Depression is one of the most common and most debilitating mental health disorders, affecting some 17 million adults in the US. It also continues to be a misunderstood, often hard-to-treat illness. Researchers have worked for decades to better understand the neurobiology underpinning depression.
For patients with severe, treatment-resistant depression, spending months or even years searching for good treatments can be totally disabling. The prevailing hypothesis for years was that depression was regulated by the neurotransmitter’s serotonin and norepinephrine.
Eventually, data began to suggest that maybe something much larger and more global was involved in the brain to account for depression, which led researchers to begin working with glutamate and GABA, the most abundant neurotransmitters in the brain. These chemicals are involved in neuroplasticity – the brain’s ability to adapt to change and protect itself against stressful events.
Neuroplasticity is a physical thing, too: it manifests itself “in terms of synapses, how these neurons are actually touching each other and communicating with each other,” explains Gerard Sanacora, PhD, MD, Director of the Yale Depression Research Program. “And we know that in depression, the number and strength of these interconnections decreases,” says Rachel Katz, MD, a professor of Clinical Psychiatry at Yale.
Ketamine – originally developed and still used as an anesthetic – works on those two neurotransmitters and was discovered to have rapid antidepressant effects. Some experience an improvement in symptoms in 24 hours or less. “We think that one of the things that Ketamine does, that helps to explain its antidepressant effects, is help the brain to regrow the synapses, the connections between nerve cells,” says John Krystal, MD, Chair of the Department of Psychiatry at Yale.
Sleep has many functions, among which are clearing the body of toxins and consolidating memory. The exact amount we need is determined by age, and genetics among another things. From what I’ve read, eight hours is required, plus or minus an hour.
That being said, there are a few among us who are super sleepers. Going back in history this probably included Mozart and Thomas Edison: They could live healthy, productive lives with as few as three or four hours of sleep. Genetic mutations, including changes to the Orexin Gene receptor account for true super-sleepers.
Familial fatal insomnia is a genetic disease operating through prion proteins, and does not illuminate the problem of insomnia. In most people there are two major forces which determine the onset of sleep, the circadian rhythm, and sleep pressure.
The TIMING of the sleep varies from morning larks to night owls. These shifts in the circadian rhythm is also genetic, involving many genes, including PER and CRY. Diurnal rhythm can apparently be changed, But with difficulty.
The sleep pressure is caused by the gradual daily accumulation of adenosine in the system, apparently resulting from the stripping away of the phosphate groups from the energy currency, ATP. This can be assuaged by caffeine containing drinks, such as tea or coffee. Caffeine temporally blocks the effect of adenosine, but when it wears off, you usually go right back to your fatigue state.
INSOMNIA occurs when you do not get as much sleep as you need, and are tired in the daytime. This is a major problem for a lot of people.
Insomnia has many causes. Stress will cause an increase in Cortisone in the bloodstream which interferes with sleep. Caffeinated drinks nicotine and other stimulants can cause you to have difficulty falling asleep, and alcohol will help you fall asleep but will often result in awakening in the middle of the night when the alcohol is metabolized.
Depression, Parkinson’s, chronic pain, gastroesophageal reflux and any other medical conditions can interfere with sleep. Sleep apnea, often associated with overweight and heavy snoring, is a special problem that sometimes needs the help of a sleep specialist.
Some poor habits such as reading in bed, doing work in bed, eating at bedtime, and heavy exercise just before bed can also be a problem. A regular routine of Preparing for sleep, such as brushing and flossing and taking a warm shower are also helpful; you can get more details by looking up “sleep hygiene”.
A lot of people take a nap, but this can cause some difficulty in going to sleep. Among things you can do to prevent insomnia include living an active life, making your bedroom comfortable for sleep, and using your bedroom ONLY for sex and sleep.
Please refer to the accompanying Mayo clinic article for more organized information.
For many people, depression turns out to be one of the most disabling illnesses that we have in society. Despite the treatments that we have available, many people are not responding that well. It’s a disorder that can be very disabling in society. It’s also a disorder that has medical consequences.
By understanding the neurobiology of depression we hope to be able more to find the right treatment for the patient suffering from this disease. The current standard of care for the treatment of depression is based on what we call the monoamine deficiency hypothesis. Essentially, presuming that one of three neurotransmitters in the brain is deficient or underactive. But the reality is, there are more than 100 neurotransmitters in the brain. And billions of connections between neurons. So we know that that’s a limited hypothesis. Neurotransmitters can be thought of as the chemical messengers within the brain, it’s what helps one cell in the brain communicate with another, to pass that message along from one brain region to another. For decades, we thought that the primary pathology, the primary cause of depression was some abnormality in these neurotransmitters, specifically serotonin or norepinephrine. However, norepinephrine and serotonin did not seem to be able to account for this cause, or to cause the symptoms of depression in people who had major depression. Instead, the chemical messengers between the nerve cells in the higher centers of the brain, which include glutamate and GABA, were possibilities as alternative causes for the symptoms of depression. When you’re exposed to severe and chronic stress like people experience when they have depression, you lose some of the connections between the nerve cells. The communication in these circuits becomes inefficient and noisy, we think that the loss of these synaptic connections contributes to the biology of depression. There are clear differences between a healthy brain and a depressed brain. And the exciting thing is, when you treat that depression effectively, the brain goes back to looking like a healthy brain, both at the cellular level and at a global scale. It’s critical to understand the neurobiology of depression and how the brain plays a role in that for two main reasons. One, it helps us understand how the disease develops and progresses, and we can start to target treatments based on that. We are in a new era of psychiatry. This is a paradigm shift, away from a model of monoaminergic deficiency to a fuller understanding of the brain as a complex neurochemical organ. All of the research is driven by the imperative to alleviate human suffering. Depression is one of the most substantial contributors to human suffering. The opportunity to make even a tiny dent in that is an incredible opportunity.
Cortisol (hydrocortisone, 17-OH-corticosterone) is produced by stress, and is a bad word these days. When I was a practicing allergist, Cortisol worked wonders with asthma, and as a salve helped my patients with eczema.
It functions in the body as a key part of the stress reaction, which preparers the animal body for “Fight or flight”. Cortisone raises the blood pressure, heart rate and blood sugar, and shuts down The immune system, which is not as necessary in times of emergency. It is this last function which helped my patients with asthma and eczema, which are diseases of excessive immune reactivity. You may have heard of the use of dexamethasone( A relative of cortisol ) in severe Covid, which is made worse by an excessive immune response.
Modern life is a pressure cooker, requiring continuous activity and deadlines. The blood Cortisone level, which is raised by stress, is helpful in the short term, but deleterious when persisting over the long term. The prolonged elevation of blood Pressure, blood sugar and heart rate, coupled with a decrease in bone and collagen formation can lead to all kinds of problems including weight gain, diabetes, cardiovascular problems, osteoporosis and mental decline.
Although cortisol in the short term can enhance memory (think of flash – bulb memory), in the long run it decreases hippocampal function, impacting memory.
For these and other reasons, Modern Life makes it desirable to reduce stress and the accompanying elevation of cortisol . Our old friends, Proper sleep, diet and exercise are critical, and help activities such as laughter and yoga to reduce stress. The following reference will cover this in more detail.
Hip fracture is an iconic bugaboo of old age. It is a chronic condition in the sense that its complications, such as Depression, blood clots and pneumonia often extend long beyond the healing process.
Predisposing factors include old age and associated risk factors like osteoporosis, sarcopenia (loss of muscle mass and strength), poor vision, poor balance and hazards in the home.
FALLING is the usual agency that produces the fracture. At the risk of being ostracized, I will point out that thousands of injuries sustained by walking or tripping over dogs (and cats) occur every year.
In my small “hilltop” group of friends, there was 1 fatality, 1 shoulder fracture-dislocation, 1 hip fracture, and 0 acknowledgements of animal causation. Members of the family are immune to blame.
Treatment of hip fracture involves surgery with pins, or the more cost-effective Hip replacement. PREVENTION is critical. Osteoporosis must be prevented by exercise, Calcium, vitamin D, and avoidance of certain medication like Corticosteroids.
Balance should be developed by exercises. Vision problems, such as cataracts,should be corrected. Muscle mass should be preserved by diet and exercise, and the home cleared of throw-rugs and obstacles removed.
Just yesterday, a friend wearing socks (reducing friction?) fell down some stairs after stepping over a dog-gate. She is scheduled to have her elbow pinned. Have I mentioned SLEEP, DIET and EXERCISE RECENTLY?
Parkinson’s Disease is a MOVEMENT DISORDER. It is grouped with a number of OTHER NEURODEGENERATIVE illnesses which can show similar symptoms. When Parkinson-like problems are present in other syndromes, it is called PARKINSONISM, to distinguish it from primary Parkinson’s disease.
There is no 100% reliable sign, symptom or diagnostic test; Rather, the gold standard of diagnosis rests on the ability of experienced neurologists to discern a PATTERN of findings which together support the likelihood of Parkinson’s disease. The accuracy is about 80-90%. The 3 characteristic symptoms of PD are BRADYKINESIA, TREMOR, and RIGIDITY. Bradykinesia means SLOW MOVEMENT.
The typical Tremor is a tapping, “pill-rolling” motion that is present at rest, and DISAPPEARS ON MOTION. The Rigidity is pervasive, and patients describe it as trying to move in thick molasses. A “lead-pipe resistance”, stiffness and PAIN in the shoulder may be a first system, and not uncommonly the patient will often go to an Orthopedist or Rheumatologist. Depression, constipation, anosmia and SLEEP Disorders are common in the years leading up to the diagnosis of Parkinson’s Disease, and DEMENTIA frequently develops.
Genetics play a role, and PD can run in Families. Environmental causes such as Trauma and anoxia can injure nerve cells, as can Toxins. MPTP contamination of a drug supply once caused a surge of Parkinsonism. Degeneration of DOPAMINERGIC nerve cells in the Substantia Nigra is the ultimate cause of PD, and accumulation of ALPHA SYNUCLEIN fibrils is a correlate of that degeneration.
Practical treatment at present aims to boost Dopamine. Administration of Levodopa, a DA precursor, if effective, a response helps to confirm the diagnosis. Magnetic and electrical stimulation of the brain have been used. Experimental injections of Dopaminergic cells into the brain is under investigation. Causing Astrocytes to differentiate into dopaminergic cells has been successful in animals.
With Celebrities such as Michael Fox and Robin Williams raising awareness, and the Mechanism understood, I am optimistic that a real cure may be found in a few years.
Unexplained weight loss is rare in our society, where weight gain is so common. Weight loss usually occurs in the context of a causative illness, like prolonged diarrhea, where it is not the main symptom, but just an associated problem. However, sometimes the loss of 5 or 10% of the body’s weight can occur in a few months without explanation or clues, and a consultation is needed.
Proper Nutrition is critical for Health, including maintenance of “normal” weight. The Gastrointestinal tract extracts nutrients from the food we eat, and illnesses such as COELIAC DISEASE, or REGIONAL ENTERITIS can prevent proper absorption. Our HORMONES regulate energy and chemical balance, and Thyroid, Parathyroid, Pancreas and Adrenal malfunction can disturb weight Homeostasis.
Chronic infection, such as AIDS and TB can sap energy quietly. NEUROLOGICAL PROBLEMS such as Depression, Dementia or Parkinsons can result in an improper diet, and subsequent weight loss. CANCER is the first thing we worry about when we unexpectedly lose weight, but Neoplasms usually betray themselves with other, more dramatic symptoms.
It is a good idea to regularly check your weight at the same time every day. Almost always it will reassure you by staying the same. Sometimes it will warn you to cut your feasting. Occasionally an unexpected drop in weight will direct you to your Doctor to find an explanation.
Sometimes I wake up in the morning with a feeling of RELAXED ENERGY. My mind is clear, I have no fatigue, and believe once more that the world is wonderful, and it’s great to be alive.
I St-re-tch, exercise my hands (I have Osteoarthritis, and they are stiff), take out my Nite guard ( I grind my teeth at night and would otherwise wear them away), take my beta blocker eye drops ( to lower my intraocular pressure) and wash down my Eliquis ( an anticoagulant to prevent stroke from my Atrial Fibrillation) with 16 oz. of water, while thinking about all of the delights awaiting me.
Yes, my body was in better shape 60 years ago; but I had much more responsibility then, and much less discretionary time. All things considered, I like to believe that I am happier now.
The KEY is to stay in GOOD HEALTH. GOOD SLEEP is critical, but it cannot be had by willpower alone. As I have discussed previously, you need a bedtime routine, good SLEEP HYGIENE.
You also need a…….. GOOD DIET. with lots of fruits, vegetables and whole grains. Fatty, spicy foods will stay in your stomach and bother you at night, particularly if you eat Late. I like to finish eating by 5 PM. Late dinner is also likely to produce GERD, and maybe Sleep Apnea.
GOOD EXERCISE is also critical. If you are not tired at the end of the day, it is hard to get good sleep. I always seem to sleep better on the day when I walk the hills for an hour, which is 3 days a week. Try not to exercise within 2 hours of bedtime. Assuming that you have a good base of SLEEP, DIET and EXERCISE, there are other mechanisms that can foul things up. INFLAMMATORY conditions often cause fatigue.
The most common inflammatory diseases are OBESITY, METABOLIC SYNDROME and DIABETES. OBESITY is the defining disease of our EXCESSIVE SOCIETY, where there is too much of everything, and excessive consumption is relentlessly advertised everywhere.
External correction is probably a pipe dream, since there is no will even to Tax Sugar-containing Beverages, the “low hanging fruit” of dietary excess. Internal correction is all that is left, and that takes WILL POWER, also in short supply.
INFECTIOUS DISEASES are a subset of inflammatory conditions. COVID 19 is the poster child of infection, and FATIGUE is one of the hallmarks of the disease. Interleukins, like TNF-alpha, IL-1, andIL-6 are some of the defense factors which cause the fatigue. AUTOIMMUNE Diseases like Rheumatoid Arthritis and Lupus are also associated with fatigue-producing interleukins.
Fatigue even has its own flagship disease, CHRONIC FATIGUE SYNDROME. Chronic viral disease has been suspected as the cause of this condition, and inflammatory cytokines may be elevated. This condition, and the similar GULF WAR SYNDROME are still poorly understood. Several CFS patients were sent to me when I was in practice, and I had some success in getting them to exercise regularly, which seemed to help. CANCER is another category of diseases where Fatigue is prominent.
Inflammation plays a role in these diseases, which also drain energy substrates from the Patients body; Cancer cells have a high metabolic requirement. MEDICATIONS, Cancer meds especially, but a variety of other Drugs are associated with FATIGUE. I went through MY MEDICATION LIST. Lo and behold, 3 of them are associated with fatigue.
Finasteride is a relic of my prostate operation, recommended to keep it from growing back. It causes fatigue, probably because of its ANTITESTOSTERONE effect. At least I can still pee, and am not bald. I take METFORMIN because of its fame in prolonging life. Its mechanism is that of interacting with the Sirtuin system, and increasing the inefficiency of mitochondria. Isn’t this surprising?
Like many other things in physiology, you place a stress on the body, and the body responds by improving its performance. If you are fatigued, you exercise. Respecting the body works with drugs as well. If you are drinking a ton of coffee and stop it, after a few weeks you will feel less fatigued.
And when you ARE FATIGUED, you drink a LITTLE coffee, and it wakes you right up. Caffeine works by displacing ADENOSINE, which causes Fatigue as it increases through the morning, peaking at SIESTA (or tea) time,at about 2 PM. OMEPRAZOLE, which I take to prevent HEARTBURN, also is related to fatigue especially if it blocks MAGNESIUM for long enough. DEPRESSION overlaps with fatigue, as does SLEEPINESS, to increase the complexity of the situation.
Many chronic LUNG, KIDNEY and LIVER diseases are associated with fatigue as a secondary concern. STAY HEALTHY!
LOS ANGELES — Modifying 12 risk factors over a lifetime could delay or prevent 40% of dementia cases, according to an updated report by the Lancet Commission on dementia prevention, intervention and care presented at the Alzheimer’s Association International Conference (AAIC 2020).
Twenty-eight world-leading dementia experts added three new risk factors in the new report — excessive alcohol intake and head injury in mid-life and air pollution in later life. These are in addition to nine factors previously identified by the commission in 2017: less education early in life; mid-life hearing loss, hypertension and obesity; and smoking, depression, social isolation, physical inactivity and diabetes later in life (65 and up).
Schneider and commission members recommend that policymakers and individuals adopt the following interventions:
Aim to maintain systolic blood pressure of 130 mm Hg or less from the age of 40.
Encourage use of hearing aids for hearing loss and reduce hearing loss by protecting ears from high noise levels.
Reduce exposure to air pollution and second-hand tobacco smoke.
Prevent head injury (particularly by targeting high-risk occupations).
Limit alcohol intake to no more than 21 units per week (one unit of alcohol equals 10 ml or 8 g pure alcohol).
Stop smoking and support others to stop smoking.
Provide all children with primary and secondary education.
Lead an active life into mid-life and possibly later life.
Reduce obesity and the linked condition of diabetes.
Falling down is common on both ends of the Human lifespan. Little kids are always falling down, but there isn’t much energy to dissipate, since their mass is small and they don’t have far to fall. Moreover, their bones are pliable.
The Elderly also fall, increasingly, as they age. They have a lot further to fall, and their bones are often brittle and osteoporotic. Injury is quite common, they often break a hip, and may slide into a peogressive deterioration leading to their demise..
Ordinary walking, a “normal gait”, is a very complex activity and requires a lot of information and coordination by the nervous system.
VISION is critical, as you are often navigating through a minefield of stairs, rug edges, slippery objects, lamp cords, tubes and pets. Cataracts may be a problem to be corrected. Multifocal glasses can be a factor.
HEARING can warn of certain hazards or warnings and is important. A FINE SENSE OF TOUCH is required to give you cues as you are walking. Peripheral neuropathy can make walking difficult.
PROPRIOCEPTION, the positional sense of where your extremities are located in space, is a sense we take for granted, but which may deteriorate in time. Proprioception is very important for a normal Gait. The inner ear, with it’s semicircular canals and vestibular apparatus is necessary for proper BALANCE.
Balance can be PRACTICED in a number of ways, like standing on one leg, or merely WALKING a lot. These MULTIPLE SENSES must be COORDINATED by the Thalamus, Corpus Striatum, medulla, Cerebellum, and Cerebral Cortex and instructions sent to the muscles of your Legs, Arms, back and abdomen.
It is mandatory to keep these muscles, your Heart and your body, STRONG and FIT. Factors that make you more likely to have a fall are mostly the reverse of the above, and are called RISK FACTORS.
–Previous Falls are the best predictor. More than 2 or 3 in a year is worrisome.
–Balance Impairment is best treated by practice.
–Decreased Muscle strength. –Visual impairment.
–Polypharmacy (more than 4 prescription Meds), or a Psychoactive drug (look up)
–Gait impairment, Walking difficulty.
–Depression, which is often treated by antidepressants or sleeping pills- Psychoactive drugs.
–Dizziness or orthostatic hypotension, which causes a drop in blood pressure on standing. and a number of other problems, often a function of age.
PREVENTION of falls is of course better than treatment of the resulting INJURY. Working on your HEALTH will help the INTRINSIC causes of falls, and that is what we have been discussing.
Preventing the EXTRINSIC causes of falls means working on: –Improving the household safety by putting in railings, getting rid of throw rugs, clutter, and maybe pets( a good friend went into a downward spiral after tripping over his Dog.
Adjusting or eliminating psychoactive drugs and antihypertensive drugs (which often include the beta blockers which worsen orthostatic hypotension.
Interestingly, VITAMIN D supplements were mentioned in 2 references I saw. Apparently Vitamin D reduces falls by increasing MUSCLE STRENGTH.
Please refer to the following Canadian article for a more complete discussion.
Empowering Patients Through Education And Telemedicine