703-844-0184 | NOVA Health Ketamine Treatment Center Fairfax, Virginia 22201 | Peptide therapies |

What are peptides? Peptides are molecules that consist of between two to fifty amino acid sequence. The first commercial peptide therapy used was insulin (1923).

What are peptide therapies? Fundamentally, peptide therapies give cells the ability to change cell behavior and to handle stress better. Peptide therapies are natural modulators of cell signaling. The cell changes behavior and can adjust to stress, aging, etc… and can manipulate the genome with signals going from the mitochondria (where energy is made by the cell) to the nucleus through MOTS-C.  You can get started and just use a growth hormone releasing peptide (GHRP), eg, Ipamorelin by itself without spending a lot of money to see if your sleep improves and bone density improves. Use a GHRP together with bio-identical hormones and get great results.  There are 7,000 natural peptides in the body. There are currently 60 FDA-approved peptides in clinical use. There are now 140 clinical trials happening at this moment in time (October 2018) and there are some 400-500 clinical studies being set up right now. It’s growing into every silo of medicine right now. As a forward-thinking medical practice, we now embrace peptide therapies as an additional mainstay treatment for acute and chronic illness. Our armamentarium of tools has increased. 

Peptide therapies have a variety of applications such as immune enhancement; accelerates injury repair to muscles, reverses sarcopenia (loss of muscle), tendons, bones, nerves; progressive fat loss and improved bone mineral density, increase in Testosterone by increasing pulse size and frequency, decrease inflammation in the brain and the rest of the body, natural release of growth hormone, improves sleep. It’s easiest to think about peptides in these easy to remember ways. Here is how: 1. Hormone optimization, 2. Weight loss, 3. Sexual Functioning, 4. Healing and Repair.

1. Hormone Optimization and Growth Hormone Secretagogues: CJC-1295 without DAC, Ipamorelin, Tesamorelin, GHRP-2, GHRP-6

2. Weight Loss options: GH-191, GHRP, GHRH/GHRP, AOD-9064, Melanotan II, Frag 176-191 (an AOD knockoff, not effective), Thymosin Alpha-1, Cerebrolysin, DSIP, PEPCK, GLP 1R agonist. 

3. Sexual Enhancement and Function: Melanotan II and PT-141.

4. Healing and Repair: GHK-Cu, BPC-157, Thymosin Beta-4, AOD +HA, LL-37, GHRH, MGF and PEG-MGF.

Peptides, as signaling substances, help reclaim efficiency of hormone receptor sites. In other words, if you take some thyroid medicine, eg, T3 (active thyroid hormone), and you don’t see improvement in the labs, it may be that the receptor site is not working properly. Peptides and certain other nutrients can help improve the functionality of the receptor so that the hormones we give work as intended. Importantly, peptide therapy works best in the background of great nutrition, cortisol balance, and the removal of environmental toxins.

The melanocortin system incudes Melanotan II and Bremelanotide (PT-141). Melanotan II increases melanogenesis for photoprotection and increased tanning, plays a role in improving autoimmune disease, eg, Lyme disease. Plays a role in sexual dysfunction and can improve libido (increases sexual arousal) and erectile dysfunction in men (and sexual desire in females) through the CNS, and not through the Cardiovascular System which is the way medicines like Cialis, and Viagra work. Has significant anti-inflammatory disease. Works through the vagal /cholinergic response and affect the immune system.   Can affect appetite and cause weight loss. Works well with intermittent fasting. Activation of the vagus nerve leads to cholinergic signaling and inhibits tumor necrosis factor (TNF) and other pro-inflammatory cytokines overproduction (Cholinergic anti-inflammatory pathway). This pathway is activated by Melanocortin 3R and 4R receptors. This pathway is critical and is significant in anti-inflammation in the brain. This plays a role in neuroprotection and is also cardioprotective, too. The melanocortin system peptides can be used with Thymosin alpha-1 to balance Th1 and Th2 issues. This can also be used with DSIP with Glycine where you can upregulate glutathione peroxidase and superoxide dismutase. This gives us new approaches to autoimmune diseases. Immune cells have melanocortin receptors 1,3,5. Melanocortin receptor 3,4 is in the brain. Melanocortin receptor 4 plays a role in appetite control. The adrenal cortex is melanocortin 2. Alpha melanin-stimulating hormone reacts with all 5 receptors. Melanotan receptor 1 is on the endothelial cell. Melanotan 1 does not cross the blood-brain barrier. Melanotan 2crosses the blood-brain barrier. Melanotan 1 will not give you sexual desire effects but will give you tanning and is responsible for melanogenesis. Melanotan 2 gives you both tanning (sunless tanning) and sexual desire. In women, they can increase pigmentation and more freckles than with men.   Nota bene: The face and hands may get darker than the rest of the body. The use of Melanotan 1 is an art, follow the skin pigmentation to determine dosing adjustments. It has the cosmetic effect of tightening the collagen in the face. Melanotan 1 and Melanotan 2 are effective for autoimmune conditions like Hashimoto’s thyroiditis (may also use Thymosin alpha-1). Psoriasis may also be treated by Melanotan 2, but when treatment is stopped, the disease will come back. Melanotan 2 works through the vagus nerve through the cholinergic anti-inflammatory pathway. Can be useful for Seasonal Allergy because of the anticholinergic effects. Can be used on a daily, or regular basis vs. PT-141 (bremelanotide) which should only be used twice weekly to prevent desensitization. Melanotan 2 is neuroprotective, as well as plays a role in decreasing opioid addiction and ethanol consumption. Melanotan 2 improves libido and erectile dysfunction in men. Melanotan 2 plays a role in appetite and metabolism.

***Caveat emptor (Buyer beware)! Swiss Analytic Labs claims to have tested most if not all peptides advertised on the internet. They say that approximately 80% of these peptides are either adulterated or fake. Be particularly skeptical of marketing for very inexpensive peptide therapies. It simply is impossible for reputable companies to manufacture these products and make money at very low prices. ***

Here are the peptide therapies: 

AOD 9064 stands for Anti-Obesity Drug and is a peptide fragment found within Growth Hormone (the last 15 amino acids),  that is responsible for the substantial weight loss effects that are seen when using Growth Hormone. Growth Hormone causes weight loss of both visceral (deep) fat and retroperitoneal fat, whereas Testosterone and exercise are responsible for the superficial fat loss. Affects lipid metabolism (women greater than men). Best for weight loss of 20-30 pounds.  Promotes chondrocyte production of collagen and proteoglycan. Enhances hyaluronic acid.  The success rate for weight loss improved with work-outs or fasting. It also helps prevent fat build up and increases the NAD+/ NADH ratio, great for the cells and for stem cell renewal. It is best used for weight loss in combination with a Growth Hormone Releasing Hormone (GHRH), and a Growth Hormone Releasing Peptide (GHRP). AOD with HA (hyaluronic acid) useful for cartilage regeneration in knee, hip, shoulder, ankle, and tendinopathies. AOD with HA-also good for trigger point injections.

Examples of GHRH’s include Sermorelin, GRF 1-29, modified GRF 1-29 (CJC-1295 without DAC(makes the pituitary follow the natural pulsatile release to increase Growth Hormone, promotes muscle growth and fat burning and may help with sleep), CJC-1295 with DAC (the DAC-drug affinity complex- increases the half-life of the product by several days and elevates Growth Hormone and IgF1 levels after a single administration), Tesamorelin. Examples of GHRP’s include GHRP-2 (reduces atrophy in muscle, potent stimulator of Growth Hormone secretion, with minimal stimulation of Prolactin and Cortisol, increases growth velocity in children, and improves appetite with weight gain in patients with anorexia ), GHRP-6 (actively increases ghrelin in the stomach, restores Growth Hormone secretion in obesity, and improves phase 2 sleep), Ipamorelin (plays a role in nitrogen retention, the mildest of the group and with large doses does not produce prolactin or cortisol elevations, but does give a large release of Growth Hormone without desensitization side effects ), and Hexarelin (has cardioprotective effects, and the strongest of the group, and gives the biggest pulse of Growth Hormone, but there may be an elevation of prolactin and cortisol transiently, and desensitization can occur regardless of dose so use sparingly).  MK-0677 is fraught with side effects such as involution of receptor sites in the brain and irreversible neurologic damage. It also elevates cortisol and increases depression and anxiety.

The GHRH’s regulate Growth Hormone production and release, the neurochemical regulation of sleep, and much more. The GHRP’s antagonize the release of Somatostatin, and enhances the release of GHRH and increases Growth Hormone release. The GHRP’s also have stress protective benefits, anti-anxiety & anti-depression effects and can stimulate to the production of Nitric Oxide (NO) from endothelial cells. Also has muscle repair function and anti-inflammatory effects.

BPC-157 (Body Protection Compound-157)  by itself does nothing which makes it very safe to use at recommended doses. It has no side effects, no toxicity, and no drug interactions. It helps the body to achieve homeostasis.  It is a powerful cell signaling messenger that decreases inflammation and accelerate healing (muscle, brain, bone, tendon, nerve, ligament, cornea, intestines, as examples). It increases fat loss, improved immune function, well being, and bone mineral density.  Some patients claim that their chronic pain has been substantially reduced. BPC-157 can help you heal faster from injury to bone, muscle, ligament, tendon, nerve, brain, teeth, intestine, cornea via cell signaling. This peptide responds specifically to injury. It also has an influence on neurotransmitters related to stress, anxiety, mood, and behavior via its effects on the serotonergic, dopaminergic, GABAergic and opioid systems. May help with depression.  It has effects on the GI tract via its anti-ulcer, cytoprotective effects. It improves GI mucosal integrity (anecdotal info for healing leaky gut 500mcg, orally, twice daily).  It improves nitric oxide (NO). Useful in weaning patients off Proton Pump Inhibitors (PPI’s) with zinc carnosine over a period of a month. Induces F-actin formation. Can be used after initial use of steroids for acute anti-inflammatory purposes thus prevents the long-term adverse effects of steroid use. Decreases neuroinflammation. Ameliorates alcohol and opioid withdrawal symptoms (may be combined with DSIP), and opposes alcohol intoxication. Helps with homeostasis of dopaminergic and serotoninergic systems.  Improves nerve (axonal and myelin sheath) regeneration. It rapidly and permanently counteracts QTc prolongation of the heart caused by neuroleptic medicines (Haldol, etc) and prokinetics. Intranasal use for Lyme and Mold brain fog.

Cerebrolysin is a neuro-regenerative and neuroprotective peptide. It has neurotrophic repair properties similar to Nerve Growth Factor (NGF) and Brain-Derived Nerve Growth Factor (BDNF). It is a low molecular weight peptide that can cross the blood-brain barrier. Can be used for Traumatic Brain Injury (TBI) and Ocular Migraine Headaches, TIA’s, Stroke, Post Stroke Recovery, and Mood Dysregulation. It can be used to increase memory and learning and can improve synaptic function and synaptic density. Protects nerves from free radicals and oxidative stress damage and improves the metabolic activity of neurons, and protects neurons from neurotoxic effects of glutamate. Improves synaptic functioning.   Enhances cognitive function, memory, learning, creativity, and motivation. It can cross the blood-brain barrier and decreases beta-amyloid formation and deposition as well as Tau protein phosphorylation. It has a positive effect on behavior and neurotrophic stimulation. It can also be used for mood dysregulation, traumatic brain injury (TBI), concussion, stroke, trans-ischemic attacks (TIA), Alzheimer’s disease. In dementia, improves neuronal cytoarchitecture which results in improved cognitive and behavioral performance. Consider doing a trial in those with Apo E 4 (3/4, or 4/4) with cognitive impairment. This can help mitigate the continued cognitive impairment. Significant improvement was seen in those with mild to moderate dementia. 

Deep (or Delta) Sleep Inducing Peptide (DSIP) This peptide not only helps regulate sleep by way of improving the circadian function of sleep (mostly stage 4, slow wave sleep, when growth hormone is released) and decreasing wake ups throughout the night. It is not a sedative drug. It is also neuroprotective (prevents neuronal death) prevents excitotoxicity,  and increases glutathione peroxidase and Superoxide dismutase (SOD) in the brain which increases oxidative phosphorylation in the brain, and hence, improves mitochondrial function and LH release which can boost Testosterone levels by 100-200 points. There are no significant side effects from treatment. Oxidative stress in the brain causes an age-associated decrease in Testosterone. DSIP improves this process in the brain, where it can also help lower feelings of stress by lowering ACTH. This peptide has also been shown to decrease alcohol and opioid withdrawal (and decreases chronic pain). It has a growth hormone releasing response in a physiologic way.

Epithalon literature is mostly from Ukraine and Russia. It regulates the cell cycle to upregulate polymerase activity. The peptide is from the pineal gland, improves the sensitivity of the hypothalamus, and normalizes the function of the anterior pituitary.  It is an anti-aging peptide for short-term use (up to 10 days a year or twice a year). 33% increase in telomere length by inducing telomerase activation and elongation and also prevents chromosome fusion. It is able to overcome the Hayflick limit of cell divisions (by 10 more divisions). Human studies for 12 years, showed decreased mortality by 28%, and a two-fold decrease in cardiovascular mortality. It also has tumor suppression activities. Epithalon combined with Thymalin over a 6 year period decreased the mortality rate 4.1 times that of the control group. In human elderly studies, Epithalon has been shown to increase SOD and Glutathione peroxidase (just like DSIP, and Kisspeptin), complete normalization of antioxidant indices, reduction of lipid peroxide oxidation products, improved melatonin and immunity (both cellular and humoral). Other studies in the elderly showed: increased glucose utilization, increased insulin sensitivity, increased HDL, lowered LDL, lower BP with decreased peripheral resistance, and improved tissue repair. In other human cancer trials: restored cellular immunity, and decreased recurrence and metastasis for 10 years. In breast cancer, patients showed partial or complete tumor regression, improved leukopenia and immune function, and prolonged patient lives.

GHK-Cu (GHK-copper) modulates copper into cells. Can accelerate change from inflammation to a healing phase via decreasing TNF alpha and beta, and decreasing IL-6.   It increases SOD (copper and zinc-dependent) and that leads to a decrease in Reactive Oxygen Species (ROS). Decreases ulcers and infections. Decreases fibrinogen and metastasis of cancer.  Increases myelin and cell regeneration and increase nerve density.  Plays a role in cosmesis and also has been shown to boost self-confidence.

IGF-1 (Insulin-like Growth Factor 1), aka, Somatomedin C.  It’s very similar to insulin. In the brain, it plays a role in neural development and myelination. It is anti-inflammatory. In the heart, it has vasodilatory effects. In muscle, plays a role in muscle development and helps rebuild muscle in a more efficient way. It mediates the effects of Human Growth Hormone. It improves muscle, bone and cartilage tissue. It helps improve connective tissue healing. It plays a role in adipocyte differentiation and regulation. It improves the anti-oxidant defense system. Utility: Conditions needing soft tissue enhancement- muscle, tendon, ligament repair from sports injuries. Looks for specific results over short periods of time. It doesn’t stop the amount of scar tissue made, however (use with TB-4, which decreases scarring). Useful for Diabetes I and Insulin Resistance. It improves insulin sensitivity. Useful for weight loss and metabolic syndrome. Improves bone density. Decreases neural-inflammation.  Low level is associated with CV events and increased mortality rate. It can play a role in those susceptible to cancer so use for short-term, specific uses. High levels are associated with cancer risks (breast -premenopausal-, prostate, colorectal). We are trying to use it in physiological levels only for best results.

Ipamorelin is a Growth Hormone Releasing Peptide (GHRP), anti-depressant, anti-anxiety, protective of stress, potentially neurologically protective.

Kisspeptin 10 was developed in Hershey, PA. (home of the Hershey kiss). This peptide increases Testosterone for men with primary hypogonadism and men who lose Testosterone from the aging process. This peptide works by increasing the pulse frequency and pulse size of LH. Testosterone levels may rise 100-250 points. Kisspeptin 10 has also been shown to be better than HCG for increasing testicular size. There is no feedback inhibition. There is physiologic Growth Hormone release, too.

LL-37 is an antimicrobial peptide classified as a Cathelicidin and is involved with our innate immune system of defense against bacterial invasion, antiviral and antifungal activity on mucous membranes, increases epithelial stiffness and decreases permeability to bacterial invasion; can improve treatment of Cystic Fibrosis. Also, improve treatment for Respiratory Syncytial Virus (RSV) and Influenza A via damaging viral envelope and disruption of viral particles. Has antifibrotic effects and inhibits pro-inflammatory responses of NF kappa beta from LPS (via decrease TNF alpha, and IL-6). Interestingly, it decreases gut permeability via improved tight junctions (claudin, occludins). Can help protect against pathogen-mediated intestinal inflammation. Powerful anti-microbial and anti-inflammatory. Useful in Crohn’s and Ulcerative Colitis. In the Diabetic gut, it improves tight junctions and microflora. With C. difficile, it can decrease inflammation (IL-6).

MGF (mechanical-growth factor) is a peptide in development. It is an isoform of IGF-1 called IGF-1Ec. It is produced locally. It is activated in the heart and the brain by ischemia to activate mRNA coding for the isoform IGF1-Ec. This acts locally to increase anabolism, increase stem cell pool, stimulates satellite cells to make new cells, not grow them as skeletal muscle fibers are unable to divide. MGF expression is significantly increased following mechanical stimuli to muscle, bone, and tendon.  Resistance exercise and skeletal muscle stretch/overload, both contribute to increases in IGF-1Ec. In response to stretching and damage to muscle, MGF is vital for protein synthesis, mRNA transcription, and activation and proliferation of satellite cells. Satellite cells are signaled to replicate by MGF. Satellite cells are prevented from going forward until they fuse with muscle fibers and when they adopt a myogenic program. It’s rapid induction followed by fall of in a couple of days in response to stretching or damage to the muscle, or by ischemia in the brain or heart. This works as a proliferator of cells. This works in concert with Growth HormoneMGF promotes endothelial cell growth. MGF has been shown to improve cardiac function post-MI (myocardial infarction commonly know as a heart attack). It prevents a decrease in left ventricular ejection fraction, reduces post-infarct expansion by inhibiting post-infarct apoptosis (cell death). Helps with the development and repair of neurons. It decreases oxidative stress in the brain as well as NMDA-expressed excitotoxicity. It is also expressed in osteoblasts in response to mechanical stress. MGF reverses sarcopenia. Applications are seen in conditions needing anabolic enhancement, soft tissue repair of ligaments, tendons, muscles from injury; muscle growth; cardiac ischemia problems, brain neuroprotection/ ischemia; age-related sarcopenia. MGF and all IGF’s decline with aging. PEG-MGF is pegylation of MGF and is a peptide in development. It is an attachment of polyethylene glycol to the peptide. The pegylation process acts as a protective coating and stabilizes the MGF molecule.  It protects the MGF molecule from enzymatic and receptor inhibition and increases PEG-MGF half-life to several days (48-72 hours). PEG-MGF is useful in muscle repair or hypertrophy (specific training). The PEG is inert and doesn’t bind to other substances in the body and has rapid urinary excretion. For effects upon muscle, use MGF 600 mcg injected SQ to muscles three times a week to increase proliferation of muscle. The day after the workout you may wish to use IGF1-LR3(100 mcg/ three times a week) that works on the recovery state of muscle. Stay below 2mg total per week.  Don’t use for more than 10 days consecutively and be cautious with hypoglycemia.

Melanotan II isa melanocortin. It works through the brain/ CNS where it causes tanning and naturally makes a woman and a man sexually aroused. Improves libido and erectile dysfunction in men. Caution: may raise blood pressure and may lead to priapism (sustained erection for over an hour) with high doses, and may cause GI upset which may be prevented by coffee, or Xantac.

PT-141 (Bremelanotide) is a melanocortin receptor agonist. Has a high affinity for melanocortin 4 receptors. Improves sexual experiences for men and for women. Improves female sexual dysfunction and erectile dysfunction in males. It acts on the CNS and elicits a more desirous sexual response. GI effects are not as pronounced as with Melanotan 2, but it has been shown that if you do experience nausea, you can use Xantac 150mg, or drink a cup of coffee prophylactically to prevent nausea, or use a lower starting dose prevents nausea. They can also develop some freckles (reversible), even though they are not supposed to become tan with this product (more pronounced in women). Caution: may raise blood pressure, and cause tachycardia, and may cause GI upset.

PEPCK stands for phosphoenolpyruvate carboxykinase. It is an enzyme used in the Krebs Cycle that converts OAA to PEP.  It is involved in the production of gluconeogenesis in the liver and brown and white fat. It plays a role in fat loss, improved performance, and endurance.  If you are trying to improve preformance, you are going to have to improve and adjust lactate threshold and PEPCK helps do this. PEPCK provides a mechanism to control lactate. If you are going to improve the NAD+/NADH ratio of the cell, you are going to increase the efficiency of the cell. PEPCK, fasting, ketone esters, GHRH’s and GHRP’s also improves the NAD+/NADH ratio. This ratio is the ultimate efficiency to evaluate cell function. PEPCK increases glycogen in muscles, decreases muscle fatigue, and increases lactate threshold.

N-Acetyl Semax is a fragment from ACTH. It is not a melanocortin. It is neuroprotective and inhibits histamine release (through its Proline-Glycine-Proline ending sequence). It also reduces vascular permeability.  Nasal spray or SQ. It elevates BDNF in the hippocampus and in the cerebral cortex. It acts as an antidepressant and anxiolytic and attenuates chronic stress. It is a potential melanocortin antagonist (3 and 4 receptors). Other medical uses: Stroke, TIA, Memory, Cognitive Disorders, Boosts Immune System, Peptic Ulcers, Optic Nerve issues. Acts as a brain anti-oxidant. It counteracts the inhibition of learning and memory occurring from toxic heavy metals and counteracts neurotoxic effects. It promotes the survival of neurons secondary to hypoxemia and glutamate neurotoxicity. It contributes to mitochondria stability when under stress. It increases the amount and mobility of immune cells. It can be alternated or mixed with Selank.

Selank shows a variety of effects such as decreased histamine response from mast cells, decreased vascular permeability,  ulcer control meaning increased ulcer healing (from alcohol or stress), allows you to relax and concentrate, helps modulate IL-6, increases brain-derived nerve growth factor (BDNF) in the hippocampus, increases neuroplasticity and stem cell differentiation, has anti-depressant, anxiolytic effects that come on quickly, useful for Generalized Anxiety Disorder (GAD) and shows no sedation/addiction/cognitive loss. has anti-viral activity, regulates inflammation and decreases tumors in breast cancer, helps balance the sleep-wake cycle. Useful to transition from Growth Hormone to using a GHRH/GHRP as it decreases anxiety.

Tesamorelin is a growth hormone releasing hormone (GHRH). It stimulates the release of growth hormone and increases the amplitude of the pulse. It is a fragile peptide so it needs to be refrigerated after being reconstituted and used immediately. Tesamorelin is a good peptide to use if you transition from the use of Growth Hormone to a GHRH (best used with a GHRP, such as Ipamorelin). It has been successfully used to treat HIV + lipodystrophy, as well as to increase lipid metabolism, improve vascular health, control inflammation, and more.

Thymosin alpha-1 modulates innate immunity boosting Natural Killer cells. If you get sore throats and colds multiple times each year, this peptide can help you. This peptide can be used for autoimmune issues in general.  It stimulates T cell production,  decreases the production of pro-inflammatory cytokines, Improves Th1 response, balances Th1/Th2. It dampens immunity (by upregulating IL-10). Enhances dendritic cells, and antibody responses. It has anti-tumor effects and decreases oxidative damage.  It improves tolerance to stress. It increases anti-oxidant and glutathione production.  It improves microcirculation as well as tissue repair and healing. Inhibits viral replication. Applications: improves autoimmune disease, chemical sensitivity,  allergies, cancers, Hepatitis B and C, HIV/AIDS, Malignant Melanoma, and other (particularly stressful situations, eg, air travel, that bring out Shingles, and Seasonal Allergy).  Also, Lyme disease, Chronic Fatigue, Fibromyalgia. Adjuvant to Flu vaccinations in Geriatrics, sepsis, Dysbiosis (along with BPC-157). Best use for Hashimoto’s Thyroiditis is to use daily to lower antibodies (600 mcg/day) instead of every 3 days as used for other conditions. Works well to decrease brain fog of chemo patient (along with BPC-157, and DSIP). There are no documented adverse effects to date (10/20/18).

Thymosin beta4 (TB4) addresses inflammation, immune dysregulation, and reactive oxygen species that underlie chronic illness and age-related decline. Promotes healing via upregulation of G-actin formation. Increases cells involved in healing. Improves cell migration to the site of injury. It decreases scar tissue fibrosis (reduces levels of myofibroblasts). Anti-inflammatory. Promotes angiogenesis and differentiation of endothelial cells. Increases collagen deposition, and is cytoprotective. Improves hair growth. Useful for stroke, and traumatic brain injury (TBI) when used with BPC-157. Also supports immunity and is neuroprotective. Useful for soft tissue repair: tendons, ligaments, muscles, also post-infarction of the myocardium and decreases sarcopenia.  Applications for venous ulcers, and ischemic strokes. Cardioprotective, and useful in Non-Alcoholic Fatty   Liver Disease (NAFLD) by decreasing hepatic fibrosis and decreases proinflammatory factors and oxidative stress. Can be used with BPC-157. Prevents adhesions & fibrous band formation in injured tissue. Protects and restores neurons post-TBI. Works like BPC-157 in that it is a cell-to-cell signaling molecule. Used for patients with sepsis in ICU’s.

Peptide therapy plus Bio-Identical hormones – SynergyPeptides help reclaim the efficiency of receptor sites so they work better (and you won’t need as much hormone to get the effects you seek).

Peptides useful for:

Hormone Optimization, Growth Hormone Secretagogues:  CJC-1295 (without DAC), Ipamorelin, Tesamorelin, GHRP-2, GHRP-6. 

Weight Loss Options: GH-191, GHRP, GHRH/GHRP, AOD-9064, Melanotan II, Frag 176-191 (a knockoff of AOD, not effective), Thymosin alpha-1, Cerebrolysin, DSIP, PEPCK, GLP 1R Agonist. 

Sexual Enhancement and Function: Melanotan II and PT-141.

Healing and Repair: GHK-Cu, BPC-157, Thymosin Beta-4, AOD+ HA, LL-37, GHRH.

Lifestyle & Supplement support for Peptide Therapies: (from lectures by Dr.  Seeds and by Dr.  LaValle)

No smoking or forget doing peptides.

Adequate sleep.

Only PROTEIN within 30 minutes of taking injections.  No fat, or carbs.

Do periodic fasts.

Exercise for best peptide therapy results. Also,  1 hour before workouts, supplements like Phosphatidic acid and works through mTOR signaling (mechanistic Target of Rapamycin) and within 1 hour after workouts (branched-chained amino acids, especially with high levels of the amino acid LEUCINE) for best exercise or stretching results. During workouts, supplement in OJ with L-glutamine,  D-Ribose). The longer the mTOR signaling the longer the net protein synthesis you create. (Ornithine ketoglutarate also works through mTOR signaling).

Creatine: drives tissue anabolism. Great for older people who lack muscle mass.

Arginine: helps make growth hormone (take with Vitamin C) by suppressing somatostatin secretion. Do not take with exercise. You will not make additional growth hormone.

Glutamine: supports GI mucosal integrity, cellular repair, and healing. Supports growth hormone levels.

Alpha-GPC: taken 90 minutes before work outs shown to increase growth hormone levels substantially. How? it increases acetylcholine. Acetylcholine increases the signal release of growth hormone. Improves memory (one of the best supplements available).  Helps to balance the sympathetic and parasympathetic nervous system.

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Weight Loss

First and foremost: balance your hormones. Testosterone helps remove superficial fat. Growth Hormone helps remove both visceral (deep) fat and retroperitoneal fat.  However, this is just the start.  As you know, achieving healthy, sustainable weight loss is not so easy. Other factors may be involved such as: food sensitivities, allergies and addictions; neurotransmitter deficiencies, the need for detoxification, reduction of inflammation, sleep deprivation, yeast issues,  the need for effective exercise and other issues that play roles in weight loss.  Each of us has different needs. The aim of our work is for you to succeed in weight loss and having a healthy, toned, slender body.

Second: we offer the Pathway Fit gene testing that determines which kind of diet works best for you (recommendations are individualized and customized) and which kind of exercise program will work best for you to achieve weight loss. The strength of the science for the recommendations is also rated. For example, a 4-star **** gene rating means that there have been over 2,000 people in a study that has been replicated at least once, a 3-star *** gene rating means that a study with at least 400 people has been done that may or may not have been replicated, etc…  The genes not only relate to metabolism but also those that showcase exercise, eating behaviors and other components that can disrupt and sabotage weight loss.  Some of us are, ‘hard-wired to fail’ at diets because we do not have this valuable information that keeps us stuck and prevents us from realizing our weight-loss goals. Knowing the best diet and best exercise program for weight loss based upon your genes gives you the information you need to know to now realize your weight-loss goals.

Here is, “Think you’re weigh thin”, by JJ Virgin. Listen to a fantastic audio that JJ has put together for 20 tips for weight loss. Implement your favorite two or three and start doing them TODAY! Listen to audio.

Third:  detoxification to remove xenoestrogens from the body which prevent you from losing weight (see Gene Testing and Other Testing section for more information about xenoestrogens). Lose the wheat, lose the weight, says New York Times bestselling author Dr. Davis in his book, ‘Wheat Belly’. Dr. Davis states that glidain and wheat germ aglutinin (found in wheat) are toxic to all human beings. Watch video.

Fourth: peptide therapy. The peptide AOD,  which stands for Anti-Obesity Drug, is really a peptide and is a fragment of amino acids found within growth hormone. This peptide plays a role in weight reduction seen in growth hormone. Growth hormone causes reduction of fat in the deep fat and retroperitoneal fat, whereas Testosterone causes a reduction in superficial fat. AOD can be combined with growth hormone releasing hormones (GHRH’s) and growth hormone releasing peptides (GHRP’s). Success is significantly augmented by exercising or fasting. See section on Peptide Therapies for more information.

Finally, the fun and pleasure part: weight loss as a function of pleasure. Do you feel like you are, ‘Stuck in a rut of sitting on your butt’? as Theresa Stevens is often quoted asking. Lose weight by dancing! Theresa further says, “As you love your body, your body will naturally become the body you love.’ To view and to purchase Theresa’s program: Watch video

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  • CAPSOL-T has 100-fold synergy compared to green tea alone.  This product is purported to inhibit the growth and division of cancer cells and not adversely affect normal cells. Useful for elevated PSA.Click here to order.
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  • METAGENICS Supplements. Outstanding products, particularly for Hot Flashes and Adrenal Formulations. Click to order
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  • PURE ENCAPSULATIONS Many excellent nutritional supplements! Call them and tell them you are a patient of Dr. Bieley’s.
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  • MYOMIN is a product that competes with xenoestrogens and prevents them from attaching to receptors and causing their disruptive effects. It also helps to prevent estrogen dominance. This product helps both men and women.  . http://chi-health.com/Products/MYOMIN.html
  • ORTHO MOLECULAR PRODUCTS. Features Bergamot product for lowering cholesterol and to improve other lipids. Order from www.fullscript.com

Annatto Tocotrienols are the best source for Tocotrientols and play a significant role in the prevention of cardiovascular disease and much more. See videos from Dr. Barry Tan, Ph.D. on Youtube.  See video. and See another Video.

By measuring your current hormone levels, treating you, and then re-measuring your subsequent hormone levelsthis is the safest method for bringing your hormones into balance. We resolve hormonal imbalance and put things into hormonal balance.

Why Should You Consider BHRT?

Bioidentical hormone replacement therapy helps improve or eliminate hormonally created symptoms, such as PMS symptoms, the symptoms of Andropause (from low male hormones such as testosterone), and the symptoms of menopause misery (the hot flashes, vaginal dryness, night sweats, belly fat, dry skin, memory loss, and fatigue) to improve your energy, memory, mood, and sexual functioning.

We can help you become more stress-resilient to avoid burnout. We can improve the function of your thyroid and can help you normalize TPO antibodies if you suffer from Hashimoto’s thyroiditis, replenish low testosterone, oestrogen, progesterone, DHEA, cortisol, pregnenolone, oxytocin, growth hormone, insulin, parathyroid hormone, and others. We use natural hormones to help create balance, which can protect you from the development of breast cancer or endometrial carcinoma.

We also offer Estrogen Metabolism Gene Testing, which can indicate what abnormal genes you have in estrogen metabolism. Once we discover your vulnerabilities, we can offer you targeted supplements to help re-route estrogen down a healthy pathway, instead of one that predisposes you to developing breast or endometrial cancer.

Gene testing, as we say, is the clarion call, the jarring gong of reality to let you know what your genetic vulnerabilities are, and what we can do about them. By undergoing gene testing, and taking proper action via targeted nutritional supplementation, we can lower the risk of breast cancer.

Who Should Do Gene Testing?

All women have this option offered to them. It is especially important if there is a previous history of breast cancer, or a family history of breast cancer. Of course, if there is an interest, all patients can do this testing now. It’s not especially pricey.

In addition, we not only offer gene testing for estrogen metabolism, but also for heart disease, stroke, and osteoporosis genes. If there is a family history of these conditions, patients are offered this kind of testing at the beginning, or anytime during their treatment. However, we often offer this before the start of bio-identical hormone replacement therapy.

Once these abnormal genes are identified, we can impact their expression through a variety of ways — be it lifestyle modifications, or through supplemental vitamins and minerals that make these pathways work properly.

In addition to these gene tests, we offer poly-pharmacy (multiple medicine) gene testing to see the likelihood of drug/drug interactions that will make the metabolism of the medicines slow down tremendously (consequently making you need less of it to treat your ailment) or speed up significantly (consequently requiring you to adjust your dosage to make them effective).

If you have never felt well, or have bouts of depression throughout your life, we look at your hormones and also offer a total methylation panel gene testing. We may uncover some relevant yet previously unknown connections, and help empower you to overcome these seemingly unsurpassable circumstances.

When we find abnormal genes, called snips (single nucleotide polymorphisms), we can give targeted nutrients that help these genes function better. Along with some proper lifestyle changes, you will have the opportunity to live the life you love.

How BHRT Helps Menopausal Women

Bioidentical hormone therapy for women: It’s not a fun experience to be visited by the ‘Seven dwarves of menopause’ Suzanne Somers wrote about: itchy, bitchy, sweaty, bloaty, sleepy, forgetful, and all dried up!

All the menopause symptoms are really a result of Progesterone deficiency. Supplementation of progesterone will help alleviate these symptoms. We look at all of the sex hormones, in addition to thyroid and adrenals, and by looking and treating the totality of your situation, we have the best chance of obtaining hormonal harmony and balance, and you become yourself again, symptom-free!

Menopausal symptom manifestation in post menopausal women is due to them typically having their ‘tank’ empty, and just flying on fumes. This means their hormone output is low, and they will benefit greatly by replenishing them through bio-identical estrogens (estradiol and estriol, to help alleviate vaginal dryness), bio-identical or natural progesterone therapy (creams or pills), and testosterone (yes, women need it too to help prevent loss of muscle and bone).

It typically takes six to nine months, in general, for hormone replenishment to occur,  and we monitor hormone levels every three months unless there is a special need for earlier testing.

The goal is not only to normalize lab results, but to have you feeling normal, like yourself, again. Remember, you are the patient, and we are treating you — you are not a lab test!

Also, we do not use synthetic estrogens, only bio-identical hormones —  the hormones your body has made all through your life. We also never use oral estrogens, which can increase the risk of gallbladder issues, and they can alter your body lipids in an unfavorable direction.

By sticking to topical application with estrogen creams, or by putting the cream in the vagina, we are able to bypass the liver and avoid these problems. We also, in the appropriate patient, treat with bioidentical hormones after breast cancer treatment.

Although controversial, many women are desperate for symptom relief. In certain groups of women, we can administer them safely with regular monitoring at different times. Clinical trials have shown this can be done safely and effectively.

Bioidentical Hormone Replacement Therapy for Men

Testosterone replacement and key nutrients help men avoid becoming the proverbial ‘grumpy old man.’ These men have a pervasive sense of fatigue and loss of mental and physical sharpness.  

Therapy reverses this, and the effect is a better quality of life. There are multiple ways to increase testosterone in men. We pay particular attention to younger men, as the causes for low testosterone are variable. Treatments offered include Clomid stimulation testing  (Clomiphene) , HCG stimulation testing (human chorionic gonadotropin), and testosterone (creams, gels, injections), and peptide therapies such as Deep or Delta Sleep Inducing Peptide (known as DSIP) and also Kisspeptin.

What is peptide therapy? This treatment sends signals to accelerate your body’s ability to heal, remember, have sexual desire, improve function, and more.

For all men to achieve the beneficial effects of testosterone replacement therapy, their total testosterone levels need to be in the upper quartile of young men.  Being within a ‘normal range’ has not been shown to obtain the beneficial effects of testosterone replacement therapy.

The benefits of testosterone therapy include: decrease in all-cause mortality, decrease in depression symptoms, and decrease in sexual dysfunction (that means good libido, sustainable erections, and orgasm).

Bioidentical Hormone Therapies for Psychological and Psychiatric Issues

For Sleep disorders, Burn-out Syndrome, Sexual Arousal, Depression, slowed progression of Alzheimer’s disease, Irritability & Anxiety, Chronic tendency to Social Withdrawal, Bipolar disorder, and Schizophrenia, the judicious use bio-identical hormones, coupled with targeted nutrient therapy, can be quite helpful.

For women, the benefits of bio-identical hormone therapy include:

  • better energy
  • better memory
  • better mood
  • improved sleep
  • prevention of frailty
  • improved muscles
  • improved bones
  • better heart health
  • improved libido and orgasms
  • better immune function
  • reduced PMS symptoms
  • reduced symptoms of menopause
  • … and more!

For men, if your hormones are out of balance, you may have some or all of the following hormone imbalance symptoms:

  1.    A pervasive sense of fatigue – you feel tired all day!
  2.    Losing mental and/or physical ‘edge’
  3.    ‘Couch potato’ after 5 pm
  4.    Workouts do not produce the results of the past
  5.    Aches and pains (particularly in the neck and shoulders)
  6.    Sexual functioning decreased- unable to obtain or maintain erections, less ejaculate, etc…
  7.    Loss of self-confidence
  8.    Poor sleep
  9.    Less focused thinking
  10. Depression

These symptoms can be reversed with bio-identical hormone replacement therapy. For example, testosterone replacement can sharpen a man’s focus and mental clarity, improve self-esteem and self-confidence, help prevent heart disease by decreasing inflammation, improve blood sugars, helps build bone, helps build muscle, workouts are more productive, and improves sexual functioning.

By combining the work of hormone replacement with nutritional assessments, environmental toxins evaluations, and gene testing for methylation issues and more, we offer you the best chance of becoming well and functioning at your best.

We also offer toxic heavy metals testing and treatment, assessment of environmental toxins, such as mold mycotoxins, and offer modern therapy to remove the offending substance, be it a metal or a mycotoxin.

Once diagnosed, chelation therapy based on the binding coefficient of the metals is offered. If mold mycotoxins are discovered to be present, we offer comprehensive therapy to kill the mold, boost your immune system, boost your overall nutritional status, and decrease the Herxheimer reaction symptoms that often accompany the die-off from the treatment.

These symptoms are usually headache, profound fatigue, stomach discomfort. We further offer brain fitness to quicken your thought processes, and improve your memory. We can add this for men and women as a regular component of their consults.

There are many nutrients, hormones, and other substances that improve  brain processing speed and we routinely take advantage of them, in the course of our consultation with our patients, should they request help in this domain.

The expression “You are only as strong as your weakest part” is demonstrated on a regular basis, so we attempt to address these issues so you can lead a better life.

You have to prime the pump with mild to moderate exercise and high-end nutrition if you want to get the best results with hormones. That means:

  • whey protein or protein with branched-chain amino acids (BCCAs — particularly the amino acid Leucine) in protein shakes with dietary choline of some form to balance the sympathetic vs. parasympathetic nervous system
  • beet crystals to increase nitric oxide to relax the endothelium and lower blood pressure
  • minerals such as magnesium and potassium to get optimal results.

We use functional needs testing and nutritional testing, which include organic acids testing, fatty acids testing, amino acids testing and the functional need for B-vitamins and oxidative stress markets. This kind of testing best predicts what your functional needs requirements are for different nutrients (vitamins and minerals and antioxidants).  

As you can see, bio-identical hormone replacement therapy does not stand alone. It is bolstered by:

  • great nutrition
  • gene testing with supplementation
  • removal of environmental toxins including overbearing stress (we do a thorough evaluation of your adrenals, with questionnaires, and saliva testing)
  • other hormone testing
  • lifestyle modification, which includes getting proper sleep totally necessary for weight loss goals
  • peptide therapies, which is the regenerative part of medicine

LINK LINK

Peptide therapies can bolster the effects of hormones and getting well physically, emotionally, and sexually.  

Northern Virginia Weight Loss | 703-844-0184 | NOVA Health Recovery |

NOVA Health Recovery | Alexandria, Va 22306 | 703-844-0184 | Call for medical weight loss

FABP2 Gene in focus

FABP2, a gene that appears in both the carbohydrate and saturated fat parts of our reports. This gene creates a protein called Fatty Acid Binding Protein-2, which is found in our small intestines. FABP2 binds to the various different fatty acids, and allows them to be absorbed into the body.

The single nucleotide polymorphism (SNP) that we are interested in occurs when an alanine nucleotide is swapped for a threonine nucleotide; this substitution causes the protein to become more efficient. So efficient, in fact, that it doubles the speed at which we absorb these fats, leading to an increase of fat in the blood stream.

So what effect does this have in the real world? One study, published in 2007 in the American Journal of Clinical Nutrition gives us some idea. The researchers got 122 elderly adults, and put them through a number of different tests to see how they tolerated different types of foods. Those with at least one A allele of FABP2 were less likely to have normal blood glucose levels, both after fasting and after having a big meal. This indicates that they were at risk of developing insulin resistance, which can eventually become type-II diabetes. If we know that A allele carriers are more likely to develop type-II diabetes, then we can give them dietary advice which might help to reduce their risk, such as consuming a diet lower in simple and refined carbohydrates.

We’ve looked at the effects of FABP2 on our carbohydrate sensitivity, but how about saturated fats? A meta-analysis published in 2010 gives us an insight into this. Meta-analyses are useful tools for researchers and medical professionals, as they analyse the data of existing research in a particular area, and summarise it to give us a better idea of the current evidence in that field. The results from this meta-analysis looked at 30 different studies, with over 14,000 subjects. It found that A-allele carriers of FABP2 were significantly more likely to have higher concentrations of total- and LDL-cholesterol (LDL cholesterol is commonly known as “bad” cholesterol), and lower levels of HDL-cholesterol (“good” cholesterol) – showing quite nicely that this gene influences how much fat we should have in our diet.

We use FABP2 alongside a number of other genes to give each person an idea of their individual response to both carbohydrates and fats, information that we can then use to determine the optimal diet type for weight management. The below table summarises the main findings regarding FABP2:

FABP2 GenotypeFindings
GGThis genotype is not associated with an increased sensitivity to saturated fats or refined carbohydrates.
GAA single copy of the A allele is associated with a moderately increased sensitivity to saturated fats and refined carbohydrates.
AATwo copies of the A allele of FABP2 means that this genotype is associated with a significantly increased sensitivity to both saturated fats and refined carbohydrates.

DNA Fit blog

DNA Fit blog

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Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

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Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

A version of the club drug is expected to be approved for depression in March. Researchers think it could help treat suicidal thinking.

Joe Wright has no doubt that ketamine saved his life. A 34-year-old high school teacher who writes poetry every day on a typewriter, Wright was plagued by suicidal impulses for years. The thoughts started coming on when he was a high schooler himself, on Staten Island, N.Y., and intensified during his first year of college. “It was an internal monologue, emphatic on how pointless it is to exist,” he says. “It’s like being ambushed by your own brain.”

He first tried to kill himself by swallowing a bottle of sleeping pills the summer after his sophomore year. Years of treatment with Prozac, Zoloft, Wellbutrin, and other antidepressants followed, but the desire for an end was never fully resolved. He started cutting himself on his arms and legs with a pencil-sharpener blade. Sometimes he’d burn himself with cigarettes. He remembers few details about his second and third suicide attempts. They were halfhearted; he drank himself into a stupor and once added Xanax into the mix.

Wright decided to try again in 2016, this time using a cocktail of drugs he’d ground into a powder. As he tells the story now, he was preparing to mix the powder into water and drink it when his dog jumped onto his lap. Suddenly he had a moment of clarity that shocked him into action. He started doing research and came upon a Columbia University study of a pharmaceutical treatment for severe depression and suicidality. It involved an infusion of ketamine, a decades-old anesthetic that’s also an infamous party drug. He immediately volunteered.

His first—and only—ketamine infusion made him feel dreamlike, goofy, and euphoric. He almost immediately started feeling more hopeful about life. He was more receptive to therapy. Less than a year later, he married. Today he says his dark moods are remote and manageable. Suicidal thoughts are largely gone. “If they had told me how much it would affect me, I wouldn’t have believed it,” Wright says. “It is unconscionable that it is not already approved for suicidal patients.”

The reasons it isn’t aren’t strictly medical. Over the past three decades, pharmaceutical companies have conducted hundreds of trials for at least 10 antidepressants to treat severe PMS, social anxiety disorder, and any number of conditions. What they’ve almost never done is test their drugs on the sickest people, those on the verge of suicide. There are ethical considerations: Doctors don’t want to give a placebo to a person who’s about to kill himself. And reputational concerns: A suicide in a drug trial could hurt a medication’s sales prospects.

The risk-benefit calculation has changed amid the suicide epidemic in the U.S. From 1999 to 2016, the rate of suicides increased by 30 percent. It’s now the second-leading cause of death for 10- to 34-year-olds, behind accidents. (Globally the opposite is true: Suicide is decreasing.) Growing economic disparity, returning veterans traumatized by war, the opioid crisis, easy access to guns—these have all been cited as reasons for the rise in America. There’s been no breakthrough in easing any of these circumstances.

But there is, finally, a serious quest for a suicide cure. Ketamine is at the center, and crucially the pharmaceutical industry now sees a path. The first ketamine-based drug, from Johnson & Johnson, could be approved for treatment-resistant depression by March and suicidal thinking within two years. Allergan Plc is not far behind in developing its own fast-acting antidepressant that could help suicidal patients. How this happened is one of the most hopeful tales of scientific research in recent memory.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Dennis Charney at Mount Sinai.PHOTOGRAPHER: MAX AGUILERA-HELLWEG FOR BLOOMBERG BUSINESSWEEK

Dennis Charney, dean of the Icahn School of Medicine at Mount Sinai in New York, works from an office filled with family pictures, diplomas, and awards from a long career in research. One thing on the wall is different from the rest: a patent for the use of a nasal-spray form of ketamine as a treatment for suicidal patients. The story of the drug is in some ways the story of Charney’s career.

In the 1990s he was a psychiatry professor, mentoring then associate professor John Krystal at Yale and trying to figure out how a deficit of serotonin played into depression. Back then, depression research was all about serotonin. The 1987 approval of Prozac, the first selective serotonin reuptake inhibitor, or SSRI, ushered in an era of what people in the industry call me-too drug development, research that seeks to improve on existing medicines rather than exploring new approaches. Within this narrow range, pharmaceutical companies churned out blockbuster after blockbuster. One in eight Americans age 12 and older reported using antidepressants within the past month, according to a survey conducted from 2011 to 2014 by the U.S. Centers for Disease Control and Prevention.

Charney was a depression guy; Krystal was interested in schizophrenia. Their curiosity led them to the same place: the glutamate system, what Krystal calls the “main information highway of the higher brain.” (Glutamate is an excitatory neurotransmitter, which helps brain cells communicate. It’s considered crucial in learning and memory formation.) They had already used ketamine to temporarily produce schizophrenia-like symptoms, to better understand glutamate’s role in that condition. In the mid-1990s they decided to conduct a single-dose study of ketamine on nine patients (two ultimately dropped out) at the Yale-affiliated VA Connecticut Healthcare System in West Haven to see how depressed people would react to the drug.

“If we had done the typical thing … we would have completely missed the antidepressant effect”

Outside the field of anesthesiology, ketamine is known, if it’s known at all, for its abuse potential. Street users sometimes take doses large enough to enter what’s known as a “K hole,” a state in which they’re unable to interact with the world around them. Over the course of a day, those recreational doses can be as much as 100 times greater than the tiny amount Charney and Krystal were planning to give to patients. Nonetheless, they decided to monitor patients for 72 hours—well beyond the two hours that ketamine produces obvious behavioral effects—just to be careful not to miss any negative effects that might crop up. “If we had done the typical thing that we do with these drug tests,” Krystal says, “we would have completely missed the antidepressant effect of ketamine.”

Checking on patients four hours after the drug had been administered, the researchers saw something unexpected. “To our surprise,” Charney says, “the patients started saying they were better, they were better in a few hours.” This was unheard of. Antidepressants are known for taking weeks or months to work, and about a third of patients aren’t sufficiently helped by the drugs. “We were shocked,” says Krystal, who now chairs the Yale psychiatry department. “We didn’t submit the results for publication for several years.”

When Charney and Krystal did publish their findings, in 2000, they attracted almost no notice. Perhaps that was because the trial was so small and the results were almost too good to be true. Or maybe it was ketamine’s reputation as an illicit drug. Or the side effects, which have always been problematic: Ketamine can cause patients to disassociate, meaning they enter a state in which they feel as if their mind and body aren’t connected.

But probably none of these factors mattered as much as the bald economic reality. The pharmaceutical industry is not in the business of spending hundreds of millions of dollars to do large-scale studies of an old, cheap drug like ketamine. Originally developed as a safer alternative to the anesthetic phencyclidine, better known as PCP or angel dust, ketamine has been approved since 1970. There’s rarely profit in developing a medication that’s been off patent a long time, even if scientists find an entirely new use for it.

Somehow, even with all of this baggage, research into ketamine inched forward. The small study that almost wasn’t published has now been cited more than 2,000 times.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
John Mann in his office at Columbia’s New York State Psychiatric Institute. 

Suicide is described in medicine as resulting from a range of mental disorders and hardships—a tragedy with many possible roots. Conditions such as severe depression, bipolar disorder, and schizophrenia are known risk factors. Childhood trauma or abuse may also be a contributor, and there may be genetic risk factors as well.

From these facts, John Mann, an Australian-born psychiatrist with a doctorate in neurochemistry, made a leap. If suicide has many causes, he hypothesized, then all suicidal brains might have certain characteristics in common. He’s since done some of the most high-profile work to illuminate what researchers call the biology of suicide. The phrase itself represents a bold idea—that there’s an underlying physiological susceptibility to suicide, apart from depression or another psychiatric disorder.

Mann moved to New York in 1978, and in 1982, at Cornell University, he started collecting the brains of people who’d killed themselves. He recruited Victoria Arango, now a leading expert in the field of suicide biology. The practice of studying postmortem brain tissue had largely fallen out of favor, and Mann wanted to reboot it. “He was very proud to take me to the freezer,” Arango says of the day Mann introduced her to the brain collection, which then numbered about 15. “I said, ‘What am I supposed to do with this?’ ”

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Some of Mann’s brain collection. 

They took the work, and the brains, first to the University of Pittsburgh, and then, in 1994, to Columbia. They’ve now amassed a collection of some 1,000 human brains—some from suicide victims, the others, control brains—filed neatly in freezers kept at –112F. The small Balkan country of Macedonia contributes the newest brains, thanks to a Columbia faculty member from there who helped arrange it. The Macedonian brains are frozen immediately after being removed and flown in trunks, chaperoned, some 4,700 miles to end up in shoe-box-size, QR-coded black boxes. Inside are dissected sections of pink tissue in plastic bags notated with markers: right side, left side, date of collection.

In the early 1990s, Mann and Arango discovered that depressed patients who killed themselves have subtle alterations in serotonin in certain regions of the brain. Mann remembers sitting with Arango and neurophysiologist Mark Underwood, her husband and longtime research partner, and analyzing the parts of the brain affected by the deficit. They struggled to make sense of it, until it dawned on them that these were the same brain regions described in a famous psychiatric case study. In 1848, Phineas Gage, an American railroad worker, was impaled through the skull by a 43-inch-long tamping iron when the explosives he was working with went off prematurely. He survived, but his personality was permanently altered. In a paper titled “Recovery From the Passage of an Iron Bar Through the Head,” his doctor wrote that Gage’s “animal propensities” had emerged and described him as using the “grossest profanity.” Modern research has shown that the tamping iron destroyed key areas of the brain involved in inhibition—the same areas that were altered in the depressed patients who’d committed suicide. For the group, this was a clue that the differences in the brain of suicidal patients were anatomically important.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Columbia’s Victoria Arango. 

“Most people inhibit suicide. They find a reason not to do it,” Underwood says. Thanks to subtle changes in the part of the brain that might normally control inhibition and top-down control, people who kill themselves “don’t find a reason not to do it,” he says.

About eight years ago, Mann saw ketamine research taking off in other corners of the scientific world and added the drug to his own work. In one trial, his group found that ketamine treatment could ease suicidal thoughts in 24 hours more effectively than a control drug. Crucially, they found that the antisuicidal effects of ketamine were to some extent independent of the antidepressant effect of the drug, which helped support their thesis that suicidal impulses aren’t necessarily just a byproduct of depression. It was this study, led by Michael Grunebaum, a colleague of Mann’s, that made a believer of Joe Wright.

“It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off”

In 2000, the National Institutes of Health hired Charney to run both mood disorder and experimental drug research. It was the perfect place for him to forge ahead with ketamine. There he did the work to replicate what he and his colleagues at Yale had discovered. In a study published in 2006, led by researcher Carlos Zarate Jr., who now oversees NIH studies of ketamine and suicidality, an NIH team found that patients had “robust and rapid antidepressant effects” from a single dose of the drug within two hours. “We could not believe it. In the first few subjects we were like, ‘Oh, you can always find one patient or two who gets better,’ ” Zarate recalls.

In a 2009 study done at Mount Sinai, patients suffering from treatment-resistant depression showed rapid improvement in suicidal thinking within 24 hours. The next year, Zarate’s group demonstrated antisuicidal effects within 40 minutes. “That you could replicate the findings, the rapid findings, was quite eerie,” Zarate says.

Finally ketamine crossed back into commercial drug development. In 2009, Johnson & Johnson lured away Husseini Manji, a prominent NIH researcher who’d worked on the drug, to run its neuroscience division. J&J didn’t hire him explicitly to develop ketamine into a new pharmaceutical, but a few years into his tenure, Manji decided to look into it. This time it would come in a nasal-spray form of esketamine, a close chemical cousin. That would allow for patent protection. Further, the nasal spray removes some of the challenges that an IV form of the drug would present. Psychiatrists, for one thing, aren’t typically equipped to administer IV drugs in their offices.

While these wheels were slowly turning, some doctors—mostly psychiatrists and anesthesiologists—took action. Around 2012 they started opening ketamine clinics. Dozens have now popped up in major metropolitan areas. Insurance typically won’t touch it, but at these centers people can pay about $500 for an infusion of the drug. It was at one time a cultural phenomenon—a 2015 Bloomberg Businessweek story called it “the club drug cure.” Since then, the sense of novelty has dissipated. In September the American Society of Ketamine Physicians convened its first medical meeting about the unconventional use of the drug.

“You are literally saving lives,” Steven Mandel, an anesthesiologist-turned-ketamine provider, told a room of about 100 people, mostly doctors and nurse practitioners, who gathered in Austin to hear him and other early adopters talk about how they use the drug. Sporadic cheers interrupted the speakers as they presented anecdotes about its effectiveness.

There were also issues to address. A consensus statementin JAMA Psychiatry published in 2017 said there was an “urgent need for some guidance” on ketamine use. The authors were particularly concerned with the lack of data about the safety of prolonged use of the drug in people with mood disorders, citing “major gaps” in the medical community’s knowledge about its long-term impact.

The context for the off-label use of ketamine is a shrinking landscape for psychiatry treatment. An effort to deinstitutionalize the U.S. mental health system, which took hold in the 1960s, has almost resulted in the disappearance of psychiatric hospitals and even psychiatric beds within general hospitals. There were 37,679 psychiatric beds in state hospitals in 2016, down from 558,922 in 1955, according to the Treatment Advocacy Center. Today a person is often discharged from a hospital within days of a suicide attempt, setting up a risky situation in which someone who may not have fully recovered ends up at home with a bunch of antidepressants that could take weeks to lift his mood, if they work at all.

A ketamine clinic can be the way out of this scenario—for people with access and means. For Dana Manning, a 53-year-old Maine resident who suffers from bipolar disorder, $500 is out of reach. “I want to die every day,” she says.

After trying to end her life in 2003 by overdosing on a cocktail of drugs including Xanax and Percocet, Manning tried virtually every drug approved for bipolar disorder. None stopped the mood swings. In 2010 the depression came back so intensely that she could barely get out of bed and had to quit her job as a medical records specialist. Electroconvulsive therapy, the last-ditch treatment for depressed patients who don’t respond to drugs, didn’t help.

Her psychiatrist went deep into the medical literature to find options and finally suggested ketamine. He was even able to get the state Medicaid program to cover it, she says. She received a total of four weekly infusions before she moved to Pennsylvania, where there were more family members nearby to care for her.

The first several weeks following her ketamine regimen were “the only time I can say I have felt normal” in 15 years, she says. “It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off.”

She’s now back in Maine, and the depression has returned. Her current Medicare insurance won’t cover ketamine. She lives on $1,300 a month in disability income. “Knowing it is there and I can’t have it is beyond frustrating,” she says.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Mark Underwood at the New York State Psychiatric Institute. 

Ketamine is considered a “dirty” drug by scientists—it affects so many pathways and systems in the brain at the same time that it’s hard to single out the exact reason it works in the patients it does help. That’s one reason researchers continue to look for better versions of the drug. Another, of course, is that new versions are patentable. Should Johnson & Johnson’s esketamine hit the market, the ketamine pioneers and their research institutions stand to benefit. Yale’s Krystal, NIH’s Zarate, and Sinai’s Charney, all of whom are on the patent on Charney’s wall, will collect royalties based on the drug’s sales. J&J hasn’t said anything about potential pricing, but there’s every reason to believe the biggest breakthrough in depression treatment since Prozac will be expensive.

The company’s initial esketamine study in suicidal patients involved 68 people at high risk. To avoid concerns about using placebos on actively suicidal subjects, everyone received antidepressants and other standard treatments. About 40 percent of those who received esketamine were deemed no longer at risk of killing themselves within 24 hours. Two much larger trials are under way.

When Johnson & Johnson unveiled data from its esketamine study in treatment-resistant depression at the American Psychiatric Association meeting in May, the presentation was jammed. Esketamine could become the first-ever rapid-acting antidepressant, and physicians and investors are clamoring for any information about how it works. The results in suicidal patients should come later this year and could pave the way for a Food and Drug Administration filing for use in suicidal depressed patients in 2020. Allergan expects to have results from its suicide study next year, too.

“The truth is, what everybody cares about is, do they decrease suicide attempts?” says Gregory Simon, a psychiatrist and mental health researcher at Kaiser Permanente Washington Health Research Institute. “That is an incredibly important question that we hope to be able to answer, and we are planning for when these treatments become available.”

Exactly how ketamine and its cousin esketamine work is still the subject of intense debate. In essence, the drugs appear to provide a quick molecular reset button for brains impaired by stress or depression. Both ketamine and esketamine release a burst of glutamate. This, in turn, may trigger the growth of synapses, or neural connections, in brain areas that may play a role in mood and the ability to feel pleasure. It’s possible the drug works to prevent suicide by boosting those circuits while also reestablishing some of the inhibition needed to prevent a person from killing himself. “We certainly think that esketamine is working exactly on the circuitry of depression,” Manji says. “Are we homing in exactly on where suicidal ideation resides?” His former colleagues at NIH are trying to find that spot in the brain as well. Using polysomnography—sleep tests in which patients have nodes connected to various parts of their head to monitor brain activity—as well as MRIs and positron emission tomography, or PET scans, researchers can see how a patient’s brain responds to ketamine, to better understand exactly what it’s doing to quash suicidal thinking.

Concerns about the side effects of ketamine-style drugs linger. Some patients taking esketamine have reported experiencing disassociation symptoms. Johnson & Johnson calls the effects manageable and says they cropped up within an hour of the treatment, a period in which a person on the drug would likely be kept in the doctor’s office for monitoring. Some patients also experienced modest spikes in blood pressure within the same timeframe.

Nasal-spray dosing brings other issues. The Black Dog Institute in Australia and the University of New South Wales in Sydney, which teamed up to study a nasal-spray form of ketamine, published their findings last March in the Journal of Psychopharmacology. The researchers found that absorption rates were variable among patients. J&J says its own studies with esketamine contradict these findings.

But in the wake of the opioid crisis, perhaps the biggest worry is that loosening the reins too much on the use of ketamine and similar drugs could lead to a new abuse crisis. That’s why Wall Street analysts are particularly excited by Allergan’s rapid-acting antidepressant, rapastinel, which is about a year behind esketamine in testing. Researchers say it likely acts on the same target in the brain as ketamine, the NMDA receptor, but in a more subtle way that may avoid the disassociation side effects and abuse potential. Studies in lab animals show the drug doesn’t lead creatures to seek more of it, as they sometimes do with ketamine, says Allergan Vice President Armin Szegedi. Allergan’s medicine is an IV drug, but the company is developing an oral drug.

For its suicide study, Allergan is working hard to enroll veterans, one of the populations most affected by the recent spike in suicides, and has included several U.S. Department of Veterans Affairs medical centers as sites in the trial. More than 6,000 veterans died by suicide each year from 2008 to 2016, a rate that’s 50 percent higher than in the general population even after adjusting for demographics, according to VA data.

“How the brain mediates what makes us who we are is still a mystery, and maybe we will never fully understand it,” Szegedi says. “What really changed the landscape here is you had clinical data showing ‘This really does the trick.’ Once you find something in the darkness, you really have to figure out: Can you do something better, faster, safer?”

If you or someone you know is having suicidal thoughts, the National Suicide Prevention hotline is 1 (800) 273 8255.

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Depression Linked With Brain Inflammation, Opening Up New Avenues For Treatment

Diagnosing a patient with clinical depression can be difficult; depression is a complex illness that can be caused by one or a mix of many things, from environmental stressors to genetics. But a new study out of the Centre for Addiction and Mental Health (CAMH) has highlighted a link between clinical depression and brain inflammation that might be crucial in better understanding stress and depression’s physical impacts on the body, as well as in developing better treatments for these mental health issues.

In the study, published in JAMA Psychiatry, the researchers found that people with clinical depression had a 30 percent increase in brain inflammation, also referred to as neuroinflammation. It’s uncertain whether the inflammation caused the depression or vice versa, or if it’s simply a correlation. But the study makes it clear that the link should be further examined.

“This finding provides the most compelling evidence to date of brain inflammation during a major depressive episode,” Dr. Jeffrey Meyer of CAMH’s Campbell Family Mental Health Research Institute said in the press release. “Previous studies have looked at markers of inflammation in blood, but this is the first definitive evidence found in the brain.”

The authors took brain scans of 20 patients who were suffering from depression but were otherwise healthy, as well as of 20 control patients. They found that people with depression were more likely to suffer a higher rate of inflammation in their brains, and people with the most severe depression had the highest rates of all. While inflammation can protect the brain and other tissues when triggered by the immune system, too much of it can cause damage.

How Stress Fosters Inflammation

Whenever the immune system is attacked by infections (viruses or bacteria), toxins, or even physical injury (such as a knee injury), it creates an inflammatory response — sending out messengers known as cytokines, which are either pro-inflammatory or anti-inflammatory. Damaged cells release chemicals including histamine, bradykinin, and prostaglandins, which cause blood vessels to leak fluid into tissues and create tissue swelling. While acute or short-term inflammation is a protective feature of the immune system, chronic inflammation can cause simultaneous destruction and healing of the tissues, ultimately wreaking havoc on your body long-term.

It’s not only physical injury or infections that can trigger an immune response; stress and emotional trauma cause inflammation as well. Long-term or chronic stress has actually been shown to change the gene activity of immune cells before they enter the bloodstream, priming them to fight infection when there is no infection. As a result, inflammation occurs unnecessarily but still wreaks havoc on tissues and body processes. Chronic inflammation is often associated with cancer and other disorders such as heart disease and high cholesterol. Brain inflammation, meanwhile, has been linked to several disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.

Treating Inflammation To Target Depression

It’s possible that depression changes immune responses and triggers inflammation similar to how stress does. It’s not entirely certain. But the notion that depression is somehow linked to inflammation isn’t a new one. In fact, though there is currently no FDA-approved medication to treat depression-related brain inflammation, researchers have examined such therapies in the past. In a 2014 study, researchers provided patients with anti-inflammatory treatment and found that it reduced depressive symptoms.

Some physicians believe that depression and inflammation are linked by a build-up of both physical injuries and emotional stress in a person’s past, and these things can be difficult to treat with one single therapy. “When remnants of old wounds are left unresolved, they build up inside the body,” Gary Kaplan, DO, an osteopathic physician and founder of the Kaplan Center for Integrative Medicine, told Prevention. “So it makes sense that a woman who was raped as a child and gets a concussion in her 20s could develop fibromyalgia and clinical depression. These events may seem unrelated, but all of them result in chronic neuroinflammation.”

Kaplan, as an osteopathic physician who takes a more holistic approach to medicine, hasn’t been waiting for an FDA-approved drug that treats brain inflammation; he’s been attempting to treat patients who have been suffering from chronic depression and inflammation on his own. His therapies often involve a mix of acupuncture, psychotherapy, several anti-inflammatory drugs like Celebrex (which is used to treat arthritis), and craniosacral therapy (massaging the head and neck to relieve tension). But the evidence of their efficacy still remains scarce, and more studies will be needed to better mold a conclusion.

“We’re not going to help people who are depressed and in pain if we don’t spend time finding out about them as whole people with histories that greatly influence their health,” Kaplan told Prevention. “Neuroinflammation is not the answer to everything, but understanding it is extremely important. It will eventually change how we treat these reversible diseases.”

Indeed, Meyer and his team who’ve published the most recent study on brain inflammation feel the same way. “Depression is a complex illness and we know that it takes more than one biological change to tip someone into an episode,” Meyer said in the press release. “But we now believe that inflammation in the brain is one of these changes that’s an important step forward.”

Source: Setiawan E, Wilson A, Mizrahi R, Rusjan P, Miler L, Rajkowska G. “Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes.” JAMA Psychiatry, 2015.

Role of Translocator Protein Density, a Marker of neuroinflammation in the brain during major depression episodes

The Brain on Fire: Inflammation and Depression

Inflammation and Its Effects on Mood

We have all had the flu or at least know what it feels like.

The miserable collection of symptoms includes lack of energy, difficulty concentrating, sleepiness, loss of appetite, and general malaise.

For most of us these symptoms disappear within a few days. For some, it takes much longer. Although we tend to blame the influenza virus for making us feel miserable, the symptoms are actually a result of our immune system trying to combat the virus.

The symptoms of the flu are brought on by proteins, pro-inflammatory cytokines, our bodies produce in order to fight the flu and other infections.

When the immune system is under attack from physical injury, infections, or toxins, the immune system generates an inflammatory response. Inflammation is a normal physiological process that is now understood to play a major role in many chronic medical illnesses, including cancer, heart disease, diabetes, asthma, and obesity. In each of these cases inflammation causes the release of cytokines. Cytokines, which come in many different classes, including anti- and pro-inflammatory, behave as messengers and signal cells of the immune system.

The effects of pro-inflammatory cytokines can cause a diverse array of physical and psychological symptoms. When this happens it is referred to as sickness behavior.

Recently, scientists have been able to demonstrate how the symptoms of sickness behavior mirror those of depression. Researchers and healthprofessionals are now beginning to understand the connection between inflammation and depression.

  1. One study found that patients with major depressive disorder had significantly higher levels of the pro-inflammatory cytokine TNF-alpha than their non-depressed counterparts. In addition, patients with depression had low levels of anti-inflammatory cytokines.
  2. Researchers have also found that eight weeks of Zoloft treatment was able to decrease some pro-inflammatory cytokines seen in depressed patients. On Zoloft, the depressed patients also saw an increase in anti-inflammatory cytokines.
  3. A study involving depressed patients classified as non-responders supplemented the patients’ standard antidepressant treatment with the addition of aspirin, an anti-inflammatory. More than 50% of these patients responded to this combination treatment. At the end of the study more than 80% of the group responsive to the anti-inflammatory went into remission.

Cytokines, the messengers during inflammation, are also used to treat infections and autoimmune disorders. So-called autoimmune disorders are clear examples of how an unregulated immune system can cause destructive damage to many different organs and tissues. Some of the most common autoimmune diseases include rheumatoid arthritis, multiple sclerosis, thyroid disease, and celiac disease.

Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection.  Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It’s been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.

In one study, nearly a third of patients with chronic hepatitis C who received interferon treatment displayed psychiatric symptoms after four weeks of treatment. Symptoms included mania, hypomania, and depression.  Over the years I have had to admit patients for inpatient psychiatric treatment for depression and suicidal behavior following interferon therapy.

It appears that inflammation and the complicated collection of immune system chemical messengers called cytokines play an important role in brain function and may cause psychological symptoms.

When the brain is aggravated by any source-stress, infections, trauma, stroke, poisons, or nutritional deficiencies-inflammation spurs the release of pro- inflammatory cytokines, which may affect mood. Scientists have proposed many mechanisms as to how this may occur.

One mechanism as to how an unregulated immune system may contribute to depression is quite well understood. Cytokines activate an enzyme, indoleamine 2,3-dioxygenase (IDO), which degrades serotonin resulting in low levels of the neurotransmitter. IDO also degrades the precursor to serotonin, tryptophan. Decreased levels of the neurotransmitter serotonin are likely the contributing factor to the development of depressive symptoms. The inflammatory process’ contribution to the constant destruction of serotonin decreases the chances of recovery.

For too many years we have tried to correlate depression with a deficiency of serotonin and related neurotransmitters in the brain. Using medications based on this theory has yielded dismal results, barely better than a placebo.  If we understand the underlying physiological abnormalities contributing to mood disorders, then we are likely to benefit from more effective solutions.

Understanding the connection between depression and inflammation gives researchers and pharmaceutical companies incentive to look for alternative medications to treat depression. In the meantime there are, however, well-researched lifestyle and nutritional interventions that are known to decrease inflammation and improve mood: exercise, stress reduction, nutritional supplements (i.e. omega-3 fatty acids), and optimizing vitamin D levels. Chronic stress is one of the major preventable contributors to inflammation and immune dysregulation.

For each individual the inflammatory response is likely precipitated by a unique and complex interaction of causative agents. Infection, stress, nutritional deficiencies, and sedentary lifestyles are the most common factors. Individual, personalized understanding of inflammation and its contributions to the physiology of mood disorders is a critical, but often neglected component of integrative therapies for depression. By neglecting the underlying cause of depression, recovery is less likely.

The immune-mediated alteration of serotonin and glutamate towards an integrated view of depression

Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation a pilot open-label study

Therapeutic Strategies for Treatment of Inflammation-related Depression

Pro- and Anti-Inflammatory Cytokine Balance in Major Depression

 

 

Chronic Stress Changes Immune Cell Genes, Leading To Inflammation: Study

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A new study provides a better understanding of why chronic stress leads to high levels of inflammation in the body.

Researchers found that chronic stress changes gene activity of immune cells before they enter the bloodstream so that they’re ready to fight infection or trauma — even when there is no infection or trauma to fight. This then leads to increased inflammation.

This phenomenon was seen in mice, as well as in blood samples from people with poor socioeconomic statuses (a predictor of chronic stress), reported the researchers from Ohio State University, the University of California, Los Angeles, Northwestern University and the University of British Columbia.

“There is a stress-induced alteration in the bone marrow in both our mouse model and in chronically stressed humans that selects for a cell that’s going to be pro-inflammatory,” study researcher John Sheridan, a professor at Ohio State University and associate director of the university’s Institute for Behavioral Medicine Research, said in a statement. “So what this suggests is that if you’re working for a really bad boss over a long period of time, that experience may play out at the level of gene expression in your immune system.”

Inflammation isn’t always bad, particularly acute inflammation in response to an injury or infection. But chronic inflammation, on the other hand, has been linked with a range of conditions such as heart disease, depression and even cancer.

For the mouse part of this study, published in the journal Proceedings of the National Academy of Sciences, researchers induced chronic stress in mice by having a bunch of male mice live together for a certain period of time. This time was enough for the mice to establish a hierarchy. Then, they introduced an aggressive male mouse to this group for periods of two hours to induce chronic stress in the mice.

After that, researchers looked at the immune cells circulating in the stressed mice’s blood stream, and found that they had four times the frequency of immune cells in their blood and spleen, versus non-stressed mice.

Researchers completed genome-wide analysis of the immune cells taken from the stressed mice’s blood. They found that compared with the non-stressed mice, 3,000 genes in the stressed mice’s immune cells were either expressed at higher or lower levels — and 1,142 of the up-regulated genes played a role in making the immune cells become more inflammatory.

Similar results were found in humans. The University of California, Los Angeles researchers looked at blood samples from both the stressed mice, as well as humans who came from differing socioeconomic statuses. Just like in the mouse part of the experiment, 387 genes were identified that had differences in activity between the people who came from low socioeconomic backgrounds and those who came from high socioeconomic backgrounds. And just like in the mice, the up-regulated genes in those who came from low socioeconomic backgrounds were pro-inflammatory.

In addition, a third of the genes that seemed to be affected by chronic stress were the same in both the humans and mice.

“This study provides a nice mechanism for how psychology impacts biology,” study researcher Nicole Powell, a research scientist in oral biology at Ohio State University, said in a statement. “Other studies have indicated that these cells are more inflammatory; our work shows that these cells are primed at the level of the gene, and it’s directly due to the sympathetic nervous system.”

Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis

 

http://www.laurapower.com/page7.html

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One more reason to treat your depression rapidly with Ketamine:

 

Depression Linked to Increased Risk of Developing Atrial Fibrillation

NEW YORK—Depression appears to be a risk factor for atrial fibrillation, the most common arrhythmia in the U.S., according to new observational data from the national Multi-Ethnic Study of Atherosclerosis (MESA) study.

Considering that 20% of U.S. adults report depressive symptoms, “our findings identify a large portion of the U.S. population that is potentially at an increased risk of developing atrial fibrillation and who may benefit from more targeted efforts to prevent atrial fibrillation,” Dr. Parveen Garg, from the Keck School of Medicine at the University of Southern California in Los Angeles, told Reuters Health by email.

He presented the study March 22 at the American Heart Association’s Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions in New Orleans.

The analysis included 6,644 adults (mean age, 62; 53% women, 38% white, 28% black, 22% Hispanic, 12% Chinese-American) with no known heart disease at baseline who were followed for a median of 13 years as part of the MESA study.

In the fully adjusted model, individuals with a Centers for Epidemiologic Studies Depression Scale (CES-D) score of 16 or higher (indicating clinically relevant depressive symptoms) had a 34% (P=0.039) higher risk of developing atrial fibrillation during follow-up compared with those with a CES-D score of less than 2. Similarly, individuals reporting antidepressant use had a significant 36% increase in their risk of developing atrial fibrillation compared with those not on the drugs.

“An important next step is to confirm these results in other studies, especially those with more comprehensive and clinically validated assessments of depression. If confirmed, then it will be important to determine if treating individuals with depression actually reduces their risk of atrial fibrillation,” Dr. Garg said.

Several mechanisms have been proposed to explain a possible link between depression and atrial fibrillation, Dr. Garg explained. Depression can increase systemic inflammation and activate the autonomic nervous system, which increases catecholamine levels, and the hypothalamic-pituitary-adrenal axis, which increases cortisol levels. Depression may also activate the renin-angiotensin-aldosterone system.

“Taken together, these changes may induce atrial fibrillation susceptibility either directly by disrupting the electrophysiologic properties of the atria or indirectly by promoting atrial fibrosis, increasing the atrial pressure,” Dr. Garg said, adding that further research is needed to fully understand the mechanisms involved.

Dr. Gordon Tomaselli, a spokesman for the American Heart Association, said this study “affirms the association between depression and atrial fibrillation in a population that I think is important because it’s a mixed population and not just the standard Caucasian population.”

“There are some associated risk factors in people with depression that might increase their risk of atrial fibrillation, including an increased incidence of hypertension in some patients who have depression as well as other disorders that might be driven by activation of the sympathetic nervous system like anxiety disorder. So there are several reasons why people might have depression and atrial fibrillation,” Dr. Tomaselli, who was not involved in the research, told Reuters Health by phone.

“One question is what should we do about it, and I’m not sure we have an answer from this study except to make sure that we are looking for symptoms of depression,” he said. “We don’t know whether treatment of depression will reduce the incidence of atrial fibrillation. There is some reason to think that it might, but there are other reasons to think that antidepressant drugs actually have some effects on the heart, the ion channels that determine the rhythm of the heart.”

The study had no commercial funding and the authors have no relevant disclosures.

SOURCE: https://bit.ly/2pCdkOA

AHA Epidemiology and Prevention – Lifestyle and Cardiometabolic Health Scientific Sessions 2018.

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Ketamine Nasal Sprays for Depression – Alexandria, Va Ketamine Provider 

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What is ketamine?

Ketamine Nasal SprayKetamine is a drug currently approved by the FDA for use as a general anesthetic during minor surgical procedures such as biopsies. It is widely known as a recreational drug because of its ability to induce cognitive-dissociative, hallucinogenic, and euphoric states in humans. Recently, it has been implicated in research as a potential therapeutic agent in depression especially in patients who have failed previous standard therapies.

Why ketamine?

Standard pharmacologic therapies for depression take several weeks of treatment before patients experience relief. Ketamine is different in that it has been shown to reduce depression symptoms and suicidal ideation in as little as forty minutes. This is considered a potentially lifesaving breakthrough in the treatment of depression because ketamine can rapidly reduce symptoms especially in emergency situations.

How does it work?

The most common medications used in depression affect serotonin in the brain. Ketamine works by a different mechanism. It has been shown to block the glutamate receptors in the brain resulting in its famous hallucinogenic effects. Ketamine has been shown to act on several other receptors, but it is theorized that at low doses, blocking glutamate receptors in the brain may be the reason for its anti-depressive effects.

Who should (and shouldn’t) take ketamine?

Ketamine has not been approved by the FDA for treatment of depression. Although, because of new studies, psychiatrists have been prescribing ketamine “off-label” for patients who did not respond to selective serotonin reuptake inhibitors (SSRIs) such has Celexa (citalopram), Zoloft (sertraline), or Prozac (fluoxetine) for immediate treatment of symptoms.

Ketamine has been shown to transiently yet significantly increase blood pressure following administration. Patients with high blood pressure should use caution when using ketamine. Ketamine has also been shown to be associated with increases in psychosis or dissociative properties.

Ketamine nasal sprays offer a quick and convenient way to administer ketamine for patients who need immediate relief, although they are currently not available commercially, so you will not find them at your local community pharmacy. Compounding pharmacies have the proper experience, equipment, and personnel to safely compound and customize this medication for you.

References

  1. Ketalar [package insert]. Chestnut Ridge, NY 10977: Par pharmaceutical; 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/016812s043lbl.pdf
  2. Browne CA, Lucki I. Antidepresssant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol December 2013.
  3. Lapidus K, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychology 2014;76:970–976
  4. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 2017;74(4):399-405.

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Prazosin for Harm Reduction in Alcohol Use Disorder?

 

 

Double-Blind Randomized Clinical Trial of Prazosin for Alcohol Use Disorder

 

Increasing doses of prazosin reduced heavy drinking, but adverse effects were common.

In some patients with post-traumatic stress disorder (PTSD), the alpha-1 noradrenergic blocker prazosin has been helpful for nightmares and, in open-label studies, has decreased stress reactivity, alcohol craving, and alcohol use. The alpha-1 noradrenergic blocker doxazosin has also been found to be useful for alcohol and other substance use disorders. These investigators conducted a randomized, placebo-controlled, double-blind, 12-week study of prazosin for alcohol use disorder in 92 outpatients without PTSD (mean age, 48; 79% men).

Participants averaged >67% heavy drinking days and 12 drinks per drinking day in the prior 90 days. After two 1-mg bedtime test doses, prazosin and placebo were up-titrated, depending on adverse effects, over 2 weeks; prazosin targets were 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime. Twelve patients dropped out during titration; of the 80 completers, 70 reached the target dose. The prazosin group took ≥1 dose on a mean of 65% of days and all 3 doses on 55% of days.

Prazosin was associated with self-reported fewer heavy drinking days and fewer drinks per week (–8 vs. –1.5 with placebo); differences in drinks per week accelerated after 8 weeks. Drinking days per week and craving showed no group differences. Mean systolic blood pressure decreased by 3.5 mm Hg with prazosin. Frequent adverse effects with prazosin were drowsiness (64% vs. 31% with placebo) and edema (20% vs. 4%). Symptomatic (1 patient in each group) and asymptomatic orthostatic hypotension did not differ between groups.

 

 

Evidence suggests that elevated brain noradrenergic activity
appears to be involved in the initiation and maintenance of
alcohol use disorder (1, 2). A clinically feasible approach to
reducing brain noradrenergic activity is to reduce activation
by norepinephrine at the postsynaptic a-1 adrenoceptor.
Prazosin is a clinically available lipid-soluble a-1 adrenoceptor
antagonist that reduces brain a-1 adrenoceptor–
mediated signaling when administered peripherally (3). In
rodents, prazosin has been shown to decrease withdrawalinduced
alcohol intake (4), alcohol drinking by alcoholpreferring
(P) rats (2), and stress-induced alcohol seeking
(5), and it has been shown to block yohimbine-induced reinstatement
of alcohol seeking (6). In human alcohol use disorder
studies, prazosin has been shown to reduce reactivity
to stress and to result in reduced craving (7), reduced drinks
per week (8, 9), and reduced drinking days per week (8). In
persons with DSM-IV alcohol dependence and comorbid
posttraumatic stress disorder (PTSD), one study found that
prazosin reduced drinking but not PTSD outcomes (10), and
another study found no prazosin effect on either outcome (11).
Doxazosin, another a-1 adrenoceptor antagonist, did
not outperform placebo on drinking outcomes in a study of alcohol treatment seekers, but among those with a high family
history density of alcohol problems, the active medication
was associated with improved drinking outcomes (12). Across
the entire sample, alcohol treatment seekers with higher
standing diastolic blood pressure receiving active medication
had better outcomes than those receiving placebo (13).
After obtaining positive results in a pilot study (8), we
conducted a 12-week randomized controlled trial comparing
prazosin and matched placebo in 92 participants who met
diagnostic criteria for alcohol use disorder but not PTSD.
Individuals with PTSD were excluded because there is evidence
that prazosin reduces symptoms of PTSD (14), and we
were interested in isolating the effects of prazosin on drinking
alone in light of evidence linking excessive drinking to
stress and the adrenergic system. Both treatment arms included
medical management (15), and daily symptoms were
monitored via a telephone-based interactive voice response
system to obtain close to real-time data regarding alcohol
consumption. Our primary hypotheses were that prazosin
would lead to a decreased likelihood over time of any drinking
and of heavy drinking (i.e., $4 drinks for women, $5 drinks
for men) as well as a decrease in number of drinks consumed.

 

 

These results indicate that prazosin has the potential to
reduce the likelihood of heavy drinking and number of
drinks per week over time but not the number of drinking
days per week. They suggest that prazosin may be most
useful in reducing heavy drinking associated with negative
consequences (29), which is consistent with a harm reduction
approach characterized by safer consumption rather
than full abstinence.

 In addition to reducing rodent self-administration of
alcohol (33), prazosin compared with vehicle has also been
shown to reduce self-administration of cocaine (34), heroin
(35), and nicotine (36). In humans, the previous positive pilot
studies of prazosin for alcohol use disorder (8, 10) and the
present study provide preliminary support for an effect of
prazosin on heavy drinking and number of drinks per week.
Another a-1 antagonist, doxazosin, has shown a signal for
reducing drinking in alcohol-dependent individuals who
have a positive family history of alcohol problems (12).
Doxazosin has also been found to reduce cocaine use in
cocaine-dependent individuals compared with placebo (37)

 

Link

 

Link

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Seasonal Affective Disorder

 

Do you find yourself getting depressed and sad in the fall and wintertime despite your best efforts? Seasonal affective disorder is common and can disrupt your lifestyle and happiness. Consider Ketamine infusions as an option for immediate relief with follow through intranasal ketamine. We can provide these solutions for people suffering from this disorder. A series of 2- 6 infusions can manage the majority of patients with rapid recover, almost within a few days. 

Seasonal Affective Disorder, or SAD, is a type of recurrent major depressive disorder in which episodes of depression occur during the same season each year. This condition is sometimes called the “winter blues.”

Definition

Seasonal affective disorder (also called SAD) is form of depression in which people experience depressive episodes during specific times of the year. The most common seasonal pattern is for depressive episodes to being in the fall or winter and diminish in the spring. A less common type of SAD, known as summer depression, usually begins in the late spring or early summer. SAD may be related to changes in the amount of daylight a person receives.

SAD is not considered as a separate disorder, but rather is a type of depression that has a recurring seasonal pattern. To be diagnosed with SAD, an individual must meet criteria for major depression coinciding with specific seasons for at least two years. The individual must experience seasonal depressions much more frequently than any non-seasonal depressions.

Seasonal affective disorder is estimated to affect 10 million Americans. Another 10 percent to 20 percent may have mild SAD. SAD is four times more common in women than in men. The age of onset is estimated to be between the age of 18 and 30. Some people experience symptoms severe enough to affect quality of life, and 6 percent require hospitalization. Many people with SAD report at least one close relative with a psychiatric disorder, most frequently a severe depressive disorder (55 percent) or alcohol abuse (34 percent).

Symptoms

Not everyone with SAD has the same symptoms, but symptoms commonly associated with the “winter blues” include the following:

  • Feelings of hopelessness and sadness
  • Thoughts of suicide
  • Hypersomnia or a tendency to oversleep
  • A change in appetite, especially a craving for sweet or starchy foods
  • Weight gain
  • A heavy feeling in the arms or legs
  • A drop in energy level
  • Decreased physical activity
  • Fatigue
  • Difficulty concentrating
  • Irritability
  • Increased sensitivity to social rejection
  • Avoidance of social situations

Symptoms of summer SAD are:

  • Poor appetite
  • Weight loss
  • Insomnia
  • Agitation and anxiety

Either type of SAD may also include some of the symptoms that are present in major depression, such as feelings of guilt, a loss of interest or pleasure in activities previously enjoyed, ongoing feelings of hopelessness or helplessness, or physical problems such as headaches and stomach aches.

Symptoms of SAD tend to reoccur at about the same time every year. To be diagnosed with SAD, the changes in mood should not be a direct result of obvious seasonal stressors (like being regularly unemployed during the winter). Usually, this form of depression is mild or moderate. However, some people experience severe symptoms that leave them unable to function in their daily lives.

Seasonal affective disorder can be misdiagnosed as hypothyroidyism, hypoglycemia, or a viral infection such as mononucleosis.

Causes

The cause for SAD is unknown. One theory is that it is related to the amount of melatonin in the body, a hormone secreted by the pineal gland. Darkness increases the body’s production of melatonin, which regulates sleep. As the winter days get shorter and darker, melatonin production in the body increases and people tend to feel sleepier and more lethargic.

Another theory is that people with SAD may have trouble regulating their levels of serotonin, which is a major neurotransmitter involved in mood. Finally, research has suggested that people with SAD also may produce less Vitamin D, which is believed to play a role in serotonin activity. Vitamin D insufficiency may be associated with clinically significant depression symptoms.

There are several known risk factors that increase an individuals chance of developing SAD. For example, SAD is more frequent in people who live far north or south of the equator. Additionally, people with a family history of other types of depression are more likely to develop SAD than people who do not have this family history.

Treatments

Treatment approaches to alleviate the symptoms of SAD typically include combinations of antidepressant medication, light therapy, Vitamin D, and counseling.

Because winter depression may be caused by a reaction to a lack of sunlight, broad-band light therapy is frequently used as a treatment option. This therapy requires a light box or a light visor worn on the head like a cap. The individual either sits in front of the light box or wears light visor for a certain length of time each day. Generally, light therapy takes between 30 and 60 minutes each day throughout the fall and winter. The amount of time required varies with each individual. When light therapy is sufficient to reduce symptoms and to increase energy level, the individual continues to use it until enough daylight is available, typically in the springtime. Stopping light therapy too soon can result in a return of symptoms.

When used properly, light therapy seems to have few side effects. The side effects that do arise include eyestrain, headache, fatigue, irritability, and inability to sleep (when light therapy is used too late in the day). People with manic depressive disorders, skin that is sensitive to light, or medical conditions that make their eyes vulnerable to light damage may not be good candidates for light therapy.

When light therapy does not improve symptoms within a few days, then medication and behavioral therapies such as CBT should be introduced. In some cases, light therapy can be used in combination with one or all of these therapies.

Self-Care

  • Monitor your mood and energy level
  • Take advantage of available sunlight
  • Plan pleasurable activities for the winter season
  • Plan physical activities
  • Approach the winter season with a positive attitude
  • When symptoms develop seek help sooner rather than later
  • Light therapy and lamps for SAD
  • IV Vitamin Therapy for rapid recovery including Vitamin D injections

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Depression results in excess Oxidative stress in the body. Clearly reversing depression may alleviate this stress. Oxidative stress results in excess aging and further diseases of aging in humans. This is a good reason to consider Ketamine as a rapid reversal agent for depression.

Serum 4-Hydroxynonenal Linked to Depression in Coronary Artery Disease

For patients with coronary artery disease, 4-hydroxynonenal may be an important marker of depression and may be involved in the progression of the depressive disorder, according to a study published in Psychiatry Research.

Assuming oxidative stress as a possible mechanism underlying depression, researchers in the current study examined the relationship between depression and markers of early lipid peroxidation, measured by lipid hydroperoxides and lipid-polymer hybrid (LPH), and late lipid peroxidation, measured by 4-hydroxynonenal and 8-isoprotane. Serum levels of lipid peroxidation markers were measured in patients with coronary artery disease (N=120) undergoing cardiac rehabilitation at the UHN Toronto Rehabilitation Institute from 2012 to 2015. Investigators used the Structured Clinical Interview for DSM Axis I Disorders- Depression Module (SCID) to diagnose baseline levels of depression, and they calculated the severity of depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D).

The researchers used multivariate mixed models to compare the trajectories of serum 4-hydroxynonenal, LPH, and 8-isoprotane between participants with and without depression who were undergoing 6 months of cardiac rehabilitation. Similar models were used to evaluate the associations between CES-D scores and serum 4-hydroxynonenal, LPH, and 8-isoprotane over the 6-month rehabilitation. Participants with depression (n=18) showed significantly higher serum 4-hydroxynonenal concentrations than participants without depression (n=102) at baseline, but no significant between-group difference was seen in serum LPH or 8-isoprotane. Furthermore, participants without depression showed a greater decrease in serum 4-hydroxynonenal than participants with depression. Increases in 4-hydoxynonenal serum concentrations over the course of 6 months were significantly associated with increased depression severity, as measured by decreases in CES-D scores during that same time period.

Study investigators conclude that these findings indicate that 4-hydoxynonenal may play a significant role in depression development and progression and could be an important marker of depression for patients with coronary artery disease. They note that “[f]uture studies should emphasize assessment of the oxidative balance by including markers of exogenous and endogenous antioxidants as well as a greater number of depressed patients.”

Reference

Rosen M, Chan P, Saleem M, et al. Longitudinal associations between 4-hydroxynonenal and depression in coronary artery disease patientsPsychiatry Res. 2018; 270:219-224.

Longitudinal associations between 4-hydroxynonenal and depression in coronary artery disease patients

Depressive symptoms in patients with coronary artery disease (CAD) attenuate the cardiovascular benefits of
cardiac rehabilitation (CR). Given that oxidative stress may be an important mechanism underlying depression,
this study aimed to understand the longitudinal relationship between lipid peroxidation markers and depression
in CAD. Serum levels of early (lipid hydroperoxides, LPH) and late (4‑hydroxy‑2-nonenal, 4-HNE; 8-isoprotane,
8-ISO) lipid peroxidation markers were measured in 120 CAD patients undergoing CR. The Structured Clinical
Interview for DSM Axis I Disorders – Depression Module (SCID) was used to diagnose depression at baseline and
the Center for Epidemiological Studies Depression Scale (CES-D) was used to measure depressive symptom
severity. Multivariate mixed models compared the trajectories of serum LPH, 4-HNE, and 8-ISO between depressed
and non-depressed CAD patients undergoing 6 months of CR. Similar models evaluated the associations
between serum LPH, 4-HNE, and 8-ISO and CES-D score over the course of CR. Serum 4-HNE decreased less in
CAD patients with depression compared to those without. In addition, a decrease in 4-HNE concentrations was
significantly associated with a decrease in CES-D scores over 6 months. These findings suggest that 4-HNE may
be an important marker of depressive symptoms in CAD and may be involved in its progression.

Highlights

Depression is an independent predictor of poorer outcomes in patients with CAD.

Antidepressants are modestly effective; oxidative stress (OS) may be a novel target.

4-HNE, an OS marker, was increased in CAD patients with depression despite exercise.

A decrease in 4-HNE was associated with an improvement in depressive symptoms.

4-HNE may predict depression in CAD; 4-HNE activity may be a future drug target.

This study assessed the relationships between depression and serum markers of lipid peroxidation over a 6-month CR program in participants with CAD. Over 6 months, those who were depressed had a significant increase in serum 4-HNE relative to those who were not depressed. Additionally, a decrease in serum 4-HNE in the overall study group was significantly associated with an improvement in depressive symptoms over the course of CR.

1. Discussion

This study assessed the relationships between depression and serum markers of lipid peroxidation over a 6-month CR program in participants with CAD. Over 6 months, those who were depressed had a significant increase in serum 4-HNE relative to those who were not depressed. Additionally, a decrease in serum 4-HNE in the overall study group was significantly associated with an improvement in depressive symptoms over the course of CR.

At baseline, depressed participants had significantly elevated 4-HNE levels compared to non-depressed participants, suggesting that depression in CAD may be associated with a pro-oxidative state. Longitudinally, there was a significant increase in 4-HNE in depressed CAD patients compared to non-depressed patients despite exercise. Additionally, a decrease in 4-HNE overall was associated with an improvement in depressive symptom severity over the course of 6 months. However, the same trend was not observed with LPH and 8-ISO levels. While previous cross-sectional studies report that levels of LPH and 8-ISO are elevated in depressed populations (Selley, 2004Vargas et al., 2013), the lack of association between LPH and depression may be due to depleted antioxidant defenses. Antioxidants such as glutathione (GSH) have been shown to be reduced in the brain of depressed patients compared to non-depressed controls in a post-mortem study (Gawryluk et al., 2011). GSH depletion may lead to a pro-oxidative state resulting in conversion of LPH to 8-ISO and 4-HNE and accumulation of these late-stage lipid peroxidation products. In addition, 8-ISO levels in the present study population may have been confounded by health and lifestyle factors (Black et al., 2016) and use of statins(Sinzinger and Oguogho, 2003).

Several mechanisms link 4-HNE and depression. First, the high degree of 4-HNE cytotoxicity stems from its ability to react with various biomolecules including DNA, lipids, and proteins. In proteins, 4-HNE can form Michael adducts with amino acids, thus impairing the function of proteins critical to mood regulation (Barrera et al., 2015). For example, in a rat model of bipolar depression, 4-HNE formed adducts with vesicular monoamine transporter 2 (VMAT2), which is responsible for packaging monoamine neurotransmitters, including serotonin into synaptic vesicles (Tan et al., 2012). Given that certain VMAT2haplotypes have been previously associated with depressive symptoms (Christiansen et al., 2007), the connection between 4-HNE and depressive symptoms may involve modulation of serotonin neurotransmission.

Another potential linkage between 4-HNE and depression involves the reduced bioavailability of the vasodilatornitric oxide (NO), which plays an important role in both CAD and depression etiology (Sherwood et al., 2005). In CAD, reduced NO levels result in impaired vasodilation, while its reduced bioavailability is suggested to alter neurotransmission involved in depression (Dhir and Kulkarni, 2011). Specifically, evidence suggests that 4-HNE modulates NO levels through increasing levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase. 4-HNE levels have been shown to positively correlate with levels of ADMA and negatively correlate with NO levels in depression (Selley, 2004). Furthermore, 4-HNE can inhibit the activity of dimethylarginine dimethylaminohydrolase-1, an enzyme responsible for catabolizing ADMA (Forbes et al., 2008).

Lastly, 4-HNE accumulation could elicit depressive symptoms through induction of apoptosis, leading to neuronal cell death (Kruman et al., 1997). Depression is associated with decreased hippocampal volume and exhibits high comorbidity with neurodegenerative diseases (Hurley and Tizabi, 2013). CAD subjects also have 13–15% reductions in hippocampal volume compared to healthy controls (Koschack and Irle, 2005). Long-term exposure to increased oxidative stress in CAD could result in accumulation of 4-HNE, leading to subsequent neurodegeneration and depression.

The biochemical mechanisms described outline an important potential role of 4-HNE in depression etiology, which may be particularly relevant in CAD patients, who likely have oxidative stress. As such, modulation of 4-HNE activity may hold important implications for future antidepressant development. For example, mitochondrial aldehyde dehydrogenase(ALDH2) plays a key role in detoxification of aldehydes produced during oxidative stress. A recent study in a rat model of depression showed that administration of ALDH2 activator 1, 3-benzodioxol-5-ylmethyl-2-6-dichlorobenzamide decreased both depressive-like behaviors and plasma levels of 4-HNE adducts (Stachowicz et al., 2016).

While a decrease in oxidative stress markers has been previously reported during CR programs (Fukuda et al., 2013), the decrease in 4-HNE was not associated with cardiopulmonary fitness in this study. This may be due to several reasons. First, the CR program at UHN Toronto Rehabilitation consisted of both aerobic exercise and resistance training, which is consistently associated with reduced oxidative stress (Cakir-Atabek et al., 2010). However, resistance training could not be assessed as a predictor of change in oxidative stress markers due to the lack of documentation. Healthy dietary changes were also encouraged during the CR program and may have contributed to the decrease in lipid peroxidation markers. For example, high antioxidant diets such as the traditional Mediterranean diet have previously been shown to reduce plasma oxidative stress markers (Fito et al., 2007). Moreover, cardiovascular medications like statins may also have antioxidant properties (Kruman et al., 1997). Thus, differences in medications and dosing may also confound the relationship between cardiopulmonary fitness and oxidative stress in the present study.

Strengths of the present study include adjustment for clinical and demographic confounders, including age, sex, BMI, cardiopulmonary fitness, history of depression and completion of the CR program. The measurement of multiple lipid peroxidation markers allowed for comprehensive profiling of lipid peroxidation that is relevant in CAD. Also, this study assessed the relationship of lipid peroxidation markers with both depression and depressive symptomology, providing an in-depth analysis of the relationship between lipid peroxidation and depression.

This study was limited by the small sample size of depressed patients compared to the non-depressed group. However, the proportion of patients who met criteria for MDD in the present study is representative of the prevalence of depression in CAD patients (Huffman et al., 2013). Another limitation of this study was that it assessed peripheral markers as indicators of brain physiology. However, it has been shown previously that peripheral lipid peroxidation markers correlate with neuropathy in psychiatric disorders (Versace et al., 2014). In addition, we have previously shown associations between peripheral oxidative stress markers and antidepressant response in patients with CAD (Mazereeuw et al., 2017), further validating peripheral markers of lipid peroxidation as predictors of depression outcomes.

In summary, we showed that in a sample of patients with CAD, 4-HNE was increased significantly in those who were depressed compared to those who were not. Additionally, a decrease in 4-HNE was correlated with a decrease in depressive symptoms over a 6-month period of CR. These findings suggest 4-HNE may be an important marker of depressive symptoms in CAD and suggest a specific role of 4-HNE in the development and progression of depression. Despite a lack of association with cardiopulmonary fitness, a decrease in 4-HNE over CR indicates that lifestyle changes and pharmacotherapy could play an important role in modulating oxidative stress. Future studies should emphasize assessment of the oxidative balance by including markers of exogenous and endogenous antioxidants as well as a greater number of depressed patients.