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Intranasal Ketamine for the Relief of Cluster Headache

Ketamine’s Mechanism of Action

Ketamine (2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride), a human and veterinary anesthetic agent, has an extremely varied set of pharmacologic actions depending on the dosage used.1 A selective uncompetitive N-Methyl-D-aspartic acid (NMDA) glutamate receptor antagonist, the drug has been in legitimate clinical use since 1963.

When administered as an appropriate pharmacologic agent, ketamine has been shown to serve as a safe anesthetic agent. At sub-anesthetic doses, ketamine acts as an uncompetitive antagonist at ionotropic NMDA-type glutamate receptors, binding to a site on the receptor while it is open. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission throughout the mammalian brain. Based on their pharmacology, there are three main classes of glutamate-activated channels:

  • α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
  • kainate receptors
  • N-methyl-d-aspartate receptors (NMDAR).

Among ion-gated receptor subtypes (iGluRs), NMDAR are exceptional in their high unitary conductance, high Ca2+ permeability, and remarkably slow gating kinetics.

Ketamine has relatively specific effects on other glutamate subtypes. Several families of these receptors also include AMPA-type and kainate receptors, and the metabotropic family of receptors, of which many exist. NMDARs, in particular, are glutamate-gated ion channels primarily for calcium ions and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several subunits. The subunit composition of NMDARs is subject to many changes, resulting in large numbers of receptor subtypes. Each subtype has distinct pharmacological and signaling properties.1 Interest and research is growing and abounds in defining specific functions of subtypes of the glutamate receptor system in both normal and pathological conditions in the central nervous system.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity.In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after ketamine infusion.

Use in Migraine, Cluster Headache, and Neuropathic Pain Disorders

In more recent years, a very small number of clinicians, including the author, have used ketamine intravenously (IV), and in some cases, via intramuscular injection, to treat migraine, cluster headache, and various other chronic pain disorders, including mixed headache and neuropathic pain clinical syndromes.3-21 In the author’s clinic specifically, ketamine has been used via IV administration for more than 20 years to treat nearly 1,000 patients with various headache and pain disorders. These include: migraine and cluster headache flare-ups; headaches associated with orofacial pain disorders, such as trigeminal neuralgia (TN); atypical face pain; temporomandibular joint disorder (TMD); and neck pain.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after a ketamine infusion.

The focus of this paper is to provide a summary of specific retrospective cases in which intranasal ketamine was used for the rescue of cluster headache in patients who had previously experienced a positive outcome from IV ketamine in the author’s outpatient clinic. Cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home. Table I outlines the outpatient clinic’s treatment of various migraine and headache types. As shown, cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home.

Retrospective Case Summaries

The dose of intranasal ketamine prescribed to patients ranged between 7.5 mg and 15 mg per 0.1 cc nasal spray (75 and 150 mg of ketamine per cc compounded in normal saline by a pharmacy). Patients were instructed to use one spray in the nostril of the affected side and wait 10 to 15 minutes to feel any effects, including side effects. They were to use the spray when they felt a cluster attack coming on. Patients were asked to use another spray of ketamine in the same nostril at 10- to 15-minute intervals until a sufficient degree of relief (at least 60 to 75%) was obtained for that cluster attack. If the attack still came on after about one hour, the instructions were for the patient to repeat the procedure. All patients were instructed not to drive after taking the medication and signed off on this agreement. Patients were also instructed to keep the nasal spray refrigerated when not in use; no efficacy loss was reported. Of the 17 patients who trialed the nasal spray, 11 elected not to have the intranasal ketamine compounded, or were lost to follow-up, leaving six case scenarios which are summarized herein.

Case 1

A 38-year-old male, with a 16-year history of cluster headache, including a family history of the same, had tried a number of acute and prophylactic agents with, at best, a shortening of the cluster episode. His attacks tended to flare in the spring and lasted up to three months at a time with 4 to 6 episodes per day. The attacks prevented him from working and he came to the outpatient clinic for IV treatment with ketamine, which resulted in a complete cessation after three days, with resolution of allodynia on the right side as well. He elected to try intranasal ketamine (15 mg) at the first onset of his next cluster episode. He reported pain relief and a feeling of calm after 2 to 3 sprays, with no adverse effects. Sometimes, he had to repeat the dosing regimen the next day.

Case 2

A 25-year-old woman was thrown from a horse during a competition and fractured her cervical spine, requiring surgery. The injury included syringomyelia between C3 and C7-T1 and left her with left-sided dystonia of the upper and lower body, abdomen, and chest wall, together with left-sided migraines, which she reported as new. Several times a year, she would awaken every night with left-sided cluster headache episodes, with facial allodynia, tearing, eyelid drooping, and increased dystonia and neck spasm; these occurred primarily in the winter season, with several up to six episodes in per night for a period of three to six weeks.

IV ketamine relieved most of her dystonic, cluster headache, and migraine symptoms, when complemented by IV and oral baclofen and tizanidine, as well as rescue opioids. Nasal spray ketamine was compounded, as well as buccal troches; both allowed her to continue working full-time in her hair salon. She reported no side effects while using the nasal spray ketamine. Liver function tests conducted every three to six months were unremarkable.

Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. (Source: 123RF)

Case 3

A 55-year-old woman with episodic cluster headache and migraine (3 to 4 attacks per week) also experienced chronic neck pain and had diagnosed TN on the right side. Her cluster headache attacks started at age 27, with tearing, allodynia, and facial numbness. On occasion, her migraine would evolve into a cluster episode that came on during sleep and was seasonal as well, lasting about 2 months on average. She was not a smoker and had no family history of cluster headache but did have a family history of migraine.

She was treated successfully for migraine, right TN, and neck pain with botulinum toxin-A injections (Botox) every 3 to 5 months, supplemented by prophylactic neuropathically active medications, but no opioids. The Botox did not affect her cluster headache, except when they evolved from a migraine, and only to a slight extent (15 to 20%). Multiple acute and prophylactic therapies were attempted to resolve the cluster headache episodes to no significant avail.

IV ketamine was tried on one occasion over a period of 4 days during a cluster headache episode. As a result, the attacks were reduced from 5 per day to 1 per day, and only 1 cluster attack the following week, which was resolved with additional oral oxcarbazepine (600 mg).

The patient agreed to trial nasal spray ketamine which was compounded at 10 mg per 0.1 cc spray with the suggestion that she spray the right nostril every 10 to 15 minutes upon attack to give the medicine time to absorb from the nasal mucosa and to repeat the process until at least 75% relief was obtained. She reported being happy with this approach as it gave her control of her hardest-to-treat symptom. She also reported that her cluster episodes became less frequent over about 1 year and that her migraine and TN also improved; her Botox injection intervals grew longer over time.

Case 4

A 70-old-male, with a 40-plus year history of right-sided cluster attacks with eyelid drooping, tearing, allodynia, neck pain, and other symptoms was treated for these symptoms for many years. Opioids provided him with partial relief, at best. He had a chronic cluster headache that typically awoke him from a sound sleep at 1 or 2 am. These episodes were especially bad in the winter and during weather changes. He had a history of facial and other traumas before the headaches started, including a car accident, but no family history of cluster headache. He also had occasional migraine, about three per month, as well as chronic neck and back pain. He was treated with IV medications, including ketamine, up to 200 mg over 5 hours, with relief of his symptoms in the clinic.

He agreed to trial a compounded nasal spray of ketamine [12.5 mg per 0.1 cc] to use at each bedtime. Two sprays were indicated before each bedtime and at the first onset of any cluster headache at night. Sprays were repeated every 10 minutes until 50 to 65% relief was achieved. He took tizanidine before bedtime for neck spasm and sleep. The patient would, on occasion, repeat one or two ketamine sprays in the morning or during the day if he felt the next cluster attack coming on. As he was on frequent IV and nasal spray ketamine, his liver functions tests were routinely monitored over the course of several years; there was no observed impact.

Case 5

A 34-year-old male who worked in construction began having episodic cluster headache episodes at age 22. He had a family history of migraine and cluster headache. His attacks were season-specific, occurring mostly in the early summer of each or every other year. He described the attacks as very disabling and often awoke from a sound sleep for several weeks at a time as a result of them. He had tried several oral medications, including opioids, for suppression of symptoms without any real benefit and many side effects. When he first presented to the clinic, he trialed IV lidocaine, IV valproate sodium, and IV magnesium sulfate with only partial success in shutting down the episode.

IV ketamine was also offered at the beginning of one of his episodes, and it proved to work more effectively than other treatments. Specifically, the patient’s cluster episode duration was reduced by more than two-thirds (6 to 7 weeks to 7 to 10 days). Based on this result, he was prescribed compounded nasal spray ketamine (7.5 mg per 0.1cc spray) and instructed to use the spray once at bedtime, with additional sprays in one nostril (the affected side of the cluster headache) every 10 minutes until relief was obtained to at least 75%. The patient was also instructed to use the same approach during the day if the cluster headache returned. He used nasal spray ketamine for several years and his overall pattern became easier to treat successfully. His episodes grew further apart and he has reported only one short cluster headache episode in the past four years.

She got extinction of the cluster episode or at least 75% reductions in the cluster headache severity with up to 4-5 nasal sprays of ketamine at the dose described above, and has also noticed a shortening and diminution of the cluster headache episodes as time has gone by.

Case 6

A 51-year-old male, with a family history of cluster headache began having episodic attacks at age 18 with strong occurrences in the spring. He was a smoker. He had tried a calcium channel blocker, lithium, and other medications to little or no avail over the years. He found that triptans taken early in the course of a cluster attack, at several doses, would sometimes abort or lighten the burden of that particular cluster series.

A 3-day course of IV ketamine at the onset of one of his episodes nearly eradicated the episode, and since he lived a great distance (6 hours each way) from the clinic, he wanted to try the nasal spray form of ketamine for at-home application. He reported that a daily dose of 1500 mg of Depakote-ER often softened the arrival of his next cluster headache episode, as did prescribed triptans. However, he did not experience an end to the attack until IV ketamine had been administered.

15 mg per 0.1cc of nasal spray ketamine were compounded for this patient. He reported some nasal burning with the nasal ketamine formulation, so was advised by his pharmacist to use one drop of 2% lidocaine and orange oil as part of the prescription. This addition alleviated the side effect. The patient has successfully used this approach for many years to date. He requires 5 to 6 nasal sprays of ketamine per day, and his episodic cluster headache pattern has markedly softened and shortened in the past few years. He has reduced his dosage of Depakote-ER to 1 or 2 per day as well and attempted to stop smoking several times.

Discussion and Recommendation

The specificity of the ketamine speaks to a unique mechanism of action primarily through the blockade of the NMDA-glutamate and other close-related receptors. This treatment approach may provide insight into the distinctive involvement of this receptor family in the generation and maintenance of this and perhaps other, more rare trigeminal autonomic cephalalgias, or TACs.21

Based on this anecdotal evidence, observed retrospectively in the author’s outpatient clinic over a period of 20 years, intranasal ketamine seems to offer a legitimate, safe pharmacologic treatment for cluster headache rescue. The medication adds a new dimension to managing out-of-control cluster headache and mixed headache/pain disorders in an outpatient setting with no monitoring. Double-blind, placebo-controlled studies are needed to confirm these primarily open-label observations. It should be noted that a small number of patients (5) were given sham nasal treatment and their cluster headache did not respond.

The author found sub-anesthetic doses of intranasal ketamine to be very useful in the control of episodic and chronic cluster headache attacks, as well as in managing certain trigeminal neuralgia symptoms. On a 0 to 10 visual analog scale, pain scores were below 60 to 65% from initial baseline pain score after the use of the intranasal ketamine spray. Efficacy, as well as safety, and tolerability, of low dose IV ketamine were seen consistently in the outpatient clinic, without significant adverse effects. In the author’s opinion, therefore, ketamine may be considered when treating this clinically disabling condition. When used under controlled conditions, ketamine in a nasal spray form may offer a safe and more effective option to patients than emergency room visits and may also serve as a substitute for more standard IV-based rescue cluster headache medications.

About Cluster Headache:Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. A series of cluster headaches can take place over several weeks to months, and may occur once or twice per year. Several of the following related symptoms may occur: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration may present as well. Attacks usually recur on the same side of the head. Cluster headaches afflict males more than females by a 2.5 to 1 ratio and have an overall prevalence of 0.4%. Onset of clusters is usually between ages 20 and 45. There is often no family history of cluster headache.

  1. Robert K, Simon C. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2005
  2. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Phamacol. 2014;77(2):357–367.
  3. Virginia Scott-Krusz, Jeanne Belanger, RN, Jane Cagle, LVN, Krusz, JC, Effectiveness of IV therapy in the headache clinic for refractory migraine, poster at 9th EFNS meeting Athens, Greece. 2005.
  4. Krusz, JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic. Curr Pain Headache Rep. 2006;10(1):47-53.
  5. Krusz JC, Cagle J, Belanger J, Scott-Krusz, V. Effectiveness of IV therapy for pain in the clinic, Poster P183 presented at 2nd International Congress on Neuropathic Pain Berlin, Germany. 2007
  6. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  7. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine in treating refractory migraines in the clinic (poster 218). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  8. Krusz JC, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic (poster 219). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  9. Krusz JC. IV ketamine in the clinic to treat Cluster Headache (poster abstract). American Academy of Neurology. Neurol. 2009;72(11):A89-90.
  10. Krusz JC, Cagle J, Scott-Krusz VB. Ketamine for treating multiple types of headaches (poster). 14th Congress International Headache Society. Cephalalgia. 2009;29(Suppl 1)163.
  11. Krusz JC. Difficult Migraine Patient. Pract Pain Manage. 2011;11(4):16.
  12. Krusz JC, Cagle J. IV Ketamine: Rapid Treatment for All TAC Subtypes in the Clinic, Abstract Poster #72, 15th Congress of the International Headache Society, Berlin, Germany, 2011.
  13. Krusz JC, Cagle J. IM ketamine for intractable headaches and migraines (poster abstract). American Headache Society Annual Meeting, Los Angeles, CA, 2012.
  14. Krusz JC. Traumatic Brain Injury: Treatment of Post-traumatic Headaches. Pract Pain Manage. 2013;13(5):57-68.
  15. Krusz JC, Cagle J, Belanger J, Scott-Krusz V. Effectiveness of IV therapy for pain in the clinic, Poster P183. European J Pain:11, Suppl 1, pS80, presented at 2nd Int’l Congress on Neuropathic Pain, Berlin, Germany. 2007.
  16. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain, 9: Suppl 2, P30, 27th Annual Scientific. American Pain Society. 2008.
  17. Krusz JC. Ketamine IV in an outpatient setting: effective treatment for neuropathic pain syndromes (poster #378). 32nd Annual Scientific Meeting, American Pain Society, New Orleans, 2013.
  18. Krusz JC. Ketamine IV – for CRPS, TN/TMD and other neuropathic pain in the outpatient clinic (poster #524). 4th International Congress on Neuropathic Pain, Toronto, Ontario, 2013.
  19. Krusz JC. The IV ketamine experience: treatment of migraines, headaches and TAC. JAMA Neurol. 2018
  20. Matharu MS, Goadsby PJ. Trigeminal Autonomic Cephalalgias: Diagnosis and Management. In: Silberstein SD, Lipton RB, Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed. New York, NY: Oxford Univ Press; 2008:379-430.
  21. Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 ;20:54-63. 

The Path from Episodic to Chronic Migraine

Although episodic migraine and chronic migraine are common, they represent distinct types of headaches on the migraine pain spectrum.1 Factors involved in the transformation from episodic to chronic migraine include frequency of episodes, failure to optimize acute treatment, overuse of acute migraine medication, lower socioeconomic status, obesity, and being female.1,2 The most common technique for managing these headache conditions is pharmacologic, however, medication overuse is also the most common reason that episodic migraine may evolve into chronic migraine, often resulting in medicine overuse headache (MOH).

According to Lipton, et al,3 patients have reported that their acute treatment of episodic migraine was poorly managed as measured by the Migraine Treatment Optimization Questionnaire, with 6.8% of patients developing chronic migraine within one year compared to 1.9% of patients reporting optimized acute treatment. These results suggested the need for more effective acute treatment strategies to manage symptoms associated with episodic and chronic type migraine. In response, several studies have since shown a potential alternative treatment involving the sphenopalatine ganglion (SPG) to be effective in reducing episodes of chronic migraine (see Figure 1).

Figure 1. The sphenopalatine ganglion (SPG). (Image courtesy of authors).

The SPG is the largest neurological ganglion outside the brain, located within the pterygopalatine fossa at the posterior attachment of the middle turbinate. This ganglion has sensory, parasympathetic, and sympathetic components that house the trigeminal nerve, branches of the palatine nerves, and various sympathetic and parasympathetic automatic branches all of which innervate the cranial cavities (eg, nose, mouth) as well as facial areas, and the nasal and pharyngeal glands.4 Based on the SPG’s anatomy and physiology, it has become evident that many associated symptoms of chronic migraine may be managed by targeting the SPG using alternative methods that aim to decrease activity in this region.

Migraine may be related, at least in part, to a hyper-excited SPG. Stimulation of the SPG has been shown to induce a pathophysiological response seen in migraine attacks, including vasodilation of intra- and extra-cranial arteries, release of substance P and neurokinin A, as well as activation of meningeal nociceptors, which may be contributing to the pain.4

Treatment Alternatives
Neurological Blockage of the SPG

Alternative treatments targeting the SPG have been developed as a means of lessening the symptoms associated with migraine. One trialed approach is a neurological blockade at the SPG with bupivacaine using a nasal applicator5,6 and topical lidocaine applied with a deep nasal anesthetic applicator (DNAA).7 Cady, et al, published two studies utilizing the device to deliver bupivacaine to the mucosa of the SPG. The first, primarily a safety study, was designed to determine acute effects. The researchers reported the bupivacaine treatment group (n = 26) decreased from pre-treatment 3.18 ± 2.79 to post-treatment at 15 minutes 2.53 ± 2.61, 30 minutes 2.41 ± 2.61, and 24 hours 2.85 ± 2.74.5

The second study was designed to determine the long-term effects of bupivacaine by delivering a set of 12 treatments over a period of six weeks. Results demonstrated that the bupivacaine treatment group (n = 25) had a significant decrease in the number of headaches in a month from 23.15 ± 5.12 to 17.44 ± 9.08 compared to 24.75 ± 4.35 to 22.82 ± 5.36 in a sham group, which was administered saline. Additionally, the average pain scores reported by the subjects in the prior 24 hours decreased from pre-treatment of 4.92 ± 2.2 to 2.86 ± 2.62 at six months after the last bupivacaine treatment.6

Lee, et al, reported 59 out of 66 cases treated with 26% lidocaine applied with DNAA had an average decrease of 4.9 pain points and 4.2 points at 15 minutes and 60 minutes post-application, respectively.7 The treatment provided rapid relief of the headache pain and decreased activity of the SPG, thereby reducing the pain associated with the migraine.5-7

Similarly, an inhibitory dose of photobiomodulation (PBM) appears to have a similar efficacy in decreasing SPG activity and may reduce migraine pain and frequency by inhibiting nerve conduction of type C pain fibers.8,9

Moving away from pharmacologic methods to treating migraine. (Source: 123RF)

Photobiomodulation

Adopted by the North American Association of Photobiomodulation Therapy, photobiomodulation refers to light therapy treatments that utilize non-ionizing light sources in the visible and infrared spectrum.8 PBM is a non-thermal process that involves endogenous chromophores which elicit photophysical and photochemical events. These events theoretically lead to beneficial therapeutic outcomes, including the alleviation of pain or inflammation and immunomodulation, as well as the promotion of wound healing and tissue regeneration.8 More specifically, PBM emits photons of light that penetrate the skin and stimulate endogenous light receptors, which result in a physiological response. Low doses of PBM stimulate tissue healing and increase blood flow9 while higher doses tend to have an inhibitory effect, which may be used therapeutically to decrease pain.9

For example, low doses of light that are delivered to the tissue stimulate the cytochrome C oxidase (CCO) within the mitochondria, resulting in an increase in adenosine triphosphate (ATP) and a release of nitric oxide (NO) and reactive oxygen species (ROS).9 The ATP provides an increase in energy availability within the cells. When NO is released from CCO and from blood vessels, the result is an increase in ATP production and vasodilation. When ROS is in low concentrations, it activates the transcription factors, which lead to cell proliferation and growth.9

The authors trialed PBM on three patients (ages 42, 53, and 72) with a history of chronic migraine. Each patient had suffered from two to five migraine attacks per week for at least the prior 10 years (see Table I). Each was successfully treated using a PBM protocol to the SPG.

Initial reported pain levels ranged from 8 to 10 out of a 10-point pain scale. All three patients completed daily activities with difficulties due to frequent and painful symptoms. All patients had previously attempted pharmacological methods of treatment with little to no relief, or with additional side effects from MOH that hindered daily functioning.

Each PBM treatment consisted of applying a laser puncture utility probe attached to a PBM-transducer (Multi Radiance Medical) that delivered the photons to the SPG. The probe was placed just inside each nostril pointing toward the posterior nasal cavity where the SPG is located (see Figure 2). The treatment frequency and number of overall treatments were tailored to each patient’s responsiveness.

Figure 2. Inhibitory photobiomodulation treatment to the sphenopalatine ganglion with probe (image courtesy of authors).

Each treatment lasted 180 seconds per nostril (23.9 joules, 0.0382 watts, 6.87J/chronic). The device characteristics were as follows: wavelength super pulsed laser 905 nm; infrared 875 nm; Red 670 nm; total power, 25W, SPL variable frequency: 1000 Hz and beam spot size 0.4. The patients were evaluated for migraine frequency and intensity both pre- and post-treatment, and throughout the duration of the treatment.

Patient 1: This 42-year old male developed a chronic migraine condition following a traumatic head injury, resulting in a skull fracture. His regimen encompassed three PBM treatments over a 4-week period. After the first treatment, the patient experienced no migraine for 2 weeks. His reported migraine pain decreased from 8 out of 10 to a 0 out of 10 after each treatment. After the full course, the patient reported no migraine for another 2 weeks and self-discharged from our care (follow-up was not possible).

Patient 2: A 53-year-old female was scheduled to receive a course of six PBM treatments over 21 days. The patient reported reduced frequency and intensity of migraine with aura after the first six treatments. This patient did not miss any work during the treatment period. It is worth noting that prior to starting the PBM treatments, Patient 2 had missed work due to pain intensity of her migraine and what she reported as mental dullness as a result of the medication used to control her migraine symptoms. Due to the decrease in frequency and intensity of her migraine attacks, PBM treatments were reduced to one per week for 4 weeks. Patient 2 was migraine-free at discharge after 8 weeks of total treatment. At 90-day follow-up, the patient reported that she had not experienced a post-treatment migraine.

Patient 3: A 72-year-old female underwent a course of eight PBM treatments over 4 weeks (two applications per week). Patient 3 reported that she was migraine free for 10 days after the month-long treatment was completed. She was prescribed a second round of treatments, which were then reduced to weekly for another 4 weeks. The patient reported being migraine-free during the continued treatment period. There was no 90-day follow-up for this patient.

Discussion and Steps Forward

Two of the main factors that may cause episodic migraine attacks to become chronic are medication overuse and improper care for acute attacks.1-3 As demonstrated in the three cases herein, PBM treatments to the SPG were shown to be effective in decreasing pain ratings from 8 out of 10 to 0 out of 10 after each treatment. If PBM could be used effectively to treat episodic migraine, patients may not overuse medications, which may ultimately prevent the transition of episodic to chronic migraine.

Overall, the PBM treatments described herein were deemed successful in treating chronic migraine (see Table I for details). Patient 1 started with two migraine attacks per week and decreased his episodes to zero attacks per week after a course of three treatments over 4 weeks. Patient 2 reduced her migraine frequency from two to three per week to zero after 10 treatments over 12 weeks. Patient 3, who had previously experienced three to five migraine attacks per week for 59 years, reduced her attack frequency to zero migraine attacks per week after 12 treatments over 8 weeks. None of the patients reported any side effects and tolerated the treatments well.

Similar to neurologic blocks of the sphenopalatine ganglion, the response to PBM is bi-phasic, stimulatory or inhibitory, and dose dependent.9 There has been strong evidence supporting PBM inhibition of acute, chronic, and neurological pain.10 As noted, light may reduce the formation of inflammatory proteins associated with pain including prostaglandin, cox 2 mRNA, and TNF α.10 Additionally, PBM works to inhibit nerve conduction along the AΔ and C nerve fibers, which are the main nerve fiber types that conduct pain.10

It appears that the SPG and associated nerves are hyperactive during migraine attacks, as suggested by Khan, et al.4 An inhibitory dose of PBM seems to restore the SPG and associated nerves back to their normal physiological levels. A similar occurrence was reported by Cady, et al,5-6 and Lee, et al,7 after treating migraine (with bupivacaine and lidocaine, respectively) applied to the posterior nasal cavity directed at the SPG. There is some evidence that the SPG may also be associated with refractory chronic post-traumatic headaches.10 For example, Sussman, et al, successfully treated a post-concussion headache utilizing intranasal lidocaine application to the SPG.11

In this case presentation, use of PBM treatment reduced migraine frequency to zero episodes per week in patients with a 10-year or greater history of migraine for whom medication failed to manage symptoms effectively. Due to a decrease in pain and episode occurrence, all three patients were able to improve their daily function following completion of individualized PBM treatment regimen to block the SPG. With a growing demand for non-pharmacological treatments for migraine pain, photobiomodulation may be a noninvasive therapeutic option for chronic migraine. To demonstrate the efficacy of this treatment protocol, large randomized control trials should be completed to confirm validity and long-term effects.

Ketamine Infusion Center Northern Virginia | 703-844-0184 | NOVA Health Recovery | Alexandria, Va 22308 | Listening to Ketamine | Esketamine Spravato Nasal Spray center | Ketamine Center in Fairfax and Arlington, Virginia

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

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.

Listening to ketamine

The fast-acting drug offers a new way to treat depression and fathom its origins. Recent approval of a nasal spray promises to expand access, but much remains unknown about long-term use and the potential for abuse.

t 32, Raquel Bennett was looking for a reason to live. She’d struggled with severe depression for more than a decade, trying multiple antidepressants and years of talk therapy. The treatment helped, but not enough to make it seem worth living with a debilitating mental illness, she says. “I was desperate.”

In 2002, following a friend’s suggestion, Bennett received an injection of ketamine, an anesthetic and psychedelic party drug also known as Special K. During her first ketamine trip, Bennett hallucinated that God inserted a giant golden key into her ear, turning on her brain. “It was as if I was living in a dark house and suddenly the lights came on,” she says. “Suddenly everything seemed illuminated.”

The drug lifted Bennett’s depression and dispelled her thoughts of suicide within minutes. The effect lasted for several months, and, she says, the respite saved her life. She was fascinated by the drug’s rapid effects and went on to earn a doctoral degree in psychology, writing her dissertation about ketamine. Today, she works at a clinic in Berkeley, California, that specializes in using ketamine to treat depression. “This medicine works differently and better than any other medication I’ve tried,” she says.

When Bennett experimented with ketamine, the notion of using a psychedelic rave drug for depression was still decidedly fringe. Since the first clinical trials in the early 2000s, however, dozens of studies have shown that a low dose of ketamine delivered via IV can relieve the symptoms of depression, including thoughts of suicide, within hours.

Even a low dose can have intense side effects, such as the sensation of being outside one’s body, vivid hallucinations, confusion and nausea. The antidepressant effects of ketamine typically don’t last more than a week or two. But the drug appears to work where no others have — in the roughly 30 percent of people with major depression who, like Bennett, don’t respond to other treatments. It also works fast, a major advantage for suicidal patients who can’t wait weeks for traditional antidepressants to kick in.

Infographic shows the relatively small percentage of people who suffer from depression who may be helped by ketamine, according to clinical studies. Of the 17 million people in the US estimated to suffer from depression, only 10 million receive treatment. Half of those are helped by that treatment, with only about a third experiencing full recovery. Treatment-resistant patients have severe disease and don’t respond to current medications. Studies suggest that about 60 percent of this group may find relief with ketamine.

“When you prescribe Prozac, you have to convince people that it’s worth taking a medication for several weeks,” says John Krystal, a psychiatrist and neuroscientist at Yale University in New Haven, Connecticut. “With ketamine, patients may feel better that day, or by the next morning.”

The buzz around ketamine can drown out just how little is known about the drug. In the April 2017 JAMA Psychiatry, the American Psychiatric Association published an analysis of the evidence for ketamine treatment noting that there are few published data on the safety of repeated use, although studies of ketamine abusers — who typically use much higher doses — show that the drug can cause memory loss and bladder damage. Most clinical trials of the low dose used for depression have looked at only a single dose, following up on patients for just a week or two, so scientists don’t know if it’s safe to take the drug repeatedly over long periods. But that’s exactly what might be necessary to keep depression at bay.

The analysis also warned about ketamine’s well-established potential for abuse. Used recreationally, large doses of the drug are known to be addictive — there’s some evidence that ketamine can bind to opioid receptors, raising alarms that even low doses could lead to dependence.

Bennett has now been receiving regular ketamine injections for 17 years, with few negative side effects, she says. She doesn’t consider herself addicted to ketamine because she feels no desire to take it between scheduled appointments. But she does feel dependent on the drug, in the same way that a person with high blood pressure takes medication for hypertension, she says.

Still, she acknowledges what most clinicians and researchers contend: There simply aren’t enough data to know what the optimal dose for depression is, who is most likely to benefit from ketamine treatment and what long-term treatment should look like. “There’s a lot that we don’t know about how to use this tool,” Bennett says. “What’s the best dose? What’s the best route of administration? How frequently do you give ketamine treatment? What does maintenance look like? Is it OK to use this in an ongoing way?”

Despite the unknowns, pharmaceutical companies have been racing to bring the first ketamine-based antidepressant to market. In March, the US Food and Drug Administration approved a ketamine-derived nasal spray, esketamine, developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. Only two of Janssen’s five phase III trials had shown a benefit greater than taking a placebo. Still, in February an independent panel recommended FDA approval. That makes ketamine the first novel depression drug to hit the market in more than 50 years, notes Carlos Zarate Jr, a psychiatrist who studies mood disorder therapies at the National Institute of Mental Health.

Photo shows the mechanized assembly line at Janssen Pharmaceutical as bottles of Spravato, the esketamine nasal spray are manufactured.
Although clinicians are hopeful that Janssen Pharmaceutical’s newly approved esketamine nasal spray, Spravato, will expand access to treatment, many also worry about the drug’s potential for abuse.CREDIT: JANSSEN PHARMACEUTICALS, INC.

Thousands of people are already flocking to private clinics like Bennett’s, which provide intravenous ketamine infusions. Because the drug was approved in the 1970s as an anesthetic, physicians can legally provide the drug as an “off-label” depression treatment. Many ketamine clinics have long waiting lists or are so swamped that they aren’t accepting new patients, and Janssen’s nasal spray could rapidly expand access to treatment.

But some researchers worry that the nasal spray won’t solve many of ketamine’s problems and could create new ones. Although the FDA is requiring that the nasal spray be administered only in a certified doctor’s office or clinic, esketamine is “every bit as habit forming as regular ketamine,” and will be difficult to keep out of the hands of abusers, says Scott Thompson, a neuroscientist at the University of Maryland and a coauthor with Zarate of a 2019 review on fast-acting antidepressants in the Annual Review of Pharmacology and Toxicology. A nasal spray can’t deliver as precise a dose as an IV infusion, Thompson notes. “If someone has got a cold, they’re not going to get the same dose.”

Scott Thompson of the University of Maryland discusses how ketamine is changing the landscape of the psychiatric treatment of severe depression.

CREDIT: VIDEO PRODUCED BY HUNNI MEDIA FOR KNOWABLE

In Thompson’s view, esketamine holds few advantages over generic ketamine, which costs less than a dollar per dose, although the IV infusions in private clinics often cost hundreds of dollars per visit. Janssen has indicated that each esketamine treatment will range from $590 to $885, not including the costs of administration and observation.

Zarate and others are still thrilled to see big pharma investing in ketamine, after decades of stalled efforts to find new psychiatric drugs. “As esketamine hits the market, venture capitalists will come up with better versions and move the field forward,” Zarate says. Several drug companies are now testing other ketamine-like compounds in hopes of developing drugs that have its potent antidepressant potential without its psychedelic and dissociative side effects.

Illustration shows a high-tech version of a neural network, with signals represented as lights. Depression, many now think, is caused by problems in the neural circuitry.

Depression, fast and slow

In 2001, writer Andrew Solomon published a haunting description of the depression that derailed his early 30s: “If one imagines a soul of iron that weathers with grief and rusts with mild depression, then major depression is the startling collapse of a whole structure,” he wrote.

When Solomon first fell ill, in the 1990s, many clinicians and researchers presumed that the pathological brain changes underlying depression were inherently slow to repair. This mind-set was rooted in the modest but controversial success of a class of slow-acting drugs that includes Prozac.

Developed in the 1950s, the drugs were first inspired by the chance observation that a hypertension drug called reserpine – an extract of the plant Rauwolfia serpentina, or devil pepper — made people intensely depressed. After discovering that reserpine depletes monoamine neurotransmitters in the brain, including serotonin and norepinephrine, scientists hypothesized that low neurotransmitter levels causedepression. They went on to develop monoaminergic antidepressants, drugs designed to increase circulating levels of these chemicals in the brain.

Today, monoaminergic antidepressants include selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Lexapro and Zoloft, as well as the older and less commonly prescribed monoamine oxidase inhibitors (MAOIs) and tricyclic and tetracyclic antidepressants. Scientists have long debated whether the drugs work at all, but the most comprehensive study to date — published in The Lancet in 2018 — suggests that they do lower depression symptoms in about 60 percent of depressed people, albeit only modestly more than taking a placebo.

The benefits start to show up only after several weeks of treatment, however, and roughly a third of people with major depression disorder – called treatment-resistant patients — don’t respond to at least two types of monoaminergic antidepressant.

By the early 2000s, the monoamine hypothesis had unraveled. This was partly due to the antidepressants’ mediocre performance in patients, and partly to experiments which showed that depleting neurotransmitter levels in healthy people does not make people depressed. Scientists now believe that drugs like Prozac do not directly treat depression’s root cause. Instead, they think the drugs work via an indirect mechanism to subtly boost the growth of synapses and the birth of new neurons, and that this somehow relieves symptoms.

Solomon’s bleak metaphor of corrosion was at least partly grounded in science. Many scientists now agree that depression slowly eats away at the neural pathways underlying our sense of worth and well-being, our desire to go to the movies or get out of bed. But research into ketamine holds out new hope that — unlike rusted iron — the depressed brain can be restored, by repairing and strengthening the neural circuits that regulate mood. —Emily Underwood

Some researchers are also testing whether ketamine works for conditions beyond depression, such as obsessive-compulsive disorder, as well as in specific subsets of patients, such as severely depressed teenagers. Other scientists are using ketamine to help untangle one of the biggest mysteries in neuroscience: What causes depression? (See sidebar.)

Seeking answers in neural wiring

Thirty years ago, the prevailing thought was that low levels of certain brain chemicals, such as serotonin, caused depression. Boosting those could remove symptoms.

“I felt that depression needed months or weeks of treatment — that the plastic changes involved in the healing process would require weeks to reset themselves,” says Todd Gould, a neuropharmacologist at the University of Maryland and a coauthor of the recent review paper. But ketamine’s speed of action casts doubt on that idea.

Newer evidence suggests that depression is caused by problems in the neural circuits that regulate mood, Gould notes. Much of the evidence for this faulty-wiring hypothesis comes from rodents. Starting in the 1990s, scientists began to discover intriguing abnormalities in the brains of mice and rats that had been exposed to certain stressors, such as bullying by a big, aggressive male.

Stress and trauma are strong predictors of depression in people, but scientists can’t ask rats or mice if they are depressed. Instead, they use behavioral tests for classic depression symptoms such as anhedonia, the inability to take joy in pleasurable activities, Thompson says. Depressed animals “give up easily” in experiments that test their willingness to work for rewards like sugar water, or their interest in the intoxicating scent of a potential mate’s urine. “They can’t be bothered to cross the cage,” he says.

Thompson and others have found that there are fewer connections, or synapses, between neurons that communicate reward signals in the brain in depressed animals. Other labs have found shriveled connections in neuronal circuits key to decision-making, attention and memory. Brain imaging studies in people with depression have also revealed abnormal activity in neural circuits that regulate emotion, suggesting that the findings in rodents may also apply to humans.

If faulty neural connections are to blame for depression, the next question is, “How do we get atrophied neural pathways to regrow?” Krystal says.

Circuit training

The answer, many scientists now believe, is the brain’s most abundant neurotransmitter, glutamate.

Glutamate is the workhorse of the brain. It relays fleeting thoughts and feelings, and enables the formation of memories by strengthening synaptic connections. Glutamate is the reason you can still ride a bike years after you learned, even if you never practiced.

Not all glutamate activity is good. Too much can cause the equivalent of an electrical storm in the brain — a seizure — and chronically high levels may lead to dementia. Abnormalities in glutamate receptors — specialized proteins on the surface of brain cells where glutamate can dock and bind — are linked to a wide array of psychiatric diseases, including depression and schizophrenia.

To maintain balance, cells called inhibitory interneurons act like brakes, releasing a neurotransmitter called GABA that quiets brain activity. Most mind-altering drugs work by changing the balance between GABA and glutamate — amphetamines and PCP enhance glutamate signaling, for example, while alcohol inhibits glutamate and boosts GABA.

By the 1990s, scientists had discovered that ketamine triggers a gush of glutamate in the brain’s prefrontal cortex. This region governs attention and plays an important role in emotional regulation. The out-of-body sensations that some people experience when they take ketamine may occur because this rapid release of glutamate “excites the heck out of a whole bunch of neurons” in the prefrontal cortex, says Bita Moghaddam, a neuroscientist at Oregon Health & Science University who discovered the drug’s glutamate-revving effect on rats while studying schizophrenia.

Scientists aren’t sure yet how ketamine forms stronger neural circuits. But the hypothesis goes roughly like this: When ketamine enters the brain, it causes a short-term burst of neuronal activity that triggers a series of biochemical reactions that create stronger, more plentiful synaptic connections between brain cells.

At first, many researchers thought ketamine’s antidepressant effects relied on a structure located on the surface of neurons, called the NMDA receptor. Like a key that fits into different locks, ketamine can bind to several types of NMDA receptor, making neurons release the excitatory glutamate neurotransmitter.

This hypothesis suffered a blow, however, when several drugs designed to bind to the NMDA receptor (as ketamine does) failed in clinical trials for depression.

A space-filling ribbon model shows the 3-D structure of the NMDA receptor, which binds glutamate in the brain and is thought to play a key role in the symptoms of depression.
Central to the controversy over how ketamine works in the brain is the NMDA receptor (illustrated here), which binds to the neurotransmitter glutamate. Some scientists believe ketamine’s antidepressant effects hinge on its ability to block NMDA receptors, but others believe the drug works via other mechanisms. Resolving that mystery is key to developing similar drugs with fewer side effects, scientists say.CREDIT: FURUKAWA LAB, CSHL

Esketamine also complicates the story. Ketamine is made up of two molecules that form mirror images of each other, R- and S-ketamine. Esketamine is made up of just the S form and binds roughly four times as effectively as R-ketamine to the NMDA receptor. Despite acting much more powerfully on the NMDA receptor, studies in rodents suggest that S-ketamine is a less potent antidepressant than R-ketamine, although it’s not yet clear whether or not R-ketamine could work better in humans.

Zarate and others now believe ketamine may work through a different receptor that binds glutamate, called AMPA. By pinpointing which receptor ketamine acts on, researchers hope to develop a similar drug with fewer side effects. One hot lead is a compound called hydroxynorketamine (HNK) — a metabolic byproduct of ketamine that does not affect NMDA receptors but still produces rapid antidepressant effects in rodents. The drug appears to lack ketamine’s disorienting side effects, and Zarate and Gould plan to launch the first small clinical trials to establish HNK’s safety in humans this year, likely in around 70 people. “I think we have a very good drug candidate,” Gould says. (Zarate and Gould, among others, have disclosed that they are listed on patents for HNK, so they stand to share in any future royalties received by their employers.)

Plastic synaptic remodelers

To alter how the brain processes mood, scientists believe ketamine must ultimately change synapses. In experiments in rodents, Ron Duman of Yale University has shown that both ketamine and HNK can harness one of the brain’s most important tools for synaptic remodeling: brain-derived neurotrophic factor, or BDNF.

BDNF is a protein intimately involved in shaping synapses during brain development and throughout the lifespan. Healthy brain function depends on having just the right amount of BDNF in the right place at the right time. Many mental illnesses, including depression, are associated with low or abnormal amounts of the protein. For example, samples of brain tissue from people who have died by suicide often contain abnormally low amounts of BDNF.

Duman and colleagues have found that both ketamine and HNK cause a sharp uptick in the amount of BDNF that is released from neurons. This increase is required for the drugs’ antidepressant effects, and for the increase in dendritic spines — the stubby protrusions that form synaptic connections with other neurons. Both ketamine and HNK also seem to reduce inflammation, which has been linked repeatedly to the stress-induced loss of synapses.

A micrograph of a portion of a rat neuron, in false colors, shows how ketamine coaxes the budding of new dendritic spines from the neuron. In a control, two dendritic spines are visible. In the ketamine-treated neuron, six dendritic spines are visible
Ketamine strengthens connections between brain cells. Compared with a control, a rat neuron (red) treated with ketamine has grown more dendritic spines (shown by yellow arrows).CREDIT: R.J. LIU, G. AGHAJANIAN & R. DUMAN

Ketamine is not the only compound that can induce rapid synaptic plasticity: Other psychedelics, such as ecstasy (MDMA), acid (LSD), and DMT also trigger similar structural changes in neurons and rapid antidepressant effects in rodents, researchers at the University of California at Davis recently found. The effects don’t hinge on getting high, the team reported in March in ACS Chemical Neuroscience. Even very small doses — too low to cause perceptual distortions — can increase synapse density and lift depression.

Traditional antidepressants such as Prozac also increase BDNF levels in the brain, but not nearly as fast as ketamine does, Duman says. That is why most antidepressants take so long to remodel synapses and relieve depression symptoms, he says.

Dissecting depression

Beyond promising new treatments, Zarate and other researchers see ketamine as a powerful tool for probing depression’s tangled neurobiology. Studies in mice and rats are a good start, but scientists need to study the drug in people to truly understand how ketamine affects the brain. Unlike traditional, slower-acting antidepressants, ketamine lends itself to short-term lab experiments.

Zarate is using neuroimaging tools such as fMRI to study the human brain on ketamine. Past studies have shown that in people with depression, communication among several key brain networks is disrupted. One network, called the default-mode network (DMN), is involved in self-referential thoughts such as ruminating about one’s problems or flaws. This network tends to be hyperactive in people with depression, and less connected to more outwardly attuned brain networks such as the salience network, which helps the brain notice and respond to its surroundings.

Before and after images show averaged brain activity of people with treatment-resistant major depression while their index finger is stroked. Before an infusion of ketamine, the patients show some activity in the front of the brain. After ketamine, the activity is more widespread and the intense, as shown in false colors on the image of the brain, and representing enhanced cortical excitability.
Ketamine appears to strengthen connections between neural networks in people with severe depression. In a study comparing neural activity prior to a ketamine infusion (left) and six to nine hours after an infusion (right), a single dose made the brain more responsive to a simple sensory stimulus, the light stroking of a finger.

In one recent study, Zarate and his colleagues found that after receiving an IV dose of ketamine, people with depression had more normal activity in the default mode network, and that it was better connected to the salience network. At least temporarily, the drug seems to help people get unstuck from patterns of brain activity associated with repetitive, negative thoughts. Zarate does caution that the study results need to be replicated.

The team has also used brain imaging to study how ketamine affects suicidal thoughts. About four hours after an infusion of ketamine, a chunk of the prefrontal cortex that is hyperactive in people with depression had calmed down, researchers found, which correlated with people reporting fewer thoughts of suicide.

Ketamine also seems to tune other brain regions that are key to effective treatment. Last year, scientists published a study in mice showing that ketamine quiets abnormal activity in the lateral habenula, a small nodule wedged deep under the cortex. Some researchers have described the lateral habenula as the brain’s “disappointment center.” The region is responsible for learning from negative experiences, and is hyperactive in people with depression, as if “broadcasting negative feelings and thoughts,” Thompson says.

Such studies remain exploratory. As to why ketamine works — and just as important, why its effects are transient — scientists are still speculating. “I think ketamine is resetting neural circuits in a way that improves the symptoms of depression, but the risk factors — whether genetic, environmental or other risk factors — are still present,” Gould says. “It seems to help reset things temporarily, but the underlying cause is not necessarily resolved.”

Helen Mayberg, a neurologist at Mount Sinai Hospital in New York who specializes in using an experimental procedure called deep brain stimulation to treat depression, suggests that ketamine may be like using a defibrillator on someone experiencing cardiac arrhythmia. “I am not addressing the fact that you have underlying heart disease, but now that your arrhythmia is gone, I can concentrate on other treatments.”

It’s important to put the potential risks of ketamine into perspective, particularly for people contemplating suicide, researchers emphasize. Most people are willing to tolerate severe side effects for other life-saving treatments, such as cancer drugs, Mayberg points out. “If you can interrupt an extreme suicidal plan and ideation, I’ll take that.”

Ketamine in teens?

For Krystal, weighing ketamine’s still largely uncharted risks and potential rewards ultimately comes down to a deeply personal question: “What would we want for ourselves? For our families? Do we want them to have to go through several failed trials over several months, or even a year, before taking a medication that might make their depression better in 24 hours?”

Some of the hardest decisions are likely to involve children and adolescents. Hospitalization for youth suicide attempts and ideation nearly doubled between 2008 and 2015, leaving many clinicians — and parents — desperate for more effective and rapid treatments. Left untreated, depression is “really bad for the brain” and can cause serious, long-term cognitive and developmental problems when it starts young, Zarate says. “The question is, is that going to be better than the long-term side effects of ketamine?”

Untreated depression is really bad for the brain, especially in the young. The question is, is that going to be better than the long-term side effects of ketamine?

Scientists don’t yet know. Ketamine has been deemed safe to use as an anesthetic in children, but there aren’t yet sufficient clinical data to show how low, repeated doses of ketamine used for depression could affect the developing brain.

On a more fundamental level, scientists don’t fully understand the neurobiology of adolescent depression, notes psychiatrist Kathryn Cullen of the University of Minnesota. It may involve abnormalities in brain development, such as the way the prefrontal cortex connects to brain regions that process emotion, but “we don’t know if the brain connection abnormalities emerge because of toxic stress induced by depression, or if these abnormalities predispose people to develop depression, or if depression itself reflects abnormal development,” Cullen says. “It’s critical to figure out how to alleviate the biological changes that are associated with [teen] depression so that the brain can get back on a healthy trajectory.”

Two recent clinical trials — one at Yale and another at Minnesota run by Cullen — have found that ketamine can lower symptoms in severely depressed teenagers, but neither study was set up to follow the teenagers long-term, says Cullen. Janssen is currently running a trial of its esketamine nasal spray with 145 youths who are suicidal, but the results of that study have not been published yet. Cullen thinks ketamine has potential for use in teens, particularly to avoid suicide, but “there are still a lot of unknowns.”

Not just a quick fix

Worldwide, depression afflicts more than 300 million people, making it the leading global cause of disability. When contemplating such overwhelming misery, the vision of a world in which depression can be cured with a single injection or squirt of nasal spray holds obvious appeal.

A photo shows a woman as she receives an infusion of the drug ketamine during a 45-minute session at an outpatient clinic in Chicago on July 25, 2018. She struggled with depression and anxiety and made several suicide attempts before starting ketamine treatments earlier in the year.
Thousands of private clinics in the United States, such as this outpatient clinic in Chicago, are offering repeated ketamine treatment off-label for depression and suicidal thoughts, but the drug’s effects are temporary and scientists still don’t know whether taking the drug over long periods is safe.CREDIT: AP PHOTO / TERESA CRAWFORD

But — despite the hype — that is not what ketamine offers, Bennett says. Based on her own experience as a patient, and her clinical work, she is troubled by the framing of ketamine as a “rapid” depression treatment if that precludes the slower, more effortful process of psychotherapy. Without psychotherapy, she says, “you’re not giving patients any tools to help themselves, just making them dependent on a molecule that has temporary effects. When the effect wears off, they have to go back for more medicine. This is going to be lucrative for the pharmaceutical company but probably not in the patient’s best interest.”

In Bennett’s clinic, ketamine is administered only alongside talk therapy, which she uses to prepare patients before they take ketamine, and afterward to help them process the experience. “I think this is the only ethical way” to administer a drug that can trigger disorienting psychedelic experiences, she says. “This isn’t a ‘take two and call me in the morning’ situation.”

There’s growing scientific interest in whether ketamine can enhance the effectiveness of therapy by increasing the brain’s ability to remodel circuits through experience, Krystal notes. And in 2017 a small Yale study found that providing cognitive behavioral therapy in tandem with ketamine can extend the drug’s antidepressant effects.

Unlike some researchers and pharmaceutical companies, which consider ketamine’s and esketamine’s hallucinogenic side effects inherently negative, Bennett thinks that for some people the visions can be positive — particularly in the context of therapy. There’s scant scientific evidence to support the idea that such hallucinations are therapeutic, and they can be deeply disturbing for some people. (If people who experience hallucinations do better, it may simply be because they have received a higher dose of ketamine, Krystal points out.)

Still, Bennett thinks researchers and clinicians need to stay open-minded about why ketamine is helping people — and be more attentive to the settings in which ketamine and esketamine are administered. “People consistently report that they experience the presence of God, or their own sacredness,” she says. “When someone comes to my office wanting to kill themselves, ready to die — and then they have a transformational moment where they believe their life is sacred — it’s indescribable how exciting that is as a clinician.”

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What is interesting for the above articles is the Magnesium and copper components associated with Depression.

The most common biomarkers found are generally related to the regulation of lipid metabolism, control of immunoinflammatory response, control of vascular function, inter and intra-cellular communication. We additionally found that biomarkers related to nutrient sensing and proteostasis are related to LLD. Altogether, these studies suggest that there are core abnormalities, which are present in the first depressive episode, continue over mid-life and late-life, and are persistent even after successful antidepressant treatment. This view is consistent with the presence of biological “scars” in depression that render individuals with major depression , age, more vulnerable to systemic illness, disability, cognitive impairment and other negative health outcomes, which are not fully ameliorated despite successful antidepressant treatment . Robust machine learning techniques showed that three proteins (C-peptide, fatty acid-binding protein, and ApoA-IV) have a very high accuracy at discriminating individuals with remitted LLD compared to never depressed control participants. In fact, our study showed the highest discriminatory power of any previous studies, including those for schizophrenia, bipolar disorder or other common mental illnesses .

http://software.broadinstitute.org/gsea/msigdb

. LLD is associated with significantly higher levels of pro-inflammatory and lower levels of anti-inflammatory markers, reduced neurotrophic support, and higher levels of oxidative stress markers and activity of glycogen synthase kinase

I nflammation is a key pathway in the initiation and progression of coronary heart disease (CHD), and inflammatory biomarkers such as C-reactive protein (CRP) and interleukin-6 (IL-6) have shown consistent associations with incident CHD events (1). In recent years, myeloperoxydase (MPO) has drawn growing attention as a new inflammatory biomarker of CHD risk (2–4). Myeloperoxydase is an enzyme produced by activated leukocytes during the innate immune response that catalyzes the formation of reactive oxidant species. It is present in human atherosclerotic plaques and exhibits a variety of proatherogenic properties (5). Increased inflammation is a key mechanism through which several risk factors increase CHD risk (6). Depression is a risk factor for CHD (7), and whether increased inflammation is involved has attracted considerable interest (8). A role of inflammation in depression was first proposed by Smith in 1991 (9). Since then, several studies have reported a link between major depressive disorder (MDD) or depressive symptoms and a variety of inflammatory and immune biomarkers (10 –15). However, others have found no independent association (16) or mixed results (17–19), and one study even found lower levels of inflammatory biomarkers in depressed cardiac outpatients (20). It is increasingly recognized that the relationship between depression and inflammation is more complex than initially conceived (21). Depression may cause inflammation through altered neuroendocrine function and central adiposity (22). However, depression may also be a consequence of inflammation, since a pathogenic role of inflammatory cytokines in the etiology of depression has been described (23). Although given less consideration, a third possibility is that depression is a marker of some other underlying dimension that is separately linked to depression and inflammation. Recently, it has been proposed that such underlying factor could be a specific genetic makeup (24,25). Evidence for a common genetic substrate for depression and inflammation would be of substantial scientific and clinical interest, because it would suggest that a common biological pathway links these two conditions. We found that MDD is associated with higher levels of inflammation and that this association is particularly robust for MPO, an inflammatory biomarker that was never studied before in relation to depression. However, we also found evidence for genetic confounding in this association. Our results are consistent with the hypothesis that there is a common genetic substrate linking MDD and inflammation, suggesting that these two phenotypes share a common pathophysiological mechanism. MPO, Other Inflammatory Markers, and Depression Myeloperoxydase is an enzyme of the innate immune system, which exhibits a wide array of proatherogenic features (5,34). Myeloperoxydase is secreted upon leukocyte activation, contributing to innate host defenses. However, it also increases oxidative stress, thereby contributing to tissue damage during inflammation and atherogenesis. Myeloperoxydase generates numerous reactive oxidants that cause lipid peroxidation, posttranslational modifications to target proteins, and decrease of nitric oxide bioavailability, resulting in oxidation of LDL and apolipoprotein A1, protein carbamylation, and endothelial dysfunction (5,35,36). Transgenic mice containing the human MPO gene show significantly larger atherosclerosis buildup than the wild-type (34,37). In humans, individuals with total or subtotal MPO deficiency, a defect with a frequency of 1 in every 2000 to 4000 whites, are less likely to develop cardiovascular diseases, and those harboring a promoter polymorphism associated with a twofold reduction in MPO expression appear cardioprotected (5,38 – 40). Consistent with these proatherogenic properties, MPO has received growing attention as a novel risk marker for future cardiovascular events (2– 4). Oxidative stress has also been linked to neuronal degeneration in the central nervous system (41,42). Myeloperoxydase is both expressed and enzymatically active in the human brain (43,44) and is associated with Alzheimer’s disease (44). Previous studies have described abnormalities of oxidant-antioxidant systems in MDD suggestive of higher oxidative stress. For example, elevated levels of antioxidant enzymes, particularly superoxide dismutase (SOD), and biomarkers of oxidation, such as malondialdehyde, were found in plasma, red blood cells, or other peripheral tissues of acutely depressed MDD patients compared with control subjects (45– 47). In some cases (46,47), but not others (45), these abnormalities were reduced with antidepressant treatment. Superoxide dismutase coenzyme concentrations are also higher in postmortem brain tissue (prefrontal cortex) of MDD patients than in control brains (48).

MOOD FOOD Project

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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

Ketamine Virginia Link

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

Ketamine Virginia Link

Ketamine-like depression treatment on track for FDA approval

 

Ketamine offers lifeline for people with severe depression, suicidal thoughtsThe drug is a close relative of ketamine, a powerful medication used in hospitals primarily as an anesthetic; recent scientific studies have also shown its potential with treatment-resistant depression and suicidal ideation. Ketamine is also used recreationally — and illegally — as a club drug known as Special K. It generates an intense high and dissociative effects.Esketamine, which is not FDA-approved for any conditions, targets a different brain pathway than approved antidepressants, many of which have been around for decades. It is expected to be used in combination with antidepressants, but the latter can take a month or two to take effect. Esketamine, on the other hand, might have an effect within hours or days, according to an FDA briefing document.The drug was designated as a breakthrough therapy in 2013, intending to “expedite the development and review of drugs for serious or life-threatening conditions,” the FDA says. First-line treatments don’t work for roughly 30% to 40% of patients with major depressive disorder, according to the briefing document.The FDA does not have to follow the recommendation of advisory committees, though it often does.

ERs 'flooded' with mentally ill patients with no place else to turn

ERs ‘flooded’ with mentally ill patients with no place else to turnHowever, the research behind esketamine has come under some criticism, with two of five key studies failing to meet their primary endpoints. Only one of these studies is a positive short-term trial, whereas most FDA-approved antidepressants are backed by at least two, according to the briefing document. But Janssen has maintained that the overall picture is positive.Adverse events tended to occur in the first two hours patients received the drug, including sedation, blood pressure increases and dissociation. For this reason, patients wouldn’t be able to pick it up at a local pharmacy; it would be given under the supervision of health care professionals who can keep an eye on the person during those first two hours.Because of the drug’s close relationship to ketamine, experts have also raised concerns about its potential for misuse and abuse. The clinical trials have not seen evidence of this risk, according to presentations made during the meeting.Advisory panelists also expressed concern that not enough long-term data was available to characterize the drug’s cognitive effects and other health impacts down the line.Get CNN Health’s weekly newsletter

There were six deaths of patients taking esketamine in trials, including three suicides, but FDA materials concluded “it is difficult to consider these deaths as drug-related.”The only current FDA-approved medication for treatment-resistant depression combines two other drugs already on the market. Other non-pharmaceutical treatments exist, such as electroconvulsive therapy.Janssen spokesman Greg Panico said no information about pricing would be available at this time. An FDA decision is expected in early March, he added.

 

CNN)A ketamine-like drug for treatment-resistant depression was backed by a US Food and Drug Administration advisory committee on Tuesday. If it is then approved by the FDA, the drug — called esketamine — may provide a new option for patients with major depressive disorder who have tried at least two other antidepressants without success.A panel of experts voted to endorse the drug, which is made in nasal spray form by the pharmaceutical company Janssen, a division of Johnson & Johnson. Fourteen members voted that the benefits outweighed the risk, with two opposed and one abstaining.

Ketamine offers lifeline for people with severe depression, suicidal thoughts
703-844-0184 | NOVA Health Recovery | Alexandria, Va 22306

Ketamine offers lifeline for people with severe depression, suicidal thoughtsThe drug is a close relative of ketamine, a powerful medication used in hospitals primarily as an anesthetic; recent scientific studies have also shown its potential with treatment-resistant depression and suicidal ideation. Ketamine is also used recreationally — and illegally — as a club drug known as Special K. It generates an intense high and dissociative effects.Esketamine, which is not FDA-approved for any conditions, targets a different brain pathway than approved antidepressants, many of which have been around for decades. It is expected to be used in combination with antidepressants, but the latter can take a month or two to take effect. Esketamine, on the other hand, might have an effect within hours or days, according to an FDA briefing document.The drug was designated as a breakthrough therapy in 2013, intending to “expedite the development and review of drugs for serious or life-threatening conditions,” the FDA says. First-line treatments don’t work for roughly 30% to 40% of patients with major depressive disorder, according to the briefing document.The FDA does not have to follow the recommendation of advisory committees, though it often does.

ERs 'flooded' with mentally ill patients with no place else to turn

ERs ‘flooded’ with mentally ill patients with no place else to turnHowever, the research behind esketamine has come under some criticism, with two of five key studies failing to meet their primary endpoints. Only one of these studies is a positive short-term trial, whereas most FDA-approved antidepressants are backed by at least two, according to the briefing document. But Janssen has maintained that the overall picture is positive.Adverse events tended to occur in the first two hours patients received the drug, including sedation, blood pressure increases and dissociation. For this reason, patients wouldn’t be able to pick it up at a local pharmacy; it would be given under the supervision of health care professionals who can keep an eye on the person during those first two hours.Because of the drug’s close relationship to ketamine, experts have also raised concerns about its potential for misuse and abuse. The clinical trials have not seen evidence of this risk, according to presentations made during the meeting.Advisory panelists also expressed concern that not enough long-term data was available to characterize the drug’s cognitive effects and other health impacts down the line.Get CNN Health’s weekly newsletter

There were six deaths of patients taking esketamine in trials, including three suicides, but FDA materials concluded “it is difficult to consider these deaths as drug-related.”The only current FDA-approved medication for treatment-resistant depression combines two other drugs already on the market. Other non-pharmaceutical treatments exist, such as electroconvulsive therapy.Janssen spokesman Greg Panico said no information about pricing would be available at this time. An FDA decision is expected in early March, he added.