Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid
Ketamine is emerging as a way to treat depression, but it appears to act like an opioid, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions.
A handful of pharmaceutical companies, including Johnson & Johnson and Allergan, are using ketamine as inspiration for new prescription drugs to treat depression.
This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as “Special K.”
Ketamine is emerging as a way to treat depression, but it appears to act like an opioid — and it may carry similar risks, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions. A handful of pharmaceutical companies are using ketamine as inspiration for new prescription drugs to treat depression. Yet the new research questions whether scientists know enough about chronic ketamine use to introduce it broadly.
The drug blocks NMDA receptors, which scientists think may treat depressive symptoms. Researchers wanted to test whether it was possible to elicit this reaction without activating the brain’s opioid receptors.
To block an opioid response, they gave participants naltrexone then infused them with ketamine. To compare that response with the normal response, they also gave participants a placebo before giving them the treatment.
Naltrexone so successfully blocked the anti-depressant effects of ketamine that researchers cancelled the study after the first interval because they felt it wasn’t ethical to continue it, said Dr. Nolan Williams, one of the study’s authors and a clinical assistant professor of psychiatry and behavioral sciences at Stanford University.
When patients took naltrexone, the opioid blocker, their symptoms did not improve, suggesting ketamine must first activate opioid receptors in order to treat depression, according to the study, published Wednesday in the American Journal of Psychiatry.
That’s not to say ketamine cannot be used occasionally, but it does raise questions about using it repeatedly over time, said Dr. Alan F. Schatzberg, co-author of the study and Stanford’s Kenneth T. Norris, Jr., professor of psychiatry and behavioral sciences. He likens it to opioid painkillers being an appropriate pain treatment when used once in the emergency room but posing problems, such as the risk of dependence, when used chronically.
“More studies need to be done to fully understand ketamine before it’s widely rolled out for long-term chronic use,” Schatzberg said.
Researchers planned on studying 30 adults but stopped enrolling patients once they decided combining ketamine and naltrexone was not only ineffective but also “noxious” for many participants. They tested a total of 12 people with both naltrexone and the placebo.
Of those 12, seven who received naltrexone experienced nausea after the ketamine infusion, compared to three in the placebo group. Two participants in each group also experienced vomiting.
Participants who received the placebo and ketamine treatment reported reduced depression symptoms. But those same participants did not see a decrease in depression symptoms after receiving ketamine and opioid-blocker naltrexone.
“We essentially blocked the mechanism for producing the anti-depressant effect, which were opioids,” said Williams.
The findings may have implications for clinics offering ketamine infusions and drug manufacturers trying to commercialize ketamine-like drugs.
Ketamine is meant to be used as an anesthetic. Since ketamine is currently not indicated to treat depression, insurance typically doesn’t cover the cost of infusions, so people tend to pay out of their own pocket. One session can run more than $500.
Meanwhile, drug giant Johnson & Johnson plans to seek approval from the Food and Drug Administration for its nasal spray esketamine this year after reporting positive results from a Phase 3 trial. Allergan plans to file its drug Rapastinel, which targets the NMDA receptors like ketamine, within the next two years. VistaGen Therapeutics is working on a similar drug.
In a statement, J&J said while the study reviewed ketamine and not esketamine, the findings “are difficult to interpret because of the study’s design.”
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.
Lauren Pestikas sits as she receives an infusion of the drug ketamine during a 45-minute session at an outpatient clinic in Chicago on July 25, 2018. Pestikas struggled with depression and anxiety and made several suicide attempts before starting ketamine treatments earlier in the year. (AP Photo/Teresa Crawford)
CHICAGO (AP) — It was launched decades ago as an anesthetic for animals and people, became a potent battlefield pain reliever in Vietnam and morphed into the trippy club drug Special K.
Now the chameleon drug ketamine is finding new life as an unapproved treatment for depression and suicidal behavior. Clinics have opened around the United States promising instant relief with their “unique” doses of ketamine in IVs, sprays or pills. And desperate patients are shelling out thousands of dollars for treatment often not covered by health insurance, with scant evidence on long-term benefits and risks.
Chicago preschool teacher Lauren Pestikas long struggled with depression and anxiety and made several suicide attempts before trying ketamine earlier this year.
The price tag so far is about $3,000, but “it’s worth every dime and penny,” said the 36-year-old.
Pestikas said she feels much better for a few weeks after each treatment, but the effects wear off and she scrambles to find a way to pay for another one.
For now, ketamine has not received approval from the U.S. Food and Drug Administration for treating depression, though doctors can use it for that purpose.
Some studies show ketamine can provide relief within hours for tough-to-treat depression and suicidal behavior and clinics promising unproven benefits have popped up nationwide. But more research is needed to know long-term benefits and risks. (Oct. 31)
Ketamine has been around since the 1960s and is widely used as an anesthesia drug during surgery because it doesn’t suppress breathing. Compared to opioids such as morphine, ketamine isn’t as addictive and doesn’t cause breathing problems. And some studies have shown that ketamine can ease symptoms within hours for the toughest cases.
Its potential effects on depression were discovered in animal experiments in the late 1980s and early 1990s showing that glutamate, a brain chemical messenger, might play a role in depression, and that drugs including ketamine that target the glutamate pathway might work as antidepressants.
Conventional antidepressants like Prozac target serotonin, a different chemical messenger, and typically take weeks to months to kick in — a lag that can cause severely depressed patients to sink deeper into despair.
A vial of ketamine, which is normally stored in a locked cabinet, on display in Chicago on July 25, 2018. AP Photo/Teresa Crawford)
Ketamine’s potential for almost immediate if temporary relief is what makes it so exciting, said Dr. Jennifer Vande Voort, a Mayo Clinic psychiatrist who has used ketamine to treat depression patients since February.
“We don’t have a lot of things that provide that kind of effect. What I worry about is that it gets so hyped up,” she said.
The strongest studies suggest it’s most useful and generally safe in providing short-term help for patients who have not benefited from antidepressants. That amounts to about one-third of the roughly 300 million people with depression worldwide.
“It truly has revolutionized the field,” changing scientists’ views on how depression affects the brain and showing that rapid relief is possible, said Yale University psychiatrist Dr. Gerard Sanacora, who has done research for or consulted with companies seeking to develop ketamine-based drugs.
But to become standard depression treatment, he said, much more needs to be known.
Last year, Sanacora co-authored an American Psychiatric Association task force review of ketamine treatment for mood disorders that noted the benefits but said “major gaps” remain in knowledge about long-term effectiveness and safety. Most studies have been small, done in research settings and not in the real world.
When delivered through an IV, ketamine can cause a rapid increase in heart rate and blood pressure that could be dangerous for some patients. Ketamine also can cause hallucinations that some patients find scary.
“There are some very real concerns,” Sanacora said. “We do know this drug can be abused, so we have to be very careful about how this is developed.”
Dr. Rahul Khare, an emergency medicine specialist in Chicago, first learned about ketamine’s other potential benefits a decade ago from a depressed and anxious patient he was preparing to sedate to fix a repeat dislocated shoulder.
“He said, ‘Doc, give me what I got last time. For about three weeks after I got it I felt so much better,’” Khare recalled.
Khare became intrigued and earlier this year began offering ketamine for severe depression at an outpatient clinic he opened a few years ago. He also joined the American Society for Ketamine Physicians, formed a year ago representing about 140 U.S. doctors, nurses, psychologists and others using ketamine for depression or other nonapproved uses.
Dr. Rahul Khare poses for a portrait at his outpatient Chicago clinic on July 25, 2018. (AP Photo/Teresa Crawford)
There are about 150 U.S. ketamine clinics, compared with about 20 three years ago, said society co-founder Dr. Megan Oxley.
Khare said the burgeoning field “is like a new frontier” where doctors gather at meetings and compare notes. He has treated about 50 patients with depression including Pestikas. They’re typically desperate for relief after failing to respond to other antidepressants. Some have lost jobs and relationships because of severe depression, and most find that ketamine allows them to function, Khare said.
Typical treatment at his clinic involves six 45-minute sessions over about two weeks, costing $550 each. Some insurers will pay about half of that, covering Khare’s office visit cost. Patients can receive “booster” treatments. They must sign a four-page consent form that says benefits may not be long-lasting, lists potential side effects, and in bold letters states that the treatment is not government-approved.
At a recent session, Pestikas’s seventh, she leaned back on a reclining white examining-room chair as a nurse hooked her up to a heart and blood pressure monitor. She grimaced as a needle was slipped into the top of her left palm. Khare reached up with a syringe to inject a small dose of ketamine into an IV bag hanging above the chair, then dimmed the lights, pulled the window curtains and asked if she had questions and was feeling OK.
“No questions, just grateful,” Pestikas replied, smiling.
Pestikas listened to music on her iPhone and watched psychedelic videos. She said it was like “a controlled acid trip” with pleasant hallucinations. The trip ends soon after the IV is removed, but Pestikas said she feels calm and relaxed the rest of the day, and that the mood boost can last weeks.
Studies suggest that a single IV dose of ketamine far smaller than used for sedation or partying can help many patients gain relief within about four hours and lasting nearly a week or so.
Exactly how ketamine works is unclear, but one idea is that by elevating glutamate levels, ketamine helps nerve cells re-establish connections that were disabled by depression, said ketamine expert Dr. Carlos Zarate, chief of experimental therapies at the National Institute of Mental Health.
A small Stanford University study published in August suggested that ketamine may help relieve depression by activating the brain’s opioid receptors.
Janssen Pharmaceuticals and Allergan are among drug companies developing ketamine-like drugs for depression. Janssen leads the effort with its nasal spray esketamine. The company filed a new drug application in September.
Meanwhile, dozens of studies are underway seeking to answer some of the unknowns about ketamine including whether repeat IV treatments work better for depression and if there’s a way to zero in on which patients are most likely to benefit.
Until there are answers, Zarate of the mental health institute said ketamine should be a last-resort treatment for depression after other methods have failed.
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.
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