First and Only Oral NDMA Receptor Antagonist for MDD Can Now Be Prescribed
| October 28, 2022 |
| FEATURED NEWS: First and Only Oral NDMA Receptor Antagonist for MDD Can Now Be Prescribed Extended-release dextromethorphan HBr-bupropion HCl (Auvelity™), the only oral N-methyl D-aspartate (NMDA) receptor antagonist approved for the treatment of major depressive disorder (MDD), is now available by prescription in the United States, maker Axsome Therapeutics Inc. announced. The drug is supplied in 105-mg tablets in 30-count bottles.On August 18th, 2022, the US Food and Drug Administration (FDA) approved dextromethorphan HBr-bupropion HCl extended-release tablets 45mg/105mg |
Psilocybin Comparable to Escitalopram in the Treatment of Depression
Four randomized, controlled clinical trials have established that psilocybin, the hallucinogenic compound in “magic mushrooms,” has anti-depressant effects. Recently, a phase 2 clinical trial compared the effects of psilocybin to a US Food and Drug Administration (FDA)–approved treatment for depression, the selective serotonin-reuptake inhibitor (SSRI) escitalopram. The study by Robin Carhart-Harris and colleagues was published in the New England Journal of Medicine in 2021.
The 59 participants in the 6-week study, which took place in the United Kingdom, had longstanding moderate-to-severe major depressive disorder. They were randomized to two groups. The psilocybin group received two separate doses of 25 mg of psilocybin 3 weeks apart, plus 6 weeks of daily placebo. The escitalopram group received two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram. (The small doses of psilocybin administered to the escitalopram group were assumed to have negligible psychiatric effects.) All participants were told they would receive psilocybin (though not the dose) in order to standardize their expectations.
In addition to the drug treatments, all participants also received psychological support, which consisted of monitoring immediately after the administration of the drugs (given the expectation that the 25mg dose of psilocybin would produce an “altered quality of conscious experience”), psychological debriefings, and an active listening session.
Psilocybin improved depression symptoms to a greater extent than escitalopram did. Among the participants, 70% of the psilocybin group responded to the treatment, compared with 48% of the escitalopram group. Remission occurred in 57% of the psilocybin group compared with 28% of the escitalopram group. These differences in the outcomes for the two groups were not statistically significant.
The FDA has designated psilocybin a “Breakthrough Therapy” for severe depression, which indicates that the therapy may be a substantial improvement over existing therapies for a serious condition. The designation is intended to speed up the drug development and review process.
The state of Oregon legalized psilocybin-assisted therapy in 2020.
Transcranial Direct Current Stimulation (tDCS) Induces Gray-Matter Increases in Depression
At the 2021 meeting of the Society of Biological Psychiatry (SOBP), researcher Mayank Jog and colleagues described a study of transcranial direct current stimulation (tDCS) in 59 patients with moderate depression. The patients received either tDCS sessions that delivered electrical current at 2mA for 20 minutes or a same-length sham stimulation delivered using a double-blind stimulator, for a total of 12 sessions over 12 consecutive working days. Jog and colleagues found that compared to the sham stimulation, tDCS induced increases in gray matter volume in the left dorsolateral prefrontal cortex (DLPFC) target area, with a statistically large effect size (Cohen’s d = 1.3). The researchers plan to follow up this study that found structural changes to the brain after tDCS with more research on the antidepressant effects of the treatment.
Good Outcomes Among Patients with Major Depressive Disorder Treated with Transcranial Magnetic Stimulation in a Large Study
At the 2021 meeting of the Society of Biological Psychiatry (SOBP), researcher Harold Sackeim and colleagues reported on data collected from patients in clinical treatment for major depression who received transcranial magnetic stimulation (TMS) at 103 practice sites. A total of 5,010 depressed patients were included in the intent-to-treat sample, and 3,814 completed the study, meaning that they either reached remission or were treated at least 20 times and went through a final assessment. “Response (58–83%) and remission (28–62%) rates were notably high across self-report and clinician-administered assessments,” and women had better outcomes than men. Sackeim and colleagues concluded, “Strong efficacy and the low side effect and medical risk profile suggest that TMS be evaluated as a first-line treatment for [major depressive disorder].”
Accelerated Intermittent Theta-Burst Stimulation (aiTBS) Quickly Improved Treatment-Resistant Depression
At the 2021 meeting of the Society of Biological Psychiatry (SOBP), researcher Nolan Williams and colleagues described a sham-controlled trial of accelerated intermittent theta-burst stimulation (aiTBS) in patients with treatment-resistant depression. Theta burst stimulation is a specific protocol for rTMS, or repeated transcranial magnetic stimulation, a non-invasive form of brain stimulation. Magnets placed on a patient’s head provide bursts of high-frequency stimulation to the brain.
Participants in the study received 50 sessions over 5 days of either aiTBS or a sham procedure. Among those who received the real aiTBS treatment, 85.7% saw an improvement in their treatment-resistant depression, compared to only 26.7% of those in the sham group. AiTBS produced a rapid antidepressant response, which Williams and colleagues suggest could be useful for the treatment of patients in emergency rooms or inpatient settings.
Transcranial Near-Infrared Light May Treat Brain Injury and Neurodegeneration
At the 2021 meeting of the Society of Biological Psychiatry, there was a symposium on treatment with near-infrared light chaired by researchers Paolo Cassano and Dan Iosifescu. The treatment is known as transcranial photobiomodulation (PBM) with near-infrared light. A device worn on the head delivers infrared light that penetrates the cerebral cortex and can modulate cortical excitability. It has a variety of effects including promoting neuroplasticity, improving oxygenation, and decreasing inflammation and oxidative stress.
A number of studies exploring the possibility that PBM could be used as a clinical treatment for conditions such as depression, brain injury, or dementia were presented at the symposium.
Researcher Lorelei Tucker discussed promising findings from an animal model in which rats with stroke or brain injuries showed improvement after being treated with PBM.
Cassano discussed studies aimed at refining which brain areas should be targeted with PBM and how much light should be delivered in order to improve depression. In double-blind, sham-controlled studies in people with major depression, targeting the dorsolateral prefrontal cortex with PBM improved their symptoms.
Researcher Benjamin Vakoc discussed a study of low-level light therapy (LLLT) using near-infrared light compared to a sham procedure in 68 people with moderate traumatic brain injury. The researchers used magnetic resonance imaging (MRI) to assess changes in white matter in the brain over time in people recovering from an acute brain injury. Patterns of changes in white matter were different for those who received LLLT compared to those who received the sham procedure.
Researcher Linda Chao described a very small study to determine whether PBM could improve symptoms of dementia. Four patients received typical dementia care while four others underwent home treatments with the commercially available Vielight Neuro Gamma device, which delivers PBM via both the scalp and an insert in the nose. After 12 weeks, the PBM group showed improvements in cognition and brain connectivity.
Editor’s Note: We will be watching the literature to follow advances in this promising novel method of neuromodulation.
Left Prefrontal Strokes Linked to Depression
In a 2021 article in the journal Stroke, researcher Julian Klingbeil and colleagues reported that left, but not right, ventrolateral prefrontal stroke lesions were associated with increased risk of depression at six months post-stroke.
The study included 270 participants who had their first-ever stroke. Six months following their strokes, 19.6% of the participants had depression. Those who scored higher on a scale of depression and anxiety symptoms in the first month after their stroke were more likely to have depression six months after the stroke.
The researchers identified a cluster of locations for stroke lesions, mostly within the left ventrolateral prefrontal cortex, that they linked to depression symptoms six months post-stroke. Klingbeil and colleagues hope that recognizing lesions in this region as risk factors for depression will help with early diagnosis of depression among people who recently had a stroke.
Editor’s Note: Antidepressants have been shown to improve post-stroke recovery of neurological functional (and depression) that is caused by the cutoff of blood supply during a stroke (ischemia). Patients and their family members should talk with their neurologist about treatment of ischemic strokes with antidepressants, especially when the lesions occur on the left side of the brain.
Increased Oxygen Improves Depression
At a recent scientific meeting, researcher R. Haim Belmaker reported that giving mildly to moderately depressed adults a nasal tube that delivers extra oxygen overnight for four weeks produced dramatic antidepressant effects. A total of 55 participants aged 18–65 years old were randomized to receive either normal room air (made up of about 21% oxygen), or hyperoxia (air containing about 35% oxygen). There was greater improvement on several different depression rating scales, including the Hamilton Depression Rating Scale, the Clinical Global Impression Scale, and the Sheehan Disability Scale, among those who received hyperoxia than among those who received normal air.
According to Belmaker, 69% of the patients who were treated with oxygen-enriched air improved on the CGI scale, compared to only 23% patients who were treated with room air. Limitations of the study were its small sample size and the lack of a clear biological mechanism for the effects of increased oxygen.
Childhood Physical Abuse Predicts Response to IV Ketamine
At a recent scientific meeting, researcher Alan Swann reported the results of a study of intravenous ketamine in people with treatment-resistant depression. The 385 participants, who received four infusions of IV ketamine at a dosage of 0.5 mg/kg, could be grouped into three based on their type of response to the treatment.
One group had moderate depression at baseline and showed little change. A second group with severe baseline depression also showed minimal improvement. A third group who also had severe baseline depression had a rapid and robust antidepressant response to the treatment. This group had high scores relating to physical abuse on the Childhood Trauma Questionnaire (CTQ), but did not differ on other clinical variables. Swann and colleagues concluded, “Our outcomes show that IV ketamine should be considered as a primary treatment option for adults presenting with severe, treatment resistant depression and a self-reported history of childhood physical abuse. IV ketamine may not be as effective for moderately depressed individuals irrespective of childhood maltreatment.”
Early Precursors of Mood Disorders in Young Children of Parents with Bipolar or Unipolar Disorder
At the 2020 meeting of the International Society for Bipolar Disorders, researcher Caroline Vandeleur presented findings from a 13-year study of children in Switzerland who have a parent with bipolar disorder or major depressive disorder. In contrast to findings from the US presented by Danella Hafeman, Vandeleur and colleagues found no evidence of psychopathology in 4 year-olds. They did find that in 7-year-olds, children of a parent with major depressive disorder were four times more likely to have a separation anxiety disorder. In an overall sample of 449 children with a mean age of 10 who were followed up for 13 years, major depression tended to be preceded by anxiety disorders. Participants who went on to be diagnosed with bipolar disorder had earlier symptoms of depression, subthreshold hypomania, conduct disorders, and drug abuse. These were especially common in those who had a parent with bipolar disorder.
Editor’s Note: These data indirectly confirm other observations in which children at high risk for mood disorders in the US showed earlier signs of psychopathology than those in other countries including the Netherlands and Canada.
