Valproate Can Cause Increases in Blood Ammonia

February 6, 2012 · Posted in Current Treatments · Comment 

red blood cellsResearcher C. Lewis reported in two posters presented at the Ninth International Conference on Bipolar Disorder (ICBD) in 2011 that in a study of patients treated with valproate, some increases in ammonia levels occurred. This condition, hyperamonaemia, was identified in 31 patients among those treated between 2005 and 2009 at the Cleveland Clinic in Cleveland, Ohio. High levels of ammonia are associated with a flapping tremor and, in some cases, encephalopathy with confusion, psychiatric symptoms, and motor incoordination.

The recommended management for hyperamonaemia is discontinuation of valproate and use of lactulose, a synthetic sugar that can lower ammonia levels. These approaches were not always used. Another option for patients who require valproate treatment is to supplement the drug with carnitine, which is available as a nutritional supplement. Lewis reported success in three such cases.

Editor’s Note: Patients on valproate presenting with a gross flapping tremor of the hands, confusion, or motor imbalance should be tested for hyperamonaemia and treated accordingly.


New Brain Stimulation Method Uses Ultrasound

February 3, 2012 · Posted in Potential Treatments · Comment 

brainAlexander Bystritsky of UCLA and colleagues at McLean Hospital and Harvard Medical School reported at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011 that low intensity focused ultrasound pulsation could eventually be used as a noninvasive intervention for diagnosing and treating brain disease.

In animal studies, the researchers used low intensity 100 Hz stimulation, which could produce a focused activation or inhibition of specific brain areas. Researchers were able to produce acute and long-term anticonvulsant effects in the animals, and when targeting the hypothalamus they could increase the animals’ heart rate and blood pressure.

Editors note:  These preliminary preclinical data raise the possibility that in the future this new mode of non-invasive and relatively precise brain stimulation may be used to treat neuropsychiatric disorders. Existing non-invasive brain stimulation methods include repeated transcranial magnetic stimulation (rTMS) and low level magnetic fields. Vagal nerve stimulation (VNS), which requires an implant in the chest, is more invasive. The most invasive and the most precisely targeted method of brain stimulation is deep brain stimulation (DBS). In this type of treatment electrodes are inserted in the brain of the patient.


Clinical Evidence May Explain the Mechanisms of Ketamine’s Rapid Acting Antidepressant Effects

February 1, 2012 · Posted in Current Treatments · Comment 

At the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011, C.G. Abdallah from SUNY Downstate Medical Center reported on a study of intravenous ketamine for treatment-resistant depression. Twelve medication-free participants aged 18-65 received 0.5mg/kg ketamine over 40 minutes. There was a rapid-onset antidepressant effect, as there has been in other studies of unipolar and bipolar depressed patients. In a subgroup of 4 patients examined with magnetic resonance spectroscopy (MRS), there were rapid increases in brain GABA followed shortly thereafter by increases in brain glutamate concentrations.

IV ketamine

Editor’s note: The rapid increases in GABA and glutamate that occur after the administration of intravenous ketamine may help account for its therapeutic effects.  Other studies have shown that brain GABA is low in depressed patients, so the rapid increase in GABA with ketamine administration could partly explain the antidepressant effects of the drug. The role of the glutamate increases remains to be further explored.

Neli and associates from Yale had reported that in animals, ketamine was able to rapidly alter synapse structure and function. In an animal model of depression, rodents are exposed to chronic and unpredictable stress and develop depressive-like behavior. The mature, mushroom-shaped spines on their dendrites (the parts of neurons that receive synapses and determine the neuron’s excitability) also lose their shape, becoming straighter and spikier like immature spines. Intravenous ketamine not only improves the animals’ behavior, but also increases the number of mushroom-shaped spines within a matter of hours, rapidly improving synaptic function. This effect of ketamine was dependent on a novel intracellular pathway involving the enzyme mTOR, which if blocked prevented the re-emergence of the mature spines.

In the brains of depressed humans studied at autopsy there is reduced neural volume in the frontal cortex, which could possibly be related to dendritic atrophy and associated changes in spine shape as it appears to be in rodents. The animal data suggest the remarkable possibility that intravenous ketamine’s rapid onset of antidepressant effects could also be associated with rapid improvement in the microanatomy of the brain.

The data on ketamine’s effects in animals and the new clinical data showing that GABA and glutamate increases occurred rapidly in depressed patients administered ketamine provide further insight into the potential mechanisms of ketamine’s effect.



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