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A recent study with 50 patients demonstrated that Ketamine has a more rapid efficacy with less cognitive decline than does ECT.
What is ECT? Here is a Youtube Video demonstrating it:
Although both treatmens work with similiar results of depression decrease in the end, ther eis less cognitive decline with Ketamine infusions in terms of attention, visual memory, and executive functions.
See the article link below :
J Psychiatr Res. 2020 Jan 16;123:1-8. doi: 10.1016/j.jpsychires.2020.01.002. [Epub ahead of print]
Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients.
While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine’s impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects.
Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment.
ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance.
Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT.
As this research employed a naturalistic study design, patients were not systematically randomized, there was no control group and patients received concurrent and partially changing medications during treatment.
CLINICAL TRIALS REGISTRATION:
Functional and Metabolic Changes in the Course of Antidepressive Treatment, https://clinicaltrials.gov/ct2/show/NCT02099630, NCT02099630.
Basso L, Bönke L, Aust S, et al. Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients. J Psychiatr Res. 2020;123:1-8.
Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.
Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.
Two Caucasian males, 28 and 45 years-old, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 h) combined with magnesium sulfate (3000 mg over 30 min) in an outpatient setting. This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for one patient and partial relief (50%) for the other patient, for 6 weeks in both cases.
The NMDA receptor is a potential target for the treatment of chronic CH. Randomized, placebo-controlled studies are warranted to establish both safety and efficacy of such treatment.
Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractable population.
Ketamine Infusions for Treatment Refractory Headache
Authors: Jared L. Pomeroy MD, MPH, Michael J. Marmura MD, Stephanie J. Nahas MD, MSEd, Eugene R. Viscusi MD Source:Headache, Dec. 27, 2016
Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractablepopulation.
This is a retrospective review of 77 patients who underwent administration of intravenous, subanesthetic ketamine for CM or NDPH. All patients had previously failed aggressive outpatient and inpatient treatments. Records were reviewed for patients treated between January 2006 and December 2014.
The mean headache pain rating using a 0-10 pain scale was an average of 7.1 at admission and 3.8 on discharge (P < .0001). The majority (55/77, 71.4%) of patients were classified as acute responders defined as at least 2-point improvement in headache pain at discharge. Some (15/77, 27.3%) acute responders maintained this benefit at their follow-up office visit but sustained response did not achieve statistical significance. The mean length of infusion was 4.8 days. Most patients tolerated ketamine well. A number of adverse events were observed, but very few were serious.
Subanesthetic ketamine infusions may be beneficial in individuals with CM or NDPH who have failed other aggressive treatments. Controlled trials may confirm this, and further studies may be useful in elucidating more robust benefit in a less refractory patient population.
Cluster headaches have an incidence of 1–3 per 10,000 with a 2.5:1 male-to-female gender ratio. Although not life threatening, the impact of the attacks on the individual patient can result in tremendous pain and disability. The pathophysiology of the disease is unclear, but it is known that the hypothalamus, the brainstem, and genetic factors, such as the G1246A polymorphism, play a role. A distinction is made between episodic and chronic cluster headaches. In a controlled setting, we treated 29 patients with cluster headaches (13 with chronic cluster and 16 with the episodic form), who had been refractory to conventional treatments, with a low dose of ketamine (an NMDA receptor antagonist) i.v. over 40 min to one hour every 2 weeks or sooner for up to four times. It was observed that the attacks were completely aborted in 100 % of patients with episodic headaches and in 54 % of patients with chronic cluster headaches for a period of 3–18 months. We postulated neuroplastic brain repair and remodulation as possible mechanisms.
Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients.
Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients. Thirteen outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point verbal analog score (VAS), 11 of 13 patients (85%) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The results demonstrate that ketamine may provide a reasonable alternative treatment for nonresponsive neuropathic pain in ambulatory outpatients.
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:
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.2 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.
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.
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)
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.
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.
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.
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.
Robert K, Simon C. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2005
Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Phamacol. 2014;77(2):357–367.
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.
Krusz, JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic. Curr Pain Headache Rep. 2006;10(1):47-53.
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
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.
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.
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.
Krusz JC. IV ketamine in the clinic to treat Cluster Headache (poster abstract). American Academy of Neurology. Neurol. 2009;72(11):A89-90.
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.
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.
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.
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.
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.
Krusz JC. The IV ketamine experience: treatment of migraines, headaches and TAC. JAMA Neurol. 2018
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.
Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 ;20:54-63.
According to the World Health Organization, depression is the leading cause of disability. Unfortunately, 30 to 60 percent of patients are not responsive to available antidepressant treatments (Krishnan & Nestler, 2008). In other words, 40 to 70 percent of patients are not helped by existing treatments. One area of research might shed some light on why a sizable portion of patients are not helped by current antidepressants.
There is growing evidence that inflammation can exacerbate or even give rise to depressive symptoms. The inflammatory response is a key component of our immune system. When our bodies are invaded by bacteria, viruses, toxins, or parasites, the immune system recruits cells, proteins, and tissues, including the brain, to attack these invaders. The main strategy is to mark the injured body parts, so we can pay more attention to them. Local inflammation makes the injured parts red, swollen, and hot. When the injury is not localized, then the system becomes inflamed. These pro-inflammatory factors give rise to “sickness behaviors.” These include physical, cognitive and behavioral changes. Typically, the sick person experiences sleepiness, fatigue, slow reaction time, cognitive impairments, and loss of appetite. This constellation of changes that take place when we are sick is adaptive. It compels us to get more sleep to heal and remain isolated so as not to spread infections.
However, a prolonged inflammatory response can wreak havoc in our bodies and can put us at risk of depression and other illnesses. There is plenty of evidence solidifying the link between inflammation and depression. For example, markers of inflammation are elevated in people who suffer from depression compared to non-depressed ones (Happakoski et al., 2015). Also, indicators of inflammation can predict the severity of depressive symptoms. A study that examined twins who share 100 percent of the same genes found that the twin who had a higher CRP concentration (a measure of inflammation) was more likely to develop depression five years later.
Doctors noticed that their cancer and Hepatitis C patients treated with IFN-alpha therapy (increases inflammatory response) also suffered from depression. This treatment increased the release of pro-inflammatory cytokines, which gave rise to a loss of appetite, sleep disturbance, anhedonia (loss of pleasure), cognitive impairment, and suicidal ideation (Lotrich et al., 2007). The prevalence of depression in these patients was high. These results add credence to the inflammation story of depression.
Subsequent careful studies showed that the increase in the prevalence of depression in patients treated with IFN-alpha was not only because they were sick. Using a simple method of injecting healthy subjects with immune system invaders, researchers found higher rates of depressive symptoms in the ones who were exposed compared to the placebo group. The subjects who were induced to have an inflammatory response complained of symptoms such as negative mood, anhedonia, sleep disturbances, social withdrawal, and cognitive impairments.
The link between inflammation and depression is even more solid for patients who don’t respond to current antidepressants. Studies have shown that treatment-resistant patients tend to have elevated inflammatory factors circulating at baseline than the responsive ones. This is clinically important; a clinician can utilize a measure like CRP levels, which are part of a routine physical, to predict the therapeutic response to antidepressants. In one study, they found that increased levels of an inflammation molecule prior to treatment predicted poor response to antidepressants (O’Brien et al., 2007).
There are environmental factors that cause inflammation and therefore elevate risk for depression: stress, low socioeconomic status, or a troubled childhood. Also, an elevated inflammatory response leads to increased sensitivity to stress. The effect has been reported in multiple studies in mice. For example, mice that have gone under chronic unpredictable stress have higher levels of inflammation markers (Tianzhu et al., 2014). Interestingly, there are individual differences that make some mice more resistant to stress, therefore initiating a calmer immune response (Hodes et al., 2014).
Depression is a heterogeneous disorder. Each patient’s struggle is unique given their childhood, genetics, the sensitivity of their immune system, other existing bodily illnesses, and their current status in society. Being on the disadvantageous end of these dimensions irritates our immune system and causes chronic inflammation. The brain is very responsive to these circulating inflammatory markers and initiates “sickness behavior.” When the inflammation is prolonged by stressors or other vulnerabilities, the sickness behavior becomes depression.
If you are a professional working with patients suffering from depression, I urge you to consider the health of your patients’ immune systems. If you are a patient suffering from an exaggerated immune disorder (e.g., arthritis), do not ignore the depressive symptoms that you might be experiencing. If you are suffering from depression, avoid anything that might exacerbate your immune response. This is another example of the beautiful dance between mind and body!
Haapakoski,R.,Mathieu,J.,Ebmeier,K.P.,Alenius,H.,Kivimäki,M., 2015. Cumulative meta-analysisofinterleukins6 and 1β,tumournecrosisfactorα and C-reactive protein in patients with major depressive disorder. Brain Behav.Immun. 49,206.
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D et al (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 111: 16136–16141.
Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature 455: 894–902.
Lotrich,F.E.,Rabinovitz,M.,Gironda,P.,Pollock,B.G., 2007. Depression following pe-gylated interferon-alpha:characteristics and vulnerability.J.Psychosom.Res.63, 131–135.https://doi.org/10.1016/j.jpsychores.2007.05.013.
O’Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., Dinan, T.G., 2007a. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326e331.
Tianzhu, Z., Shihai, Y., Juan, D., 2014. Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evid. Based Complement. Altern. Med. 2014, 438506.
A new large-scale study casts doubt on a widely reported association.
Why some people develop major depressive disorder and others do not is a complex and not well-understood process. Several factors have been discussed to contribute to depression, among them:
Genetic variation: Individuals carrying one or two copies of a specific risk allele on one or more “depression gene/s” have a higher risk of developing depression.
Environmental influences: Negative life events such as trauma, negligence, or abuse increase the risk of developing depression.
Gene-by-environment interactions: Negative life events only lead to depression in individuals with a specific genetic set-up that makes them risk-prone to develop depression.
The gene most commonly associated with depression is the serotonin transporter gene SLC6A4 (Bleys et al., 2018). Serotonin is a neurotransmitter affecting multiple physiological processes and cognitivebrain functions, among them mood and emotions, which is why it has been linked to mood disorders such as depression. Indeed, low serotonin levels have been associated with depressed mood (Jenkins et al., 2016), and selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. SSRIs block the reuptake of serotonin during cellular communication in the brain, making more serotonin available, and thus in theory helping to reduce depression.
Along these lines, the idea that the serotonin transporter gene could affect depression risk or severity intuitively made sense. Specifically, many scientists focused on the so-called 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene to research the effects of this gene on depression. Genetic polymorphism means that at a specific location in the genome, different people might have slight variations in their DNA which could affect how well the protein that the gene produces could do its job. In the case of the 5-HTTLPR polymorphism, there is a short allele (s) and a long allele (l). Already back in the 1990s, researchers showed that people with two or one short alleles have a higher chance of developing depression than those with two long alleles, as the short allele leads to reduced expression of the serotonin transporter (Collier et al., 1996).
This initial study sparked interest in the 5-HTTLPR polymorphism, but not all empirical works could find a clear association. In 2003, a surprising finding seemingly resolved this controversy. In a widely cited study, Caspi and colleagues were able to show that the effects of 5-HTTLPR polymorphism genotype on depression were moderated by a so-called gene-by-environment interaction (Caspi et al., 2003). This means that the genotype would only have an effect if individuals were also subjected to specific environmental conditions. Specifically, the scientists found that individuals reacted differently to highly stressful life events, depending on the 5-HTTLPR genotype. People with at least one short allele on the 5-HTTLPR polymorphism developed more depressive symptoms if they experienced a highly stressful life event than people with two long alleles. However, without a stressful life event, the genotype did not have an effect on the probability to develop depression.
This study further increased the interest in the 5-HTTLPR polymorphism and its relation to depression, leading to more studies on this topic. However, a problem of many of these studies was that their sample sizes were comparably small for genetic studies, potentially leading to erroneous results and overblown effects.
Almost a decade ago, Risch and co-workers (Risch et al., 2009) conducted a so-called meta-analysis, a statistical integration of empirical studies. They analyzed 14 studies on the 5-HTTLPR polymorphism and its relation to depression and on whether this relation was influenced by stressful life events as had been suggested by Caspi et al. (2003). Their result was clear: While more stressful life events led to a higher risk of depression, there was no effect of the 5-HTTLPR genotype on depression and no gene-by-environment interaction effect between genotype and stressful life events.
Despite this finding, hundreds of studies on the 5-HTTLPR polymorphism and depression have been published since 2009 (the scientific search engine PubMed lists more than 800 hits for the search term “5-HTTLPR depression” as of early May 2019). A new study recently published by Richard Border and colleagues in The American Journal of Psychiatry(Border et al., 2019) aimed to resolve the controversy about whether or not the 5-HTTLPR genotype affects depression and whether there is a gene-by-environment interaction between this genotype and stressful life events once and for all. To avoid the statistical problems of previous studies, they obtained data from several large genetic datasets available to researchers, leading to a sample size of several hundred thousand individuals. The results of the analysis were clear as well: There was no statistical evidence for a relation between the 5-HTTLPR polymorphism and depression, and there was also no evidence that traumatic life events or adverse socioeconomic conditions might show a gene-by-environment interaction with this genotype.
This, of course, does not mean that there is no relationship between serotonin and depression (there clearly is, as shown by the treatment success of SSRIs), but it lends further support to an emerging insight in psychiatry genetics: Mental illness is a highly complex process that is likely influenced by a large number of genetic and non-genetic effects. As such, it is unlikely that single genetic variations such as the 5-HTTLPR polymorphism have a huge impact on whether or not an individual develops depression or any other form of mental illness. Future psychiatry genetic studies will need to take this complexity into account by analyzing genetic variation across the whole genome and epigenome and relating it to mental illness (Meier & Deckert, 2019).
The newest FDA-approved medication to treat severe depression, a nasal spray based on the anesthetic (and misused hallucinogenic party drug) ketamine, will soon be available to veterans treated within the Department of Veterans Affairs.
In a move that may help thousands of former service members with depression that has not improved with other treatments, VA officials announced Tuesday that the department’s doctors are now authorized to prescribe Spravato, the brand name for esketamine, a molecular variation of ketamine.
The decision to offer a drug hailed by many as a breakthrough in treatment for its speedy results — often relieving symptoms in hours and days, not weeks — shows the VA’s “commitment to seek new ways to provide the best health care available for our nation’s veterans,” Secretary Robert Wilkie said in a release.
“We’re pleased to be able to expand options for Veterans with depression who have not responded to other treatments,” Wilkie added.
The treatment will be available to veterans based on a physician’s assessment and only will be administered to patients who have tried at least two antidepressant medications and continue to have symptoms of major depressive disorder.
An estimated 16 million Americans have had at least one major episode of depression, and of those, 1 in 3 are considered treatment-resistant. In the veteran population of 20 million, the estimated diagnosis rate of depression is 14 percent — up to 2.8 million veterans. Between one-third and half of those veterans may be treatment-resistant.
The lack of effective medications for difficult-to-treat patients prompted the Food and Drug Administration to place esketamine on a fast track, expediting its review of the drug to ensure that it went to patent as soon as safely possible, according to administration officials.
“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process, including a robust discussion with our external advisory committees, were important in our decision to approve this treatment,” said Dr. Tiffany Farchione, acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products, in a release.
As with any other medication, there are risks. Spravato carries a boxed warning for side effects that include misuse, the reason it is administered under a doctor’s supervision. The list of side effects includes sedation and blood pressure spikes and disassociation, such as feelings of physical paralysis and out-of-body experiences. It also can cause suicidal thoughts and behaviors.
Acknowledging the dangers, FDA made esketamine available only through a restricted distribution system.
A veteran prescribed Spravato would inhale the nasal spray at a medical facility while under supervision of a medical provider, and would be monitored for at least two hours after receiving the dose. A typical prescription includes twice-weekly doses the first month, followed by a single dose weekly or biweekly as needed. Spravato cannot be dispensed for home use.
Spravato is made by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first major antidepressant medication to hit the market in 30 years.
NOVA Heath Recovery Ketamine Treatment Center | Call 703–844-0184 for a Ketamine Treatment | Alexandria, Va 22306 | 7 days a week and evening appointments as well! We also evaluate depression, ADHD, PTSD. Intranasal Ketamine available. The email is EMAIL@novahealthrecovery.com
Ketamine for Depression: Does it work?
What is Ketamine?
Ketamine, also known as Ketalar, Ketaset, and Ketanest, is a medication that’s currently FDA approved only as an anesthetic but it’s showing great potential as a treatment for severe depression. In fact, numerous Ketamine Clinics have begun to appear throughout the United States to solve this problem. Depressed patients with stubborn symptoms get relief within hours rather than weeks with conventional anti-depressants. Doctors can only prescribe ketamine for depression off-label because studies are relatively new, but experts are saying that ketamine is one of the biggest breakthroughs in severe depression treatment to come along in decades .
Ketamine is a powerful pain reliever and a relaxant, but at higher doses it can also induce unconsciousness and disturbances in how a person experiences sight and sound. In high doses, it can produce hallucinations and delusions and its ability to create strong dissociative experiences have made it popular in the club scene where it’s known as “Special K”. An overdose of ketamine can be fatal and it can be addictive if patients don’t follow their doctor’s prescription guidelines. Currently, ketamine is scheduled as a class III drug and it’s created a lot of controversy among experts who disagree about whether it’s safe for doctors to prescribe it as a treatment for chronic depression. Despite the intrigue and the need for additional research to establish its safety and efficacy, ketamine clinics are now offering infusion treatments to patients all over the United States .
Effects of Ketamine
As a street drug, ketamine creates a sense of dissociation and can change a person’s sense of hearing and sight, but for patients with severe depression, ketamine relieves mood problems within hours or sometimes moments for about 85% of those treated. While conventional anti-depressants can take several weeks to take effect, studies have shown that ketamine often improves depression symptoms almost immediately. Patients typically feel better within hours .
Doctors, dentists, and psychiatrists prescribe ketamine to help their patients achieve a variety of different health goals. Doctors often use ketamine in FDA approved situations such as procedures involving cardiac catheterization, orthopedics, skin grafting, or diagnostics involving the eye, ear, nose, and throat. Surgical dentists may also use ketamine as an anesthesia during tooth extractions. After other treatment options have been attempted and failed, doctors may use ketamine to treat certain types of seizures in patients with status epilepticus .
Researchers demonstrated in 2014 that ketamine reduced symptoms of post-traumatic stress disorder in 41 patients and there are other exciting possibilities on the horizon in terms of PTSD treatment. Treatment-resistant depression and substance use disorders could both be treated with this drug, though many medical professionals view ketamine treatment for these mental health issues as controversial .
Ketamine for Pain Management (CRPS)
Central Sensitization is a process the central nervous system goes through which causes Complex Regional Pain Syndrome (CRPS/RSD) and other types of chronic pain. In central sensitization the number of NMDA receptors increases which amplifies a patients’ experience of pain. Ketamine interferes with NMDA receptors which puts a damper on pain signaling, providing pain relief and a desensitization to pain for patients affected by CRPS .
At low doses, ketamine can relieve chronic pain and potentiate the effects of sedatives. Researchers believe that ketamine could provide an alternative to more addictive painkillers like morphine if the FDA approves it for this use .
Ketamine for Anesthesia
In the 1960’s doctors used ketamine as an anesthetic on the battlefields in Vietnam because administration lends itself well to use in disaster zones; doctors don’t need electricity, an oxygen supply, or even highly trained staff to give patients ketamine. Since that time, the FDA has only approved ketamine for use as an anesthetic in hospitals and medical settings. As an anesthetic, ketamine doesn’t lower the patient’s breathing rate or blood pressure, which makes it safer than other anesthesia options. It’s for this reason that veterinarians use ketamine more than any other type of anesthetic for surgery on animals .
Ketamine for Depression
Depression is a major issue in the United States and though there are many anti-depressants on the market, about one-third of patients don’t experience any relief from their symptoms using the drugs that are currently available. Ketamine acts on depression by rebalancing a different set of neurotransmitters and receptors (the NMDA/glutamate receptors and GABA receptors) than the old-school Selective Serotonin Reuptake Inhibitors (which function by blocking reabsorption of serotonin). By blocking glutamate receptors in the brain, the majority of patients with ‘Treatment Resistant Depression’ are able to experience relief from their symptoms using ketamine .
Even though ketamine has yet to be approved by the FDA for use in treating depression, patients are flocking to ketamine clinics to receive the treatment off-label. It provides fast relief, which is vitally important in cases where patients feel suicidal and for depressed patients who have tried all of the other anti-depressants available with no luck, ketamine offers new hope. Infusion treatments take about 1 hour at a clinic, but the results are long-lasting with most patients returning only once every one to two weeks over a specified period of time. The treatment is expensive, but the results are promising enough that patients are willing to pay out-of-pocket for it .
The FDA hasn’t yet approved ketamine for use as an anti-depressant, but both Esketamine and Rapastinel (developed by Johnson & Johnson and Allergan respectively) have been fast-tracked as breakthrough drugs. The demand for these two medications is projected to grow rapidly in the coming years. Still, doctors can only prescribe ketamine for depression off-label since ketamine has been FDA approved for use as an anesthetic, not as an anti-depressant. Researchers have cautioned doctors to avoid over-prescribing this drug because the long-term health and well-being of patients could be at risk. Ketamine has a high potential for abuse, after all and experts claim that the evidence does not exist to prove that this drug is safe .
Ketamine as Drugs of Abuse
Ketamine is abused as a recreational drug and it has effects that are similar to Phenylcyclidine (PCP), LSD, dextromethorphan (DXM) and nitrous oxide (laughing gas). Ketamine is a dissociative anesthetic that can alter one’s sense of sight and sound and also produce profound relaxation, hallucinations, and delusions for about an hour. The effects of the drug come on almost immediately. It has been used as a rape drug that can render women unable to speak or to move .
People who abuse ketamine have developed serious bladder and kidney problems such as ulcerative cystitis, stomach issues, and memory loss. In fact, street users even risk developing depression as a result of addiction and dependence on the drug .
How is Ketamine used for depression?
Doctors may prescribe ketamine by itself or in tandem with other anti-depressants . Many experts on depression recommend that ketamine only be used as a short-term depression treatment option while other anti-depressants are taking effect. Though there are convenient ketamine nasal sprays in research and development by Johnson & Johnson, the high-potential for abuse of this drug has made many doctors and psychiatrists wary of using this drug to treat depression long-term. Further, some medical organizations are concerned that the long-term effects of chronic ketamine use is not well-understood. According to these organizations, more research is needed to establish the safety of this drug .
Promising Remedy for ‘Treatment Resistant Depressions’
Thomas Insel, the director of the National Institute of Mental Health says, “Recent data suggest that ketamine, given intravenously might be the most important breakthrough anti-depressant in decades.” Conventional anti-depressants aren’t able to help about one-third of patients with major depression, but new ketamine drugs such as esketamine (in development by Johnson and Johnson) may offer new hope. Infusion therapies available through ketamine clinics across the United States report a high success rate of 60% to 70% treating Treatment Resistant Depression as well as Major Depression with risk of suicide .
Fast-Tracked by FDA
Two drugs, Johnson & Johnson’s Esketamine and Allergan’s Rapastinel, were both upgraded to ‘fast-track’ status by the FDA in 2016 due to their importance and promise in treating treatment resistant depression.
Depression is the leading cause of disability in the world and currently, 12% of Americans (about 29 million people) are taking anti-depressant medications. The suicide rate is higher now than it has been in over 30 years. And about one-third of depressed Americans don’t experience relief taking conventional anti-depressants. In the interest of capitalizing on the market value of depression, which is projected to almost double by the year 2024, the FDA will review the use of these new ketamine-based depression drugs in 2018 and 2019, allowing Johnson & Johnson and Allergan to go through an abbreviated version of the normally lengthy FDA approval process for new drug therapies .
Drug trials have shown that 60% to 70% of patients with Treatment-Resistant Depression have been responsive to ketamine. Esketamine, a nasal spray developed by Johnson & Johnson, is in Phase III clinical trials right now. They are expected to receive FDA approval later in 2018, and once that happens, it will open doors for administering ketamine outside a clinic setting.
Rapastinel, which was developed by Allergan, is out of Phase III and awaiting FDA approval. The drug can be administered within 30 seconds intravenously and Allergan is working to develop an oral version of the drug as well .
How Ketamine Therapy Works
Ketamine therapy is usually performed at a ketamine clinic. Patients receive an intravenous infusion of the drug with relief from depression symptoms that can last for several weeks.
Ketamine Infusion or Intravenous Therapy (Infusion Process)
Ketamine can be injected directly into muscle tissue or it can be given intravenously. Researchers for Johnson & Johnson have also recently developed new treatment protocol called Esketamine that’s awaiting FDA approval. Using Esketamine, patients will be able to self-administer the drug as a nasal mist .
Patients must receive a referral from a doctor to go to a ketamine clinic. There, patients can receive an intravenous infusion of ketamine. On the first visit, a doctor will assess the patient before hooking the patient up to a ketamine IV. Patients then experience a variety of sensations during the infusion and for up to 2 hours following the infusion. Many patients report feeling a sense of deep relaxation and the ability to reflect on past traumas and anxieties calmly .
How does it work?
Researchers have demonstrated that a deficiency in certain vital connections between certain neurons in the brain may cause depression. Ketamine works as an NMDA receptor antagonist (NMDA is a glutamate receptor also known as N-methyl-d-aspartate) and an AMPA receptor stimulator. As such, ketamine stimulates the development of new receptors and synapses in the brain which helps patients regulate their mood, sleep better, and experience better focus .
Ketamine works by interfering with and rebalancing the glutamatergic system (glutamate and GABA) to stimulate new synaptic connections, better memory, and brain plasticity . During ketamine infusions, patients may feel capable of exploring traumatic memories more calmly to reframe the past or they may feel a pleasant sensation of relaxation or floating . Effects from an infusion can last for up to a week or two.
Intranasal ketamine formulas work by binding to a receptor called N-methyl-d-aspartate. In the brain, ketamine blocks the neurotransmitter glutamate which causes communication between the conscious mind and other parts of the mind (such as mood centers) to be blocked. In low doses, it relieves depression, but in higher doses, it can cause patients to feel an uncomfortable sense of dissociation from the body similar to a near death experience .
While most anti-depressant medications must build up in the body over the course of several weeks in order to have an effect, ketamine’s mood-altering benefits happen as the drug leaves the body. Researchers don’t know why this is the case, or even exactly how the drug achieves its strong anti-depressant effects but the fact is, ketamine works quickly to relieve depression symptoms in 85% of patients who are resistant to other forms of therapy . Standard anti-depressants target the neurotransmitters serotonin, norepinephrine, and dopamine, but ketamine is different. Ketamine blocks glutamate and stimulates synaptic plasticity or the ability of the brain to change and grow .
Doctors don’t fully understand how ketamine works or the potential effects that patients may experience from taking tiny doses of this drug over and over again. What is known is that recreational users can suffer ulcerative cystitis or cognitive issues as a result of prolonged use .
Ketamine Infusion Dose/Dosage
Researchers are working to find the perfect ketamine dose for depression patients. The risk of overdosing on this drug is high for the recreational user because there is only a slight difference between a dosage that leads to desirable effects and one that can cause a lethal overdose. The goal for researchers is to find an exact dosage that’s high enough to get rid of symptoms of depression but low enough to prevent patients from experiencing hearing and sight disturbances as well as the other negative effects from the drug . Ketamine produces only temporary effects on severe depression. Patients must continue to return to the clinic for infusions every few weeks to keep their depression symptoms in check .
Ketamine therapy cost? Is ketamine therapy covered by insurance?
Ketamine therapy is rarely covered by insurance and it’s pricey. Patients typically pay between $400 and $800 per infusion in many centers.
Ketamine Infusion Side-Effects
Ketamine use can cause a variety of side effects including:
Extreme fatigue or exhaustion
Nervousness or restlessness
Puffy or swollen eyelids, lips, or tongue
Hives, itching, or rash
Difficulty thinking or learning
Loss of appetite
Fast heartbeat, slow heartbeat, irregular heartbeat
Chest pain or discomfort
Inability to control eye movement
Difficulty urinating, frequent urination, cloudy or bloody urine
Paleness, bluish lips, skin, or fingernails
Increased pressure in the brain and the eyes 
Off-label ketamine infusion therapy is an unregulated business that has gotten the attention of both clinicians and medical organizations. There are currently ketamine clinics in a number of cities throughout the United States .
s ketamine therapy addictive?
Patients who use ketamine long-term may develop a tolerance and addiction to the drug over time. In medical settings, ketamine is safe to use because the dosage is carefully calibrated and monitored, but there is a high potential for abuse when patients use ketamine recreationally as a street drug. If patients don’t follow their doctor’s prescription for ketamine it can have extremely negative mental and physical effects particularly on the brain and bladder .
Ketamine-Based Drugs in Late Stage Trials
Both Rapastinel and Esketamine are ketamine-based drugs that have been ‘fast-tracked’ by the FDA because the FDA has identified them as “breakthrough drugs” .
Allergan developed Rapastinel, a ketamine drug that can be administered in 30 seconds intravenously. It works on the same receptors as ketamine, but it doesn’t produce hallucinations. An oral version of Rapastinel is also in development. The FDA considers Rapastinel to be a “breakthrough drug” which means that Allergan can speed through the lengthy drug approval process and get the drug to market by 2019 .
The FDA has designated Esketamine a “breakthrough therapy”, which means that the drug developers, a subsidiary of Johnson & Johnson, can speed through the lengthy drug approval process to get the drug on the market more quickly. Esketamine can be administered like a nasal decongestant, which would make it more convenient than intravenous therapy for depression patients. Experts feel that Esketemine would be most appropriately used as an adjunct therapy in combination with other anti-depressant medications, not as a standalone treatment for depression .
According to one recent study, when administered in combination with other oral antidepressants, Esketamine reduced patients’ depression symptoms more than oral anti-depressants alone. The anti-depressant effects of using a conventional anti-depressant in conjunction with Esketamine occurred within only about 1 week. When used alone, Esketamine effects seem to last 1 to 7 days in most patients. Esketamine is in Phase 3 testing with the FDA for use as a drug for ‘Treatment Resistant Depression’ and Major Depression with risk of suicide. Johnson & Johnson will file for FDA approval for this drug as a depression treatment in 2018 .
Risks of Ketamine Abuse
Ketamine abuse is a serious problem. It is possible to become addicted to ketamine. Patients may begin to need higher doses of the drug in order to experience the positive effects. An overdose of ketamine can be deadly. The effects of using ketamine chronically over a long period of time have not been established, but recreational drug users who have used ketamine long-term have developed ulcerative cystitis as well as cognitive issues .
The Ketamine Controversy
While ketamine can literally save lives by relieving the symptoms of major, Treatment Resistant Depression, including the risk of suicide, research still has not established the safety of ketamine for long-term use. The lethal dose of ketamine is only slightly higher than the therapeutic dose and its addictive properties mean that it could cause depressed patients more problems than it solves. Ketamine clinics have popped up all over the country to cash in on the high demand for a depression treatment that really works, but the research hasn’t demonstrated that this drug is safe for chronic use. So this is an instance where the buyer needs to beware. The FDA has fast-tracked these drugs because it’s constituents see market potential, but important research still needs to be done on this drug to demonstrate it’s safety and long-term efficacy.
Two new studies suggest the psychiatric benefits of ketamine treatment may extend beyond just the targeting of depression. The research demonstrates ketamine may be helpful in targeting both anxiety- and substance abuse-related depression.
Although ketamine is a relatively old drug, originally developed in the 1950s as an anesthetic, over the last decade a growing body of research has affirmed its unique, and rapid, antidepressant effects. The anecdotal effects of the drug on depression have raced ahead of scientific research so quickly that ketamine clinics have popped up all across the United States, where the drug can be administered for up to US$1,000 a dose.
Much is still unknown about how efficacious ketamine actually is for depression. We don’t know ideal dosages, how long the treatments last, or how safe long-term usage is. Two newly published studies are adding to our knowledge about ketamine’s psychiatric uses, adding weight to the drug’s burgeoning new potential.
The first study, led by a team from Massachusetts General Hospital and Harvard Medical School, set out to study how effective ketamine is at treating patients with anxiety-based treatment-resistant depression. This is an important question to resolve, as many traditional antidepressants do not consistently improve anxiety-based symptoms in cases of major depression.
The study took 99 subjects with treatment-resistant depression, half of whom suffered from high anxiety and half of whom displayed no anxious symptoms. The study randomly administered subjects either one of four different intravenous ketamine doses, or midazolam, a general sedative that could serve as a control.
As well as demonstrating ketamine’s novel antidepressant qualities, the study revealed the drug worked equally well in both anxious and non-anxious subjects. This suggests that ketamine’s antidepressant effects are uniquely effective across different types of treatment-resistant depression, something that cannot be said for many major antidepressant drugs.
“In contrast to reports from monoaminergic antidepressants, our data suggest that patients with anxious depression respond equally as well to ketamine compared to those with non-anxious depression,” write the researchers in the published study.
The second new study comes from a team at Yale University School of Medicine. This research investigated whether ketamine could be effective in treating addiction-related depression when administered in tandem with naltrexone.
A study in 2018 offered a small but significant finding, revealing that ketamine was ineffective in treating depression when administered alongside naltrexone. These results were important because they suggested that part of ketamine’s antidepressant effects may be related to the activation of opioid receptors, which would mean long-term ketamine use may potentially result in problems with addiction, something that many researchers have long argued against.
Naltrexone, an opioid receptor blocker, is often administered effectively to combat serious substance abuse problems, so if it rendered ketamine ineffective then that would cast doubt on much research into how ketamine actually works to reduce symptoms of depression. The new Yale research was small, with a sample of only five patients, but its results strongly suggest ketamine and naltrexone do not cancel each other out.
All five subjects suffering from alcohol use disorder and depression displayed significant depressive relief from ketamine dosages despite long-term naltrexone consumption. Senior author on the study, John Krystal, says although larger studies still need to be completed the research does suggest ketamine and naltrexone may be a complimentary combination that helps treat substance abuse and its related depression.
“[The results] raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” says Krystal.
Although this new study only consisted of five subjects, the prior research linking ketamine to the opioid system was generated from just 12 subjects. So we are still in uncharted territory regarding ketamine’s mechanistic effects of the brain. But the Yale research should assuage some fears that ketamine may be, “merely another opioid in a novel form.”
To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment‐resistant depression (TRD).
In a multisite, double‐blind, placebo‐controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six‐item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety‐Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion.
N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73).
In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.
Ketamine is a medication that is used to induce loss of consciousness, or anesthesia. It can produce relaxation and relieve pain in humans and animals.
It is a class III scheduled drug and is approved for use in hospitals and other medical settings as an anesthetic.
However, it is also a commonly abused “recreational” drug, due to its hallucinogenic, tranquilizing and dissociative effects.
Controversy has arisen about using ketamine “off-label” to treat depression. Off-label uses of drugs are uses that are not approved by the the United States, (U.S.) Food and Drug Administration (FDA).
Ketamine is safe to use in controled, medical practice, but it has abuse potential. Used outside the approved limits, its adverse mental and physical health effects can be hazardous. Prolonged use can lead to tolerance and psychological addiction.
Fast facts on ketamine:Here are some key points about ketamine. More detail is in the main article.
Ketamine is similar in structure to phencyclidine (PCP), and it causes a trance-like state and a sense of disconnection from the environment.
It is the most widely used anesthetic in veterinary medicine and is used for some surgical procedures in humans.
It is considered a “club drug,” like ecstasy, and it has been abused as a date-rape drug.
Ketamine should only be used as prescribed by a doctor.
What is ketamine?
Ketamine can produce feelings of dissociation when used as a drug of abuse.
Ketamine belongs to a class of drugs known as dissociative anesthetics. It is also known as Ketalar, Ketanest, and Ketaset.
Other drugs in this category include the hallucinogen, phencyclidine (PCP), dextromethorphan (DXM), and nitrous oxide, or laughing gas.
These types of drugs can make a person feel detached from sensations and surroundings, as if they are floating outside their body.
Ketamine is most often used in veterinary medicine. In humans, it can induce and maintain general anesthesia before, during, and after surgery.
For medical purposes, ketamine is either injected into a muscle or given through an intravenous (IV) line.
It is considered safe as an anesthetic, because it does not reduce blood pressure or lower the breathing rate.
The fact that it does not need an electricity supply, oxygen, or highly trained staff makes it a suitable option in less wealthy countries and in disaster zones.
In human medical practice, it is used in procedures such as:
diagnostic procedures on the eye, ear, nose, and throat
minor surgical interventions, such as dental extractions
It has been used in a hospital setting to control seizures in patients with status epilepticus (SE), a type of epilepsy that can lead to brain damage and death. However, researchers point out that ketamine is normally used for this purpose after 5 to 6 other options have proven ineffective. Ketamine for the treatment of refractory status epilepticus
It is also an analgesic, and, in lower doses, it can relieve pain.
Researchers are looking into other possible medical uses of ketamine, particularly in the areas of treatment-resistant depression, suicide prevention, and substance use disorders. However, this use is controversial.
Researchers for the American Psychological Association (APA) noted in April 2017 that a number of doctors prescribe ketamine “off-label,” for people with treatment-resistant depression.
However, they caution:
“While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”
The FDA has not yet approved it for treating depression.
In a study published in BMC Medical Ethics, researchers urge doctors to “minimize the risk to patients” by considering carefully the evidence before prescribing ketamine off-label for patients to treat depression and prevent suicide.
Citing “questionable practice” regarding the prescription of ketamine, they point out that there is not enough evidence to prove that ketamine is safe, and that some studies supporting its use have not been sufficiently rigorous in terms of research ethics.
They call for open debate, more research, and for doctors to try all other options first, before prescribing ketamine.
The National Institutes of Health (NIH) are currently supporting research into whether ketamine may help people with treatment-resistant depression.
Ketamine use can have a wide variety of adverse effects, including:
changes in perceptions of color or sound
hallucinations, confusion, and delirium
dissociation from body or identity
difficulty thinking or learning
dilated pupils and changes in eyesight
inability to control eye movements
involuntary muscle movements and muscle stiffness
slow heart beat
increased pressure in the eyes and brain
It can also lead to a loss of appetite, upset stomach, and vomiting.
When used as an anesthetic in humans, doctors combine it with another drug to prevent hallucinations.
Ketamine is considered relatively safe in medical settings, because it does not affect the protective airway reflexes, and it does not depress the circulatory system, as other anesthetic medications do.
However, some patients have reported disturbing sensations when awakening from ketamine anesthesia.
Ketamine can cause an increase in blood pressure and intracranial pressure, or pressure in the brain.
People with the following conditions cannot receive ketamine for medical purposes:
brain lesion or tumor
It is used with caution in those with:
coronary artery disease
increased blood pressure
chronic alcohol addiction
acute alcohol intoxication
These effects may be stronger in people aged over 65 years.
Some people may have an allergy to the ingredients. Patients with any type of allergy should tell their doctor before using any medication.
Anyone who is using this drug for therapeutic purposes on a regular basis should have regular blood pressure checks.
As a drug of abuse
Ketamine is most often used in the dance club setting as a party drug. It produces an abrupt high that lasts for about an hour. Users report euphoria, along with feelings of floating and other “out of body” sensations. Hallucinations, similar to those experienced with LSD, are common.
In 2014, 1.4 percent of 12th graders reported using ketamine for recreational purposes. This was down from 2002, when 2.6 percent reported using it.
Street names include:
The horse tranquilizer
It is taken orally as a pill, snorted, smoked with tobacco or marijuana, or mixed into drinks. Most often, it is cooked into a white powder for snorting. Taken orally, it can cause severe nausea and vomiting.
Regardless of how it is ingested, its effects begin within a few minutes and last for less than an hour.
Higher doses can produce more intense effects known as being in the “K-hole,” where users become unable to move or communicate and feel very far away from their body.
Some users seek out this type of transcendental experience, while others find it terrifying and consider it an adverse effect.
As the user can become oblivious to their environment, ketamine abuse puts the person at risk of accidental injury to themselves and vulnerable to assault by others.
Problems with co-ordination, judgment, and the physical senses can continue for up to 24 hours. If an individual is using ketamine in a recreational setting, a sober friend should remain with them to ensure their safety.
Long-term effects include bladder and kidney problems, stomach pain, and memory loss.
If addiction and dependence develop, there is also a risk of depression.
Frequent, illegal use of ketamine can lead to serious mental disorders and major physical harm to the bladder, known as ketamine-induced ulcerative cystitis.
Ketamine and alcohol
Ketamine toxicity alone is unlikely to lead to death, according to the WHO. However, combining it with other substances, such as alcohol, can increase the sedative effects, possibly leading to a fatal overdose.
In the U.S., 1,550 emergency department (ED) visits were due to illegal ketamine use, and 71.5 percent of these also involved alcohol.
The risk of overdose is high, because, for a recreational user, there is only a slight difference in dosage between obtaining the drug’s desired effects and an overdose.
Ketamine is a Class III controlled substance. Prolonged use can cause dependence, tolerance, and withdrawal symptoms. Quitting can lead to depression, anxiety, insomnia, and flashbacks.
Chronic users have been known to “binge” their ketamine use in an attempt to experience again the dissociative, euphoric effects of their early first use.
The complications of long-term use can be fatal.
A final word
Ketamine is an anesthetic drug, used in human and veterinary medicine. It is important to distinguish the valid medical uses from the non-medical, recreational use of the drug.
When properly administered by a trained medical professional, ketamine is a safe and valuable medication.
Used in recreational settings, however, ketamine abuse can produce unpredictable physical and mental health results. In the long term, it can lead to psychological damage and, in some cases, death.
Any drug use should be prescribed by a doctor who knows the patient’s full medical history.
At NOVA Health recovery [703-844-0184 | Fairfax, Va 22306 ] we offer our patients cutting-edge treatment options for their depression, and one of our main stars is IV (intravenous) ketamine. But why does it have to be IV? “I don’t like needles, why can’t I just take this as a pill or as that nasal spray everyone is talking about?” you may be thinking. IV is the best route for your brain to receive ketamine because of something called bioavailability. In addition, it is also more effective, more precise, and safer for you.
What is bioavailability? It is the amount of medication that your body and brain is actually able to use, which is sometimes different than the amount of medication that your body receives. When you take any medication, parts of the active ingredients in them don’t go to your bloodstream; they get digested, altered into an unusable form, metabolized and excreted into your body. This is particularly prevalent in oral and intranasal medications. In fact, receiving a medication intravenously is the only way to have 100% bioavailability. Let’s take a look at the different bioavailability percentages based on what route you receive ketamine:
When we give ketamine intravenously, we know exactly where your entire dose is going: straight to your brain. The same cannot be said for other forms of ketamine. Intranasal ketamine has to bypass several layers of tissue before it can reach your brain, and too many things can happen that could cause you to lose some or most of your dose: sneezing, dripping, running down the back of your throat, etc. The same can be said for an oral pill and an intramuscular injection; these routes are just too unpredictable, and when it comes to treating your depression, we don’t want the results to be unpredictable.
When you receive IV ketamine in our office setting, it is given slowly over one hour. By doing this, we are able to monitor you closely, and if you experience any unpleasant side effects and want to stop the infusion, we are able to do that. By contrast, a dose of ketamine via intranasal spray would be done at home with no physician or nursing supervision, so side effects cannot be immediately addressed if they arise. The same is true for intramuscular or oral dosing – after you take the pill, or receive a shot of ketamine into your muscle, there is no way to stop the absorption of the medication into your bloodstream as the full dose is administered within seconds.
IV ketamine is by far the safest and most effective approach in using ketamine to treat depression. You are in a comfortable setting with healthcare providers with you the whole time, the potential for side effects is low, and you are certain that the dose you receive is the dose that is going to your brain, maximizing the benefits of this cutting-edge treatment.
However, we do offer the other routes of administration and take – home prescriptions for Ketamine therapies for those who are in our program. Contact us today at 703-844-0184 to get started on your treatment.
Researchers observed no long-term adverse effects in a small sample of patients with severe and treatment-resistant mood disorders who received ketamine infusions as clinical treatment.
Although the response and remission rates after a four-infusion protocol were lower than those reported in most clinical trials, the small size and racial homogeneity of the study population limit the generalizability of these findings, according to data published in Journal of Clinical Psychiatry.
“Ketamine is being used as an off-label treatment for depression by an increasing number of providers, yet there is very little long-term data on patients who have received ketamine for more than just a few weeks,” Samuel T. Wilkinson, MD, from the department of psychiatry, Yale School of Medicine and Yale Psychiatric Hospital, told Healio Psychiatry.
“Controversy remains about whether ketamine should be used outside of research protocols due to concerns regarding potential negative clinical outcomes for repeated use, including impaired cognition, delusions and interstitial cystitis,” Wilkinson and colleagues wrote in their article.
At first, patients received a single- or double-infusion protocol (0.5 mg/kg over 40 minutes IV); but in early 2015, the researchers transitioned to a four-dose protocol over 2 weeks based on emerging evidence supporting the safety of a multiple-infusion protocol. They tracked symptom severity and set cognitive assessments at baseline and after every 6 to 12 treatments.
From October 2014 through February 2017, 54 patients received ketamine, with 518 total infusions performed. Ketamine infusions given at 0.5 mg/kg over 40 minutes were well-tolerated. Two patients discontinued treatment prematurely: one for intolerable dissociative effects and one for transient hypertension.
In the subset of 44 patients with mood disorders who began the four-infusion protocol, 45.5% responded and 27.3% remitted by the fourth infusion, which were lower rates than those reported in most previous clinical trials, according to the authors. Patients showed a significant reduction in symptoms over time. The overall mean score, as measured by the Quick Inventory of Depressive Symptomatology (Self-Report), dropped by 37.9% and the overall mean depression score dropped by 37.8%.
“While our paper has a number of limitations, one of its strengths is the long-term follow-up of a small cohort of patients who have received ketamine for depression, some for over a year,” Wilkinson told Healio Psychiatry. “Though we were not able to follow patients with the same level of rigor as a sponsored clinical trial, we observed no obvious adverse long-term effects on cognition, development of psychosis, or new-onset cases of ketamine abuse.”
In a subsample of 14 patients who received long-term ketamine infusions ranging from 12 to 45 total treatments over a course of 14 to 126 weeks, there was no evidence of cognitive decline, increased inclination for delusions or emerging symptoms consistent with cystitis.
“Given that racemic ketamine hydrochloride no longer has patent protections, it is unlikely that large and long-term clinical trials will be conducted to provide such long-term safety data,” they continued. “The formation of a registry combining data from community and academic sites is therefore the most realistic way of capturing long-term data on the effectiveness and safety of ketamine as a treatment for mood disorders.” –
Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid
Ketamine is emerging as a way to treat depression, but it appears to act like an opioid, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions.
A handful of pharmaceutical companies, including Johnson & Johnson and Allergan, are using ketamine as inspiration for new prescription drugs to treat depression.
This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as “Special K.”
Ketamine is emerging as a way to treat depression, but it appears to act like an opioid — and it may carry similar risks, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions. A handful of pharmaceutical companies are using ketamine as inspiration for new prescription drugs to treat depression. Yet the new research questions whether scientists know enough about chronic ketamine use to introduce it broadly.
The drug blocks NMDA receptors, which scientists think may treat depressive symptoms. Researchers wanted to test whether it was possible to elicit this reaction without activating the brain’s opioid receptors.
To block an opioid response, they gave participants naltrexone then infused them with ketamine. To compare that response with the normal response, they also gave participants a placebo before giving them the treatment.
Naltrexone so successfully blocked the anti-depressant effects of ketamine that researchers cancelled the study after the first interval because they felt it wasn’t ethical to continue it, said Dr. Nolan Williams, one of the study’s authors and a clinical assistant professor of psychiatry and behavioral sciences at Stanford University.
When patients took naltrexone, the opioid blocker, their symptoms did not improve, suggesting ketamine must first activate opioid receptors in order to treat depression, according to the study, published Wednesday in the American Journal of Psychiatry.
That’s not to say ketamine cannot be used occasionally, but it does raise questions about using it repeatedly over time, said Dr. Alan F. Schatzberg, co-author of the study and Stanford’s Kenneth T. Norris, Jr., professor of psychiatry and behavioral sciences. He likens it to opioid painkillers being an appropriate pain treatment when used once in the emergency room but posing problems, such as the risk of dependence, when used chronically.
“More studies need to be done to fully understand ketamine before it’s widely rolled out for long-term chronic use,” Schatzberg said.
Researchers planned on studying 30 adults but stopped enrolling patients once they decided combining ketamine and naltrexone was not only ineffective but also “noxious” for many participants. They tested a total of 12 people with both naltrexone and the placebo.
Of those 12, seven who received naltrexone experienced nausea after the ketamine infusion, compared to three in the placebo group. Two participants in each group also experienced vomiting.
Participants who received the placebo and ketamine treatment reported reduced depression symptoms. But those same participants did not see a decrease in depression symptoms after receiving ketamine and opioid-blocker naltrexone.
“We essentially blocked the mechanism for producing the anti-depressant effect, which were opioids,” said Williams.
The findings may have implications for clinics offering ketamine infusions and drug manufacturers trying to commercialize ketamine-like drugs.
Ketamine is meant to be used as an anesthetic. Since ketamine is currently not indicated to treat depression, insurance typically doesn’t cover the cost of infusions, so people tend to pay out of their own pocket. One session can run more than $500.
Meanwhile, drug giant Johnson & Johnson plans to seek approval from the Food and Drug Administration for its nasal spray esketamine this year after reporting positive results from a Phase 3 trial. Allergan plans to file its drug Rapastinel, which targets the NMDA receptors like ketamine, within the next two years. VistaGen Therapeutics is working on a similar drug.
In a statement, J&J said while the study reviewed ketamine and not esketamine, the findings “are difficult to interpret because of the study’s design.”