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Ketamine can rebuild spine and synaptic proteins in the brain and restores regulatory processes for patients with mood disorders.
Stress causes a reduction or retraction of spines and synapses, and the administration of ketamine produces an almost immediate formation of spines and synaptic proteins. This restores regulatory emotional functioning in the brain.
Studies of chronic unpredictable stress models in mice demonstrate that ketamine administration rapidly ameliorates stress-induced anhedonia and anxiety. Stress decreases synaptic proteins and spines and results in decreased electrical activity in the prefrontal cortex (the CEO of the brain involved in executive functioning) all of which is reversed by ketamine.
- Major Depressive Disorder (MDD) affects 17 % of the population in the United States.
- Only one-third of patients demonstrate complete response to an anti-depressant.
- Three studies below demonstrate Ketamine can produce antidepressant results within hours of administration:
Antidepressant effects of ketamine in depressed patients
Results: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment).
Intravenous ketamine therapy in a patient with a treatment-resistant major depression
Results: Following the administration of ketamine the subject experienced a significant improvement of his symptoms peaking on the 2nd day post infusion (HDRS from 36 to 16; -56.6%, BDI from 26 to 9; -65.4%). The subject first reported improvements 25 min. into the infusion and continued to describe positive effects throughout the subsequent 7 days.
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression
Results: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.
In a chronic unpredictable stress model (CUS), the results of stress in mice are anhedonia, which is a key symptom of depression that responds to chronic antidepressants but not acute administration. This chronic stress results in atrophy of hippocampal and prefrontal cortex neurons:
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression
Conclusions: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex.
Stress-Induced Alterations in Prefrontal Cortical Dendritic Morphology Predict Selective Impairments in Perceptual Attentional Set-Shifting This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.
Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress. These results suggest that stress-induced dendritic plasticity in the medial PFC is reversible and may have implications for the functional recovery of medial PFC function following prolonged psychological stress.
Repeated stress and structural plasticity in the brain
Here we review how repeated stress produces alterations in brain plasticity in animal models, and discuss its relevance to behavioral changes associated with these regions. Interestingly, prolonged stress produces opposing effects on structural plasticity, notably dendritic atrophy and excitatory synapse loss in the hippocampus and prefrontal cortex, and growth of dendrites and spines in the amygdala. The granule cells of the dentate gyrus are also significantly affected through a decrease in the rate neurogenesis following prolonged stress.
Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex We estimate that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress. A decrease in medial PFC dendritic spines may not only be indicative of a decrease in the total population of axospinous synapses but may impair these neurons’ capacity for biochemical compartmentalization and plasticity in which dendritic spines play a major role. Dendritic atrophy and spine loss may be important cellular features of stress-related psychiatric disorders where the PFC is functionally impaired.
There is a decreased volume of the prefrontal cortex and hippocampus reported in brain imaging studies of MDD patients, hence the brain fog, poor working memory, and difficulty concentration seen in depressive states. The studies below demonstrate these findings:
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression Major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex.
Hippocampal atrophy in recurrent major depression Depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
Subgenual prefrontal cortex abnormalities in mood disorders Positron emission tomographic (PET) images of cerebral blood flow and rate of glucose metabolism to measure brain activity, we have now localized an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depressives and familial unipolar depressives. This decrement in activity was at least partly explained by a corresponding reduction in cortical volume, as magnetic resonance imaging (MRI) demonstrated reductions in the mean grey matter volume in the same area of 39 and 48% in the bipolar and unipolar samples, respectively. This region has previously been implicated in the mediation of emotional and autonomic responses to socially significant or provocative stimuli, and in the modulation of the neurotransmitter systems targeted by antidepressant drugs.
Hippocampal volume and depression: a meta-analysis of MRI studies Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder. Bipolar patients did not seem to show a reduction in hippocampal volume, but this has been much less investigated.
Reduced volume of orbitofrontal cortex in major depression. There is smaller orbitofrontal cortical volume in depression.
Ketamine can increase the density and function of dendritic spines and synaptic junctions in the PFC through the mTOR pathway to increase synaptic plasticity. The mTOR pathway is critical in the formation of dendritic spines and neuronal plasticity.
mTOR Signaling: At the Crossroads of Plasticity, Memory, and Disease
Ketamine infusions can reverse chronic stress diminution of dendritic spines for up to 7 days after a single administration as seen in some studies.
The functioning of ketamine depends on appropriate functioning of AMPA receptors.
Also, Ketamine increases Brain Derived Neurotrophic Factor (BDNF) to increase neuronal synapses.
Ketamine promotes antidepressant and anti-anxiolytic effects as well.
Ketamine increases synaptic protein levels and produces antidepressant behavioral actions. These effects are mTOR dependent.
Chronic stress exposure decreases levels of synapsin I, GluR1 and PSD95, and this is rapidly reversed by ketamine. These proteins are important in the production of dendritic spines and synapse formation and become diminished in depression. Rapamycin paradoxically produces an antidepressant response in certain studies, even though it shuts of mTOR.
Administration of ketamine rapidly and completely reversed these deficits in spine density and function, indicating a causal relationship between the morphological and physiological responses. The dendritic atrophy seen in the PFC in CUS is correlated with the decreased PFC volume seen in depressed patients. This may be reversed with appropriate treatment:
REPEATED STRESS ALTERS DENDRITIC SPINE MORPHOLOGY IN THE RAT MEDIAL PREFRONTAL CORTEX
Reduced volume of orbitofrontal cortex in major depression
There is a smaller orbitofrontal cortical volume in depression.
Neuronal atrophy and loss of spines and synapses in the PFC underlies some of the behavioral deficits observed in depressed patients, such as cognitive functions and loss of inhibitory control of emotions that may be mediated by amygdala circuitry:
Ketamine:
- Increases synaptogenesis.
- Increases neuroplasticity.
- Increases the formation of new synapses.
- Reverses dendritic atrophy seen in chronic stress and depression.
- The structural deficits caused by, and implicated in the pathophysiology of mood disorders, including treatment resistant depression, are reversible and that the rapid actions of ketamine are mediated by increased synaptogenesis.
The treatment frequency of ketamine to intervene and maintain the antidepressant effects can be twice or three times a week:
Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.
A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression
Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours post infusion and continued to remain significant for 1 week.
Neuroplasticity Video links can be found below:
Neuroplasticity: How to rewire your brain
BrainHQ Neuroplasticity Training
Ketamine administration allows for the rapid reversal of defects found during depressive episodes, which include decreased neural connectivity, decreased neuronal synapses, lower dendritic spine numbers, and smaller cortical volumes. These changes result in emotional dysregulation, brain fog, and poor decision-making. Ketamine allows for these changes to be rapidly corrected in doses of 0.5 mg/kg IV over 40 minutes 2-3 times per week initially.