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Is Bipolar Disorder Partly a Vascular Disease?

Heather is 43-year-old woman with bipolar disorder attending her follow-up appointment in your clinic. You have been treating her since her first hospitalization for mania a decade ago. Whether it is depression, mania, anxiety, or the occasional intervals of excessive alcohol use, each appointment brings a new treatment target. Thankfully, Heather has finally enjoyed an extended recovery from her mood symptoms for the past 2 years. You are surprised to learn that, since your last appointment, Heather has, despite her young age, experienced a relatively significant myocardial infarction.

The above scenario is not as uncommon as we might hope, according to data from a recent study that my colleagues and I conducted of the incidence of new-onset cardiovascular disease in a large, representative, epidemiologic sample of the Unites States population. In this study, adults with bipolar I or II disorder were markedly more likely than either adults without mood disorders or those with major depressive disorder to be diagnosed with new-onset cardiovascular disease between baseline and 3-year follow-up. Additionally, new-onset cardiovascular disease occurred extremely prematurely among adults with bipolar disorder—on average, 8–11 years earlier than in adults with major depressive disorder and 14–17 years earlier than in adults without mood disorders. The question arises, why?

Among people with bipolar disorder, rates of cardiovascular risk factors, such as smoking and obesity, are higher than in the general population. The physiologic strain of mania and depression may contribute to the excessive burden of heart disease in bipolar disorder. Many of the medications used to treat bipolar disorder also precipitate weight gain and other metabolic disturbances that contribute to cardiovascular risk. But maybe all of these considerations are only part of the story. Maybe bipolar disorder and cardiovascular disease have shared etiopathology, ie, they are geographic strangers but mechanistic family.

In our study, many people with bipolar disorder had never received treatment for their condition, and most had never received antimanic medications, suggesting that these findings cannot be explained by medications alone. This was not a highly distilled sample of patients in tertiary care settings but rather a representative community sample. The large sample afforded us the rare luxury of controlling for many potential confounding variables. Even after taking into account demographic variables, smoking, obesity, hypertension, and alcohol and drug use disorders, the odds of people with bipolar disorder developing cardiovascular disease were twice that of people with major depressive disorder and over two and a half times that of the general population without mood disorders.

What does this all mean? Clearly, we need to help patients optimize their lifestyle, and we need to minimize the metabolic burden conferred by our medications. But we also need to recognize—in our conceptualizing of bipolar disorder, in our advocacy efforts toward reducing stigma, and in the design of envelope-pushing clinical trials and biological research—that bipolar disorder is in part a vascular disease and needs to be approached as such.

Financial disclosure: Dr Goldstein had no relevant personal financial relationships to report.​

Prevention of Perinatal Mood and Anxiety Disorders

During the last few years, many articles have been written on the etiology of postpartum depression (PPD) and other perinatal mood and anxiety disorders (PMADs). Biochemical and psychosocial causes have been noted in much of the research. Interestingly, a paucity of information remains regarding how to lower the incidence of, decrease the severity of, and possibly prevent these illnesses. That is where my focus lies. Why not attempt to circumvent the suffering in the first place?

For almost 3 decades, stemming from my own personal experiences with suicidal depression following the births of my children, my message has been one of hope. Not only are PPD and related illnesses completely treatable with proper help, their incidence rates can be minimized, and in some cases they can even be prevented so that the nightmare never begins. In Postpartum Depression For Dummies, I outlined many preventive steps for women who know they are at high risk for a bout of illness following a delivery.

Although chemical and life factors place women at high risk for PPD and other PMADs, no one is immune. Even women with no previous personal or family mental health issue can be hit hard. Therefore, regardless of risk factors, every new mother should arrange certain pieces of a wellness strategy, ideally before the baby comes. These basic steps can help to ward off emotional and psychological problems after delivery. The first 7 steps are for all mothers, and the last 2 are for those who are already suffering or know they are at high risk.

  1. Have realistic expectations of motherhood—throw out the myths and fantasies.
  2. Discuss wishes and concerns with your partner—communicate expectations and make an agreeable plan together.
  3. Pay attention to nutrition (including supplements) to feed the body and brain, such as the right proteins, complex carbohydrates, omega-3 fatty acid, vitamin D, folate, etc.
  4. Plan for nighttime sleep to protect brain chemistry—even a breastfeeding mom can get a few hours of uninterrupted nighttime sleep with a good plan.
  5. Exercise or use special breathing to oxygenate the brain.
  6. Find emotional support, ie, people to lean on and be “real” with.
  7. Find logistical support, ie, people to give you regular breaks to nurture yourself and “recharge your batteries.”
  8. Seek psychotherapy with a professional who specializes in perinatal disorders (if you are at high risk).
  9. Take medication or alternative/complementary treatments (if necessary).

When a pregnant woman or new mom contacts me with concerns that she will develop depression, anxiety, or another PMAD, we develop an individualized wellness plan using the above steps. Each woman needs a plan that will work with her particular circumstances, beliefs, chemistry, and level of support. So much unnecessary suffering can be avoided when these basics are in place!

Financial disclosure: Dr Bennett is a perinatal psychologist ( and is the author of Postpartum Depression For Dummies; she had no other relevant personal financial relationships to report.​

The Business of Medicine

Most psychiatrists (and physicians in general) receive little information in their training about the business of medicine. This is particularly problematic if one decides to go into private practice, as I did.

Issues that enter one's life in private practice include learning where to get the best loans, finding an office, buying office equipment, hiring and managing staff, handling accounting records, selecting malpractice policies, and dealing with health insurers like Medicare (including becoming 'approved' by insurers and facing the hassle of prior authorizations). Throughout one’s time in practice, questions arise such as which insurers reimburse better and in a timely way, what electronic billing/prescribing/charting companies are the best, what should I look for in joining another practice or taking on an associate, and should I continue to take insurance or go to cash only.

By virtue of finishing medical school and training, doctors believe ourselves smart … and we are. But being smart does not mean we know everything. Generally, I have found doctors to be among the worst businesspeople because we make dumb mistakes in areas where we really don't have much expertise.

I know one young doctor who, when I asked how his practice was going, became indignant. He felt that talking about the business side of his practice was beneath him.

"I'm here to help people," he bristled. I know he's dedicated and well intentioned. We all become physicians so we might help people. That's not the issue.

Someone once said to me, "No one watches your money better than you do." We can be dedicated to helping, but we also need to be circumspect in how we run our practices as well as informed about how we (and accountants and financial advisers) manage our hard-earned money (eg, paying off loans, investing, building our savings, handling mortgages, planning for vacations).

I’d like to have a forum to discuss the business of medicine with colleagues and share what works and what doesn't.

To address one issue I raised above, I have not gone to an all-cash basis in my practice but certainly have considered it. Dealing with the various health insurance plans is generally an onerous task. Some years back, an employee of mine who had worked for one of the insurance industry leaders shared that her instructions there were to take a certain percentage of daily claims and shred them. The object, of course, was to delay payment as long as possible and keep the money in the insurer's accounts. Prior to electronic billing, I received claim forms that had been rejected because I had not kept my signature within the lines or didn't sign the form with the signature that the insurer thought was right. With electronic billing, those wily contortions to avoid payment have not really gone away. Now, some insurers simply forget to pay or dance around and say certain things aren't covered.

Dealing with insurance companies requires a lot of personnel time and adds much overhead cost. Hence, some of my colleagues have gone to cash-only practices and believe that the patients they lost are made up for by the new patients who are willing to pay in full. A compromise is to accept patients who have insurance but, instead of dealing with insurers yourself, give patients a superbill so that they submit the claims.

My feeling is that physicians have become servants of the insurance companies—passively accepting the limitations decreed and the payments accorded per the insurers' dictation—all under the guise of cost effectiveness, but medical costs are going out of control.

I have a fantasy that if a vast number of doctors refuse to recognize health insurance, then insurers would disappear since we really control their existence. What do you think?

Financial disclosure: Dr Kapuchinski had no relevant personal financial relationships to report.

Do Long-Acting Injectable Antipsychotics Improve Adherence and Related Outcomes?

The high incidence of inconsistent medication-taking among patients with chronic illnesses is well established, but nonadherence is especially problematic in schizophrenia. Total and partial, overt and covert nonadherence is a serious public health concern because poor adherence is a major reason for relapse and rehospitalization, with all of the attendant negative consequences. Logic suggests that adherence would be improved by using medication that patients do not have to take every day.

We have conducted several reviews of the evidence as to whether long-acting injections (LAIs) of antipsychotic medications lead to better outcomes than oral antipsychotics (OAs). Evidence from randomized controlled trials (RCTs) and mirror-image studies has been examined in meta-analyses, with over 5,000 patients in each meta-analysis. Studies comparing LAIs and OAs provide conflicting evidence, but the results differ by trial design. In general, RCTs tend to show equivalence for the two treatments, whereas mirror-image studies show consistent advantages for LAIs. These diverging results highlight strengths and weaknesses of each design.

Reasons for the seeming contradiction between results from RCTs and those from mirror-image studies seem to lie in the selection, assessment, and treatment of patients. Because the goal of treatment with LAIs is the improvement of adherence over that with OAs, potential problems arise for the generalizability of results from RCTs. Although the traditional RCT is usually considered the “gold standard” design for trials, it might not be the most informative methodology to compare the effectiveness of OAs and LAIs due to selective recruitment of more adherent patients who are able and willing to consent to a double-blind, double-dummy design study. Moreover, in RCTs, patients are seen frequently, are often handed the medication, and know that their adherence is being monitored.

The mirror-image study, on the other hand, utilizes each patient as his or her own control by comparing the frequency of a specific outcome (eg, hospitalization or duration of inpatient stay) during an equal period of time before and after the implementation of the new treatment. A potential problem with this design is that changes that are unrelated to the study might take place over time (such as hospitalization rates declining due to the availability of fewer beds or more rigid application of “medical necessity” to reduce rates of potentially unnecessary hospitalization). Additionally, expectation bias or greater surveillance in the prospective mirror–phase may limit usefulness of this design. However, results from retrospective mirror-image studies that are highly generalizable are fully consistent with the remaining mirror-image data, confirming the significant advantages of LAI treatment in patients selected for clinical eligibility for LAI treatment in usual care settings.

The best approach to determining comparative effectiveness of LAIs versus OAs may be a pragmatic RCT , a large, simple trial with broad inclusion criteria and few exclusion criteria in order to minimize selection bias. Such a trial can mirror “real world” naturalistic treatment without elements of traditional RCTs like research assessments, more frequent follow-up visits, appointment reminders, and assistance obtaining oral medication. Although such studies have rarely been conducted, they are sorely needed. Another opportunity for showing the adherence-enhancing and relapse-reducing effects of LAIs compared to OAs may be a focus on first-episode and early-phase patients with schizophrenia, who tend to benefit substantially from antipsychotic treatment but who also frequently stop taking antipsychotics. For example, a recent 1-year RCT in first-episode schizophrenia patients demonstrated significant and impressive advantages of risperidone LAI over oral risperidone, translating to a number needed to treat of 4 for prevention of psychotic exacerbation or relapse. “Excellent” adherence was found in 95% of patients receiving risperidone LAI compared to 33% taking oral risperidone.

Financial disclosure: Dr Correll is a consultant for AbbVie, Acadia, Actavis, Alkermes, Genentech, Gerson Lehrman, IntraCellular Therapies, Janssen/J&J, Lundbeck, MedAvante, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, and Takeda; has received grant/research support from Bristol-Myers Squibb, Otsuka, and Takeda; has received honoraria from MedScape; is a member of the advisory boards for AbbVie, Acadia, Actavis, Alkermes, Genentech, IntraCellular Therapies, Lundbeck, Otsuka, Reviva, Roche, Sunovion, and Supernus; and has provided expert testimony for Janssen.

Dr Kishimoto is a consultant for Dainippon Sumitomo, Novartis, and Otsuka; has received grant/research support from Pfizer, Takeda, Tanabe-Mitsubishi, Dainippon-Sumitomo, Otsuka, and Mochida; and has received honoraria from Banyu, Eli Lilly, Dainippon Sumitomo, Janssen, Novartis, Otsuka, and Pfizer.

Dr Kane is a consultant for Alkermes, Eli Lilly, Forum, Forest, Genentech, Lundbeck, Intracellular Therapies, Janssen, Johnson & Johnson, Otsuka, Reviva, Roche, and Teva; has received honoraria for lectures from Janssen, Genentech, Lundbeck, and Otsuka; and is a stock shareholder of MedAvante and Vanguard.

A Diagnostic Dilemma: The Child With Aggressive Outbursts

Clinicians who work with children frequently come across a particularly vulnerable group of youngsters. The following vignette describes a “typical” patient in this group:

Jordan is an 8-year old boy who has just gotten suspended from 1st grade for the 2nd time (and it’s only October) for fighting. He was accidentally bumped by a classmate while waiting in a line and responded by angrily striking the classmate multiple times. You learn from his parents that similar events happen elsewhere. In fact, this youngster had to change preschools several times due to his aggression. Although Jordan is a bit more fidgety than other children his age, what is really causing him trouble is his “short fuse” and “explosions” that often culminate in destruction of property or physical aggression against others. No external circumstances readily explain these chronic difficulties. The patient’s mother describes Jordan’s temperament as “sweet” and “kind,” but, as her son’s aggressive behaviors continue over time, she notes that her child is becoming more surly and mean-spirited. When you interview the child, he initially comes across as irritable and defiant, but, with time, he becomes kinder. Jordan sadly expresses that he knows that his peers, teachers, and even his family think of him as being “bad.”

When the dysfunctionally aggressive child is brought to clinical attention, a key challenge is to apply a diagnosis or diagnoses that best suits this child. The patient may meet diagnostic criteria for attention-deficit/hyperactivity disorder, but that diagnosis does not seem to get at the core of what the key difficulty is for children like Jordan—violent, affectively-charged reactions to minor provocations.

At one time, this child could have been given the diagnosis of conduct disorder. Conduct disorder has been shown to be a valid diagnosis, even in preschool-aged children. However, this diagnosis isn’t commonly used to describe such children. Clinicians might not want to use this diagnosis as it may suggest that the child has premeditated antisocial behavior and/or is destined to develop antisocial personality disorder.

With these considerations in mind, using the DSM-IV diagnosis of bipolar disorder not otherwise specified might have seemed more appropriate to some clinicians. Several diagnostic features of bipolarity are manifest in these patients—irritability, impulsivity, distractibility, and risk-taking behavior.

These factors may have led, in part, to the increased use of a bipolar diagnosis in children. As a result of its increased use, concerns were raised about the overdiagnosis of bipolar disorder in youths. What is not clear is whether clinicians believed that these patients actually had the same diagnosis as seen in adults or rather that this diagnosis was simply the most suitable categorization based on practical considerations.

Subsequently, the diagnosis of disruptive mood dysregulation disorder (DMDD) entered the psychiatric nosology in the DSM-5. This mood disorder is primarily characterized by childhood-onset chronic irritability and temper outbursts. However, concerns have been raised about the utility of the DMDD diagnosis. Data suggest that DMDD has substantive overlap with disruptive behavior disorders and does not appear to be diagnostically stable over time.

Since DMDD is a mood disorder, one might expect that the onset of temper outbursts or tantrums would develop at the same time or after the onset of irritable mood. I rarely see such a patient. The much more common presentation is like the case vignette I described above—a child who becomes chronically irritable subsequent to the onset of temper outbursts.

We do not seem to have a satisfactory diagnosis in our current clinical nosology to describe this prevalent group of children. Ultimately, we need a precise, meaningful, and empirically based means by which to characterize these children.

Financial disclosure: Dr Findling in the last 12 months, has received research support from, acted as a consultant for, and/or served on a speakers’ bureau for Alcobra, American Psychiatric Press, Bracket, CogCubed, Cognition Group, Coronado Biosciences, Elsevier, Forest, Guilford Press, Johns Hopkins University Press, KemPharm, Lundbeck, Merck, NIH, Neurim, Novartis, Otsuka, Oxford University Press, Pfizer, Purdue, Roche, Sage, Shire, Sunovion, Supernus, Validus, and WebMD.

<span class="svspan"> Blog</span>How Do Symptoms of PTSD Cluster in <em>DSM-5</em>?

Most people have experienced some type of trauma in their lives and have subsequently felt aftereffects, which we have come to term posttraumatic stress. If the posttraumatic stress is persistent and impairs functioning, it can become a disorder. But many different types of posttraumatic stress symptoms exist, and we continue to refine which symptoms constitute posttraumatic stress disorder (PTSD). The latest refinement occurred in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). The DSM-5 introduced several new PTSD symptoms and tinkered with a few previously described symptoms to better define how to diagnose the disorder. However, how these new and refined symptoms cluster with other symptoms was unclear. Knowing how different symptoms of PTSD cluster together would help us conceptualize the major symptom components of the disorder. When symptoms often overlap with others, they presumably together represent a broader symptom component. To make a medical analogy, when symptoms of a sore throat, cough, and excess phlegm are found together, they represent disruptions in the respiratory system that can mean the patient has a cold.

Veterans are an important and ideal population in which to study posttraumatic stress not only because of their higher potential exposure to trauma than the general public but also because we care about the well-being of those who have served. My colleagues and I conducted a study using a nationally representative sample of 1,484 US veterans to understand the prevalence of DSM-5 PTSD, the major symptom components of the disorder, and how different symptom components are related to important outcomes. Using a web-based survey, we assessed various mental health symptoms, including those of PTSD, and other aspects of their lives, such as quality of life.

We found that 12% of US veterans screened positive for lifetime PTSD and 5.2% screened positive for past-month PTSD. In analyzing how DSM-5 PTSD symptoms cluster, we found 6 major symptom components that we called re-experiencing symptoms, avoidance symptoms, emotional numbing symptoms, externalizing behaviors, dysphoric arousal symptoms, and anxious arousal symptoms. Furthermore, we found that these major symptom components were related to different outcomes. For example, emotional numbing symptoms were more strongly related to depression, suicidal thoughts, and decreased quality of life than other symptom components, and externalizing behaviors were more strongly related to hostility than other symptom components.

These findings may help further efforts to understand, diagnose, and treat PTSD. Different symptom components may exist differently in our neurobiology, making some better targets for certain treatments than others. Because PTSD is a complex disorder, we should expect to continually refine how we understand and conceptualize it.

Financial disclosure: Dr Tsai had no relevant personal financial relationships to report.

How Does Neuroscience Research Relate to Psychoanalysis?

Basic neuroscience research is sometimes, but mistakenly, thought to be singularly devoted to finding medications that will treat neurologic and psychiatric diseases. Although some basic neuroscience does suggest new molecular targets for medications, perhaps an even greater proportion of this research has helped us to understand the enduring effects of stress and potential psychosocial remedies. In fact, neuroscience research now appears capable of validating and exploring two of the central pillars of psychoanalytic theory: (1) that much of mental life is unconscious but nevertheless fully capable of affecting waking emotion and behavior and (2) that early life experiences have important implications for adult function and happiness.

An interesting example of a way in which neuroscience research may relate to psychoanalysis is the molecular biology of conditioned fear memory reconsolidation. In the laboratory, rats and mice can fairly easily be conditioned to fear a conditioned stimulus, like a loud tone, if it is paired a few times with an unconditioned stimulus, such as a mild electric shock. After conditioning, the animal responds to the tone by freezing in place, just as it did when given the shock. The process by which fear conditioning becomes part of permanent memory is called consolidation and requires a chain of molecular events, including gene expression and protein synthesis, in the amygdala. Blocking these events during conditioning, such as by administering a protein synthesis inhibitor like anisomycin, prevents the consolidation of fear memory, and no conditioned response can subsequently occur.

The amygdala is also activated in humans when they are presented with fearful stimuli. Patients with anxiety disorders have especially robust amygdala activation when their brain activity is monitored with functional magnetic resonance imaging (fMRI). Conditioned fear in rats responds to selective serotonin reuptake inhibitors (SSRIs) in almost the same temporal pattern as is seen in anxious patients. Thus, conditioned fear in animals is considered by many to be a model of human fear and anxiety.

Conditioned fear responses can be extinguished if the conditioned stimulus is presented multiple times without reinforcement by the unconditioned stimulus. That is, if the tone is presented to the rat over and over again without any electric shock, the animal eventually stops freezing. In this case, it has learned that tone and shock are not paired, a process that involves both the medial prefrontal cortex (mPFC) and the amygdala. But, importantly, the original fear memory is not abolished; rather, the original memory and the new extinction memory exist side by side in a delicate balance. At first, extinction dominates, and the animal does not freeze to the tone, but, after a period of time of no testing, the conditioned fear response can be easily reactivated by a single presentation of the conditioned stimulus.

In 2000, Karim Nader, PhD, and colleagues published a seminal article showing that a reactivated fear memory is temporarily labile and can be blocked from re-entering permanent memory. For the inactive memory to be returned to permanent memory, it must go through the consolidation process all over again. If this reconsolidation is blocked, for example as Nader and colleagues did by administering anisomycin right after memory reactivation, the animal will subsequently not freeze when the tone is presented. What is critically different between extinction and reconsolidation blockade, however, is that in the latter case the fear memory is permanently abolished.

In a 2011 article , Steven P. Roose, MD, and I proposed that psychoanalytic interpretations function in a manner similar to blocking the reconsolidation of fear memory. During psychoanalytic therapy, the patient gradually recovers memory of unconscious conflicts based on early traumatic experiences. When these memories become conscious, we speculated, the memories are labile. Psychoanalytic interpretation reframes them so that, when they are reconsolidated into permanent memory, they are no longer as disturbing and capable of producing negative or aversive emotions and self-destructive behavior. Hence, a successful interpretation should offer patients some measure of permanent relief.

Psychoanalysis is a complex theory, and no single model can ever truly be said to be an adequate model. But the idea that at least one aspect of psychoanalysis may be represented in the laboratory opens up intriguing possibilities for experimental study. I hope the reconsolidation hypothesis stimulates thinking about the neuroscientific basis of psychotherapy.

Financial disclosure: Dr Gorman is a consultant for Care Management Technologies and has received royalties from Oxford University Press.

Alzheimer’s Care: It Starts With a Conversation and Involves Everyone

Almost all clinicians will see a patient with symptoms of Alzheimer’s or another dementia at some point in their careers, either in an outpatient or inpatient setting. According to the latest figures from the Alzheimer's Association , there are 5.1 million Americans aged 65 years and older with the disease, and that number will climb to more than 13.8 million by 2050. Yet only 45% of Alzheimer’s patients or their caregivers report that they received the initial diagnosis directly from their doctor.

Giving a patient this diagnosis is undoubtedly among the most difficult conversations a doctor may ever have. The first time I ever told a patient that she had Alzheimer’s, it didn’t go well. I’m sure I squirmed and used some vague and evasive language. But, after decades of experience with Alzheimer’s patients, I can now confidently say that patients are grateful when their doctor is direct and honest about what is happening. They can face the facts. They can work with their clinicians and their families to plan what’s next, explore what treatments are available, and determine how they will try to shape their new lives.

While “what’s next” involves both medical and nonmedical interventions, we at Banner Alzheimer’s Institute (BAI) believe that about 80% of what is needed is the nonmedical assistance for the patient, caregiver, and family. This approach, part of our “Model of Care,” is centered on both the patient and family and is consistent with guidelines such as those published by the American Psychiatric Association in its October 2014 Guideline Watch for the treatment of patients with Alzheimer’s and other dementias.

Based on years of experience in caring for these patients, we have now developed a model for the primary care setting called the “Dementia Care Initiative.” In this model, primary care providers are trained to evaluate a patient for a diagnosis of Alzheimer’s disease or another dementia; determine if it’s mild, moderate, or advanced; and then implement a treatment plan that is a mix of interventions that successfully address a patient’s needs in terms of behavior and psychological state, daily function, cognition, and stimulation. This checklist-type plan is tailored to the severity of the patient’s dementia and his or her unique needs.

For example, a primary care physician will see a patient with mild dementia and identify potential triggers for depression, anxiety, and irritability. A case worker will work with this patient to assess his ability to perform activities of daily living and will provide the patient with educational resources and review topics such as power of attorney and long-term care.

For a patient who has moderate Alzheimer’s, these interventions go one step further. The physician will evaluate the patient for any new behavioral problems and determine the need for medications. The case manager will assess any changes in the patient’s ability to perform activities of daily living and recommend additional help, if needed, for tasks such as meal preparation and personal care. The case manager will also continue to discuss the importance of a power of attorney and, if the patient lives alone, ensure that the patient is placed in a more secure setting.

We know how important it is not only to educate family and caregivers about the progression of the disease and equip them to help the patient, but also how important it is to help teach caregivers how to take care of themselves. The success of BAI’s Model of Care and the primary-care-setting Dementia Care Initiative is due in large part to the simple act of listening to patients and family members and giving priority to their most pressing needs. Time and time again, patients and family members tell us that they feel relieved to know that they have really been heard. They are relieved that clinicians are finally listening to both the patient and family, working with them to help them fully understand what they will all be going through, and helping to improve patients’ quality of life and maintain their dignity.

Financial disclosure: Dr Tariot is a consultant for Abbott, AbbVie, AC Immune, Boehringer Ingelheim, California Pacific Medical Center, Chase, CME Inc, Corium, GliaCure, Lundbeck, Medavante, Otsuka, and Sanofi-Aventis; is a consultant for and has received research support from AstraZeneca, Avanir, Bristol-Myers Squibb, Cognoptix, Janssen, Merck, and Roche; has received research support only from Baxter Healthcare, Functional Neuromodulation, GE, Genentech, Novartis, Pfizer, and Targacept; has received other research support from NIA and AZ Department of Health Services; is a stock shareholder of Adamas; and is a contributor to a patent owned by the University of Rochester, “Biomarkers of Alzheimer’s Disease.”

<span class="svspan"> Blog</span>Inadequate Trials of Prazosin: Potential Missed Opportunities for Veterans With PTSD

The 2010 VA/DoD Clinical Practice Guideline recommends that clinicians consider the use of prazosin, an alpha 1 adrenergic receptor antagonist used to treat hypertension, for PTSD-related nightmares. Sleep problems are common in PTSD and may be a core feature. Research has suggested that, although prazosin has been steadily disseminated in the VA, it still may be underutilized and underdosed. In our recent study, we examined a cohort of veterans with PTSD initiating prazosin to characterize their dosing patterns and duration of use.

Administrative data identified veterans with PTSD according to ICD-9 codes. Prazosin use following initiation utilized refill data, and prazosin doses were calculated based upon total milligrams and day’s supply dispensed.

A total of 12,844 veterans with PTSD were new prazosin users during 2010. On average, the patients were 53 years of age, 92% male, and taking 6 medications at the time of prazosin initiation.

Prazosin doses generally increased during treatment, reaching an average maximum dose of 3.6 mg/d. However, only 14% reached the minimum guideline-recommended dose of 6 mg/d for an adequate trial.

Regarding duration of use, 20% of the patients never refilled their initial prazosin prescription, and 18% discontinued within 6 months. The remaining 61% took prazosin for more than 6 months, with 38% of the total sample persisting for at least 1 year. Patients with concurrent SSRI/SNRI antidepressants were more likely to maintain prazosin treatment for a year compared to non-antidepressant users. Additionally, one-year users were older and had more concurrent medications.

Recent work by Murray A. Raskind, MD, and colleagues has noted that pretreatment physiological parameters such as blood pressure in patients with PTSD may serve as a clinically useful biomarker for helping to predict the response to prazosin. Patients who had higher baseline blood pressure and smaller baseline blood pressure drop (standing for 2 minutes for supine) showed substantially greater PTSD symptom improvement associated with prazosin treatment. Although preliminary, these findings suggest that increased peripheral noradrenergic tone is a potential biomarker for a clinically therapeutic response to prazosin in PTSD, and they may also account for varied findings using prazosin for nightmares.

Although large pharmacy databases are very useful for addressing some questions, they cannot answer others. In the present case, we don’t know why the drug was discontinued after one year in two-thirds of the patients. Was it because patients and/or providers found it ineffective at lower doses? Was it because of side effects? Was it because prescribers did not titrate the dose to optimal levels to achieve full symptom response?

Our findings justify further investigation to identify factors related to the common failure to reach recommended prazosin dosage guidelines for PTSD-related nightmares. The answer to this question and others would provide clinicians who treat patients with PTSD a vital opportunity for more optimal use of this low-cost, guideline-recommended treatment.


Raskind MA, Peskind ER, Millard S, et al. Baseline blood pressure is associated with PTSD symptom response to prazosin in active duty combat soldiers. Poster presented at: 53rd Annual American College of Neuropsychopharmacology Meeting; December 9, 2014; Phoenix, AZ.

Financial disclosure: Drs Bernardy and Friedman had no relevant personal financial relationships to report.

Pellagra: Niacin Deficiency and Mental Illness

In our previous post, we stated that a single nutrient is unlikely to have a profound effect on a serious mental health condition, but the fascinating story of niacin and pellagra is an exception to that rule.

Pellagra (meaning rough skin) was first described in 1735 by a Spanish physician, Don Gaspar Casal, and was called “mal de la rosa” due to the characteristic red rash on the hands and feet. Early researchers linked pellagra with poverty and a corn-based diet, suggesting that spoiled maize was at fault. Almost 2 centuries later, a pellagra epidemic occurred in the southern United States. Despite the link to the poor person’s diet , the wisdom at that time was that pellagra was contagious and perhaps hereditary, and pellagrins, as they were called, were shunned.

The relevance of pellagra to psychiatry is that symptoms can include confusion, psychosis, and depression. Pellagra typically affects the skin, the gut, and the brain, with a characteristic manifestation referred to as the 3 Ds—dermatitis, diarrhea, and dementia—and it may lead to death.

In 1914, Joseph Goldberger, a physician and clinical epidemiologist, was invited by the US Surgeon General to investigate pellagra. Careful reviews of the literature indicated to him that pellagra was a dietary disease , not an infectious one. Cases were being reported in mental hospitals and orphanages in which the residents, eating a mainly corn-based diet, would get the disease, whereas the staff, despite daily contact with the patients, would not. Outbreaks also appeared in cotton mill villages where the diet was mostly cornmeal, molasses, salted pork, and lard.

Goldberger began running trials in orphanages and asylums by manipulating their diets, and those given fresh meat, milk, and legumes were no longer sick. He also conducted experiments in which he showed he could induce pellagra in healthy men (prisoners who were offered pardons for participating) by feeding them a corn-based diet. Thus, Goldberger established that pellagra was a disease of a faulty diet, not infection.

Despite his repeated controlled experiments using diet manipulation, people continued to hold to the prevailing wisdom that pellagra was infectious. And so, in 1916, he and volunteers (his wife being one of them) were exposed to the blood, urine, feces, and epidermal scales of people with pellagra, and not a single person developed it. Goldberger, however, was unable to isolate the ingredient that was causing the condition. In 1937, another scientist, Conrad Elvehjem, determined that niacin was the essential dietary factor. Fortification of food with niacin began in 1941.

Although underreporting of pellagra was typical, records suggest that at least 3 million cases had occurred, with over 100,000 deaths, in America in the 40 years until its true cause was determined. One state hospital, in Goldsboro, NC, estimated that nearly 1 in 5 admissions between 1930 and 1932 were solely because of pellagra psychosis, an easily preventable/treatable nutrient deficiency.

The Diagnostic and Statistical Manual of Mental Disorders acknowledges that nutritional conditions such as niacin deficiency can cause neurocognitive disorders. But, we wonder, while niacin therapy has been accepted for the eradication of pellagra, is it not possible that a combination of nutrients may have had far superior effects? And, if Walter Mertz was correct when he declared in 1994 that the era of single-nutrient cures for disease was over, what other mental symptoms might be eradicated with combinations of nutrients as treatment? We will cover these topics in future blog entries.

This blog entry is adapted from a previous entry that can be found at

Financial disclosure: Drs Kaplan and Rucklidge had no relevant personal financial relationships to report, and no company has ever funded any of their studies.

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