors.  VistA revolutionized clinical and epidemiological research by centralizing all data.[64]

Thirty years later, it is clear that the impact of VistA on medical care has been extensive.  Electronic medical records are standard practice and soon the paper chart will be extinct.   The program’s technological success prompted the adoption of EMRs as a centerpiece of the Affordable HealthCare Act.  Medicare and Medicaid incentivize medical practices, both private and public, to adopt electronic records.  The magnitude of VistA along with the structural obstacles blocking its adoption and the lengthy development process make it unlikely that the private sector could have borne the initial costs.[65] 

Conclusion

          The future of the VA parallels the larger debate in this country about the size and scope of the federal government.  At present, the discussion is at low tide; the VA’s funding is sacred after war when the plight of wounded veterans is raw.  This protected status became evident early in the Republican primary season, when Mitt Romney criticized the VA during an early campaign stop.  Romney was met with a barrage of hostility from various political factions and no further critical comments by him is found by search engines.[66]  The election season did not stop his ally, Rep. Paul Ryan from holding hearings on deep cuts to VA funding.[67] Traditionally, opposition to the VA intensifies in peacetime and the issue will be reignited in a conservative administration.

          To be sure, the idea of granting vouchers to veterans for care in private facilities has allure.  As an example, Chelsea Hospital, a non-teaching facility in Washtenaw Country, offers greater creature comforts than the cross-town VA Hospital.  A case could be made that consolidating the two hospitals would create efficiencies and a larger civilian hospital could accommodate the needs of veterans. This reform would be short sighted.  The VA has a laudable record of responding to clinical need and expanding access to health care. It has advanced medical research tailored to conditions afflicting the veteran population.  It has sponsored technological innovation and maintained a steadfast commitment to high ethical principles.  These events have occurred because the VA has been driven by popular mandate and not by profit motivations.  Privatizing the VA would disrupt a robust site of training and impede veterans’ access to health care.  

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Endnotes and Works Cited

[1] Starr, Paul. “Introduction.” Remedy and Reaction: The Peculiar American Struggle over Health Care Reform. New Haven: Yale UP, 2011. 17-21. Print.

[2] Gronvall, John A. “The VA’s Affiliation with Academic Medicine: An Emergency Postwar Strategy

Becomes a Permanent Partnership.” Academic Medicine 64.2 (1989): 61-66. Print.

[3] Cannon, Michael F. “Curing Walter Reed Syndrome; A Proposal Even Anti-War Doves Should Embrace.” The Cato Institute. 19 Mar. 2007. Web. 15 Apr. 2012. <http://www.cato.org/publications/commentary/curing-walter-reed-syndrome-proposal-even-antiwar-doves-should-embrace&gt;.

[4] The Origin of the VA Motto. US Department of Veterans Affairs, Washington D.C. Web. 15 Apr. 2012. <http://www.va.gov/opa/publications/celebrate/vamotto.pdf&gt;.

[5] “Civil War Resources – Soldier’s and Sailor’s Homes Records.” Bentley Historical Library, University of Michigan. Web. 15 Apr. 2012. <http://bentley.umich.edu/research/genealogy/cw/soldiershome.php&gt;.

[6] Zimmeth, Mary. “A Testimonial to the Worth and Services of Her Sons.” Seeking Michigan. Web. 15 Apr. 2012. <http://seekingmichigan.org/look/2011/11/29/michigan-soldiers-home&gt;.

[7] Zimmeth

[8] Bentley Historical Library, Civil War Resources

[9] Jones, S.E. In The Beginning: A History of the VA Hospital, Ann Arbor, Michigan. Ann Arbor: Bentley Historical Library, 1973. Print.

[10] Jones

[11] Gronvall

[12] Ducharme, Erin E. “Thanksgiving Day Post-The History of Veterans Healthcare.” Clinical Correlations. NYU Langone, 27 Nov. 2008. Web. 15 Apr. 2012. <http://www.clinicalcorrelations.org/?p=969&gt;.

[13] Ducharme

[14] Appointment of Gen. Omar N. Bradley as Administrator of the Veterans’ Affairs, 79^th Congress House of Representatives, 1^st Session, Report No. 840

[15] Downs, Frederick. “Prosthetics in the VA: Past, Present, and Future.” Feb. 2008.  57-59. Web. 15 Apr. 2012. <http://www.usni.org/magazines/proceedings/2008-02/prosthetics-va-past-present-and-future&gt;.

[16] Worthen, David M. “The Affiliation Partnership between U.S. Medical Schools and the Veterans Administration.” The Alabama Journal of Medical Sciences 24.1 (1987): 83-89. Print.

[17] Gronvall

[18] Worthen

[19] Gronvall

[20] Policy Memorandum No. 2:  Policy in Association of Veterans’ Hospitals With Medical Schools (1946). Print.

[21] Worthen

[22] Rabinowitz, Jonathan. “Huge VA Project to Boost Med School Admission.” Office of Communications and Public Affairs Stanford University, 24 Oct. 2011. Web. 30 Mar. 2012. <http://med.stanford.edu/ism/2011/october/veterans-1024.html&gt;.

[23] Young, Eric (6 April 2012). Personal conversation with Chief of Staff, VA Ann Arbor Healthcare System

[24] Gronvall

[25] Jones, 10

[26] Jones

[27] “J.D. Hedin Construction Compnay, Inc., For Its Own Use and for the Use of Fischbach & Moore, Its Subconstrator v. United States.” Professor Schooner’s Government Contracts Homepage. Web. 15 Apr. 2012. <http://docs.law.gwu.edu/facweb/sschooner/hedin.html&gt;.

            * The conflict between the Hedin and the government was not fully resolved until 1965 in a detailed Federal Court decision that is often cited as the standard for resolving liability over delays for government projects.

[28] Jones, 16

[29] Photo from archives of The Detroit Times, Friday October 16 1953

[30] Veterans Administration Hospital. Information Guide: Welcome to Ann Arbor Veterans Administration Hospital. By Morley Beckett. Vol. Archives, Ann Arbor Veterans Administration Health Systems. Ann Arbor, 1953. Print.

[31] Gronvall

[32] Worthen

[33] Demsky, Ian. “Hurdles Ahead for Health Care Reform Primary Care Model, U-M Study Shows.” University of Michigan Health System, 11 Nov. 2010. Web. 17 Apr. 2012. <http://www2.med.umich.edu/prmc/media/newsroom/details.cfm?ID=1826&gt;.

[34] Philpott, Tom. “VA Care End Eyed for 1.3 Million Vets.” 7 Apr. 2011. Web. 17 Apr. 2012. <http://www.military.com/features/0,15240,229352,00.html&gt;.

[35] “Contract Notice: Department of Veterans Affairs (Michigan) Issues Solicitation for “Homeless Program” Ann Arbor (Toledo)”. US Federal News Service. ProQuest. 11 Mar. 2011. Web. 17 Apr. 2012.

[36] Bomey, Nathan. “Ann Arbor’s VA Hospital Seeking 26,000 Square Feet for Research Center.” AnnArbor.com. 9 Dec. 2011. Web. 17 Apr. 2012. <http://www.annarbor.com/business-review/ann-arbors-veterans-affairs-hospital-seeking-26000-square-feet-for-research-center/&gt;.

[37] Iglehart, John. “Reform of the Veterans Affairs Health Care System.” The New England Journal of Medicine 335.18 (1996): 1407-11. Print.

[38] W.E. Longo. “The Role of the Veterans Affairs Medical Center in Patient Care, Surgical Education, Research and Faculty Development.” American Journal of Surgery. Web. 17 Apr. 2012. <http://www.ncbi.nlm.nih.gov/pubmed/16226937&gt;.

[39] Worthen, 85

[40] Longo

[41] Young, Eric (6 April 2012).  Personal conversation with Chief of Staff, VA Ann Arbor Healthcare System.

[42] Perlman, Lawrence (16 April 2012).  Phone conversation with former clinical psychologist, VA Ann Arbor Healthcare System.

[43] “The Report of the Blue Ribbon Panel on VA-Medical School Affiliations: Transforming an Historic Partnership for the 21st Century.” (2009). Veterans Health Administration Office of Academic Affiliations.

[44] “History of Blind Rehabilitation Service – Blind Rehabilitation Service.” U.S. Department of Veterans Affairs, 17 Dec. 2012. Web. 17 Apr. 2012. <http://www.va.gov/BLINDREHAB/BRS_History.asp&gt;.

[45] History of Blind Rehabilitation Service, 4

[46] History of Blind Rehabilitation Service, 6

[47] Downs

[48] “Edward Hines, Jr. VA Hospital.” United States Department of Veterans Affairs. Web. 17 Apr. 2012. <http://www.hines.va.gov/services/blind/hbrhistory.asp&gt;.

[49] “Veterans In Partnership (VISN11) Healthcare Network Home.” Web. 17 Apr. 2012. <http://www.visn11.va.gov/&gt;.

[50] “VA Center for Clinical Management Research.” Web. 17 Apr. 2012. <http://www.annarbor.hsrd.research.va.gov/&gt;.

[51] Downs, 58

[52] Keegan, John. “Walt Whitman and Wounds.” The American Civil War: A Military History. New York: Alfred A. Knopf, 2009. 314-15. Print.

[53] “Brief Chronology of our Contemporary Mission.” Journal of Rehabilitation Research and Development 46. 4 Nov. 2009. Web. <http://www.rehab.research.va.gov/jour/09/46/4/mcaleer.html&gt;.

[54] “Brief Chronology of our Contemporary Mission.” Journal of Rehabilitation Research and Development 46. 4 Nov. 2009. Web. <http://www.rehab.research.va.gov/jour/09/46/4/mcaleer.html&gt;.

[55] Young, E. (6 April 2012).  Personal conversation with Chief of Staff, VA Ann Arbor Healthcare System.

[56] Jones, Bentley Historical Library (Ann Arbor)

[57] Herodotus. Herodotus: The Histories. Harmondsworth, Middlesex: Penguin, 1954. 400-402. Print.

[58] Audoin-Rouzeau, Stéphane, and Annette Becker. 14-18: Understanding the Great War. New York: Hill and Wang, 2003. Print.

[59] “Opportunities in the Veterans Administration for Professional Counslers.” The Vocational Guidance Journal 24.8 (1946): 491-97. Print.

[60] Andreasen, Nancy C. Brave New Brain: Conquering Mental Illness in the Era of the Genome. Oxford: Oxford UP, 2001. Print.

[61] Henkin, Cheryl S. “Mental Disorders and Mental Health Treatment Among U.S. Department of Veterans Affairs Outpatients: The Veterans Health Study.” The American Journal of Psychiatry 156.12 (1999). Print.

[62] Kristof, Nicholas D. “A Veteran’s Death, the Nation’s Shame.” The New York Times. 14 Apr. 2012.

[63] KFBB News Team. “VA Mental Health Facility Sitting Two-Thirds Empty.” 7 Mar. 2012. Web. <http://www.kfbb.com/news/local/VA-Mental-Health-Facility-Sitting-Two-Thirds-Empty-141838353.html&gt;.

[64] Longman, Phillip. Best Care Anywhere: Why VA Health Care Is Better than Yours. Sausalito, CA: PoliPointPress, 2007. Print.

[65] Young, E. (6 April 2012). 

[66] McAuliff, Michael. “Mitt Romney: Maybe Veterans’ Health Care Should Be Privatized.” The Huffington Post. 11 Nov. 2011. Web. 18 Apr. 2012. <http://www.huffingtonpost.com/2011/11/11/mitt-romney-veterans-health-care-privatization_n_1089061.html&gt;.

[67] Philpott

On Friday, we saw an 81-year-old male for a consult on his memory problems and depression. PMHx is significant for DM and COPD, among other conditions. He is on many medications, including paroxetine 40 mg.

His mood has been “terrible” and that he is “always thinking of bad stuff.” He has been waking up three times per night. He is worried about household chores, his wife’s health, and his son. He always feels guilty, and he has difficulty concentrating. He denied anhedonia and suicidal ideation. The PHQ-9 and GAD-7 questionnaires demonstrated severe depression and anxiety, respectively.

His memory is declining. He had gotten lost in a store recently, his wife will not let him drive, and he is unable to help with household chores such as cooking. Upon administration of the Montreal Cognitive Assessment (MOCA), the patient scored 19/30. This falls in between the mean for Mild Cognitive Impairment (22.1) and Alzheimer’s Disease (16.2). He had difficulty with recall, short-term memory, and visuospatial skills. He could not correctly identify the current month or year.

During our A+P conversation, we considered if he could benefit from a medication adjustment. The patient has been taking paroxetine for decades. We could increase his dose to 50 mg, which is the maximum. Another option is vortioxetine, a newer antidepressant that was FDA-approved in 2013. This medication is also believed to possess pro-cognitive effects.

Vortioxetine is an SSRI and a serotonin receptor modulator (SERT). It inhibits 5-HT reuptake and acts as a 5-HT1A receptor agonist and a 5-HT receptor antagonist. The precise mechanism is unknown. It has an efficacy comparable to older antidepressants. “Vortioxetine appears to be effective for treating symptoms of MDD in the elderly,” according to a 2015 article I reviewed. Since then, ongoing studies have demonstrated favorable tolerability profiles in the elderly. The most notable side effect is nausea in the first weeks of dosing.

There have also been studies on vortioxetine in the treatment of cognitive decline. It has shown a beneficial effect on cognition and mood in elderly AD patients. According to one Toronto psychiatrist: “Right now, vortioxetine is the only medication with strong evidence for its direct effects on cognition in MDD.” There may be an association between vortioxetine and increased short-term episodic memory.

In conclusion, this patient may benefit from a switch to vortioxetine. However, it is likely that the anti-depressant effects will be comparable to paroxetine. Potential pro-cognitive effects may not be observable, as he is already in significant decline. Also, Trintellix (vortioxetine) is not yet generic. It costs $451 for a 30-day supply, versus $25 for paroxetine. This could be prohibitive. It was also recommended that the patient participate in psychotherapy. He said he would be willing to try it.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542474/

https://www.ajgponline.org/article/S1064-7481(13)00602-7/pdf

https://clinicaltrials.gov/ct2/show/NCT03779789

https://link.springer.com/article/10.14283/jpad.2019.24

https://pubmed.ncbi.nlm.nih.gov/29634095/

My name is Ben. I’m a medical student from Michigan and these are some of my writings from across the years.

Title

Lisdexamfetamine is an effective monotherapy for moderate to severe binge eating disorder

Clinical-Social Context

Johanna Toma (pseudonym) is a 26-year-old Chaldean-American woman with a past medical history of obesity and disordered eating. She presented to the internal medicine clinic with an interest in controlling her binge eating behaviors and improving her weight management. At a BMI of 36 (Class II obesity),[1] she was at her highest weight and expressed shame over her appearance. “I am too embarrassed and fatigued to go to parties or even work out at the gym.” Johanna is a physician associate student who trains long hours and cares for her ailing parents. Johanna has adequate transportation and food security, but she believes that her mother undermines her weight loss goals by insisting on the family’s traditional high-calorie diet. As she recently aged out of coverage under her parents’ health insurance, she is unsure of the quality of her new plan and whether it covers non-generic medications.

Johanna has a strong understanding of healthy eating, and despite her busy schedule tries to prepare her own food. Her breakfasts include egg whites and tomatoes. For lunch she prepares salads, and often grills fish for dinner. “I do fine until 11 PM. At least five nights during the week I will eat thousands of calories in a less than half an hour. Last week I went to the drive-thru and ate two Whoppers, french fries, and a large shake in the parking lot. I felt physically disgusting after that. And then I did it again three times this week.”

Johanna was told by her primary care physician that this eating pattern constituted obsessive compulsive disorder. She agreed to a trial of fluoxetine up to 40 mg/day but discontinued six months later after realizing the selective serotonin reuptake inhibitor (SSRI) offered no symptom relief and a ten-pound weight gain.

Through social media, Johanna became aware of binge eating disorder (BED) and identified that her symptoms were consistent with this diagnosis. Prior to her clinic visit, she completed the Binge Eating Scale, a 16-question instrument available online.[2] Her score was 28, placing her in the “severe binge eating symptoms” category. As most of her recent care had been provided through her student health center, she questioned whether another primary care clinic was the proper venue to explore weight-related concerns. Johanna believed that weight loss was encouraged by clinicians, yet the strategies she had been given were confined to informational tear sheets about portion control or vague recommendations about regular exercise. She subscribed to the motivational calorie-tracking app, Noomâ, but soon discovered that manually inputting her dietary intake was cumbersome and anxiety-provoking. Since her past efforts at SSRIs, psychotherapy, and self-help were unfruitful, Johanna inquired whether an available medication could help achieve better control over her binge eating. 

Clinical Question

Is there a pharmacological monotherapy that can reduce the frequency of bingeing in patients diagnosed with Binge Eating Disorder?

Research Article Citation

McElroy SL, Hudson J, Ferreira-Cornwell MC, et al. Lisdexamfetamine Dimesylate for Adults with Moderate to Severe Binge Eating Disorder: Results of Two Pivotal Phase 3 Randomized Controlled Trials. Neuropsychopharmacology. 2016;41(5):1251-1260. doi:10.1038/npp.2015.275³

Description of Related Literature

A PubMed search was undertaken in April 2022 using the keywords “binge eating disorder medication treatment”, yielding 987 results. Using additional filters for clinical trial, randomized controlled trial, meta-analysis and publication date within the past ten years, the search was refined to 109 abstracts. As Johanna explicitly discounted non-pharmacological modalities, abstracts focusing on psychotherapy, diet control, physical exercise, purely sociological observations, and other eating disorders were scanned and excluded. This reduced the pertinent publications to 23. Of these, early phase trials, retrospective analyses and redundant publications about the same study were discarded, leaving seven articles for deeper appraisal.

The 2015 McElroy et al. study was a randomized, placebo-controlled trial comparing armodafinil (150-250 mg/day) to placebo for patients diagnosed with BED.⁴ 60 participants were randomized in a ten-week, prospective, parallel-group, double-blind, flexible-dose, single-center trial. The primary outcome measure, improvement in binge eating day frequency, was not statistically different between active agent and placebo. However, armodafinil was more effective in decreasing the frequency of binge eating episodes. Furthermore, armodafinil was associated with greater reduction of obsessive-compulsive features of binge eating and overall BMI. Armodafinil was well-tolerated by the patient population. As the primary outcome measure was not realized, interest in this therapeutic waned, and no further studies are reported in the literature. The medication was never submitted for FDA-approval.

In 2020, McElroy et al.⁵ evaluated the efficacy and safety of dasotraline versus placebo in a randomized, flexible-dose, multicenter clinical trial in adults with BED. The subjects (n=315) were assigned to either 4, 6, or 8 mg per day of dasotraline or placebo over a 12-week double-blind study. Compared to placebo, dasotraline was associated with greater reduction in binge eating days by study’s end (P <0.0001). Although this study was positive, dasotraline encountered other challenges during clinical development and support for the medicine was withdrawn, thus not making this a realistic option for Johanna.

Brownley’s 2013 study examined the dietary supplement chromium-picolinate for BED. 24 overweight adults were enrolled in a six-month, double-blind, placebo-controlled trial.⁶ Subjects received either “high-dose” chromium (1000 mcg), “moderate-dose” chromium (600 mcg), or placebo. In this small single-site trial, the study drug did not demonstrate a statistically significant improvement in binge frequency, weight loss, or symptoms of depression. High-dose groups showed a trend toward improvement in fasting glucose. Although chromium-picolinate is widely available, this study was not chosen for deeper analysis as its preliminary findings did not support a reduction in binge eating frequency.

In 2021, Grilo et al.⁷ evaluated naltrexone and bupropion (NB) for the treatment of BED with obesity.  This was a randomized, placebo-controlled, fixed-dose study (naltrexone + bupropion XL 50/300 mg per day) that investigated 22 adult patients over three months and a six-month post-treatment period. The primary outcome measure was change from baseline of binge eating frequency and overall weight. This study did not reveal significant differences between NB and placebo, although the percentage of subjects on study agent who attained a 3% weight loss was greater than placebo. Johanna’s primary concern was reducing the frequency of her binges. This study found that frequency was unaffected by NB. As the trial was not directly on point, and other agents have emerged as more promising treatments for BED, the Grilo study was not selected for critical appraisal.

In 2019, Safer et al.⁸ published a randomized, placebo-controlled, crossover trial of phentermine-topiramate ER in 22 patients with BED and bulimia nervosa. In this study, participants were randomized to either PHEN/TPM-ER (3.75 mg/23mg – 15 mg/92 mg) or placebo over a 12-week study period. The primary outcome measure was number of binge-eating days over four weeks, with binge abstinence as the secondary outcome measure. The study revealed a statistically significant decrease in the primary outcome measure (P<0.0001). Notably, subjects on active treatment experienced more weight loss than the placebo group. The dropout rate was comparable for both placebo and active agent, and the drug was well-tolerated. This research suggests that PHEN/TPM-ER addresses many of Johanna’s concerns. The product has been commercially available since 2012 (Qsymiaâ). This article was not chosen because the findings of this single-site study were limited by the small sample size. The medication can cause fetal harm and is relatively contraindicated in women with childbearing capacity. It has not been widely adopted by clinicians.

The question as to which monotherapy is most appropriate for symptom management is best answered by McElroy’s 2016 original investigation. This paper outlines the safety and efficacy of lisdexamfetamine (LDX) for BED in two contemporaneous, double-blind, placebo-controlled, multicenter trials. In both studies, which enrolled a combined total of 773 adult subjects, LDX (50 or 70 mg per day) was superior to placebo in decreasing the number of bingeing days per week. Subjects had 2.51 fewer binge days with placebo but 3.87 fewer binge days with LDX, an effect size calculated at 0.97 (P<0.0001; 95% CI). Treatment emergent adverse events (dry mouth, insomnia, headache) were congruent for both studies and mirrored previously published data on the side effects of LDX. This was the largest study to date for the condition and proved pivotal in the FDA’s first approval of a monotherapy for BED.

The use of LDX for BED deserves an A grade according to the SORT system.⁹

Critical Appraisal

McElroy details two prospectively registered studies performed over a 12-week period with weekly visits.¹⁰ 1342 subjects were assessed for eligibility and 569 were excluded soon thereafter. 383 subjects were randomized into study #1 and 390 subjects into study #2. Across both studies, 82 subjects in the placebo arm discontinued and 82 subjects in the LDX arm discontinued, due to adverse events, protocol violations, study withdrawal, lack of efficacy, and other reasons. No subjects of the active arm ended their participation because of lack of efficacy. Subjects on active treatment completed the study at a higher rate.

Subjects were recruited from investigator databases and national advertising. Eligible participants were men and non-pregnant women (ages 18-55) who met American Psychiatric Association guidelines for moderate to severe BED with functional impairment. Other inclusion criteria were BMI between 18 and 45 and a Clinical Global Impressions-Severity score of 4 or greater. Subjects were excluded if they had a non-BED eating disorder, major depression or had recently began receiving supportive therapies.¹¹ Johanna falls squarely within these recruitment parameters.

The randomization was well-executed. Patients were recruited in a consecutive manner using gold-standard rating scales. Comparisons were completed in a blind fashion and the inclusion/exclusion criteria was consistently applied across the many clinical sites. As the two studies were done contemporaneously and produced similar results, the trial can be viewed as highly reproducible. Both LDX and placebo groups had equivalent representation of Whites, Blacks, Asian-Americans, and Native Americans. Women constituted about 85% of the studied population, a number consistent with the current understanding of those who seek treatment for BED.¹² Nonetheless, active recruitment efforts of men would have been advisable as the condition may be even more stigmatized in this group.

The primary outcome in this 12-week study was change in number of binge-eating days from baseline to study end. It appears that all clinically relevant outcomes were reported. The statistical method employed was a mixed-effects model for repeated measures. In both studies, the least squares mean treatment difference significantly favored LDX. LDX was superior to placebo with a robust effect size of 0.97. Other psychotropic medications, such as antidepressants, typically have an effect size range between 0.3 and 0.5.¹³ Secondary outcomes related to binge-eating behavior: changes in weight, vital signs, tolerability, and compliance were also achieved.

Potential biases must be considered. This large research initiative was funded by the pharmaceutical company Shire (now Takeda) and was undertaken to achieve commercial approval. As the study enrollment targets were high, sites of variable quality were included and the data from several sites had to be excluded. Variability between trial sites might have compromised the integrity of the clinical findings. Furthermore, subjects recruited from an investigator’s local database may feel obligated to participate in a manner that nationally recruited subjects may not. Another limitation is that this study obtained short-term data; most patients with BED require long-term treatment. Gasior’s 2017 study reported on the open-label 12-month extension study of the McElroy trials. The researchers found LDX safe and efficacious over the next year, noting a slight but persistent increase in blood pressure from baseline.¹⁴

Although other eating disorders were excluded, the authors did not aggressively exclude the participation of patients with attention deficit and hyperactivity disorder (ADHD). LDX has been approved for ADHD since 2008. BED and ADHD share the common symptom of impulsivity and it is possible that the robust response to LDX was due to the undetected presence of ADHD among study participants. If this is true, the study supports what was already known.

Clinical Application

My interaction with Johanna was limited to a single visit due to the brief duration of my outpatient rotation. During our interview she expressed anguish over her frequent binges and high BMI. She had little confidence that behavioral approaches alone would help her gain control over her disordered eating. She desired a pharmacological intervention and was skeptical that the outpatient clinic was the proper venue for her issues.

Johanna tasked me with exploring whether a viable medication option existed. LDX can cause side effects such as dry mouth, insomnia, and dyspepsia. In McElroy’s trials, 3.1% discontinued treatment due to unwanted side effects and 1.5% had serious treatment emergent adverse events. The activating properties and well-tolerated side effect profile of LDX would likely be acceptable to her. 

I was fortunate to deliver a presentation on LDX for BED to my residents and attendings, which later inspired this paper.

New Knowledge Related to Clinical Decision Science

Johanna had a firm idea of what she wanted when she presented to the clinic. After poor results with behavioral interventions, she desired a pharmacological option to treat her disordered eating. Johanna had limited barriers to care, high health literacy, and motivation to try a new medication. These factors improved her likeliness to succeed if her new insurance made a branded medication feasible.

In general, Johanna’s medical team did not feel comfortable treating her binge eating and elevated BMI with a schedule II drug. Oftentimes, patients with obesity experience implicit bias that they are “lazy” or unwilling to make personal sacrifices for what is considered a lifestyle problem. Physicians might believe that LDX makes patients’ more dependent on external help. It is not hard to imagine how a less-informed patient or one with financial and transportation limitations would experience even greater resistance from their care team.

There is universal acceptance in primary care that high BMI is a risk factor for many medical conditions and that addressing obesity and disordered eating confers direct benefit. One might speculate that ambulatory clinics are uncomfortable using psychiatric medications, particularly controlled substances. Logistic factors play a role; ongoing management of controlled medications require monthly refills and frequent clinic checkups, clear obstacles in a clinic driven by rotating resident physicians. My colleagues were intrigued that LDX was an accepted treatment with an enduring track record of safety and efficacy. Further inroads integrating psychiatric and primary care approaches should be a priority if patients like Johanna are to be comprehensively managed.

Conflict of Interest Statement

The author reports no conflicts of interest.

References

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1. Weir, C. B., & Arif, J. (n.d.). BMI classification percentile and cut off points. NCBI Bookshelf., from https://www.ncbi.nlm.nih.gov/books/NBK541070/

1. Gormally, J., Black, S., Daston, S., & Rardin, D. (1982, January 01). Binge eating scale (BES)., https://psychology-tools.com/test/binge-eating-scale
2. McElroy SL, Hudson J, Ferreira-Cornwell MC, et al. Lisdexamfetamine Dimesylate for Adults with Moderate to Severe Binge Eating Disorder: Results of Two Pivotal Phase 3 Randomized Controlled Trials. Neuropsychopharmacology. 2016;41(5):1251-1260. doi:10.1038/npp.2015.275
3. McElroy SL, Guerdjikova AI, Mori N, et al. Armodafinil in binge eating disorder: a randomized, placebo-controlled trial. Int Clin Psychopharmacol. 2015;30(4):209-215. doi:10.1097/YIC.0000000000000079
4. McElroy SL, Hudson JI, Grilo CM, et al. Efficacy and Safety of Dasotraline in Adults With Binge-Eating Disorder: A Randomized, Placebo-Controlled, Flexible-Dose Clinical Trial. J Clin Psychiatry. 2020;81(5):19m13068. Published 2020 Sep 8. doi:10.4088/JCP.19m13068
5. Brownley KA, Von Holle A, Hamer RM, La Via M, Bulik CM. A double-blind, randomized pilot trial of chromium picolinate for binge eating disorder: results of the Binge Eating and Chromium (BEACh) study. J Psychosom Res. 2013;75(1):36-42. doi:10.1016/j.jpsychores.2013.03.092
6. Grilo, C. M., Lydecker, J. A., Morgan, P. T., et al. Naltrexone + bupropion combination for the treatment of binge-eating disorder with obesity: A randomized, controlled pilot study. Clinical Therapeutics. 2021; 43(1): 112-122.e1 doi:10.1016/j.clinthera.2020.10.010
7. Safer DL, Adler S, Dalai SS, et al. A randomized, placebo-controlled crossover trial of phentermine-topiramate ER in patients with binge-eating disorder and bulimia nervosa. Int J Eat Disord. 2020;53(2):266-277. doi:10.1002/eat.23192
8. Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. The Journal of the American Board of Family Medicine. 2004;17(1):59-67. https://doi.org/10.3122/jabfm.17.1.59 18
9. SPD489 in adults aged 18-55 years with moderate to severe binge eating disorder. https://clinicaltrials.gov/ct2/show/NCT01718509
10. “Treatment for Binge Eating.” American Psychological Association, American Psychological Association, http://www.apa.org/topics/eating-disorders/binge.
11. Thapliyal P, Mitchison D, Mond J, et al. Gender and help-seeking for an eating disorder: findings from a general population sample. Eat Weight Disord. 2020;25(1):215-220. doi:10.1007/s40519-018-0555-5
12. McGough JJ, Faraone SV. Estimating the size of treatment effects: moving beyond p values. Psychiatry (Edgmont). 2009;6(10):21-29.
13. Gasior M, Hudson J, Quintero J, et al. A Phase 3, Multicenter, Open-Label, 12-Month Extension Safety and Tolerability Trial of Lisdexamfetamine Dimesylate in Adults With Binge Eating Disorder. J Clin Psychopharmacol. 2017;37(3):315-322. doi:10.1097/JCP.0000000000000702

Dutch Criteria

Very tangible. Points are distributed into categories that flow with your HPI. Adds up concretely. More of a checklist than a calculator. Ideal for clinic.

Does the patient have elevated cholesterol, family history of FH, and/or family history of premature cardiac death? If yes, then continue.

Family History

(1 point) First-degree relative with premature coronary and/or vascular disease

(1 point) Male relative <55 years, female relative <60 years

(1 point) First-degree relative with known LDL >95th percentile for age and sex

(1 point) First-degree relative with tendon xanthomata and/or arcus cornealis

(1 point) Children <18 years with known LDL >95th percentile for age and sex

Clinical History

(2 points) Patient with premature coronary artery disease

(1 point) Patient with premature cerebral or peripheral vascular disease

Physical Examination

(6 points) Tendon xanthomata

(4 points) Arcus cornealis at age <45 years

Cholesterol Level

(8 points) LDL-C ≥8.5 (330)

(5 points) LDL-C 6.5 – 8.4 (250 – 329)

(3 points) LDL-C 5.0 – 6.4 (190 – 249)

(1 point) LDL-C 4.0 – 4.9 (155 – 189)

DNA Analysis

(8 points) Functional mutation of LDLR, apoB or PCSK9 gene

32 possible points. Greater than 8 = Definite familial hypercholesteremia. Between 6-8 = Probable familial hypercholesteremia. Between 3-5 = Possible Familial Hypercholesteremia. Less than 3 = Unlikely familial hypercholesteremia.

Simon-Broome Diagnostic Criteria

More of a calculator than a checklist. You need a computer or smartphone for this. Some of the criteria are convoluted and the specifiers make you think twice. Must know which cholesterol values are considered high/moderate/low if you are using this freehand. The official diagnostic criteria uses mmol/L as opposed to mg/dL. Fewer categories of specification compared to Dutch Criteria.

You must enter the patients age (are they older or younger than 16?). Then you must enter their total cholesterol. Then you must enter their LDL cholesterol. After that, you must answer select Yes or No for the following:

+1 points: Total cholesterol > 290 or LDL-C > 190

+1 points: Tendon xanthomas in the patient or tendon xanthomas in a 1^st/2^nd degree relative

+1: DNA-based evidence of an LDL-receptor mutation/defective apo B-100/PCKS9 mutation

+1 points:  Family history of MI before age 50 in a 2^nd degree relative or before age 60 in a 1^st degree relative

+1 points:  Family history of elevated total cholesterol >289.6 mg/dL (7.5 mmol/L) in adult 1st or 2nd degree relative or >258.7 mg/dL (6.7 mmol/L) in a child or sibling <16 years

Definite FH:

Cholesterol >7.5 mmol/L or LDL-cholesterol >4.9 mmol/L in adult

Cholesterol >6.7 mmol/L or LDL-cholesterol >4.0 mmol/L in a child under 16 years of age

PLUS

Tendon xanthomas in patient or a 1st degree relative (parent, sibling, child),

or in a 2nd degree relative (grandparent, uncle, aunt)

OR

DNA based evidence of a functional LDLR, PCSK9 and APOB mutation

Probable FH:

Cholesterol >7.5 mmol/L or LDL-cholesterol >4.9 mmol/L in adult

Cholesterol >6.7 mmol/L or LDL-cholesterol >4.0 mmol/L in a child under 16 years of age

PLUS

Family History of myocardial infarction (MI) before 50 years of age in a 2nd degree relative

or below age 60 in a 1st degree relative

OR

Family history of raised total cholesterol – >7.5 mmol/L in adult 1st or 2nd degree relative

or >6.7 mmol/L in a child or sibling aged <16 years

US (MEDPED) Diagnostic Criteria for Familial Hypercholesterolemia

Simple calculator with three parameters. The easiest of the bunch to enter on a computer. Requires the least amount of information, and yields the weakest results.

Diagnostic Criteria:

Age: <20; 20-29; 30-39; >40

Closest degree relative with confirmed FH diagnosis: 1^st degree; 2^nd degree; 3^rd degree

Total cholesterol:

AN is a 34-year-old male with a PMHx of spina bifida, hydrocephalus, and Arnold Chiari malformation. The patient has been wheelchair-bound his entire life. Like many with myelomeningocele who survive in adulthood, AN has acquired chronic ischial/decubitus pressure ulcers. His condition has been further compounded by infections and chronic osteomyelitis. Poor executive functioning is a known association in patients with SB, and this was apparent.

RD had been discharged from the ED after a bout of severe headaches. During his visit, he requested a referral for a homecare provider, repairs on his wheelchair, and a script for more catheters. After combing through the patient’s history and researching spina bifida I learned that poorly managed patients with severe SB tend to follow a predictable course. A preventable inciting event (i.e., infection) leads to a chronic pattern of deterioration. Despite good treatment, with each hospital visit their condition regresses. Finally, the patient succumbs to a complication.

On physical examination, it was obvious that AN’s wounds had been neglected. His time is divided up between three locales: at home with his mother and aunt, nursing home, and at the hospital. Over the course of the past few months, he received care in a nursing home. AN mentioned how it was boring and that he was always the youngest person there. During his stay, he failed to follow up with his wound care, as a return to the nursing home would entail a mandatory 14-day quarantine. He did not want that degree of isolation. Since his release from the facility, he was not able to find transportation to his wound care clinic because his brother’s girlfriend’s car broke down. He mentioned that his mom had diabetes and expressed gratitude that his aunt brought him a couple pieces of pizza the other day. I sensed that AN’s poverty of care at home was related to his frequent in-patient visits.

AN is dependent on the system. He does not have the benefit of the reliable middleman that is family. As he ages, his trajectory is becoming more apparent. His medical record is populated with intensive hospital visits, several times per month and for days on end. He has been admitted to the ED 14 times in the past two years. His Risk of Admission has reached 90%. EMS picked him up a couple days after our appointment. He is currently back in the hospital and is receiving IV fentanyl.

A 2014 article in the NEJM, “The Hospital-Dependent Patient,” helped put this patient’s story into perspective. HDPs are not on life support or ventilation. They are not necessarily old and do not have a terminal illness. Rather, HDPs are characterized by multiple chronic conditions and frequent readmission after less than 30 days. This is not an indictment of the care they receive in the hospital, but rather on its irreproducibility when they return home. A passing analogy here might be like an inmate who would rather return to the controlled environment of prison than the streets. HDPs are “precariously and transiently compensated while hospitalized.” The hospital becomes their home; doctors and nurses become family. There is no feasible alternative. The answer is not in skilled nursing facilities or more social work involvement or better transportation services.

This reflection does not aim to find any epiphanies regarding AN’s care. I have been looking for a meaningful intervention but could not find anything. Every measure has been taken to preserve his life. But even modern medical care has its limits. The increasing frequency of his hospital admissions and his inability to care for himself leads me to believe that AN is approaching a breaking point.

I expect to see AN in the hospital over the next couple of months. I hope to have the opportunity to get to know him and to better understand his wants and needs.

MK is a 59-year-old male who presented with a chief complaint of epistaxis. He has a past-surgical history of carotid artery endarterectomy and percutaneous coronary stent placement. He had a total occlusion of the RCA and a 70% occlusion of the LAD that approached 90% at the ostium. Two drug-eluting stents were inserted into the LCX in December 2020, and a third was placed in the proximal LAD this past February. A third PCI/DES is planned imminently.

MK had been on dual anti-platelet therapy (aspirin + ticagrelor) since the beginning of March. Over the past week or so, he presented to the Garden City ER after he began experiencing nose bleeds. No blood work was performed, and the patient was instructed to put gauze in his nares. In his follow-up visit to the clinic on April 20, MK brought his medications. ROS was positive for nosebleeds but negative for hemoptysis/hematochezia/hematuria. He had recently acquired a bottle of clopidogrel although this med was not found in his chart. Between the aspirin, clopidogrel, and ticagrelor, the patient was confused as to which pills to take and when. We instructed him to discontinue the ticagrelor. Instead, we clarified that he is to take one aspirin and one clopidogrel per day. His next visit with his cardiologist is on May 27.

What is this patient asking us to “get smart” about? On the most immediate level, he wants us to help him lower his risk of minor bleeding (i.e. from the nose). We take that one step further by also considering the possibility of major bleeding. A goal is a pharmaceutical alternative that ameliorates epistaxis while first and foremost maintaining stent integrity. We must also consider that the patient has many co-morbidities, is a poor historian, and his medication compliance is uncertain.

Both ticagrelor and clopidogrel are PGY12 inhibitors that prevent platelet aggregation. This class is indicated for finite periods of time in high-risk patients after the placement of a coronary stent. Anti-platelet agents reduce the risk of thrombosis and therefore Major Acute Coronary Events (MACE).

I reviewed an original investigation from JAMA Internal Medicine: Association of Ticagrelor vs Clopidogrel with Major Adverse Coronary Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (2020). The study compared the risk of MACE in patients prescribed one of the two drugs after PCI. All subjects took aspirin concurrently. It concluded that outpatient use of ticagrelor is not superior to clopidogrel in lowering the risk of MACE. The adjusted analysis demonstrated that ticagrelor does increase the risk of major bleeds compared to clopidogrel. There was no mention of nosebleeds.

In the study of over 11,000 subjects, clopidogrel was the more frequently prescribed anti-platelet after PCI (63.6%). Clopidogrel users were more likely to have serious co-morbidities. Ticagrelor users were younger and tended toward fewer cardiac risk factors and comorbidities. Patients taking ticagrelor were reported to have higher adherence. However, 14% of ticagrelor users switched their anti-platelet during the course of the study; this only occurred in 2.3% of the clopidogrel arm. Ticagrelor was associated with a higher incidence of major bleeding, and its users were more likely to report to the ED for dyspnea.

MK would be optimally served with an anti-platelet plus aspirin. Clopidogrel and ticagrelor are equivalent when it comes to preventing post-PCI MACE. The best choice for him is a matter of adherence, which could be encouraged with a written-out medication schedule and blister packs. The patient mentioned how he did not like taking ticagrelor twice a day. The clopidogrel dose calls for one a day. It has the added benefit of lowering his risk for major bleeding, and to that end minor bleeding.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2758798

A 55-year male-old with PMHx of hand surgery, hypothyroidism, COPD, asthma, OSA, pre-DM, CAD with LCX stent, shoulder surgery, and chronic pain presents to the clinic with a chief complaint of chronic hand swelling.

His physician is tempted to diagnose early rheumatoid arthritis. Some risk factors are there: heavy smoker, family history of RA, and prior autoimmune disease. Parts of the description match up: painful/swollen hands and fingers, morning stiffness, symmetric joint involvement, decreased physical functioning, and QoL.

It passes the Squeeze Test: pain is elicited at the MCP joints when the physician grips the patient’s hand, above the wrist and below the proximal knuckles. (This is a casual clinical test and has low specificity).

There is only one problem. It fails the Pulp Test (not an actual test). In other words, all pertinent labs are negative. ESR is 2. CRP is 3. Anti-citrullinated protein antibody is within the reference range.

Well, two problems. Imaging also discourages the diagnosis of RA. From a December 2020 X-Ray:  Bone mineralization is normal. There is no fracture or dislocation. Joint spaces are maintained overall. Carpal alignment and interspacing are maintained. Mild osteoarthritic changes of the first IP joint noted bilaterally, right worse than left. IMPRESSION: No acute abnormality.

This patient is suffering from some form of arthritis. But we wanted to know if it is possible to diagnose Rheumatoid Arthritis without relying on labs. Yes, it is. Barely. You must have many joints affected to make up for negative serology.

According to a 2018 JAMA paper, Diagnosis and Management of Rheumatoid Arthritis, no diagnostic criteria exist for RA. There is, however, a quick table of classification criteria joint-authored by the American College of rheumatology and the European Union League Against Rheumatism. Another paper, Annals of Internal Medicine: Rheumatoid Arthritis (2019), provided a more detailed explanation of this table. Please see the attachment. I have highlighted and underlined select pages and sections that are most vital for making a diagnosis in this patient.

The table uses the following categories to diagnose RA: 1) joint involvement and distribution 2) serology 3) acute phase reactants 4) duration of symptoms. Our patient scored six out of 10. Six is the minimum score to pass for “definite RA.” He earned most of those points from the joint involvement category. Interestingly, joint involvement nets up to five points; serology and acute phase reactants combine for only four. Duration of symptoms accounts for the last point.

Given the importance of assessing the small joints one by one, next time I would perform the squeeze test five times per hand, each time asking about the middle joint, thumb joint, etc. That would enable me to count the number of joints affected, rather than making assumptions about the entire hand. I gave the patient the highest score in this department, but that was an estimation.

It turns out the labs and imaging are not as important as I initially thought. 30% of patients with RA have normal labs. Synovial fluid analysis is not required to make a diagnosis. Radiographic findings are not required to make a diagnosis.

We are still not sure if our patient has RA, as there are several disease processes that can cause hand pain and swelling. He has been referred to a rheumatologist.

In 2009, the NIH launched the Human Connectome Project. This endeavor centers on the functional mapping of white matter circuitry in the human brain. Like other esoteric neologisms sandwiched between “Human” and “Project,” we should automatically assume that the summit will prove elusive. Our current technological capabilities have allowed us to capture the form of unknowable biological systems, but the dizzying extent of function is another story. Although the Human Genome Project was completed in 2003, its aftershock is still reverberating. Now researchers are grappling with the epigenome and the transcriptome and non-coding RNA. This is the era of personalized medicine, and it is easy to see parallels here with the experts studying in vivo nuances of diseased, aging, and healthy brains. In theory, a fully-realized connectome could make neurology and CNS surgery a purer science. Despite great leaps in the field of imaging, the project remains incomplete. But that is an unsatisfying characterization. There are many scenic vistas to gawk at on the journey to the top – and we are a mile up from the bottom.

In their 2017 NMR in Biomedicine paper “Diffusion MRI fiber tractography of the brain,” Jeurissen and colleagues discuss the current landscape and limitations of white matter fiber tracking. This burgeoning field has been fruitful for the clinical research and surgical treatment of a variety of neurological conditions like epilepsy and Alzheimer’s, but the authors present a balanced argument that will surely deflate the temerity of those who may consider d-MRI tractography the last frontier of neuroscience. There is a difference between a “tractogram” (awesome reality) and the “connectome” (fantasy?) Let’s say a patient with a neurodegenerative brain disease is looking for answers about his diagnosis. He asks his neurologist: “where?” That question can be addressed with sophisticated neural cartography. He then follows up with “how?” and “why?” The physician pauses. “You are your connectome.”¹ Now we are entering murkier, borderline-philosophical waters. Until his aphorism can be boiled down even the most eminent researchers are relegated to educated estimation. 

White matter is sheathed in myelin, a fatty coating of sterols and glycolipids that insulates the axon and restricts the movement of water molecules. Myelin water molecules are “bound;” they collide infrequently and have a shorter spin-spin relaxation, yielding a rather long correlation time. Therefore, a very brief echo time is required to detect the myelin water signal. These functions help distinguish white matter from its gray counterpart and cerebrospinal fluid. White matter tractography utilizes a special form of MRI called Diffusion MRI or, specifically, Diffusion Tensor Imaging (DTI). Mori and Tournier state that “the concepts behind DTI are commonly difficult to grasp, even for magnetic resonance physicists.”2 That assertion checks out, but if you can gauge the rate of water diffusion inside the brain, the shape and orientation of fatty axonal fibers can be deduced in any given voxel. A sizeable collection of voxels is then pieced together to create a three-dimensional map of computed vector fields. In DTI, eigenvalues and eigenvectors are used to assess the diffusion properties of tissue. A starting or “seed point” is chosen in the white matter, or alternatively, the white-gray matter barrier and the orientation is calculated in order to depict the streamline or the estimated path of the fiber. 

According to the authors, this recently posed a major problem. Older DTI technology was only capable of showing a single fiber population per voxel. That might have been fine for regions of sparsely populated fibers, but it is known that shorter fibers are densely packed and entangled entities. They cross over and under each other. This leads to false positives (assuming the track continues) and false negatives (assuming the track ends when it does not). But over the past few years, advanced modeling methods have managed to represent multiple fiber populations per voxel. This development is key to traversing the subcortical labyrinth. Surprisingly, old-school DTI still reigns supreme in clinical practice. One has to believe that the higher-order models will take the throne soon. Perhaps DTI-based tractography is less expensive, more familiar, and just flat-out good enough for all intents and purposes. 

After fiber orientations have been acquired, their trajectories must be established. This is done by Euler integration for outmoded DTI, or Runge-Kutta integration for the latest iterations. The goal is to collate the distances (step size) from one point on the fiber to the next. When employing large step sizes, interpolation errors become more pronounced and track-tracing veers off course. Therefore, higher-order integration methods and small step sizes seem to be the best recipe for accuracy. We can see how technological advancements in these methods – be it in modeling or integration – have launched the connectome industry into a truly HD age. Still, a review of interpolation methods reminds us that these measurements are nevertheless approximations. On one hand, we have the error-prone nearest-neighbor interpolation, and on the other, the more precise trilinear interpolation. Errors from tri-linearly interpolated streamlines do not stray as far from the seed point. 

But a tract without a good seed point is like the scribble of a toddler who takes a crayon to his Denny’s menu maze at a spot other than the designated entryway. How do experts know where to begin? Well, they need a deep knowledge of neuroanatomy and a ballpark understanding of functional connectivity. Then they can designate regions of interest (ROIs), which may be local or global. The global method is known as whole-brain tractography, and if one really wants to achieve connectome actualization, it is necessary to visualize this big picture. Researchers should be wary about their method of seeding though. White matter seeding leads to overemphasis of the most prominent bundles. White-gray interface seeding provides better contrast, but due to the relative lack of seeds, may contain errors while failing to capture the entirety of the white matter circuit. In those circumstances, the researcher needs to know when to terminate the track. Older DTI used fractional anisotropy to gauge precipitous drops in white matter; the leading-edge models utilize the continuous fiber orientation function.

Once mapped, a variety of techniques are used to “virtually dissect” and group the white matter bundles into coherent anatomical structures. Algorithms estimate the relatedness of a given tract to its seed of origin, thus making inferences on the degree of functional connectivity between the two points. These algorithms are a topic of contention. A researcher may subscribe to the straightforward deterministic approach. He might believe that the fiber orientation data contain self-evident structural truths. He might not worry about the shortcomings of the local approach to tractography, exemplified by streamlining, which can be done quickly, but is prone to interpolation missteps and may sometimes highlight phantom fiber tracks. A different researcher may idealize a global approach to tractography, but this brand also carries baggage. Global methods offer a better signal-to-noise ratio and minimize artifacts, but their implementation can be infinitely complicated to the point of being impractical. And they, too, can lead to phantom fiber tracks.

Pragmatists though, as the authors claim to be, would likely support a more agnostic ideology. Probabilistic tractography maintains that there is a chance that the fibers have a particular orientation, but also a chance that they do not. The proof is in the k-space distribution and is dependent on the particular faction of probabilistic fiber tracking to which they belong. Some adhere to the notion that there is a “dominant” fiber orientation in a given voxel, while others hold that each voxel contains a diverse array of orientations. The latter school, based on the continuous fODF model, is associated with more anatomically accurate tractograms. That makes sense; white matter fibers are not interstate highways. There are curves and complexity and randomness to account for, so to assume a dominant orientation would be to ignore the fact that fibers can be more like winding country roads. The authors maintain that while the two schools of thought have different aims, they in fact complement each other. I can see that too. There will always be opposing viewpoints in science and academia. To solely endorse one over the other would be like a present-day psychologist claiming to be a Freudian or a Jungian or a Skinnerite. Each pioneer enriched and influenced the field. None of them ran away with it.

No singular method for demystifying the connectome predominates because they are all fraught with quantification problems. There are too many confounding variables. If you’re targeting the frontal pathways, orientation data from the temporal pathway will suffer. And it seems that advanced imaging techniques are still stymied by unpredictable regions of crisscrossed fibers. Track density imaging (TDI) has offered a solution, one that offers vivid anatomical contrast and high resolution. But of course, there is a trade-off. TDI uses millions of seed points, which actually “hides” noise and can therefore give the mere illusion of accurate mapping. It is also biased toward long-fiber tracks. The authors go so far as calling TDI fundamentally non-quantitative, unless used it in short-track mode with globalist filtering techniques. One gets the impression that no tracking program is universally perfect in isolation, but when supplemented with further refinement processes, the end result will be a pretty good set of images.

But those working on the Human Connectome Project seek more than just a static representation of anatomical structure. We are living in the post-structural age, after all. We are looking for function, for connection, for meaning. Will dominant-pathway tracking deliver? Definitely not. It oversimplifies the subcortical terrain. What about global tracking? There’s more potential here, but water follows the path of least hindrance. Two entangled fibers will influence and blur each other’s diffusion pattern. This creates errors over the long game. Diffusion blurring adds ambiguity to white fiber architecture, making it exceedingly difficult to follow distant connections. We should “curb our enthusiasm,” the authors say. One solution is the application of biologically realistic priors, which ideally terminate in the gray matter. These anatomical constraints offer a template that prevents coloring outside the lines, as it were. As the connectome project has matured, researchers have started to think beyond the white matter itself; where tracks start and end are of paramount importance to functional connectivity. The most recent models utilize multiple diffusion weighting strengths to account for the differences in brain matter composition.

For all its ingenuity, dMRI is at its core a qualitative method. That’s not a bad thing. When rendered and colorized, its images are at once masterful artworks and informative atlases worthy of their ubiquitous splashing on the covers of new textbooks and journals. To fault dMRI for its imperfection in quantification is like criticizing the cameras on the International Space Station for not being able to exact the edges of a pebble. White matter fibers branch, kiss, bottleneck, cross over and under each other. Spatial and angular resolution limitations underrepresent their manifold dimensions of repose. False positives and false negatives abound. The truth is that today’s non-invasive technology cannot isolate tangled neurons. At least on the practical level required for a connectome eureka. Even if they could, then what? Alfred Korzybski said it best: “The map is not the territory.”

It is no surprise that the Human Connectome Project is a work in progress. This is new stuff. It is going to take time. And money. Speaking of which, where is the money? Cutting-edge neuroimaging is not a cheap pursuit. For this project, the NIH awarded less than $40 million in grant money across several institutions over five years. That’s $8 million per year, which is about 0.0002% of the budget. Chum change. But it’s understandable. Diabetes and oncology research presents a more immediate public need and benefits from foreseeable interventions. Connectome funding will follow once breakthroughs in technology translate into solutions for medicine. On the HCP’s website, they list as their number one goal to “develop sophisticated tools to process high-angular diffusion (HARDI) and diffusion spectrum imaging (DSI) from normal individuals to provide the foundation for the detailed mapping of the human connectome.”³ The authors of this year-old paper described many of these sophisticated tools, but did not so much as mention HARDI and DSI. Perhaps it was beyond their scope. Or perhaps the sands of neuroimaging technology are shifting quicker than medicine can keep pace. 

This has been a review of the following publication:

Jerrissen B, Descoteaux M, Mori S, Leemans A. Diffusion MRI fiber tractography of the brain.

NMR in Biomedicine. 2017;e3785.

Other Citations:

¹: Dr. Francis Collins

²: Introduction to Diffusion Tensor Imaging (Second Edition) by Susumu Mori and J-Donald    Tournier, 2014

³: www.humanconnectomeproject.org

A Review of a Novel and Needed Treatment Option

Benjamin Young

Master of Science in Basic Medical Sciences

Wayne State University

September 2018

Table of Contents

Introduction…………………………………………………………………………..….……1

Search Methods…………………………………………………………………….….…….3

Background on Treatments for Depression: Medications………………………….………..3

Background on Treatments for Depression: Somatic Therapies…………………….………4

Patient Non-Responsiveness to Treatment: The STAR*D Study……………….………..…5

A Brief History of Ketamine…………………………………………………………………6

Glutaminergic Transmission………………………………………………………….………8

Ketamine Pharmacology………………………………………………………….….………8

Animal Models Lead to Initial Human Subject Studies …………………………………….9

First Ketamine Study in Depression…………………………………………………………11

Epidemiology and Morphology in Treatment-Resistant Depression…………………….…12

Ketamine Trials in TRD……………………………………………………………………..12

Ketamine and Suicidality……………………………….…………………………………….13

Ketamine as an Adjunct to ECT …………………………………………….………………..14

Development of Esketamine…………………………………………………………………15

First Clinical Trial of Esketamine in TRD …………………………………………………16

Ketamine in PTSD…………………………………………………………………………….16

The March to FDA Approval……………………………………………………………. ….18

Safety Concerns……………………………………………………………………….………18

Is the Anti-Depressant Effect Mediated by Opioid System?……………………………………………19

Summary and Conclusions……………………………………………………….………….20

Figures/References………………………………………………………………………..……22

Biographical Sketch…………………………………………………………………………26

Introduction

The old is new again, and ketamine, a 50+ year-old anesthetic for humans and animals, is now under active consideration for patients with treatment-resistant depression (TRD) and post-traumatic stress disorder (PTSD). Modern life has become decentralized, digitized, and depressed, phenomena that collectively contribute to the growing prevalence of psychiatric conditions. Major Depressive Disorder (MDD) affects nearly 7% of the American population per year and is the leading cause of disability worldwide.[i] TRD is a common subtype of the condition in which the patient has gained little or no relief from depressive symptoms after two or more trials of traditional antidepressant medications. It is estimated that one-third of depressed individuals experience treatment resistance.[ii] These patients endure recurrent episodes of depression, poor quality of life, and functional impairment.[iii] PTSD is a psychological disorder that can develop in any person who has experienced a life-threatening event. Those affected have severe anxiety, flashbacks, insomnia, intrusive thoughts, and tend to avoid triggering stimuli.[iv] Woven within this constellation of symptoms is an epidemic of opiate abuse and high rates of suicide. Outpatient clinics and emergency rooms are saturated with patients requiring immediate relief from their symptoms. Although psychiatric conditions have traditionally been stigmatized, American society is finally recognizing the public health impact of mood disorders. Initiatives like the Mental Health Parity Act and the Affordable Health Care Act were designed to and are succeeding at improving access to care.

Innovation is the human response to need. Interest has peaked in the ketamine molecule, an antagonist of the N-methyl-D-aspartate receptor (NMDAR), after reports of its rapid-onset antidepressant properties. Original basic science and clinical research of the topic has been prodigious with scores of articles emerging in the past few years. This attention has been spurred by the growing realization that currently available antidepressant medications and somatic treatment modalities have limited efficacy in vast segments of the psychiatric population. 

The purpose of my paper is to explore the current landscape of therapeutic ketamine in light of an evolving understanding of TRD and PTSD. I will offer some background on the limitations of current antidepressant treatments and why ketamine is now entering the conversation. The history of ketamine, from synthesis to animal studies to recently published human trials, will be examined, and the proposed mechanism of action will be elucidated.  I argue that the bulk of available data suggests that clinical administration of ketamine is safe and worthwhile, particularly for imminently suicidal patients. Its presence on formularies will offer clinicians a sharp contrast to familiar medications, and in some circumstances, ketamine will outperform mainstream treatments. Yet resistance against the rapid adoption of ketamine is necessary to ground both practitioners and mental health consumers. This check is particularly needed in light of the commercial interests propelling the development of a potential blockbuster.[v] Caution is amplified by recent reports that ketamine exerts its therapeutic benefits via the endogenous opioid system. While this might account for its analgesic effect and rapid mood improvement, chronic administration may promote dependency and prove deleterious.[vi] For these reasons, the pending adoption of esketamine by the FDA should be met with healthy skepticism. Until more is known, ketamine should be approved only for short-term use in acute TRD. Clinicians who specialize in the diagnosis and long-term management of depression and related conditions should play a central role in ketamine’s emerging application.

Search Methods

Using Google Scholar and Pubmed, literature searches were conducted for the years 2000-2018. Keywords entered were “ketamine for depression,” “esketamine,” “treatment-resistant depression,” “PTSD,” “ECT” and “opioids/opiates.” These words were combined with “selective serotonin reuptake inhibitors,” “glutamate and depression,” and “new antidepressant medications.” In addition to scholarly sources, searches of the popular press such as The Washington Post and certain trade periodicals were included. These articles often served to explain the larger context of more focused scientific findings.

Background on Existing Treatment for Depression: Medications

The principles behind the treatment of depression are changing. Since the 1960s, the monoamine hypothesis has been dominant. This theory maintains that symptoms of depression are caused by a deficiency of the neurotransmitters serotonin, dopamine, and norepinephrine.[vii] To correct this “chemical imbalance,” monoamine oxidase inhibitors (MAOs) and tricyclics (TCAs) emerged during the mid-20^th century. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitor (SNRIs) were famously introduced two decades later. Lacasse and Leo argued that Pfizer’s brilliant marketing strategy for Zoloft (sertraline) misled the public into believing that a serotonin deficiency is the root cause of depression.[viii] Indeed, the monoamine hypothesis provides a simplified explanation of the actual biochemical mechanisms which drive affective disorders in the central nervous system.[ix] Furthermore, the clinical success rates of these ubiquitous medications are underwhelming. Many patients with complicated depression undergo sequential courses of medication from different antidepressant classes in an effort to augment efficacy and minimize side effects. Monoamine antidepressants, prototypically the SSRIs, fluoxetine and sertraline, and the SNRIs, venlafaxine and duloxetine, diminish libido and cause weight gain. They have a long latency of onset and often fail to address the full range of depressive symptomology. With the exception of vortioxetine in 2013, there has been minimal development of novel antidepressants in the new millennium.[x] Pharmaceutical companies have shifted research and development to other pressing and more lucrative opportunities in oncology and diabetes. Before the recent ground swell of interest in ketamine, few “new” antidepressants were on the horizon.[xi]

Background on Existing Treatments for Depression: Somatic Therapies

Somatic treatments are chosen when medication trials have been exhausted. Electroconvulsive therapy (ECT) has been a mainstay for more than 60 years. Vagus nerve stimulation (VNS) and repeated transcranial magnetic stimulation (rTMS) have been introduced in the last 15 years.[xii] Historically, the most rapid means for mitigating severe depression has been electroconvulsive therapy. ECT was first implemented in 1940s to treat schizophrenia, later gaining adoption for mood disorders. Immortalized by dramatic depictions in films such as One Flew Over the Cuckoo’s Nest (1975) and Requiem for a Dream (2000), ECT remains a controversial and stigmatized practice. ECT machinery is considered a “high-risk medical device” by the FDA and the procedure is generally used as a last resort for treatment-resistant depression.[xiii] ECT involves unilateral or bilateral placement of electrodes onto the skull. A series of electrical pulses is administered, putting the brain into a controlled seizure. It is proposed that ECT alters the pattern of blood flow and stimulates the production of neurotrophic factors in the medial temporal lobe, resulting in the changes to the hippocampus.[xiv] General anesthetics are required, usually short-acting barbiturates, Propofol, or at times ketamine. Major side effects include retrograde amnesia and cognitive impairment. These cognitive consequences may be due to widespread saturation of the glutamate receptors, which play a role in learning and memory.[xv]

Efforts have been made to develop better-tolerated somatic treatments for mood disorders. Transcranial magnetic stimulation (TMS) is a non-invasive procedure which uses repeated electromagnetic induction to stimulate a targeted region of the prefrontal cortex. Despite early high hopes, the clinical utility in mild to moderately depressed patients is equivocal, with little confidence that the treatment is appropriate for TRD. Vagal Nerve Stimulation (VMS) sends electrical signals to the vagus nerve, the tenth cranial nerve. This procedure requires surgical intervention and demands that the patient adapt to an implanted nerve stimulator. Patients must tolerate periodic hoarseness when the modulation is active. Insurance coverage has been spotty for this elaborate program and uptake by the psychiatric community has been minimal.[xvi]

Patient Non-Responsiveness to Treatment: The STAR*D Study

Although fluoxetine and its successor analogues proved helpful in treating uncomplicated depression, clinical concerns have shifted toward SRI non-responders. In 2006, the National Institute of Mental Health completed a large-scale study that examined how patients responded to subsequent treatment after the first round of antidepressant medications had failed. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study involved over 4,000 subjects and was conducted across 41 clinical sites in the United States. The objective of this seven-year study was to determine the efficacy of available medications.[xvii]

The elaborate study design involved four different treatment levels. At level one, subjects were given the SSRI, citalopram for up to 14 weeks. Responders (50% reduction in depressive symptoms) were diverted into a naturalistic study, but non-responders were encouraged to enter level two. In level two, patients were randomized to several different medications (sertraline, bupropion-SR, or venlafaxine-XR) and given the option to participate in concurrent cognitive behavioral therapy (CBT). Subjects who did not respond entered level three, where their antidepressants were augmented by either lithium or triiodothyronine. Those who were still symptomatic proceeded to level four and were given either tranylcypromine, a MAO inhibitor antidepressant, or a combination of venlafaxine-XR and mirtazapine. Only 142 subjects remained in the study to level four.

The STAR*D study revealed that the response rate to antidepressants was much lower than anticipated. Remission rates were only 33% for level one. Level two revealed that combinations of antidepressants acted more rapidly than adding CBT to one antidepressant. Remission rates in levels three and four were 12.3% and 13% respectively. The authors glumly conclude that “patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish with every additional treatment strategy needed.”[xviii] 

The STAR*D study had limitations. The protocol did not include any somatic treatment such as ECT or rTMS. The study was conducted over such a long period that less than a tenth of the participants survived to the end. Notably, STAR*D muted the enthusiasm for existing therapies and spurred interest in alternative avenues. Next-generation treatments needed to be more rapidly-acting, better tolerated, and exert improved remission rates for treatment-resistant patients.[xix]

A Brief History of Ketamine

The ketamine molecule was synthesized in the early 1960s by Wayne State University professor Calvin Lee Stevens.[xx] Prior to this development, phencyclidine (PCP) saw widespread use as a surgical anesthetic and experimental psychoactive medication. PCP had serious postoperative effects, such as paranoia, convulsions, agitation, and disorientation upon emerging from induction. Initial tests of ketamine as an anesthetic began in 1964, when University of Michigan researchers Edward Domino and Guenter Corssen examined the clinical effects on 130 surgical patients ranging in age from 6 weeks to 86 years.[xxi] They discovered that subjects experienced greater tolerability with ketamine compared to its sister NMDAR antagonist, PCP. The most notable adverse effects associated with ketamine – elevated heart rate, nausea, a feeling of unreality, and disorientation – were transient.[xxii] The new drug received the green light as an anesthetic from the FDA in 1970.

Deemed a “dissociative anesthetic,” ketamine proliferated worldwide. It was adopted as a quick-acting and easily-administered analgesic during the Vietnam War, where it was favored over morphine due to its limited effect on respiratory depression. In 1985, the World Health Organization (WHO) included ketamine in the Model List of Essential Medicines. Veterinary clinics incorporated the anesthetic into daily practice. Ketamine is still used and researched in animal medicine.[xxiii]

Ketamine’s descent into controversy began when New Age practitioners became intrigued with ketamine’s euphorigenic and dissociative properties for use in psychotherapy.[xxiv] Owing to its “essential medicine” status and stockpiling at veterinary clinics, the drug was exploited for recreational purposes. The array of psychedelic symptoms – detachment, disorientation, loss of inhibition, word slurring, and a floating sensation – is colloquially known as a “K-hole.” Ketamine became a notorious club drug and “date-rape” agent.[xxv] Skepticism delayed clinical explorations in psychiatry and it was not until the turn of the 20^th century that serious research began on ketamine’s antidepressant effects.

Glutaminergic Transmission

Ketamine targets the glutaminergic system, and it is important to understand how it affects the glutamate receptors in depression and other mood disorders. Glutamate is the most abundant neurotransmitter and is considered the “master switch” of the CNS.[xxvi] It enhances synaptic connections in the brain and plays a fundamental role in learning, memory and neuroplasticity. Glutamate is highly concentrated in the synaptic terminals, where its two most significant ionotropic receptors reside: the NMDA receptor is more slowly activated and is permeable to calcium, while AMPA is impermeable and quick-acting. Under normal circumstances, the binding of glutamate (and glycine) to the NMDAR permits calcium influx via allosteric dissociation of the gatekeeping Mg+ plug.[xxvii] Depressed patients have lower mitochondrial energy production in their glutamatergic neurons, which results in dysfunctional clearance and metabolism of glutamate.

Ketamine Pharmacology

Ketamine ((R,S)-2-(2-Chlorophenyl)-2-methylaminoclyclo-hexanone) is a noncompetitive NMDA receptor antagonist. It is both water and lipid soluble and can be absorbed through all standard routes of administration. It selectively binds to the PCP-binding site on the NMDAR with a tenfold lower potency than PCP itself. Ketamine modulates pain through complex interactions with numerous classes of receptors, including opioid receptors, nicotinic/muscarinic receptors, the monoaminergic system, and the GABAergic system. Ketamine preferentially blockades the NMDAR, and consequent disinhibition of pyramidal GABAergic neurons permits AMPA receptor upregulation and increased downstream glutamatergic signal transmission.[xxviii] The synaptic cleft experiences an increase in glutamate that heretofore would have been directed toward the NMDAR. Instead, a concurrent increase in post-synaptic AMPA density allows for an signaling cascade that activates mammalian target of rapamycin (mTOR) and neurotrophins such as brain-derived neural growth factor (BDNF) (see Fig. 1). The proliferation of these downstream pathways increases synaptogenesis, amplifies translation of neurotrophic proteins, and ultimately reduces depressive symptoms.[xxix] Through calcium channel inhibition, ketamine diminishes pain sensitivity.[xxx]

Ketamine’s most important interactions are with the NMDAR, but it also has an affinity for the opioid receptors, binding to the m, k, s  receptors. This relationship may provide clues about ketamine’s strong analgesic effect. However, relatively high binding to the m receptor raises the question as to whether the clinical benefit is from the glutaminergic or opioidergic pathways. This is an important distinction that will be discussed later.

Animal Models Lead to Initial Human Subject Studies

It is proposed that when organisms face chronic stress, repeated depolarization of NMDAR unleashes a flood of post-synaptic glutamate. This phenomenon is called “excitotoxicity.” Too much glutamate in these permeable receptors causes excessive calcium influx, which damages cell structures and precipitates neuronal apoptosis. Over time, excitotoxicity lead to a number of central nervous system diseases.

Whereas “escapable stress” is acute and prompts the fight-or flight response, “inescapable stress” is chronic and leads to behavioral depression. In 1990, Trullas and Skolnick posited that overstimulation of the NMDA receptor could contribute to depressive symptoms of inescapable stress. To simulate this, rodent subjects were placed in a series of unfamiliar and crowded cages. They later administered either a competitive antagonist, a noncompetitive antagonist, or a partial agonist to decrease NMDA neurotransmission in their rodent models. They found that the resultant synaptic connections in the CA1 region in the hippocampus could transform from a state of Long-Term Depression (LTD) to one of Long-Term Potentiation (LTP). They proposed that drugs that inhibit the NMDAR could parallel the effects of established antidepressants.[xxxi]

Studies in rodents allow insight into the behavioral effects of ketamine administration. Ketamine-dosed rats subjected to the Forced Swim Test (FST) were more likely to try to escape than controls. Compared to TCAs, SSRIs, or MAOs, ketamine demonstrated the most rapid-onset reduction in learned helplessness behaviors. In one study, it was shown that rats were less likely to choose a sugary drink over plain water when placed under conditions of chronic stress. This behavior is consistent with the loss of pleasure frequently exhibited by depressed patients. When injected with ketamine, previously anhedonic rats had renewed interest in sucrose consumption. Taken together, these rodent studies give credence to ketamine’s effect of ameliorating anxiety, depression, and anhedonia.[xxxii]

Bench research and animal models are essential steps in the identifying potentially useful therapeutic agents in humans. Still, certain limitations exist; the animal model relies on primarily on assessing locomotion, and unlike humans, rodents cannot express the emotional symptoms of depression. We should proceed cautiously with the model that “chronic stress” in the rodent translates clinically to the human condition of TRD or PTSD.

First Ketamine Study in Depression

While ketamine had been used as a surgical anesthetic and recreational drug for decades, serious research into its efficacy as a treatment for severe depression is more recent. In 2000, Berman and colleagues organized the first double-blind trial to examine the effects of subanesthetic ketamine hydrochloride on seven depressed human subjects. The ketamine group received intravenous 0.5 mg/kg doses and the control group received saline solution over 48 hours. The ketamine group demonstrated statistically significant improvement on the Hamilton Depression Rating Scale within 72 hours of infusion, a finding not shared by the placebo group. This small but positive study affirmed NMDAR antagonism as a valid therapeutic approach and spurred other larger and more sophisticated trials.[xxxiii]

Epidemiology and Morphology in Treatment-Resistant Depression

The Berman study focused on patients with major depression. A more perplexing issue facing psychiatry is the nature of treatment-resistant depression. TRD is characterized by extended duration and severity of the depressive episode. The designation is given after an inadequate response to at least two courses of two different classes of antidepressants.[xxxiv] In a large meta-analysis, nearly 60,000 patients were studied comparing treatment-resistant to treatment-responsive depression. Resistant patients had greater number of prior depressive episodes and lower scores on quality of life assessments (see Figure 2). Both variants of depression significantly reduce economic productivity, with a total estimate of societal cost as high as $118 billion per year.[xxxv] Beyond the objective human suffering associated with chronic depression, TRD patients are at greater risk of suicide. Suicidal ideations tend to emerge episodically, even within the context of chronic low mood. For this reason, rapid-onset therapies to relieve suicidal ideations are of premium importance.

Morphological findings in TRD have been elucidated by neuroimaging. Changes to the caudate nucleus, the right superior and middle temporal gyri, and the subgenual anterior cingulate cortex (ACC) have been correlated with recurrent depression. Most significantly, hippocampal volume has been shown to shrink under these circumstances. It has been noted that patients with notable reduction in the hippocampus – a classic biomarker of severe depression indicative of glutamate dysfunction – respond poorly to treatment with traditional antidepressants.[xxxvi] Several studies suggest that modulators of the glutaminergic system such as ketamine are more therapeutic for patients with smaller hippocampal volume. Notably, Murrough and colleagues used fMRI to analyze emotion perception in subjects with TRD. In the control condition, subjects showed reduced neural activity in the right caudate when presented with photos of smiling faces. After being infused with ketamine, this same brain region showed greater activation.[xxxvii]

Ketamine Trials in TRD

Established depression rating scales are more practical than neuroimaging for ascertaining treatment response. In the last several years, ketamine has been subjected to numerous controlled trials. In a single site study, Zarate and colleagues recruited depressed adults who had failed two antidepressant trials and scored 18 or above on the 21-item Hamilton Depression Scale (HDS). Following a two-week washout period, 18 subjects received intravenous infusions of either saline solution or 0.5 mg/kg of ketamine hydrochloride. The infusions were administered one week apart using a randomized double-blind crossover design. Subjects were rated using the HDS and other secondary outcome measures one hour before infusion and again at specified time post dose. Results revealed statistically significant improvement of ketamine over placebo. The effect size was large after 24 hours (d =1.46) and after 1 week (d = 0.68). Adverse events were more common in the ketamine-treated group and included perceptual disturbances, confusion, elevated blood pressure, euphoria, dizziness and increased libido. Still, the side effects were transient and well-tolerated.[xxxviii]  These results fortified Berman’s preliminary finding that hinted at ketamine’s rapid antidepressant response.

Murrough sought to expand on this finding with a two-site study of 72 patients with TRD. In this trial ketamine was compared to midazolam. Midazolam, a sedative without mood-altering properties, was chosen as an active control because like ketamine it has obvious anxiolytic effects. Therefore, subjects were less likely to speculate into which group they were randomized; this ambiguity promoted the blind nature of the study and the quality of the findings. The trial revealed that the ketamine group had greater mood improvement than the midazolam group 24 hours after treatment.[xxxix] Adverse events were similar to the Zarate study.

Ketamine and Suicidality

Given the rapid onset of ketamine’s effects, it was logical to pursue studies in patients with suicidal thoughts. The WHO estimates that 800,000-1 million people take their own lives each year.[xl] Cognizant of the predisposition to suicide of patients with major depression, Grunebaum and colleagues studied 80 adults with MDD and a score ³ 4 on the Scale of Suicide Ideations (SSI), of whom 43 were on active antidepressant treatment. Subjects were randomized to intravenous ketamine or midazolam groups. One day after treatment the reduction in the SSI was 4.96 points greater for the ketamine group. (d = 0.75). Clinical response was defined as having a 50% reduction in the SSI score. Using this metric, the proportion of responders in the ketamine group was 55% compared to 30% for the midazolam group. The authors concluded that ketamine adjunctive to existing antidepressant medications could lead to a clinically significant reduction in suicidal ideations when compared to midazolam.[xli]

Ketamine as an Adjunct to ECT

As a group, TRD patients are clinically challenging and they typically require polypharmacy or other elaborate treatments. ECT has been considered the gold standard of last-ditch treatment and researchers speculated that ketamine added to ECT would augment response and mitigate the cognitive side effects of ECT.

Unfortunately, controlled trials did not prove any of these hypotheses. Anderson and colleagues conducted a three-year, 79-subject study of patients with severe unipolar depression. They found no conclusive evidence that the anti-depressive effects of ECT were enhanced by sub-anesthetic doses (0.5 mg/kg) of ketamine. They conceded that their sample size was smaller than expected, however, and they did not rule out a potential benefit.[xlii] McGirr et al reached similar negative findings in a larger meta-analysis that determined that ketamine did not have any pro-cognitive effects in patients undergoing ECT.[xliii] Perhaps the negative outcome was attributable to the fact that ketamine raised seizure threshold, which would have directly interfered with ECT’s core objective of placing the depressed brain into controlled convulsion. Given the concurrent use of ketamine as an induction anesthetic, it is not surprising that ECT treatment-centers would assess the additive effects of the two anti-depressants modalities. Despite expectations, these two studies do not support ketamine added to ECT. The findings should guide future studies that examine which existing treatment pairs most favorably with ketamine.

Development of Esketamine

Ketamine in its traditional form is a racemic mixture consisting of equal parts R- and S- ketamine. This form of the drug has been long-approved by the FDA and is widely used via intravenous administration for surgical anesthesia and pain management. For surgical patients, ketamine infusion provides sympathetic stimulation necessary for keeping the cardiovascular system functioning. The latest development in the field is esketamine, the S-(+) enantiomer of the molecule. Both the racemic and enantiomeric formulations similarly affect the glutaminergic system, but S-ketamine inhibits the NMDAR with 400% greater effectiveness than R-ketamine.

Unlike ketamine, esketamine, does not interact with central sigma receptors. The enantiomer has greater affinity for the PCP binding site on the NMDA receptor than does the racemic mixture.[xliv] Clinically, S-ketamine has been shown to have less marked hallucinogenic and other disorienting psychomimetic effects.[xlv]

Another difference is that esketamine can be absorbed via internasal administration. Johnson & Johnson’s subsidiary, Janssen, has been conducting ambitious multicentered clinical studies for several years. While ketamine is a viable molecule to develop for psychiatric indications, it is a generic and no company will invest hundreds of millions into a product they do not have exclusive rights to manufacture. The Janssen esketamine nasal spray is currently in Phase III and has received FDA fast-track status. It is on pace to receive full approval for a 2019 market release. The expected indications would be as an adjunct to antidepressant medication and for acute suicidal ideations associated with major depression.[xlvi] Ketamine will remain a less expensive alternative to esketamine, albeit without formal FDA indication. Patients are expected to embrace the intranasal method of drug delivery.[xlvii]

First Clinical Trial of Esketamine in TRD

The first randomized clinical trial of intranasal esketamine adjunctive for TRD was published in 2018. Daly et al screened 67 subjects in a three-period study. In the first period, participants were randomized into a 3:1:1:1 format; 33 participants received placebo, 11 received 28 mg of ketamine, 11 received 56 mg and 12 received 84 mg. Nasal inhalations were administered twice weekly. In the second period, participants who received placebo during the first period were given active agent, although a small number of the placebo patients with mild symptoms remained on placebo. All other participants continued to receive treatment. In the third and final period all participants were given esketamine in an open label. Dosing frequency in the open label phase decreased from bi- weekly to weekly. 

The results were robust and positive. In all three dosing strategies, depression scores in the esketamine treated groups improved to a statistically significant extent. These improvements were dose-dependent. Onset was rapid, and scores did not fall when the dosing frequency decreased during period three. Three out of the 56 completers dropped out due to adverse events.[xlviii]

Ketamine in PTSD

Posttraumatic stress disorder (PTSD) is a psychological disorder that occurs after trauma. It is typically associated with combat veterans who have witnessed death and destruction but can develop in any person who has experienced a life-threatening event. Exposure to natural disaster and chronic sexual and emotional abuse also constitute provocative factors. Women suffer at higher rates than men. Those affected have severe anxiety, flashbacks, insomnia, intrusive thoughts, and tend to avoid triggering stimuli.[xlix]

PTSD is notoriously difficult to treat and substantial investment by the Department of Veterans Affairs since the Vietnam War have not yielded anticipated results. Most regimens consist of a combination of individual cognitive behavioral therapy, group therapy, Eye Movement Desensitization and Reprocessing (EMDR) and SRI medication.[l] The high rates of psychiatric disability that persist testify to the limitations of available therapies, and the epidemic of veteran suicide amplifies this complicated story.

Intravenous ketamine, however, may provide a therapeutic option. Feder et. al organized a trial in which forty-one subjects with PTSD were recruited. Subjects were infused with 0.5 kg/kg of ketamine or 0.045 mg/kg of midazolam as a control. Results concluded that ketamine infusion provided a more rapid and marked decrease in PTSD symptoms. Comorbid symptoms of depression also abated.[li] Albott et. al examined the efficacy of ketamine infusions for combat veterans with comorbid TRD and PTSD. As expected, repeated ketamine injections briefly increased feelings of dissociation, although none of the subjects reported a worsening of their PTSD symptoms. The authors concluded that sustained ketamine administration could be improve quality of life for patients suffering from both TRD and PTSD.[lii]

A recent study at Columbia University Medical Center hints at creative potential for ketamine in clinical practice.  Mice were injected one week prior to a traumatic event and demonstrated a diminished condition fear response afterward. While this is an animal study, the heuristic implications of “inoculating” soldiers or others certain to experience psychological trauma is intriguing.[liii] Other researchers rooted in an interest in the psychedelic experience are investigating the dissociative properties of ketamine infusion during exploratory psychotherapy.[liv]

The March to FDA Approval

The sheer number of positive safety and efficacy trials involving esketamine have paved the path for imminent FDA approval. The fast-track trajectory allows a quicker entrance into the marketplace for drugs that can treat serious or life-threatening conditions. The anti-regulatory philosophy of the current executive administration has guided the approval of a record number of new drug and generic applications over the past 18 months.[lv] Fueled by online publications and social media, the interest in ketamine in the lay community has surged and scores of ketamine clinics have popped up throughout the country. Marketing their services to depressed patients, the clinics are typically run by anesthesiologists or pain medicine specialists with experience administering IV ketamine, but with little experience treating TRD patients at high suicide risk. The American Psychiatric Association recently issued a non-binding consensus statement ahead of the medication’s formal approval. The APA guidelines conclude that the bulk of available research supports the efficacy of ketamine for short-term use. Ketamine should be administered in a medical setting under the auspices of trained physicians. Because of the dissociative side effects, it should not be self-administered at home.[lvi] The cautionary language appears appropriate for a number of reasons.

Safety Concerns

There have been questions raised about ketamine’s safety, tolerability, and abuse potential. Both ketamine and esketamine cause transient dissociative symptoms and for this reason, ketamine will need to be administered in a supervised outpatient setting. This represents a significant departure from self-administered oral antidepressants. The need for monitoring will increase costs and tangle logistics. Other glutaminergic agents do not share this undesirable side effect.[lvii]

On the other hand, evidence supports that beyond the transient psychedelic effects of ketamine, the drug is well-tolerated. A 2015 study by Wan (n = 97) found that a single low dose of ketamine (0.1-1.0 mg/kg) resulted in a 50-70% improvement in TRD symptoms. A total of 205 intravenous subanesthetic doses infusions were conducted to assess the various dissociative and psychotomimetic effects. The most common short-term side effects included drowsiness, dizziness, loss of coordination, blurred vision, and feelings of unreality. After the trial, study participants were interviewed on their reactions to ketamine treatment.[lviii] Only one of the them claimed that the treatment increased their level of anxiety and dysphoria. No participant reported increased cravings for the drug after treatment. This encouraging finding dampened the claim that therapeutic ketamine will have high rates of abuse.

Is the Antidepressant Effect Mediated by the Opioid System?

The reassurances derived from Wan’s post-trial interviews were challenged by an August 2018 report from Stanford University. Dr. Alan Schatzberg, former president of the APA, understood ketamine to have dual properties of an NMDAR antagonist and an activator of opioid receptors. His team conducted a double-blind crossover of 30 adults with TRD using standard ketamine dosing. Half the subjects were pretreated with the opioid receptor antagonist naltrexone. In an interim analysis, subjects given naltrexone plus ketamine had significantly better reductions in their HAM-D scores than the ketamine plus placebo group. Naltrexone did not impact the dissociative effect seen in either group.[lix]

In an interview, Schatzberg speculated that ketamine activates the opioid system, and this explains its rapid antidepressant effect. The glutamate system may be responsible for the psychomimetic effects and sustaining the clinical benefits once the ketamine is metabolized. “Before we did the study, I wasn’t sure that ketamine really worked to treat depression. Now I know the drug works, but it doesn’t work like everyone thought it was working.” He cautions that the activation of the endogenous opioid system by ketamine might create dependency and that the FDA would be wise to limit the use of ketamine to acute rather than chronic depressive symptoms.[lx]   

Summary and Conclusions

Depression and other mental health conditions are on the rise. Uncomplicated cases respond to available antidepressant treatment, but the monoamine hypothesis of depression has proven inadequate and simplistic. Existing antidepressant medications take too long to start working and cause undesirable side effects. The STAR*D study revealed that significant percentages of depressed patients have treatment-resistant conditions that were unresponsive to available drugs on the market. Appropriate attention has shifted to the role of glutamate modulation in depression. Ketamine exerts its effects both on the NMDAR and the opioid receptor system, which in this addiction-averse climate muddies enthusiasm for its widespread use in the near future.

Solid research supports ketamine as treatment for treatment-resistant depression. The initial studies by Berman in 2000 identified a new mechanism for depression and catapulted a movement dedicated to uncovering the mysteries of TRD. Murrough isolated morphological changes using fMRI and Zarate extended these findings in larger studies. Grunebaum demonstrated improvement in suicidality. Trials of esketamine have been resoundingly positive and its introduction to the marketplace will likely occur in the next year.

Still, caution should be exercised. Several studies reveal that ketamine does not improve depression when used as an adjunct to ECT. Ketamine causes dissociative effects which will raise cost and lower access to the drug. Concerns have been raised about its interaction with the opioid receptors, and much more research is required to unravel the long-term abuse potential. Ketamine has had a winding journey from the Detroit laboratory bench to branded intranasal formulation. It will undoubtedly become a vital asset in the antidepressant arsenal desperately in need of innovation.

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[xliv] Vollenweider, 2011

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[liv] Kolp, E., Friedman, H. L., Krupitsky, E., Jansen, K., Sylvester, M., & Young, M. S. (2014). Ketamine psychedelic psychotherapy: Focus on its pharmacology, phenomenology, and clinical applications. International Journal of Transpersonal Studies, 33(2), 84-140. doi:10.24972/ijts.2014.33.2.84

[lv] King, R. (2018, February 22). FDA reduces regulations, approves record number of new generics. Retrieved from https://www.washingtonexaminer.com/fda-reduces-regulations-approves-record-number-of-new-generics

[lvi] Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., & Schatzberg, A. F. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry, 74(4), 399. doi:10.1001/jamapsychiatry.2017.0080

[lvii] Murrough, J., Lapidus, K., & Soleimani, L. (2013). Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatric Disease and Treatment, 1101. doi:10.2147/ndt.s36689

[lviii] Wan, L., Levitch, C. F., Perez, A. M., Brallier, J. W., Iosifescu, D. V., Chang, L. C., … Murrough, J. W. (2014). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. The Journal of Clinical Psychiatry, 247-252. doi:10.4088/jcp.13m08852

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[lx] Price, K. (2018, August 28). Ketamine’s antidepressive effects tied to opioid system in brain. Retrieved from https://med.stanford.edu/news/all-news/2018/08/ketamines-antidepressive-effects-tied-to-opioid-system-in-brain.html

Biographical Sketch

I graduated from the University of Michigan in 2013 with a degree in history. I then pursued my premedical studies at Oakland University while working in psychometric testing. I enrolled in Wayne State’s MS in Basic Medical Sciences in 2016. I am currently applying to medical school. I have learned so much in the BMS program and feel well-prepared for the journey ahead. In my free time, I enjoy reading, technology, running, sports, and playing with my two golden retrievers.