Persistent, Severe Postpartum Depression Increases Risk of Adverse Outcomes in Children

Children whose mothers reported severe symptoms of postpartum depression lasting at least eight months after childbirth may be more likely to experience behavioral problems and depression compared with children whose mothers’ postpartum depression was not persistent or severe, suggests a study published today in JAMA Psychiatry.

“Health care professionals should identify these women for further referral because early and effective treatment could reduce the continued exposure of the child,” wrote Elena Netsi, D.Phil., of the University of Oxford and colleagues.

To determine whether differing levels of persistence and severity of postpartum depression are associated with subsequent maternal depression and child outcomes, Netsi and colleagues analyzed data contained in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is an ongoing population-based study examining the overall health of children born in southwest England between April 1991 and December 1992.

Maternal depression was measured using the self-rated Edinburgh Postnatal Depression Scale (EPDS) at two and eight months. The authors separated the group into three levels of depression severity, based on EPDS score: moderate (13 to 14 points), marked (15 to 16), and severe (17 or more points). Postnatal depression was considered persistent when an individual scored above the EPDS threshold at both the two- and eight-month postnatal assessment.

The authors compared the following outcomes in the children born to women with varying degrees of postpartum depression: child behavioral problems at 3.5 years (based on maternal report), math scores at age 16 (extracted from records of public exams), and offspring depression at 18 (based on self-report). These three offspring outcomes were shown to be associated with postnatal depression in this sample. Children of women with persistent and severe depression had a fourfold increased risk of having behavioral problems at 3.5 years, a twofold increased risk of having lower math scores at 16 years, and a sevenfold increased risk of depression at 18 years.

They also compared the trajectories of later EPDS scores in women with varying degrees of postpartum depression. They found that regardless of the severity level, women with persistent postpartum depression showed elevated depressive symptoms up to 11 years after childbirth compared with women who did not meet the threshold for moderate postpartum depression.

“These results are important because they suggest a change from the current U.S. Preventive Task Force recommendations of universal screening for depression in all pregnant women to universal screening for depression beyond pregnancy,” Myrna M. Weissman, Ph.D., of Columbia University College of Physicians and Surgeons wrote in an accompanying editorial.

Weissman continued, “Having established a highly vulnerable group of mothers still does not answer the question of what to do about interventions or who, when, or how to treat”—a subject she noted is of some debate within the field. “Whether to treat maternal depression first, when to intervene with the mother and her infant and young children, and what treatment to use are open, researchable questions of considerable public health importance, which are worth expenditures of public funds.”

For related information, see the Psychiatric News article “Early Postpartum Depression Screenings Not Enough to Identify High-Risk Women.”

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Depression, ADHD, Anxiety Medications Not Overprescribed in Children, Study Shows

Psychiatric medications—especially stimulants and antidepressants—do not appear to be overprescribed to children and adolescents, according to a report published Monday in the Journal of Child and Adolescent Psychopharmacology.

“Among young people, the population level prescribing rates as well as age and sex distributions [of children who received stimulant and antidepressant prescriptions] are broadly consistent with known epidemiologic patterns of their established indications for ADHD, anxiety, and depression,” wrote lead author Ryan Sultan, M.D, of Columbia University and colleagues.

The researchers analyzed data contained in the 2008 IMS LifeLink LRx Longitudinal Prescription database on U.S. youth aged 3 to 24 years of age who had filled at least one prescription for stimulants, antidepressants, or antipsychotics during the study year. In total, the 2008 IMS LRx database included 131,291 younger children (aged 3 to 5), 2,140,289 older children (6 to 12), 2,163,202 adolescents (13 to 18), and 1,916,700 young adults (19 to 24) who filled at least one stimulant, antidepressant, or antipsychotic prescription.

The analysis revealed that 4.6% of older children and 3.8% of adolescents were prescribed stimulants; this is well below published national community ADHD prevalence estimates of 8.6%. Similarly, just 2.8% of adolescents, 1% of older children, and 0.1% of younger children received a prescription for an antidepressant; yet the prevalence rates for depression among adolescents alone range from 4% to 5%, while the prevalence rates for anxiety disorders in children and adolescents range from 15% to 20%.

Although annual antipsychotic prescription percentages were lower than antidepressant or stimulant percentages for all age groups, with a peak in adolescence (age 16 = 1.3%), it remains unclear whether antipsychotic prescribing is above or below prevalence rates of the disorders for which these medications are prescribed. “Patterns of antipsychotics are more complex and may reflect the heterogeneity of the approved and off-label conditions and disorders treated with this medication class,” the authors wrote.

“Overall, the findings provide some reassurance regarding population level prescribing patterns of psychotropic medications in youth in relation to the epidemiologic distribution of major child and adolescent mental disorders,” they wrote. “However, we should continue to monitor psychotropic medication prescriptions over time to assess whether U.S. prescribing practices remain broadly consistent with underlying disorder prevalence.”

For related information, see the Psychiatric News article “Prescribing for Mentally Ill Children Generally in Line With Best Practices.”

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Circadian Dysfunction Precedes Cognitive Changes in Patients With Preclinical Alzheimer’s Disease

People with Alzheimer’s disease (AD) tend to experience significantly fragmented sleep patterns that suggest underlying problems with their circadian clocks. A study published today in JAMA Neurology suggests that these changes in sleep patterns begin long before people show cognitive symptoms of AD.

“Our findings suggest that circadian dysfunction could contribute to the earliest stages of AD pathogenesis, and that understanding this association could open the door to new diagnostic and therapeutic strategies,” wrote lead author Erik Musiek, M.D., Ph.D., of Washington University School of Medicine and colleagues.

Musiek and colleagues assessed 189 cognitively normal older adults who were participating in longitudinal studies of memory and aging at the Washington University Knight Alzheimer’s Disease Research Center. The participants were all given wrist activity monitors, which measured a range of sleep parameters for 7 to 14 days. The participants also underwent amyloid beta imaging and had cerebrospinal fluid (CSF) analyzed to determine if they had preclinical AD (Previous studies have shown that amyloid plaque pathology in the brain precedes symptomatic cognitive impairment by 15 to 20 years). Of the 189 participants in the study, 139 were amyloid negative.

The authors found that several measures of sleep disturbances were associated with positive amyloid status, even after factoring in sleep problems associated with older age.

“Among the several circadian endpoints examined, we found that the nonparametric IV [intradaily variability] index was most consistently sensitive to both aging and AD pathology,” Musiek and colleagues wrote. “Intradaily variability was designed to detect fragmentation of rest-activity rhythm, suggestive of more periods of daytime rest (or sleep) and increased nighttime activity (or wake).” The authors also noted that interdaily stability, which measures how consistent circadian rhythms are on a day-to-day basis, increased with older age, but only in amyloid-positive participants.

To read more about this topic, see the Psychiatric News article “Study to Examine Amyloid PET Scans as Diagnostic Tool for Alzheimer’s.”

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Meta-Analysis Finds Childhood Abuse, Neglect Associated With Self-Injurious Behavior

Understanding patients’ history of childhood abuse or neglect may help determine their risk of non-suicidal self-injury, according to a meta-analysis published in the January issue of Lancet Psychiatry.

Non-suicidal self-injury—defined as direct and deliberate destruction of one’s own bodily tissue without suicidal intent—is estimated to affect more than 5% of adults, 17% of adolescents, and 30% of adolescents with a mental disorder. Moreover, non-suicidal self-injury is known to be one of the strongest predictors for future suicide attempts, Richard T. Liu, Ph.D., of Brown University and colleagues wrote. While most patients who engage in repeated self-injurious behavior stop within a few years, about one-fifth of patients develop a chronic pattern of self-injury.

The meta-analysis by Liu and colleagues included 71 studies that evaluated the association between childhood maltreatment (including sexual abuse, physical abuse, physical neglect, emotional abuse, and emotional neglect) and non-suicidal self-injury. The researchers found that overall childhood maltreatment was positively associated with non-suicidal self-injury (odds ratio [OR] = 3.42). The association was strongest for emotional abuse (OR = 3.03) and weakest for emotional neglect (OR = 1.84), although the analysis for emotional neglect included the fewest studies.

The association of maltreatment with non-suicidal self-injury was found to be stronger in community samples than in clinical samples, suggesting that “screening for history of childhood maltreatment might be of most benefit in community settings,” they wrote.

In an accompanying commentary, Lianne Schmaal, Ph.D., and Sarah Bendall, Ph.D., of Orygen and the University of Melbourne wrote that “Disclosure of past childhood maltreatment to a health professional can be a distressing experience. Because non-suicidal self-injury might function to distract from distress in some people, disclosures of distressing maltreatment have the potential to raise the risk of non-suicidal self-injury afterwards.” Therefore, such assessments should be done in accordance with principles of trauma-informed care.

For related information, see the American Journal of Psychiatry article “Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence.”

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Youth Later Diagnosed With Psychotic Disorders May Show Up in Acute Care Settings First

Most people receiving a first diagnosis of a psychotic disorder have had some indication of mental health problem in the previous year. A study published today in AJP in Advance suggests that as many as two-thirds of adolescents and young adults who are diagnosed with psychotic disorder may have sought mental health care during the year prior to diagnosis.

While similar patterns of health care use were seen in patients who were later diagnosed with unipolar depression, the authors did find that people who would go on to develop a psychotic disorder received specialty mental health services in inpatient and emergency department settings more frequently. 

Gregory Simon, M.D., M.P.H., of Kaiser Permanente Washington Research Institute and colleagues reviewed the medical records of all diagnoses made in youth/young adults (aged 15 to 29) between Jan. 1, 2007, and Dec. 31, 2013, among participants in the Colorado, Northern California, Northwest, Southern California, and Washington regions of Kaiser Permanente. During this period, they identified 624 confirmed cases of a first diagnosis of a psychotic disorder, which included 105 diagnoses of a schizophrenia spectrum disorder, 78 diagnoses of a mood disorder with psychosis, and 441 diagnoses of other psychotic disorders. For comparison, they also examined data from 1,862 patients who had received a diagnosis of first unipolar depression and 1,851 control patients selected from all health plan members who had at least one outpatient visit during the study period.

Of the patients with a first diagnosis of a psychotic disorder, 29% had received mental health outpatient care in the previous year, 8% had received mental health inpatient care, 24% had received emergency department mental health care, and 29% made a primary care visit that involved a mental health diagnosis. 

Patients who received a first diagnosis of unipolar depression had similar rates of previous mental health outpatient or primary care visits, but the patients who later developed a psychotic disorder were far more likely to have received inpatient and emergency mental health services. Specifically, compared with patients receiving a first diagnosis of unipolar depression, those with a first diagnosis of psychosis were 2.96 times more likely to have received mental health inpatient care in the previous year, and 3.74 times more likely to have received mental health emergency department care. 

“The strong and specific association between use of acute care mental health services and subsequent presentation with psychotic symptoms suggests the potential value of assessment for prodromal or early psychotic symptoms in people receiving inpatient or emergency care for mental health concerns,” Simon and colleagues wrote. “Systematic assessment following emergency department or inpatient mental health care may hasten identification and engagement in appropriate specialty care.”

For more information, see the Psychiatric News article “Early Identification of People With Psychosis Linked to Educating Outpatient Providers” and the Psychiatric Services article “Is the Clinical High-Risk State a Valid Concept? Retrospective Examination in a First-Episode Psychosis Sample.”

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Speech Analysis Program May Improve Psychosis Prediction in At-Risk Youth

A speech analysis software program is able to predict which youth at risk for schizophrenia will transition to psychosis with about 80 percent accuracy, according to a report in World Psychiatry.

“In psychosis, the very structure of language can be disturbed, including semantic coherence (for example, derailment and tangentiality) and syntactic complexity (for example, concreteness),” wrote Cheryl Corcoran, M.D., of the Icahn School of Medicine at Mount Sinai and colleagues. “Our findings support the utility and validity of automated natural language processing methods to characterize disturbances in semantics and syntax across stages of psychotic disorder.”

A pilot study by Corcoran and colleagues published in 2015 demonstrated that using speech analysis software on transcripts of interviews with 34 New York youth at risk for psychosis could be a reliable tool to identify the youth most likely to convert to psychosis within a couple of years. The software was designed to identify semantic problems, such as short sentences, incoherence between phrases, and reduced usage of pronouns.

To see whether their software was effective at predicting psychosis transition in a larger sample, the researchers analyzed transcripts obtained from a cohort of 59 at-risk youth from a University of California, Los Angeles (UCLA) clinical site. Of this group, 19 developed a psychotic disorder within two years, and 40 did not.

In this UCLA cohort, transcripts were generated from an exercise in which the participants listened to a story and then retold it and answered questions about it. Since the format of the story exercise resulted in responses that were generally short (about 20 words or fewer for each individual response), the software was not able to use sentence length as one of the predictive elements.

Still, the speech analysis software was able to classify the participants as converters or nonconverters with 83% accuracy overall, including 11 of 19 converters (58%). When the software was retested on the 34 youth in the New York sample using the same parameters as for the UCLA youths, it had a similar accuracy (79% overall, including 60% of converters), despite not using sentence length in the prediction.

“This technology has the potential to improve prediction of psychosis outcome among adolescents and young adults at clinical high risk and may have broader implications for medical research and practice at large,” Corcoran and colleagues concluded.

To read more about this topic, see the Psychiatric News article “Innovation Lab Winner Uses Speech Analysis to Diagnose Psychosis.”

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Uptick in Reproductive-Aged Women on ADHD Medications Raises Questions About Risks to Offspring

The percentage of privately insured U.S. women aged 15 to 44 who filled at least one prescription for attention-deficit/hyperactivity disorder (ADHD) medications increased 344% between 2003 and 2015, according to data recently released by the Centers for Disease Control and Prevention.

“The substantial increase in the percentage of reproductive-aged women filling ADHD medication prescriptions from 2003 to 2015, across age groups and U.S. geographic regions, is of public health concern given the high percentage of unintended pregnancies and uncertainty concerning the safety of ADHD medication exposure before and during pregnancy,” Kayla N. Anderson, Ph.D., and colleagues wrote.

Anderson and colleagues used the Truven Health MarketScan Commercial Database to examine outpatient pharmacy prescription drug claims for ADHD medications among women aged 15 to 44 years from 2003 to 2015. (The MarketScan data reflect health service use by people with private employer-sponsored insurance and their dependents in the United States.) Outpatient pharmacy claims for ADHD medications were identified using national drug codes, irrespective of the indication for use.

The final analysis included 2.3 to 6.8 million privately insured reproductive-aged women each year from 2003 to 2015. The percentage of women in the sample who filled a prescription for any ADHD medication increased from 0.9% in 2003 to 4.0% in 2015 (344%). The largest increase in ADHD prescriptions filled during this period occurred among women aged 25 to 29 years (700%).

“Among reproductive-aged women who filled any ADHD medication prescription in the given year, the percentage who filled a prescription for mixed amphetamine salts and lisdexamfetamine increased from 2003 to 2015, while the percentage who filled a prescription for methylphenidate and atomoxetine decreased over the same period,” the authors noted.

The authors acknowledged several limitations of the findings, including the fact the analysis was limited to only privately insured women with prescription drug coverage, who may or may not be prescribed ADHD medications at similar rates as those who are publicly insured. Nonetheless, they concluded, “The increasing trend toward prescribing ADHD medications to reproductive-aged women highlights the importance of research examining ADHD medication safety in this population, including safety before and during pregnancy.”

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

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APA Voices Concerns About Broadening Religious-Based Exemptions in Health Care

APA today issued a statement expressing concerns that broadening religious exemptions for health care providers would allow them to discriminate and deny care because of a patient's gender identity, sexual orientation, or reproductive health decisions.

The statement comes one day after the Department of Health and Human Services announced the creation of the Conscience and Religious Freedom Division within the Office of Civil Rights. It will be responsible for handling complaints by health care workers who feel their beliefs conflict with the care they are being asked to provide.

“I am deeply concerned that our patients—many of whom already face unique health challenges—may now be denied care because of their providers’ personal beliefs. We know that discriminatory policies harm our patients’ mental health and well-being,” APA CEO and Medical Director Saul Levin, M.D., M.P.A., said in the statement. “Laws allowing religious refusals of care must avoid harming patients’ health or imposing another’s moral beliefs on patients.”

In a November 2017 letter from APA to HHS, Levin wrote, “The mission of DHHS is ‘to enhance and protect the health and well-being of all Americans,’ and we are concerned about any regulatory changes that would roll back protections to ensure all patients are treated with dignity and respect and have access to care without fear of discrimination.”

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Catatonia Often Goes Undiagnosed, Untreated in General Hospitals

Physicians fail to diagnose the majority of cases of catatonia in a general hospital setting, which may result in suboptimal treatment for these patients, according to an article in the Journal of Neuropsychiatry and Clinical Neurosciences. However, psychiatric consultation can significantly decrease the odds of failure to diagnose the condition, the study found.

Diagnosing catatonia is challenging because it requires clinical suspicion and physical examination, according to researchers Joan Roig Llesuy, M.D., of New York University School of Medicine and colleagues. While catatonia is often reversible when treated with lorazepam and/or electroconvulsive therapy (ECT), its underrecognition and subsequent lack of treatment might lead to dangerous medical complications, the authors wrote.

Moreover, failure to recognize catatonia may lead to improper treatment with antipsychotics, which can increase the risk for developing malignant catatonic features or neuroleptic malignant syndrome. “Thus, awareness about catatonia for all clinicians is relevant to improve patient care,” the authors wrote.

The study involved a retrospective chart review of adult inpatients at the University of Chicago general hospital between 2011 and 2013. The presence of three or more keywords in the chart describing catatonia-related signs was used to flag cases for review. Of 133 cases found meeting DSM-5 criteria for catatonia, 79 (nearly 60%) were not diagnosed with the condition.

Additional analysis revealed that patients meeting DSM-5 criteria for catatonia who underwent a psychiatric consultation during the admission process were more than 44 times as likely to be correctly diagnosed with catatonia, compared with those who did not receive a consultation. Still, more than one-third of undiagnosed patients (37%) had received a psychiatry consult, supporting “the need for greater recognition of catatonia across disciplines,” the researchers wrote.

Physicians may be unaware of the cluster of signs and symptoms that constitute catatonia: the presence of grimacing, agitation, or echolalia symptoms was associated with a 4 to 6 times greater likelihood that the catatonia would go undiagnosed.

Regardless of diagnosis of catatonia, none of the 133 subjects received ECT. Also, no differences were found in the rate of lorazepam treatment between diagnosed or undiagnosed patients: half of those with catatonia did not receive lorazepam. However, the total dose of lorazepam was significantly lower in the undiagnosed group, who received 0.4 mg a day on average versus those diagnosed with catatonia, who received an average of 1.3 mg a day. High doses of lorazepam for several days or longer might be needed to treat catatonia effectively, the researchers wrote.

“Improving detecting and treatment of catatonia could help improve clinical outcomes of patients with this reversible syndrome in the general hospital,” concluded the authors.

For related information, see the Journal of Neuropsychiatry and Clinical Neurosciences article “Suspected Delirium Predicts the Thoroughness of Catatonia Evaluation.”

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Depression May Increase Risk of Death Following Heart Procedure, Study Suggests

Older patients with depression may be at greater risk of death following a procedure to replace a damaged aortic valve of the heart, reports a study published today in JAMA Cardiology.

“The clinical implications of our findings support active screening for depression before and after aortic valve procedures to identify patients who may benefit from further psychiatric evaluation for the diagnosis and treatment of a depressive disorder,” wrote Jonathan Afilalo, M.D., M.Sc., of Jewish General Hospital, Montreal, and colleagues.

The study included patients who were at least 70 years of age with symptomatic aortic stenosis and who had undergone transcatheter or surgical aortic valve replacement. As part of a larger prospective cohort study, these patients completed a preprocedural assessment of frailty, disability, comorbidity, cognitive function, and mood. Depressive symptoms were assessed using the five-item Geriatric Depression Scale Short Form (GDS-SF) at baseline and follow-up at six and 12 months. The authors defined a GDS-SF score of at least 2 of 5 as indicative of clinically relevant depression.

Of the 1,035 patients (427 men and 608 women; mean age of 81.4 years) included in the analysis, 326 patients (31.5%) screened positive for depression. Compared with patients without depression, those with depression were more likely to have diabetes, chronic kidney disease, hypertension, chronic obstructive pulmonary disease, and/or cerebrovascular disease. Patients with depression were also more likely to be physically frail and to be cognitively impaired compared with those without depression.

After adjusting for clinical and geriatric confounders, the researchers found that baseline depression increased risk of death at one month (odds ratio [OR], 2.20) and at 12 months (OR, 1.532). Persistent depression—defined as baseline depression that remained six months after the procedure—was associated with a threefold increase in mortality at 12 months (OR, 2.98).

“Given the prognostic implications and diagnostic challenges, coordinated care involving cardiovascular and psychogeriatric specialists is indicated to provide optimal management to patients undergoing TAVR [transcatheter aortic valve replacement] and SAVR [surgical aortic valve replacement] who exhibit depressive symptoms,” the authors wrote.

For related information, see the Psychiatric News article “Can Collaborative Care Really Help Patients With Depression and Diabetes or Heart Disease?” by David Katzelnick, M.D., Rebecca Rossom, M.D., M.S., and Leif Solberg, M.D.

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Propranolol May Help Patients With PTSD

While exposure therapy is recognized as one of the best strategies for treating patients with posttraumatic stress disorder (PTSD), many continue to experience significant problems. A study published in AJP in Advance suggests that patients with PTSD who take propranolol (a noradrenergic beta-receptor blocker) prior to recalling their traumatic event may experience greater PTSD symptom reduction than those who do not take the medication.

“PTSD participants who actively recalled their traumatic event under the influence of propranolol once a week for up to six weeks showed a substantial decrease in symptom ratings compared with placebo,” wrote Alain Brunet, Ph.D., of McGill University and colleagues. “The decrease was evident from both the clinician’s and the participant’s perspective.”

Sixty adults diagnosed with long-standing PTSD were randomized to receive either propranolol or placebo 90 minutes before a brief memory reactivation session, once a week for six consecutive weeks. Patients in the treatment arm received 0.67 mg/kg of conventional (short-acting) propranolol, plus 1.0 mg/kg of long-acting propranolol. The patient-rated PTSD Checklist Specific (PCL-S) scale was administered at the beginning of each treatment session, before propranolol was administered. The Clinician-Administered PTSD Scale (CAPS) was used one week before and one week after the six-week trial.

Sixty minutes after ingesting the medication or placebo, the participants were asked to write a one-page trauma narrative in the present tense, first-person singular, focusing on the event’s most disturbing moments and including five or more bodily sensations drawn from a checklist. The participants were then asked to read the narrative aloud once to the therapist “as if they were back in the event.”

Patients in the propranolol and placebo groups had similar PCL-S and CAPS scores at baseline. At the posttreatment assessment, the scores had decreased in both groups, but the decreases were significantly greater in the propranolol group. At the six-month follow-up, the mean CAPS scores were 52.0 for the propranolol group and 69.2 for the placebo group. Mean PCL-S scores were 38.4 for the propranolol group and 69.0 for the placebo group.

“The effect sizes obtained for pre-reactivation propranolol in our study compare well to those obtained with the best evidence-based treatment for PTSD, namely, cognitive-behavioral therapy, as well as those obtained with the most recommended pharmacological treatment for PTSD, namely, SSRIs,” Brunet and colleagues wrote. “Should these results be replicated in further studies, propranolol blockade of reconsolidation [of traumatic memories] may become a new therapy for some patients with PTSD.”

For related information, see the Psychiatric News article “New Research Shows Multiple Genes May Be Associated With PTSD.”

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Escalating Symptoms of Anxiety May Point to Older Patients at Greatest Risk of Alzheimer’s

Older adults experiencing worsening anxiety may have higher levels of a protein fragment implicated in Alzheimer’s disease, according to a study published today in AJP in Advance.

Past studies have suggested depression and other neuropsychiatric symptoms may be predictors of Alzheimer’s progression during its “preclinical” phase—a period marked by the accumulation of brain deposits of fibrillar amyloid and pathological tau in a patient’s brain. 

In the current study, Nancy J. Donovan, M.D., of Brigham and Women’s Hospital and colleagues examined the association between brain amyloid beta and depression symptoms over time in cognitively normal, older adults.

A total of 270 participants aged 62 to 90 underwent baseline positron emission tomography (PET) scans to measure cortical aggregate amyloid beta and annual depression assessments with the 30-item Geriatric Depression Scale (GDS). The team calculated total GDS scores as well as scores for three GDS item clusters: apathy-anhedonia, dysphoria, and anxiety-concentration. These scores were examined over a span of five years.

“Rather than just looking at depression as a total score, we looked at specific symptoms such as anxiety,” Donovan said in a press release. “When compared to other symptoms of depression such as sadness or loss of interest, anxiety symptoms increased over time in those with higher amyloid beta levels in the brain.”

“These results suggest a direct or indirect association of elevated amyloid beta levels with worsening anxious-depressive symptoms and provide support for the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer’s disease,” the researchers wrote. “Further longitudinal follow-up is necessary to determine whether these escalating depressive symptoms give rise to clinical depression and/or MCI and dementia stages of Alzheimer’s disease over an extended period.”

For related information, see the Psychiatric News article “Alzheimer’s-Associated Protein Might Help Brain Fight Infections.”

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Study Suggests Hormone Therapy May Reduce Risk of Depression During Menopause Transition

The risk of depression is known to increase among women as they enter the menopause transition and early postmenopausal period. A study published yesterday in JAMA Psychiatry found that perimenopausal and early postmenopausal women treated with estrogen plus progestin hormone therapy (HT) for 12 months were about half as likely to develop depression as women treated with placebo.

“The findings of this study confirm that perimenopausal and early postmenopausal women are at high risk for developing clinically significant depressive symptoms,” wrote Jennifer L. Gordon, Ph.D., of the University of Regina, Canada, and colleagues. “Health care professionals should be alert to the high risk for clinically significant depressive symptoms in this population.”

Gordon and colleagues randomly assigned 172 healthy perimenopausal and early menopausal women aged 45 to 60 years to either continuous transdermal estradiol (0.1 mg/d) plus oral micronized progesterone every two to three months or placebo. Depressive symptoms were assessed at seven visits throughout the year using the Center for Epidemiological Studies-Depression Scale (CES-D).

During the one-year study, women assigned to placebo were more likely than those assigned to the HT regimen to report clinically significant depressive symptoms, defined as a CES-D score of at least 16 (32% versus 17%). Women assigned to placebo were also more likely to have a higher mean CES-D score across the 12-month study compared with those receiving HT. Additional analysis revealed that women in the early stage of perimenopause were most likely to experience mood benefits from the HT regimen for prevention of depression, Gordon and colleagues reported. In fact, the mood-enhancing benefit of HT was not evident among women in the late menopause transition or postmenopausal women studied. The beneficial effect of HT was also more apparent in those with a greater number of stressful life events.

The authors noted that there were three severe adverse events requiring study termination and medical treatment: two cases of major depressive disorder in the placebo group and, in the HT group, one case of an acute deep vein thrombosis—a known risk of HT.

“We commend the authors for investigating the efficacy of a biologically rational strategy to prevent depressive symptoms in women at increased risk owing to reproductive stage using a randomized clinical trial design,” Hadine Joffe, M.D., M.Sc., of Brigham and Women’s Hospital, and Martha Hickey, M.D., of the University of Melbourne, Australia, wrote in a related editorial.

However, Joffe and Hickey cautioned, “Hormone therapy is U.S. Food and Drug Administration–approved for treatment of hot flashes and vaginal dryness, but not for treatment or prevention of mood disturbance. The recommendation by Gordon et al that HT be considered off-label for the prevention of depressive symptoms … is inconsistent with accumulating high-level evidence that HT should not be used for the prevention of chronic disease.”

For related information, see the Psychiatric News article “Discontinuing Hormone Therapy May Increase Risk of Depression in Some Women.”

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AJP Articles Make NEJM Journal Watch Psychiatry, BBRF’s Top 10 for 2017

The American Journal of Psychiatry has once again received recognition from New England Journal of Medicine (NEJM) Journal Watch Psychiatry and the Brain and Behavior Research Foundation (BBRF) for the publication of outstanding research in the past year that advances the clinical practice of psychiatry. Two AJP articles were named “top stories of 2017” by NEJM Journal Watch Psychiatry, and four were listed as representing “top advances and breakthroughs” by the Brain and Behavior Research Foundation.

One article—“Adjunctive Bright Light Therapy for Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Trial,” by Dorothy K. Sit, M.D., et al.—appeared on both lists. As Sit and colleagues explained in the AJP article, there is a growing interest in nonpharmacological approaches to treat bipolar depression, after many medications used to treat the disorder have proven ineffective and/or produce adverse effects, including mood switching. The researchers discovered that exposing patients with bipolar depression on stable antimanic medications to midday bright white light led to reductions in their depression scores after six weeks compared with those in the control group. Importantly, no hypomania, dramatic mood switching, or serious side effects were observed during the study.

The other study named on NEJM Journal Watch Psychiatry’s Top 10 list was “KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia,” by Robert A. Hauser, M.D., M.B.A., et al. This study found that once-daily treatment with valbenazine at 80 mg/day significantly improved the symptoms of tardive dyskinesia compared with placebo in a population of patients with schizophrenia, schizoaffective disorder, or a mood disorder. The medication was generally well tolerated, even among patients taking concomitant antipsychotics, and the psychiatric status of the patients remained stable throughout the trial.

In addition to the article by Sit and colleagues referenced above, the following studies were selected by BBRF in its list of the top advancements and breakthroughs by Foundation grantees in 2017 (in chronological order):

• “Multimodal Neuroimaging of Frontolimbic Structure and Function Associated With Suicide Attempts in Adolescents and Young Adults With Bipolar Disorder,” by Jennifer A.Y. Johnston, M.A., et al. Relying on multiple MRI techniques, the authors of this study compared brain images of 68 participants aged 14 to 25 with bipolar disorder who did or did not have a prior suicide attempt. Their analysis revealed significant differences in brain structure and connectivity between these two groups. Intriguingly, among suicide attempters, reduced connections to the left or right prefrontal cortex were correlated with more serious suicidal ideation or suicide attempts, respectively.

• “Effect of a Novel NMDA Receptor Modulator, Rapastinel (Formerly GLYX-13), in OCD: Proof of Concept,” by Carolyn I. Rodriguez, M.D., Ph.D., et al. In this small, open-label trial, Rodriguez and colleagues found that unmedicated patients with obsessive-compulsive disorder who received a single intravenous dose of rapastinel reported a drop in obsessive-compulsive, depression, and anxiety severity scores within 90 minutes of the infusion. The effects were short-lived, however, with no significant effects on symptoms seen one week later.

• “The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis,” by Samuel T. Wilkinson, M.D., et al. A single infusion of ketamine appears to significantly reduce suicidal thoughts in depressed patients in as little as one day, with benefits lasting for up to one week, according to this meta-analysis. Notably, after controlling for improvement in severity of depressive symptoms, ketamine’s effects on suicidal ideation remained significant. This suggests that ketamine has a specific effect on suicidal ideation that depends only partly on change in overall severity of depressive symptoms.

To see a list of the AJP articles that were recognized last year, click here.

Social Skills Training May Reduce Negative Symptoms in Patients With Schizophrenia

Social skills training (SST) is effective for treating negative symptoms in schizophrenia, according to a meta-analysis in Schizophrenia Bulletin comparing SST and other interventions on a number of outcomes.

“The effect sizes reported are impressive for a group-based psychological intervention suggesting that SST may have potential as a cost-effective alternative to individual therapies addressing negative and general symptoms in health care systems struggling to provide routine psychological intervention,” lead author David T. Turner, Ph.D., of Vrije University, The Netherlands, and colleagues wrote.

In recent years, addressing negative symptoms—passive or apathetic social withdrawal, communication difficulties, blunting of affect, and rigid or stereotypical thinking—has been recognized as central to improving quality of life and long-term recovery for patients with schizophrenia. During this time, trials of SST, originally developed in the 1970s to address interpersonal and social functioning, have been expanded to include studies of effects on negative symptoms.

Turner and colleagues searched the literature for randomized, controlled trials of social skills training, including those that compared SST against active controls (such as cognitive-behavioral therapy [CBT]), treatment as usual (standard treatment offered in the clinical setting), and waiting-list controls. Twenty-seven randomized, controlled trials with 1,437 participants were included in the analysis.

SST demonstrated superiority for negative symptoms and for scores on general psychopathology over both treatment-as-usual and active controls, as well as when all comparators were pooled. The effect sizes reported for SST for negative symptoms were “marginally greater than those reported for CBT for positive symptoms and marginally smaller than those reported for antipsychotics,” according to the report. “If we consider CBT as an intervention addressing positive symptoms and SST for negative symptoms, each intervention has effects of roughly equivalent magnitude for its target area,” the researchers stated.

“The meta-analysis by Turner and colleagues … reconfirms the efficacy of social skills training for improving social skills and reducing negative symptoms in people with schizophrenia,” Philip Harvey, Ph.D., of the University of Florida and Eric Granholm, Ph.D., of the University of California, San Diego wrote in a related editorial. “These consistently-replicated findings that SST improves social skills, negative symptoms, and functioning relative to standard care suggests that existing standard services for schizophrenia can be improved by adding SST.”

For related information, see the Psychiatric News article “Study Suggests Cariprazine May Have Direct Effects on Negative Symptoms.”

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Adjunctive Intranasal Esketamine Rapidly Decreases Depression Symptoms

Intranasal esketamine taken twice weekly can rapidly reduce symptoms of people with treatment-resistant depression, according to a study in JAMA Psychiatry.

Esketamine is the mirror image molecule of ketamine. The two molecules are very similar biologically, but esketamine is reported to produce fewer psychomimetic side effects like delirium or hallucinations.

Ella Daly, M.D., of Janssen Research and Development and colleagues recruited 67 adults with treatment-resistant depression; treatment resistance was defined as having a history of inadequate response to two or more antidepressants. The patients were randomly divided so that half received placebo while the other half received 28 mg, 56 mg, or 84 mg of esketamine twice weekly for two weeks. All participants continued the antidepressants they were receiving at study entry during the trial.

The researchers found that all three esketamine doses produced significantly greater reductions in the participants’ Montgomery-Asberg Depression Rating Scale scores from baseline after one week. The improvements escalated with dose, with 4.2, 6.3, and 9.0-point improvements for the 28 mg, 56 mg, and 84 mg doses, respectively.

After 15 days, all participants were invited to enroll in a 60-day open-label period, during which they received esketamine twice weekly for two weeks, weekly for three weeks, and then every two weeks thereafter. The improvements in depressive symptoms were maintained during the open-label period despite the reduced dosing frequency, and for up to two months after the discontinuation of esketamine.

“In general, the esketamine doses used in this study appeared to be safe, with no new or unexpected safety concerns observed,” the authors wrote. “Overall, transient increases in blood pressure after the dose, particularly increases in systolic blood pressure, support an increase in cardiac output as the underlying mechanism, consistent with previous reports of ketamine.”

To read more about this topic, see the Psychiatric News article “Ketamine Is a Potent Antidepressant, but How Does It Work?”

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APA Releases New Practice Guideline on AUD Pharmacotherapy

APA today released a new practice guideline for the pharmacological treatment of alcohol use disorder (AUD). Despite the high prevalence of AUD and its significant public health consequences, patients with this disorder remain undertreated.

“This new guideline is an important step in bringing effective, evidence-based treatments for alcohol use disorder to many more people and in helping address the public health burden of alcohol use,” APA President Anita Everett, M.D., said in a press release.

The guideline aims to increase physician and public knowledge on the effectiveness and risks of the five medications that may be used for the treatment of AUD: acamprosate, disulfiram, gabapentin, naltrexone, and topiramate.

• Of these five, naltrexone and acamprosate have the best available evidence related to their benefits, and both have minimal side effects. As such, they should be considered the preferred pharmacological options for patients with moderate to severe AUD who want to reduce drinking or achieve abstinence. However, acamprosate should be avoided in patients with significant renal impairment, and naltrexone should be avoided in patients with acute hepatitis or liver failure, or in patients currently taking opioids or who may be expected to take opioids.
• Disulfiram, gabapentin and topiramate are also options for treatment of AUD but should typically be considered after trying naltrexone and acamprosate, unless the patient has a strong preference for one of these medications. Disulfiram is a special case as it does cause a series of adverse reactions if alcohol is consumed within 12 to 24 hours of taking the medication; the reactions include elevated heart rate, flushed skin, headache, nausea, and vomiting. Therefore, disulfiram is suggested only to patients who wish to achieve abstinence from drinking. Patients taking topiramate are at an increased risk of cognitive dysfunction, dizziness, and loss of appetite, whereas patients taking gabapentin may experience fatigue, insomnia, and headache.

While the guideline focuses specifically on evidence-based pharmacological treatments for AUD, it also includes recommendations and suggestions related to psychiatric evaluation of patients with AUD and developing a person-centered treatment plan. Evidence-based psychotherapeutic treatments for alcohol use disorder also play a major role in treatment and peer support groups such as Alcoholics Anonymous, and other 12-step programs can be helpful for many patients. However, specific recommendations related to these treatments are outside the scope of this guideline.

The full guideline, executive summary, and related materials are available here.

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Use of Folic Acid and Multivitamins During Pregnancy May Lower Autism Risk

Women who take folic acid and multivitamins before and during pregnancy appear to reduce their risk of having a child with autism, according to a large study in Israel.

Compared with women who had no exposure to supplements during pregnancy, women who took folic acid and/or multivitamins had a significantly reduced risk of having offspring with autism spectrum disorder (ASD), with a relative risk of 0.27, according to the study published yesterday in JAMA Psychiatry. Mothers who took folic acid and vitamin supplements before pregnancy had a relative risk of 0.41 compared with mothers who did not.

For the study, researchers followed 45,300 Israeli children born between 2003 and 2007, until 2015; 1.3% were diagnosed with ASD, according to the study by Stephen Z. Levine, Ph.D., of the University of Haifa, Israel, and colleagues.

Women are routinely advised to take folic acid or multivitamins during pregnancy to avoid neural tube defects in their children, but previous studies of an association between the supplements and the risk of ASD in their offspring have been inconsistent.

For this observational study, children with ASD were compared with children without it to identify whether maternal use of folic acid and multivitamin supplements might play a role. The researchers examined health care organization data, including pharmacy dispensation of folic acid and multivitamin prescriptions, to pregnant women.

They examined whether supplements were dispensed to the pregnant women before pregnancy (540 days to 271 days before childbirth) and during pregnancy (9 months before childbirth, up to the date of birth). A diagnosis of ASD of their children was made after evaluation by a panel of experts, including a behavioral pediatrician.

Among offspring whose parents had a psychiatric disorder, folic acid supplementation before pregnancy did not provide the same protective effect against ASD, the researchers found. They theorized this finding might reflect noncompliance with the vitamin regimens, or possibly higher rates of vitamin deficiency or poor nutrition among persons with psychiatric conditions.

The researchers found that most supplement dispensations occurred around the first trimester. Only 26% of children were born to mothers who took folic acid and/or multivitamin supplements before pregnancy; about 48 percent were born to mothers who took folic acid and/or multivitamins during pregnancy.

For related information, see the Psychiatric News article “Folinic Acid May ImproveVerbal Skills in Children With ASD.”

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Transcranial Direct Current Stimulation May Improve Outcomes in Patients With Bipolar Depression

Patients with bipolar depression who are not responding to pharmacotherapy may benefit from add-on transcranial direct current stimulation (tDCS), according to a study in JAMA Psychiatry. tDCS is a low-cost, noninvasive technique that applies weak, direct currents into the brain via electrodes placed over the scalp.
In this small study, patients with bipolar depression who received active tDCS showed superior improvement after six weeks of treatment compared with those who received sham treatment. Additionally, active tDCS did not induce more manic/hypomanic episodes—which the authors noted is a significant concern when treating bipolar depression.

Bernardo Sampaio-Junior, M.D., of the University of São Paulo and colleagues recruited patients with type I or II bipolar disorder who were experiencing a major depressive episode and receiving a stable pharmacological regimen. Only those aged 18 to 65 with Hamilton Depression Rating Scale (HDRS-17) scores higher than 17 and who did not show a clinical response after one or more pharmacotherapies in the acute depressive episode were included in the trial.

During tDCS sessions, patients were fitted with electrodes over the left and right dorsolateral prefrontal cortex (DLPFC)—a brain area whose metabolism increases after successful antidepressant treatment. The patients received 10 consecutive daily 30-minute, 2-mA sessions of active or sham tDCS on weekdays, followed by two sessions at weeks 4 and 6. Sham tDCS was delivered using the same protocol and current intensity, but the period of active stimulation was only 30 seconds.

Participants were assessed by blinded psychiatrists and psychologists at baseline, week 2, week 4, and the end point (week 6). Adverse events were recorded at weeks 2 and 6.

Of the 59 patients included in the trial, 52 (26 in each group) completed all 12 tDCS sessions as well as the final assessment. Active tDCS was superior to sham for sustained response (defined as a sustained >50% reduction from baseline HDRS-17 score since time this outcome was first achieved through week 6); cumulative response rates were 67.6% in the active group versus 30.4% in the sham group. Active tDCS was not found to be superior to sham for sustained remission (defined as sustained HDRS-17 score ≤7 from time this outcome was first achieved through week 6); remission rates were 37.4% versus 19.1%, respectively.

Patients who received active tDCS were more likely to develop skin redness than those in the sham group (54% versus 19%); however, the frequency of other adverse events did not differ. There were nine treatment-emergent affective switches throughout the trial: five (19%) in the sham and four (15%) in the active group. “However, these episodes did not meet the criteria for a major depressive episode with mixed features, hypomania, or mania per DSM-5 guidelines and required no hospitalization, trial discontinuation, or specific treatment,” the authors reported.

They concluded, “Although preliminary, our results are promising and encourage further trials to examine the efficacy of tDCS in a large bipolar disorder sample.”

For related information, see the Psychiatric News article “Adjunctive Light Therapy Found Effective for Bipolar Depression” and the AJP article “Low-Intensity Transcranial Current Stimulation in Psychiatry.”

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SSRIs in Late Pregnancy Linked to Increased Risk for Anxious, Depressed Behaviors at Age 5

Children whose mothers took selective serotonin reuptake inhibitors (SSRIs) during the last trimester of pregnancy may be more likely to experience anxious and depressed symptoms by age 5 years compared with children who were not exposed to the medications, according to a report in the Journal of the American Academy of Child and Adolescent Psychiatry. However, the study found no evidence for such an effect following SSRI exposure earlier than 29 weeks, and no effect on externalizing, social, and emotional problems.

“It is reassuring that prenatal SSRI did not confer a substantial increased risk for greater externalizing behaviors in preschool-age children or for more problematic temperament in terms of emotionality, sociability, activity, or shyness, and this was consistently evident across the various exposure windows,” Angela Lupattelli, Ph.D., of the University of Oslo, Norway, and colleagues wrote. 

Lupattelli and colleagues examined data from the Norwegian Mother and Child Cohort Study, a prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health. The analysis included data on 7,944 women who reported having depressive/anxiety disorders before and/or during pregnancy and 8,359 pregnancy-child dyads. A total of 605 women took SSRIs at some point during pregnancy. The outcomes of children born to women who took SSRIs in early (0-16 weeks), mid- (weeks 17-28), or late pregnancy (week 29 or later) were compared with those of children who were not exposed to medication.

Mothers were asked to assess their child’s development at ages 1.5, 3, and 5 years using the Child Behavior Checklist for preschool children and the short form of the Emotionality, Activity, and Shyness Temperament Questionnaire.

The results showed for each year increase in age, children exposed to SSRIs late in gestation had an increased risk of anxious or depressed behaviors compared with unexposed children, reaching statistical significance at age 5.

There was no such association with other developmental outcomes or with any developmental outcome following mid- or early-pregnancy SSRI exposure. Moreover, there appears to be a protective effect of SSRI exposure against attention problems, though it diminishes as the child ages, according to the report. 

“Our findings, coupled with those in animal models, may point to a plausible late-pregnancy fetal vulnerability to SSRI and/or susceptibility to serotonin disruption,” Lupattelli and colleagues wrote. “This association has to be confirmed or refuted by future research, but at present may provide some insights into potentially important periods of fetal vulnerability to SSRI exposure. This potential risk needs to be balanced against a potential detrimental effect of untreated maternal depression. …[T]his information may assist clinicians when evaluating the risk of treatment with SSRI at specific timing during gestation.”

For further information, see the Psychiatric News article “Study Reports on Risks, Benefits of SSRIs Taken During Pregnancy.”

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