American Journal of Psychiatry

Ketamine Spray Effective for Suicidality, but Abuse Concerns Linger

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Intranasal esketamine, when added to standard antidepressant therapy, rapidly reduces symptoms of major depression and suicidality in patients at imminent risk for suicide, but experts are concerned about its potential for abuse.

“The results of this proof-of-concept study reinforce the potential of esketamine as an acute treatment for patients with major depressive disorder and suicidal ideation, a condition for which there is an urgent public health need and currently no approved treatment,” lead investigator Carla Canuso, MD, from Janssen Research and Development, LLC, which funded the study, told Medscape Medical News.

The study was published online April 16 in the American Journal of Psychiatry.

In an accompanying editorial, members of the editorial board of the journal, led by Robert Freedman, MD, of the University of Colorado School of Medicine in Aurora, note that “if positive, longer-duration results emerge for intranasal esketamine, it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies.”

However, “a framework to ensure the safe use of the drug will be critical, as the potential for abuse and diversion are real,” they write.

The study involved 66 adults aged 19 to 64 years with major depressive disorder who presented to an emergency department or inpatient psychiatric unit and were assessed as being at imminent risk for suicide.

All participants were severely depressed at enrollment, as evidenced by a high total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (mean score, 38.6). They were assessed as having current active suicide ideation with intent to act on those thoughts. Forty-four (66.7%) participants reported having thoughts about suicide that were “severe,” and 36 (54.5%) reported having such thoughts “very often.” Half of the participants required suicide precautions in addition to hospitalization.

Participants were randomly allocated to receive intranasal esketamine 84 mg (35 patients) or placebo (31 patients) twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment.

The primary efficacy outcome was change in MADRS total score from baseline to 4 hours after initial dose. The MADRS score decreased (indicating improvement of symptoms) from baseline to 4 hours after the first dose in both the esketamine group (mean, -13.4) and the placebo group (mean, -9.1). There was significantly greater improvement in the esketamine group (least-square mean difference, -5.3; effect size, 0.61).

A statistically significant difference in the MADRS total score favoring esketamine over placebo was also seen at 24 hours (least-square mean difference, -7.2; effect size, 0.65), but not at day 25 (least-square mean difference, -4.5; effect size, 0.35).

Intranasal esketamine also showed a rapid and statistically significant effect on suicidal ideation, as measured by the MADRS suicidal thoughts item at 4 hours after initial dosing (effect size, 0.67), but not at 24 hours (effect size, 0.35) or at day 25 (effect size, 0.29).

Analysis of clinician global judgment of suicide risk rating using a ranked analysis of change from baseline showed numerically greater, but not statistically significant, decreases in ratings in the esketamine group compared with the placebo group at 4 hours (effect size, 0.31) and 24 hours after the first dose (effect size, 0.56).

In a post hoc analysis, a greater number of participants in the esketamine group compared with the placebo group achieved resolution of suicide risk (clinician global judgment of suicide risk scores of 0 – 1) at 4 hours (21.2% and 9.7%, respectively) and 24 hours after the first dose (40.0% and 6.5%, respectively). This suggests that esketamine “may be an important treatment to bridge the efficacy gap created by the delayed onset of action of standard antidepressants,” write the investigators.

The acute effects of intranasal esketamine seen in this study are similar to those achieved with intravenous ketamine.

Intranasal esketamine was generally well tolerated, the researchers report. Common adverse events were nausea, dizziness, dissociation, unpleasant taste, and headache.

Janssen is developing esketamine nasal spray for both treatment-resistant depression and major depressive disorder with imminent risk for suicide. “Esketamine nasal spray is currently being evaluated in two global phase 3 clinical studies for patients with major depressive disorder who are at imminent risk for suicide. There is also a phase 2 clinical study for adolescents with major depressive disorder who are at imminent risk for suicide,” Canuso told Medscape Medical News.

Drug-Seeking Already an Issue

In their editorial, Freedman and colleagues note that ketamine “drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. Some patients use the intravenous formulation intranasally repeatedly without supervision,” they point out. In addition, diversion of ketamine is occurring already.

“Nonetheless, as in the case of oxycodone, the onus remains on individual physicians to assess appropriate use and to avoid creating dependence and abuse,” they write.

Last year, as reported by Medscape Medical News, the American Psychiatric Association issued a consensus statement on ketamine for mood disorders. “Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder,” the statement reads.

Although physicians have the responsibility to provide a suicidal patient with the “fullest range” of effective interventions, “the protection of the public’s health is part of our responsibility as well, and as physicians, we are responsible for preventing new drug epidemics,” write Freedman and colleagues.

Janssen’s Canuso is confident that a framework for the safe use of esketamine can be developed. If approved, “several measures will be in place to help ensure the safe and appropriate use of esketamine,” she told Medscape Medical News.

Esketamine nasal spray would be administered under the observation of a healthcare professional in a medical setting. It will not be accessed by patients at their pharmacy, Canuso said.

“Esketamine nasal spray will be delivered through a metered, single-use, disposable nasal spray device that does not require priming, preventing multiuse and leaving minimal remaining drug in the device container after administration, minimizing potential for abuse,” she noted.

“We have generated comprehensive long-term safety data and will be discussing our safety profile and any mitigation plans with regulatory authorities in the coming months,” said Canuso.

Prolonged, Disabling Fatigue in Teens Common, Undertreated.

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Extreme, persistent fatigue in US adolescents is common, highly disabling, and often coexists with mood disorders, new research shows.

A survey conducted by investigators from the National Institute of Mental Health showed that prolonged fatigue, defined as lasting 3 months or longer, was reported in 3% of teens aged 13 to 18 years, and more than half of these youth reported severe or very severe difficulties in school, family, or social situations.

Among teens with prolonged fatigue, 1.4% had prolonged fatigue alone, and 1.6% had prolonged fatigue with comorbid depression or anxiety.

“Many parents complain their adolescents are ‘lazy’ because they tend to sleep late on weekends and do not seem to have much energy. Our data suggest that fatigue may be an indicator of either physical or mental disorders that should be followed up by their physician,” Kathleen Merikangas, PhD, from the National Institute of Mental Health, told Medscape Medical News.

The study is published in the May issue of the American Journal of Psychiatry.

The investigators studied the prevalence and correlates of prolonged fatigue in a representative sample of 10,123 US adolescents aged 13 to 18 years. They defined prolonged fatigue as extreme fatigue with at least 1 associated symptom, including pain, dizziness, headache, sleep disturbance, inability to relax, and irritability, that does not resolve by rest or relaxation and lasts at least 3 months.

Dr. Merikangas said what she found most interesting was “the extent to which persistent fatigue alone, without comorbid anxiety or depression, was associated with disability in adolescents from the general population.”

Nearly 60% of the adolescents with prolonged fatigue only had severe or very severe disability, and their rates of poor physical and mental health were on par with those of adolescents with mood or anxiety disorders, the investigators say.

Adolescents with prolonged fatigue plus a mood or anxiety disorder had significantly greater disability, poorer mental health, and more health service use than those with either condition alone.

“Extreme fatigue that continues even after rest and interferes with adolescents’ ability to participate academically, socially, or at home is a pathological condition, yet it’s not being recognized and treated,” Dr. Merikangas commented in a statement. “Also, teens with a depressive or anxiety disorder plus persistent fatigue appear to be sicker than those without fatigue.”

“Fatigue should be routinely assessed by healthcare providers. Among youth with mood or anxiety disorders, fatigue may be an important indicator of negative health behaviors (eg, smoking, drug use) and disability,” she said.

In an accompanying editorial, Gijs Bleijenberg, PhD, and Hans Knoop, PhD, of Radboud University Nijmegan Medical Centre, the Netherlands, write that the prevalence of persistent fatigue without anxiety or depression was “surprisingly high.”

Perhaps of even greater concern was that 60% of this group had disabling fatigue, yet most did not seek medical help.

They note that is not unusual for adolescents to engage in extreme behavior and exhaust themselves. However, fatigue that does not resolve when teens modify their behavior has significant health implications for social, emotional, and intellectual development and warrants medical attention.

Source: medscape.com

 

Implications of New Autism Diagnosis in DSM-5.

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Most children with an existing diagnosis of pervasive developmental disorder (PDD) will still qualify for an autism diagnosis under the proposed fifth edition of the Diagnostic and Statistical Manual of Mental Disorders — contrary to earlier concerns that many children would be excluded and therefore lose access to social services — according to an American Journal of Psychiatry study.

Researchers analyzed parental behavior reports for three groups of children, comprising nearly 4500 with PDD diagnoses and 700 with non-PDD diagnoses under DSM-IV. The DSM-5 criteria correctly identified 91% of children with PDD. When using parental report or clinical observation, the sensitivity increased to roughly 99%.

The authors write: “These results … provide evidence that the proposed criteria would likely be able to correctly classify a phenotypically wide range of children” with autism.

DSM-5 is expected to take effect in May 2013, the New York Times reports.

Source: American Journal of Psychiatry