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Post-Traumatic Stress Disorder (PTSD) is surprisingly prevalent in our country. PTSD is a mental health condition that often develops after a traumatic life experience. Inciting events frequently include a life-threatening situation, physical accident, natural disaster, sexual assault, combat, and witnessing of death. Patients suffering from PTSD experience symptoms of impending doom, panic attacks, difficulty sleeping, and difficulty performing normal daily activities. Often times, the inciting event becomes consuming in many aspects of life, and patients tend to experience hyperactive responses to tactile and auditory stimuli. Symptoms can begin immediately following the inciting event and last for months to years.

According to the National Center for PTSD[i]:

• About 7 or 8 out of every 100 people will have PTSD at some point in their lives.
• About 8 million adults have PTSD during a given year. This is only a small portion of those who have gone through a trauma.
• About 10 of every 100 women (or 10%) develop PTSD sometime in their lives compared with about 4 of every 100 men (or 4%).
• The number of Veterans with PTSD varies by service era, but roughly 10-30% of Veterans that have been deployed suffer from PTSD.

     PTSD has enormous negative effects on psychosocial functioning and quality of life and has led to disability in millions of people[ii][iii][iv].  PTSD is the fifth most prevalent mental disorder in the United States[v][vi]. 

     Thus far, treatment of PTSD has focused mainly on psychotherapy, cognitive processing therapy, eye movement desensitization and reprocessing (EMDR), and management via medications including anti-depressants and anti-anxiety(benzodiazepine) regimens. There are two medications currently approved for the treatment of PTSD by the U.S Food and Drug Administration (FDA): Sertraline (Zoloft) and Paroxetine (Paxil).  The two medications are both Serotonin Reuptake Inhibitors and have the same mechanism of action.  Furthermore, they only seem to produce reduction in symptom severity rather than remission of PTSD symptoms[vii][viii].  Therefore, many psychiatrists have resorted to treating PTSD with other off-label medications which have not been studied adequately for the treatment of PTSD.  Ultimately, many people today continue to suffer from the devastating effects of PTSD.

     In 2017, The PTSD Psychopharmacology Working Group made a consensus statement: “It is time to address the crisis in the pharmacotherapy of Posttraumatic Stress Disorder”[ix].  It continued, “Despite this high prevalence [of PTSD] and costly impact, there seems to be no visible horizon for advancements in medications that treat symptoms or enhance outcomes and persons with diagnosis of PTSD.”

     Over the past several years, health care professionals have developed new innovative approaches for the treatment of PTSD.  While these treatments are not specifically FDA-approved for PTSD, they utilize FDA-approved medications and/or procedures that can be used off-label to successively treat PTSD.  There are numerous studies that confirm this.

KETAMINE INFUSIONS TO TREAT PTSD

     The use of ketamine to treat PTSD was first considered about 10 years ago, when injured soldiers from Operation Iraqi Freedom received ketamine for anesthesia during surgical procedures. The case studies showed that soldiers treated with ketamine had lower incidence of PTSD[x].  A few years later, a case report showed a young veteran with treatment-resistant PTSD showed rapid improvement following a single infusion of ketamine treatment.  He experienced 56% reduction in PTSD symptoms, which lasted for 15 days after one treatment[xi]. Ketamine at these low doses was shown to be safe and well tolerated with no evidence of worsening PTSD symptoms[xii]

     In 2014, a randomized clinical trial study analyzed the efficacy of intravenously administered ketamine (“IV ketamine”) for the treatment of PTSD.[xiii] The study found that a single infusion of IV ketamine led to a significant improvement in PTSD symptoms 24 hours post-infusion.  It concluded: “This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion with patients with chronic PTSD.”

     Although the precise mechanism is still unclear, there is a hypothesis that people with PTSD might have a stress related “synaptic disconnection syndrome” that results in their symptoms.  In other words, the nerves are not communicating with each other like they used to.  “Ketamine may work as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity.”[xiv]

STELLATE GANGLION BLOCKS (SGB) TO TREAT PTSD

     Another emerging treatment of PTSD is the Stellate Ganglion Block (also called “SGB”).  The Stellate Ganglion is a bundle of nerves (called sympathetic nerves) located on both sides of the neck.  These nerves control the body’s “fight or flight” response to stress. During periods of stress, such as when a person experiences PTSD, the sympathetic nerves are activated and “fight or flight” signals are sent to the brain through the Stellate Ganglion, resulting in a surge of the stimulating chemicals. This, in turn, causes an increase in blood pressure, heart rate, and feelings of panic and dread.  Stopping the transmission of hyperactive nerve signals through the Stellate Ganglion reduces the surge of norepinephrine and nerve growth factor in the brain—both of which are believed to contribute to chronic PTSD.

     SGD has been studied and used as a treatment for certain nerve-mediated pain of the face and upper extremities dating as far back as the 1920s. In the 1940s, SGB was used to treat depression,[xv] and only recently has regained traction in psychiatric therapy. Numerous case reports, case studies, and retrospective studies demonstrate a reduction in PTSD symptoms following SGB.  For example, in 2014, a large study of active duty military patients suffering from combat-related PTSD symptoms indicated a 79% response rate within the first week, 82% response rate at 1-2 months, and 74% response rate at 3-6 months.[xvi]  And the United States Army Medical Research Acquisition Activity currently is completing a multi-centered, randomized controlled study to further investigate SGB’s efficacy at treating PTSD.[xvii]  In short, there is growing evidence that SGB can alleviate certain PTSD symptoms such as hyperarousal, exaggerated startle response, and anxiety. 

How is SGB performed?

     SGB should only be performed by a skilled physician. The procedure takes approximately ten minutes and is performed under ultrasound guidance for accuracy. At Optimum Ketamine Center, SGB procedures are performed in our AAAASF-credentialed surgical suite by board-certified physicians. The majority of our patients prefer to be administered mild sedation through an IV catheter for the procedure which ensures maximal comfort. 

     After receiving sedation while lying on the back, the right side of the neck is cleansed with a sterilizing solution. Under ultrasound guidance, the stellate ganglion are visualized, and the skin is numbed. Then, a small needle is passed through the skin towards the stellate ganglion and a long-acting local anesthetic is injected around the nerve bundle with live ultrasound visualization. After injection of the local anesthetic used to “block” the Stellate Ganglion, the needle is then removed, and a small bandage is placed over the neck. Patients are fully awake or slightly sleepy immediately after the procedure and are usually discharged within one hour.

     SGB has limited side effects and is relatively safe when administered by a properly trained physician. 

What are the side effects?

SGB can have a number of side effects, including:

• Bruising and bleeding from the needle insertion site
• Temporary drooping eyelid on the side of the injection
• Temporary red or “bloodshot” eye on the side of the injection
• Nasal stuffiness
• Temporary hoarse voice
• Temporary feeling of a “lump” in your throat
• Warmth or tingling in your arm and hand

These effects usually subside within a few hours of the procedure.

Disclaimer:  Dr. June Lee is the Medical Director of Optimum Ketamine Center.  She is a board certified with the American Board of Anesthesiologists and a member of the American Society of Ketamine Physicians.   Optimum Ketamine Center website does not provide medical advice, diagnosis, or treatment.  Dr. Lee’s blog is not intended for medical diagnosis or treatment.  The information provided on this website is intended for general consumer understanding only. The information provided is not intended to be a substitute for professional medical advice.  For medical advice or assistance, readers should consult their healthcare professional.

Optimum Ketamine Center
665 W. North Ave, #101
Lombard, IL 60148
(708) 244-8663

www.optketamine.com

[i]  https://www.ptsd.va.gov/understand/common/common_veterans.asp

[ii] Fang SC et al. (2015) Psychosocial functioning and Health related quality-of-life associated with posttraumatic stress disorder and male and female Iraq and Afghanistan war veterans: the VALOR registry. Jay women’s health 24:1038–1046.

[iii] Goldberg J et al.  (2014) The association of PTSD with physical and mental health functioning and disability (VA cooperative study #569: The course and consequences of Posttraumatic Stress Disorder in Vietnam era veterans twins). Qual Life Res 23:1579-1591

[iv] Nock MK et al. Prevalence and Corlett of suicidal behavior among soldiers: results from the army study to assess risk and resilience and service members (Army STARRS). JAMA Psychiatry 71: 514-522.

[v] Perkonigg et al. (2000)  Dramatic events and post dramatic stress disorder in the community: prevalence, risk factors and comorbidity. Acta Psychiatr Scand 101:46-59.

[vi] Atwoli et al (2015) epidemiology of post Trumatic stress disorder: prevalence, correlates and consequences.  Curr Opin Psychiatry 28: 307-311.

[vii] Friedman MJ et al.(2014) Randomized, double blind comparison of sertraline and placebo for posttraumatic stress disorder in a department of Veterans Affairs setting. J Clin Psychiatry 68:711-720

[viii] Bowers ME (2015) an overview of translational he informed treatments for post dramatic stress disorder: animal models of Pavlovian fear conditioning to human clinical trials.  Bio Psychiatry 78:E15-E27

[ix] Krystal et al (2017) it is time to address the crisis in the pharmacotherapy of post dramatic stress disorder: a consensus statement of the PTSD pharmacology working group.  Biological Psychiatry pp e51-e57

[x] McGhee et al. The Correlation Between Ketamine and Posttraumatic Stress Disorder in Burned Service Members. The Journal of Trauma: Injury, Infection, and Critical Care: Bed 2008-V 64- Issue 2 pS195-S199.

[xi] D’Andrea etal. Transient Resolution of Treatment-Resistant Posttraumatic Stress Disorder Following Ketamine Infusion. Biol Psychiatry. 2012;71:37-e8.

[xii] Zeng et al. Acute stress symptoms do not worsen in posttraumatic stress disorder and abuse with a single subanesthetic dose of Ketamine. Biol Psychiatry. 2013;;73:e37-e38.

[xiii] Feder et al. (2014) efficacy of intravenous ketamine for treatment of chronic post Trumatic stress disorder. A randomized clinical trial. Jama;71(6):681-688

[xiv] Krystal et al. Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Current Psychiatry Reports October 2017, 19:74

[xv] Karnosh et al. The effects of bilateral stellate ganglion block on mental depression: report of 3 cases. Cleve Clin Q 1947; 14 (3):133-138

[xvi] Mulvaney et al. The use of stellate ganglion block in the treatment of panic/anxiety symptoms with combat-related post-traumatic stress disorder;premlimiary results of long-term follow-up: a case series. Pain Pract 2010;10(4): 350-365. Doi:10.1111/j.1533-2500.2010.00373.x.

[xvii] https://www.rti.org/impact/study-stellate-ganglion-block-treatment-ptsd-symptoms

The post Post-Traumatic Stress Disorder first appeared on Optimum Ketamine Center.

Alcohol addiction is deadly, we know this.  It does not just punish the addict, it punishes their family and society.  For those who find sobriety alone or with help from a detox program, staying sober is a lifelong challenge. Relapse occurs when one resumes drinking and is a detrimental problem that deserves more attention. Understanding some basics of alcohol addiction and how to help prevent relapse can be a bit complicated.  The next section on “choice” will summarize an article on the neurobiology of addiction by Xavier Noel [i].  It simplifies some popular thoughts about how and why addiction works in the brain.  Then, we can see how to target effective treatment with ketamine to help prevent relapse.

Is alcoholism a choice?

The impulse/habit system:

How does the compulsion to drink develop?  A part of our brain, called the amygdala-striatum neural complex, motivates us to achieve rewards. This area is driven by dopamine, a naturally produced neurotransmitter in our bodies that has many effects, including feelings of pleasure, or reward. Alcohol, and other addictive drugs, increase overall dopamine levels in our brain. Therefore, a link forms between automatic, repetitive behaviors, such as pouring a drink, and increased dopamine. These actions are saved in our brain as rewarding. And the brain loves rewards.

Increasing dopamine activity also accelerates the change between the first steps of choosing to have a drink and later craving a drink.  New pathways in the brain form with repetitive behavior. Cues and memories in the environment to drink are noticed more quickly, like hearing glasses clink, or walking in the front door after work. These cues drive the compulsion to drink. The brain’s automatic response is to seek this reward, but can’t we control this behavior?

The control/decision making system:

The decision-making part of our brain is found in the prefrontal cortex. It is also known as the “reflective system”, or executive function system, where we can control impulses. This means we can trade short term rewards, like a drink, for possibly greater long-term goals, such as avoiding a DUI charge.  One explanation is that there is a balance between a “cool” and “hot” system that works out how we respond to triggers or cravings.  The “cool” refers to basic working memory and inhibition of impulses.  The “hot” involves numerous emotional responses that are possible. Damage to either of these systems may impair the ability to say “no” to situations, or drugs like alcohol, that can harm us. Either the impulse side or the emotional side wins when we lose a health balance.

When/How impulse overpowers control:

Poor decision making in alcoholics may also be explained by yet another system called the insular cortex. It responds to imbalance in our bodies from things like sleep deprivation, anxiety and stress. These stressors may hijack our impulse/habit system and increase cravings while promoting decisions to seek out alcohol. Repeated cycles of increased cravings can also essentially rewire brain circuits, reinforcing continued destructive behavior.

Addiction as a “Pathology of Choice”

Other studies support that “faulty brain connections related to decision-making can lead to addictive behaviors and relapse.” [ii]  There is a definite shift from blaming addiction on cravings to finding abnormalities in decision making areas of the brain. Thus, the brain is not able to make the right decisions to ignore the craving.

NMDA receptors are at fault too?

Family history of alcoholism is a risk factor for developing alcohol addiction. A study by Petrakis et al showed one answer may lie in the NMDA (N-Methyl-D-Aspartate) receptor, which is vital to the glutamate system in the brain.  Alcohol alters this receptor’s function, but if the receptor is not normal, that person may be more susceptible to alcohol abuse.[iii]

How can ketamine help?

Ketamine can play a key role in preventing relapse in those who have either completed a detoxification program or managed to stop themselves.

Over-write memories that drive addiction

It is possible a rewarding memory of taking a drink, for example, can be triggered repeatedly by seeing a glass of beer, going to a restaurant, or maybe returning home from work.  These triggers lead to the urge to drink.  Ravi Das from University College London explains why people often quit but return to drinking. “The main problem is the really high relapse rate after treatment,” said Das. “People can successfully quit using over the short term while they’re being monitored in the hospital … but when they return home they’re exposed to those environmental triggers again.”[iv] The good news, is that each time the brain accesses that rewarding memory, the neural connections that code the memory are destabilized.  It is at this moment that ketamine, which blocks the brain receptor required for the formation of memories (NDMA), can help weaken or even erase the memory. In other words, ketamine will help break the power of that trigger.

The psychedelic experience

The benefits from the psychedelic experience while receiving a ketamine treatment may hold benefits.  Dr. Tobias Stevens, in his presentation on ketamine as a treatment for alcohol use disorder, postulates the hallucinations and altered mental state from ketamine may help change lifestyle choices.  He suggests the experience may alter perceptions and break routine behaviors.[v]  Therefore, a combination of psychotherapy with ketamine, (ketamine psychotherapy or KPT) may prove helpful for some folks. KPT allows the psychedelic effects from ketamine to enhance a psychotherapy session and is shown to be effective helping those with addiction, including heroin and alcohol by Dr. Evgeny Krupitsky.[vi]

Ketamine allows learning

Psychotherapy is a vital mainstay of alcoholism recovery treatment, but why are relapse rates so high?  Maybe, postulates McAndrew et al, the alcoholic brain simply can’t learn the new skills.[vii]  There is a proven decrease in neural growth factors in the brain, BDNF, with alcohol addiction.  With fewer connections between nerves, and less ability to make new connections, the brain cannot learn new skills.  With ketamine and synaptogenesis, which happens to peak 24 hrs after a treatment, well timed psychotherapy can have a greater impact.

What does ketamine for relapse prevention look like?

Ketamine is not a solitary treatment for alcohol relapse prevention.  To say so would oversimplify the disease.  Current studies include interesting combinations with ketamine.

KARE – Ketamine for reduction of Alcoholic Relapse

KARE is a multi-site project running in England that is a clinical trial seeking to explore psychotherapy combined with low dose ketamine as a possible treatment for alcoholism.[viii]  Participants who completed alcohol detoxification receive IV ketamine 3 times interspersed with 7 therapy sessions.  The psychotherapy model, developed by Dr.s Rob Hill and Jen Harris included 3 key areas:

• Risk reduction strategies: Identify high risk situations, cope with cravings, or restructure unhelpful thinking
• Wellness promotion: planning weeks, problem solving, relaxation, and mindfulness
• Education: what is addiction, biological effects of alcohol both acute and chronic, alcohol and sleep, and how alcohol interacts with the brain

Combining ketamine with other medications?

Combining ketamine with other prescription drugs is debatable as there is conflicting evidence.  For example, naltrexone is frequently used with alcohol dependence. It binds opioid receptors and is supposed to take away cravings for opioids and alcohol which can take away reward effects.[ix] In reality, it does reduce overall total alcohol consumption, but not necessarily abstinence. Nimodipine is a calcium channel blocker that is also studied for its’ ability to decrease alcohol-type effects from ketamine treatment.[x]  Additionally, some providers prescribe Baclofen to help suppress cravings.

But, isn’t ketamine addicting?

Are we just trading alcohol addiction for ketamine addiction? This is not true according to several studies.  A study by Krystal, et al in 1998 clearly showed ketamine did not increase cravings on recovering alcohol dependent patients.[xi]  Recently detoxified alcoholics given ketamine did not go on to abuse the drug. Keep in mind, ketamine for alcohol abuse is given by trained providers in a medical setting at doses far less than what one may find on the street. The body does not become physically dependent on ketamine, meaning there are no physical withdrawal symptoms when one stops. However, there is always a possibility of mental dependence on a treatment that is helping.  But, lets put this in perspective.  Many people are dependent, or “addicted”, to a variety of activities, like exercise, weight loss, meditation, because these things reward them, (ie their brain).

Conclusion

Reducing alcohol dependence and relapse has far reaching benefits from decreased personal injury from liver disease, to depression and anxiety, to family relationships, to work stability, or to alcohol related death from accidents.  Once detoxification is complete, ketamine can help people maintain sobriety when used in part with a comprehensive program.  Alcoholics Anonymous (AA), psychotherapy, adjuvant medications and physician oversight can all help cut cravings and save lives.

About The Author

Dr. Van Praag is the medical director of Spring Center of Hope, a ketamine center located in Houston, TX. She is a practicing anesthesiologist with 13+ years of experience caring for patients of all ages.

Visit: https://springcenterofhope.com/about-dr-van-praag/ for additional information.

[i] Noël X,Brevers D, et al. A neurocognitive approach to understanding the neurobiology of addiction Curr Opin Neurobiol . 2013 August ; 23(4): 632–638. doi:10.1016/j.conb.2013.01.018. link

[ii] Bergland C, The Neuroscience of Making a Decision: Various brain regions work together during the decision-making process. Psychology Today online, 05/06/2015. link

[iii] Petrakis I, Limoncelli D, et al Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. The American Journal of Psychiatry Oct-2004 161 1776–1782 0002-953X link

[iv] Devlin H, Radical ketamine therapy could treat alcohol addiction. Theguardian.com, 01/24/2017. link

[v] Stevens T. Ketamine as a Treatment For Alcohol Use Disorder. Breaking Convention 2017, YouTube 09/13/2017. link

[vi] Krupitsky E, Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. Journal of S/ubstance Abuse Treatment 23 (2002) 273–283.link

[vii] McAndrew A, Lawn W, et al. A proof-of-concept investigation into ketamine as a pharmacological treatment for alcohol dependence: study protocol for a randomised controlled trial. Trials (2017) 18:159 DOI 10.1186/s13063-017-1895-6. link

[viii] KARE: Ketamine for reduction of Alcoholic Relapse. University of Exeter, England. link

[ix] Krystal J, Madonick S, et al. Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism. Neuropsychopharmacology (2006) 31, 1793–1800 link

[x] Krupitsky E, Burokov A, et al. Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men: Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists. [Neuropsychopharmacology 25:936-947, 2001  link

[xi] Krystal J, Petrakis I et al.  Dose Related Ethanol-like Effects of the NMDA Antagonist, Ketamine, in Recently Detoxified Alcoholics. Arch Gen Psychiatry Vol 55, April 1998, 354-360  link

Disclaimer: This article represents an informed opinion of the author and/or the opinion of others. It does not constitute medical advice and should not be relied upon to make decisions about medical care. Please consult your physician for questions regarding your specific conditions and possible treatments

Photo Credits:
Headline: Gerd Altmann from Pixabay
Baby: Michal Jarmoluk from Pixabay
Clock: Michal Jarmoluk from Pixabay
Sign: Gerd Altmann from Pixabay

The post Understanding Alcohol Addiction and How Ketamine Can Help Prevent Relapse first appeared on Optimum Ketamine Center.

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Spravato is a new antidepressant medication manufactured by Johnson & Johnson’s pharmaceutical company, Janssen, for management of Treatment Resistant Depression. According to the FDA, “Patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment are considered to have treatment-resistant depression.”

How is Spravato administered?

Spravato comes as an intranasal spray.  The FDA set strict guidelines for the administration of Spravato which has a Boxed Warning.  The Boxed Warning states that “the patients are at risk for sedation and difficulty with attention, judgement and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.”  Therefore, the patient must self-administer Spravato at a doctor’s office and the patient cannot take the medication home.  After self-administration, the patient must be watched and monitored for 2 hours after administration.  In addition, the patient must arrange for a driver since they will not be allowed to operate any heavy machinery after the treatment.  The frequency of the administration is as follows: the first month- the medication must be taken twice a week; the second month- the medication must be taken once a week; and thereafter- once every other week.  Click here for Janssen’s prescribing package insert

Does Spravato work?

The FDA reported 3 short-term (four week) clinical trials and one longer-term maintenance-of-effect trial.  “In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. In light of the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trails did not meet the pre-specified statistical tests for demonstrating effectiveness.  In the longer-term maintenance-of-effect trial, patient in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.” [1]

What is the cost of Spravato?

The wholesale acquisition cost, or list price, will be between $590 and $885 per session.  This means the first month of treatment will range from $4720 to $6785.  This does not include the costs of a physician visit and monitoring.  The medication will most likely be added to most major health insurance plan’s formulary.  There is no information yet regarding in what specialty tier Spravato will be placed and what the out of pocket expenses will be for the patients.  In addition, we are uncertain what the pre-authorization approval process from the insurance companies will entail.

Where can I get Spravato? 

The FDA says, “due to safety concerns, the drug will only be available through a restricted distribution system and must be administered by a certified medical office where the health care provider can monitor the patient.”  Only clinics that are certified in REMS (Risk Evaluation and Mitigation Strategy) can treat and monitor patients enrolled in REMS.  In addition, only specialty pharmacies that are certified in REMS will be allowed to dispense Spravato directly to the medical offices.  REMS is a program required by the FDA to manage known or potential serious risks associated with a drug product.

Will Optimum Ketamine Center become a REMS center and offer Spravato?

We are currently obtaining more information regarding this process.  We already know it is a multistep process that will require some time. In addition, we have yet to receive any information from the Center for Medicare and Medicaid Services (CMS), who is responsible for coding and setting the fee schedules for Medicare.  All private insurers follow the guidelines set by CMS.  Therefore, there are still quite a few unanswered questions regarding the logistics of treating with Spravato.   We hope to have more answers for you in the coming months.

What is Esketamine, the main compound in Spravato?

Esketamine is half of the active ingredient of the medication Ketamine.  Ketamine is a medication containing equal parts R-ketamine and S-ketamine (Esketamine).  R-ketamine and S-ketamine are mirror images of each other. The pharmaceutical company Janssen isolated the S-ketamine molecule to create a medication they can patent and sell.  At Optimum Ketamine Center, we use Ketamine (containing both active components) to treat mood disorders. This includes both the R-ketamine and the S-ketamine.

Pixabay/JamesDeMers

What is Ketamine?

Ketamine is a medication that is FDA approved for anesthesia.  It is being used off-label for the management of treatment resistant depression.  It is a NMDA (N-methyl-D-Aspartate) receptor antagonist.  NMDA receptors are found on nerve cells where they transmit and receive signals. They are critical for the development of the central nervous system, generation of rhythms for breathing and movement, and the processes underlying learning, memory, and neuroplasticity[2] (your brain’s ability to adapt to new situations or injury).

Are Esketamine (S-ketamine) and R-ketamine the same?

 No. They have different properties.[3] [4]

The studies we have so far regarding R vs S Ketamine have all been from mice and rat models. Nevertheless, it appears that the R- and not the S-Ketamine is the more potent anti-depressant and has longer lasting antidepressant effects.  Furthermore, the S-Ketamine exerts a greater dissociative effect than R-ketamine.

Is Ketamine and Esketamine absorption the same whether it is given intranasal or intravenously?  

No. Intranasal administration has been shown to be less predictable with greater variability in onset times and peak blood levels[5] than with intravenous administration.  The amount available after intranasal administration varies anywhere from 8% to 45%[6][7] whereas the amount available after intravenous administration is nearly 100%.

Disclaimer:  Dr. June Lee is the Medical Director of Optimum Ketamine Center.  She is a board certified with the American Board of Anesthesiologists and a member of the American Society of Ketamine Physicians.   Optimum Ketamine Center website does not provide medical advice, diagnosis, or treatment.  Dr. Lee’s blog is not intended for medical diagnosis or treatment.  The information provided on this website is intended for general consumer understanding only. The information provided is not intended to be a substitute for professional medical advice.  For medical advice or assistance, readers should consult their healthcare professional.

Optimum Ketamine Center
665 W. North Ave, #101
Lombard, IL 60148
(708) 244-8663
www.optketamine.com

[1] FDA approves new nasal spray medication for treatment-resistant depression; available only at a cerfified doctor’s office or clinic. March 5 2019 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm

[2] Activation Mechanisms of the NMDA Receptor. Blanke and VanDongen, Biology of the NMDA receptor. CRC Press/Taylor & Francis; 2009.  https://www.ncbi.nlm.nih.gov/books/NBK5274/

[3] R-Ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Yang, Shirayamata et al. Transl Psychiatry (2015) 5, e632;doi:10, 1038, published on-line 1 September 2015 https://www.nature.com/articles/tp2015136.pdf

[4] R (-) ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Zhang, Li, Hashimoto.  Pharmacol Biochem Behav. 2014 Jan;116:137-41. E published 3 December 2013https://www.sciencedirect.com/science/article/pii/S0091305713003328?via=ihub

[5] S-ketamine and s-norketamine plasma concentrations after nasal and I.V. administration in anesthetized children.  Weber et al.  Pediatric Anesthesia, December 2004 Volume 14, Issue 12 p983-988

[6] Plasma concentration profiles of ketamine and norketaminafter administration of various ketamine preparations to healthy Japanese volunteers.  Yanagihara et al Biohpar Drug Dispos, 2003 Jan: 24(1):37-43

[7] Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients.  Yeaman et al. Emerg Med Australas. 2014 June;26(3):237-42

The post Spravato Esketamine: What We Know So Far first appeared on Optimum Ketamine Center.

Ketamine therapy is not just a passing fad in the treatment of depression, suicidal thoughts, PTSD and other mental health issues.  Each week continues to bring more studies to support the breakthrough use of this time-honored drug.  Ketamine has been in use over 50 years in emergency rooms, operating rooms and the battlefield.  It has the powerful ability to relieve pain and in larger doses, induce anesthesia. In very recent years scientists have discovered it has profound neuroregenerative effects on the brain.  Chronic trauma, anxiety and depression can change the brain by destroying nerve cells. Ketamine helps form new connections to rebuild and alleviate the symptoms of these mood disorders.^[1]  While it is easy to find a front-page article or a long list on Google search to support these facts, there is a key component of healing that is often missing in these articles: psychotherapy.

It may seem logical to some that psychotherapy should accompany a medication to treat depression. However, many have viewed ketamine as a quick fix, magic drug that will alone reverse suicidal thoughts or depression. Let us think about high blood pressure treatment as a comparison. Yes, taking a pill can reduce the pressure, but losing weight, changing diet and adding exercise may have a more profound effect for many. Ketamine therapy is essentially the same idea.  True, some will do great with just the drug and no other changes in their life, but for many adding in the necessary psychotherapy will reveal more substantial results.  And, here is the key, the results will last longer with possibly less ketamine needed over time.

Working Together

Ketamine is a legal medication out of a handful of psychedelic drugs that have found a niche in psychotherapy. And, within this niche there are big differences in how these drugs are used.  While some may use ketamine to experience personal growth through a psychedelic journey with their therapist, many are using ketamine plus psychotherapy to assist with healing depression, PTSD, suicidal thoughts and so forth. This is achieved in two ways:

1. KAP, or ketamine assisted psychotherapy, is a guided psychotherapy session under a low dose of ketamine which induces a mild trance-like state where the patient can interact with the therapist and gain physiological anti-depressant effects of ketamine.^[2]
2. Psychotherapy provided before and after the ketamine treatment may allow for higher dosing to increase physiological change. The patient does not have to interact while under the effects of ketamine. Discussion and interpretation of events under treatment may occur immediately after a treatment and in the following days to weeks.

This synergy between psychedelics and psychotherapy is formally studied by many respected groups such as KRIYA (Ketamine Research Institute) link, Ketamine Research Foundation link, and MAPS (Multidisciplinary Association for Psychedelic Studies) link. With MAPS, the drug MDMA is currently used in an FDA approved trial with psychotherapy to treat PTSD.  The purpose of the MDMA is to decrease fear and allow the patient to experience emotions and visit the trauma without heightened anxiety.^[3]

What About the Side Effects?

The nature of ketamine is a dissociative medication that causes an out of body experience, and with higher doses can induce hallucinations. Drug companies are actively searching for a new drug that works like ketamine, but without the “side effect” of dissociation. Alternatively, many argue the journey under ketamine is precisely what helps one heal from past trauma and ongoing anxiety or depression. There are three ways to view the effects of ketamine according to Raquel Bennett, a psychologist and founder of KRIYA Institute in California.^[4]

1. Ketamine is a purely medical treatment where we give the drug to patients and try to eliminate annoying dissociation by giving counteracting drugs.
2. It is a “shamanic” approach and what the patient experiences under treatment is important to healing.
3. Combining both above, ketamine is correcting neurochemical pathways while a mental health professional helps guide the patient through the experience, gaining insight.

How the Therapist Aids the Healing Process

Preparation: Any ketamine treatment program should include a time for education. The patient learns about the method of delivery, how to prepare themselves, what to expect, what to avoid, time for questions and answers and how to take care of themselves afterward.  A mental health professional adds to this by ensuring a trusting relationship, setting goals, and teaching relaxation, breathing or other techniques to manage anxiety.

Manage challenges: While most ketamine experiences are interesting, calming or fascinating, some include revisiting past or current stressors. According to a recent article by Gold and Sienknecht, “The healing process is not about avoiding challenges but rather engaging them in new ways…Challenging experiences can be incredibly valuable and important, sometimes even essential, to the journey towards wholeness.”^[5]

Integration: The healing process continues beyond the day of treatment. Gold and Sienknecht also explain the integration process that follows the psychedelic experience will allow one to explain their experience, collect insights and implement new changes. The therapist can help with this process and maintain positive ground.

Long Term Benefits

One small study by Dr. Wilkinson, et al, out of Yale School of Medicine explored the strategy of combining cognitive behavioral therapy (CBT) with ketamine treatments to extend the anti-depressant effects.^[6]  They found a strong connection between ongoing CBT and depression relief.  Given ketamine causes new connections to form between neurons in the brain, Dr. Wilkinson states “It may be possible to exploit this critical period of induced plasticity to initiate attempts at modifying cognitions and behaviors that require synaptic plasticity.” In other words, CBT and ketamine working together boosts relief.

A second benefit of long-term effects discussed in this Yale study, is the possibility to limit ketamine exposure over time when combined with psychotherapy. This makes sense.  If one feels better with combined therapy and ketamine, the need for ketamine boosters may decrease in frequency over time.  This is important considering long term studies are not available concerning the effects of repeated ketamine exposure over years in an individual.  Dr. Wilkinson refers to mixed studies about long term cognitive effects.  We just don’t have the answers yet.

Final Thoughts

Ketamine plays one part in the whole treatment plan for depression, PTSD, suicidal thoughts OCD, etc. It has a powerful physiological effect to relieve depression.  Now, we also need to focus on the psychological component by incorporating a trained mental health professional in the treatment plan.  A therapist will prepare the individual, manage challenges during ketamine therapy, and integrate positive changes into daily life.  Taking advantage of this synergy may allow greater success and possibly less ketamine overall.

Disclaimer: This article represents my informed opinion and/or the opinion of others. This does not constitute medical advice and should not be relied upon to make decisions about medical care. Please consult your physician for questions regarding your specific conditions and possible treatments.

About The Author

Dr. Van Praag is the medical director of Spring Center of Hope, a ketamine center located in Houston, TX. She is a practicing anesthesiologist with 13+ years of experience caring for patients of all ages.

Visit: https://springcenterofhope.com/about-dr-van-praag/ for additional information.

^[1] Nanxin L, Boyoung L, et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists.Science 2010;Vol. 329 Issue 5994: 959-964 link

^[2] Wolfson M.D., Phil.(2016) Opportunities and Strategies for a Ketamine Psychotherapeutics (KAP). The Ketamine Papers. (p339-359) Santa Cruz, CA: MAPS

^[3] Mithoefer, M.C. (2016). MDMA-assisted psychotherapy treatment manual (Version 8.1). Santa Cruz, CA: Multidisciplinary Association for Psychedelic Studies. link

^[4] Velasquez-Manoff, M. (05/08/2018) Ketamine Stirs Up Hope – and Controversy – As a Depression Drug. WIRED. link

^[5] Gold, V., Sienknecht, E.(12/13/2018) Ambassadors to Hidden Territories: Set and Setting in Psychedelic-Assisted Psychotherapy. Chacruna.net link

^[6] Wilkinson, S T, Wright DS, et al. Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression. Psychother Psychosom 2017; 86:162-167.

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Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD), a severe mood disorder, is characterized by mental health and physical symptoms in the week before the onset of menstruation and affects millions of women worldwide[i]. It is a much more intense form of PMS.

Emotional and mood related symptoms include:

• Mood swings, tearfulness, sensitivity to rejection
• Irritability or anger
• Marked depressed mood, hopelessness, self-depreciating thoughts
• Anxiety or tension
• Loss of interest in usual activities
• Lack of energy
• Changes in appetite
• Changes in sleep

Physical symptoms include:

• Breast tenderness
• Breast swelling
• Bloating
• Water retention

Most women experience the greatest severity of symptoms from 3-4 days prior to onset of period to up to 3 days’ post-period onset. Symptoms are absent in the post-menstrual week.

Why do some women get this disorder? The etiology is still unclear. Many experts believe it is a combination of genetic factors, stress, and the hormonal fluctuation that lead to most of the symptoms.

What Hormonal Fluctuations?

Estrogen exerts potent effects on the brain and is involved in regulating mood, cognition, sleep, eating, and other aspects of behavior.  The fluctuations of this hormone during the menstrual cycle, especially during the luteal phase (after ovulation through onset of period)  when the levels steadily decline, could be a key factor in the etiology of PMDD[2].

Estrogen has many beneficial traits such as:
• Increasing serotonin and number of serotonin receptors in the brain
• Modifying the production and effects of endorphins- the ‘happy’ hormones
• Protecting nerves from damage, and possibly stimulating nerve growth

Right after ovulation, your progesterone levels acutely increase and then suddenly fall with menstruation.  Research shows that chronic progesterone exposure followed by rapid withdrawal may be another one of the key factors in the etiology of PMDD[3].

How is PMDD treated?

1) First line of treatment for PMDD are Selective Serotonin Reuptake Inhibitors (SSRIs)[4]. Unlike with other mood disorders, patient’s with PMDD experience rapid onset of action from SSRI (as opposed to the typical 2-3 week onset time)[5].  Therefore, people with PMDD benefit from intermittent dosing.  Administering the medication only during the luteal phase, from the time of ovulation until menstruation onset alleviates many of the symptoms[6].
2) Hormonal therapy: Some women with PMDD respond well to oral contraceptive. In 2006, YAZ, an oral contraceptive, received US Food and Drug Administration (FDA) approval for the treatment of PMDD in women desiring oral contraception. Not all women respond to oral contraceptives and not all oral contraceptives improve symptoms. Please speak with your gynecologist regarding the best options for you.
3) Psychotherapy: A study showed that cognitive-behavioral therapy, one type of psychotherapy, was associated with increased use of effective coping strategies and shift in perception of premenstrual symptoms[7].
4) Supplements: Calcium was shown to improve PMDD[8] along with Vitamin B6[9] and Magnesium[10].

Unfortunately, many women with PMDD do not respond to the traditional treatment options. PMDD can cause substantial signs of depression for days or even weeks every month and millions of women are forced to cope with a crippling condition that is very difficult to treat.

Recent research shows that Ketamine administered at the onset of PMDD may alleviate the treatment resistant symptoms.

Why Ketamine may be an option

Recent data shows that Ketamine actually activates estrogen receptors[11].

Why is this important?  As mentioned above, the declining levels of estrogen during the luteal phase may be a contributing factor to PMDD.  By administering ketamine at the start of the luteal phase or when symptoms of PMDD become apparent, we may be able to effectively treat one of the big contributing factors.

The same study showed that Ketamine works with estrogen to increase glutamate levels.

What is glutamate? Glutamate is a neurotransmitter (chemicals that transmit signals in the brain) that may be uniquely central to the biology behind major depression.   The lack of glutamate in certain regions of the brain has been strongly linked to depression[12].  Ketamine has been shown to activate glutamate transmission in the brain and is thought to be a key mechanism in its anti-depressant effects[13].  Ketamine may have direct impact on mood and other signs of depression if administered at the onset of PMDD.

This is an exciting time as more information becomes available regarding the benefits of Ketamine. More research needs to be done to find definitive answers, but the data we have so far gives us hope that Ketamine may have a beneficial role in the treatment of PMDD.

Disclaimer:  Dr. June Lee is the medical director of Optimum Ketamine Center.  Optimum Ketamine Center website does not provide medical advice, diagnosis, or treatment.  Dr. Lee’s blog is not intended for medical diagnosis or treatment.  The information provided on this website is intended for general consumer understanding only. The information provided is not intended to be a substitute for professional medical advice.  For medical advise or assistance, readers should consult their healthcare professional.

[1]  Dennerstein L, Lehert P, Heinemann K. Epidemiology of premenstrual symptoms and disorders. Menopause Int. 2012;18:48–51. [PubMed]
[2]  Shanmugan S, Estrogen and the prefrontal cortex: towards a new understanding of estrogen’s effects on executive functions in the menopause transition. Epperson CNHum Brain Mapp. 2014 Mar; 35(3):847-65.
[3] Smith SS, Ruderman Y, Frye C, Homanics G, Yuan M. Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha, 5beta-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology (Berl) 2006;186:323–33.
[4] ACOG: ACOG Practice Bulletin Premenstrual syndrome.  Clinical management guidelines for obstetrician-gynecologists. Int J Obstet Gynecol. 2001;73:183-91.
[5] Steinberg EM, Cardosos GMP, Martinez PE, Rubinow DR Rapid response to fluoxetine in women with premenstrual dysphoric disorder. Depress Anxiety. 2012;29:531-40.
[6] Freeman EW. Luteal phase administration of agents for the treatment of premenstrual dysphoric disorder. CNS Drugs. 2004;18:453-68.
[7] Kleinstauber M Witthoft M. Cognitive-behavioral and pharmacological interventions for premenstrual syndrome or premenstrual dysphoric disorder: a met-analysis.   J Clin Psychol Med Settings.  2012;19:308-19.
[8] Thy-Jacobs S, Starkey P Calcium carbonate and the premenstrual syndrome effects on premenstrual and menstrual symptoms. Premenstrual syndrome study group.  Am J Obstet Gynecol 1998; 179:444-52
[9] Kleijnen J, Ter Riet G et al. Vitamin B6 in the treatment of the premenstrual syndrome- a review. Br J Obstet Gynaecol 1990;97:847-52.
[10] Khine K, Rosenstein DL et al. Magnesium retention and mood effects after intravenous infusion in premenstrual dysphoric disorder. Biol Psychiatry 2006;59:327-33.
[11] Ho, Correia, Ingle Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression. Biovhem Parmacol. 2018 June;152:279-292.
[12] Murrough JW et al. Targeting glutamate signaling in depression: progress and prospects. Nat Rev Drug Discov. 2017;17:472-86
[13] Abeallah et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neurpsychopharmacology 2018. 43, 2154-2169

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