Study Examines Efficacy of Esketamine-Antidepressant Combo in Older Adults With Treatment-Resistant Depression

A subset of individuals 65 years or older with treatment-resistant depression who took a new oral antidepressant plus intranasal esketamine showed greater improvement of symptoms than those who took an antidepressant and intranasal placebo, according to a report in the American Journal of Geriatric Psychiatry. However, the overall difference between the esketamine and placebo groups in symptom score reduction was not statistically significant, indicating a need for further research, wrote lead author Rachel Ochs-Ross, M.D., of Janssen Research & Development and colleagues.

The study was funded by Janssen, who markets intranasal esketamine. (The drug was approved by the Food and Drug Administration earlier this year for treatment-resistant depression.)

The researchers randomly assigned 138 patients 65 years or older with treatment-resistant depression to take intranasal esketamine or placebo twice weekly in addition to a new oral antidepressant daily for four weeks. Patients initially received 28 mg of esketamine or the placebo nasal spray, but the investigators increased the esketamine dose to 56 mg or 84 mg based on the patients’ response to the treatment. The primary endpoint was change in the Montgomery- Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Secondary measures included the percentage of patients who showed a treatment response (defined as a 50% or greater reduction in MADRS score) and rates of remission (defined as a MADRS score of 12 or less).

The average change in MADRS score for patients taking antidepressant plus esketamine was 10 points compared with 6.3 for patients taking antidepressant plus placebo. Treatment response was observed in 27% of patients receiving esketamine and 13.3% receiving placebo. Remission rates were 17.5% in the esketamine group and 6.7% in the placebo group.

The difference between the esketamine and placebo groups on the primary endpoint of overall symptom reduction was not statistically significant. This failure to achieve statistical significance may be related to lower dosing required in older patients and a need for longer treatment duration, the researchers wrote.

Additional analysis revealed that there was a greater reduction in total symptom scores among individuals aged 65 to 74 treated with esketamine compared with placebo that was not observed in patients aged 75 years or older, suggesting that the combination may benefit a younger subset of seniors.

“Given the need for treatments for [treatment-resistant depression in older adults] and the potential role of esketamine, future studies are needed to establish if esketamine is effective in [treatment-resistant depression in older adults] and if so the optimal induction/optimization/maintenance dosing and duration of treatment,” Helen Lavretsky, M.D., M.S., of the Semel Institute for Neuroscience and Human Behavior at UCLA and Steven P. Roose, M.D., of New York State Psychiatric Institute, wrote in an accompanying editorial. “There is much work to do but the exciting news is that studies are underway and hopefully new esketamine studies will be initiated that will provide the clinician with the information necessary to alter the deleterious trajectory associated with this high-risk population and difficult to treat population,” they wrote.

For related information, see the Psychiatric News article “Esketamine Approved For Treatment-Resistant Depression.”

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Ketamine Found to Rapidly Reduce Suicidal Thoughts in Depressed, Suicidal Patients in ER

Patients presenting to an emergency room with complaints of suicidal thoughts may experience relief from these thoughts within 90 minutes of a single, low-dose infusion of ketamine, suggests a small study in Depression & Anxiety.

While previous studies have demonstrated the potential of ketamine to reduce suicidal thoughts in patients with depression (including this 2017 paper published in the American Journal of Psychiatry), this new study examined the effectiveness of a low-dose infusion administered in an emergency department. “A single infusion of ketamine, administered in the emergency department, is a safe and feasible treatment option for depressed, suicidal patients,” wrote Yoav Domany, M.D., of Tel Aviv University and colleagues.

The study included 18 depressed patients aged 18 to 65 who were hospitalized after reporting suicidal ideation in an emergency room setting. After completing baseline assessments, the patients were randomly assigned to receive ketamine (0.2 mg/kg) or placebo (saline) intravenously over five minutes, under the supervision of an emergency department physician. The researchers evaluated the severity of the patients’ suicidal ideations (using the Beck Scale for Suicidal Ideation and item 10 of the Montgomery–Åsberg Depression Rating Scale, or MADRS), feelings of depression and anxiety (using the MADRS and Beck Anxiety Index), dissociative symptoms, blood pressure, and more 15, 30, 60, 90, 120, 180, and 240 minutes after the infusion. The patients were evaluated again 1, 2, 3, 7, and 14 days later.

Domany and colleagues found that patients in the ketamine group reported fewer suicidal thoughts than those in the placebo group 90 to 180 minutes after the infusion. “Notably, 90 minutes after infusion, 88% of the ketamine‐receiving subjects were no longer actively suicidal compared with 33% of the controls,” the authors wrote. A total of 22% of patients in the ketamine group experienced what the authors referred to as “transient elevated systolic blood pressure” (higher than 140 mm/Hg), compared with 11% in the placebo group. There were no differences in psychiatric symptoms or dissociative symptoms between the two groups at any time point following the infusion.

“Our findings are consistent with others who demonstrated the antisuicidal effect of ketamine. … We, however, suggest here a more feasible way of administration, which is more appropriate for an emergency department setting (even before administration to psychiatric ward),” they wrote.

The authors noted the main limitation of the study was the small sample size of the trial and called for additional studies to examine the effectiveness of ketamine for reducing suicidal thoughts in this patient population.

For related news, see the Psychiatric News article “Ketamine Shown to Reduce Suicidal Ideation in Severely Depressed Patients” and the American Journal of Psychiatry article “Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial.”

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Many Women With Schizophrenia Do Not Receive Mammograms, Meta-Analysis Suggests

Women with schizophrenia are only half as likely as women in the general population to receive mammograms, reports a meta-analysis published in Psychiatric Services in Advance.

“Lower screening rates could explain why women with schizophrenia and other serious mental illnesses are found to have more advanced breast cancer at time of diagnosis,” wrote Alison Hwong, M.D., Ph.D., and colleagues at the University of California, San Francisco. “Given the high prevalence of breast cancer and the promising prognosis of breast cancer if detected early, mammography screening is a key first step in improving diagnosis and treatment for people living with schizophrenia.”

Hwong and colleagues compiled data from 11 clinical studies that looked at mammography screening rates in women with schizophrenia or other psychotic disorders. The 11 studies were conducted in four countries with diverse health care systems (United States, Canada, England, and Denmark) and totaled more than 470,000 women; this included 25,447 women with a diagnosis of schizophrenia or other psychotic disorders.

“With time constraints, primary care providers and psychiatrists may not prioritize cancer screening for patients with serious mental illness,” Hwong and colleagues wrote. Physicians may focus on psychiatric and metabolic symptoms first, which “may lead to deferring routine preventive screening discussion for future visits, but the future discussion never occurs.”

The authors called for research on the inequity in breast cancer screening and the development of novel strategies to promote mammography screening of these women.

To read more on this topic, see the Psychiatric News article “UCSF Psychiatrists Bring OB-GYN Care to Patients With SMI.”

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Ketamine Infusion Combined With Mindfulness Program May Improve Cocaine Abstinence

Adding a single infusion of ketamine to a program of mindfulness-based relapse prevention (MBRP) may promote abstinence in patients who use cocaine, according to a study published in the November American Journal of Psychiatry.

In a five-week trial conducted by Elias Dakwar, M.D., of Columbia University Medical Center and colleagues, 55 patients who met the DSM-IV criteria for cocaine dependence were randomized to receive a 40-minute intravenous infusion of either ketamine or midazolam (a preoperative sedative). They received their infusions on the second day of a five-day hospitalization in a psychiatric research unit. During their hospitalization, they began MBRP, which includes cognitive-behavioral strategies that help patients become aware of feelings as they occur. The goal of MBRP is to enable patients to make choices that improve wellness rather than react automatically in ways that may be detrimental to their health and abstinence.

After their five-day hospitalization, patients returned to the hospital twice a week for four more weeks of MBRP sessions, physician visits, and drug testing. At the end of the five-week trial, researchers assessed the patients’ cravings to use cocaine. At six months, patients participated in a follow-up telephone interview.

During the last two weeks of the trial, 48.2% of patients in the ketamine group had remained abstinent from cocaine use, compared with only 10.7% in the midazolam group. At the end of five weeks, craving scores were 58.1% lower in the ketamine group than in the midazolam group. At the six-month follow-up interview, 12 patients in the ketamine group reported abstinence compared with none in the midazolam group.

“These sustained benefits, in some cases lasting several months, suggest the potential of ketamine for effecting long-term behavioral changes,” the researchers wrote. “Moreover, the integrated treatment framework was well tolerated, and MBRP appeared to enhance certain ketamine-related benefits, such as reductions in cocaine craving scores.”

The researchers noted several limitations to their study, namely that it was small, most of the patients belonged to the same race and sex (black males), and the patients tended not to have any other psychiatric conditions.

“While the selection of patients with no comorbidities might hamper the extension of our findings to a more psychiatrically complicated population, it is likely that cocaine-dependent individuals with depression or anxiety would respond even more robustly to ketamine given [prior] evidence supporting its psychiatric efficacy,” the researchers wrote.

For related information, see the American Journal of Psychiatry article “Searching for Treatments for Cocaine Use Disorder: The Quest Continues.”

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Genetic Data Can Improve Psychosis Prediction Tool

Incorporating genetic data into a clinical tool that predicts whether a person will develop schizophrenia can improve the accuracy of this tool, according to a study appearing in AJP in Advance.

Diana Perkins, M.D., M.P.H., of the University of North Carolina and colleagues assessed whether polygenic risk scores (PRS) could be used as part of a clinical assessment of schizophrenia risk. A PRS reflects how many individual genetic variants associated with schizophrenia a person has; the higher an individual’s PRS, the greater his or her genetic risk of developing schizophrenia. They looked at health data from 764 young adults (average age 18) considered at high risk for developing psychosis. These young adults were participants in the North American Prodrome Longitudinal Study (NAPLS 2). As part of the NAPLS 2, these individuals were prospectively followed for two years to identify traits that might help predict the onset of schizophrenia.

On the basis of NAPLS 2 data, the researchers developed a risk calculator that was able to predict which high-risk youth might develop schizophrenia with about 70% accuracy. The risk calculator included variables such as age, history of trauma and stressful life events, family history of psychotic disorders, the degree of disordered thoughts, and performance on tasks assessing verbal learning and information processing speed.

The NAPLS 2 participants also provided blood samples, and Perkins and colleagues used these to extract DNA and compute PRS scores for each participant. They found that PRS scores by themselves could predict schizophrenia onset with about 62% accuracy in Europeans and 57% accuracy in non-Europeans. When added to the risk calculator, however, PRS improved the accuracy of these tools.

“Use of a schizophrenia PRS in clinical practice hinges on improved accuracy, especially in persons of non-European ancestry, and [genetic studies] that include individuals from diverse populations are essential,” Perkins and colleagues wrote. “With further improvements and given the relatively low cost and wide availability of genotyping, potential applications of the genetic risk scores to individualized psychosis risk screening warrant further investigation,” they concluded.

For related information on predicting patients most likely to develop psychosis, see the Psychiatric News article “Imaging Advances Could Aid Prediction of Outcome in High-Risk Patients.”

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Concussions May Raise Risk of Suicide in High School Students

Having a concussion within the past year may raise the risk of suicidal ideation and behavior in high school students, according to a study in the Journal of Affective Disorders.

Dale S. Mantey, M.P.A., of the University of Texas School of Public Health and colleagues used data from more than 13,000 respondents in grades 9 through 12 who participated in the 2017 Youth Risk Behavior Surveillance Survey (YRBSS). The national YRBSS is conducted every two years by the Centers for Disease Control and Prevention to monitor health behaviors that contribute to the leading causes of death, disability, and social problems among youth and adults in the United States.

For this study, researchers analyzed the respondents’ answers to the question “During the past 12 months, how many times did you have a concussion from playing a sport or being physically active?” They then compared those answers with answers to questions designed to determine whether over the past 12 months the students had depressive symptoms, suicidal ideation, planned suicide attempts, attempted suicide, and/or were treated by a doctor or nurse for an injury, poisoning, or overdose following a suicide attempt.

Overall, 15% of the respondents reported a sports-related concussion in the previous 12 months. Compared with their peers who did not report concussions, these participants were 20% more likely to have experienced depressive symptoms, 25% more likely to have had suicidal ideation, and 60% more likely to have attempted suicide. They were also more than twice as likely to have been treated by a doctor or nurse for a suicide attempt. The risk of a suicide attempt and a suicide attempt treated by a doctor or nurse were more pronounced in boys than girls: Boys with a history of concussion were twice as likely to have a suicide attempt and more than three times as likely to have been treated by a doctor or nurse for a suicide attempt than boys with no history of concussion.

“Though further research is needed to explore the relationship observed in this study, [the] findings suggest a critical need for expanded education, awareness, monitoring, and treatment of sports-related concussions,” the researchers wrote. “[S]uicide awareness, education, and prevention efforts should incorporate history of sports-related concussions (or other traumatic brain injuries) as risk factors for interventional programs. Furthermore, organized physical activities (e.g., sports) should ensure proper monitoring of suicidal risk factors (e.g., changes in mood) following the diagnosis of concussion in youth participants.”

For related information, see the Psychiatric News article “New Analysis Suggests There Is No Such Thing as Harmless Head Contact in Football.”

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Anxiety in Older Adults With MDD on Venlafaxine Doesn’t Reduce Chance of Remission, Study Finds

The presence of comorbid anxiety symptoms does not appear to predict the likelihood that older patients with major depressive disorder (MDD) will respond to the antidepressant venlafaxine, according to a study in Depression & Anxiety.

“[R]emission of depression was just as likely in more and less anxious participants,” Yasmina M. Saade, M.D., of Washington University in St. Louis and colleagues wrote.

Previous studies show that older depressed adults with comorbid anxiety often have more severe depression symptoms and cognitive decline and are at greater risk of suicide compared with older depressed adults without anxiety. To examine whether comorbid anxiety influences response to treatment in older adults, Saade and colleagues analyzed data from the Incomplete Response in Late‐Life Depression: Getting to Remission (IRL‐GRey) study, a large prospective antidepressant trial.

For the first phase of the IRL-GRey study, 468 adults aged 60 years or older with MDD received open‐label treatment with venlafaxine extended release, a selective serotonin and norepinephrine reuptake inhibitor. The participants were started at a dose of 37.5 mg/day and titrated up to 300 mg/day if they did not go into remission. Those who were taking a previously prescribed low-dose benzodiazepine were permitted to continue its use. Before starting on venlafaxine, the researchers evaluated the participants using Montgomery-Åsberg Depression Rating Scale (MADRS), the Brief Symptom Inventory anxiety subscale (BSI‐anxiety), the 19‐item Scale for Suicide Ideation (SSI), the Anxiety Sensitivity Index (ASI), and the Penn State Worry Questionnaire (PSWQ). The participants were reassessed using the MADRS, BSI-anxiety, and SSI weekly or biweekly throughout the 12- to 14-week open-label phase.

Baseline anxiety scores did not predict the likelihood of the participants’ remission of depressive symptoms (defined as a MADRS score ≤10 at both of the final two consecutive visits) on venlafaxine, the authors wrote. Similarly, the baseline anxiety scores did not predict time to remission. Participants who expressed some suicidality at baseline, however, tended to have more severe symptoms of depression and anxiety.

“In older adults with MDD, comorbid anxiety symptoms are associated with symptom severity but do not affect antidepressant remission or time to remission,” Saade and colleagues wrote. “The presence of comorbid anxiety should prompt an intensive course of treatment, including frequent follow‐up visits and maximizing the antidepressant dosage before declaring nonresponse. We also speculate that the use of a dual‐reuptake inhibitor may be preferable in depression with comorbid anxiety symptoms.”

For related information, see the American Journal of Psychiatry article “Norepinephrine Transporter Gene Variants and Remission From Depression With Venlafaxine Treatment in Older Adults.”

Pfizer contributed venlafaxine extended-release capsules for this study.

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