Category Archives: Depression

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Depression may be, in part, a chemical imbalance in the brain, such as aberrant serotonin (‘the happy neurotransmitter) or dopamine (the molecule of reward) levels. However, depression can be initiated at several levels, including the gut, due to alterations in the gut microbiome and general inflammation. It has been found that elevated markers of inflammation, such as C-reactive protein (CRP) and Interleukin-6 (IL-6) can be markers of and lead to increased depression. These markers rise in stress, obesity, general medical illness, and from gut dysbiosis (poor microbial health in the gut) to name a few. This can lead to brain fog, poor motivation, difficulty with concentration, memory loss, difficulty making decisions (executive functioning), poor processing speed, and even weight gain.  

Over 7 % of the nation suffers from depression – that is about 16.1 million people, per the National Institutes of Mental Health. Women are twice as likely to be depressed as are men. Some of this may be due to hormonal imbalances. The chance of women becoming depressed in their lifetime is 21-45 % while it is 10-30% for men. 

There are multiple causes for depression, which include stress, poor nutrition, genetics, medications, general medical illness, obesity, lack of exercise, poor sleep, drugs and alcohol, leaky gut, hormonal imbalances, inflammation, and several other factors.  

We frequently assess depression by using the basic PHQ-9 – the physicians health questionnaire that is 9 questions based on a scale of 0-3. The questions are based on the last two weeks of feelings: Link to a PHQ calculator 

1.Little interest or pleasure in doing things 

2.Feeling down, depressed or hopeless 

3.Trouble falling asleep, staying asleep, or sleeping too much 

4.Feeling tired or having little energy 

5.Poor appetite or overeating 

6.Feeling bad about yourself – or that you’re a failure or have let yourself or your family down 

7.Trouble concentrating on things, such as reading the newspaper or watching television 

8.Moving or speaking so slowly that other people could have noticed. Or the opposite – being so fidgety or restless that you have been moving around a lot more than usual 

9.Thoughts that you would be better off dead or of hurting yourself in some way 

These are scored on a scale of 0-3: 

0 – for not at all 

1- For several days in the past two weeks 

2- For more than half the days 

3–  For nearly every day. 

The score results are graded as the following: 

Score Depression Severity Treatment 
0 – 4 None-minimal None 
5 – 9 Mild Watchful waiting; repeat PHQ-9 at follow-up 
10 – 14 Moderate Treatment plan, considering counseling, follow-up and/or pharmacotherapy 
15 – 19 Moderately Severe Active treatment with pharmacotherapy and/or psychotherapy 
20 – 27 Severe Immediate initiation of pharmacotherapy and, if severe impairment or poor response to therapy, expedited referral to a mental health specialist for psychotherapy and/or collaborative management 

The importance of treating depression is several fold. One is to get you feeling better. Many patients will eat excessively and gain weight to comfort themselves. Excess adipose tissue results in inflammation in the brain that leads to further depression and cognitive deficits. Others may resort to self-medication with alcohol or opioids that leads to addiction. In other cases, the person may continue a downward spiral in both their personal life, with family discord and personal unfulfillment, as well as work-related loss, such as absenteeism and presenteeism (showing up but not doing their job). The ability to concentrate and focus is much worse when depression sets in. In fact, depression has been found to physically decrease the size of the hippocampus on MRI(the memory center of the brain) as well as the prefrontal cortex (involved with decision-making and executive functioning).  See the following general mainstream article: Chronic Depression Shrinks the Brain’s Memories and Emotions  (ENIGMA research) .  

An individual who is depressed and sitting in a room will continue to have their hippocampus and prefrontal cortex shrink due to depression and the inflammation that results. Such individuals will have difficult with memory, emotional regulation, processing speed, and decision-making. Aggressive treatment for depression should be sought as it is possible to regenerate these vital areas of the brain with treatment, such as Ketamine therapy and lifestyle interventions like exercise and nutrition. Concerning nutritionhigh adherence to dietary recommendations, anti-inflammatory diet, fish consumption, exclusion of processed foods, and adequate intake of folic acid, magnesium different fatty acids, were associated with a reduced risk of mental illness. Suggestions for nutritional changes can be found at nutritionfactshealthyplacenutritionkits, and everydayhealth as a few options for ideas. 

Ketamine therapy, as a series of infusions, demonstrates rapid reversal of depression and suicidality. It is an anti-inflammatory agent that increases Brain Derived Neurotrophic Factor (BDNF) to increase neuroplasticity and allows the formation of new connections in the brain. This decreases depression and can be seen on MRI’s to increase the volume and functioning of the hippocampus (memory center). We will discuss more information regarding ketamine therapies in upcoming articles. Refer to NOVA Health Recovery for more information as well. 

Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment  

J Psychiatry Neurosci. 2010 Sep; 35(5): 337–343.doi: 10.1503/jpn.100002 

Redlich, R., Opel, N., Bürger, C. et al. The Limbic System in Youth Depression: Brain Structural and Functional Alterations in Adolescent In-patients with Severe Depression. Neuropsychopharmacol. 43, 546–554 (2018). https://doi.org/10.1038/npp.2017.246 

Hippocampal Volume and Depression: A Meta-Analysis of MRI Studies  

Jacka, F.N., Cherbuin, N., Anstey, K.J. et al. Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med 13, 215 (2015). https://doi.org/10.1186/s12916-015-0461-x 

Gujral S, Aizenstein H, Reynolds CF 3rd, Butters MA, Erickson KI. Exercise effects on depression: Possible neural mechanisms. Gen Hosp Psychiatry. 2017 Nov;49:2-10. doi: 10.1016/j.genhosppsych.2017.04.012. PMID: 29122145; PMCID: PMC6437683

Evidence of the Importance of Dietary Habits Regarding Depressive Symptoms and Depression Ljungberg T, Bondza E, Lethin C. Evidence of the Importance of Dietary Habits Regarding Depressive Symptoms and Depression. Int J Environ Res Public Health. 2020;17(5):1616. Published 2020 Mar 2. doi:10.3390/ijerph17051616 

Huang Q, Liu H, Suzuki K, Ma S, Liu C. Linking What We Eat to Our Mood: A Review of Diet, Dietary Antioxidants, and Depression. Antioxidants (Basel). 2019;8(9):376. Published 2019 Sep 5. doi:10.3390/antiox8090376 

Koebnick C, Black MH, Wu J, et al. A diet high in sugar-sweetened beverage and low in fruits and vegetables is associated with adiposity and a pro-inflammatory adipokine profile. Br J Nutr. 2018;120(11):1230-1239. doi:10.1017/S0007114518002726 

Vermeulen E, Stronks K, Snijder MB, Schene AH, Lok A, de Vries JH, Visser M, Brouwer IA, Nicolaou M. A combined high-sugar and high-saturated-fat dietary pattern is associated with more depressive symptoms in a multi-ethnic population: the HELIUS (Healthy Life in an Urban Setting) study. Public Health Nutr. 2017 Sep;20(13):2374-2382. doi: 10.1017/S1368980017001550. Epub 2017 Jul 20. PMID: 28724468. 

Opie RS, Itsiopoulos C, Parletta N, Sanchez-Villegas A, Akbaraly TN, Ruusunen A, Jacka FN. Dietary recommendations for the prevention of depression. Nutr Neurosci. 2017 Apr;20(3):161-171. doi: 10.1179/1476830515Y.0000000043. Epub 2016 Mar 2. PMID: 26317148. 

Depression Nutrition Fact Sheet  

Healthy Eating and depression 

Eating your way to recovery in depression 

Food For the Brain 

Ketamine and its effects on the brain and mental health 

Zhou, Y., Wu, F., Liu, W. et al. Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis. Transl Psychiatry 10, 264 (2020). https://doi.org/10.1038/s41398-020-00945-9  

Ionescu DF, Felicione JM, Gosai A, et al. Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. Harv Rev Psychiatry. 2018;26(6):320-339. doi:10.1097/HRP.0000000000000179 

https://www.researchgate.net/publication/264794534_Hippocampal_Volume_And_The_Rapid_Antidepressant_Effect_Of_Ketamine

Prefrontal Cortex Connectivity and BDNF Fluctuations May Play a Role in Ketamine Mechanism of Action 

Corriger A, Pickering G. Ketamine and depression: a narrative review. Drug Des Devel Ther. 2019;13:3051-3067. Published 2019 Aug 27. doi:10.2147/DDDT.S221437 

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Recent research has shown that ketamine has considerable promise for treating a wide range of treatment-refractory neuropsychiatric disorders, including obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), bipolar disorder, suicide ideation, addiction and, most notably, treatment-resistant major depressive disorder (MDD). Although this research has taken place almost exclusively within the past two decades, evidence of ketamine’s neuropsychiatric effects appeared long before this. For example, ketamine was used throughout the 1970s in Mexico as part of psychedelic therapy sessions that combined traditional healing practices with psychoanalytic techniques.

In 2000, researchers found that ketamine had strong, fast-acting, and long-term effects in depression. In a randomized, placebo-controlled, crossover design study, patients with depression received 0.5 mg/kg of ketamine or saline on the first day of testing. Treatments were switched 1 week later. Researchers found that the antidepressant effects of ketamine began within 4 hours, peaked at 72 hours, and lasted for 1 to 2 weeks thereafter.1 In a 2006 study, this finding was replicated in an independent group of 18 patients with major depressive disorder who were resistant to other treatments. Compared with participants who received placebo, those who received ketamine showed significant improvement in symptoms within 110 minutes, with 35% maintaining significant response for at least 1 week.

Many of today’s depression treatments are monoaminergic-based, including monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. These treatments have been proven effective for a large number of patients. However, a significant subset of patients with major depressive disorder do not respond to these agents. Despite its undisputed value to the field, the monoamine hypothesis of depression cannot fully explain the heterogeneity of MDD. In the 1990s, animal models began to implicate glutamate – one of the major excitatory neurotransmitters in the mammalian central nervous system (CNS) – as well as its ionotropic NMDA receptor in the etiology and treatment of mood disorders .

Existing antidepressant treatments [MAOIs, TCAs, SSRIs, and serotonin-norepinephrine reuptake inhibitors (SNRIs)] are monoaminergic-based treatments. Although they have been in use for decades and have helped many patients, a significant subset of MDD patients showed little to no therapeutic benefit in response to these agents. For instance, the NIMH-funded, communitybased Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of >4000 MDD patients found that, even after four unique medication trials, augmentation, or switch, 33% of the patients did not respond to standard monoaminergic-based treatments .

In 2000, Berman and colleagues discovered that ketamine exerted rapid, robust, and relatively sustained antidepressant effects in depressed patients . Using a randomized, placebo-controlled, crossover design, each patient received an i.v. infusion of 0.5 mg/kg of either ketamine or saline on the first test day. On the following test day, which took place at least 1 week later, treatments were switched. The authors found that ketamine exerted antidepressant effects that began within 4 h of the infusion, peaked at 72 h, and persisted for 1–2 weeks post-infusion. .Ketamine has also been shown to have distinct and independent antisuicidal and anti-anhedonic effects in patients with mood disorders .

Another limitation of currently available antidepressants is that their clinical effects take more time to reach their full therapeutic potential (for instance, the mean onset for paroxetine is 13 days). This is a substantial disadvantage during an acute depressive crisis. Furthermore, even when these agents do alleviate depressive symptoms, evidence regarding their ability to successfully reduce suicide ideation and behavior remains inconclusive . In contrast, a single dose (0.5 mg/kg) of i.v. ketamine exerts rapid and profound antidepressant effects within hours to days of administration . Ketamine also rapidly reduces suicidel ideation, an effect that appears to occur independently of its antidepressant properties . Ketamine has dose-dependent neuropsychological effects even at subanesthetic doses, with antidepressant properties peaking at 0.5–1.0 mg/kg.

Ketamine’s pan-therapeutic effects also include alleviating fatigue and anhedonia as well as improving sleep measures such as circadian rhythm and slow-wave activity in MDD patients .

The positive effects of Ketamine has led to research into other rapidly acting antisdepressants, including nasal ketamine. Lapidus and colleagues demonstrated that intranasal ketamine had antidepressant effects and led to sufficiently high ketamine plasma concentrations. We use a compounded intranasal ketamine miuxture in our office at NOVA Health Recovery. There is also an FDA approved version more recently, which has only the S-Ketamine in it . There are heavy restrictions and high costs to the FDA approved version, yet efficacy may not be any better.

Noitrois Oxide also has antidepressant effects. Like ketamine, it exhibits NMDA receptor antagonism, has partial agonism for mu, kappa, and delta opioid receptors, inhibits AMPA, kainite, and gamma-aminobutyric acid receptors A and C (GABAA, GABAC), affects serotonin-3 receptors (5-HT3), and releases dopamine . In a double-blind, placebo-controlled, crossover trial, depressive symptoms improved for participants receiving nitrous oxide within 2 h compared with those receiving placebo, an effect that remained significant at 1 day post-treatment. Phase I and II trials are ongoing to determine optimal dose, safety, and efficacy.

Sarcosine also has antidepressant effects. t, sarcosine (also known as N-methylglycine), is an amino acid that functions as a glycine transporter-1 inhibitor and a 6- week, double-blind, randomized, citalopram-controlled trial in 20 MDD patients found that sarcosine possessed superior antidepressant properties compared with citalopram after 2 weeks . Notably, and in contrast to ketamine, sarcosine did not result in rapid-acting effects on the timescale of several days. Sarcosine has co-agonistic properties at the NMDA receptor and is an agonist at the inhibitory glycine receptor. It also exhibits NMDA-enhancing properties, suggesting that AMPA-receptor-mediated or other downstream mechanisms might elicit antidepressant effects. NMDA receptor downregulation might also play a part .

Suboxone (Buprenorphine) also has antidepressant effects as well. Intrigued by the potential of nonaminergic antidepressant mechanisms, researchers have begun to re-evaluate the role of endogenous opioids in depression. For instance, buprenorphine (BUP), a drug currently used to treat opioid addiction and pain disorders, is being explored as a treatment for MDD. The compound has a wide variety of actions throughout the brain, including partial agonism at the mu opioid receptor and antagonism at the kappa and delta opioid receptors ; these are connected to intracellular signaling cascades that potentially mediate antidepressant effects Several open-label studies of BUP in MDD have shown promising preliminary results, and a double-blind, randomized, placebo-controlled trial examining the effect of low-dose BUP on suicidal ideation similarly yielded positive results .

NOVA Health Recovery has used buprenorphine succesfully in the treatment of depression.

Ketamine and Future Depression Treatments

1. Kraus C, Wasserman D, Henter ID, Acevedo-Diaz E, Kadriu B, Zarate CA Jr. The influence of ketamine on drug discovery in depression [published online August 2, 2019]. Drug Discov Today. doi: 10.1016/j.drudis.2019.07.007

2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depressionArch Gen Psychiatry. 2006;63(8):856-64.

3. Nagele P, Duma A, Kopec M, et al. Nitrous oxide for treatment-resistant major depression: a proof-of-concept trialBiol Psychiatry. 2015;78(1):10-18.

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Treating Alcohol Use with Ketamine? New Research Finds It May Help

  • Results from new studies suggest that ketamine may be effective in treating alcohol use disorder.
  • Researchers found that when participants were treated with ketamine instead of midazolam, a sedative that helps with alcohol withdrawal, they had higher rates of stopping drinking following treatment.
  • They were also less likely to relapse, had fewer days of drinking, and had fewer days of heavy drinking.

Once derided as a “club drug,” the anesthetic ketamine is facing a surge of interest from doctors and researchers who say it could treat certain psychiatric disorders. The most prominent among them: depression.

However, a pair of new studies show promise for a new area of ketamine therapy: alcohol use disorder.

Both studies are early indicators that ketamine could, along with other alcohol interventions like therapy, some day help people decrease or stop drinking. But there’s a lot more research to be done.

The first study, published earlier this month in The American Journal of Psychiatry, was a pilot study, the first of its kind, to test the effects of ketamine and mindfulness practice against a control for alcohol use disorder.

The study included 40 participants who, on average, consumed about 5 drinks per day. Most of the participants were white, and most were employed.

Participants were randomly assigned to either receive a single infusion of ketamine along with a 5-week regimen of motivational enhancement therapy, or midazolam, a sedative that helps with alcohol withdrawal, and the same therapy.

Researchers found that participants who received ketamine rather than midazolam had higher rates of abstinence (stopping drinking) following treatment, were less likely to relapse, had fewer days of drinking, and had fewer days of heavy drinking.

The beneficial results of the ketamine also persisted for several weeks after the single dose infusion.

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‘Nothing less than transformational:’ Ketamine brings relief to people with severe depression

Ketamine gave Rachel Morgan her life back.

The 33 year old has struggled to beat back severe depression and post-traumatic stress disorder for much of her life. She’s tried more than 30 psychiatric medications, none of which helped. Her inner pain reached a level so unbearable that she retreated from the world. She stayed in bed. She stopped doing the dishes and taking out the trash, which piled up in her San Francisco apartment. She stopped socializing.

She lost the will to live.

“I had gotten to a point where I disappeared, mentally and physically,” Morgan said. “My psychiatrist kind of put his hands up in the air and said, ‘There’s nothing else I can do for you.'”

But he did suggest something different she could try, albeit not through him: ketamine. The only legally available psychedelic in the U.S., the drug is widely used as an anesthetic in hospitals and medical settings. But it has been found to give people with severe mood disorders, including treatment-resistant depression and suicidal ideation, almost unbelievably fast-acting relief from their symptoms — some with a single dose, though more commonly it takes several treatments.

Morgan received her first ketamine infusion in a Palo Alto psychiatry clinic in June. By her second treatment, she took out the trash for the first time in months. After several infusions, friends told her she was talking more than she had in a year.

For the first time in her life, “I felt like there is a future for me,” Morgan said. “It’s left me a different person than I was a year ago.”

Ketamine is starting to shed its reputation as a psychedelic club drug and experimental mental health treatment as more patients like Morgan see results and more research is conducted on the drug’s impact on the brain. A watershed moment came in March when the U.S. Food and Drug Administration (FDA) approved Spravato, or esketamine, a ketamine nasal spray for adults with treatment-resistant major depression. One short-term clinical trial showed the spray had a statistically significant effect on depression compared to a placebo, and patients saw some effect within two days, according to the FDA.

A handful of local private psychiatry clinics, including in Palo Alto, Menlo Park and Woodside, have in recent years started offering ketamine. They are working at the forefront of a promising new treatment in psychiatry, a field that has seen little medication innovation for decades.

Many of the psychiatrists who run these clinics said they were initially skeptical of the drug’s potential, with little still known about how exactly ketamine works as an antidepressant and its long-term effects, but became believers when they saw life-changing improvements in patients for whom nothing else had worked.

“I think we’re on the brink of an amazing revolution in psychiatry,” said Alex Dimitriu, who offers ketamine treatments at his Menlo Park private psychiatry clinic. “We’re on the brink of understanding that a lot of drugs that previously we thought were drugs of abuse are actually turning out to be some very powerful agents.”

Exploring ketamine’s potential

Ketamine was developed in 1962 as a fast-acting anesthetic and continues to be widely used as such today, particularly for surgery and pain relief, including with children and in veterinary medicine. The drug is a schedule III controlled substance, meaning its medical use is accepted and it has moderate to low potential for abuse. The World Health Organization has included ketamine on its list of essential medicines since 1985 and calls it “possibly the most widely used anesthetic in the world.” As an anesthetic, it is incredibly safe (it does not depress breathing or blood pressure) and is easy to administer, according to the World Health Organization.

In higher doses, ketamine produces a “dissociative” state that can include hallucinations and out-of-body experiences. The drug’s conscious-altering potential led to its recreational use in the psychedelic era of the 1960s and 1970s.

Reports of ketamine use to treat psychological or psychiatric disorders first emerged in the 1970s, including in Argentina, Mexico and Russia, according to a study co-authored by Jennifer Dore, who offers ketamine at her private Helios Psychiatry practice in Woodside.

In 2000, a group of Yale University researchers published a seminal but small-scale study that found seven patients with major depression who received ketamine showed significant improvement in their symptoms within 72 hours, suggesting the drug could be used as an antidepressant.

Six years later, a National Institute of Mental Health study showed that ketamine reduced depression symptoms more quickly than a placebo.

Dore, who trained as a resident at the Stanford University Department of Psychiatry, became curious about ketamine several years ago while treating patients with severe PTSD and treatment-resistant depression. They simply weren’t getting better.

Dore dug into the available research on the drug’s antidepressant effects, which suggested that ketamine inhibits the action of the brain’s NMDA receptors and triggers glutamate production, which causes the brain to form new neural connections. She reached out to Phil Wolfson, director of the Center for Transformational Psychotherapy in San Anselmo, who pioneered ketamine-assisted psychotherapy, in which ketamine is administered while simultaneously patients receive therapy. She was compelled by taking this approach rather than the more medical model of providing the drug in isolation.

The results with her early patients in 2016 were like nothing she had ever seen.

“They had immediate relief,” she said.

Dore said her clinic was the first on the Peninsula to offer ketamine-assisted psychotherapy. She now offers trainings for other providers and sits on the board of the Ketamine Research Foundation.

In March, Dore published a five-year study with two other psychiatry practices that found patients who received ketamine saw clinically significant improvements in depression and anxiety, particularly so for people who came in with more severe symptoms like suicidality and a history of psychiatric hospitalization. At their clinics, they saw the drug help people suffering from obsessive compulsive disorder, bipolar disorder, personality disorders, substance abuse, psychological reactions to physical illness and even relationship issues and social anxiety.

“Ketamine promotes a time-out from (the) ordinary, usual mind, relief from negativity, and an openness to the expansiveness of mind with access to self in the larger sense,” Dore’s study states. “These effects enhance a patient’s ability to engage in meaningful psychotherapy during and after administration.”

Dore is a staunch champion of combining ketamine with psychotherapy, which she believes is necessary to harness the full potential of the drug. She doesn’t see ketamine as a magic bullet, but rather one tool she can use in concert with others — talk therapy, medication, nutrition — to treat people in serious psychological pain.

Before patients start ketamine, Dore carefully evaluates them to determine if it’s an appropriate next step in their treatment, as recommended by the American Psychiatric Association, including through therapy sessions, psychological tests and a review of their medical history. If they choose to proceed, Dore requires patients to sign a lengthy consent form that explains how ketamine works and its potential benefits and risks.

During a patient’s initial treatment, Dore monitors their physical and emotional responses, including blood pressure and heart rate, to decide on an appropriate dose going forward. The highest doses can produce the dissociative state, or the dream-like sensation of disconnecting from reality, Dore said. (Some people believe they have died and are in a new reality, she said. One patient described it as being in a lucid dream.) At lower doses, it can feel more like having a glass of wine, she said. The peak effects last about 15 to 30 minutes, according to Dore.

Patients can take the ketamine via a small lozenge that dissolves under their tongues, intravenously or an intra-muscular injection.

They receive the ketamine in a large second-floor space at Dore’s practice. It resembles a homey living room more than a psychiatric setting — a reflection of the importance of creating “set and setting” for a psychedelic experience, including a comforting physical environment. A large, soft corner couch is strewn with pillows, including one that says “anger” and another, “love.” During treatments, Dore pulls down the blinds on the windows, adjusts the temperature and offers patients weighted blankets, eyeshades and quiet music. The sessions last two to three hours.

Gaining a new perspective

Andy Mathis was at the end of his mental rope when he found Dore. A father, husband and successful tech industry executive, he had quietly suffered from self-doubt and insomnia since he was a young child. By the time he reached his mid-40s, it had escalated to depression. He felt his well-being and very brain chemistry was at risk.

A friend of a friend referred him to Dore, who prescribed him antidepressant and anti-anxiety medications that finally helped him sleep. But she suspected there was more to understand about the root causes of his symptoms, he said, and suggested ketamine as a means for exploring that.

A former professional tennis player, Mathis said he had never taken any drugs before. He did his own research on ketamine and thought it sounded “groundbreaking.” He was more curious than fearful about embarking on a psychedelic experience.

He received his first infusion two and a half years ago and continues to get ketamine every four to eight weeks today.

“It was indeed transformational,” Mathis said. “Nothing less than transformational.”

Mathis described the experience as taking him out of his own ego, a “tilt(ing) of the prism on how I see things.”

“It allowed me to have a detached, philosophical view on all things — me, my place in the world, my relationships,” he said.

This helps him make sense of his emotions “in a way that can be extremely difficult and sometimes even impossible to do when I am inside of myself,” referring to his default, day-to-day mental state.

Over the course of the infusions, Mathis started feeling more comfortable in his own skin, which he said improved his relationships and even his work performance. He realized he has a love for music and at age 47, started to learn how to play the saxophone. He came to a better understanding of his relationship to food and how he had used it as a coping mechanism.

Combining the ketamine-induced realizations with therapy was crucial, Mathis said.

“It was the post-experience discussions that we would have that would also unravel and unwind some of the unhealthy habits,” he said. “I’m 47 now, almost 48. I am healthier now than I was probably, maybe, ever.”

Dore likened ketamine’s power as a catalyst for psychological change to “a year of psychotherapy in three hours.”

Unlike antidepressants, patients don’t have to take ketamine every day and do not experience significant side effects; they can become nauseous or slur their words during the treatment, psychiatrists said. They require patients to have someone to drive them home after the treatment.

Mathis, for his part, did not experience any negative side effects. A patient at another local psychiatry clinic, Lisa Ward, however, said her mind feels “foggy” if she has two infusions in a single week. According to the FDA, the most common side effects experienced by patients treated with Spravato, the esketamine nasal spray, in clinical trials including disassociation, dizziness, nausea, lethargy and increased blood pressure.

“It would be inhumane,” Dore said, to not offer ketamine to people in intractable mental anguish. “We need things that are transformative, that aren’t putting a Band-Aid on a problem.”

Psychiatrist calls it ‘life-changing’

When Rameen Ghorieshi first looked into ketamine as an option for a patient with treatment-resistant depression about five years ago, it was still “very much fringe,” he said. His colleagues at Stanford, where he completed his psychiatric training, knew about the drug but had no idea how to actually use it as a treatment.

He decided to offer ketamine at his small private practice in downtown Palo Alto, Palo Alto Mind Body. He trained with an anesthesiologist and started with two patients. One suicidal young woman who had dealt with a chronic illness since childhood and didn’t intend to live past 30 years old, he said, got to the point where she was working four days a week, socializing and planning to go back to school.

“That just blew my mind,” Ghorieshi said. “I knew it would help just reading the studies but seeing it firsthand was pretty incredible.”

He has done more than 1,000 ketamine infusions at his downtown Palo Alto practice. Eighty-seven percent of patients rated their improvements as significant and 35% of those described it as “life-changing.” It particularly helped suicidal patients, he said. About 13% of patients said the improvement in their symptoms was not worth the time and effort of the infusions.

“This is a bit of a departure for me. I’m a very conservative prescriber,” Ghorieshi said. “My patients tend to be on one, two, maybe three medications. … But it was so remarkable that it seemed hard not to offer it to people.”

Ghorieshi said his was the first clinic in the Bay Area to treat someone with the tightly controlled, FDA-approved nasal spray. A handful of his patients have since received it, with good results, he said.

Esketamine is attached to a federal Risk Evaluation and Mitigation Strategy, which the FDA “can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.” Providers and patients must register and the drug must be administered in a certified medical office under the supervision of a health care professional.

At Palo Alto Mind Body, patients receive eight ketamine infusions over several weeks. They are strongly encouraged to also pursue therapy but it’s not part of the treatment itself, Ghorieshi said.

He or a nurse supervises patients over the course of the 90-minute appointments. Morgan likes to sit upright on the couch in Ghorieshi’s office, covered by a blanket that keeps her warm and gives her a sense of emotional security. She listens to relaxing elevator music. After, she goes home and naps off the residual effects.

Years ago, she was given much higher doses of ketamine as a pain treatment for chronic physical illnesses and had horrible hallucinations, which she described as “having my head slammed against a wall repeatedly by a slime monster from a deep black bog.”

At the dose Ghorieshi gives her, she feels like the floor and ceiling switch. Her inhibitions dissolve. Afterwards, she feels more open to trying new experiences, from coping mechanisms for her depression to new foods. She feels her perfectionism, which for a long time had prevented her from being vulnerable with others, soften.

“To me, that’s the magic of ketamine,” Menlo Park psychiatrist Dimitriu said of the drug’s tendency to destabilize entrenched behaviors. “I think that speaks to the magic of future psychedelic research, which is down the pipeline, in that it increases our openness to new experience. The general belief here is if you’re depressed severely, you get stuck in maladaptive patterns.”

Lisa Ward didn’t see immediate relief from her life-long depression after her first ketamine infusion with Ghorieshi in March.

Then, a week later as the drug continued to work in her system, “the whole cloud just lifted,” she said. (It takes most patients several treatments to see results, according to Ghorieshi.)

She had more energy. She felt more productive. The benefits extended to her loved ones, as she’s engaged more with her two young children, husband, her parents and her sister.

“It’s enough for me to have more fun with my kids. It’s enough for me to spend more time with my husband instead of going to bed because I just can’t deal with the day anymore,” she said. “Being in depression you don’t realize it but it takes a big toll on other people.”

For Ward, a photographer, the effects of ketamine last about five weeks before she feels the cloud returning. There was one period where the ketamine seemed to stop working all together. Because she lives in Hollister — a three-hour round trip drive from Palo Alto, not including the time of the session itself — and pays out of pocket for the expensive treatment, gaps between her appointments stretch longer than she’d like.

She actually doesn’t enjoy the experience of being on ketamine, which she described as mind-bending and often intense. But she said the disruption of her depression allows her to focus on shifting the underpinning behavior and thought patterns.

Ketamine “doesn’t magically lift all … your problems away,” Ward said. “You’re more apt to make changes when you’re thinking clearly and you’re not so focused on the depression.”

While esketamine, the nasal spray, is covered by insurance because of the FDA approval, most other ketamine administrations are not. Morgan pays almost $1,000 out of pocket for each infusion, though Ghorieshi said some of his patients have been reimbursed for their treatments. Dore charges patients for her time as a provider, about $1,000 for a several-hour session, rather than for the drug itself.

Morgan felt strongly about using her full name in this article to dispel stigma around ketamine in the hopes it will be more widely accepted — and thus available to more people in need.

“Just because you hear something in one context, like ketamine being used as an illicit drug, doesn’t mean it doesn’t exist in another,” she said. “I think that’s what scares insurance companies away from covering it for patients. And that’s what makes me angry because I wish this treatment was out there for everybody to see. I’m lucky enough to be able to handle the financial portion, but the average person might not be.”

The as-yet-unknown risks

Despite the success stories, ketamine has not yet been fully accepted by the broader psychiatric community. The unanswered questions and possible risks that surround ketamine — how it works as an antidepressant, the long-term effects, the potential for abuse — are cause for caution, said Alan Schatzberg, a Stanford School of Medicine psychiatry professor and former president of the American Psychiatric Association.

“Rarely has there been so much anticipation for a new antidepressant as has been seen for intranasal esketamine,” he wrote in the American Journal of Psychiatry in May about the newly FDA-approved ketamine nasal spray.

“Do we have clear evidence of efficacy? Maybe. How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear.

“Taken together,” he wrote, “there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice.”

In an interview, Schatzberg said he’s concerned about repetitive, extended use of any form of ketamine and the drug’s potential for dependence. The American Psychiatric Association has said that the literature on ketamine’s longer-term effectiveness and safety is so limited that the organization cannot “make a meaningful statement” on such use.

“The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment,” an American Psychiatric Association task force wrote in a consensus statement on ketamine in 2017.

Schatzberg co-authored a 2018 study that suggests ketamine’s antidepressant effects are tied to the brain’s opioid system and said the implications of this for dependency should be studied further.

“This is the same as any potential drug of abuse, any kind of opioid type drug. Serial use is less the issue. It’s when you get into repetitive use that one needs to be careful,” Schatzberg said. “That’s the clarion call that we’ve been sounding.”

One of his study co-authors, Carolyn Rodriguez, a Stanford associate professor of psychiatry and behavioral sciences, has been blown away by the rapid benefits of ketamine in studies she’s conducted with patients with obsessive compulsive order, or OCD. In the first-ever randomized clinical trial of ketamine compared to placebo in OCD, she found that a single low dose of ketamine prompted a decrease in OCD symptoms within hours for all participants.

Yet she remains cautious and said more research is needed to fully understand the powerful drug. She’s currently studying the mechanisms of how ketamine works so quickly on OCD patients, with funding from the National Institute of Mental Health.

“I believe that the state of the field of ketamine and how it works on OCD is not at the point yet where I would recommend it clinically because I always like to see science, (including) my own science, replicated,” Rodriguez said.

With pause about the long-term effects, she and other researchers have suggested a national registry be created to monitor side effects.

Ghorieshi said he is frank with his patients about the unknowns and potential downsides of ketamine, which must be weighed against other risks.

“We do know the immediate mortality and morbidity of things like suicide and depression.

I think that’s, as with anything, the risk-benefit. What are the risks of suicide, but also depression and anxiety in general?” he said. “You have to balance that versus these unknown risks of ketamine.”

Mathis, for his part, said he’s not concerned about the long-term effects of taking ketamine.

“What I worry about,” Mathis said, “is what my health would have done without it.”



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Ketamine could be first of new generation of rapid acting antidepressants, say experts

Ketamine is the first truly new pharmacological approach to treating depression in the past 50 years and could herald a new generation of rapid acting antidepressants, researchers have predicted.

“We haven’t had anything really new for about 50 or 60 years,” said Allan Young, professor of mood disorders at the Institute of Psychiatry, Psychology and Neuroscience at King’s College, London, at a briefing on 12 July at London’s Science Media Centre.

Most of the new launches have been “tinkering with drugs which were really discovered in the ’50s and ’60s,” he explained. “Even the famous Prozac, which came in in the late ’80s, is really just a refinement of the tricyclic antidepressants that came in the ’50s. People say we are still in the age of steam, and we need to go to the next technological advance.”

Slow onset

In the past few years the focus has fallen on ketamine, which is used for pain relief and anaesthesia but is better known for being a horse sedative and a “club drug” that can induce hallucinations and calmness. It has been found to have rapid antidepressant effects and to be effective in many patients with treatment resistant depression.

US clinics increasingly offer IV infusions of ketamine off label, and in March esketamine, a nasal ketamine based drug, was approved by the US Food and Drug Administration for treatment resistant depression,1 at a cost of £32 400 (€36 060; $40 615) per patient per year.

Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the US National Institute of Mental Health, who has been a key figure in the discovery and evaluation of ketamine as an antidepressant, said that one of the main problems with current antidepressants was their speed of onset in terms of antidepressant and anti-suicidal effects.

He explained that it took 10-14 weeks to see significant improvement with monoaminergic based antidepressants. “In my mind that is too slow,” he said. “We are focusing on treatments that can produce results within hours. That is where we are heading with the next generation of antidepressant, and ketamine is now the prototype for future generation antidepressants which will have rapid, robust antidepressant effects—rapid within a few hours.”

Efficacy and tolerability

Zarate said that, besides correcting chemical imbalances of serotonin and norepinephrine, the new generation of ketamine based antidepressants had other effects such as enhancing plasticity and restoring the synapses and dendrite circuits that shrivel in depression.

When ketamine is given to patients it binds to the N-methyl-D-aspartate (NMDA) receptor, causing a series of transient side effects including decreased awareness of the environment, vivid dreams, and problems in communicating. But the half life of ketamine is only two to three hours, so these side effects quickly subside, whereas the therapeutic effects of the drug last seven days or longer.

Zarate’s team is now focusing on the 24 metabolites of ketamine to hone the drug’s efficacy and tolerability. One of these, hydroxynorketamine, has already been shown to have similar antidepressive effects to ketamine in animals, without the side effects, and it is due to be tested in patients this autumn.

“Ketamine may actually be a prodrug for hydroxynorketamine,” said Zarate.

High cost

A few dozen patients with treatment resistant depression have been treated with ketamine in UK trials, and the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency are due to reach a decision on authorising esketamine for marketing in October. If the drug is approved private clinics will be able to provide it. But it would be unlikely to be available through the NHS until at least 2020, if at all, as the National Institute for Health and Care Excellence would need to deem it cost effective.

Rupert McShane, consultant psychiatrist and associate professor at the University of Oxford, said that, as well as the likely high cost of esketamine, patients treated with it must be observed in a clinic for two hours after each administration. This would require substantial clinical time, as esketamine is given twice a week for the first month, once a week for the second month, and once a week or once a fortnight from then on.

McShane also recommended that, if approved, a multidrug registry should be set up to monitor the long term safety and effectiveness of ketamine based drugs. Patients would be asked to input their use of any prescribed ketamine, esketamine, or any other future ketamine based product, as well as any self medication with illicit ketamine.

References


    1. Silberner J
    . Ketamine should be available for treatment resistant depression, says FDA panel. BMJ2019;364:l858.doi:10.1136/bmj.l858 pmid:30796014FREE Full TextGoogle Scholar



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Study Finds Ketamine Nasal Spray Effective For Treating Depression: What You Should Know

ASSOCIATED PRESS



A new study finds that a nasal spray formulated from the anesthetic ketamine is a safe, fast-acting and effective treatment for treatment-resistant depression. Researchers presented the findings this week at the annual meeting of the American Psychiatric Association.

Esketamine, the intranasal formulation of ketamine, recently received FDA approval as a depression treatment when used with an oral antidepressant, based in part on findings from this study. The results open the door to a potential new alternative for the estimated 30% of depression patients suffering from treatment-resistant depression.

The study included 197 adults from 39 outpatient centers over a two-year period. All of the participants had either moderate or severe depression and hadn’t responded well to at least two antidepressants in the past. Participants were randomly assigned to one of two groups: The first switched from their current antidepressant treatment to esketamine nasal spray and a new oral antidepressant; the other switched from their current treatment to a placebo nasal spray and a new antidepressant.

The results showed significant improvements in depression symptoms among those in the esketamine group compared to the placebo group four weeks into the study, with signs of improvement starting much earlier.

“The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression,” the study concluded.

“Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” said Michael Thase, M.D., one of the study authors. “The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpins just how important this development is for patients with difficult-to-treat depression.”



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The Brain on Fire: Depression and Inflammation

According to the World Health Organization, depression is the leading cause of disability. Unfortunately, 30 to 60 percent of patients are not responsive to available antidepressant treatments (Krishnan & Nestler, 2008). In other words, 40 to 70 percent of patients are not helped by existing treatments. One area of research might shed some light on why a sizable portion of patients are not helped by current antidepressants.

There is growing evidence that inflammation can exacerbate or even give rise to depressive symptoms. The inflammatory response is a key component of our immune system. When our bodies are invaded by bacteria, viruses, toxins, or parasites, the immune system recruits cells, proteins, and tissues, including the brain, to attack these invaders. The main strategy is to mark the injured body parts, so we can pay more attention to them. Local inflammation makes the injured parts red, swollen, and hot. When the injury is not localized, then the system becomes inflamed. These pro-inflammatory factors give rise to “sickness behaviors.” These include physical, cognitive and behavioral changes. Typically, the sick person experiences sleepiness, fatigue, slow reaction time, cognitive impairments, and loss of appetite. This constellation of changes that take place when we are sick is adaptive. It compels us to get more sleep to heal and remain isolated so as not to spread infections.

However, a prolonged inflammatory response can wreak havoc in our bodies and can put us at risk of depression and other illnesses. There is plenty of evidence solidifying the link between inflammation and depression. For example, markers of inflammation are elevated in people who suffer from depression compared to non-depressed ones (Happakoski et al., 2015). Also, indicators of inflammation can predict the severity of depressive symptoms. A study that examined twins who share 100 percent of the same genes found that the twin who had a higher CRP concentration (a measure of inflammation) was more likely to develop depression five years later.  

Doctors noticed that their cancer and Hepatitis C patients treated with IFN-alpha therapy (increases inflammatory response) also suffered from depression. This treatment increased the release of pro-inflammatory cytokines, which gave rise to a loss of appetite, sleep disturbance, anhedonia (loss of pleasure), cognitive impairment, and suicidal ideation (Lotrich et al., 2007). The prevalence of depression in these patients was high. These results add credence to the inflammation story of depression.

Subsequent careful studies showed that the increase in the prevalence of depression in patients treated with IFN-alpha was not only because they were sick. Using a simple method of injecting healthy subjects with immune system invaders, researchers found higher rates of depressive symptoms in the ones who were exposed compared to the placebo group. The subjects who were induced to have an inflammatory response complained of symptoms such as negative mood, anhedonia, sleep disturbances, social withdrawal, and cognitive impairments.

The link between inflammation and depression is even more solid for patients who don’t respond to current antidepressants. Studies have shown that treatment-resistant patients tend to have elevated inflammatory factors circulating at baseline than the responsive ones. This is clinically important; a clinician can utilize a measure like CRP levels, which are part of a routine physical, to predict the therapeutic response to antidepressants. In one study, they found that increased levels of an inflammation molecule prior to treatment predicted poor response to antidepressants (O’Brien et al., 2007).

There are environmental factors that cause inflammation and therefore elevate risk for depression: stress, low socioeconomic status, or a troubled childhood. Also, an elevated inflammatory response leads to increased sensitivity to stress. The effect has been reported in multiple studies in mice. For example, mice that have gone under chronic unpredictable stress have higher levels of inflammation markers (Tianzhu et al., 2014). Interestingly, there are individual differences that make some mice more resistant to stress, therefore initiating a calmer immune response (Hodes et al., 2014).

Depression is a heterogeneous disorder. Each patient’s struggle is unique given their childhood, genetics, the sensitivity of their immune system, other existing bodily illnesses, and their current status in society. Being on the disadvantageous end of these dimensions irritates our immune system and causes chronic inflammation. The brain is very responsive to these circulating inflammatory markers and initiates “sickness behavior.” When the inflammation is prolonged by stressors or other vulnerabilities, the sickness behavior becomes depression.

If you are a professional working with patients suffering from depression, I urge you to consider the health of your patients’ immune systems. If you are a patient suffering from an exaggerated immune disorder (e.g., arthritis), do not ignore the depressive symptoms that you might be experiencing. If you are suffering from depression, avoid anything that might exacerbate your immune response. This is another example of the beautiful dance between mind and body!

References

Haapakoski,R.,Mathieu,J.,Ebmeier,K.P.,Alenius,H.,Kivimäki,M., 2015. Cumulative meta-analysisofinterleukins6 and 1β,tumournecrosisfactorα and C-reactive protein in patients with major depressive disorder. Brain Behav.Immun. 49,206.

Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D et al (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 111: 16136–16141.

Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature 455: 894–902.

Lotrich,F.E.,Rabinovitz,M.,Gironda,P.,Pollock,B.G., 2007. Depression following pe-gylated interferon-alpha:characteristics and vulnerability.J.Psychosom.Res.63, 131–135.https://doi.org/10.1016/j.jpsychores.2007.05.013.

O’Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., Dinan, T.G., 2007a. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326e331.

Tianzhu, Z., Shihai, Y., Juan, D., 2014. Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evid. Based Complement. Altern. Med. 2014, 438506.

The Serotonin Transporter Gene and Depression

A new large-scale study casts doubt on a widely reported association.

Why some people develop major depressive disorder and others do not is a complex and not well-understood process. Several factors have been discussed to contribute to depression, among them:

Genetic variation: Individuals carrying one or two copies of a specific risk allele on one or more “depression gene/s” have a higher risk of developing depression.

Environmental influences: Negative life events such as trauma, negligence, or abuse increase the risk of developing depression.

Gene-by-environment interactions: Negative life events only lead to depression in individuals with a specific genetic set-up that makes them risk-prone to develop depression.

The gene most commonly associated with depression is the serotonin transporter gene SLC6A4 (Bleys et al., 2018). Serotonin is a neurotransmitter affecting multiple physiological processes and cognitivebrain functions, among them mood and emotions, which is why it has been linked to mood disorders such as depression. Indeed, low serotonin levels have been associated with depressed mood (Jenkins et al., 2016), and selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. SSRIs block the reuptake of serotonin during cellular communication in the brain, making more serotonin available, and thus in theory helping to reduce depression.

Along these lines, the idea that the serotonin transporter gene could affect depression risk or severity intuitively made sense. Specifically, many scientists focused on the so-called 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene to research the effects of this gene on depression. Genetic polymorphism means that at a specific location in the genome, different people might have slight variations in their DNA which could affect how well the protein that the gene produces could do its job. In the case of the 5-HTTLPR polymorphism, there is a short allele (s) and a long allele (l). Already back in the 1990s, researchers showed that people with two or one short alleles have a higher chance of developing depression than those with two long alleles, as the short allele leads to reduced expression of the serotonin transporter (Collier et al., 1996).

This initial study sparked interest in the 5-HTTLPR polymorphism, but not all empirical works could find a clear association. In 2003, a surprising finding seemingly resolved this controversy. In a widely cited study, Caspi and colleagues were able to show that the effects of 5-HTTLPR polymorphism genotype on depression were moderated by a so-called gene-by-environment interaction (Caspi et al., 2003). This means that the genotype would only have an effect if individuals were also subjected to specific environmental conditions. Specifically, the scientists found that individuals reacted differently to highly stressful life events, depending on the 5-HTTLPR genotype. People with at least one short allele on the 5-HTTLPR polymorphism developed more depressive symptoms if they experienced a highly stressful life event than people with two long alleles. However, without a stressful life event, the genotype did not have an effect on the probability to develop depression.

This study further increased the interest in the 5-HTTLPR polymorphism and its relation to depression, leading to more studies on this topic. However, a problem of many of these studies was that their sample sizes were comparably small for genetic studies, potentially leading to erroneous results and overblown effects.

Almost a decade ago, Risch and co-workers (Risch et al., 2009) conducted a so-called meta-analysis, a statistical integration of empirical studies. They analyzed 14 studies on the 5-HTTLPR polymorphism and its relation to depression and on whether this relation was influenced by stressful life events as had been suggested by Caspi et al. (2003). Their result was clear: While more stressful life events led to a higher risk of depression, there was no effect of the 5-HTTLPR genotype on depression and no gene-by-environment interaction effect between genotype and stressful life events.

Despite this finding, hundreds of studies on the 5-HTTLPR polymorphism and depression have been published since 2009 (the scientific search engine PubMed lists more than 800 hits for the search term “5-HTTLPR depression” as of early May 2019). A new study recently published by Richard Border and colleagues in The American Journal of Psychiatry(Border et al., 2019) aimed to resolve the controversy about whether or not the 5-HTTLPR genotype affects depression and whether there is a gene-by-environment interaction between this genotype and stressful life events once and for all. To avoid the statistical problems of previous studies, they obtained data from several large genetic datasets available to researchers, leading to a sample size of several hundred thousand individuals. The results of the analysis were clear as well: There was no statistical evidence for a relation between the 5-HTTLPR polymorphism and depression, and there was also no evidence that traumatic life events or adverse socioeconomic conditions might show a gene-by-environment interaction with this genotype.

This, of course, does not mean that there is no relationship between serotonin and depression (there clearly is, as shown by the treatment success of SSRIs), but it lends further support to an emerging insight in psychiatry genetics: Mental illness is a highly complex process that is likely influenced by a large number of genetic and non-genetic effects. As such, it is unlikely that single genetic variations such as the 5-HTTLPR polymorphism have a huge impact on whether or not an individual develops depression or any other form of mental illness. Future psychiatry genetic studies will need to take this complexity into account by analyzing genetic variation across the whole genome and epigenome and relating it to mental illness (Meier & Deckert, 2019).



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Ketamine Virginia Link

Long known as a party drug, ketamine now used for depression, but concerns remain

A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.

The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.

Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.

The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.

“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”

Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.

Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.

Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.

About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.

But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.

“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.

“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.

Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.

“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”

Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.

In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.

Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.

“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”

The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.

She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.

Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.

Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.

“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”



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NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

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Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

From Popular Anesthetic to Antidepressant, Ketamine Isn’t the Drug You Think It Is

An hour before we spoke, Darragh O’Carroll, an emergency room physician from Hawaii, had just given an elderly patient a sedating shot of ketamine. The man had pneumonia and was acting confused and fidgety, making him hard to treat.

“Not only it was a pain control for him when I was putting needles into his neck, but it also kept him still,” O’Carroll says. “And with very minimal risk of lowering his blood pressure.”

Ketamine’s use as an anesthetic — and not as a party drug — is widespread, though not commonly known. In fact, the World Health Organizationestimates ketamine is the most widely used anesthetic in the world and keeps it on their list of essential medicines, a category of drugs that all developed countries should have on hand.

O’Carroll has described ketamine as his “favorite medicine of all time” in an article for Tonic, not only because the anesthetic is incredibly safe and effective, but also because of its versatility. It’s most widely used in surgery, but could also help treat severe asthma, chronic pain, and may even possess anti-tumor properties. In the last two decades, ketamine has also emerged as a potent antidepressant, able to treat symptoms of some mental illnesses in less than 72 hours.

“I think the more research that goes into ketamine, the more uses that we find for it,” O’Carroll says.

From PCP to Painkiller

Ketamine’s story begins with a drug called PCP. Yes, that PCP — phencyclidine or so-called “angel dust,” a drug that when smoked can cause a trance-like state, agitation and out-of-body hallucinations. After it was first synthesized by medicinal chemist Victor Maddox in 1956, the drug was briefly approved as an anesthetic by the FDA for its sedative properties. In tests with a wild rhesus monkey, for example, researchers put their fingers in the previously aggressive animal’s mouth and watched its jaw remain slack.

But while it was safe and effective for pain relief, the side effects of PCP soon became too obvious to ignore.

Some patients under the influence of PCP would feel like they lost their arms or legs or that they were floating in space. It could also cause seizures and delirium. Scientists began seeking a shorter-acting anesthetic without convulsant properties. In 1962, chemistry professor Calvin Stevens discovered a PCP analogue that fit the bill: ketamine.

Ketamine is a potent, sedating painkiller that can cause amnesia and is mostly used in surgery and veterinary medicine. During the Vietnam Invasion, ketamine saw widespread use in the U.S. military because it has several advantages over opioids. First, unlike morphine, ketamine doesn’t suppress blood pressure or breathing. It also doesn’t need to be refrigerated, making it useful in the field or in rural areas that don’t have access to electricity.

Ketamine’s benefits extend beyond use as an anesthetic, though — in some cases it can serve as a balm for the mind as well. A 2008 analysis found that burn victims who were given ketamine were less likely to develop symptoms of post-traumatic stress disorder, even if their injuries were more severe. Those findings have been replicated, such as a 2014 clinical trial of 41 patients, who saw their PTSD symptoms diminish within 24 hours, an effect that lasted for two weeks.

“When somebody gets one of their limbs dramatically blown off or is shot in the face, it’s a very traumatic event,” O’Carroll says. In such a situation, giving ketamine not only provides instant pain relief, it could prevent long-lasting trauma.

Because its chemical structure is so similar to PCP, ketamine can still give lucid hallucinations, such as feeling that your mind has separated from the body — a dissociative state users sometimes call a “K-hole.” One recent study based on users’ written reports even indicated that this kind of experience might be a close analogue to a near-death experience. However, these dissociative states only happen at high doses — the amount of ketamine used to for surgery and to treat depression is typically much lower.

But ketamine’s side effects are less common and easier to manage than PCP. In fact, ketamine is one of the safest drugs used in medicine today and can even be given to young children. For example, ketamine was used to sedatethe boys’ soccer team trapped in a cave in Thailand last year. Putting the kids in a tranquilized state made it easier to rescue them, and ketamine is safer than the opioids or benzodiazepines that are also commonly used as sedatives.  

Ketamine as Antidepressant

But it wasn’t until the 1990s that what could turn out to be ketamine’s most important function was discovered. A team from Yale University School of Medicine was examining the role of glutamate, a common neurotransmitter, in depression, and discovered something remarkable: ketamine could rapidly relieve depression symptoms.

“To our surprise, the patients started saying, they were better in a few hours,” Dennis Charney, one of the researchers, told Bloomberg. This rapid relief was unheard of in psychiatry.

Glutamate is associated with neural plasticity, our brain’s ability to adapt and change at the level of the neuron. Ketamine blocks certain glutamate receptors, but not others, and the end effect could be to promote the growth of new neurons while protecting old ones. This could explain how ketamine can help reset the brain, though the theory hasn’t yet been definitively proven.

The prescription meds currently on the market for depression have some major drawbacks. Drugs like Prozac or Wellbutrin can take a few weeks or months to kick in while worsening symptoms in the short term — not a good combination, especially for someone who is extremely depressed, or even suicidal.

It took around a decade for mainstream science to take notice of these early ketamine-depression studies. But once it did, ketamine clinics began popping up all across North America, offering fast relief for depression, anxiety and other mental illnesses. Patients are given an infusion — an IV drip that lasts about an hour — and many people, but not everyone, have seen rapid relief of their symptoms.

Suddenly, ketamine infusions became trendy, though the science to back up some of the medical claims is still inconclusive, according to STAT. However, ketamine infusions are rarely covered by insurance, although that is changing. A typical session can run $700, with many patients taking six sessions or more. But many of these patients have so-called treatment-resistant depression. They’ve tried other medications or therapies without success and some see ketamine as a last resort.

Steven Mandel, a clinical psychologist and anesthesiologist, has used ketamine on patients since it first came on the market around 50 years ago. In 2014, he began using it for patients with depression and opened Ketamine Clinics of Los Angeles, one of the oldest and largest clinics in the country. They’ve done over 8,000 infusions so far.

“Our success rate is better than 83 percent,” Mandel says. For his clinic, success means a 50 percent improvement of depression symptoms for longer than three months.

Ketamine’s success as an antidepressant couldn’t help but attract the attention of major pharmaceutical companies as well. In 2009, Johnson & Johnson began developing their own version of the drug they called esketamine. Rather than an infusion through a vein, it’s dispensed through a nasal spray. The FDA approved their formulation in early March. It was thefirst drug in 35 years to fight depression using a different approach than traditional drugs.

“Esketamine is a giant step forward,” Mandel says. “It means we’re not going to be demonizing mind-altering substances used for therapeutic purposes. It opens the door to research on LSD, on psilocybin, on MDMA and many other agents that could possibly relieve a great deal of suffering.”

But many clinicians have raised concerns about long-term side effects, such as heart and bladder toxicity. Others have been critical of esketamine, saying there isn’t enough data yet to suggest the drug is safe or effective. Husseini Manji, a neuroscientist who helped develop the drug for Johnson & Johnson at their subsidiary Janssen, has pushed back against these claims.

“When you line up the totality of the studies, it was really an overwhelming amount of data that was all in the same direction,” Manji says in a call. Though just two of the five late-state clinical trials showed significant results, the changes in mood in the three that fell short were “almost identical in magnitude” to the others, Manji says. It was enough for the drug to meet standards for FDA approval.

We can probably expect other ketamine-related drugs to come to market soon. ATAI Life Sciences, a company funding research on the use of magic mushrooms for depression, is developing their own ketamine depression drug. The pharmaceutical company Allergan also developed rapastinel, another ketamine-like drug, though it failed to show any real benefits for patients in later trials. Manji says this is unfortunate for people who could be helped by these kinds of drugs.

“From a patient standpoint, we were hoping it would work,” he says, even though he was not involved in rapastinel’s development. “But sometimes if you really haven’t got the mechanism right and you haven’t really threaded the needle, then sometimes you don’t see these results.”

Drug of Abuse?

Even though ketamine’s medical uses are well-established, most people have only heard of ketamine in the context of a party drug. Because of this bad reputation — and what’s perceived as growing misuse of the drug — several countries, such as China and the UK, have tried to place greater restrictions on ketamine. This would make it harder to study and more expensive in clinical use.

“If it was to ever be rescheduled, places that would be first affected would be you know places that need it most,” O’Carroll says. The WHO has asked at least four times for countries to keep access to ketamine open. “The medical benefits of ketamine far outweigh potential harm from recreational use,” Marie-Paule Kieny, assistant director general for Health Systems and Innovation at WHO, said in 2015.

So far, no countries have put greater restrictions on ketamine, and that’s probably a good thing. Ketamine has a rich history, but its future is still being written.