Ketamine offers a new option for people with stubborn depression that doesn’t respond to other medications.
Many people know of ketamine as a hallucinogenic and addictive street drug, which, when abused, can put people in medical peril. But today, doctors are increasingly looking to ketamine as a potentially lifesaving treatment for people with severe, treatment-resistant depression, who may be at high risk for suicide.
“Ketamine has been shown to be effective in people who have not responded to antidepressant treatment,” says Dr. Cristina Cusin, an assistant professor of psychiatry at Harvard Medical School. The fast-acting treatment has shown promise — sometimes improving depressive symptoms within hours of the first intravenous treatment.
While ketamine can offer hope to some, it’s not for everyone. The use of ketamine to treat depression is still controversial in some circles. “Some prescribers would never consider the use of a controlled substance for this purpose, because of the potential for abuse,” says Dr. Cusin. “But as with opiates, a drug is not good or bad, per se.” Still, ketamine does need to be carefully matched to the right patient for the right use to avoid harm, and treatment should be closely monitored over time.
A variety of uses
The use of ketamine in medicine isn’t new. It’s routinely used in hospitals both for anesthesia and for pain relief.
Currently, the use of ketamine for depression is “off label.” This means that although ketamine is approved by the FDA for some medical purposes, it’s not approved specifically to treat depression. However, that may soon change. Under its “fast track” drug approval process, the FDA is reviewing the results of clinical trials of esketamine, a ketamine-based nasal spray, to treat depression, says Dr. Cusin.
For now, people who undergo ketamine treatment for depression typically receive the drug at specialized clinics, either intravenously or as a nasal spray. Effects from the nasal spray last for a single day or a few days, while the intravenous treatment may last for a few weeks to a month. In both instances the dose is significantly lower than would be used for anesthesia or when used illicitly.
How ketamine works
Studies have shown that ketamine is effective in treating people whose depression has not responded to other interventions, says Dr. Cusin. Such treatment-resistant depression is estimated to affect from 10% to 30% of people diagnosed with the condition.
Experts believe that ketamine works through a unique mechanism, directly modulating the activity of a brain chemical called glutamate. Glutamate is believed to play a role in stimulating the growth of new brain connections that may help alleviate depressive symptoms.
People who have taken ketamine to treat their depression experience varying success, depending on their personal history—how long they’ve been depressed, how severe their symptoms are, and how many drugs they’ve tried without seeing improvement, says Dr. Cusin.
For people with less severe depression, ketamine may be effective in as many as 60% of those who try it. Among those with more persistent and significant disease, a smaller number, 30% to 40%, may experience relief, says Dr. Cusin. “The expectation should not be that it will magically cure depression in everybody,” she says. “Ketamine is not a perfect fix. It’s like any other medication.” In other words, it works for some people, and it won’t work for others.
To be effective, treatment with ketamine must typically continue indefinitely and involve careful monitoring. Clinicians who prescribe ketamine for depression should screen patients carefully to ensure the drug is appropriate for the individual, says Dr. Cusin. “Not everybody who wishes to try ketamine will be a good candidate,” she says.
Among those who should not use ketamine are people with
a history of substance abuse
a history of psychosis
elevated blood pressure
an uncontrolled medical condition.
Who can benefit?
Because ketamine is a newer treatment, there are still a lot of questions surrounding its use, says Dr. Cusin. For instance:
Which people respond best to treatment?
How much should be given, and how often?
What are the long-term effects of treatment?
Because the medication is being used off label for depression, there are no clearly defined safety recommendations either for home use or for its use in specialized clinics, she says. This means that it’s up to individual providers to guide the patient in making informed decisions about treatment. Choosing a qualified provider is essential. JAMA Psychiatrypublished a statement in 2017 outlining best practices for doctors to follow in ketamine treatment, such as performing a comprehensive assessment, obtaining informed consent, and documenting the severity of depression before starting the medication. These guidelines are aimed at increasing the safe use of ketamine for depression, and providers can use them to help ensure that the treatment is a good match for your condition.
As with any other medical intervention, anyone considering ketamine should also consider the drawbacks of treatment along with the potential benefits. Ketamine’s drawbacks include these:
Cost. It’s expensive and not covered by insurance. “The cost ranges from $400 to $1,200 per dose for the intravenous drug, and you may need as many as 12 to 18 doses a year,” says Dr. Cusin.
Unknowns. Ketamine hasn’t been used to treat depression for long enough for doctors to know whether there are any harmful long-term consequences of taking the medication. More time and study are needed to truly understand how it affects people over the long term.
Treatment failure. Many people with treatment-resistant depression view ketamine treatment as their last option, so if this therapy fails to improve their depression, they can be emotionally devastated. Realistic expectations and follow-up support are essential.
Even if ketamine does produce results, it’s still important to understand what it can and can’t do. “-Ketamine isn’t going to eliminate all frustrations and stress from your life. While it may lift some symptoms of depression, the life stressors will still be there,” says Dr. Cusin. You’ll still need support to help you manage them.
Side effects. While ketamine is viewed as safe in a controlled setting, it can frequently increase blood pressure or produce psychotic-like behavior, which may result in delusions or hallucinations. Serious adverse events are rare because the drug is used at such low doses, says Dr. Cusin.
However, provided you are an appropriate candidate for the treatment and your doctor monitors you closely, you could find that it improves your mood. “Ketamine could make a huge difference in the quality and duration of life and can be very effective for people who are thinking about suicide,” says Dr. Cusin.
Now that the days are getting shorter, the air is getting cooler, Virginians have had the first glimpse of cold for the season, some of us begin to feel the winter blues. These feelings of low energy and sleepiness may actually be Seasonal Affective Disorder, or SAD.
SAD is a form of depression related to the changing seasons. It usually starts in the late fall, especially in our northern climes. The decreasing hours of sunlight, along with the cold and snow, cause our bodies to retreat into the warmth and coziness of our homes. We tend to crave carbohydrates, eat comfort foods, and socially withdraw as we sleep more, and move less; much like we are hibernating!
Those most at risk for SAD are people already suffering from major depression or bipolar disorder. Risk factors include being female, family history, young age, and the further you live from the equator, the higher your risk. However, there are ways to decrease your risk, and increase your mood.
What can you do to improve your mood? Soak up the sun! When the weather allows, go for a walk on those bright, crisp sunny days. If the temperature or the ice and snow don’t allow you to venture outside, open the curtains and let the sun shine in. Exercise and eating healthy are both options to make you feel better. Vitamins, especially vitamin D, the sunshine vitamin can help with mood. Be social, visit with friends. A phone call, visit, or even a vacation to visit your “snowbird” friends will keep you socially involved.
So, if these options aren’t working or you just need something more to improve your mood, your healthcare provider may recommend seeking help from a psychotherapist. They may offer medications, light box therapy, or talk therapy.
Ketamine therapy is an option to help make it through dark times when nothing else seems to work. Contact 703-844-0184 for a consultation.
Seasonal Affective Disorder
Seasonal Affective Disorder (SAD) is a type of depression that comes and goes with the seasons, typically starting in the late fall and early winter and going away during the spring and summer. Depressive episodes linked to the summer can occur, but are much less common than winter episodes of SAD.
Signs and Symptoms
Seasonal Affective Disorder (SAD) is not considered as a separate disorder. It is a type of depression displaying a recurring seasonal pattern. To be diagnosed with SAD, people must meet full criteria for major depression coinciding with specific seasons (appearing in the winter or summer months) for at least 2 years. Seasonal depressions must be much more frequent than any non-seasonal depressions.
Symptoms of Major Depression
Feeling depressed most of the day, nearly every day
Feeling hopeless or worthless
Having low energy
Losing interest in activities you once enjoyed
Having problems with sleep
Experiencing changes in your appetite or weight
Feeling sluggish or agitated
Having difficulty concentrating
Having frequent thoughts of death or suicide.
Symptoms of the Winter Pattern of SAD include:
Having low energy
Craving for carbohydrates
Social withdrawal (feel like “hibernating”)
Symptoms of the less frequently occurring summer seasonal affective disorder include:
Poor appetite with associated weight loss
Episodes of violent behavior
Attributes that may increase your risk of SAD include:
Being female. SAD is diagnosed four times more often in women than men.
Family history. People with a family history of other types of depression are more likely to develop SAD than people who do not have a family history of depression.
Having depression or bipolar disorder. The symptoms of depression may worsen with the seasons if you have one of these conditions (but SAD is diagnosed only if seasonal depressions are the most common).
Younger Age. Younger adults have a higher risk of SAD than older adults. SAD has been reported even in children and teens.
The causes of SAD are unknown, but research has found some biological clues:
People with SAD may have trouble regulating one of the key neurotransmitters involved in mood, serotonin. One study found that people with SAD have 5 percent more serotonin transporter protein in winter months than summer months. Higher serotonin transporter protein leaves less serotonin available at the synapse because the function of the transporter is to recycle neurotransmitter back into the pre-synaptic neuron.
People with SAD may overproduce the hormone melatonin.Darkness increases production of melatonin, which regulates sleep. As winter days become shorter, melatonin production increases, leaving people with SAD to feel sleepier and more lethargic, often with delayed circadian rhythms.
People with SAD also may produce less Vitamin D. Vitamin D is believed to play a role in serotonin activity. Vitamin D insufficiency may be associated with clinically significant depression symptoms.
Treatments and Therapies
There are four major types of treatment for SAD:
These may be used alone or in combination.
Selective Serotonin Reuptake Inhibitors (SSRIs) are used to treat SAD. The FDA has also approved the use of bupropion, another type of antidepressant, for treating SAD.
Light therapy has been a mainstay of treatment for SAD since the 1980s. The idea behind light therapy is to replace the diminished sunshine of the fall and winter months using daily exposure to bright, artificial light. Symptoms of SAD may be relieved by sitting in front of a light box first thing in the morning, on a daily basis from the early fall until spring. Most typically, light boxes filter out the ultraviolet rays and require 20-60 minutes of exposure to 10,000 lux of cool-white fluorescent light, an amount that is about 20 times greater than ordinary indoor lighting.
Cognitive behavioral therapy (CBT) is type of psychotherapy that is effective for SAD. Traditional cognitive behavioral therapy has been adapted for use with SAD (CBT-SAD). CBT-SAD relies on basic techniques of CBT such as identifying negative thoughts and replacing them with more positive thoughts along with a technique called behavioral activation. Behavioral activation seeks to help the person identify activities that are engaging and pleasurable, whether indoors or outdoors, to improve coping with winter.
At present, vitamin D supplementation by itself is not regarded as an effective SAD treatment. The reason behind its use is that low blood levels of vitamin D were found in people with SAD. The low levels are usually due to insufficient dietary intake or insufficient exposure to sunshine. However, the evidence for its use has been mixed. While some studies suggest vitamin D supplementation may be as effective as light therapy, others found vitamin D had no effect.
Everyone occasionally feels blue or sad. But these feelings are usually short-lived and pass within a couple of days. When you have depression, it interferes with daily life and causes pain for both you and those who care about you. Depression is a common but serious illness.
Many people with a depressive illness never seek treatment. But the majority, even those with the most severe depression, can get better with treatment. Medications, psychotherapies, and other methods can effectively treat people with depression.
There are several forms of depressive disorders.
Major depression,—severe symptoms that interfere with your ability to work, sleep, study, eat, and enjoy life. An episode can occur only once in a person’s lifetime, but more often, a person has several episodes.
Persistent depressive disorder—depressed mood that lasts for at least 2 years. A person diagnosed with persistent depressive disorder may have episodes of major depression along with periods of less severe symptoms, but symptoms must last for 2 years.
Some forms of depression are slightly different, or they may develop under unique circumstances. They include:
Psychotic depression, which occurs when a person has severe depression plus some form of psychosis, such as having disturbing false beliefs or a break with reality (delusions), or hearing or seeing upsetting things that others cannot hear or see (hallucinations).
Postpartum depression, which is much more serious than the “baby blues” that many women experience after giving birth, when hormonal and physical changes and the new responsibility of caring for a newborn can be overwhelming. It is estimated that 10 to 15 percent of women experience postpartum depression after giving birth.
Seasonal affective disorder (SAD), which is characterized by the onset of depression during the winter months, when there is less natural sunlight. The depression generally lifts during spring and summer. SAD may be effectively treated with light therapy, but nearly half of those with SAD do not get better with light therapy alone. Antidepressant medication and psychotherapy can reduce SAD symptoms, either alone or in combination with light therapy.
Bipolar depression, also called manic-depressive illness, is not as common as major depression or persistent depressive disorder. Bipolar disorder is characterized by cycling mood changes—from extreme highs (e.g., mania) to extreme lows (e.g., depression).
Most likely, depression is caused by a combination of genetic, biological, environmental, and psychological factors.
Depressive illnesses are disorders of the brain. Brain-imaging technologies, such as magnetic resonance imaging (MRI), have shown that the brains of people who have depression look different than those of people without depression. The parts of the brain involved in mood, thinking, sleep, appetite, and behavior appear different. But these images do not reveal why the depression has occurred. They also cannot be used to diagnose depression.
Some types of depression tend to run in families. However, depression can occur in people without family histories of depression too. Scientists are studying certain genes that may make some people more prone to depression. Some genetics research indicates that risk for depression results from the influence of several genes acting together with environmental or other factors. In addition, trauma, loss of a loved one, a difficult relationship, or any stressful situation may trigger a depressive episode. Other depressive episodes may occur with or without an obvious trigger.
Signs & Symptoms
“It was really hard to get out of bed in the morning. I just wanted to hide under the covers and not talk to anyone. I didn’t feel much like eating and I lost a lot of weight. Nothing seemed fun anymore. I was tired all the time, and I wasn’t sleeping well at night. But I knew I had to keep going because I’ve got kids and a job. It just felt so impossible, like nothing was going to change or get better.”
People with depressive illnesses do not all experience the same symptoms. The severity, frequency, and duration of symptoms vary depending on the individual and his or her particular illness.
Signs and symptoms include:
Persistent sad, anxious, or “empty” feelings
Feelings of hopelessness or pessimism
Feelings of guilt, worthlessness, or helplessness
Loss of interest in activities or hobbies once pleasurable, including sex
Fatigue and decreased energy
Difficulty concentrating, remembering details, and making decisions
Insomnia, early-morning wakefulness, or excessive sleeping
Overeating, or appetite loss
Thoughts of suicide, suicide attempts
Aches or pains, headaches, cramps, or digestive problems that do not ease even with treatment.
Who Is At Risk?
Major depressive disorder is one of the most common mental disorders in the United States. Each year about 6.7% of U.S adults experience major depressive disorder. Women are 70 % more likely than men to experience depression during their lifetime. Non-Hispanic blacks are 40% less likely than non-Hispanic whites to experience depression during their lifetime. The average age of onset is 32 years old. Additionally, 3.3% of 13 to 18 year olds have experienced a seriously debilitating depressive disorder.
“I started missing days from work, and a friend noticed that something wasn’t right. She talked to me about the time she had been really depressed and had gotten help from her doctor.”
Depression, even the most severe cases, can be effectively treated. The earlier that treatment can begin, the more effective it is.
The first step to getting appropriate treatment is to visit a doctor or mental health specialist. Certain medications, and some medical conditions such as viruses or a thyroid disorder, can cause the same symptoms as depression. A doctor can rule out these possibilities by doing a physical exam, interview, and lab tests. If the doctor can find no medical condition that may be causing the depression, the next step is a psychological evaluation.
The doctor may refer you to a mental health professional, who should discuss with you any family history of depression or other mental disorder, and get a complete history of your symptoms. You should discuss when your symptoms started, how long they have lasted, how severe they are, and whether they have occurred before and if so, how they were treated. The mental health professional may also ask if you are using alcohol or drugs, and if you are thinking about death or suicide.
Other illnesses may come on before depression, cause it, or be a consequence of it. But depression and other illnesses interact differently in different people. In any case, co-occurring illnesses need to be diagnosed and treated.
Anxiety disorders, such as post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, panic disorder, social phobia, and generalized anxiety disorder, often accompany depression. PTSD can occur after a person experiences a terrifying event or ordeal, such as a violent assault, a natural disaster, an accident, terrorism or military combat. People experiencing PTSD are especially prone to having co-existing depression.
Alcohol and other substance abuse or dependence may also co-exist with depression. Research shows that mood disorders and substance abuse commonly occur together.
Depression also may occur with other serious medical illnesses such as heart disease, stroke, cancer, HIV/AIDS, diabetes, and Parkinson’s disease. People who have depression along with another medical illness tend to have more severe symptoms of both depression and the medical illness, more difficulty adapting to their medical condition, and more medical costs than those who do not have co-existing depression. Treating the depression can also help improve the outcome of treating the co-occurring illness.
Once diagnosed, a person with depression can be treated in several ways. The most common treatments are medication and psychotherapy.
Antidepressants primarily work on brain chemicals called neurotransmitters, especially serotonin and norepinephrine. Other antidepressants work on the neurotransmitter dopamine. Scientists have found that these particular chemicals are involved in regulating mood, but they are unsure of the exact ways that they work. The latest information on medications for treating depression is available on the U.S. Food and Drug Administration (FDA) website .
Popular newer antidepressants
Some of the newest and most popular antidepressants are called selective serotonin reuptake inhibitors (SSRIs). Fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), paroxetine (Paxil), and citalopram (Celexa) are some of the most commonly prescribed SSRIs for depression. Most are available in generic versions. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are similar to SSRIs and include venlafaxine (Effexor) and duloxetine (Cymbalta).
SSRIs and SNRIs tend to have fewer side effects than older antidepressants, but they sometimes produce headaches, nausea, jitters, or insomnia when people first start to take them. These symptoms tend to fade with time. Some people also experience sexual problems with SSRIs or SNRIs, which may be helped by adjusting the dosage or switching to another medication.
One popular antidepressant that works on dopamine is bupropion (Wellbutrin). Bupropion tends to have similar side effects as SSRIs and SNRIs, but it is less likely to cause sexual side effects. However, it can increase a person’s risk for seizures.
Tricyclics are older antidepressants. Tricyclics are powerful, but they are not used as much today because their potential side effects are more serious. They may affect the heart in people with heart conditions. They sometimes cause dizziness, especially in older adults. They also may cause drowsiness, dry mouth, and weight gain. These side effects can usually be corrected by changing the dosage or switching to another medication. However, tricyclics may be especially dangerous if taken in overdose. Tricyclics include imipramine and nortriptyline.
Monoamine oxidase inhibitors (MAOIs) are the oldest class of antidepressant medications. They can be especially effective in cases of “atypical” depression, such as when a person experiences increased appetite and the need for more sleep rather than decreased appetite and sleep. They also may help with anxious feelings or panic and other specific symptoms.
However, people who take MAOIs must avoid certain foods and beverages (including cheese and red wine) that contain a substance called tyramine. Certain medications, including some types of birth control pills, prescription pain relievers, cold and allergy medications, and herbal supplements, also should be avoided while taking an MAOI. These substances can interact with MAOIs to cause dangerous increases in blood pressure. The development of a new MAOI skin patch may help reduce these risks. If you are taking an MAOI, your doctor should give you a complete list of foods, medicines, and substances to avoid.
MAOIs can also react with SSRIs to produce a serious condition called “serotonin syndrome,” which can cause confusion, hallucinations, increased sweating, muscle stiffness, seizures, changes in blood pressure or heart rhythm, and other potentially life-threatening conditions. MAOIs should not be taken with SSRIs.
How should I take medication?
All antidepressants must be taken for at least 4 to 6 weeks before they have a full effect. You should continue to take the medication, even if you are feeling better, to prevent the depression from returning.
Medication should be stopped only under a doctor’s supervision. Some medications need to be gradually stopped to give the body time to adjust. Although antidepressants are not habit-forming or addictive, suddenly ending an antidepressant can cause withdrawal symptoms or lead to a relapse of the depression. Some individuals, such as those with chronic or recurrent depression, may need to stay on the medication indefinitely.
In addition, if one medication does not work, you should consider trying another. NIMH-funded research has shown that people who did not get well after taking a first medication increased their chances of beating the depression after they switched to a different medication or added another medication to their existing one.
Sometimes stimulants, anti-anxiety medications, or other medications are used together with an antidepressant, especially if a person has a co-existing illness. However, neither anti-anxiety medications nor stimulants are effective against depression when taken alone, and both should be taken only under a doctor’s close supervision.
Report any unusual side effects to a doctor immediately.
IV Ketamine Therapy
One of the most exciting new treatment options for depression is with a long known drug, ketamine. Ketamine has been used historically as an anesthetic. Recently, it has emerged as an effective treatment option for severe depression (citations below). The mechanism of action for ketamine’s antidepressant effects is not fully understood and hotly debated. However, studies of the neurobiology of depressed patients have revealed possible abnormalities that may have a causal link to depression such as increased inflammatory cytokines, decreased BDNF, and reduced hippocampal volume. Interestingly, there is much overlap in the neurobiology of depression and known consequences of ketamine treatment. Ketamine has been found to reduce neuroinflammation, increase BDNF production and hippocampal volume. Thus, it is highly likely that ketamine possesses a robust pharmacological profile that works collectively to correct abnormalities common to severe depression. Although only FDA-approved as an anesthetic, ketamine is used off-label by many physicians in cases of severe, treatment-resistant depression.
Depression is more common among women than among men. Biological, life cycle, hormonal, and psychosocial factors that women experience may be linked to women’s higher depression rate. Researchers have shown that hormones directly affect the brain chemistry that controls emotions and mood. For example, women are especially vulnerable to developing postpartum depression after giving birth, when hormonal and physical changes and the new responsibility of caring for a newborn can be overwhelming.
Some women may also have a severe form of premenstrual syndrome (PMS) called premenstrual dysphoric disorder (PMDD). PMDD is associated with the hormonal changes that typically occur around ovulation and before menstruation begins.
During the transition into menopause, some women experience an increased risk for depression. In addition, osteoporosis—bone thinning or loss—may be associated with depression. Scientists are exploring all of these potential connections and how the cyclical rise and fall of estrogen and other hormones may affect a woman’s brain chemistry.
Finally, many women face the additional stresses of work and home responsibilities, caring for children and aging parents, abuse, poverty, and relationship strains. It is still unclear, though, why some women faced with enormous challenges develop depression, while others with similar challenges do not.
How do men experience depression?
Men often experience depression differently than women. While women with depression are more likely to have feelings of sadness, worthlessness, and excessive guilt, men are more likely to be very tired, irritable, lose interest in once-pleasurable activities, and have difficulty sleeping.
Men may be more likely than women to turn to alcohol or drugs when they are depressed. They also may become frustrated, discouraged, irritable, angry, and sometimes abusive. Some men throw themselves into their work to avoid talking about their depression with family or friends, or behave recklessly. And although more women attempt suicide, many more men die by suicide in the United States.
How do older adults experience depression?
Depression is not a normal part of aging. Studies show that most seniors feel satisfied with their lives, despite having more illnesses or physical problems. However, when older adults do have depression, it may be overlooked because seniors may show different, less obvious symptoms. They may be less likely to experience or admit to feelings of sadness or grief.
Sometimes it can be difficult to distinguish grief from major depression. Grief after loss of a loved one is a normal reaction to the loss and generally does not require professional mental health treatment. However, grief that is complicated and lasts for a very long time following a loss may require treatment. Researchers continue to study the relationship between complicated grief and major depression.
Older adults also may have more medical conditions such as heart disease, stroke, or cancer, which may cause depressive symptoms. Or they may be taking medications with side effects that contribute to depression. Some older adults may experience what doctors call vascular depression, also called arteriosclerotic depression or subcortical ischemic depression. Vascular depression may result when blood vessels become less flexible and harden over time, becoming constricted. Such hardening of vessels prevents normal blood flow to the body’s organs, including the brain. Those with vascular depression may have, or be at risk for, co-existing heart disease or stroke.
Although many people assume that the highest rates of suicide are among young people, older white males age 85 and older actually have the highest suicide rate in the United States. Many have a depressive illness that their doctors are not aware of, even though many of these suicide victims visit their doctors within 1 month of their deaths.
Most older adults with depression improve when they receive treatment with an antidepressant, psychotherapy, or a combination of both. Research has shown that medication alone and combination treatment are both effective in reducing depression in older adults. Psychotherapy alone also can be effective in helping older adults stay free of depression, especially among those with minor depression. Psychotherapy is particularly useful for those who are unable or unwilling to take antidepressant medication.
How do children and teens experience depression?
Children who develop depression often continue to have episodes as they enter adulthood. Children who have depression also are more likely to have other more severe illnesses in adulthood.
A child with depression may pretend to be sick, refuse to go to school, cling to a parent, or worry that a parent may die. Older children may sulk, get into trouble at school, be negative and irritable, and feel misunderstood. Because these signs may be viewed as normal mood swings typical of children as they move through developmental stages, it may be difficult to accurately diagnose a young person with depression.
Before puberty, boys and girls are equally likely to develop depression. By age 15, however, girls are twice as likely as boys to have had a major depressive episode.
Depression during the teen years comes at a time of great personal change—when boys and girls are forming an identity apart from their parents, grappling with gender issues and emerging sexuality, and making independent decisions for the first time in their lives. Depression in adolescence frequently co-occurs with other disorders such as anxiety, eating disorders, or substance abuse. It can also lead to increased risk for suicide.
An NIMH-funded clinical trial of 439 adolescents with major depression found that a combination of medication and psychotherapy was the most effective treatment option. Other NIMH-funded researchers are developing and testing ways to prevent suicide in children and adolescents.
Childhood depression often persists, recurs, and continues into adulthood, especially if left untreated.
How can I help a loved one who is depressed?
If you know someone who is depressed, it affects you too. The most important thing you can do is help your friend or relative get a diagnosis and treatment. You may need to make an appointment and go with him or her to see the doctor. Encourage your loved one to stay in treatment, or to seek different treatment if no improvement occurs after 6 to 8 weeks.
To help your friend or relative
Offer emotional support, understanding, patience, and encouragement.
Talk to him or her, and listen carefully.
Never dismiss feelings, but point out realities and offer hope.
Never ignore comments about suicide, and report them to your loved one’s therapist or doctor.
Invite your loved one out for walks, outings and other activities. Keep trying if he or she declines, but don’t push him or her to take on too much too soon.
Provide assistance in getting to the doctor’s appointments.
Remind your loved one that with time and treatment, the depression will lift.
How can I help myself if I am depressed?
If you have depression, you may feel exhausted, helpless, and hopeless. It may be extremely difficult to take any action to help yourself. But as you begin to recognize your depression and begin treatment, you will start to feel better.
To Help Yourself
Do not wait too long to get evaluated or treated. There is research showing the longer one waits, the greater the impairment can be down the road. Try to see a professional as soon as possible.
Try to be active and exercise. Go to a movie, a ballgame, or another event or activity that you once enjoyed.
Set realistic goals for yourself.
Break up large tasks into small ones, set some priorities and do what you can as you can.
Try to spend time with other people and confide in a trusted friend or relative. Try not to isolate yourself, and let others help you.
Expect your mood to improve gradually, not immediately. Do not expect to suddenly “snap out of” your depression. Often during treatment for depression, sleep and appetite will begin to improve before your depressed mood lifts.
Postpone important decisions, such as getting married or divorced or changing jobs, until you feel better. Discuss decisions with others who know you well and have a more objective view of your situation.
Remember that positive thinking will replace negative thoughts as your depression responds to treatment.
Researchers from the University of Minnesota and The Mayo Clinic found that ketamine caused an average decrease of 42% on the Children’s Depression Rating Scale(CDRS)—the most widely used rating scale in research trials for assessing the severity of depression and change in depressive symptoms among adolescents. The study recruited adolescents, 12-18 years of age, with treatment-resistant depression (TRD; failure to respond to two previous antidepressant trials). The teens were administered intravenous ketamine (0.5 mg/kg) by infusion six times over two weeks.
The study reported that the average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response (defined as >50% reduction in CDRS-R). Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. The ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Interestingly, higher dose was a significant predictor of treatment response.
“Adolescence is a key time period for emergence of depression and represents an opportune and critical developmental window for intervention to prevent negative outcomes,” the authors wrote in the study.
“Unfortunately, about 40% of adolescents do not respond to their first intervention and only half of non-responders respond to the second treatment,” they said. “Because standard interventions require prolonged periods (e.g., weeks to months) to assess efficacy, serial treatment failures allow illness progression, which in turn worsens the outcome. Hence, novel treatment strategies to address treatment-resistant depression in adolescents are urgently needed.”
The authors concluded that their results demonstrate the potential role for ketamine in treating adolescents with TRD. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose
Yale study found no safety issues with long-term ketamine treatment
Researchers at Yale published a new study titled “Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital” in Clinical Psychiatry. In late 2014, Yale began providing ketamine as an off-label therapy on a case-by-case basis for patients who could not participate in research protocols. The authors observed 54 patients that received IV ketamine infusion for the treatment of severe and treatment-resistant mood disorders such as depression.
“Ketamine is being used as an off-label treatment for depression by an increasing number of providers, yet there is very little long-term data on patients who have received ketamine for more than just a few weeks,” Samuel T. Wilkinson, MD,from the department of psychiatry, Yale School of Medicine and Yale Psychiatric Hospital, told Healio Psychiatry.
The Yale researchers studied the acute and longer-term outcomes in this patient population. Importantly, a subset of patients (n=14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks. The researchers found no evidence of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subset of long-term ketamine patients. They also reported that the infusions were generally well-tolerated.
Although this study population was relatively small, limiting the conclusions that can be drawn, this is still an important first step in establishing the long-term safety of ketamine for the treatment of a myriad of diseases that it’s being used to treat
CNN featured a segment on the use of ketamine for treating suicidal ideation–a novel, off-label use for ketamine that is currently being explored in human clinical trials. The segment featured Dr. Sanjay Gupta sharing the story of Alan Ferguson. Mr. Ferguson discussed his experience with suicidal ideation, stating that he had planned his own suicide prior to a psychiatrist suggesting the off-label use of ketamine. Fortunately, ketamine worked for him as it has for many others, completely eliminating all thoughts of suicide and depression.
While ketamine is a long-known, FDA-approved anesthetic, new uses for this old drug have recently been discovered. The new indication that is probably the farthest along is for the treatment of depression. It’s even undergoing phase III clinical trials for the treatment of depression, which are expected to be completed next year. In depression, ketamine’s mechanism of action is still being explored. Scientists know that ketamine antagonizes the NMDA receptor, which causes a number of downstream cascades that may be relevant to it’s antidepressant effects. Ketamine also increases important neuronal growth factors that can create new synaptic connections.
While there are numerous anti-depressants that are already FDA-approved, they don’t always work and–even when they do–it takes weeks to see the effect. This is what’s special about ketamine. The anti-depressant effects of ketamine are instantaneous. In the case of Alan Ferguson, his depression went from severe to mild after the first infusion, and was gone after the second. In cases of depression that involve suicidality, this rapid improvement can be the difference between life and death. Even though ketamine is not yet approved for the treatment of depression or suicidal ideation, there is an abundance of data showing that it works and it’s already being used off-label in the clinic.
Australian researchers completed the world’s first randomized control trial (RCT), assessing the efficacy and safety of ketamine as a treatment for depression in elderly patients.
In this double-blind, controlled, multiple-crossover study with a 6-month follow-up, 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted. Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months.
The results, published in the latest American Journal of Geriatric Psychiatry, provide preliminary evidence that ketamine is effective as an antidepressant – when delivered in repeated intravenous doses.
“What we noticed was that ketamine worked incredibly quickly and incredibly effectively,” Professor Colleen Loo, who led the pilot program told ABC News. “By incredibly effective, we mean going rapidly from severely depressed to being completely well in one day.”
“Some people think, ‘oh maybe it was just a drug induced temporary high’ — and it wasn’t,” she said. “You had the woozy effects in the first hour or so, but the antidepressant effects kicked in later.”
None of the participants experienced problematic side effects, according to the research team who administered the drug through a small injection under the skin.
“Our results indicate a dose-titration method may be particularly useful for older patients, as the best dose was selected for each individual person to maximize ketamine’s benefits while minimizing its adverse side effects,” she said.
The authors noted that further study is needed, however, to understand the risks of ketamine use and possible side effects, such as its impact on liver function in the elderly.
PTSD Treatment – Ketamine is a novel treatment for several psychiatric disorders including: Major Depressive Disorder, Bipolar Depression, Postpartum Depression, Obsessive-Compulsive Disorder (OCD), and Posttraumatic Stress Disorder or PTSD. It was originally FDA approved for anesthesia but is now frequently used off-label due to its positive effects on the various disorders listed above. PTSD is an devastating disorder that has become more and more common but medical treatments overall are still lacking.
What is PTSD?
PTSD is a disorder that develops after a traumatic experience. Such trauma sometimes involves combat, car accidents, natural disasters or sexual assaults. Up to 80% of individuals in their life will experience at least one traumatic event but, fortunately, most people do not go on to develop PTSD. The lifetime prevalence of developing PTSD is about 10% and women are twice as likely as men to develop PTSD. Those who do go on to develop PTSD typically will have one or more of the following symptoms:
• traumatic nightmares
• flashbacks taking them back to the event
• distress after exposure to traumatic reminders or stimuli
• avoidance of certain thoughts and situations
• negative thoughts and mood including shame, despair and depression.
A constellation of these symptoms must persist for at least a month for a diagnosis of PTSD to be made.
Most PTSD Treatment are ineffective for some patients and their all generally slow acting—meaning that the patient must wait weeks to have a meaningful impact on the patient’s wellness. Ketamine has now been shown to be effective at managing PTSD in several clinical studies. Moreover, physicians are beginning to present case reports where ketamine has helped their patients. One of the largest benefits of using Ketamine off label for the treatment of depression is that it is generally very fast-acting. Patients typically report feeling better after the first infusion or two. Sometimes, they report feeling 100% better after 5 days of IV ketamine therapy.
Geuris “Jerry” Rivas, a native of New York, was diagnosed with severe obsessive-compulsive disorder when he was 15. Obsessions with organizing and reorganizing the belongings in his bedroom — posters, comic books, videos — took over most of his life.
Forced by germ obsessions to compulsively wash and rewash his hands, he started wearing gloves all day to both protect him from the germs and stop him from washing his hands raw. Now, at 36, OCD symptoms continue to cost him jobs and relationships. He’s managed to turn his organizational skills into a profession — he’s a home organizer and house cleaner — but still he struggles daily with his obsessions.
“It’s caused me a great deal of suffering,” Rivas says. “I’ve tried many, many medications. I’ve wasted so much of my life.”
In 2012, running out of answers, Rivas took part in the first clinical trial to test ketamine as a treatment for OCD. While ketamine is approved by the U.S. Food and Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse. Over the past 10 years, dozens of small studies of ketamine’s ability to treat a variety of mood and anxiety disorders have reported remarkable results — including the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.
With a single infusion of the drug, Rivas experienced for two weeks what it was like to live without the compulsions and obsessions that had for years controlled his life.
“I felt like, for the first time, I was able to function like a regular person,” he says.
Pros and cons
Ketamine has brought hope to a psychiatric field desperate to find new treatments for severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.
“Severe OCD takes such a toll on patients,” says Carolyn Rodriguez, MD, PhD, who as a researcher at Columbia University ran the OCD trial. Now an assistant professor of psychiatry and behavioral sciences at Stanford, she has continued to explore the pros and cons of using ketamine to treat OCD. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”
Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It remains a mystery just how the drug works in the brain, and there are safety concerns. There is evidence from people who take the drug routinely — in much higher doses — that chronic, high-frequency ketamine use may be associated with increased risk of bladder inflammation and cognitive impairment, Rodriguez says. And if taken regularly, it can lead to dependence.
But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez says. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”
‘Right out of a movie’
Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants.”
Rodriguez, intent on searching for better, faster treatments for her patients like Rivas with OCD, took note. There was an emerging theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she says. Perhaps ketamine could help regulate OCD symptoms as well as depression.
In 2013, Rodriguez and colleagues published their results from that first clinical trial of ketamine in OCD patients. The trial randomized 15 patients with OCD to ketamine or placebo.
In those patients who were given ketamine, the effect was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. … This is amazing, unbelievable. This is right out of a movie.” And while nearly all initially had dissociative effects like feelings of unreality, distortions of time or hallucinations, they were gone within two hours after the start of the infusion.
“Carolyn’s study was quite exciting,” Zarate says, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and post-traumatic stress disorder.
“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he says.
So how does it work?
Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. Exactly what it does remains unclear.
“There’s a recognition that people like me and others are using the drug to treat patients now. There’s an incredible need for something.”
Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they’ve been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects.
Ultimately, Rodriguez says, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.
Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.
“Ketamine is a complicated drug that works on many different receptor sites,” she says. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”
In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depressionlike symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate says.
“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez says.
Beyond the clubs
Meanwhile, dozens of commercial ketamine clinics have popped up across the country, making treatments available to patients who are searching for help to stop their suffering now. Medical insurance companies usually cover ketamine’s FDA-approved use as an anesthetic but won’t cover its use for other purposes, such as mental health disorders. So patients who have run out of treatment options are paying hundreds of dollars a dose for repeated ketamine infusions.
“The fact that these clinics exist is due to the desperation of patients,” says Rodriguez.
She and other researchers are calling for guidelines to protect patients and more research to learn how to use the drug safely.
“I think it’s a game changer, and it’s here to stay,” says David Feifel, MD, PhD, professor emeritus of psychiatry at UC-San Diego, who studies the effect of ketamine on clinical depression. Feifel began prescribing the drug for patients with treatment-resistant depression in 2010.
“I’ve found it to be very safe,” Feifel says, adding that the American Psychiatric Association this year issued safety guidelines on how to use ketamine clinically for treatment of depression.
“There’s a recognition that people like me and others are using the drug to treat patients now,” he says. “There’s an incredible need for something.”
The drug hasn’t worked for everyone he’s treated, Feifel says, but for many it’s been “life-changing.”
Rodriguez says she understands what motivates the clinicians to prescribe the drug now to patients in dire straits — those who are suicidal or who have tried every possible medication and therapeutic option and continue to suffer each day.
“I see it as a way to treat people whose OCD is very, very severe,” she says. “People who can’t come out of the house, who are suicidal, who have no other options.
“I just don’t like the idea of people being in pain,” Rodriguez adds. “I want to see science translated into treatments now.”
Meanwhile, researchers are learning more about the drug. Janssen Pharmaceutical is testing the efficacy of a version of ketamine, known as esketamine, as a therapy for treatment-resistant depression and for major depressive disorder with imminent risk for suicide. The FDA has fast-tracked both investigations. At Stanford, Alan Schatzberg, MD, a professor of psychiatry and behavioral sciences, along with other faculty including Rodriguez, is studying the mechanism of action for ketamine in treating depression.
Rodriguez is also interested in using ketamine to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.
Relaxation and other techniques also help patients tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.
“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez says. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she says.
Rivas well remembers that infusion of ketamine he received during Rodriguez’s first clinical trial to test the drug. The rush made him feel “like Superman.”
“I felt like my body was bigger, that I was more muscular, that I could tackle anything,” he says. But that feeling only lasted the duration of the 40-minute infusion. His OCD symptoms disappeared immediately and were still gone for two weeks after.
“I was amazed that something like that would work and work so fast,” he says. His OCD symptoms today are still intrusive, but he manages to keep them under control by taking antidepressants and seeing a therapist. Still, each day when he comes home from work, he has to put gloves on before he enters his apartment building, and as soon as he enters his apartment, he must wash his hands.
“It’s a ritual now,” he says. “There has never been a time that I haven’t done that, except those two weeks after the ketamine.”
When he heard that certain private ketamine clinics are now offering the drug as treatment for OCD, he said he understands why patients take the risks and pay the high prices. As more research has become available, he’s begun considering it himself.
“I’ve been suffering through my OCD for so long, I’ve gotten to the point where I’d try anything,” he says.
USING KETAMINE TO TREAT SEVERE MENTAL ILLNESSA conversation with Stanford psychiatrist Carolyn Rodriguez, MD, PhD, about how she got interested in the use of ketamine to treat obsessive-compulsive disorder and how she is determined to find out why, in studies, the drug has provided relief from symptoms.
Intravenous Ketamine is proving to be a tremendous treatment for intractable depression as well as chronic pain. About half the patients treated respond positively with results lasting up to a week in most of the responders.
It has emerged as a treatment option for a variety of chronic pain conditions including fibromyalgia, small fiber neuropathy, Complex Regional Pain Syndrome (CRPS), Reflex Sympathetic Dystrophy (RSD) and psychiatric conditions including depression, Post Traumatic Stress Disorder (PTSD), suicidal ideation, and Obsessive-Compulsive Disorder (OCD).
Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease, diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510 control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp). MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews. Compared with control subjects (mean bp = 5541), sociodemographic-adjusted TL was shorter among remitted MDD patients (mean bp = 5459; P = 0.014) and current MDD patients (mean bp = 5461; P = 0.012). Adjustment for health and lifestyle variables did not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity (P<0.01) and longer symptom duration in the past 4 years (P = 0.01) were associated with shorter TL. Our results demonstrate that depressed patients show accelerated cellular aging according to a ‘dose–response’ gradient: those with the most severe and chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD had shorter TL than controls
In this large cohort study we demonstrated that currently
depressed persons had shorter TL than never-depressed controls.
Based on an estimated mean telomere shortening rate of 14–20
bp per year as found in this and other studies,20,23,26 the
differences observed indicate 4–6 years of accelerated aging for
the current MDD sample as compared to controls. We also showed
evidence for the imprint of past exposure to depression since
those with remitted MDD also had shorter TL than control
subjects. These observed associations remained significant after
controlling for lifestyle and somatic health variables, suggesting that the shortened telomeres were not simply due to unhealthylifestyle or poorer somatic health among depressed persons.
Finally, the association between MDD and TL showed a ‘dose–
response’ gradient, since the most severely and chronically
depressed patients had the shortest telomeres.
MDD is thus associated with shortened TL, which resembles
accelerated biological aging. The disorder has previously also been
associated with dysregulations of the hypothalamus–pituitary–
adrenal (HPA) axis,43,45 the immune system,46,47 the autonomic
nervous system (ANS)48,49 and increased oxidative stress.50
Shortened telomeres, in turn, are suggested to be a consequence
or a concomitant of these dysregulated biological stress systems.
In line with this, several in vitro and in vivo studies found increased
cortisol,51 oxidative stress52 and pro-inflammatory cytokines53
to be associated with shorter TL. Dysregulations of these stress systems could contribute to telomere shortening in MDD patients.9,12
However, the exact biological mechanisms that mediate the relation
between depression and telomere shortening, as well as the
direction of the link, remain to be further explored.
Studies of the World Health Organization suggest that in the year 2020, depressive disorder will be the illness with the highest
burden of disease. Especially unipolar depression is the psychiatric disorder with the highest prevalence and incidence, it is cost-intensive and has a relatively high morbidity. Lately, the biological process involved in the aetiology of depression has been the focus of research.
Since its emergence, the monoamine hypothesis has been adjusted and extended considerably. An increasing body of evidence points to
alterations not only in brain function, but also in neuronal plasticity. The clinical presentations demonstrate these dysfunctions by accompanying cognitive symptoms such as problems with memory and concentration. Modern imaging techniques show volume reduction of the hippocampus and the frontal cortex. These findings are in line with post-mortem studies of patients with depressive disorder and they point to a significant decrease of neuronal and glial cells in cortico-limbic regions which can be seen as a consequence of alterations in
neuronal plasticity in this disorder. This could be triggered by an increase of free radicals which in turn eventually leads to cell death and consequently atrophy of vulnerable neuronal and glial cell population in these regions. Therefore, research on increased oxidative stress in unipolar depressive disorder, mediated by elevated concentrations of free radicals, has been undertaken. This review gives a comprehensive overview over the current literature discussing the involvement of oxidative stress and free radicals in depression.
Membrane damage in blood of patients with depression has
been shown by elevated of omega 3- fatty-acids  and by increased
lipid peroxidation products in patients with DD [42, 45,
[46, 47]. Furthermore, DNA-strand brakes have been reported in
the blood of these patients . DD has been linked to increased
serum levels of malondialdehyde (MDA), a breakdown product of
oxidized apolipoprotein B-containing lipoproteins, and thus a
marker of the rate of peroxide breakdown [49, 50].
In patients with DD (Depressive Disorders), elevated levels of MDA adversely affect
the efficiency of visual-spatial and auditory-verbal working memory,
short-term declarative memory and delayed recall declarative
memory . Higher concentration of plasma MDA in patients
with recurrent depression is associated with the severity of depressive
symptoms, both at the beginning of antidepressant pharmacotherapy,
and after 8 weeks of treatment. Statistically significant
differences were found in the intensity of depressive symptoms,
measured on therapy onset versus the examination results after
8 weeks of treatment . Although this is used as a marker of lipid peroxidation, it is considered to be less stable than 8-iso-PGF2a, and more susceptible to confounding factors such as antioxidants from diet . Therefore, the best way to investigate oxidative disruptions to lipids in humans is via assessing levels of F2-
isoprostanes [52-54]. These are stable compounds produced in the
process of lipid peroxidation [52, 54]. 8-iso-PGF2a are specific F2-
isoprostane molecules produced during the peroxidation of arachnidonic acid. However, the mean serum level of 8-iso-PGF2a was shown to be significantly higher in a group of patients with DD,
controlling for lifestyle variables such as body mass index, alcohol
consumption, and physical activity [55, 56]. Cerebral membrane
abnormalities and altered membrane phospholipids have been suggested by an increased choline-containing compound seen in the
putamen of patients with DD  which has been interpreted as a
result of increased oxidative stress in patients with DD.
115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin,
high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy
(p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After
antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were
This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher
than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The
pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.
Some studies have demonstrated that depressed patients’ oxidative product levels in their peripheral blood [3, 4], red blood cells (RBC) , mononuclear cells , urine , cerebrospinal
fluid  and postmortem brains  were abnormal. Antioxidant system disturbance in peripheral blood has also been reported . Autoimmune responses against neoepitopes
induced by oxidative damage of fatty acid and protein membranes have been reported [10, 11].
Lower glutathione (GSH) levels  and a negative relationship between anhedonia severity
and occipital GSH levels  were found through magnetic resonance spectroscopy (MRS).
Oxidative stress is defined as a persistent imbalance between oxidation and anti-oxidation, which leads to the damage of cellular macromolecules [14, 15]. The free radicals consist of reactive
oxygen species (ROS) and reactive nitrogen species (RNS). The main ROS includes superoxide anion, hydroxy radical and hydrogen peroxide, and the RNS consists of nitric oxide
(NO), nitrogen dioxide and peroxynitrite. Nitrite is often used as a marker of NO activity. Interestingly, the brain appears to be more susceptible to the ROS/RNS because of the high
content of unsaturated fatty acids, high oxygen consumption per unit weight, high content of key ingredients of lipid peroxidation (LP) and scarcity of antioxidant defence systems .
The oxidative products include products of oxidative damage of LP, protein and DNA in depression. As a product of LP, abnormal malondialdehyde (MDA) levels in depression have
been reported . 8-F2-isoprostane (8-iso-PGF2α) is another product of LP  that is considered
to be a marker of LP because of its chemical stability . The protein carbonyl (PC), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydroguanosine (8-oxoGuo) are
the markers of protein, DNA and RNA oxidative damage, respectively [3, 20, 21]. The oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to the generation of new epitopes modified (neoepitopes). The antibodies against oxidative neoepitopes
in depression have been found [10, 11, 22–24]. On the other hand, the antioxidant defence systems can be divided into enzymatic and non-enzymatic antioxidants. The nonenzymatic
antioxidants include vitamins C and E, albumin, uric acid, high-density lipoprotein cholesterol (HDL-C), GSH, coenzyme Q10 (CoQ10), ceruloplasmin, zinc, selenium, and so on.
The enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GR), paraoxonase 1 (PON1), and so on.
The present findings support oxidative stress may be disordered in depressed patients, which is demonstrated by abnormal oxidative stress marker levels. In this meta-analysis, at first we
found in depressed patients: 1) the serum TAC, PON, uric acid, albumin, HDL-C and zinc levels were lower than controls; 2) the serum peroxide, MDA, 8-iso-PGF2α and RBC MDA levels
were higher than controls. To explore the effect of the antidepressant therapy to oxidative stress
markers, we reviewed the studies which had changes. And it came to the conclusions: 1) the serum uric acid, albumin, and vitamin C levels were increased; 2) the serum nitrite, RBC and
serum MDA levels were decreased.
The serum antioxidant levels are significantly lower in depression in our study and previous
reports, including PON, albumin, zinc, uric acid HDL-C, CoQ10  and GSH [4, 38].
Meanwhile, the oxidative damage product levels are significantly higher. The body couldn’t
scavenge the excess free radicals (peroxide), leading to damages of main parts of cellular macromolecules
such as fatty acids, protein, DNA, RNA and mitochondria. The longitudinal antidepressant
therapy can reverse these abnormal oxidative stress parameters. It has proved
these phenomena occur in depression, such as increased levels of MDA, 8-iso-PGF2α, 8-oxoGuo
and 8-OHdG [3, 21]. Oxidative stress plays a crucial role in the pathophysiology of
depression. Some genes may be a potential factor. Lawlor et al (2007) reported the R allele of
PON1Q192R was associated with depression . In addition, poor appetite, psychological
stressors, obesity, metabolic syndrome, sleep disorders, cigarette smoking and unhealthy lifestyle
may also contribute to it . Furthermore, oxidative stress activates the immuneinflammatory
pathways . But some studies supported decrease in albumin, zinc and
HDL-C levels was probably related to increased levels of pro-inflammatory cytokines (such as
interleukin-1 (IL-1) and IL-6) [59, 70–72, 117] during an acute phase response, which illustrated the activated immune-inflammatory pathways also activates the oxidative stress. These two mechanisms influence each other. On the other hand, the oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to generation of newepitopes modified (neoepitopes). Oxidative neoepitopes reported up to now include the conjugated oleic and azelaic acid, MDA, phosphatidyl inositol (Pi), NO-modified adducts and oxidized low density lipoprotein (oxLDL) [11, 22–24]. Maes et al reported the levels of serum IgG antibody against the oxLDL and IgM antibodies against the conjugated oleic and azelaic acid, MDA, Pi and NO-modified adducts were increased in depression [11, 22–24]. Depleted antioxidant defence in depression suggests that antioxidant supplements may be useful in clinical management. Preliminary evidence has indicated that patients treated with CoQ10 showed improvement in depressive symptoms and decrease in hippocampal oxidative DNA damage . In our analyses, vitamin C and E levels did not differ between depressed patients and controls, but many studies have reported that vitamin C and E supplements could improve depressive moods [150, 151].
Oxidative stress has been implicated in the cognitive decline, especially in memory impairment. The purpose of this study was to determine the concentration of malondialdehyde (MDA) in patients with recurrent depressive disorders (rDD) and to define relationship between plasma levels of MDA and the cognitive performance. The study comprised 46 patients meeting criteria for rDD. Cognitive function assessment was based on: The Trail Making Test , The Stroop Test, Verbal Fluency Test and Auditory-Verbal Learning Test. The severity of depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Statistically significant differences were found in the intensity of depression symptoms, measured by the HDRS on therapy onset versus the examination results after 8 weeks of treatment (P < 0.001). Considering the 8-week pharmacotherapy period, rDD patients presented better outcomes in cognitive function tests. There was no statistically significant correlation between plasma MDA levels, and the age, disease duration, number of previous depressive episodes and the results in HDRS applied on admission and on discharge. Elevated levels of MDA adversely affected the efficiency of visual-spatial and auditory-verbal working memory, short-term declarative memory and the delayed recall declarative memory. 1. Higher concentration of plasma MDA in rDD patients is associated with the severity of depressive symptoms, both at the beginning of antidepressants pharmacotherapy, and after 8 weeks of its duration. 2. Elevated levels of plasma MDA are related to the impairment of visual-spatial and auditory-verbal working memory and short-term and delayed declarative memory.
Antioxidant /Antidepressant-like Effect of Ascorbic acid (Vitamine C) and Fluoxetine
Another study investigated the influence of ascorbic acid
(which is an antioxidant with antidepressant-like effects in animals)
on both depressive-like behaviour induced by a chronic unpredictable
stress (CUS) paradigm and on serum markers of oxidative
stress and in cerebral cortex and hippocampus of mice . The
CUS-model is an animal model for induced depression-like behaviour
in animals. Depressive-like behaviour induced by CUS was
accompanied by significantly increased lipid peroxidation (cerebral
cortex and hippocampus), decreased catalase (CAT) (cerebral cortex
and hippocampus) and glutathione reductase (GR) (hippocampus)
activities and reduced levels of glutathione (cerebral cortex).
Repeated ascorbic acid as well as fluoxetine administration significantly
reversed CUS-induced depressive-like behaviour as well as
oxidative damage. No alterations were observed in locomotor activity
and glutathione peroxidase (GPx) activity in the same sample.
These findings pointed to a rapid and robust effect of ascorbic acid
in reversing behavioural and biochemical alterations induced in an
animal model . Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.
The average response rate in published studies testing ketamine for adult TRD is 67% (Wan et al. 2015), which is considerably higher than TRD interventions (e.g., the average response rate for transcranial magnetic stimulation is 45% (Conelea et al. 2017).
Background: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.
Methods: Adolescents, 12–18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children’s Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS).
Results: Thirteen participants (mean age 16.9 years, range 14.5–18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response.
Conclusions: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.
Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.
Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients
Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.
“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”
It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.
Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.
The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.
The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.
While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.
“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”
She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”
Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.
The findings were published online last week in the American Journal of Psychiatry.
According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.
“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”
Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.
The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.
Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.
Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.
“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine’s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”
Abstract Objective To review the published literature on the efficacy of ketamine for the treatment of suicidal ideation (SI). Methods The PubMed and Cochrane databases were searched up to January 2015 for clinical trials and case reports describing therapeutic ketamine administration to patients presenting with SI/suicidality. Searches were also conducted for relevant background material regarding the pharmacological function of ketamine. Results Nine publications (six studies and three case reports) met the search criteria for assessing SI after administration of subanesthetic ketamine. There were no studies examining the effect on suicide attempts or death by suicide. Each study demonstrated a rapid and clinically significant reduction in SI, with results similar to previously described data on ketamine and treatment-resistant depression. A total of 137 patients with SI have been reported in the literature as receiving therapeutic ketamine. Seven studies delivered a dose of 0.5 mg/kg intravenously over 40 min, while one study administered a 0.2 mg/kg intravenous bolus and another study administered a liquid suspension. The earliest significant results were seen after 40 min, and the longest results were observed up to 10 days postinfusion. Conclusion Consistent with clinical research on ketamine as a rapid and effective treatment for depression, ketamine has shown early preliminary evidence of a reduction in depressive symptoms, as well as reducing SI, with minimal short-term side effects. Additional studies are needed to further investigate its mechanism of action, long-term outcomes, and long-term adverse effects (including abuse) and benefits. In addition, ketamine could potentially be used as a prototype for further development of rapid-acting antisuicidal medication with a practical route of administration and the most favorable risk/benefit ratio. Key Points Preliminary data from randomized controlled trials have demonstrated that ketamine may rapidly and effectively control treatment-resistant depression, though the effects are transient. A small subset of studies has demonstrated similar results in the effects of ketamine on suicidal ideation. Ketamine has potential as a rapid treatment for suicidal ideation and/or a possible model compound for future drug development.
4 Discussion With an estimated prevalence of mood disorders ranging from 3.3 to 21.4 % and the substantially increased risk of suicide among patients with mood disorders, treatment is certainly warranted . Current treatment options for suicidality are limited. They include brain stimulation therapeutics, such as ECT, and pharmacological intervention (lithium, clozapine). The efficacy of lithium in treating suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48 studies . Clozapine has also been shown to reduce suicide risk in patients with schizophrenia [23, 24]. The limitations of both lithium and clozapine include a longer time to efficacy in this psychiatric emergency/urgency, compared with the early response to ketamine . Ketamine seems to be gaining substantial evidence as a pharmacological option for depression with a fast onset of action, but its long-term effects need further investigation. In addition, ketamine probably offers a faster onset of action in terms of SI, but further work is certainly needed in this area. Given the risk of suicide and even the increasing rates of suicide in certain subgroups, such as soldiers and veterans [26, 27], there is an urgent need for faster therapeutics for SI and TRD. Importantly, suicidality and suicide pose a high global burden of patient suffering to families and society. Although several small-to-moderate sized studies, in addition to several reviews, have been published that have examined the efficacy of ketamine in TRD, there are considerably fewer published data specifically examining ketamine in patients presenting with SI. Notably, only three studies have directly examined SI as the primary outcome [11, 16, 17], while the rest examined SI as the secondary outcome [4, 15, 18], not including case reports. This review summarizes the current published literature regarding ketamine as a treatment for SI. The data so far show promising trends of ketamine being an effective and rapid treatment with minimal side effects. Pharmacologically, ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It has been used for anesthesia in the USA since the 1970s. At subanesthetic doses, ketamine has been shown to increase glutamate levels . This mechanism is relevant, as glutamate regulation and expression are altered in patients with major depressive disorder (MDD). Studies have also demonstrated an abnormal glutamate–glutamine–gamma-aminobutyric acid cycle in patients with suicidality . Furthermore, ketamine has also been shown to work on nicotinic and opioid receptors . No other class of antidepressant medication works to modulate the glutamatergic system, and research continues into this, with the goal of characterizing the full mechanism of action of ketamine and perhaps developing other compounds that would have similar effects. Thus, even if the approval and marketing of ketamine as a rapidacting antisuicidal and antidepressant medication is not realized, it could well be a prototype for development of other medication(s) that retain the mechanism of action with more favorable qualities and a lesser adverse effect profile (such as a longer duration of action or less or no addictive potential). Although the mechanisms explaining the antisuicidal effect and the NMDA receptor antagonism of ketamine are still unclear, some of the initial evidence points to an anti-inflammatory action via the kynurenic acid pathway. Strong suggestions as to the causal relationship between inflammation and depression/suicidality has come from studies demonstrating that cytokines [30, 31] and interferon-b  induce depression and suicidality. Other recent studies have added to the notion of implicating brain immune activation in the pathogenesis of suicidality. For instance, one study showed microglial activation of postmortem brain tissue in suicide victims . Another study found increased levels of the cytokine interleukin-6 in cerebrospinal fluid from patients who had attempted suicide . Higher levels of inflammatory markers have been shown in suicidal patients than in nonsuicidal depressed patients [33, 35]. Inflammation leads to production of both quinolinic acid (an NMDA agonist) and kynurenic acid (a NMDA antagonist). An increased quinolinic acid to kynurenic acid ratio leads to NMDA receptor stimulation. The correlation between quinolinic acid and Suicide Intent Scale scores indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality . Small randomized controlled trials have demonstrated the efficacy of ketamine in rapidly treating patients with both TRD and/or bipolar depression [4, 8, 9, 11, 16–18]. Some studies have also examined suicide items as a secondary measure in their depression rating scales [4, 7]. In total, the studies examining ketamine and TRD have nearly consistently demonstrated that ketamine provides relief from depressive and suicidal symptoms, starting at 40 min and lasting for as long as 5 days. Questions still remain as to the long-term effects of this treatment, how much should be administered and how often, any serious adverse effects, and the mechanism of action. Pharmacologically, ketamine has poor bioavailability and is best administered via injection . In their landmark study, Berman et al.  found that a subanesthetic dose (0.5 mg/kg) rapidly improved depressive symptoms. Most of the subsequent studies have delivered ketamine as a constant infusion for 40 min at a rate of 0.5 mg/kg. Others have examined its efficacy after multiple infusions and observed similar results [8, 13, 16, 38]. Currently, it is recommended that ketamine be administered in a hospital setting .
Characterizing the course of suicidal ideation response to ketamine
2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:
Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine. Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers. Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders. Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used. Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine.
1. Introduction Suicide poses a serious threat to public health. Worldwide, suicide accounts for approximately 1 million deaths, and 10 million suicide attempts are reported annually (World Health Organization, 2014). In the United States, the national suicide rate has increased by approximately 28% over the last 15 years (Curtin et al., 2016). At the same time, relatively few interventions for suicide risk exist. While treatments such as clozapine and lithium have demonstrated effects on suicidal behavior over weeks to months, these effects may be limited to specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently, no FDA-approved medications exist to treat suicidal ideation (SI), leaving those who experience a suicidal crisis with limited options for a reprieve of symptoms. Consequently, a critical need exists for rapid-acting treatments that can be used in emergency settings. A promising off-label agent for this purpose is the rapid-acting antidepressant ketamine, which past studies have suggested reduces suicidal thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price et al., 2009). A recent meta-analysis of 167 patients with a range of mood disorder diagnoses found that ketamine reduced suicidal thoughts compared to placebo as rapidly as within a few hours, with effects lasting as long as seven days (Wilkinson et al., 2017). These results are reinforced by newer findings of reduced active suicidal ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era of personalized medicine, two important issues must be addressed. First, little is known about the acute course of SI following ketamine. The speed with which antidepressant response occurs, and how much improvement can be expected on average, has been documented for single administrations of ketamine (Mathew et al., 2012; Sanacora et al., 2017); in the limited available literature, researchers have emulated previous studies examining antidepressant effect, where a cutoff of 50% improvement demarcated response (Nierenberg and DeCecco, 2001). Nevertheless, it remains unknown whether this categorization accurately reflects the phenomenon of suicidal thoughts. Empirically-derived approaches to the description of SI trajectory after ketamine may be useful in operationalizing “response” in future clinical trials. Second, identifying demographic, clinical, or biological predictors of SI response to ketamine would allow researchers and clinicians to determine who is most likely to exhibit an SI response to ketamine. A broad literature describes clinical and demographic predictors for suicide risk (Franklin et al., 2017), and a smaller literature connects suicidal thoughts and behaviors to plasma markers such as brain-derived neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015; Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini et al., 2013). However, no biomarkers have been shown to predict SI/ behavior response to intervention, a finding reinforced by the National Action Alliance for Suicide Prevention’s Research Prioritization Task Force’s Portfolio Analysis (National Action Alliance for Suicide Prevention: Research Prioritization Task Force, 2015). Notably, predictor analyses have the potential to reveal insights into personalized treatments for suicidal individuals, as well as the neurobiology of SI response. With respect to antidepressant response, for example, this approach yielded the observation that individuals with a family history of alcohol dependence may be more likely to exhibit an antidepressant response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip et al., 2014). The goals of this study were to elucidate trajectories of SI response and identify predictors of that response, with the ultimate goal of adding to the growing literature surrounding ketamine’s specific effects on SI. In particular, we sought to determine whether the heterogeneous patterns of change in SI after ketamine administration were better explained by a model with two or more latent groups of trajectories rather than a single average trajectory, using secondary analyses from previously published clinical trials. These classes were then used to evaluate potential clinical, demographic, and plasma biomarker predictors of SI response to ketamine in order to generate hypotheses.. Discussion This analysis used a data-driven approach to characterize SI response to ketamine. The data were best explained by three trajectory classes: one with severe average baseline SI and little to no response to ketamine (Non-Responders), one with moderate average baseline levels of SI and significant response to ketamine (Responders), and a third with moderate average baseline levels of SI and complete remission of SI by two days post-ketamine (Remitters). These findings suggest a diversity of post-ketamine changes in SI that may not be captured under traditional methods of categorizing response to treatment. Furthermore, we found evidence that SI response and antidepressant response could be distinguished from each other; one subset of participants experienced improvement in SI that was partially explained by improvements in Depressed Mood, while the other group’s improvements in SI occurred independently of antidepressant response. With regard to predictors of SI response trajectory, preliminary results suggest the individuals least likely to experience improvement in SI postketamine were those with the most severe SI and a history of self-injury. Few plasma markers emerged as predictors of SI response in this study, highlighting the limitations of connecting SI ratings of response with biological markers. The growth mixture modeling approach used here underscored the heterogeneity of SI response to ketamine, which would not have been captured by simply calculating the average trajectory. The class assignment from this approach also differed from the definition of response (50% reduction in symptoms) traditionally used in the antidepressant literature, which often focuses on a specific timepoint rather than the entire symptom trajectory. In comparing classification using a 50% response at Day 1 and Day 3 with the latent trajectory classes, we found representation of almost every SI class across each responder group, highlighting the potential limitations of the 50% response approach. Further study is needed to determine which of these approaches will prove more fruitful. Complete remission of SI has previously been used as an outcome measure in clinical trials and in a meta-analysis of ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018; Wilkinson et al., 2017), as well as in a study examining the relationship between SI response to ketamine and changes in nocturnal wakefulness (Vande Voort et al., 2017). One strength of the present study is that this data-driven approach provides classifications that directly reflect the phenomena under study as they are, as opposed to what they should be. Especially when used in larger samples than the current study, this approach is particularly promising in its ability to provide a more nuanced understanding of the nature of SI response to ketamine. Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable by baseline Depressed Mood scores; patients with the most severe SI did not differ meaningfully in Depressed Mood scores from those with the mildest SI. Second, while previous analyses of these data documented that BMI and family history of alcohol dependence predicted antidepressant response (Niciu et al., 2014), SI response was not associated with these variables in the current analysis. Third, the antidepressant response profiles of the SI classes suggest that SI response and antidepressant response are not wholly redundant. This aligns with previous clinical trials and meta-analytic reviews of the literature suggesting that SI response to ketamine occurs partially independently of antidepressant response (Grunebaum et al., 2018; Wilkinson et al., 2017). Nevertheless, this independence did not hold true across both SI response groups. Specifically, antidepressant and SI response were clearly linked in Remitters, with depression accounting for half of the changes in SI; however, in Responders, improvements in SI occurred independently from improvements in Depressed Mood. These discrepancies could be related to ketamine’s complex neurobiological mechanisms or to the potentially low levels of clinical severity observed in the Remitters. Interestingly, the current analyses found no baseline demographic variables that reliably distinguished Responders from Remitters. Some phenotypic characteristics were uniquely associated with belonging to the Non-Responder group, suggesting that a long-standing history of self-injury or SI may indicate resistance to rapid changes in SI. Relatedly, a recent, randomized clinical trial of repeat-dose ketamine compared to placebo found that ketamine had no effect on SI in a sample of patients selected for their longstanding, chronic history of SI (Ionescu, 2017). These results highlight the importance of patient selection, particularly for suicide risk. It should be stressed, however, that SI does not necessarily translate to suicidal attempts or deaths; to our knowledge, no study has yet linked ketamine with reduced risk of suicidal behavior. Indeed, in the present study the SI Non-Responders experienced limited antidepressant effects in response to ketamine, but may nevertheless have improved on other, unmeasured symptoms that could provide important benefit and relief. As the ketamine literature develops, it will be important to identify which clinical symptom profiles are most likely to have a robust anti-SI and anti-suicidal behavior response to ketamine and which ones may benefit from other interventions. While we evaluated a range of potential plasma markers previously linked to suicidal ideation and behavior, in the present analysis only IL5 was associated with the SI Responder subgroup. Ketamine is known to have anti-inflammatory effects (Zunszain et al., 2013), but the relationship between antidepressant response and change in cytokine levels remains unclear (Park et al., 2017). Cytokines have been linked to suicidal behavior in the past; a recent meta-analysis found that lower levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large number of comparisons and lack of precedent in the literature, this result may have been spurious and should be interpreted with caution. A number of other results may reflect meaningful relationships, but the high degree of variability—and the associated wide confidence intervals—suggests that larger sample sizes are needed to better elucidate the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13, p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly, plasma BDNF levels were not associated with responder class. Previous studies of bipolar, but not MDD, samples found that plasma BDNF levels were associated with SI response after ketamine (Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed diagnostic composition of this study may explain differences from previous work. Studies exploring the relationship between BDNF and antidepressant response to ketamine have also yielded mixed findings (Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven approaches have considered both biological and behavioral variables in characterizing depression (Drysdale et al., 2017); a similar approach might prove useful for predicting SI response. The present study is associated with several strengths as well as limitations. Strengths include the relatively large sample size of participants who received ketamine, the use of composite SI scores from previous exploratory factor analyses as opposed to individual items, and the combination of clinical and biological markers as potential predictors of class membership. Limitations include patient selection methods, as these patients were part of an antidepressant trial and were not selected for active suicidal thoughts, as well as the exploratory nature of the analysis. As stated above, suicidal thoughts do not necessarily equate to suicidal behavior, and class membership would thus not necessarily correspond with an overall reduction in suicide risk. Another limitation is that results were collapsed across several clinical trials with slight variations in study design, and findings were thus only extended to Day 3 rather than a week after ketamine administration. As a result, only a subset of the sample could be used for predictive analyses. In addition, plasma—rather than CSF—markers were used, and the latter might better indicate underlying biology due to proximity to the brain, though certain markers such as plasma BDNF may be related to platelet storage, rather than the brain (Chacón-Fernández et al., 2016). Comparison of results to trajectories of suicide-specific measures, such as the Scale for Suicide Ideation (Beck et al., 1979), may also give further insight into specific SI content. Finally, many clinical predictors were collected upon hospital admission; future analyses could use formal assessments, such as the Childhood Traumatic Questionnaire (Bernstein et al., 1994), assessment of personality disorders, or diagnoses such as post-traumatic stress disorder (PTSD) as potential indicators of response. Despite these limitations, the study demonstrates the utility of a data-driven approach for characterizing the heterogeneity of SI response to a rapid-acting intervention. This allows for a more finegrained analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at 50% reduction in symptoms. This study identified several findings of note. These included distinguishing at least three patterns of SI response to ketamine and finding that subjects who exhibited more severe SI at baseline were not likely to experience an SI response to ketamine.
Ketamine Treatment Center | 703-844-0184 | Ketamine treatment for depression, PTSD | Neograft Hair Transplantation | FUE | Hair Care | Hair Loss Treatment | Hair Loss Center | Addiction Medical Treatment Center | Suboxone | Sublocade | Vivitrol | IV Vitamin Drip | IV Doctor in Fairfax, Va | 22306 | Pain management | Suboxone | Sublocade |Probuphine | Vivtrol | Alcohol addiction | Opioid Addiction treatment |