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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.

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

The post Premenstrual Dysphoric Disorder: How Ketamine May Help first appeared on Optimum Ketamine Center.