Oxidative stress has been implicated in a wide range of illnesses, but what is it exactly? Our bodies use the oxygen we breathe to burn the fuel we get from food, and while this is a natural process, it produces byproducts known as free radicals, which are unstable molecules that can strip electrons from other molecules in a process called oxidation. Antioxidants (such as vitamin C) act as a source of electrons, helping keep other cells stable and healthy. Oxidative stress refers to the stress on our bodies from the normal effects of free radicals combined with environmental stressors like tobacco smoke or radiation.
In work presented at the 2013 meeting of the Society of Biological Psychiatry, Anna Andreason showed that over-activity of neurons increases oxidative stress through the production of reactive oxygen species (ROS). These are a type of free radicals that can damage cells in two ways: nitrosylation of proteins (adding nitric oxide to a thiol molecule), and oxidation, which results in more lasting effects on synaptic structures. The chemical compound rotenone damages mitochondria by producing ROS, and Andreason found that lithium was able to reverse this production and reverse the adverse effects of oxidative stress.
Lithium Has an Amazing Array of Positive Effects
Editor’s Note: The ability of lithium to protect mitochondria (the energy storehouse of a cell) adds to an increasingly long list of lithium’s neurotropic and neuroprotective benefits. Lithium increases cell survival factors BDNF and Bcl-2, increases markers of neuronal integrity such as N-Acetylaspartic acid (NAA), increases the volume of the hippocampus and cortex, and now helps protect mitochondria from oxidative stress. Lithium also increases the length of telomeres, which cap the ends of chromosome and protect them from damage during the DNA replication that occurs each time a cell divides. Short telomeres are associated with many kinds of medical and psychiatric diseases, as well as shorter life spans. No wonder that in addition to preventing mania and depression it has other clinical benefits, such as preventing memory deterioration, medical mortality, and suicide.
Brooks R. Keeshin from a research group led by Frank Putnam presented a poster at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) on neuroendocrine function in recently sexually abused adolescent girls with and without post-traumatic stress disorder (PTSD). Average age of the girls was 15 and they had experienced the sexual abuse six months to one year before the study. The researchers found that morning cortisol awakening response was flattened in the girls, and this was associated with PTSD severity and the severity of intrusive symptoms. Increased adversity prior to the sexual abuse experience was also associated with flattening of the cortisol awakening response.
The researchers suggest that alterations in the hypothalamic pituitary adrenal axis (HPA) appear around the time of the abuse and are associated with the severity of PTSD symptomatology in sexually abused adolescent girls.
At the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in October 2010, Nadine Schwartz reported that in a rare type of encephalitis, antibodies specifically target and bind to N-methyl-D-aspartate (NMDA) receptors, the major receptors for excitatory neurotransmission in the brain. Individuals usually develop psychiatric symptoms before neurological ones, and were previously often thought to be malingering or inventing their illness. Eventually they may develop profound cognitive and motor deterioration and many may require treatment in an intensive care unit in order to provide adequate respiration. Studies show that children with this syndrome appear to respond to anti-immune therapeutic approaches including steroids, plasmaphoresis, and antimetabolites.
Editor’s Note: The recognition that auto-antibodies can attack the major receptors for excitatory neurotransmission in brain brings to light another potential mechanism that could explain neurochemical dysregulation in the neuropsychiatric disorders.
At the 65th Annual Scientific Convention of the Society of Biological Psychiatry, researcher Christian Carmeli reported that N-acetylcysteine (NAC, 2 gm/day for six months) increased electroencephalogram (EEG) synchrony over the frontal cortical and left temporal regions in patients with schizophrenia. The EEG measures the frequency and amplitude of electrical activity on both sides of the brain.
Editor’s note: These data provide a neurophysiological mechanism that could explain the positive effects of NAC previously observed by researcher Mike Berk and associates in both schizophrenia and bipolar disorders and published in Biological Psychiatry in 2008. NAC is both a glutathione precursor providing antioxidant effects and a modulator of hyper-responsive glutamate reactivity in the n. accumbens or ventral striatum, the reward area of the brain. In placebo-controlled studies NAC appears effective in treating cocaine, heroin, and gambling addiction, as well as trichotillomania (compulsive hair-pulling). These effects are thought to be related to NAC’s dampening of glutamate responses in the n. accumbens, which, along with the dorsal striatum, appears to mediate habit memory. Read more
In a study of rodents exposed to stress (by being forced to enter another rodent’s territory) and given the opportunity to self-administer cocaine, those exposed to a few brief episodes of stress increased their cocaine use and engaged in binge-like episodes, while those exposed to stress chronically showed suppressed cocaine use.
At the American College of Neuropsychopharmacology meeting in December 2009, Klaus Miczek and colleagues from Tufts University in Boston presented a fascinating study indicating that the temporal aspects of the experience of social stress may have dramatic impact not only on defeat stress behaviors and the associated biochemistry, but also on the likelihood that an animal adopts cocaine self-administration. These investigators compared episodic versus chronic defeat stress in rodents.
Episodic social defeat stress consisted of four brief confrontations between an intruding animal and an aggressive resident rat over the course of a period of ten days. In contrast, chronic subordination stress involved the continuous exposure of the intruder rat to an aggressive resident over five weeks, during which time the intruder lived in a protective cage within the resident’s home cage.
The episodically defeated intruder rats showed increases in intravenous cocaine self-administration and prolonged binge-like episodes, along with increases in brain-derived neurotropic factor (BDNF), which is necessary for long-term learning and memory, in the midbrain ventral-tegmental area (VTA) and increased dopamine release in the nucleus accumbens, the reward area of the brain. In contrast, the continuously subordinate rats showed the opposite pattern of suppressed cocaine intake, suppression of dopamine release in the n. accumbens, and reduced BDNF in the VTA.