Low Levels of Acetyl-L-Carnitine Associated with Insulin Resistance in Traumatized Children

January 22, 2019 · Posted in Risk Factors · Comment 

childhood traumaResearcher Carla Nasca and colleagues from the Rockefeller University reported at a late-2018 scientific meeting that depressed patients with a history of childhood adversity had low levels of the amino acid acetyl-L-carnitine and also exhibited insulin resistance. This is noteworthy because in a series of small studies, acetyl-L-carnitine supplements have had antidepressant effects. In laboratory animals, acetyl-L-carnitine also sensitizes insulin receptors. This suggests the possibility that the supplements could provide a two-for-one benefit in depressed patients with a history of adversity in childhood.

Scientific Mechanisms of Rapid-Acting Antidepressants

January 10, 2019 · Posted in Neurochemistry · Comment 
pyramidal cell

A pyramidal cell (Photo by Bob Jacobs, Laboratory of Quantitative Neuromorphology Department of Psychology Colorado College)

At a recent symposium, researcher Francis McMahon provided electrophysiological evidence that several different types of rapid-acting antidepressants—low-dose ketamine, scopolamine, and rapastinel (a partial agonist of the neurotransmitter NMDA)—act by decreasing the inhibitory effects of GABAergic interneurons on excitatory neurons called pyramidal cells, thus increasing synaptic firing.

Researcher Ronald Duman further dissected these effects, showing that ketamine and its active metabolite norketamine reduce the steady firing rate of GABA interneurons by blocking NMDA receptors, while the partial agonist rapastinel acts on the glutamate neurons directly, and both increase the effects of a type of glutamate receptors known as AMPA. These effects were demonstrated using a virus to selectively knock out GluN2B glutamate receptor subunits in either GABA interneurons or glutamate neurons.

Increasing AMPA activity increases synapse number and function and also increases network connectivity, which can reverse the effects of stress. Duman and colleagues further showed that when light is used to modulate pyramidal cells (a process called optogenetic stimulation) in the medial prefrontal cortex, different effects could be produced. Stimulating medial prefrontal cortex cells that contained dopamine D1 receptors, but not D2 receptors, produced rapid and sustained antidepressant effects. Conversely, inhibiting these neurons blocked the antidepressant effects of ketamine. Stimulating the terminals of these D1-containing neurons in the basolateral nucleus of the amygdala was sufficient to reproduce the antidepressant effects. These data suggest that stimulation of glutamate D1 pyramidal neurons from the medial prefrontal cortex to the basolateral nucleus of the amygdala is both necessary and sufficient to produce the antidepressant effects seen with ketamine treatment.

Researcher Hailan Hu reported that NMDA glutamate receptors drive the burst firing of lateral habenula (LHb) neurons, which make up the depressogenic or “anti-reward center” of the brain and appear to mediate anhedonic behavior (loss of interest or enjoyment) in animal models of depression. Ketamine blocks the burst firing of the LHb neurons, which disinhibits monoamine reward centers, enabling ketamine’s rapid-onset antidepressant effects. This may occur because inhibitory metabotropic glutamate receptors (mGluR-2) are activated, decreasing the release of glutamate.

MGluR-2 may also help explain the antidepressant effects of acetyl-L-carnitine supplements. L-carnitine is an amino acid that is low in the blood of depressed patients. The supplement acetyl-L-carnitine (ACL) activates the DNA promoter for mGluR-2, increasing its production and thus decreasing excess glutamate release. The acetyl group of the ACL binds to the DNA promoter for mGluR-2, thus this process seems to be epigenetic. Epigenetic mechanisms affect the structure of DNA and can be passed on to offspring even though they are not encoded in the DNA’s genetic sequence.

Nutritional Supplement ALC Improves Depression

March 26, 2018 · Posted in Potential Treatments · Comment 

vitamin

A meta-analysis of 12 studies suggests that the nutrient acetyl-l-carnitine (ALC), when taken as a nutritional supplement, has antidepressant effects. The meta-analysis by researcher Nicola Veronese and colleagues appeared in the journal Psychosomatic Medicine in 2017. Veronese and colleagues found that in nine randomized controlled trials, ALC reduced depressive symptoms significantly compared to placebo. In three randomized controlled trials that compared ALC with established antidepressants, ALC showed similar effectiveness at reducing depressive symptoms while producing 79% fewer side effects. Doses of ALC ranged from 1 to 4 grams per day, and higher doses led to greater improvement.

In the comparisons with antidepressants, the other treatments included fluoxetine (Prozac), duloxetine (Cymbalta), and amisulpride (which is not approved by the US Food and Drug Administration).

Low ALC has been linked to depression. According to Veronese and colleagues, ALC deficiency can dysregulate the transport of fatty acids across the inner membrane of mitochondria. The researchers suggest several ways that ALC might contribute to an improvement in depression. One is that is seems to promote neuroplasticity in cerebral regions implicated in depression, such as the hippocampus. It could also work by increasing brain-derived neurotrophic factor (BDNF), which protects neurons and is important for learning and memory. ALC decreases release of the neurotransmitter glutamate by increasing the production of the inhibitory metabotrophic glutamate receptor (mGluR-2) on presynaptic glutamate neurons . Another way ALC might work is by normalizing lipid metabolism. Or it could modulate neurotransmitters, increasing serotonin and dopamine and protecting against stress.

In the meta-analysis, ALC produced more improvement in older patients than in younger ones. The researchers stressed the need for better treatments for older people, which may experience falls, cardiovascular disease, or increased mortality from antidepressants.

ALC also seems to improve pain syndromes, making it a good option for patients with both depression and pain symptoms.

Veronese and colleagues cited another meta-analysis that found that taking ALC in addition to an antidepressant led to lower rates of adverse events than the antidepressants alone, which helped patients adhere to their drug regimen.

Supplement Acetyl-L-Carnitine May Treat Stress and Depression

April 7, 2017 · Posted in Potential Treatments · Comment 

stressed woman

N-acetylcysteine (NAC), an antioxidant sold in health food stores, has several beneficial effects on brain and behavior. It improves depression and can reduce cravings for cocaine, alcohol, marijuana, and nicotine, and can also help control habit-driven behaviors such as gambling, compulsive hair-pulling, and symptoms of obsessive-compulsive disorder (OCD).

New research, particularly by researcher Nascaa and colleagues in 2014 and 2016, has identified a related compound, acetyl-l-carnitine (ALC), as an anti-stressor and antidepressant in animals, and researchers have begun to explore its use in people. ALC has been found to improve mitochondrial function and improve recovery from peripheral nerve damage. ALC also inhibits the release of glutamate, which can prevent depressive behaviors following stress.

A 2004 study by P. Ruggenenti and colleagues in the journal Hypertension found that in people, 1 gm of ALC taken twice daily safely improved arterial hypertension, insulin resistance, impaired glucose tolerance, and low levels of adiponectin in the blood (a risk factor for diabetes) in subjects at increased cardiovascular risk.

In a 2014 article in the Journal of Psychiatric Research, researcher S.M. Wang and colleagues reviewed evidence that ALC improves mild depression. Two randomized clinical trials indicated that ALC was more effective than placebo for mild depression. Two other randomized clinical trials showed that ALC was as effective as the antidepressants fluoxetine and amisulpride for mild depression. The supplement was as tolerable as placebo and better tolerated than fluoxetine and amisulpride. Wang and colleagues suggested that more clinical trials are needed to confirm that ALC is effective in depression.

Editor’s Note: If further clinical trials confirm the antidepressant effects of ALC, it could represent a new way to treat chronic stress and depression and regulate insulin. Together these effects could reduce the cardiovascular risks that accompany depression.

Acetly-l-carnitine May Be Effective in Treatment-Resistant Depression

June 12, 2014 · Posted in Potential Treatments · Comment 

acetyl-l-carnitine pillsNot all patients with unipolar depression respond to the currently available antidepressants. Acetyl-l-carnitine is a compound that enhances mitochondrial function and neuroplasticity and is effective in the treatment of peripheral neuropathy (damage to the peripheral nerves, which sometimes occurs in chemotherapy or diabetes). It is now being investigated as an antidepressant for patients who have not responded to typical antidepressants.

According to a review of the treatment by S.M. Wang et al. published in the Journal of Psychiatric Research in 2014, acetyl-l-carnitine treated depression better than placebo did in four randomized clinical studies. It was better than placebo and equally as effective as the antidepressant fluoxetine and the atypical antipsychotic amisulpride in various studies of dysthymic disorder. It also improved depressive symptoms in people with fibromyalgia and minimal hepatic encephalopathy (liver damage). The usual dose of acetyl-l-carnitine is 1 to 2 grams/day.

Editor’s Note: The role acetyl-l-carnitine will play in treating people with treatment-resistant unipolar or bipolar depression remains to be better clarified.