Experts Suggest Cautious Response to a Study Linking Contraceptives and Depression

A study of more than one million young women in Denmark published this week in JAMA Psychiatry suggested that women using hormonal contraception were more likely to be diagnosed with depression or prescribed an antidepressant for the first time than those not taking the medication. However, experts who spoke with Psychiatric News say clinicians and patients should be cautious about jumping to conclusions about the results.

Compared with nonusers, users of combined oral contraceptives experienced a relative risk (RR) of a first use of antidepressants of 1.2, wrote Charlotte Wessel Skovlund, M.Sc., and colleagues from the Department of Gynecology at the University of Copenhagen. Women using medroxyprogesterone acetate depot had the highest relative risk at 2.7. The RRs of a first diagnosis of depression were slightly lower or similar. The authors noted an important age difference, as well.

“Our data indicate that adolescent girls are more sensitive than older women to the influence of hormonal contraceptive use on the risk for first use of antidepressants or first diagnosis of depression,” wrote Skovlund and colleagues. “This finding could be influenced by attrition of susceptibility, but also that adolescent girls are more vulnerable to risk factors for depression.”

Former APA President Nada Stotland, M.D., said the findings should not result in precipitate action by patients or their physicians. While the effects are significant, clinicians must compare them to what could happen if women were not on hormonal contraceptives, she added.

“Women, especially adolescents, who are not taking these contraceptives may instead experience anxiety about negotiating with partners or getting pregnant,” said Stotland. “We must take into account the importance of contraception as an important element of women’s overall health, including mental health.”

Maureen Van Niel, M.D., president of the APA Women’s Caucus and a private practitioner in Cambridge, Massachusetts, agreed. “The relative risk is indeed elevated in women who have used contraceptives but the degree of elevation is not alarming,” she said. 

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Multimodal Diagnostic Approach May Improve Ability to Predict Transition to Psychosis

Despite best efforts to identify patients at greatest risk of developing psychosis, studies suggest that less than one-third of patients who display subthreshold psychotic symptoms that meet ultra-high risk for psychosis (UHR) criteria will transition to psychosis within three years.

A study in Translational Psychiatry now suggests that using a multimodal diagnostic approach that combines a person’s historical risk factors (such as family history of psychosis), clinical assessments (such as Positive and Negative Syndrome Scale), and blood biomarkers (including measures of oxidative stress and fatty acids) may be able to better predict UHR patients most likely to develop psychosis.

In an assessment of 40 people classified as UHR, researchers who used this multimodal approach were able to identify eight of the 11 people who transitioned to psychosis within one year; they also diagnosed one false positive among the 29 who did not transition. This yielded an accuracy of 70% compared with 28% identified by standard UHR criteria.

The authors also noted that their model classified 77% of patients as low or high risk using only the historical and clinical information.

“A staged approach to risk assessment would then be the most efficient, using fatty-acid markers only when the probability following history and clinical assessment is between 0.1 and 0.9, that is, 23% of participants in the current study,” the authors wrote. “Extending this staged approach, resource-intensive neuroimaging or electrophysiology could be reserved for cases that remain at intermediate risk based on clinical and blood biomarker assessments.”

For more on ongoing efforts to accurately identify people at highest risk of developing psychosis, see the American Journal of Psychiatry articles “An Individualized Risk Calculator for Research in Prodromal Psychosis” and “Personalized Prediction of Psychosis: External Validation of the NAPLS-2 Psychosis Risk Calculator With the EDIPPP Project,” and the Psychiatric News article “More Than Words: Automated Speech Analysis May Offer Clinical Insight.”

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Youth With Bipolar Disorder Found to Be No More Overweight Than Those Without Disorder

Although prior studies suggest an association between bipolar disorder (BD) and obesity in adults, a study published Tuesday in the Journal of the American Academy of Child and Adolescent Psychiatry found that adolescents with BD appear to be no more likely to be overweight than adolescents without the disorder. The findings, according to the authors, suggest that there is “a window of opportunity to prevent excessive obesity among adolescents with bipolar disorder.”

To assess the prevalence and clinical correlates of overweight/obesity (OW/OB) among adolescents with bipolar disorder, Benjamin Goldstein, M.D., Ph.D., of the University of Toronto and colleagues analyzed data collected as part of the National Comorbidity Survey-Adolescent Supplement, a face-to-face survey of mental disorders from 2001 to 2004.

The sample included youth aged 13 to 17 with bipolar I or bipolar II (n=295), major depressive disorder (n=1,112), or controls with neither mood disorder (n=8,716). Weight status was defined based on standard categories of obesity (body mass index [BMI] equal or greater than 95 percentile) or overweight (BMI 85 to less than 95 percentile) versus normal weight (BMI 5 to less than 85 percentile) or underweight (BMI less than 5 percentile) using the gender-specific BMI-for-age Centers for Disease Control and Prevention growth charts, compared against the percentile for children of the same sex and age in the United States.

The authors found that there were no significant differences in weight category across the groups; for example, the prevalence of obesity was 17.1% for adolescents with BD, 17.1% for adolescents with major depressive disorder, and 15.1% for adolescents with neither condition.

Additional analysis revealed that among youth with BD, being overweight/obese (OW/OB) was associated with an increased risk of suicide attempts, physical or sexual abuse, binge eating or bulimia, and conduct disorder.

“The similar prevalence of OW/OB among adolescents with and without BD suggests that this potent association in adults likely comprises a consequence of BD or its correlates,” the authors wrote. “In contrast, the strong association of OW/OB with proxies for depression severity, including suicide attempts and hospitalization, is already evident even in this young, non-clinical sample. Studies are warranted to determine whether early intervention of OW/OB in BD may optimize both physical and mental health.”

For related information, see the Psychiatric News article “Bipolar Patients More Likely to Take Medications for Comorbid Conditions.”

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Fear of Mental Health Diagnosis on Record May Keep Physicians From Seeking Care

“I would never want to have a mental health diagnosis on my record.”

That was the signature quote from a survey of women physicians who reported fear regarding stigma about mental illness that would inhibit them from seeking treatment or reporting their illness to licensing authorities. The survey was published in General Hospital Psychiatry.

Katherine Gold, M.D., of the Department of Family Medicine at the University of Michigan and colleagues surveyed a convenience sample of female physician-parents on a closed Facebook group. The group had approximately 57,000 members at the time of the survey, though not all members were active on the site at any time. The researchers developed an anonymous, 24-question survey that asked about mental health history and treatment, perceptions of stigma, opinions about state licensing questions, and personal experiences with reporting; they posted four invitations to participate with electronic links to the questions. The survey was open for eight weeks from February through April 2016.

A total of 2,109 group participants completed the survey; 357 of the respondents also provided qualitative comments.

Almost 50% of women believed they had met criteria for mental illness but had not sought treatment. Top reasons for not seeking treatment included women’s belief that they could manage independently, had limited time, or the diagnosis was embarrassing or shameful. Two of every five physicians in this study who believed they had met criteria for a mental illness but had not sought treatment reported that one reason for this was that they did not ever want to have to report mental illness or treatment to a state medical licensing board.

Only 6% of physicians who reported having been given a prior mental health diagnosis or undergone treatment said they had disclosed their mental health condition to the state medical board.

“Our findings raise ethical concerns about broad requirements for mental illness disclosure given potentially serious risks to physicians who forgo needed mental health treatment out of fear of adverse consequences, even when it is not clear that such reporting offers any significant protection to patients,” the authors wrote.

In a column appearing September 14 in Psychiatric News, APA President Maria A. Oquendo, M.D. (pictured above), wrote of physicians’ hesitation to seek mental health care. She noted “stigma is alive and well among physicians.” Her column drew attention to the problem of licensing board questions.

In comments to Psychiatric News about the survey, Oquendo said, “I applaud Dr. Gold for shining a light on this very serious problem among physicians. The sample used was one of convenience so it is possible that the problem of untreated psychiatric conditions is even more widespread than found in the Facebook group. That is because these are individuals who are seeking support from an online community, which may be less likely among those who are seriously depressed or anxious.”

For more information, see Oquendo’s latest Psychiatric News From the President column “Why `Physician Heal Thyself’ Does Not Work.”

Experts Offer Several Strategies for Treating Premenstrual Exacerbations of Mood Disorders

The fluctuation of psychiatric symptoms across the menstrual cycle is an important, yet often overlooked aspect of treatment, Elizabeth Fitelson, M.D., an assistant professor of psychiatry at Columbia University Medical Center,l and Laura G. Leahy, Dr.N.P., A.P.R.N., a family psychiatric advanced practice nurse in psychopharmacology at APNSolutions LLC, wrote in a recent column appearing in Psychiatric News PsychoPharm. In the article, Fitelson and Leahy described several strategies to help patients experiencing premenstrual exacerbations of mood disorders.

An estimated 3 to 8 percent of women with severe premenstrual symptoms meet the diagnostic criteria for premenstrual dysphoric disorder—a syndrome characterized by the emergence of mood lability, irritability, dysphoria, and anxiety symptoms that occur repeatedly during the premenstrual phase, interfere with daily life, and remit after the onset of menses. Other patients with underlying mood disorders will experience a worsening of symptoms over the course of the menstrual cycle, known as premenstrual exacerbation (PME).

By asking patients about their menstrual cycle and mood changes around those times, the authors noted that clinicians will likely be better able to differentiate PME symptoms—including irritability, anger, anxiety, tearfulness, depressed mood, social withdrawal, impaired cognition, fatigue and lack of energy, food cravings, and disrupted sleep—from those of other psychiatric illnesses.

“Although little is known about potential remedies to treat PME of mood disorders, practitioners can optimize symptom relief and improve the quality of life for women with PME and psychiatric comorbidities by drawing on current dosing strategies for SSRIs,” Leahy wrote. “One recommended approach for the treatment of this patient population is semi-intermittent dosing, which involves treating continuously with an SSRI whose dose is increased during the luteal phase and then reduced to the prior level upon the onset of menses.” Leahy goes on to describe the dosing strategy for treating patients suspected of having PME at the clinic where she works.

Fitelson added, “[M]any of the strategies that are helpful for PMDD patients are also helpful for women with premenstrual exacerbations. Some of these strategies include dietary changes, supplementation with calcium and magnesium, exercise, herbal formulations, cognitive-behavioral strategies, and intermittent light therapy. In addition, women on hormonal contraception or who have an indication for it may consider switching formulations or working with their gynecologists to discuss whether they may benefit from continuous dosing of the oral contraceptive, decreasing the number of menstrual cycles (and possibly the related mood disruptions) in the year.”

For related information, see the American Journal of Psychiatry article “Toward the Reliable Diagnosis of DSM-5 Premenstrual Dysphoric Disorder: The Carolina Premenstrual Assessment Scoring System (C-PASS).”

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Depression in Early Pregnancy Linked to Gestational Diabetes, Postpartum Depression

Depression early in pregnancy appears to increase the risk for gestational diabetes, which in turn increases the risk for postpartum depression, according to a report appearing online in Diabetologia.

Stephanie Hinkle, Ph.D., and colleagues at the National Institute of Child Health and Human Development assessed longitudinal associations between depression early in pregnancy and the risk for gestational diabetes (GDM), as well as GDM and subsequent risk of postpartum depression. They analysed data from the prospective National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort (2009–2013), which had been collected at 12 U.S. clinical centers.

The sample consisted of 2,477 pregnant women without psychiatric disorders, diabetes, or other chronic conditions before pregnancy. Depression was assessed in the first (8–13 gestational weeks) and second (16–22 weeks) trimesters and at 6 weeks postpartum using the Edinburgh Postnatal Depression Scale.

Comparing the highest and lowest quartiles of first-trimester depression scores, the researchers found that the scores from the highest quartile were associated with a significant 1.72-fold increased risk for GDM after adjusting for confounding factors; the second-trimester results were similar. The risk was stronger and significant in both trimesters among nonobese women, and women with persistently high depression scores in both trimesters had the greatest risk of GDM.

The researches then matched 162 women with GDM and healthy controls and followed them up at 6 weeks postpartum. Postpartum depression was defined as a depressive symptom score of 10 or greater or antidepressant medicine use after delivery.

They found that GDM was associated with an adjusted 4.62-fold increased risk of subsequent postpartum depression.

“Our data suggest that screening early in pregnancy may be particularly important even among women without a history of mental health conditions,” the researchers wrote. “In addition, women with GDM may require closer monitoring postpartum given their elevated risk of postpartum depression. Taken together, our work extends previous data supporting depression and glucose intolerance as comorbid conditions among nonpregnant individuals to women during pregnancy and postpartum, a critical time window for the health and well-being of both women and their offspring.”

For related information see the Psychiatric News article "Link Seen Between Mental Disorders, Diabetes in New Study."

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Review Reveals Complex Association Between Hypnotic Medications and Suicidality

Modern hypnotic medications are associated with suicidality, but the association may often be confounded by the presence of mental illness. Moreover, many hypnotic-associated suicides have also involved use of other sedatives or alcohol. Finally, hypnotic-associated suicide may also occur specifically at times of peak drug effect—an occurrence that might be mitigated by judicious prescription and use of hypnotic medications.

Those are among the complex findings around the association of hypnotic medications and risk of suicide from a review of literature and Food and Drug Administration (FDA) adverse-event reports published in AJP in Advance. The review also includes a list of 10 recommendations for safe prescribing of hypnotics.

Insomnia is associated with increased risk for suicide, and the FDA has mandated that warnings regarding suicide be included in the prescribing information for hypnotic medications. The researchers found that toxicology studies from the United States and elsewhere show that modern hypnotics have frequently been taken before death by suicide, although the hypnotics are often taken in combination with other sedatives or alcohol. At the same time, death is possible when hypnotics are used as a single agent for self-poisoning, and examples of this were found for flurazepam, temazepam, triazolam, and zolpidem.

Retrospective case series have consistently shown that hypnotic users are overrepresented among suicide victims, with odds ratios in the range of 2 to 3, but these studies have been unable to disentangle the confounding effect of treatment for mental illness.

Importantly, published case reports and FDA adverse-event reports show that some suicidal behaviors and suicide deaths occur during a period of confusion, amnesia, hallucination, or paranoia in the first few hours after ingestion of a hypnotic—that is, suicide is linked to hypnotic-induced parasomnia during the time of peak drug effect, according to the review.

“The principal new contribution of this review is the clarification regarding the timing of suicide risk related to ingestion of hypnotics,” the authors stated. “Under specific conditions, hypnotics may induce or exacerbate suicidality by altering consciousness or disinhibition at the time of peak drug effect and at the same time may reduce or prevent suicidal ideation in persons with insomnia and mental illness after appropriate drug metabolism.”

For related information, see the Psychiatric News article “Novel Suicide-Prevention Treatment Targets Poor Sleep.”

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Depressed Patients May Be At Highest Risk of Suicide Following Hospital Discharge

Patients recently discharged from psychiatric hospitals for the treatment of depressive disorders and bipolar disorder may be at the greatest short-term risk of suicide, particularly if they appear to have had little contact with the health care system for months before their hospitalization, according to a study published today in JAMA Psychiatry.

“Knowledge of which mental disorders … put adults at highest short-term risk for suicide after psychiatric hospital discharge might shed light on the mechanisms of acute risk for suicide and guide interventions to prevent suicide,” lead author Mark Olfson, M.D. (pictured left), of Columbia University Medical Center and colleagues wrote.

Olfson and colleagues used Medicaid claims data from January 1, 2001, to December 31, 2007, to examine suicide risk during the first 90 days after inpatient hospital discharge for adults aged 18 to 64 with a diagnosis of a mental disorder (depressive disorder, bipolar disorder, schizophrenia, substance use disorder, and other mental disorders). This risk was then compared with the short-term suicide risk of inpatients with a diagnosis that was not a mental disorder. A total of 370 deaths from suicide took place during the study period.

Based on an analysis of more than 1.8 million people—including 770,642 adults with mental disorders—the authors found that short-term suicide rates in the groups of adults with depressive disorder (235.1 per 100,000 person-years), bipolar disorder (216.0 per 100,000 person-years), schizophrenia (168.3 per 100,000 person-years), substance use disorder (116.5 per 100 000 person-years), and other mental disorders (160.4 per 100,000 person-years) were higher than the rates in the inpatients who were not diagnosed with a mental disorder (11.6 per 100,000 person-years) or the U.S. general population (14.2 per 100,000 person-years).

Additional analyses showed that the 90-day rate of suicide was nearly twice as high for men as women. Psychiatric inpatients who did not receive any outpatient health care in the six months prior to hospitalization were also found to be at increased risk of suicide.

“These patterns suggest that complex psychopathologic diagnoses with prominent depressive features, especially among adults who are not strongly tied into a system of care, may pose a particularly high risk,” the authors wrote. “As with many studies of completed suicide, however, the low absolute risk for suicide limits the predictive power of models based on clinical variables. These constraints highlight the critical challenge of predicting suicide among recently discharged inpatients based on readily discernible clinical characteristics.”

In a related editorial, Merete Nordentoft, D.M.Sc., and colleagues wrote, “Psychiatric patients should not be considered cured at the time of discharge. They are still ill, many of their symptoms continue, treatment is ongoing, and their need for care remains. ... It is, therefore, very important to carefully plan and initiate referrals for aftercare. Ideally, outpatient treatment should be introduced before discharge, so that the patient is familiar with the persons who will care for them after discharge.”

For related information, see the Psychiatric News article “Two-Part Assessment May Help Predict Suicidal Behavior, Study Finds.”

(Photo courtesy of Columbia University Medical Center)

Patients With Alcohol Dependence Who Like Sweets May Respond Better to Naltrexone

Individuals with alcohol dependence who like sweets may be more likely to respond positively to treatment with naltrexone, according to a report in JAMA Psychiatry.

Determining whether a patient has a “sweet-liking (SL) phenotype” and/or a high level of craving for alcohol may represent practical tools clinicians can use when deciding whether to prescribe naltrexone for alcohol dependence, lead author James C. Garbutt, M.D., of the Department of Psychiatry at the University of North Carolina, and colleagues wrote.

The researchers randomized 80 patients with alcohol dependence to naltrexone hydrochloride (50 mg/daily) or placebo for 12 weeks. Both groups of patients were tested to determine whether they fell into the sweet-liking or sweet-disliking (SDL) phenotype. Participants’ sensitivity and response to sweet taste was tested using five concentrations of sucrose presented in five separate blocks for a total of 25 tastings. Participants were categorized as having an SL phenotype if they rated the highest concentration of sucrose as the most pleasurable.

They found naltrexone resulted in 4.8 fewer heavy drinking days over placebo (an effect that was not statistically significant), but the SL phenotype moderated the effect of naltrexone on heavy drinking—those with the SL phenotype had 6.1 fewer heavy drinking days and 10.0 more days of abstinence. They also found that high craving for alcohol at baseline moderated the effect of naltrexone on heavy drinking, with 7.1 fewer heavy drinking days among those with high craving. 

The combination of the SL phenotype and high craving was associated with the strongest response to naltrexone, with 17.1 fewer heavy drinking days and 28.8 more abstinent days compared with placebo.

“The results of the present trial support the hypothesis that the SL phenotype is a moderator of the response to naltrexone in alcohol dependence and that this effect is most apparent in the presence of a high subjective craving for alcohol,” Garbutt and colleagues wrote. “If these findings are confirmed, an assessment of the SL/SDL phenotype could be clinically useful. The phenotype shows good stability and reproducibility; is simple, safe, and inexpensive to assess; and could evolve as a simple tool to help clinicians with medication decisions.”

For related information on treating alcohol use disorder, see the Psychiatric News article “An Underutilized, Evidence-Based Treatment for Alcohol Use Disorder” by Cornel N. Stanciu, M.D. 

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Study Highlights How Children at High Risk of Suicide May Differ From Adolescents

Although suicide in elementary school–age children (aged 5 to 11) is rare, little is known about the factors precipitating suicide in this age group. A study published today in Pediatrics suggests that children who died by suicide were more likely to have been diagnosed with attention-deficit disorder (ADD) or attention-deficit/hyperactivity disorder (ADHD) than early adolescents (aged 12 to 14) who died by suicide. 

“These findings raise questions about impulsive responding to psychosocial adversity in younger suicide decedents, and they suggest a need for both common and developmentally specific suicide prevention strategies during the elementary school–aged and early adolescent years,” Arielle Sheftall, Ph.D., of Ohio State University and colleagues wrote.

The researchers analyzed suicide data recorded in the National Violent Death Reporting System from 2003 to 2012 in 17 U.S. states and compared individual characteristics and precipitating circumstances of suicide in children aged 5 to 11 to those aged 12 to 14.

About one-third of the children and young adolescents were recorded in the system as having had a current mental health problem, but while depression—a well-known risk factor for suicide—was the most common diagnosis among adolescents (65.6%), young children who died by suicide were most likely to have ADD or ADHD (59.3%).

“Assuming the diagnoses are accurate, this result would suggest that suicide in young children may be more related to impulsive behavior, a hypothesis that warrants further research,” David Fassler, M.D., a child and adolescent psychiatrist and professor at the University of Vermont College of Medicine, told Psychiatric News.

“[S]uch research could have important implications for suicide prevention efforts in childhood and potentially diminish the relevance of traditional strategies focused primarily on identifying and treating depression as a means of mitigating suicide risk,” the study authors wrote.

Other characteristics that were more common in younger children who died by suicide were being male, black, suicide by hanging/strangulation/suffocation, and having died at home.

Fassler noted that because suicide is relatively rare in young children, it can be a challenging population to study. “Despite significant methodological challenges, the study represents an important contribution to the literature on suicide in young children and adolescents,” he said.

For a related story on suicide, see the Psychiatric News article “U.S. Experiences Uptick In Rates of Suicide.”

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Collaborative Care Lessens Sports Concussion Symptoms

A small study of 49 adolescent patients with persistent postconcussive symptoms indicates that they may benefit from collaborative care that includes cognitive-behavioral therapy, case management, and psychopharmacological consultation, according to a study in the October issue of Pediatrics.

To better represent real-world conditions, patients were recruited at least a month after their concussion occurred. They were randomized to receive the intervention or usual care managed by a concussion specialist, wrote Carolyn McCarty, Ph.D., a research associate professor of pediatrics and adjunct research associate professor of psychology at the University of Washington in Seattle, and colleagues.

The intervention arm used the services of a care manager, a CBT interventionist, a pediatrician, and a supervising psychiatrist, who could draw on the expertise of another psychiatrist who specialized in pediatric psychopharmacology.

Evaluated at six months after baseline, only 13 percent of intervention patients reported high levels of postconcussive symptoms compared with 41.7 percent of control patients. About 78 percent of intervention patients had a greater than 50 percent reduction in depressive symptoms, compared with 45.8 percent of patients in the usual care group. There were no significant differences in anxiety symptoms.

“Larger-scale randomized clinical trials are needed in this understudied and critical aspect of adolescent medicine,” concluded the researchers. “Our findings prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion.”

For more in Psychiatric News about postconcussion care, see “Baseline Somatization May Predict Sports-Related Concussion Recovery.”

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Addressing Psychosocial Variables May Improve Care for Patients With Mental Illness, Diabetes

There is limited research on how to best match medically complex patients who have serious mental illness with the right treatments. A study published today in Psychiatric Services in Advance describes how considering psychosocial variables such as a patient’s social support, self-efficacy, and attitude regarding possible treatment outcomes could help to guide care for patients with serious mental illness and diabetes.

Researchers from the Case Western University School of Medicine analyzed baseline data from 200 individuals with serious mental illness (including schizophrenia, schizoaffective disorder, bipolar disorder, or major depression) and comorbid diabetes involved in a study comparing a self-management intervention versus treatment as usual. As part of the trial, participants were asked questions about their symptoms as well as their perception of social support, perception of their ability to manage their conditions, and outcome expectancy related to treatment.

The analysis revealed two conceptually distinct subgroups of patients within the study. Patients with the most severe depression had “less confidence that they could manage both their psychiatric illness and diabetes, had lower expectations for treatment, and had lower perceived social support. This group scored significantly worse on measures of psychiatric symptom severity, general functioning, and diabetes control compared with the other group,” according to the authors.

“Consideration of all of these factors can personalize care for specific challenges and strengths among patients with comorbid serious mental illness and diabetes and may inform treatment approaches that can advance care for this vulnerable group of individuals,” they concluded.

For related information, see the Psychiatric News article “Bipolar Patients More Likely to Take Medications for Comorbid Conditions.”

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Patient Expectations of Antidepressants May Mediate Placebo Effects

How well a patient responds to medication may be partially mediated by his or her expectation about whether and how much he or she will improve, according to a study published in AJP in Advance. The findings, say the study authors, suggest that developing interventions capable of modifying patient expectancy may not only help to reduce placebo response in clinical trials, but also improve treatment outcomes in clinical practice.

To examine the relationship between patient expectancy and placebo effects, Bret Rutherford, M.D., of Columbia University College of Physicians and Surgeons and colleagues enrolled 54 patients with major depressive disorder (aged 24 to 65) in an eight-week citalopram trial. Before being randomly assigned to the placebo-controlled or open group, participants were asked questions to assess how much they believed depression symptoms would improve by the end of the trial. 

In an effort to manipulate patient expectancy, the participants were informed of their group assignment before starting medication but instructed to refrain from revealing this assignment to anyone in the study group. Expectancy of treatment outcome was then measured once again before patients began taking citalopram (20 mg/day) or pill placebo for eight weeks.

Participants were assessed using the Hamilton Rating Scale for Depression (HAM-D) throughout the trial. Treatment response was defined as decrease of 50% or more from the baseline HAM-D score; patients who had a HAM-D score of 7 or less at week 8 were considered to be in remission.

Although mean prerandomization expectancy scores did not differ significantly between the open group (mean=11.2 [SD=1.1]) and placebo-controlled group (10.8 [SD=1.9]), postrandomization expectancy scores were significantly higher in the open group (mean=12.1 [SD=2.1]) compared with the placebo-controlled group (mean=11.0 [SD=2.0]), when adjusted for baseline HAM-D scores. This, according to the authors, suggests “the experimental design succeeded in manipulating expectancies.”

The authors found that response rates were 25% for placebo-controlled placebo, 45% for placebo-controlled citalopram, and 53.8% for open citalopram. Remission rates were 0% for placebo-controlled placebo, 20% for placebo-controlled citalopram, and 34.6% for open citalopram. After adjusting for covariates, the average participant treated with citalopram in the open group experienced 6.2 points of additional improvement in HAM-D score by week 8 compared with the average participant treated with citalopram in the placebo-controlled group.

“Strikingly, despite receiving the identical antidepressant medication, being treated by the same study clinicians, and visiting the same treatment site, depressed subjects who knew they were receiving citalopram improved on average 6 HAM-D points more than those receiving citalopram who were aware they had a chance of receiving placebo,” the authors wrote. 

“To the extent that expectancy mediates placebo responses in antidepressant studies, limiting patient expectancy may be a useful strategy to reduce placebo response in phase III trials. ... Conversely, the optimal strategy in clinical practice may be to combine active medication with a presentation that enhances patient expectancy, leading to greater medication response,” they concluded.

For related information, see the Psychiatric News PsychoPharm article “Unraveling the Mystery Behindthe Nocebo Effect: Placebo’s Evil Twin.” 

Researchers Propose Rethinking Fear May Advance Treatment of Anxiety Disorders

A new neuroanatomical model for understanding fear and anxiety could have implications for how drugs are tested for anxiety disorders and could lead to new treatments, Joseph LeDoux, Ph.D., and Daniel Pine, M.D., wrote in a recent article in AJP in Advance.

While the physiological and behavioral responses to an imminent threat that comprise the `fight-or-flight’ phenomenon are regulated by subcortical neural networks centered on the amygdala, LeDoux and Pine propose that the subjective experience of fear is regulated by higher order cortical networks responsible for cognitive processes such as attention and working memory.

This new model would replace the long-accepted “fear circuit” model, in which both physiological reactions and the subjective experience of fear are regulated by one circuit centered on the amygdala. LeDoux and Pine make the same distinction for anxiety and other emotions—different circuits underlie the conscious feelings of these emotions and those that underlie the behavioral and physiological responses that occur in tandem.

If LeDoux and Pine are correct it suggests that animal models used to test medications for treating anxiety disorders—founded on the more traditional unitary fear circuit theory—may not adequately capture the subjective experience of fear and anxiety as felt by humans.

“This is a really important paper,” Murray Stein, M.D., vice chair for clinical research in the Department of Psychiatry at the University of California, San Diego, told Psychiatric News. “[L]eDoux and Pine suggest we have been going down the wrong path ... because what we are modeling in animals isn’t what we are measuring, assessing, and trying to treat in humans.”

“Animal research is important and useful, especially if we know how to use it,” LeDoux said. “Our ability to understand the brain is only as good is our understanding of the psychological processes involved. If we have misunderstood what fear and anxiety are, it is not surprising that efforts to use research based on this misunderstanding to treat problems with fear and anxiety would have produced disappointing results.”

For related information, see the Psychiatric News article “Humans, Rodents Pay Close Attention to Fear, Anxiety Expressed by Parents.”

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Study Reveals PTSD Trajectories for 9/11 Responders Over 12-Year Period

Tens of thousands of trained and untrained disaster responders were involved in the rescue, recovery, and cleanup following the attacks on the World Trade Center (WTC) on September 11, 2001. A study in the Journal of Psychiatric Research demonstrates how the long-term follow-up of this unique cohort of responders continues to yield new insights into risks and trajectories of posttraumatic stress disorder (PTSD). Researchers hope this information will serve to inform prevention, monitoring, and treatment efforts.

A total of 1,874 police and 2,613 other responders involved during and after the WTC attacks were given the PTSD Checklist Specific-Stressor (PCL-S) as part of a health survey three, six, eight, and 12 years after 9/11. Participants also answered questions about various life stressors that took place in the year before and since 9/11. 

Among police responders, WTC-related PTSD symptoms grouped into four distinct trajectories, with 76.1% reporting continual no/low symptoms, 4.4% continual high symptoms, 12.1% worsening over time, and 7.5% improving over time. For non-police responders, five distinct PTSD symptom trajectories emerged over time. A total of 55.5% reported no/low symptoms; 10.8% high symptoms; 19.3% and 5.9% with subtly and steeply worsening trajectories, respectively; and 8.5% reported symptom improvements.

Many variables were consistent predictors of PTSD trajectories across both responder groups; for example Hispanic ethnicity, psychiatric history prior to 9/11, greater  exposure to the devastation caused by WTC attacks, and maladaptive coping (such as substance use) strongly increased the risk of a symptomatic PTSD trajectory (everything but no/low symptoms). In contrast, higher perceived preparedness and a greater sense of purpose lowered the risk of symptomatic PTSD.

There were also notable differences between the responder groups; female police responders, but not other female responders, had a greater risk of worsening and continually high trajectories, while being widowed, separated, or divorced was a strong risk for chronic PTSD, but only among non-police responders. Coping mechanisms also differed between the groups, with police responders showing a strong association between active coping strategies and improving PTSD symptoms, while non-police responders who engaged in positive emotion-based coping (such as humor, reframing, or acceptance) had far less risk of high or steeply worsening symptoms.

“Taken together, these findings can inform recommendations for future disaster preparedness and planning, including pre-screening and education of responders about the potential impact of preexisting anxiety and depressive disorders; decisions about who might be best suited for front-line disaster response versus other supportive roles; and maximizing training and preparedness, especially for non-traditional disaster responders such as clean-up workers,” the authors wrote.

For related information, see the Psychiatric News article “Risk of PTSD Symptoms Among Police May Be Predictable Years Ahead.”

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Electronic Health Records Help Predict Suicidal Behavior

The extensive databases in Denmark, Sweden, and Finland have long been mined by researchers looking for the patterns in health and illness that can improve care.

Now a study of more than 1.7 million Boston-area patients suggests the value of long-term health histories embedded in electronic health records in the United States for predicting risk of suicidal behavior.

Researchers used data on 16,588 case subjects from Massachusetts General Hospital and Brigham and Women’s Hospital. Their model predicted suicidal behavior with a 33 to 45 percent sensitivity and 90 to 95 percent specificity three to four years in advance, wrote Yuval Barak-Corren, M.S., of the Predictive Medicine Group at Boston Children’s Hospital Informatics Program, and the Israeli Institute of Technology in Haifa, Israel, in a study posted today in the AJP in Advance.

The study was released during National Suicide Prevention Week, whose goal is to promote the understanding and prevention of suicide and support those who have been affected by it.

Mental illness including substance abuse was associated with higher risk, as expected, but so were a number of infections and injuries.

This model is not “a specific quantitative prediction of suicide risk,” wrote Barak-Corren and colleagues. “Rather, we envision an alert system by which patients exceeding thresholds of predicted risk could be flagged as at relatively higher risk to encourage clinicians to conduct more targeted assessments of suicide risk.”

For more in Psychiatric News on prediction of suicidality, see “Two-Part Assessment May Help Predict Suicidal Behavior, Study Finds.”

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ADHD Symptoms From Childhood May Lead to Greater Challenges for Adults

Although adults who were diagnosed with attention-deficit/hyperactivity disorder (ADHD) as children generally tend to report greater social and emotional challenges than those who were not diagnosed with ADHD, these outcomes can vary widely. A study in the Journal of the American Academy of Child and Adolescent Psychiatry now suggests that persisting ADHD symptoms in adulthood are associated with greater functional impairments.

The study also underscores the importance of treating people with ADHD to remission and not just improvement because symptom remission appears to be somewhat protective against anxiety, depression, and substance use disorder, according to the authors.

As part of the Multimodal Treatment Study of Children With ADHD (MTA), researchers tracked 579 children aged 7 to 9 with ADHD and 258 age- and sex-matched classmates without ADHD through childhood and adolescence and into adulthood (when participants were aged 19 to 28).

At age 18 and after, participants and their parents completed Conners’ Adult ADHD Rating Scale (CAARS) and the Diagnostic Interview Schedule for Children–Parent version (DISC-P) and Young Adult version (DISC-YA). From these assessments, researchers obtained information on educational, occupational, emotional outcomes, and more. DSM-5 symptom-count criteria—five symptoms reported either by the participant or the parent in either the Inattention and/or Hyperactive-Impulsive domain on the CAARS—were used to identify participants with persistent symptoms of ADHD; those who did not meet the ADHD threshold in either the Inattention and/or Hyperactive-Impulsive domain were considered to be in remission (symptom desistence). 

Overall, participants with persistent symptoms of ADHD tended to fare worse with regard to educational and occupational outcomes (including post-secondary education and income), followed by those whose ADHD symptoms were in remission, and controls. Participants in the symptom-persistent ADHD subgroup also scored worse on impulsivity/emotional lability (self- and parent-report) and neuroticism, and endorsed higher rates of mood (7.8% versus 1.8%) and anxiety disorders (14.2% vs. 5.0%) than the symptom-desistent subgroup, which exhibited outcomes similar to the controls.

“These findings suggest that functional outcomes in adults who were diagnosed with ADHD in childhood are not uniform but differ across domains, giving rise to different patterns of outcomes,” Lily Hechtman, M.D., and colleagues wrote. “[B]oth ADHD symptoms and functioning need to be targets of appropriate, innovative, and ongoing intervention in this chronic condition.”

For related information, see the Psychiatric News article “Better Ways to Treat Child ADHD, New Thinking for Adults Needed.”

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Study Finds Aripiprazole Lauroxil Carries Low Risk of Metabolic Side Effects

Last year, results from a phase 3 clinical trial showed the long-acting injectable aripiprazole lauroxil to be effective and safe in treating symptoms of acute schizophrenia. Now, new findings from the phase 3 trial suggests that the antipsychotic may have an added benefit of having a low risk for metabolic abnormalities.

“[T]hese findings of a low risk for metabolic abnormalities with aripiprazole lauroxil are important when considering overall patient health in the management of schizophrenia,” Henry Nasrallah, M.D., chair of the Department of Psychiatry and Behavioral Neuroscience at St. Louis University School of Medicine, and colleagues wrote.

The study included 622 adult patients with schizophrenia (DSM-IV-TR criteria) who were experiencing an acute exacerbation or relapse of symptoms less than two months prior to the study and who had responded to an antipsychotic medication other than clozapine in the past year. The patients were randomly assigned to aripiprazole lauroxil (441 mg or 882 mg) or placebo intramuscularly on days 1, 29, and 57 of the study. Outcome measures included baseline to week 12 changes in body weight, prolactin, fasting plasma glucose and serum lipids, glycosylated hemoglobin (HbA1c), and incidence of treatment-emergent adverse events. 

The results showed that while body weight increased modestly in both aripiprazole lauroxil groups compared with placebo over the course of the trial (change of mean body weight from baseline to 12 weeks = 0.7 kg [aripiprazole lauroxil, 441 mg], 0.9 kg [aripiprazole lauroxil, 882 mg], and 0.01 kg [placebo]), both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels from baseline to week 12, whereas placebo was not. No clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with either dose of aripiprazole lauroxil or placebo. 

Treatment-emergent adverse events related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. Most common treatment-emergent adverse events related to metabolic parameters included increases in blood glucose and serum triglycerides.

“Aripiprazole lauroxil represents an important option for the treatment of schizophrenia, with demonstrated efficacy and tolerability and a low risk of metabolic side effects that often impede maintenance of long-term antipsychotic treatment and may lead to higher cardiovascular risk,” the authors concluded.

For related information, see the Psychiatric News article “Exposure to Antipsychotics May Increase Risk of Type 2 Diabetes in Youth.”

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CSF Metabolic Abnormalities May Contribute to Treatment-Refractory Depression

Metabolic abnormalities in cerebrospinal fluid (CSF) may be an unrecognized contributor to treatment-refractory depression, according to a study in AJP in Advance.

The findings, if replicated, suggest that early identification and treatment of an underlying metabolic abnormality early in the course of psychiatric illness could prevent long-term emotional and cognitive complications, say Lisa Pan, M.D., of the University of Pittsburgh Medical Center and colleagues at several other institutions.

In the study, participants aged 14 to 40 with depression who had not responded to at least three maximum-dose medication trials of at least six weeks each were recruited by advertisement through the Clinical and Translational Science Institute’s Research Participant Registry at the University of Pittsburgh or by clinical referral.

CSF metabolic testing was compared in 33 adolescent and young adult patients with histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments) and 16 healthy comparison subjects. Testing for CNS-specific metabolic abnormalities included 5-methyltetrahydrofolate, tetrahydrobiopterin, neopterin, pyridoxal-5-phosphate, 5-hydroxyindoleacetic acid, homovanillic acid, and amino-adipic semialdehyde.

CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (n=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate levels. All patients with cerebral folate deficiency showed improvement in depression symptom inventories after treatment with folinic acid. None of the healthy comparison subjects had a metabolite abnormality.

The study was prompted by the case of a young adult with treatment-refractory depression and multiple suicide attempts who was found to have a severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. After treatment with sapropterin, a tetrahydrobiopterin analogue, the patient experienced a dramatic and long-lasting remission of depression.

“If these findings are replicated, they suggest that the identification of new inborn errors of metabolism or secondary disorders of metabolism contributing to psychiatric illness may allow repurposing of currently approved orphan drugs,” the researchers stated.

For related information, see the Psychiatric News article "Metabolites Offer New Clues About Medication Response."

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Review Finds Measurement-Based Care Improves Patient Outcomes

Measurement-based mental health care significantly improves outcomes, provided that symptom severity data are collected frequently and the results are provided to the clinician shortly before or during the clinical encounter, according to a literature review published Thursday in Psychiatric Services in Advance.

Moreover, the authors of the review said measurement-based care (MBC)—the systematic administration of symptom rating scales and use of the results to drive clinical decision making at the level of the individual patient—can be used to enhance professional development at the provider level, facilitate practice-level quality improvement, demonstrate the value of mental health services to purchasers and payers, and positively influence reimbursement policy. 

John Fortney, Ph.D., of the University of Washington and colleagues reviewed 51 articles on the use of MBC. They found that randomized, controlled trials with frequent and timely feedback of patient-reported symptoms to the provider during the clinical encounter significantly improved outcomes or showed trends toward significance; these findings were robust and consistent across patient groups, providers, and settings.

While Fortney told Psychiatric News that measurement-based care has been widely adopted by large integrated systems of care, other settings have been slower to adopt this approach. “Given the rapid changes being made by accreditation agencies and payers, those health care organizations that have not yet started to develop systems to support measurement-based care should begin identifying tools and protocols that meet their patients’ needs before such systems are imposed from outside their organizations,” he advised.

“The time is long overdue for the field of mental health to embrace MBC and live up to the medical testing and treat-to-target principles applied by other medical specialties,” the study authors wrote. “The cost of routinely administering symptom severity scales is minimal, yet the benefits of MBC accrue to all the stakeholders involved, including patients, providers, purchasers, and payers.” 

Measurement-based care is at the heart of the collaborative care model and advances the ability of clinicians to provide robust treatment for patients, said Lori Raney, chair of the APA Work Group on Integrated Care. Measurement-based care is “absolutely necessary for reporting outcomes to payers in the changing health care environment where value-based purchasing is the wave of the future,” she told Psychiatric News. 

For related information, see the Psychiatric News article “Collaborative Care Model Prepares Psychiatrists for Value-Based Care” and series “Changing Practice/Changing Payment” on the APA website.

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Important Changes in DSM-5 to Become Effective October 1

Each year on October 1, the International Classification of Diseases, Tenth Edition, Clinical Modification (ICD-10), is updated to reflect diagnostic  changes in medicine. Since 2010, no major updates have been permitted so that physician practices, facilities, and payers in the United States could update their systems during the transition from ICD-9 to ICD-10, which went into effect on October 1, 2015.

APA has advocated that changes be made to ICD-10 to reflect the updated diagnoses in DSM-5. These include changes to align the terminology used in DSM-5 with that used in the mental health chapter of ICD-10. In response, the Fiscal Year 2017 version of ICD-10, which takes effect October 1, will include most of DSM-5’s terminology.

In some cases, new codes have been added to ICD-10 to accommodate the new diagnoses that were added to DSM-5. The new codes will allow more accurate diagnostic recording, improved communication among clinicians, and better means for collecting prevalence data.

As of October 1, the codes for the DSM-5 disorders in the chart below will no longer be valid. The new codes listed in the chart must be used in their place.

A printable version of the list is available at http://APAPsy.ch/ICD-DSM and includes the diagnoses in both alphabetical order and the order in which they appear in the DSM-5 classification.