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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. “
Accelerated iTBS Treats Bipolar Depression in 5 Days
Yvette Sheline, of the University of Pennsylvania Perelman School of Medicine, reported that 10 intermittent theta burst stimulations (iTBS) per day for 5 days yielded dramatic improvement in patients with bipolar depression – both immediately after the iTBS as well as at 4 weeks.
Resting-state functional MRI was used to individually target the left dorsolateral prefrontal cortex (dlPFC), the region most anticorrelated with the subgenual anterior cingulate cortex (sgACC).
THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA IS BECOMING CLEARER
David Lewis of U. Pittsburgh showed that the glutamate neurons in the prefrontal cortex of patients with schizophrenia are deficient in the gamma (30-50 Hz) oscillations that are responsible for normal working memory.
Not only are dendrites and spines deficient in these neurons in layer 3 of the cortex, but there is a deficit in parvalbumin GABA inhibitory neurons. The GABA enzyme GAD 67 is lower, producing less inhibition. The frontal neurons are hypoactive and there is less BDNF and oxidative phosphorylation present, yielding decreases in mitochondrial function.
A DESEASE MODIFYING DRUG, LECANEMAB, IS NOW AVAILABLE FOR ALZHEIMER’S DISEASE
C. H. van Dyck from Yale talked about the diagnosis and treatment of Alzheimer’s dementia.
New brain imaging data have revealed that Lecanemab cannot only highly significantly delay memory decline but also improve PET measures of amyloid and tau. Early illness in those with mild cognitive impairment (MCI) can be detected; results indicate better effects of treatment Lecanemab in those with earlier and milder illness compared to those with more severe illness.
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. “
Influence of Childhood Maltreatment on Morphometry and Brain Network Architecture in Bipolar Disorder
Martin Teicher of McLean Hospital, Harvard Medical School, reported on the influence of childhood maltreatment on morphometry and brain network architecture in Bipolar Disorder.
“Childhood maltreatment (MAL) is common in individuals with bipolar disorder (BP) and is associated with earlier onset, more severe course, and more comorbidities.” They found that reduced hippocampal volume and white matter alterations were present in those with a history of childhood maltreatment. They concluded that “MAL may act as a sensitizer promoting the emergence of bipolar symptoms in individuals with less severe network abnormalities” than in BP patients with no MAL.
Lithium Is Unparalleled in It Range of Efficacy in the Mood Disorders
Most clinicians are aware of lithium’s superiority over other mood stabilizers in bipolar illness prophylaxis. New data suggests this might also apply to the atypical antipsychotics.
Lithium is also not only an effective adjunct to antidepressant in unipolar depression, but has some of the best data for its use in long term prevention. In bipolar disorder prophylaxis it is particularly effective in those with classical presentations of discrete episodes of euphoric mania, treatment early in the course of illness, lack of anxiety and substance comorbidities, and a positive history of mood disorder in first-degree relatives.
New data indicates that it is also effective in childhood onset mania, and open long term follow ups indicate that it is more effective than other mood stabilizers or atypical antipsychotics.
Despite the compelling effectiveness data and many ancillary benefits, survey data indicates very low levels of current lithium use in both adult and child bipolar disorder. The conventional view, shared by most patients and many clinicians, underestimates its range of effectiveness and potential benefits while overestimating it is side effects. A more balanced view is needed as neglect of wider use of lithium is detrimental to the long term outcome of immense numbers of patients.
Robert M. Post, MD
Adolescent Cannabis Use is Associated with Regional Decreases in Cortical Volume and Greater Decreases in Males than Females
Mona Darvishi of The Ohio State University reported that adolescent cannabis use is associated with regional decreases in cortical volume in 10 of 42 brain regions.
In two of these regions, the superior frontal gyrus and the caudal middle frontal gyrus, there was a significant drug-by-sex interaction with males having significantly greater volume reductions. They conclude “Our findings, combined with existing research on marijuana users, suggest that marijuana use is associated with brain structure, with potential sex-specific effects”
“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.
Lithium vs Anticonvulsants Lamotrigine and Valproate on 10 year physical illness
In a study by lars Kessing in (European Neeuropsychopharmcology Volume 84, July 2024, Pages 48-56) on 169,285 patients taking either lithium or the anticonvulsants Lamotrigine (LTG) or Valproate (VPA) for at least 10 years, there was no difference in physical outcome in any physical outcome, including chronic kidney disease, except for a higher incidence of myxedema.
Other diagnoses that showed no difference included stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, osteoporosis, dementia, Parkinson’s disease, chronic kidney disease and cancer (including subtypes).
Editors Note: This data further supports an already robust existing literature that lithium is not more likely to cause chronic kidney disease or other physical illnesses than other anticonvulsant treatments with the exception of hypothyroidism. Patient should be made aware of these and the related long term data that lithium is no more likely to cause chronic kidney disease than other treatments and, in some cases, these other treatments cause more end-stage renal failure. The misapprehension that lithium is more toxic than other treatments has led to the vast underutilization of this treatment. Lithium is the treatment of choice for bipolar illness and should be used earlier, more often, and more persistently. When this is done illness outcomes and patient’s well being are significantly improved.
