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The US Food and Drug Administration (FDA) sent a Complete Response Letter (CRL) regarding the supplemental new drug application (sNDA) for pimavanserin (Nuplazid) for the treatment of hallucinations and delusions associated with Alzheimer disease psychosis (ADP), according to Acadia Pharmaceuticals.

The CRL indicated that the FDA has completed review of the application and could not approve the sNDA in its present form. The FDA recommended that Acadia conduct an additional trial in ADP.

“We are disappointed with this outcome. The treatment of Alzheimer disease psychosis continues to be an area of high unmet need, for which there is no approved therapy,” said Steve Davis, chief executive officer. “We want to express our gratitude to all of the patients, their families and investigators who have participated in our clinical trials.”

In Study 019, the FDA agreed the results demonstrated a statistically significant treatment effect on its primary endpoint, but the agency concluded there are limitations in the interpretability of said results. The FDA also stated that the positive treatment effect of pimavanserin on dementia-related psychosis in Study 045 (HARMONY) appeared to be driven by the robustly positive results in the Parkinson disease dementia subgroup, a condition they stated is subsumed within the currently approved Nuplazid Parkinson disease psychosis (PDP) indication.

This recent sNDA was Acadia's second attempt to secure approval for expanded use of the drug. In early 2021, the FDA rejected Acadia’s clinical trial data, which they stated were not sufficient to support approval of pimavanserin in patients with dementia-related psychosis.

1. Acadia Pharmaceuticals receives complete response letter from U.S. FDA for supplemental new drug application for pimavanserin for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. Business Wire. August 4, 2022. Accessed August 8, 2022. 

https://www.businesswire.com/news/home/20220804006095/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Alzheimer’s-Disease-Psychosis

2. U.S. FDA declines to approve expanded use of Acadia's antipsychotic drug. Reuters. August 5, 2022. Accessed August 8, 2022. 

https://www.reuters.com/business/future-of-health/us-fda-declines-approve-expanded-use-acadias-antipsychotic-drug-2022-08-05/

Alzheimer disease psychosis treatment pimavanserin receives Complete Response Letter from the FDA. 

Caution Ahead: FDA Asks for More Info on Expanded Use of Antipsychotic Drug

“Don’t throw out the baby with the bathwater.”

Today is my wife’s 75th birthday. I just passed my 76th. We, as most people our age, are wary of developing Alzheimer disease and losing our very sense of who we are and our ability to take care of ourselves.

No wonder, then, that society, especially its elders, desperately wants a “cure” for the increasing prevalence of Alzheimer disease. Psychopharmacology desperately needs some new breakthrough medications in psychiatry. Clearly, psychiatry and the rest of medicine became more of a big business when for-profit managed care emerged in the new millennia.

 All of those factors provide a vulnerable situation for questionable research, and that is what we may have in the plaque theory of Alzheimer disease and the related new medications.

Last year, on an internet broadcast for Talk Ten Tuesday, I presented my concerns about the potential FDA approval of a new Alzheimer medication. Though I am not an expert in this area, the research findings seemed questionable even to me, and the projected costs astronomical. Now, a whistleblower—a neuroscientist at Vanderbilt—has raised more sophisticated and scientific concerns.

Back in 2006, a study suggested that Alzheimer disease stemmed from a group of proteins causing plaques in the brain. Most of the ensuing drug development followed that theory, though none that emerged in real life seemed particularly effective. The latest has been aducanumab (Aduhelm). Now, the original research has been questioned in that the images of the proteins role in that prior research look like they may have been misleading, intentionally or not.

Goodness knows, psychiatry has been accused more broadly by critics of being misleading about some so-called antipsychotics and antidepressants. Criticism has included ghostwriting of psychopharmacology research results, the strong influence of pharma reps on prescribers, the questionable etiologic theories, the misinterpretation of some outcomes, and unrecognized long-term risks.

Time will hopefully tell if we have been on the wrong etiologic path for the treatment of Alzheimer disease and other neuropsychiatric disorders. However, any misguided research does not reduce the need for better biological treatments, whether medication or other interventions. Shying away from those approaches would be like throwing out the baby with the dirty bathwater.

At a time when science is being questioned and alternative facts embraced by many, it is more important to continue research, but also to be as sure of the veracity of the findings over time.

is an award-winning psychiatrist who has specialized in the cultural and ethical aspects of psychiatry. A prolific writer and speaker, he received the one-time designation of Hero of Public Psychiatry from the Assembly of the American Psychiatric Association in 2002. He is an advocate for mental health issues related to climate instability, burnout, Islamophobia, and anti-Semitism for a better world. He serves on the Editorial Board of

The Ethical Way: Challenges and Solutions for Managed Behavioral Healthcare

Research backing experimental Alzheimer’s drug was first target of suspicion.

Is our research about Alzheimer disease wrong? 

Buyers Beware in Alzheimer Disease Neuroscience

A study found that brain inflammation may create a link between sleep disturbance and Alzheimer disease, which may help with prevention and early detection efforts.

The multisite research study aimed to explore the potential effects of inflammation on fast sleep spindles, which research shows promote long-term memory retention. Although sleep disturbance, brain inflammation, and disrupted brain waves have been associated with Alzheimer disease in prior research, this study is the first to investigate the specific interactions.

The study included 58 participants in their 50s and 60s (mean ± SD; 61.4 ± 6.3 years; 38 females and 20 males) who had a parental history of or genetic risk factor for Alzheimer disease, but were not experiencing cognitive impairment and had no β-amyloid plaques or neurofibrillary tau tangles. The researchers recorded participants’ sleep with high-density electroencephalography to map participants’ brain wave expression during sleep and assess their overnight memory retention. The researchers also examined cerebrospinal fluid biomarkers of β-amyloid and tau proteins, neuronal integrity, and central nervous system inflammation through lumbar puncture.

The researchers found that the activation of microglia and astrocytes—2 types of glial cells that trigger brain inflammation—was associated with the disrupted expression of fast sleep spindles. As the researchers identified these relationships in individuals who had no accumulation of β-amyloid plaques or neurofibrillary tangles, the researchers concluded that inflammation and sleep deficits may be early warning signs of Alzheimer disease.

“Our findings indicate that age-related increases in brain inflammation have a downstream effect on Alzheimer’s disease-related tau proteins and neuronal synaptic integrity. This results in deficits in the brain’s capacity to generate fast sleep spindles, which contribute to age-related memory impairment in older adults,” said Bryce Mander, PhD, assistant professor of psychiatry and human behavior at the University of California, Irvine, and lead and co-corresponding author on the study.

“We don’t know yet whether anyone in this study will develop Alzheimer’s disease dementia, but one of the reasons that our studies enroll participants in midlife is so that we can potentially detect problems before people develop disease symptoms,” added Barbara Bendlin, PhD, professor of medicine at the University of Wisconsin-Madison and co-author on the study. The authors concluded that detecting signs of Alzheimer disease early may help stop cognitive decline associated with age and the disease.

 “Discovering these mechanisms is an important step in identifying at-risk individuals as early as possible and developing targeted interventions,” Mander said.

1. Research reveals how brain inflammation may link Alzheimer’s risk, sleep disturbance. University of California, Irvine. News release. July 13, 2022. Accessed July 19, 2022. 

https://news.uci.edu/2022/07/13/research-reveals-how-brain-inflammation-may-link-alzheimers-risk-sleep-disturbance/

2. Mander BA, Dave A, Liu KK, et al. Inflammation, tau pathology, and synaptic integrity associated with sleep spindles and memory prior to β-amyloid positivity. 

. Published online June 7, 2022. Accessed July 19, 2022. 

https://academic.oup.com/sleep/advance-article-abstract/doi/10.1093/sleep/zsac135/6603598?redirectedFrom=fulltext&login=false

Study shows promising results for early detection and prevention efforts.

Brain Inflammation May Link Alzheimer Disease With Sleep Disturbance

The first patient has been dosed in the TRANQUILITY II study of an acute treatment for agitation in patients with Alzheimer disease.

The TRANQUILITY II study, led by BioXcel Therapeutics, focuses on BXCL501, an orally dissolving thin film formulation of dexmedetomidine. In research incorporating multiple measurement scales, BXCL501 has demonstrated statistically significant reductions in agitation with no severe adverse events at doses of both 30 mcg and 60 mcg.

 The US Food and Drug Administration (FDA) granted BXCL501 breakthrough therapy designation for the acute treatment of agitation in connection with dementia in March 2021.

“We believe the recent FDA approval of BXCL501 for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults has laid a strong foundation for pursuing this Alzheimer’s-related agitation program to potentially address this debilitating symptom for patients,” Robert Risinger, MD, chief medical officer of BioXcel Therapeutics, said in a press release. “Importantly, we are also expanding TRANQUILITY II to more than 10 clinical trial sites in the US, and with no current FDA-approved treatments for agitation associated with this disease, we are making strong and swift efforts to potentially bring BXCL501 and its proven ability to address agitation to this large market.”

TRANQUILITY II is 1 of 2 studies—along with TRANQUILITY III—in BioXcel Therapeutics’ Phase 3 TRANQUILITY program, in which both studies measure the efficacy of BXCL501 in adults aged 65 years and older currently in assisted living facilities or nursing homes. BioXcel has reported that top-line data for TRANQUILITY II is expected in late 2022 or early 2023, and patient enrollment in TRANQUILITY III will begin later in 2022.

BioXcel Therapeutics announces first patient dosed in TRANQUILITY II phase 3 trial for acute treatment of agitation in patients with Alzheimer’s disease

. News release. GlobeNewswire. May 3, 2022. Accessed May 3, 2022.

BioXcel Therapeutics receives FDA Breakthrough Therapy Designation for BXCL501 for the acute treatment of agitation associated with dementia

. News release. BioSpace. March 15, 2021. Accessed May 3, 2022.

Top-line data for study is expected in late 2022, early 2023.

Phase 3 Study on Treatment of Agitation in Alzheimer Disease Doses First Patient

Reviewed by Barbara Schildkrout, MD, and Karen Greenberg, MD

Amy Bloom does not waste any time. Within 3 pages, readers learn the arc of her story—that Brian, the author’s husband, has developed Alzheimer disease; that he is charming, spirited, and vital; that Amy and Brian love to travel, sharing gum and water on their airplane trips, including one to Switzerland; that they are in love; and that Brian has decided to end his life by “accompanied suicide” at Dignitas in Zurich.

Then, the epigraph: “‘Please write about this,’ my husband said.”

Sunday, January 26, 2020, Zurich, Switzerland

Why read such a book? The whole story is foretold at the outset. There are no surprises. The subject is terribly controversial and downright depressing. But 

 is not about death. It is about life—an ode to Amy and Brian’s deep and touching intimacy that endures to the end. The book is creatively crafted, shifting back-and-forth in time, the way associative memory moves from past to present and from inner thoughts to outer realities. Along the way, there is a lot for psychiatrists to learn.

Alzheimer disease moves in with a family, quietly at first. Even once a patient or family member finds the courage to seek medical consultation, they likely will still have doubts about whether something is really the matter. If they enter a psychiatrist’s office—for the first time or the hundredth time—they might be thinking that cognitive changes are due to depression, anxiety, stress (of which there is no shortage), transient postanesthesia memory impairment, sleepless nights, or normal aging. They might describe increasing tension with a spouse, a boss, or adult children. Would you recognize the early signs of this degenerative disease in such presentations?

Approximately 6.5 million Americans are living with Alzheimer disease today, and that number is projected to rise to about 13 million by 2050.

 Whatever your practice may be, you will surely see patients with Alzheimer disease or their family members. We now know that brain changes that characterize the disease begin to appear approximately 10 years before clinical symptoms—long before mild cognitive impairment and very long before mild dementia. Brain MRI, neuropsychological testing, and amyloid and tau PET scans are useful diagnostic tools, and in most cases, it is possible to make a definitive diagnosis based on cerebrospinal fluid biomarkers. Numerous blood assays have already been developed and are being studied to determine which are the best predictors of cognitive decline.

The US Food and Drug Administration (FDA) recently approved Aduhelm (aducanumab) for the treatment of early Alzheimer disease. Aduhelm is a monoclonal antibody that targets beta-amyloid plaques in the brain. Approval of the drug has been controversial, largely because of its small effect size in combination with a high incidence of serious side effects, as well as its $28,000/year price tag: Medicare will only cover Aduhelm for patients in clinical trials. Nonetheless, the indications for this medication are a wake-up call to clinicians: It is prescribed only for the treatment of mild cognitive impairment or early dementia caused by Alzheimer disease. Early identification is crucial. And while we do not yet have an altogether safe and effective pharmacologic treatment that is widely available, we do know that early diagnosis of Alzheimer disease will be even more essential once such a medication is developed.

Bloom paints a word picture—as only a gifted writer can—of the early signs of Alzheimer disease and her emerging realization that there really was something wrong with Brian. Or was she just imagining it? Why was she so irritable with him? Why were they fighting so much? Why had his boss asked her accomplished architect husband with such a high IQ to take an early retirement? Why did her gregarious soulmate not want to see friends? Why was he only talking about the past? As psychiatrists, we get to peer into the very beginnings of Brian’s disintegration and the widening ripples, then tidal waves, that his disintegration caused in Amy and Brian’s life together:

I could feel him through a glass, and I was banging on it, screaming at him: Why is there a glass between us? Where did it come from? Take it down! And Brian looked at me with puzzled, irritated concern and said, in effect, What glass? And, Please please stop complaining about this thing that isn’t even there.

I called the neurologist and made an appointment.

 revolves around the pivotal decision that followed Brian’s Alzheimer disease diagnosis: “It took Brian less than a week to decide that the ‘long goodbye’ of Alzheimer’s was not for him.” Brian was a lover of life—a “big, handsome man with a big laugh” who thrived on good food and good conversation. When he joined his men’s book club, he announced the reason: “I love a good read, and I love intimacy.” Only 66 years old, he was unwavering in his plan: “I’d rather die on my feet than live on my knees….” He did not want the onslaught of his disease to steal his ability to end it all.

Given Brian’s slipping cognition, he asked Amy to find an effective way for him to end his own life without implicating her in a murder. He wanted Amy at his side, and he wanted the method to be peaceful and 100% foolproof in order to avoid catastrophic disability. Amy’s painstaking research uncovered a truth that most Americans do not know: It is simply not possible to end one’s life on one’s own terms in the United States if you have a dementing illness.

Medical aid in dying (MAID) is legal in 10 states and the District of Columbia—areas comprising 22% of the US population—under statutes using language such as “death with dignity” as opposed to the more provocative physician-assisted suicide (PAS). However, all MAID laws in the United States require that a patient have a prognosis of 6 months or less to live and 

 be competent to make an informed life-and-death decision. Individuals with neurodegenerative diseases are effectively excluded.

Here is where Dignitas (“To live with dignity—to die with dignity”) comes in. Brian said, “I don’t want to end my life… but I’d rather end it while I am still myself, rather than become less and less of a person.” Switzerland is one of the many countries that do not require individuals to be terminally ill to access MAID, but it is the only country in the world where foreigners are eligible—hence Amy and Brian’s trip to Zurich, where Dignitas, a nonprofit organization, is headquartered.

The Dignitas admissions process is arduous and includes extensive paperwork, doctors’ letters, multiple telephone interviews, and dental records for identification after death. Once in Zurich, Brian still had to meet twice with a Dignitas physician to get final approval. At each point, Brian was in charge of the choices. After he and Amy took a car to the Dignitas apartment on the outskirts of town, Brian chose to swallow the prescribed antiemetic followed by sodium pentobarbital. With Amy holding his hand, Brian ended his life, as 3000 others had done before him. For Amy and Brian, access to Dignitas was at once a gift and a tragedy.

How would you have worked with Brian and Amy? Are all suicides the same? Is a thoughtfully planned, accompanied suicide different from a suicide motivated by mental illness and excruciating psychic pain? 

 leaves us with much to contemplate and reflect upon.

The book describes Amy and Brian’s encounters with numerous physicians, 2 of whom Amy says, “are for me the villains of this story”: Brian’s neurologist and psychiatrist, who, along with his internist, “failed him.” For Amy, there is also a hero: her psychiatrist, who interviewed Brian and wrote a decisive letter to Dignitas describing Brian’s life story and mental status. Would you have written such a letter, participating in the Dignitas process and potentially facilitating Brian’s accompanied suicide?

 has been hosting a spirited debate on this topic since 2018, which is summarized in “

Physician-Assisted Suicide: A Pressing Question of Ethics and Humanity

 is a short but compelling read that is likely to elicit strong feelings on both sides of the debate.

is an assistant professor of psychiatry, part-time, at Harvard Medical School in the Department of Psychiatry at Brigham and Women’s Hospital. She is the author of several books and a blog. 

is an affiliated physician, Beth Israel Deaconess Medical Center; part-time instructor, Harvard Medical School; and fellowship alumna, HMS Center for Bioethics.

1. Alzheimer’s disease facts and figures. Alzheimer’s Association. Accessed April 15, 2022. 

https://www.alz.org/alzheimers-dementia/facts-figures

2. Leuzy A, Mattsson-Carlgren N, Palmqvist S, et al. (2022). 

Blood-based biomarkers for Alzheimer's disease

3. Kuntz L. Physician-assisted suicide: a pressing question of ethics and humanity. 

. January 29, 2022. Accessed April 15, 2022. 

https://www.psychiatrictimes.com/view/physician-assisted-suicide-a-pressing-question-of-ethics-and-humanity

Compelling new book discusses love, Alzheimer disease, and medical aid in dying.

In Love: A Memoir of Love and Loss

Depression is a common comorbidity for patients with late-onset 

, and individuals with depression are at greater risk to develop late-onset Alzheimer disease.

 Although the genetic heterogeneity of depression cooccurrence with late-onset Alzheimer disease and genetic etiologies predisposing the comorbid conditions are largely unknown, previous research suggests interactions between the 2 conditions.

Using statistics from a genome-wide association study, investigators created polygenic risk scores (PRS) using datasets from the Religious Orders Society and Rush Memory and Aging Project (ROSMAP, n = 1708) and National Alzheimer’s Coordinating Center (NACC, n = 10,256) as discovery and validation cohorts. The data were used to assess the PRS performance in predicting depression onset in patients with late-onset Alzheimer disease.

Standalone models showed marginal results for predicting 

 onset in both ROSMAP (AUC = 0.540) and NACC (AUC = 0.527). Full models—with baseline age, sex, education, and APOEε4 allele count—showed improved prediction of depression onset in both ROSMAP (AUC: 0.606) and NACC (AUC: 0.581). In time-to-event analysis, standalone PRS models showed significant effects in ROSMAP (P = 0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in late-onset Alzheimer disease for both datasets (P < 0.001 for all).

“This study provided new insights into the genetic factors contributing to depression onset in [late-onset Alzheimer disease] and advanced our knowledge of the genetics underlying the heterogeneity of depression in [late-onset Alzheimer disease],” said the authors.

As individuals with depression are more likely to develop late-onset Alzheimer disease, this suggests treating depression may delay development of Alzheimer disease. Further studies needed to confirm and replicate findings.

Polygenic risk score effectively predicts depression onset in Alzheimer’s disease based on major depressive disorder risk variants.

2. Lyketsos CG, Carrillo MC, Ryan JM, et al. 

Neuropsychiatric symptoms in Alzheimer’s disease.

Individuals with depression may be at a greater risk to develop late-onset Alzheimer disease, but a new study suggests depression onset may help predict Alzheimer disease. 

Predicting Depression and Alzheimer Disease Through Major Depressive Disorder Risk Factors

Breaking bad news to patients and those who care for them, a stressful event for clinicians of every specialty, presents special challenges when the bad news is a diagnosis of dementia. One definition of medical 

 is “any information that produces a negative alteration to a person’s expectations about their present or future.”

 A diagnosis of major neurocognitive disorder, or 

 in common language, implies changes that will profoundly alter the present and future for an individual with dementia and their caregivers.

Given the cognitive and emotional consequences of this news, particular attention must be paid both to its initial delivery and subsequent processing. Successful communication about a dementia diagnosis requires a complex conversation that includes both discussion of the diagnosis and planning for the future, and it often must transpire over a series of encounters. Preparation for and implementation of this conversation is widely recognized as one of the most demanding tasks in health care.

Physicians’ approach to the disclosure of bad news has evolved considerably over the past several decades, incorporating contributions from many countries and multiple specialties.

 During the 1950s and the 1960s, a diagnosis of cancer was shared reluctantly—if at all—by many physicians. A survey of 180 hospital physicians in Boston published in 1970 reported that only 25% of respondents “always” informed patients about their malignancy—66% informed their patients “sometimes,” and 9% “never” informed patients of their fatal disease.

An influential book published in 1992 by oncologist Rob Buckman, MD, 

How to Break Bad News: A Guide for Health Care Professionals

, helped transform the discourse from “whether to tell” to “how to tell.”

 In this book, delivery of bad news was presented as a skill that clinicians could both learn and teach. Buckman’s influential 6-point protocol for delivering difficult news will be discussed later in this article.

As a consequence of several factors, the need for effective disclosure and discussion of medical diagnoses in general—and dementia in particular—has gathered new immediacy in our current decade. First, the explosive increase in electronic access to information has meant that patients and families now arrive with more informed assumptions and questions, including questions about new tests and treatments. In the case of dementia, emerging tests are increasing clinicians’ accuracy in earlier and more specific diagnosis. Treatment options have broadened, and many patients wish to know about clinical trials and newly approved therapies.

Second, the 21st Century Cures Act, signed into law by President Barack Obama in 2016, requires that all health care providers give their patients access to all health information available in their electronic health records (EHRs). The immediate accessibility to patients of the information in their EHRs means that patients may first learn about their diagnosis from the online medical record if it has not previously been discussed with them in person by their clinician. Confusion, misunderstanding, and unwarranted anxiety can result when a diagnosis is learned in this way, making it more important than ever for clinicians to time their diagnostic discussion thoughtfully.

Finally, the updated quality measure set for dementia care recently endorsed by the American Psychiatric Association and the American Academy of Neurology includes an element entitled “disclosure of diagnosis.” This measure is defined as the percentage of patients with a diagnosis of a qualifying dementing disorder or disease who have been told (1) that they have dementia and (2) what disease is believed to be causative. The inclusion of this calculation in the measure set reflects the belief that disclosure is a component of good care and the observation that such disclosure often does not occur.

Patients Want Information, But Disclosure is Not Risk-Free

In the management of neurocognitive disorders, there is evidence that patients and their families desire accurate diagnostic and prognostic information. Eighty-seven percent of respondents without cognitive impairment in a recent study indicated a desire to know of a dementia diagnosis. Among individuals referred to a memory clinic or diagnosed with dementia, 84% “considered full disclosure of a diagnosis of dementia preferable.”

Broadly speaking, arguments proposed in favor of disclosure are of 3 types. The 

 creates a duty for clinicians to provide patients with information about their health that is needed in order to make health care decisions and to plan for the future. In this light, failing to disclose a diagnosis as significant as dementia may be seen as unethical. From the standpoint of 

, many additional benefits of disclosure have been suggested (

Surveys indicate that patients believe it is important for them to be told the diagnosis so that they can obtain more information, plan, and participate in discussions of therapeutic options. With information and the perspective of a skilled clinician, patients and caregivers are in a better position to engage in shared decision-making.

Finally, anecdotal evidence supports the idea that disclosure promotes 

 noted that “diagnosis (is) an important transition, as it marks a shift from the uncertainty and ambiguity about the early signs and symptoms of dementia to a phase in which the person with the illness and family members can learn to adapt.”

 reported several cases in which disclosure set the stage for productive psychotherapy leading to relief of anxiety, and to cognitive and behavioral adaptations that improved quality of life. A 66-year-old woman with a strong family history of dementia who presented to him for evaluation of forgetfulness, for example, feared that “health professionals would try to keep information from her and… (that) she would no longer be listened to or involved in decisions relating to her care.” Following the evaluation and the disclosure of her dementia diagnosis, she reported feeling less anxious: “At least I know what it is, I’m not imagining it, and I know what I’m facing.” In her ensuing psychotherapy, “she valued the opportunity to talk about the diagnosis and what it meant to her.” She was able to focus in psychotherapy on “how she could continue to maintain a useful role within her family and social circle, given… her memory dysfunction. This involved negotiating compromises with herself,” which she learned to see as an achievement rather than a failure.

The desire for diagnostic and prognostic information is not independent of expectation, since negative news is more difficult to accommodate. One influential study reported that patients wanted to receive necessary medical information, but also that they were hoping to receive encouraging news.

 Those with serious and advanced disease are often overly optimistic about their own prognosis and less eager to hear bad news.

 Patients’ receptivity to negative news may be affected by how long they expect to live. A study of 214 patients over age 60 with terminal cancer, for example, found that 83% of those who believed they had less than 1 year to live wanted to discuss their prognosis, while only 53% of those who thought they had 2 to 5 years to live wanted to be told their actual prognosis.

 Interestingly, physicians who are in the patient role may illustrate this paradoxical preference to know optimistic news, but avoid discouraging news. In a recent survey, only 72% to 77% of physicians affirmed a wish for disclosure of their own dementia diagnosis; 9% to 13% indicated they would 

 want to be informed; and the remainder were undecided.

For patients with progressive impairment of memory and comprehension, the disclosure of a diagnosis can also produce unanticipated consequences. Indeed, concern has been raised by some clinicians and researchers about potential adverse effects of bad news on individuals with dementia and their caregivers. The diagnosis discussion often includes advice that may be difficult to hear about autonomy, driving, and employment. Long-term care insurance or admission to certain long-term residential facilities, for example, may become unavailable. The diagnosis of dementia is associated with considerable public fear and stigma, and it may undermine a patient’s sense of self-esteem and personal value. Feelings of anxiety, depression, increased vulnerability, hopelessness, and burdensomeness can occur. Faced with the possibility of disability, dependence, and progressive decline, some individuals have even become suicidal.

Three studies illustrate the increase in risk of attempted or completed suicide that has been linked with the early phase of dementia. A large analysis of data from adults aged 50 and older derived from cross-linked registers in Denmark showed a relationship between suicide and the presence of a dementia diagnosis. The correlation of suicide with dementia diagnosis was particularly elevated shortly after diagnosis and was threefold higher among adults aged 70 and older. This correlation remained significant when controlled for the presence of mood disorders. The relative risks were even higher among men aged 50 to 69 (RR=8.5) and women aged 50 to 69 (RR=10.8). This study suggested that the initial interval after a dementia diagnosis might usher in a period of increased suicide risk because 26% of the male suicides and 14% of the female suicides occurred within 3 months of dementia diagnosis.

Another study reviewed findings obtained by linking data from the Georgia Alzheimer’s Disease and Related Dementias registry to data in Georgia’s Vital Records and Violent Death Reporting System. During the study period, 2013 to 2016, 91 individuals with dementia were reported to have died by suicide. In agreement with the observation of Erlangsen and colleagues, one of the identified risk factors identified by Annor and colleagues was a recent diagnosis of dementia.

 Similarly, researchers who studied a large cohort derived from databases associated with the US Department of Veterans Affairs and the Centers for Medicare & Medicaid Services reported on several years of follow-up, which revealed rates for attempted suicide of 0.7% among those with mild cognitive impairment (MCI; 138) and 0.6% of those with dementia (400), compared with only 0.4% of those without MCI or dementia. After adjusting for demographics, medical/psychiatric comorbidities, and earlier diagnosis of MCI or dementia, the suicide attempt risk was found to be highest for those patients with a recent MCI or dementia diagnosis.

The findings of these 3 studies certainly suggest that the interval following a diagnosis of dementia is a time of increased risk for suicide attempts or completed suicide, but they leave unresolved whether the diagnostic disclosure itself increases or decreases that risk.

Caregivers, typically family members, face additional stresses as a result of disclosure of a dementia diagnosis. Informing family members about the patient’s diagnosis inevitably alters the nature of family relationships. Trust and patient confidentiality may become an issue, especially when the patient wants to take charge of informing, or not informing, family members. With disclosure, family and others may treat the patient in a different way, shifting focus from the individual to their disease and undermining traditional lines of authority and decision-making in the family. The potential for patient abuse or abandonment increases. Family caregivers may also experience more anxiety or depression as they anticipate the burden of what may lie ahead. In addition, some family members may develop fears regarding their own actual or perceived cognitive difficulties or their risk for future decline.

Disclosure Presents Obstacles to Clinicians

According to a recent meta-analysis, only 34.2% of general physicians and 48.3% of specialists usually, regularly, or always told PWDs of their diagnosis.

 Furthermore, disclosure that did occur was often couched in vague, euphemistic terms, using words such as “confusion,” “memory problems,” or “slowing down due to aging” rather than more specific clinical terms such as 

Clinicians are reluctant to break bad news for many reasons. Some invoke “therapeutic privilege” out of concern that risks of disclosure outweigh its benefits. Others may defer disclosure to avoid burdening a patient with bad news.

 Clinicians sometimes defer discussion of a diagnosis that may be stressful, stigmatizing, or destructive to the doctor/patient relationship. The fear that treatment options are of limited value may discourage disclosure. At times, family members have urged the clinician to withhold a fearsome diagnosis from the patient out of concern that disclosure will increase the difficulty of care at home.

Clinicians, too, may have difficulty handling their own discomfort and sense of hopelessness about a dementia diagnosis. They may explain their avoidance of disclosure on the basis of diagnostic uncertainty. A study of 343 physicians practicing in outpatient hospice settings found that physicians tended to be inaccurate in their prognoses, and that prognostic errors were more likely to be overly optimistic than overly negative. In addition, prognostic errors tended to increase with increased duration of the doctor/patient relationship.

Frequently, the reason for the reluctance is the lack of training about how best to disclose a difficult diagnosis, but appropriate clinician training can dispel clinicians’ reservations and improve their disclosure skills. A Cochrane review and meta-analysis of randomized controlled trials and controlled before-and-after trials showed that communication skills training could increase the use of open-ended questions and improve empathy in oncology clinicians.8 More recently, a meta-analysis of 17 studies demonstrated that communication skills training improves physician proficiency and confidence in delivering difficult news.

 summarizes important barriers to clinicians’ disclosure of a dementia diagnosis.

How to Disclose the Diagnosis of Dementia

The actual disclosure process and discussion of a dementia diagnosis can be very stressful events for everyone involved: the patient, the caregivers, and the health care providers. To increase the likelihood of a positive outcome, the clinician can prepare for the clinical encounter by recognizing that disclosure is a process rather than an event, by examining the barriers to disclosure, and by providing information and resources in a way that considers the needs and preferences of the patient and care system.

Even cognitively intact individuals misunderstand or forget much of the clinical information conveyed during a medical discussion. During a disclosure process, caregivers may be personally overwhelmed or distracted by the patient’s discomfort or anxiety. The patient is at an even greater disadvantage in terms of comprehension and knowledge retention. Without appropriate accommodations, they may fail to recall the results, analysis, and suggestions shared by the clinician. It is easy for the patient and caregivers to leave a disclosure discussion with confused or incorrect information.

Absorption and acceptance of difficult information takes time and a recurrent discussion process that gradually evolves and deepens as additional questions arise, as new symptoms evolve, and as new data become available. The initial discussion, therefore, should be conceptualized as the beginning of a dialogue between patients, caregivers, and the health care system. When the initial discussion takes place in a specialist’s office and the patient will be referred back to primary care for follow-up, it may be necessary to direct further questions to the primary care clinician, with an offer of additional support to the primary care clinician from the evaluating specialist.

Delivering complex and disturbing information effectively requires clinicians to overcome a variety of obstacles.

 Clinicians are understandably reluctant to share the bad news of a progressive and usually terminal diagnosis. This is especially the case when the clinician feels the diagnosis is untreatable or that the patient will be unable to make use of the information imparted.

 When the diagnosis of cognitive impairment is uncertain or incomplete, a clinician may delay discussion while awaiting further test results or additional consultations.

Many primary care clinicians and general psychiatrists find themselves in the position of discussing a dementia diagnosis despite limited knowledge of the symptoms, causes, treatment options, and prognosis of the multiple diseases that present with cognitive symptoms. Limited knowledge can create reticence about what to say or how to be helpful. In an effort to delay or avoid creating pain for a patient, clinicians may speak in euphemistic terms, talking about “senior moments” or “age-related memory loss” rather than giving a more precise name to symptoms severe enough to warrant a more accurate designation. The brief time allotted to an appointment can discourage a clinician from tackling a conversation that is unlikely to be finished easily or quickly.

Some evidence suggests, too, that clinicians’ likelihood of disclosing a dementia diagnosis can be influenced by racial and ethnic factors. Lin and colleagues, for example, reported that a higher proportion of non-Hispanic Black and Hispanic patients with dementia were unaware of their condition.

 Recognizing hazards such as these will help clinicians avoid engaging in an incomplete or uninformative discussion.

Meeting the patient’s specific needs requires preparation. First, clinicians can assess patients’ and caregivers’ awareness of relevant symptoms, related health concerns, and lifestyle issues. The values and beliefs of patients and caregivers will affect the ensuing discussion. Understanding the preferences of patients who retain the capacity to make meaningful choices allows clinicians to frame or modify a disclosure discussion and tailor the content to the level of detail desired by the patient.

Families and patients very often come to the disclosure appointment with a strong suspicion regarding an explanation for the behaviors and deficits they have observed. Confirming their hunches can be sad and anxiety-provoking, but also, at a certain level, reassuring and validating. A clear diagnosis may allow caregivers to understand and avoid blaming a cognitively impaired individual whose behavior has become inattentive, inconsiderate, bizarre, uncooperative, frustrating, or even aggressive. An additional decision for more capable patients is who to involve and when they should be included in the sharing of information. When the patient with dementia no longer retains capacity to make appropriate choices in this respect, the clinician will begin discussion with the appropriately chosen surrogate decision-maker.

In discussing diagnosis, clinicians can avoid running short on time by making sure an adequate appointment has been allotted. The discussion, too, can be conducted over more than 1 visit

 following the initial disclosure visit, with an additional visit scheduled in the near future. The level of detail disclosed should match the comprehension and language skills of the participants. Understanding of the important information can be verified through using a “teach back” approach. Clinicians can invite questions and note the emotional reactions of patient and caregiver. Printed resources offer the patient and caregiver additional help in understanding, retaining, and digesting the information discussed. Such materials must be appropriate to the patients’ and caregivers’ language, literacy, and comprehension. A follow-up plan and planned future appointments, whether in specialty or primary care, will help patients and caregivers feel supported during the stressful time of adjustment that follows establishment of a serious medical diagnosis.

The disclosure discussion is grounded in shared, objective, and understandable information. Patients’ reported symptoms, results of diagnostic tests, clinicians’ opinions about the cause of symptoms and which cause is most probable, the expected course of the illness, and the treatment options should all be reviewed, with the goal of reaching a consensus about what is known and what is to be expected. Clinicians, and perhaps especially generalists, may focus excessively on diagnosis, while caregivers’ deeper concerns are about how to obtain emotional and practical supports.

 Caregivers often raise questions about important planning issues such as what to do about employment, residential plans, home safety, driving, financial decisions, and end-of-life planning. Discussion of advance planning, including estate decisions, advance directives, and a will, may be appropriate.

A burning question, often, is how long the patient is likely to survive and what symptom progression should be anticipated. One useful tool for survival prediction was developed and made accessible as a web-based application by Haaksma and colleagues.

 offers an additional schema for discussing the expected symptoms. Keep in mind that the earlier these discussions take place, the more meaningful the patient’s involvement will be in the planning.

One popular framework for the disclosure of difficult news is the SPIKES approach (

Adaptation of this intervention to discussion of a dementia diagnosis has been described by Peixoto and colleagues,

the interview for a patient with dementia often requires the presence of a trusted family member because cognitive impairment may limit understanding of the diagnosis discussion. Other companions or clinicians can play helpful roles in the communication as well. Assessing the patient’s 

 of this diagnosis requires evaluation of language and comprehension capacity for understanding complex information. When comprehension is sufficiently intact, the discussion should be addressed to the patient. An attempt at obtaining the patient’s 

 is possible even when comprehension is somewhat impaired, and a patient who prefers not to have a diagnostic discussion may wish to delegate this to a caregiver with whom a later communication can be scheduled. Giving 

to the patient with dementia is a more palatable experience when hope is nurtured by emphasizing some aspects of dementia that are less negative. These include the variable, sometimes slow progression; preservation of personality and capacity for enjoyment in many individuals; availability of palliative treatments; and options for preserving autonomy to the extent possible. Addressing the patient’s 

 with empathic responses includes addressing the emotions of the caregiver, who may be experiencing great distress. And discussion of 

 includes options for rehabilitation and residential choices; legal and safety issues including the stressful, but necessary discussion of driving; and distribution of written information and lists of resources.

The ongoing care of a patient with dementia is a team effort requiring participation of the patient, caregivers, health care providers, and others who will each contribute specialized services. Clinicians can prepare patients and their caregivers for the future by providing lists of helpful books, websites, advocacy organizations, care managers, adult day programs, options for emergency or respite care, and other resources that they may need as the clinical status of the patient evolves.

An important pitfall to avoid with cognitively impaired individuals is that of inappropriate redisclosure. Although a surrogate decision-maker must remain aware of the patient’s deficits, the patient may be unable to understand and retain that information. Repeated questions from the patient about what is wrong, met with a repeated upsetting diagnostic label such as 

may serve to heighten anxiety without beneficial learning. Each new disclosure may be met with shock, fear, or sadness, and these disturbing emotions may linger even after the individual’s cognitive awareness of the cause has faded. It is not necessary or advisable to reexpose an individual to stressful information that cannot be processed and stored. When such questions come up from a patient who has already been informed of the diagnosis, it is preferable to respond with reassurance and redirect the conversation to other topics.

Finally, affirmation of appropriate hope is one of the most valuable contributions clinicians can make. One of the deepest fears the patient will have when diagnosed with a progressive illness is the fear of dependence and possible abandonment. Although the likelihood of a cure cannot be offered at present, the reassuring confirmation of ongoing care and non-abandonment can be provided. There are often means for reducing suffering such as care management, companionship, respite care, symptomatic medications, nonpharmacologic therapies, and exercise. Clinicians can offer some reassurance by emphasizing that much of an individual’s essence remains far into the course of a dementing illness.

With preparation and care, disclosure of dementia diagnosis provides an opportunity for clinicians to educate, relieve suffering, and help patients and caregivers prepare for the future. At present, there is no cure for the common causes of dementia. However, the condition’s increasing prevalence, the growing accessibility of medical information, and our patients’ right to know of their diagnosis require that we engage our patients and their caregivers early in this discussion. Doing so can ease a stressful journey and provide essential support.

is a professor of clinical psychiatry and vice chair of clinical business development in the Department of Psychiatry and Behavioral Sciences at The Johns Hopkins University School of Medicine. 

is clinical director of the Division of Geriatric Psychiatry and Neuropsychiatry, and associate professor of psychiatry and behavioral sciences at Johns Hopkins Medicine in Baltimore, Maryland. 

is a clinical assistant professor at Boston University School of Medicine, an adjunct clinical assistant professor at Tufts University School of Medicine, and a part-time lecturer at Harvard Medical School in Boston, Massachusetts. 

holds the Swank Foundation Endowed Chair in Memory Care and Geriatrics, Christiana Care Health System, in Wilmington, Delaware, and is a professor of psychiatry and human behavior at Sidney Kimmel Medical College, Thomas Jefferson University, in Philadelphia, Pennsylvania.

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