Naltrexone Augmented with Prazosin Is Highly Effective for Alcohol Use Disorder
Murray Raskind, of the VA Northwest Mental Illness Research, Education, and Clinical Center, conducted a translational proof-of-concept randomized controlled trial (RCT) of the mu-opioid receptor antagonist, naltrexone, augmented with the alpha-1 adrenergic receptor antagonist, prazosin, for alcohol use disorder in veterans.
“Prazosin was titrated over 2 weeks to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS. Naltrexone was administered at 50 mg QD…. In the NAL-PRAZ condition, % reductions from baseline for all three primary outcome measures exceeded 50% and were at least twice as large as % reductions in the NAL-PLAC condition.
They concluded: “These results suggest that prazosin augmentation of naltrexone enhances naltrexone benefit for AUD. They are consistent with preclinical studies in rodent models of AUD and strengthen rationale for an adequately powered definitive RCT. “
Intramuscular versus Intravenous Ketamine for the Management of Treatment-Resistant Depression and Suicidal Ideation
Cristina Albott of the University of Minnesota Medical School reported relatively similar efficacy of intramuscular versus intravenous ketamine for the management of treatment-resistant depression and suicidal ideation in outpatient settings.
“Intramuscular (IM) delivery represents an underexplored and promising route of administration given its high bioavailability and low cost….Sixty-six patients underwent a series of 7 to 9 IV (n=35) or IM (n=31) administrations of 0.5mg/kg ketamine during a 21-28 day period. Both IV and IM showed similar magnitudes of improvement in depression, but surprisingly only the IM route was associated in a significant improvement in suicidal ideation in a within subjects change.”
“No adverse events occurred throughout the treatment series for either administration route…. This clinical case series provides preliminary support for the effectiveness and safety of IM compared to IV ketamine in TRD. “
“Epigenetic Changes After Trauma May Be Adaptive, Contribute to Resilience”
Originally From Psychiatric News Update
In recent years, research throughout the scientific and medical community has suggested a link between trauma and epigenetic changes, chemical modifications that affect gene activity without actually changing the gene’s DNA sequence. The assumption has been that epigenetic changes in the context of trauma are inherently bad, a form of damage that gets passed from generation to generation. But according to Rachel Yehuda, Ph.D., Endowed Professor of Psychiatry and Neuroscience of Trauma at the Icahn School of Medicine at Mount Sinai, these changes may also be adaptations that promote resilience.
“Sometimes the biological changes in response to trauma or intergenerational trauma are there to help deal with the problem of trauma, not compound its effects,” Yehuda said. “The survival advantage of this form of intergenerational transmission depends in large part on the environment encountered by the offspring themselves.”
Yehuda described this phenomenon as a paradox.
“Parental or ancestral trauma may heighten vulnerability to mental health challenges, but epigenetic adaptations may simultaneously facilitate coping mechanisms,” she said. “Trauma increases susceptibility for psychological distress, but also produces adaptations that help us cope with them.”
Yehuda described research she and her colleagues have conducted to tease out how trauma in parents can affect offspring in the context of the biology of posttraumatic stress disorder (PTSD) in Holocaust survivors and their children. As the research unfolded, Yehuda and colleagues found that survivors’ adult children were more likely to have mood disorders, anxiety disorders, and PTSD than Jewish people whose parents did not directly experience the Holocaust. This was especially true of children of Holocaust survivors who had PTSD. The researchers also found that many children of Holocaust survivors had low levels of the stress hormone cortisol, particularly if their parents had PTSD.
Yehuda and colleagues then conducted a series of studies that looked at the role of glucocorticoid receptors — the proteins to which cortisol must bind to exert its effects — and found evidence that these receptors were more sensitive in people with PTSD.
“In practical terms this means that even though someone with PTSD might have lower circulating levels of cortisol in their blood, their cells might react more strongly to the cortisol that is present,” Yehuda said.
Yehuda said that epigenetics provided further insight on the relationship between hypersensitive glucocorticoid receptors, cortisol, and PTSD. She explained the potential role of methylation, which is a chemical reaction in the body in which a small molecule called a methyl group gets added to DNA or DNA-associated proteins.
“Increased methylation generally impedes RNA transcription, whereas less methylation enhances gene expression,” Yehuda said.
In 2015, Yehuda and colleagues conducted a study involving combat veterans who had PTSD and found lower methylation on an important region on the participants’ glucocorticoid receptor gene. The changes were associated with cortisol and glucocorticoid receptor sensitivity in the study participants, suggesting a potential epigenetic explanation for the association between the trauma of combat and PTSD.
Yehuda said that stress-related epigenetic changes may be reversible. For example, one of the studies conducted by her team revealed that combat veterans with PTSD who benefited from cognitive-behavioral psychotherapy showed treatment-induced changes in the methylation of a gene that regulates glucocorticoid receptor sensitivity. Yehuda said that this finding confirmed that healing is also reflected in epigenetic change.
“That we can transform to meet environmental challenge is a superpower. That is resilience,” Yehuda said.” ?
Yehuda then went on to describe the striking and lasting effects of the psychedelics psilocybin and MDMA in trauma and in helping patients confront their fears in a positive and hopeful fashion. These agents which are given with intensive psychotherapeutic support are not yet FDA approved, but preliminary data suggest that they can have dramatic therapeutic effects in trauma and depression. They can help patients change their attitudes to themselves and the world.
GLP-1s Might Decrease the Incidence of Depression and Anxiety
Lisa O’Mary of WebMD wrote: “People taking a popular type of drug for weight loss or to manage diabetes have a lower likelihood of being newly diagnosed with depression or anxiety, according to an analysis of millions of people’s health records.
The findings were published this week by researchers from the electronic health record company Epic. Researchers looked for new diagnoses of depression or anxiety among people who started taking drugs from a class called GLP-1 agonists that can help manage blood sugar or treat obesity by mimicking hormone levels in the body that can affect appetite and blood sugar. Many people who take the drugs experience significant weight loss.
The researchers found that people with diabetes who started taking most versions of GLP-1 agonists were between 11% and 65% less likely to be newly diagnosed with depression than people with diabetes who didn’t take one of the drugs. The greatest reduction in likelihood of a new depression diagnosis was observed among people taking tirzepatide, which is sold under the brand names Mounjaro and Zepbound.”
Vitamin B6 Plus Lithium Helps Ease Mania Symptoms in Patients With Bipolar Disorder
Daily vitamin B6 (40mg/day), but not B1 (100mg/day), as an adjunctive therapy to lithium was associated with the improvement of mood symptoms in hospitalized patients with bipolar disorder experiencing a manic episode, according to a study published in the Journal of Affective Disorders 2024; 345 103-111: Zandifar et al.
Changes in brain structure in remitted bipolar patients
Macoveanu et al reported in the Journal of Affective Disorders (2023) that compared to controls that remitted bipolar patients had “a decline in total white matter volume over time and they had a larger amygdala volume, both at baseline and at follow-up time. Patients further showed lower cognitive performance at both times of investigation with no significant change over time….Cognitive impairment and amygdala enlargement may represent stable markers of BD early in the course of illness, whereas subtle white matter decline may result from illness progression.”
Lumateperone for Bipolar I or Bipolar II Depression: Few Extrapyramidal and Motor Symptoms
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Tobie Escher of Intra-Cellular Therapies, Inc. reported on the excellent tolerability of lumateperone (42mg/day) in a “short-term population comprised 746 patients in pooled monotherapy trials (placebo, 374; lumateperone, 372) and 352 patients in the adjunctive study (adjunctive placebo, 175; adjunctive lumateperone, 177). Reported EPS [extrapyramidal symptom]-related TEAEs [treatment-emergent adverse events] were 1 patient (0.3%) with mild dyskinesia (lumateperone monotherapy), 1 (0.6%) with mild akathisia (adjunctive lumateperone), and 1 (0.3%) with severe akathisia (placebo monotherapy).”
Beneficial Cognitive Effects of Transcranial Infrared Laser Stimulation (TILS) in Bipolar Disorder
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Michael Gentry of The University of Texas At Austin reported on 30 individuals with remitted bipolar disorder (type I or type II). TILS was administered weekly to each participant over six consecutive weeks (1064 nm wavelength; bilaterally to the frontal poles; 10 minutes per weekly session)….. after six weeks of TILS administration, participants demonstrated decreased impulsivity on the Stop Signal Task and improved abilities to select correct responses on the Multitasking Test.
Intranasal Oxytocin for Internalizing Symptoms in Youth With Disruptive Behavior Disorders
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
E. Kendall reported that “Fifty-two youths with diagnoses of DBD [Disruptive Behavior Disorders] participated in [this] study, and twenty-five completed three weeks of treatment of intranasal OXT [oxytocin] and twenty-seven placebo (PBO)…. Youth who received OXT showed a significantly greater reduction of depression [ p=0.012] and anxiety [p=0.031] compared to the [placebo] group.”
They concluded that “Intranasal OXT can show efficacy in reducing internalizing symptoms in youth with DBD. This was accompanied by neural level changes implicated in emotion regulation (mPFC [medial prefrontal cortex] and ACC [anterior cingulate cortex]).”
Lumateperone Normalizes Pathological Levels of Acute Inflammation and Stimulates Important Pathways Involved in Mood Regulation
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
Sophie Dutheil of Intra-Cellular Therapies, Inc. reported that “In male and female C57BL/6 mice subjected to an acute stress or immune challenge, lumateperone reduced elevated levels of key proinflammatory cytokines. A number of key genes and pathways associated with the maintenance of tissue integrity and blood-brain barrier function were also altered by a single dose of lumateperone. Furthermore, we found that lumateperone administration conferred anxiolytic- and antianhedonic-like properties while enhancing the mTORC1 signaling pathway in the PFC.”
