Vitamin D3 tends to be low in children and adolescents with mania, but supplements may help. In a small open study published in the Journal of Child and Adolescent Psychopharmacology in 2015, Elif M. Sikoglu and colleagues administered 2000 IU of vitamin D3 per day to youth aged 6–17 for eight weeks. Sixteen of the participants had bipolar spectrum disorders (including subthreshold symptoms) and were exhibiting symptoms of mania. Nineteen participants were typically developing youth.
At the beginning of the study, the youth with bipolar spectrum disorders had lower levels of the neurotransmitter GABA in the anterior cingulate cortex than did the typically developing youth. Following the eight weeks of vitamin D3 supplementation, mania and depression symptoms both decreased in the youth with bipolar spectrum disorders, and GABA in the anterior cingulate cortex increased in these participants.
Editor’s Note: GABA dysfunction has been implicated in the manic phase of bipolar disorder. While larger controlled studies of vitamin D supplementation are needed, given the high incidence of vitamin D deficiency in youth in the US, testing and treating these deficiencies is important, especially among kids with symptoms of bipolar illness.
At the 2015 meeting of the International Society for Bipolar Disorders, researcher Martin McInnis described how stem cells can be used to identify biochemical abnormalities in patients with bipolar disorder. In this research, the stem cells, or IPSCs (for induced pluripotential stem cells), are created when cells from skin fibroblasts, which produce connective tissue, are treated with chemicals that cause them to de-differentiate back into stem cells.
McInnis identified several abnormalities in the stem cells of patients with bipolar disorder. Stem cells with the gene CACNA1C, which is associated with vulnerability to bipolar disorder, fired more rapidly than non-CACNA1C stem cells. There were other abnormalities at the NMDA glutamate receptor and an imbalance of the neurotransmitter GABA in the cells. When the cells were treated with lithium, some of these abnormalities were reversed. In the cells with the CACNA1C gene, lithium normalized the firing rate. Lithium aslo re-balanced the distribution of GABA in the cells.
McInnis hopes that this stem cell research will shed light on the abnormalities associated with bipolar disorder, help explain how lithium corrects some of these, and lead to the development of new therapeutic approaches.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Scott Russo described characteristics of rodents who showed depression-like behavior after 10 days of exposure to a larger, more aggressive animal (a phenomenon known as defeat stress). These animals exhibited many behaviors that resembled human depression, including anxiety-like behaviors while navigating a maze; activation of the hypothalamic-pituitary-adrenal axis; circadian rhythm abnormalities; metabolic changes such as glucose intolerance; susceptibility to addiction; anhedonia, a lack of interest in sucrose, sex or intracranial self-stimulation; and profound and permanent social avoidance.
In susceptible animals, Russo found anatomical changes in the GABAergic neurons of the nucleus accumbens (also known as the ventral striatum), including increased numbers of synapses and a greater number of stubby spines on dendrites (the branched projections of neurons where electrical signals are passed from one cell to the next), as well as greater excitability of glutamatergic input, observed as excitatory post-synaptic potentials.
Russo’s attempt to identify these key neurons among the billions of neurons and the 100 to 500 trillion synapses in the brain was like the search for a needle in a haystack, but thinks he found it. The medium spiny neurons of the nucleus accumbens contain GABA and receive synapses from the prefrontal cortex, amygdala, and intralaminar nucleus of the thalamus (ILT), in addition to dopamine inputs from the VTA, and cholinergic, somatostatin, and orexin inputs. Russo found that it was the ILT inputs that conveyed susceptibility to defeat stress, and their presynaptic endings showed increased levels of glutamate transporters (VGLUT-2). Driving the ILT was sufficient to cause the rodents to display the depression-like behaviors, and silencing the ILT during defeat stress prevented the susceptible behaviors (like social avoidance) and promoted resilience.
Sherman Brown of the University of Texas Southwestern reports that the neurosteroid allopregnanolone has positive effects in bipolar depression. Patients in Brown’s study received doses of 100mg capsules twice daily during the first week, then one capsule in the morning and two capsules in the evening during the second week, and two capsules in the morning and three capsules in the evening during the third week.
Neurosteroids can change the excitability of neurons through their interactions with the neurotransmitters that carry signals from neurons across synapses. Among the various types of neurotransmitters, GABA plays an inhibitory role, while glutamate is responsible for excitability. Allopregnanolone, which is naturally produced in the body, has positive effects on GABA receptors and inhibitory effects on glutamate NMDA receptors, so that it increases the balance of inhibition (GABA) over excitation (glutamate).
Vitamin D3 is low in children and adolescents with mania, but taking a supplement could help. Vitamin D3, which we absorb via food and sunlight, is converted by the liver to a form called 25-OH-D. In a small study, Elif Sikoglu et al. found that children and teens with mania had lower levels of 25-OH-D in their blood compared to typically developing youth of similar ages. This deficit was associated with lower brain GABA levels measured with magnetic resonance spectroscopy. GABA dysfunction has been implicated in the manic phase of bipolar disorder. An 8-week trial of Vitamin D3 supplements significantly reduced manic symptoms and tended to increase GABA levels.
Editor’s Note: Other data have suggested that children with psychosis have low Vitamin D3, and in a recent clinical trial in adults, Vitamin D3 supplementation improved antidepressant response more than placebo. Many children in the US are Vitamin D deficient. Test them and, if necessary, treat them, especially if they have bipolar disorder.
T.L. Lauriat reported at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011 that low baseline levels of the neurotransmitter GABA in the brains of depressed patients were associated with greater response to antidepressants. GABA was measured using magnetic resonance spectroscopy (MRS).
These data raise the possibility that easily observed neurobiological markers, such as levels of GABA or the neurotransmitter glutamate, may ultimately be helpful in predicting clinical response to particular treatments.
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.
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.
At the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in October 2010, Hanna Stevens of the Yale Child Study Center reported that rat pups in utero who experienced prenatal stress (i.e., when the pregnant rat was restrained during the last week of pregnancy) had fewer neurons containing GABA, which is the main inhibitory neurotransmitter in the brain, than control pups. This deficit may reflect a delay in the neurons’ ventral to rostral migration or in their maturation. These deficits in GABAergic neurons following prenatal stress are noteworthy in light of the deficits in GABAergic neurons found in adults with bipolar illness. This research is unusual in that it suggests that prenatal stress can affect neuronal numbers.
Editor’s Note: Stevens was aware of data from the renowned neuroanatomist Pasco Rakic, also at Yale. Some years ago Rakic reported that ultrasonic stimulation of the brain had major disorganizing effects on neuronal migration in the primate brain. Since prenatal stress and ultrasonic stimulation can affect neuronal migration, and dysregulation of neuronal migration has been implicated in autism, these data raise the hypothesis (so far untested) that one possible reason for the recent increases in the incidence of autism is the increased use of sonograms to monitor various aspects of prenatal growth and development during pregnancy. These preclinical findings deserve to be further studied for their potential relevance to humans.