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Ketamine infusion well-tolerated in small sample with mood disorders

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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.

Ketamine treatments were given in an electroconvulsive therapy suite. In late 2014, Yale began providing ketamine as an off-label therapy on a case-by-case basis for patients who could not participate in research protocols. In the current article, the authors assessed the participants’ experience over 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders.

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.

“There remains an urgent need for more powerful and comprehensive long-term safety data on ketamine from much larger samples,” Wilkinson and colleagues wrote.

“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.” – by Savannah Demko

Disclosure : Wilkinson reports support from the Brain and Behavioral Research Foundation, the National Institute of Mental Health, the Robert E. Leet and Clara Guthrie Patterson Trust and Yale-New Haven Hospital. Please see the study for all other authors’ relevant financial disclosures.

 


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Trippy depression treatment? Hopes and hype for ketamine

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Lauren Pestikas sits as she receives an infusion of the drug ketamine during a 45-minute session at an outpatient clinic in Chicago on July 25, 2018. Pestikas struggled with depression and anxiety and made several suicide attempts before starting ketamine treatments earlier in the year. (AP Photo/Teresa Crawford)

CHICAGO (AP) — It was launched decades ago as an anesthetic for animals and people, became a potent battlefield pain reliever in Vietnam and morphed into the trippy club drug Special K.

Now the chameleon drug ketamine is finding new life as an unapproved treatment for depression and suicidal behavior. Clinics have opened around the United States promising instant relief with their “unique” doses of ketamine in IVs, sprays or pills. And desperate patients are shelling out thousands of dollars for treatment often not covered by health insurance, with scant evidence on long-term benefits and risks.

Chicago preschool teacher Lauren Pestikas long struggled with depression and anxiety and made several suicide attempts before trying ketamine earlier this year.

The price tag so far is about $3,000, but “it’s worth every dime and penny,” said the 36-year-old.

Pestikas said she feels much better for a few weeks after each treatment, but the effects wear off and she scrambles to find a way to pay for another one.

For now, ketamine has not received approval from the U.S. Food and Drug Administration for treating depression, though doctors can use it for that purpose.

Some studies show ketamine can provide relief within hours for tough-to-treat depression and suicidal behavior and clinics promising unproven benefits have popped up nationwide. But more research is needed to know long-term benefits and risks. (Oct. 31)

Ketamine has been around since the 1960s and is widely used as an anesthesia drug during surgery because it doesn’t suppress breathing. Compared to opioids such as morphine, ketamine isn’t as addictive and doesn’t cause breathing problems. And some studies have shown that ketamine can ease symptoms within hours for the toughest cases.

Its potential effects on depression were discovered in animal experiments in the late 1980s and early 1990s showing that glutamate, a brain chemical messenger, might play a role in depression, and that drugs including ketamine that target the glutamate pathway might work as antidepressants.

Conventional antidepressants like Prozac target serotonin, a different chemical messenger, and typically take weeks to months to kick in — a lag that can cause severely depressed patients to sink deeper into despair.

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A vial of ketamine, which is normally stored in a locked cabinet, on display in Chicago on July 25, 2018. AP Photo/Teresa Crawford)

Ketamine’s potential for almost immediate if temporary relief is what makes it so exciting, said Dr. Jennifer Vande Voort, a Mayo Clinic psychiatrist who has used ketamine to treat depression patients since February.

“We don’t have a lot of things that provide that kind of effect. What I worry about is that it gets so hyped up,” she said.

The strongest studies suggest it’s most useful and generally safe in providing short-term help for patients who have not benefited from antidepressants. That amounts to about one-third of the roughly 300 million people with depression worldwide.

“It truly has revolutionized the field,” changing scientists’ views on how depression affects the brain and showing that rapid relief is possible, said Yale University psychiatrist Dr. Gerard Sanacora, who has done research for or consulted with companies seeking to develop ketamine-based drugs.

But to become standard depression treatment, he said, much more needs to be known.

Last year, Sanacora co-authored an American Psychiatric Association task force review of ketamine treatment for mood disorders that noted the benefits but said “major gaps” remain in knowledge about long-term effectiveness and safety. Most studies have been small, done in research settings and not in the real world.

When delivered through an IV, ketamine can cause a rapid increase in heart rate and blood pressure that could be dangerous for some patients. Ketamine also can cause hallucinations that some patients find scary.

“There are some very real concerns,” Sanacora said. “We do know this drug can be abused, so we have to be very careful about how this is developed.”

Dr. Rahul Khare, an emergency medicine specialist in Chicago, first learned about ketamine’s other potential benefits a decade ago from a depressed and anxious patient he was preparing to sedate to fix a repeat dislocated shoulder.

“He said, ‘Doc, give me what I got last time. For about three weeks after I got it I felt so much better,’” Khare recalled.

Khare became intrigued and earlier this year began offering ketamine for severe depression at an outpatient clinic he opened a few years ago. He also joined the American Society for Ketamine Physicians, formed a year ago representing about 140 U.S. doctors, nurses, psychologists and others using ketamine for depression or other nonapproved uses.

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Dr. Rahul Khare poses for a portrait at his outpatient Chicago clinic on July 25, 2018. (AP Photo/Teresa Crawford)

There are about 150 U.S. ketamine clinics, compared with about 20 three years ago, said society co-founder Dr. Megan Oxley.

Khare said the burgeoning field “is like a new frontier” where doctors gather at meetings and compare notes. He has treated about 50 patients with depression including Pestikas. They’re typically desperate for relief after failing to respond to other antidepressants. Some have lost jobs and relationships because of severe depression, and most find that ketamine allows them to function, Khare said.

Typical treatment at his clinic involves six 45-minute sessions over about two weeks, costing $550 each. Some insurers will pay about half of that, covering Khare’s office visit cost. Patients can receive “booster” treatments. They must sign a four-page consent form that says benefits may not be long-lasting, lists potential side effects, and in bold letters states that the treatment is not government-approved.

At a recent session, Pestikas’s seventh, she leaned back on a reclining white examining-room chair as a nurse hooked her up to a heart and blood pressure monitor. She grimaced as a needle was slipped into the top of her left palm. Khare reached up with a syringe to inject a small dose of ketamine into an IV bag hanging above the chair, then dimmed the lights, pulled the window curtains and asked if she had questions and was feeling OK.

“No questions, just grateful,” Pestikas replied, smiling.

Pestikas listened to music on her iPhone and watched psychedelic videos. She said it was like “a controlled acid trip” with pleasant hallucinations. The trip ends soon after the IV is removed, but Pestikas said she feels calm and relaxed the rest of the day, and that the mood boost can last weeks.

Studies suggest that a single IV dose of ketamine far smaller than used for sedation or partying can help many patients gain relief within about four hours and lasting nearly a week or so.

Exactly how ketamine works is unclear, but one idea is that by elevating glutamate levels, ketamine helps nerve cells re-establish connections that were disabled by depression, said ketamine expert Dr. Carlos Zarate, chief of experimental therapies at the National Institute of Mental Health.

A small Stanford University study published in August suggested that ketamine may help relieve depression by activating the brain’s opioid receptors.

Janssen Pharmaceuticals and Allergan are among drug companies developing ketamine-like drugs for depression. Janssen leads the effort with its nasal spray esketamine. The company filed a new drug application in September.

Meanwhile, dozens of studies are underway seeking to answer some of the unknowns about ketamine including whether repeat IV treatments work better for depression and if there’s a way to zero in on which patients are most likely to benefit.

Until there are answers, Zarate of the mental health institute said ketamine should be a last-resort treatment for depression after other methods have failed.

___

https://youtu.be/ENEeoLw-030




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Ketamine and Depression

ketamine

ketamine

Introduction

What comes to mind when you think of Ketamine? A drug of abuse? A horse tranquiliser? An anaesthetic agent? In reality it is all three. It usually has short-term hallucinogenic effects or causes a dissociative feeling (e.g. detachment from reality, sedation, or  inability to move). However, with frequent use over time it can cause permanent problems such as ‘ketamine bladder’, resulting in pain and difficulty passing urine.

What we already know

 

Ketamine’s effects are mainly mediated via NMDA (N-methyl-D-aspartate) receptor antagonism, although it is also an agonist at some opioid receptors and interacts with various other receptors, including noradrenaline, serotonin and muscarinic cholinergic receptors.

It is a class B illicit substance and was, in fact, upgraded from class C in June 2014 following a review of its harmful effects. Ketamine (either intramuscularly or intravenously) is licensed for use as an anaesthetic agent in children, young people and adults, but over the last few years interest has been growing in the role of Ketamine as an antidepressant agent. It is not currently licensed for this purpose.

Areas of uncertainty

A study published in 2013 suggested that a single injected dose of Ketamine was associated with a rapid-onset antidepressant effect in patients with treatment-resistant depression (Murrough et al). The biggest challenge in terms of research with ketamine is that it remains tricky to compare against a placebo, given the fairly obvious side effects of taking a hallucinogenic drug, but this study compared Ketamine with Midazolam and this is probably the best comparator so far.

The following year, an open label study was published, which found similar antidepressant effects but a whole host of adverse effects were identified (Diamond et al), including anxiety and panic symptoms, increased suicidal ideation, vomiting, headaches and the anticipated feelings of detachment, confusion and dissociative symptoms.

There was a paucity of good quality information until, in 2015, a systematic review and meta-analysis of 21 studies  showed that single ketamine infusions produced a significant anti-depressant effect for up to seven days. Beyond this time, there was no evidence to suggest a prolonged effect.

What’s in the pipeline

There is some evidence to suggest that Ketamine may also work for Post-Traumatic Stress Disorder and Obsessive Compulsive Disorder. Another proposed use for Ketamine (currently being researched at the University of Manchester) is as an adjunct for Electroconvulsive Therapy (ECT), potentially minimizing the cognitive impairments experienced post-ECT.

Ketamine remains one of the most promising new treatments for depression, both unipolar and bipolar, but it is not without its problems. Requiring specialist referral and a stay in hospital overnight for a single dose clearly has financial and logistical implications far beyond those of antidepressant tablets with a stronger evidence base behind them. We also need more information about safety and adverse effects, before it can be introduced to a wider market.

References

Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum. Psychopharmacol Clin Exp. [Abstract]

Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, Geddes JR and McShane R. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic (PDF). J Psychopharmacol, 0269881114527361, first published on April 3, 2014. [PDF]

Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M. et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression; a two-site randomized controlled trial. Am J Psychiatry, 170, 1134-1142. [Abstract]

The antidepressant effects of ketamine are confirmed by a new systematic review and meta-analysis

shutterstock_18453376In recent times, few drugs have caused more excitement among clinical researchers than ketamine. It’s well known for its role in anaesthesia and veterinary surgery (“horse tranquilizer”), as well as its illicit use, but progress has been ongoing for about 15 years to repurpose it as an antidepressant.

As a consequence, many new studies are published every month that evaluate to what extent ketamine lives up to its promise as a new antidepressant drug (Aan Het Rot, Zarate, Charney, & Mathew, 2012). To make sense of the flood of new information, naturally intrigued mental elves clearly need researchers to provide timely updates of the current state of knowledge. To this end, Coyle and Laws (2015) have recently published an extensive systematic review and the first meta-analysis that summarises the latest, methodologically sound research.

The key questions of interest to these researchers were:

  • Does ketamine have an immediate effect in reducing depressive symptoms?
  • Are the antidepressant effects of ketamine sustained over time?
  • Are repeat infusions more effective in reducing depressive symptoms?
  • Do primary diagnosis and experimental design moderate the impact of ketamine on depressive symptoms?
  • Do men and women experience differences in the antidepressant effect of ketamine?

This review looked at how well the effects of ketamine are maintained over

This review looked at how well the effects of ketamine are maintained over 4 hours, 24 hours, 7 days and 12-14 days.

Methods

The authors followed PRISMA guidelines and scanned all relevant medical databases for studies assessing the antidepressant potential of ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). To evaluate possible methodological factors and design variables, the authors also specifically assessed whether studies were: repeat/single infusion, diagnosis, open-label/participant-blind infusion, pre-post/placebo-controlled design and patients’ sex.

Effect sizes were calculated either relative to placebo or relative to baseline, in case no control group was provided. To correct for bias in small studies, a Hedge’s g procedure with random effects was used. Statistical heterogeneity, publication bias and moderator variables were assessed to have an idea of other variables that might influence the reported antidepressant potential of ketamine. Statistical heterogeneity among studies was assessed using I² values, with values above 50% generally representing substantial heterogeneity.

Results

In total, 21 studies enrolling 437 patients receiving ketamine were identified that satisfied inclusion criteria:

  • 17 were single infusion studies and the majority reported data collected at 4h (11) and 24h (13) after ketamine treatment
  • 6 studies had follow-up for 7 days
  • 4 studies had follow-up for 12-14 days

In general, there are grounds to assume publication bias for single infusion studies at 4h and 24h.

Of the 21 included studies, 2 were judged to be at a high risk of bias, 13 medium risk and 6 low risk of bias.

  • In general, ketamine had a large statistical effect on depressive symptoms that was comparable across all time points
  • Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days
  • For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days
  • The overall pooled effect sizes for single and repeated ketamine infusions found no difference at any time point, suggesting that the antidepressant effects of ketamine are maintained for at least 12-14 days

table3

Moderator analyses suggest that responsiveness to ketamine may vary according to diagnosis. Specifically, while ketamine produced moderate to large effects in both MDD and BD patients, the effect of a single infusion was significantly larger in MDD than BD after 24h. On the other hand, after 7 days, this pattern reversed and ketamine showed higher efficacy in BD patients. However, the small number of studies makes it tricky to draw any conclusions.

In addition, single-infusion pre-post comparisons did not differ in effect size estimation from placebo-controlled designs except for at 12-14 days, where only one study was available. In a similar vein, there were no effect size differences between single infusion studies with open-label and blinded infusions.

Of note, the meta-analysis found the percentage of males in the group was positively associated with ketamine’s antidepressant effects after 7 days, although this finding warrants replication with more data points.

There's huge room for improvement in the primary research, but this analysis shows ketamine in a promising light as an antidepressant.

There’s plenty of room for improvement in the primary research, but this meta-analysis shows ketamine in a promising light as an antidepressant.

Conclusions

The authors conclude:

Single ketamine infusions elicit a significant anti-depressant effect from 4h to 7days; the small number of studies at 12-14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis – 24 h for MDD and 7 days for BD. The majority of published studies have used pre-post comparison; further placebo-controlled studies would help to clarify the effect of ketamine over time.

Limitations

This meta-analysis suffers from several limitations that are inherent in the available studies:

  • For one, there were only four studies that assessed the effect of repeated ketamine infusions, which is a shame given that maintenance of antidepressant effects is one of the key drawbacks of rapidly acting interventions
  • In addition, the authors note that their results suggest publication bias, which may be taken to indicate that several negative findings have not been published and thus could not be included in this meta-analysis
  • Also, more information about adverse effects would have been useful, especially to evaluate whether ketamine can be safely applied in a broader clinical context

Summary

This is the first meta-analysis to evaluate ketamine’s antidepressant effects. For single infusion specifically, ketamine exerts large antidepressant effects in MDD as well as BD patients that seem to last at least 7 days, while too few studies are available beyond this time point.

It’s noteworthy that the effect sizes did not differ between time points, which indicates that the effect of a single infusion remains relatively stable in the short-term. While repeated infusions were shown to provide higher effects than single infusions at least for the first week, more studies are needed to corroborate the supremacy of repeated treatment.

Before ketamine can become a clinically viable treatment option, however, this review makes it clear that more methodologically refined studies (especially RCTs with adequate placebo controls) need to be conducted. With this in mind, researchers should take these findings as an incitement to action!

High quality

High quality placebo controlled trials are needed to drive forward progress in this field.

Links

Primary paper

Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysisHum. Psychopharmacol Clin Exp, doi: 10.1002/hup.2475. [PubMed abstract]

Other references

Aan Het Rot, M., Zarate, C. a, Charney, D. S., & Mathew, S. J. (2012). Ketamine for depression: where do we go from here? Biological Psychiatry72(7), 537–47. doi:10.1016/j.biopsych.2012.05.003


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The use of Ketamine for depression has been increasingly utilized and found effective for suicidal thoughts and treatment -resistant depression. The article below discusses the use of Ketamine in other mood disorders and the manner with which it is given:

 

Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders

Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders

JAMA. 2017;318(9):793-794. doi:10.1001/jama.2017.10697

Agrowing number of small clinical trials have demonstrated that subanesthetic doses of ketamine can produce antidepressant effects in patients with mood disorders who have demonstrated refractoriness to standard therapies.1 Patients in these trials have been diagnosed with major depressive disorder and bipolar disorder, and the sample sizes have ranged from 8 to 99. While there is broad agreement that ketamine-like drugs hold considerable promise as novel antidepressant agents, the increasing number of clinicians from a variety of medical specialties offering ketamine as an off-label treatment for psychiatric disorders2 has raised concern.

Although ketamine has been approved by the US Food and Drug Administration (FDA) as an anesthetic for more than 45 years, there remain concerns about the safety of repeated ketamine dosing. These concerns stem in part from reports of cognitive impairment and bladder dysfunction associated with repeated administration of the drug in rodent models and in humans with ketamine use disorder. Furthermore, concerns of spawning a substantial increase in iatrogenic ketamine use disorder related to wider use of ketamine for treating mental health disorders have led some to suggest more restricted use until additional data are available.

However, the lack of patent protection surrounding the use of racemic ketamine hydrochloride as a treatment for mood disorders makes it unlikely that larger phase 3 trials required for FDA consideration or standard postmarketing surveillance studies addressing issues of longer-term safety and effectiveness will ever be completed. In light of these facts, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments issued a consensus statement on the off-label use of ketamine for the treatment of mood disorders.3 This Viewpoint summarizes a number of important issues related to the clinical use of ketamine for the treatment of psychiatric disorders addressed in the consensus statement and provides suggestions for addressing remaining concerns.

Who Should Be Considered for Ketamine Treatment?

There was strong agreement among the contributors to the consensus that appropriate patient selection is a critical and necessary factor in optimizing the risk/benefit ratio of this novel treatment strategy. This requires a comprehensive evaluation and thorough consideration of the individual’s potential risks and benefits, considering the medical, psychological, and social factors specific to each patient. Considering the limited longer-term safety and efficacy data, only patients who have not responded to adequate trials of more standard antidepressant treatments should be candidates. Agreement was also reached that patients should be informed of the extent of the existing evidence regarding the use of ketamine in the treatment of psychiatric disorders before they provide consent to treatment. This should include acknowledgment of the relative dearth of published data on any diagnosis other than major depressive episodes, the limited evidence of long-term effectiveness, the possible or likely need for repeated administrations to maintain response, and the concerns regarding cognitive impairment, cystitis, and abuse liability.

Clinical Experience, Training, and Treatment Setting

No published guidelines exist delineating required clinician training prior to providing subanesthetic doses of ketamine as a treatment. Considering the delivery regimen most commonly used in published research protocols (0.5 mg/kg infused intravenously over 40 minutes) typically results in peak ketamine serum levels that are an order of magnitude below the peak levels used for anesthesia,4 it does not seem reasonable to impose the same training requirements as would be used in the case of ketamine anesthesia. However, even subanesthetic doses of ketamine can induce potentially concerning transient elevations in both heart rate and blood pressure.5 In addition, patients may also experience prominent psychoactive effects (such as perceptual and cognitive disturbances, derealization, and depersonalization) that can persist for 30 to 120 minutes following infusion cessation.

In consideration of these risks, the consensus statement recommended that, at a minimum, clinicians who administer ketamine be prepared to manage both cardiovascular and behavioral events should such arise, and suggested certification in Advanced Cardiac Life Support for clinicians delivering the treatment. The consensus statement also suggests that ketamine be provided by a clinician who can administer Drug Enforcement Agency Schedule III medications (in most states, this is a licensed physician with an MD or DO degree). The treatment facility should have a means of providing basic cardiac and respiratory monitoring as well as an established plan for providing stabilization and rapid transfer of patients with sustained alterations in cardiac functioning.

Dose and Delivery Procedure

Most evidence available to date has supported the use of 0.5-mg/kg ketamine hydrochloride given intravenously over 40 minutes. Comparatively little research has been published on other doses, routes of administration, or infusion durations. The only available randomized clinical data comparing various doses come from 2 small trials of 99 and 71 patients that suggest both lower and higher ketamine doses (0.1-1.0 mg/kg) may have some efficacy. Nevertheless, it should be noted that in both studies, the more commonly used 0.5-mg/kg dose was at least numerically more efficacious.6,7 Furthermore, the increased efficacy of the 0.5-mg/kg dose may be more pronounced in patients with severe depression compared with lower doses.7 However, lower doses do appear to have few associated adverse events. Thus, because of limited data, it is not possible to clarify the relative benefits and risks of doses other than 0.5 mg/kg delivered intravenously over 40 minutes.

To ensure patient safety, site-specific standard operating procedures should be developed and should include assessments of baseline vital signs, confirmation of preprocedural informed consent, criteria for acceptable baseline vital signs prior to initiating treatment, and criteria for prematurely stopping an infusion. Posttreatment assessments should confirm that each patient returns to a mental state that will allow for a safe return to the current living situation and a responsible adult should be available to transport the patient home if treatments are done on an outpatient basis.

Course of Treatment Planning

The only existing study to date examining dosing frequency suggests that dosing thrice weekly is no better than twice weekly induction dosing, although this evidence comes from a comparatively small (n = 68) randomized clinical trial.5 While some clinicians have reported more frequent dosing strategies,2 there is currently no published evidence to support the benefits of this practice over lower-frequency treatments.

Most published data supporting the use of ketamine as a treatment for mood disorders are based on trials that have followed up patients for just 1 week after a single administration of the drug.1 While a few small trials (7 trials with sample sizes ranging from 9 to 68) have demonstrated the relative safety of repeated infusions (4-6 total infusions over a couple of weeks), there is very little published data on the efficacy and safety of longer-term use. Most of these repeated dosing trials have shown that the majority of benefit experienced by patients occurs within the first 2 weeks of treatment. Hence, it may be reasonable to discontinue treatment after 2 weeks if no meaningful benefit is achieved.

As most trials to date suggest that a short course of ketamine does not usually provide long-lasting benefits to patients with a chronic disease, many clinicians currently offer maintenance ketamine treatment.2 However, there is insufficient evidence to meaningfully inform long-term treatment with ketamine. Considering the liability of the potential for abuse as well as concerns for cognitive impairment and cystitis associated with chronic high-frequency exposure, it is reasonable to suggest that clinicians limit the administration to the minimum effective dosing frequency and use recurring assessments of cognition, bladder functioning, and substance use when long-term treatment is provided until more information on the longer-term safety is available. Moreover, during this early stage of clinical development, the consensus statement strongly cautions against the practice of take-home, self-administration of ketamine.

Conclusions

While the discovery of ketamine’s robust and rapid-acting antidepressant effects has appropriately led to considerable enthusiasm among some clinicians and considerable hope among some patients, this enthusiasm for this promising treatment should be coupled with caution given the limitations of the existing knowledge base and the potential adverse effects of long-term treatment. However, considering the tremendous individual and societal burden of mood disorders, the high percentage of patients that do not achieve satisfactory responses from the currently available approved treatments, and the recent evidence of rising rates of suicide, expedited research into this potentially transformative treatment is needed. Several ongoing studies (such as NCT01945047NCT03113968, and NCT00088699) are attempting to address these knowledge gaps and enrollment in these trials should be encouraged when possible. In addition to the standard randomized clinical trials, the creation of a registry of patients receiving ketamine off-label as a treatment for mood disorders could serve as an efficient way to learn more about the longer-term effectiveness and safety of the treatment and could be beneficial in guiding the rational use of the treatment.

References
1.

Newport  DJ, Carpenter  LL, McDonald  WM, Potash  JB, Tohen  M, Nemeroff  CB; APA Council of Research Task Force on Novel Biomarkers and Treatments.  Ketamine and other NMDA antagonists.  Am J Psychiatry. 2015;172(10):950-966.PubMedGoogle ScholarCrossref
2.

Wilkinson  ST, Toprak  M, Turner  MS, Levine  SP, Katz  RB, Sanacora  G.  A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders.  Am J Psychiatry. 2017;174(7):695-696.PubMedGoogle ScholarCrossref
3.

Sanacora  G, Frye  MA, McDonald  W,  et al; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments.  A consensus statement on the use of ketamine in the treatment of mood disorders.  JAMA Psychiatry. 2017;74(4):399-405.PubMedGoogle ScholarCrossref
4.

Vuyk  J, Sitsen  E, Reekers  M. Intravenous anesthetics. In: Miller  RD, ed.  Miller’s Anesthesia. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:821-863.
5.

Singh  JB, Fedgchin  M, Daly  EJ,  et al.  A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression.  Am J Psychiatry. 2016;173(8):816-826.PubMedGoogle ScholarCrossref
6.

Fava  M, Freeman  MP, Flynn  M,  et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression. Presented at: Annual Meeting of the American Society of Clinical Psychopharmacology; May 30, 2017; Miami, Florida.
7.

Su  TP, Chen  MH, Li  CT,  et al.  Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression [published online May 11, 2017].  Neuropsychopharmacology. doi:10.1038/npp.2017.94PubMedGoogle Scholar

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

Gerard Sanacora, MD, PhD1Mark A. Frye, MD2William McDonald, MD3et alSanjay J. Mathew, MD4,5Mason S. Turner, MD6Alan F. Schatzberg, MD7Paul Summergrad, MD8Charles B. Nemeroff, MD, PhD9; for the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments
JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080

Abstract

Importance  Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.

Observations  This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. 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.

Conclusions and Relevance  The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Introduction

The American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments found that the data from 7 published placebo-controlled, double-blind, randomized clinical studies on ketamine hydrochloride infusion therapy in the treatment of depression comprising 147 treated patients provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient.”1(p958) Reports of ketamine’s unique antidepressant effects, combined with frequent media coverage promulgating the potential benefits of ketamine treatment, have generated substantial interest and optimism among patients, families, patient advocacy groups, and clinicians alike. This interest has led to a rapidly escalating demand for clinical access to ketamine treatment and an increasing number of clinicians willing to provide it. However, many in the field suggest that caution should be used with this approach, as the numbers of patients included in these published studies and case series remain relatively small (the eTable in the Supplement compares other recently developed treatments), and ketamine treatment for mood disorders has not been tested in larger-scale clinical trials to demonstrate its durability and safety over time.2,3 Moreover, the treatment approach has not been subject to the scrutiny of a US Food and Drug Administration review or approval for an on-label psychiatric indication, and, despite more than 45 years of clinical experience with ketamine as an anesthetic agent, there are no postmarketing surveillance data on the use of ketamine for any psychiatric indication to provide information on its safety and effectiveness.

The relatively unique nature of this situation presents an urgent need for some guidance on the issues surrounding the use of ketamine treatment in mood disorders. This review by the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments Subgroup on Treatment Recommendations for Clinical Use of Ketamine is intended to complement the recent American Psychiatric Association meta-analysis1 and other recent reviews410 and aims to provide an overview and expert clinical opinion of the critical issues and considerations associated with the off-label use of ketamine treatment for mood disorders. Because relatively limited high-quality, published information on this topic exists, to our knowledge, this report is not intended to serve as a standard, guideline, clinical policy, or absolute requirement. The main intent of the report is to highlight the current state of the field and the critical issues to be considered when contemplating the use of ketamine for treatment-resistant depression. Use of this report cannot guarantee any specific outcome and is not endorsed or promulgated as policy of the American Psychiatric Association.

Patient Selection

There are no clearly established indications for the use of ketamine in the treatment of psychiatric disorders. However, the selection of appropriate patients for ketamine treatment requires consideration of the risks and benefits of the treatment in the context of the patient’s severity of depression, duration of current episode, previous treatment history, and urgency for treatment. To date, the strongest data supporting ketamine’s clinical benefit in psychiatric disorders are in the treatment of major depressive episodes without psychotic features associated with major depressive disorder.1,11 Even these data are limited by the fact that most of those studies evaluated efficacy only during the first week following a single infusion of ketamine. However, emerging studies suggest that repeated dosing can extend the duration of effect for at least several weeks.12,13 Although some limited data on the use of ketamine in treating other psychiatric diagnoses exist (eBox 1 in the Supplement), we do not believe there are sufficient data to provide a meaningful review of the assessment of risks and benefits of ketamine use in these other disorders at present.

In addition to diagnostic considerations, appropriate patient selection requires an assessment of other medical, psychological, or social factors that may alter the risk to benefit ratio of the treatment and affect the patient’s capacity to provide informed consent. For these reasons, we recommend that each patient undergo a thorough pretreatment evaluation process (Table)1417 that assesses several relevant features of the patient’s past and current medical and psychiatric condition before initiating ketamine treatment. We also recommend that an informed consent process be completed during this evaluation. Rationale for the suggestions listed in the Table are provided in eBox 1 in the Supplement.

Clinician Experience and Training

There are considerable differences in the experience and clinical expertise of the clinicians currently administering ketamine to patients for the treatment of mood disorders. At present, there are no published guidelines or recommendations outlining the specific training requirements that clinicians should complete before administering doses of ketamine that are lower than those used in anesthesia. In attempting to balance the needs for treatment availability and patient safety, one must consider the information available regarding the use of ketamine at the relevant dose range in similar patient populations to formulate an advisory on clinical credentialing for ketamine administration for the treatment of mood disorders.

The peak plasma ketamine hydrochloride concentrations of 70 to 200 ng/mL seen with the typical antidepressant dose of 0.5 mg/kg delivered intravenously (IV) during 40 minutes (0.5 mg/kg per 40 minutes IV) do not produce general anesthetic effects. The concentrations are well below the peak plasma ketamine hydrochloride concentrations generally used for surgical anesthesia (2000-3000 ng/mL) and below the concentrations associated with awakening from ketamine hydrochloride anesthesia (500-1000 ng/mL).1820 Reporting on 833 ketamine infusions in healthy individuals resulting in peak plasma ketamine concentrations in the same general range as those achieved with a dose of 0.5 mg/kg per 40 minutes IV, Perry et al21 found 3 individuals who became nonresponsive to verbal stimuli, but all remained medically stable during the infusion and none required any form of respiratory assistance. A second, more recent study reported no persistent medical complications or significant changes in oxygen saturation among 84 otherwise healthy patients with depression who received a total of 205 infusions of ketamine hydrochloride, 0.5 mg/kg per 40 minutes IV.9 However, transient mean (SD) peak increases in systolic (19.6 [12.8] mm Hg) and diastolic (13.4 [9.8] mm Hg) blood pressure were reported during the infusions, with blood pressure levels exceeding 180/100 mm Hg or heart rates exceeding 110 beats per minute in approximately 30% of the patients treated. A single serious adverse cardiovascular-related event was reported in this study (0.49% of infusions), but it was considered to be attributable to a vasovagal episode following venipuncture for a blood draw, and it resolved without complications.

The data available from these studies and other case reports in the literature suggest that the dose of ketamine hydrochloride typically used in the treatment of mood disorders (0.5 mg/kg per 40 minutes IV) does not appear to have significant effects on the respiratory status of healthy individuals or patients with depression who are otherwise generally medically healthy. However, ketamine treatment could have meaningful effects on blood pressure and heart rate for some patients. Considering the potential risks associated with ketamine hydrochloride administration at the dose of 0.5 mg/kg per 40 minutes IV, it is recommended that clinicians delivering the treatment be prepared to manage potential cardiovascular events should they occur. Based on this information, we suggest that a licensed clinician who can administer a Drug Enforcement Administration Schedule III medication (in most states this is an MD or DO with appropriate licensing) with Advanced Cardiac Life Support certification should provide the treatments.

Because it is also possible for patients to experience prominent transient dissociative or even psychotomimetic effects while being treated with ketamine,22 clinicians should also be familiar with behavioral management of patients with marked mental status changes and be prepared to treat any emergency behavioral situations. Furthermore, it is suggested that an on-site clinician be available and able to evaluate the patient for potential behavioral risks, including suicidal ideation, before discharge to home. Finally, treating clinicians should be able to ensure that rapid follow-up evaluations of patients’ psychiatric symptoms can be provided as needed.

In addition to the minimal general training requirements, it is also recommended that clinicians develop some level of experience with the specific method of ketamine administration before performing the procedure independently. Precise delineation of required experience and documentation of this experience should be based on local community standards of practice and/or clinical practice committees. Reports such as the Statement on Granting Privileges for Administration of Moderate Sedation to Practitioners Who Are Not Anesthesia Professionals, published by the American Society of Anesthesiologists,23 can be used to inform the development of these standards.

Treatment Setting

Although the administration of ketamine at peak plasma concentrations similar to those produced by a dose of 0.5 mg/kg per 40 minutes IV has proven to be relatively safe to date, the potentially concerning acute effects on cardiovascular function and behavior suggest that the clinical setting should provide sufficient means of monitoring the patients and providing immediate care if necessary. Although there are relatively low levels of evidence to support the use of any specific monitoring methods in reducing the risks of ketamine treatment with doses that are lower than those used in anesthesia, it should be expected that such a facility have a means of monitoring basic cardiovascular (electrocardiogram, blood pressure) and respiratory (oxygen saturation or end-tidal CO2) function. It should also be expected that there would be measures in place to rapidly address and stabilize a patient if an event should arise. These measures would include a means of delivering oxygen to patients with reduced respiratory function, medication, and, if indicated, restraints to manage potentially dangerous behavioral symptoms. Moreover, there should be an established plan to rapidly address any sustained alterations in cardiovascular function, such as providing advanced cardiac life support or transfer to a hospital setting capable of caring for acute cardiovascular events. Patients deemed at higher risk for complications based on pretreatment evaluation should be treated at a facility that is appropriately equipped and staffed to manage any cardiovascular or respiratory events that may occur.

Medication Delivery

Dose

Most clinical trials and case reports available in the literature have used the ketamine hydrochloride dose of 0.5 mg/kg per 40 minutes IV that was cited in the original report by Berman et al.24 Limited information is available regarding the use of different routes of delivery and doses of ketamine. A meta-analysis of 6 trials assessing the effects of the standard dose of 0.5 mg/kg per 40 minutes IV and 3 trials assessing very low doses of ketamine hydrochloride (50-mg intranasal spray, 0.1-0.4 mg/kg IV, and 0.1-0.5 mg/kg IV intramuscularly or subcutaneously) reported that the dose of 0.5 mg/kg per 40 minutes IV appears to be more effective than very low doses in reducing the severity of depression.4 However, there is substantial heterogeneity in the design of the clinical trials, and the total number of participants included in that analysis is very few, markedly limiting the ability to draw any firm conclusions from this report.

Although there is now a growing number of reports examining the effects of various doses and rates of ketamine infusion, including studies showing lower doses and reduced infusion rates2527 to be effective and studies showing higher doses and extended infusion rates28,29 to have clinical benefit, at present we believe that insufficient information was provided in those studies to allow any meaningful analysis of any specific dose or route of treatment compared with the standard dose of 0.5 mg/kg per 40 minutes IV. Considering the lower-level evidence for doses and routes of administration other than 0.5 mg/kg per 40 minutes IV, if alternative doses are being used, that information should be presented to the patient during the informed consent process, and appropriate precautions should be made in managing any increased risk associated with the changes in ketamine administration. However, the use of alternative doses and routes of administration could be appropriate for individual patients under specific conditions.

One example of a rationale for dose adjustment is related to the dosing of ketamine for patients with a high body mass index (calculated as weight in kilograms divided by height in meters squared). The fact that greater hemodynamic changes were observed in patients with a body mass index of 30 or higher who were receiving a dose of 0.5 mg/kg per 40 minutes9suggests that adjusting the ketamine dosing to ideal body weight (using the person’s calculated ideal body weight and not actual body weight to determine dosing) may be an appropriate step to help ensure safety for patients with a body mass index of 30 or higher. However, there is currently very limited information supporting this approach.

Delivery Procedure

To help best ensure patient safety and to minimize risks, it is strongly advised that site-specific standard operating procedures be developed and followed for the delivery of ketamine treatments for major depressive episodes. The standard operating procedure should contain predosing considerations covering the following: (1) confirmation of preprocedural evaluation and informed consent; (2) assessment of baseline vital signs, including blood pressure, heart rate, and oxygen saturation or end-tidal CO2; (3) criteria for acceptable baseline vital signs before initiation of medication delivery (eBox 2 in the Supplement); and (4) incorporation of a “time-out” procedure in which the name of the patient and correct dosing parameters are confirmed.

Supplement

Standard operating procedures should also include specifically defined ongoing assessments of patients’ physiological and mental status during the infusion process, including the following: (1) assessment of respiratory status (ie, oxygen saturation or end-tidal CO2); (2) assessment of cardiovascular function (blood pressure and heart rate, reported on a regular basis); (3) assessment of the level of consciousness (ie, Modified Observer’s Assessment of Alertness/Sedation Scale30) or other documented assessment of responsiveness; and (4) delineation of criteria for stopping the infusion (eBox 3 in the Supplement) and a clear plan for managing cardiovascular or behavioral events during treatment.

Immediate posttreatment evaluations, assessments, and management should ensure that the patient has returned to a level of function that will allow for safe return to his or her current living environment. This assessment should include documentation of return to both baseline physiological measures and mental status. It is also critical to ensure that a responsible adult is available to transport the patient home if the treatment is being administered on an outpatient basis. Recommendations regarding driving and use of heavy machinery, as well as use of concomitant medications, drugs, or alcohol, should also be reviewed before discharge. It is also important to review follow-up procedures and ensure that the patient has a means of rapidly contacting an appropriately trained clinician if necessary.

Follow-up and Assessments

Efficacy Measures of Short-term Repeated Administration

The existing data surrounding the benefits of repeated infusions of ketamine remain limited.1,11 Although an increasing number of small case series evaluate the efficacy of repeated ketamine administration for the treatment of major depressive episodes, there is a very small number of randomized clinical trials in the literature.1 The lack of clinical trials in this area makes it difficult to provide suggestions on the frequency and duration of treatment with even moderate levels of confidence. Most studies and case reports published to date on this topic have examined the effects of less than 1 month of treatment.12,26,3134

A recent randomized, placebo-controlled clinical trial (using saline as the placebo) of 68 patients with treatment-resistant major depressive disorder examined the efficacy of ketamine, 0.5 mg/kg per 40 minutes IV, both 2 and 3 times weekly for up to 2 weeks and found both dosing regimens to be nearly equally efficacious (change in mean [SD] Montgomery-Åsberg Depression Rating Scale total score for ketamine 2 times weekly, –18.4 [12.0] vs placebo, –5.7 [10.2]; and ketamine 3 times weekly, –17.7 [7.3] vs placebo, –3.1 [5.7]).13 After 2 weeks of treatment, patients treated with ketamine 2 times weekly showed a 69% rate of response and 37.5% rate of remission vs placebo, at 15% and 7.7%, respectively, and those treated with ketamine 3 times weekly had a 53.8% rate of response and 23.1% rate of remission vs placebo, at 6% and 0%, respectively. In the ensuing open-label phase of the study, patients were allowed to continue with active medication at the dose frequency they were originally assigned for an additional 2-week period. At the end of 4 weeks of treatment, the 13 patients who received ketamine 2 times weekly and continued to receive the additional 2 weeks of treatment had a mean 27-point reduction in the Montgomery-Åsberg Depression Rating Scale score compared with a 23-point decrease for the 13 patients who received ketamine 3 times weekly. Although this was clearly not a definitive study, it is the best evidence currently available, to our knowledge, to suggest that twice-weekly dosing is as efficacious as more frequent dosing for a period of up to 4 weeks. In general, most of the available reports describing the effects of repeated treatments showed the largest benefits occurring early in the course of treatment, but some reports did show some cumulative benefit of continued treatment.31

Very limited data exist to suggest a clear point of determining the futility of treatment, but there are a few reports of patients responding after more than 3 infusions. Based on the limited data available, patients should be monitored closely using a rating instrument to assess clinical change to better reevaluate the risk to benefit ratio of continued treatment. In addition, only 1 report suggests that an increased dose of ketamine (beyond 0.5 mg/kg per 40 minutes) may lead to a response to treatment in patients who had previously not responded.28 Equally few data are available to suggest a standard number of treatments that should be administered to optimize longer-term benefit of the treatment.

Efficacy of Longer-term Repeated Administration

To our knowledge, there are extremely limited published data on the longer-term effectiveness and safety of ketamine treatment in mood disorders. This literature is confined to a few case series that do not allow us to make a meaningful statement about the longer-term use of ketamine.35,36 Several clinics providing such treatments are currently using a 2- or 3-week course of ketamine delivered 2 or 3 times per week, followed by a taper period and/or continued treatments based on empirically determined duration of responses for each patient. However, there remain no published data that clearly support this practice, and it is strongly recommended that the relative benefit of each ketamine infusion be considered in light of the potential risks associated with longer-term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration. The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment.

Safety Measures and Continuation of Treatment

Based on the known or suspected risks of cognitive impairment37 and cystitis38 associated with chronic high-frequency use of ketamine and the known substance abuse liability of the drug, assessments of cognitive function, urinary discomfort, and substance use39 should be considered if repeated administrations are provided (eBox 4 in the Supplement).

Considering the known potential for abuse of ketamine40 and recent reports of abuse of prescribed ketamine for the treatment of depression,41 clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow-up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicion of ketamine abuse is present. Moreover, the number and frequency of treatments should be limited to the minimum necessary to achieve clinical response. Considering the evidence suggesting that the mechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice of frequent ketamine administration. The previously mentioned report showing twice-weekly dosing to be at least as effective as dosing 3 times a week13 for up to 4 weeks appears to support this idea instead of more frequent dosing schedules.

At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected. Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected.

Future Directions

The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain in our knowledge about the longer-term efficacy and safety of ketamine infusions. Future research is needed to address these unanswered questions and concerns. Although economic factors make it unlikely that large-scale, pivotal phase 3 clinical trials of racemic ketamine will ever be completed, there are several studies with federal and private foundation funding aiming to address some of these issues. It is imperative that clinicians and patients continue to consider enrollment in these studies when contemplating ketamine treatment of a mood disorder. It is only through these standardized clinical trials that we will be able to collect the data necessary to answer some of the crucial questions pertaining to the efficacy and safety of the drug. A second means of adding to the knowledge base is to develop a coordinated system of data collection on all patients receiving ketamine for the treatment of mood disorders. After such a registry is created, all clinicians providing ketamine treatment should consider participation.


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The pros and cons of ketamine

Geuris “Jerry” Rivas, a native of New York, was diagnosed with severe obsessive-compulsive disorder when he was 15. Obsessions with organizing and reorganizing the belongings in his bedroom — posters, comic books, videos — took over most of his life.

Forced by germ obsessions to compulsively wash and rewash his hands, he started wearing gloves all day to both protect him from the germs and stop him from washing his hands raw. Now, at 36, OCD symptoms continue to cost him jobs and relationships. He’s managed to turn his organizational skills into a profession — he’s a home organizer and house cleaner — but still he struggles daily with his obsessions.

“It’s caused me a great deal of suffering,” Rivas says. “I’ve tried many, many medications. I’ve wasted so much of my life.”

In 2012, running out of answers, Rivas took part in the first clinical trial to test ketamine as a treatment for OCD. While ketamine is approved by the U.S. Food and Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse. Over the past 10 years, dozens of small studies of ketamine’s ability to treat a variety of mood and anxiety disorders have reported remarkable results — including the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.

With a single infusion of the drug, Rivas experienced for two weeks what it was like to live without the compulsions and obsessions that had for years controlled his life.

“I felt like, for the first time, I was able to function like a regular person,” he says.

Illustration of a giant K being painted by a man in a white coat

Pros and cons

Ketamine has brought hope to a psychiatric field desperate to find new treatments for severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.

“Severe OCD takes such a toll on patients,” says Carolyn Rodriguez, MD, PhD, who as a researcher at Columbia University ran the OCD trial. Now an assistant professor of psychiatry and behavioral sciences at Stanford, she has continued to explore the pros and cons of using ketamine to treat OCD. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”

Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It remains a mystery just how the drug works in the brain, and there are safety concerns. There is evidence from people who take the drug routinely — in much higher doses — that chronic, high-frequency ketamine use may be associated with increased risk of bladder inflammation and cognitive impairment, Rodriguez says. And if taken regularly, it can lead to dependence.

But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.

“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez says. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”

‘Right out of a movie’

Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.

“What most excites me about ketamine is that it works in a different way than traditional antidepressants.”

Rodriguez, intent on searching for better, faster treatments for her patients like Rivas with OCD, took note. There was an emerging theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she says. Perhaps ketamine could help regulate OCD symptoms as well as depression.

In 2013, Rodriguez and colleagues published their results from that first clinical trial of ketamine in OCD patients. The trial randomized 15 patients with OCD to ketamine or placebo.

In those patients who were given ketamine, the effect was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. … This is amazing, unbelievable. This is right out of a movie.” And while nearly all initially had dissociative effects like feelings of unreality, distortions of time or hallucinations, they were gone within two hours after the start of the infusion.

“Carolyn’s study was quite exciting,” Zarate says, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and post-traumatic stress disorder.

“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he says.

So how does it work?

Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. Exactly what it does remains unclear.

“There’s a recognition that people like me and others are using the drug to treat patients now. There’s an incredible need for something.”

Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they’ve been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects.

Ultimately, Rodriguez says, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.

Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.

“Ketamine is a complicated drug that works on many different receptor sites,” she says. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”

In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depressionlike symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate says.

“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez says.

Beyond the clubs

Meanwhile, dozens of commercial ketamine clinics have popped up across the country, making treatments available to patients who are searching for help to stop their suffering now. Medical insurance companies usually cover ketamine’s FDA-approved use as an anesthetic but won’t cover its use for other purposes, such as mental health disorders. So patients who have run out of treatment options are paying hundreds of dollars a dose for repeated ketamine infusions.

“The fact that these clinics exist is due to the desperation of patients,” says Rodriguez.

She and other researchers are calling for guidelines to protect patients and more research to learn how to use the drug safely.

“I think it’s a game changer, and it’s here to stay,” says David Feifel, MD, PhD, professor emeritus of psychiatry at UC-San Diego, who studies the effect of ketamine on clinical depression. Feifel began prescribing the drug for patients with treatment-resistant depression in 2010.

“I’ve found it to be very safe,” Feifel says, adding that the American Psychiatric Association this year issued safety guidelines on how to use ketamine clinically for treatment of depression.

“There’s a recognition that people like me and others are using the drug to treat patients now,” he says. “There’s an incredible need for something.”

The drug hasn’t worked for everyone he’s treated, Feifel says, but for many it’s been “life-changing.”

Rodriguez says she understands what motivates the clinicians to prescribe the drug now to patients in dire straits — those who are suicidal or who have tried every possible medication and therapeutic option and continue to suffer each day.

“I see it as a way to treat people whose OCD is very, very severe,” she says. “People who can’t come out of the house, who are suicidal, who have no other options.

“I just don’t like the idea of people being in pain,” Rodriguez adds. “I want to see science translated into treatments now.”

Meanwhile, researchers are learning more about the drug. Janssen Pharmaceutical is testing the efficacy of a version of ketamine, known as esketamine, as a therapy for treatment-resistant depression and for major depressive disorder with imminent risk for suicide. The FDA has fast-tracked both investigations. At Stanford, Alan Schatzberg, MD, a professor of psychiatry and behavioral sciences, along with other faculty including Rodriguez, is studying the mechanism of action for ketamine in treating depression.

Rodriguez is also interested in using ketamine to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.

Relaxation and other techniques also help patients tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.

“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez says. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she says.

Rivas well remembers that infusion of ketamine he received during Rodriguez’s first clinical trial to test the drug. The rush made him feel “like Superman.”

“I felt like my body was bigger, that I was more muscular, that I could tackle anything,” he says. But that feeling only lasted the duration of the 40-minute infusion. His OCD symptoms disappeared immediately and were still gone for two weeks after.

“I was amazed that something like that would work and work so fast,” he says. His OCD symptoms today are still intrusive, but he manages to keep them under control by taking antidepressants and seeing a therapist. Still, each day when he comes home from work, he has to put gloves on before he enters his apartment building, and as soon as he enters his apartment, he must wash his hands.

“It’s a ritual now,” he says. “There has never been a time that I haven’t done that, except those two weeks after the ketamine.”

When he heard that certain private ketamine clinics are now offering the drug as treatment for OCD, he said he understands why patients take the risks and pay the high prices. As more research has become available, he’s begun considering it himself.

“I’ve been suffering through my OCD for so long, I’ve gotten to the point where I’d try anything,” he says.

USING KETAMINE TO TREAT SEVERE MENTAL ILLNESSA conversation with Stanford psychiatrist Carolyn Rodriguez, MD, PhD, about how she got interested in the use of ketamine to treat obsessive-compulsive disorder and how she is determined to find out why, in studies, the drug has provided relief from symptoms.

AUDIO Interview


Ketamine – re-visiting the way it works | 703-844-0184 | KETAMINE FOR DEPRESSION | IV KETAMINE | ALEXANDRIA, VA 22306 | Springfield, Va | | KETAMINE IV | KETAMINE CENTER | KETAMINE DRIP |

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Ketamine’s role in treatment of depression: Study

The anaesthetic drug Ketamine has been shown to be beneficial in some cases of depression and suicidal ideation which have typically failed to respond to other standard antidepressant medications. A new study has explored the actual workings of ketamine in depression and found that the drug can act on the same receptors as opioid pain relievers.

The latest study was published in the American Journal of Psychiatry.

For this the researchers from the Stanford’s Neurosciences Institute included 12 volunteers at first. These cases were all of treatment-resistant depression.

The participants were all given infusion of Ketamine. In addition some were administered naltrexone and others normal saline infusion. Naltrexone is a drug that can block the effects of opioids.

Results showed that those on ketamine and saline combination found relief from their depressive symptoms quickly compared to those on ketamine and naltrexone combination. In fact those on ketamine and saline placebo reported at least a 90 percent reduction in their symptoms within the first three days of the infusion.

No such improvement was seen among those on ketamine and naltrexone. This proved that when the opioid actions are blocked, the ketamine cannot function as an antidepressant. Both groups faced certain side effects of ketamine such as an “out-of-the-body” experience, dysphoric feelings, tripping etc. This also showed that the antidepressant action of Ketamine was separate from its usual actions, which were seen in all participants in either group.

The initial trial plan was to include 30 patients. Due to the dramatic improvement seen in one group and no changes in the other, the team decided to stop the trial prematurely. This was to spare patients useless treatment.

Ketamine has been in news recently due to its unexplored potential as an antidepressant. If proven, researchers believe, this could impact depression research significantly. Ketamine has gathered interest mainly because it does not change the brain chemistry unlike other antidepressants. Co-author Boris Heifets, a clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford explained that ketamine blocks the brain’s receptors for glutamate. Glutamate is an important neurotransmitter in the brain. Many researchers have thought that glutamate could be the key zone where ketamine acts as an antidepressant. Heifets added that ketamine is not a simple drug and has varied targets which could be responsible for its antidepressant activities. A lot of money has been spent on developing agents that could work on the glutamate receptors and try to mimic ketamine’s antidepressant actions.

This study shows that the approach is incorrect and glutamates are not the target lead author Nolan Williams explained. Co-senior study author Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford explained that the ketamine was not working as “everyone thought it was working.”

Heifets noted that ketamine is a drug of abuse (called “Special K” in party circuits) that has been in use for a long time and there is an abuse potential of this drug acting on the opioid receptors to provide such effects. He warned that this abuse potential should be kept in mind before ketamine comes into the market as an antidepressant.

However the whole team agrees that this new study shows how ketamine can help patients who have intractable depression. New drugs could be developed in the same lines they explain. These drugs could possibly activate the opioid receptors without having abuse potential they add. Williams added that ketamine has been seen to provide relief of symptoms in other mental ailments such as obsessive compulsive disorders and now is the time to explore if opioids play a role in these diseases as well.

Mark George, a professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina in an editorial accompanying the article wrote that this study is a small one and so should be confirmed in larger trials before conclusions could be drawn.


VA Using Ketamine for PTSD and Depression | IV Ketamine for Depression | 703-844-0184 | Alexandria, Va | 22306 | Ketamine therapy | IV Ketamine center | Ketamine doctor | Springfield, Va | Fairfax, Va 22314 22304

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The VA Recognizes Ketamine As An Emergency Treatment For PTSD And Depression Patients At High Suicide Risk

CLEARWATER, Fla., Sept. 27, 2018 /PRNewswire/ — Long used as an safe and effective sedative for surgery, Ketamine has found new life as a treatment for severe depression, PTSD and suicidal ideation. Praised by some mental health experts, the drug so far has achieved very good results in clinical trials. The military now recognizes its’ potential, and last fall Brooke Army Medical Center in San Antonio became part of study on its effects. BAMC will treat active-duty troops with Ketamine, while a VA hospital near Yale will treat veterans. Another study is currently underway at a Veterans Affairs medical center in Cleveland, Ohio. The VA is trying to stem the tide of rising suicide rates among veterans, which average 22 per day – that’s one suicide every 65 minutes.

A staff psychiatrist at the Louis Stokes Cleveland VA Medical Center in Ohio, Dr. Punit Vaidya stated “30% of individuals with major depression don’t respond to traditional medications, so people can become desperate for things that work, because they can have a huge impact on their quality of life, and their overall functioning. The effects of the ketamine infusion can often be seen within a day, if not hours,” Vaidya explained. “If you look at their depression ratings and suicidal ratings given right before treatment and even four hours later you can see a significant reduction and I think that’s really quite remarkable,” Vaidya said.

Dr. Ashraf Hanna, a board certified physician and director of pain management at the Florida Spine Institute in Clearwater, Florida discusses PTSD and Treatment-Resistant Depression: “There are many forms of depression that can be treated by a psychiatrist with various modalities, anti-depressants and psychotherapy. IV Ketamine therapy is only reserved for those patients that have Treatment-Resistant Depression that have failed conventional therapy. IV Ketamine infusion therapyhas offered a new hope to patients that had no hope.”

When asked what prompted his use of IV Ketamine for PTSD and Depression and if any universities were involved in its development, Dr. Hanna went on to say: “There have been multiple universities involved in the research such as Harvard, Yale and Stanford that have proven the success rate of IV Ketamine for treatment-resistant depression. Since I was already successfully using IV Ketamine for CRPS/RSD,FibromyalgiaNeuropathy, and Post-Treatment Lyme Disease Syndrome, with over 10,000 infusions to date, I wanted to expand the treatment for PTSD, Depression, bipolar and Obsessive Compulsive Disorders. Since I am not a psychiatrist, I do not treat depression, but I work with qualified psychiatrists, and if he or she feels the patient has failed other treatment modalities, I then administer IV Ketamine for treatment-resistant depression.”

Dr. Bal Nandra and Ketamine patient Jason LaHood on how Ketamine is redefining the way patients are treated for depression

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Links for Ketamine Articles

  1. NYMag.com – What It’s Like to Have Your Severe Depression Treated With a Hallucinogenic Drug
    http://nymag.com/scienceofus/2016/03/what-its-like-to-treat-severe-depression-with-a-hallucinogenic-drug.html
  2. Huffington Post – How Ketamine May Help Treat Severe Depression
    http://www.huffingtonpost.com.au/2017/04/05/how-ketamine-may-help-treat-severe-depression_a_22027886/
  3. Murrough, Iosifescu, Chang et al. Antidepressant Efficacy in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial  Am J Psychiatry. 2013 Oct 1, 170(10): 1134-1142
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/
  4. Murrough, Perez, Pillemer, et al.. Rapid and Longer0Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression Biol Psychiatry 2013 Aug 15; 74(4): 250-256
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725185/
  5. Murrough, Burdick, Levitch et al. Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial Neuropsychopharmacology 2015 Apr; 40(5): 1084-1090
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367458/
  6. Feder, Parides, et al. Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder A Randomized Clinical Trial Jama Psychiatry 2014 June;71(6): 681-8
    http://jamanetwork.com/journals/jamapsychiatry/fullarticle/1860851
  7. Schwartz, Murrough, Iosifescu Ketamine for treatment-resistant depression: recent developments and clinical applications Evid Based Ment Health 2016 May; 19(2):35-8
    http://ebmh.bmj.com/content/ebmental/19/2/35.full.pdf
  8. Rodriguez, Kegeles, et al Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept Neuropsychopharmacology 2013 Nov; 38(12): 2475-2483
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799067/pdf/npp2013150a.pdf
  9. Singh, Fedgchin, Daly et al. A Double-Blind, Randomized, Pacebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression American Journal of Psychiatry 2016 August; 173(8): 816-826
    http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2016.16010037
  10. Taylor,  Landeros-Weisenberger, Coughlin et al. Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial  Neuropsychopharmacology 2017 August;
    https://www.ncbi.nlm.nih.gov/pubmed/28849779

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WHAT CAN I EXPECT AT AN INFUSION VISIT?

We will ask you to fast for 8 hours before your infusion. Once you have checked in, you will complete a questionnaire to assess your current status. The IV will be started in your hand or your arm using a small catheter. This may feel like a sting from a small bug bite. The Ketamine will be administered through your IV over a period of 40 minutes. We will take your vital signs before, during, and after the infusion. After resting for an additional 15-20 minutes after the infusion, you will be discharged home with your driver.

  1. What is Ketamine? 
    Ketamine is an anesthetic drug that has been available since the 1960’s. In high doses, it can cause a ‘dissociative anesthesia” which induces hypnosis like states as well as unconsciousness. Around 2000, scientists started looking at Ketamine IV infusions carefully when its clinical usefulness was expanded to include a role in the management of mood disorders as well as chronic pain.
  2. Why can I not drive the day of the infusion?
    Ketamine is a potent anesthetic. As with any anesthetic, we advise our patients to NOT operate any heavy machinery for the remainder of the day due to potential residual effects.
  3. What are the side effects?
    Less than 2% of people will experience side effects. Some of the common side effects are: drowsiness, nausea, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Most of these symptoms dissipate after the first hour of receiving the infusion.
  4. Are there certain conditions that are contra-indications for Ketamine treatment?
    Yes. If you have a history of cardiovascular disease, uncontrolled hypertension, history of psychosis, history of failed Ketamine infusion treatment, history of substance abuse or dependence within the year (patients will undergo a screening process) you will not qualify for Ketamine infusion treatments.
  5. How will I know if I need a booster infusion and how frequently will I require them?
    The duration of antidepressant efficacy after the initial treatment is different for everyone. The studies show that the variance can be 15 days to indefinitely. This is quite a range and unfortunately, there are no predictors for the duration.
  6. Is there a guarantee that this will work for me?
    Unfortunately, we cannot give guarantees.  Studies have shown that 70% of people will obtain efficacy.  After the first 2 infusions, we will be able to ascertain whether the infusions will work for you. We will not advise you to continue your treatment after the first 2 infusions if we do not see a certain amount of improvement.
  7. Isn’t Ketamine addictive? 
    Ketamine has the potential to be addictive. Studies have shown that at these doses and frequency, Ketamine is not addictive.
  8. Do I have to continue my current treatments for depression? 
    Yes. We advise that you alert your current health care provider that you are undergoing these treatments and that you maintain your current regimen.  It can be dangerous to stop taking your medications without the care of a physician. Our patients have a brighter outlook and a positive drive after their treatment that has allowed them to have higher success rates with psychotherapy. We will be happy to work with your current health care provider to provide the optimal outcome.

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VA Using Ketamine for PTSD and Depression


Strategies for Depression | Ketamine for Depression | 703-844-0184 | Alexandria, Va | 22306 | Ketamine therapy | IV Ketamine center | Ketamine doctor | Springfield, Va

ketamine virginia
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CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

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The Psychopharmacology of Depression: Strategies, Formulations, and Future Implications

 

With well over two dozen traditional antidepressants available in the US, and an ever-growing list of other psychotropic compounds with apparent antidepressant properties, pharmacological options for treating clinical depression today are broad and vast. However, recent findings suggest that the magnitude of efficacy for most antidepressants compared with placebo may be more modest than previously thought.1Most depressed patients do not respond fully to a first antidepressant trial, and with each consequent trial, there is less chance of symptom remission.2 About one-third of patients receiving long-term treatment report persistent moderate-to-severe depression.3 Hence, there remains more than a little room for improvement.

Since the late 1950s, the traditional view of treating depression has focused on the role of monoamines (serotonin, norepinephrine, and dopamine) as the main targets for medications. Newer treatments are looking beyond effects on monoamines as potential strategies to leverage depressive symptoms.

A major challenge for progress in novel pharmacotherapies has been our lack of a full understanding about the causes of depression. Advances in functional neuroimaging and genetic markers have begun to shed new light on brain regions and pathways associated with aberrant neural functioning in depression, but not in ways that have led to treatments aimed at remedying its pathogenesis. This makes it hard to think of antidepressant medications as “treating” the pathophysiology of depression (as when antibiotics eliminate the cause of an infection); rather, antidepressant relieve symptoms by counteracting or compensating for depression’s consequences (as when diuretics alleviate peripheral edema regardless of its etiology).

Gone are the days of oversimplified theories that depression is caused by a “chemical imbalance.” More likely, depression involves changes in brain architecture and the interplay of complex circuits in which chemicals, or neurotransmitters, are the messengers of information, rather than the causes of faulty functioning. Table 1 summarizes some of the major conceptual shifts that have occurred in thinking about the probable causes of depression (or at least its neurobiological context), which sets the stage for new ways to consider innovative treatment strategies. Looking beyond the role of monoamines as treatment targets in depression, a number of novel therapeutic strategies have begun to receive growing interest in preclinical and clinical trials. Key points about emerging novel depression pharmacotherapies are summarized in Table 2, and described more fully below.

Subanesthetically dosed intravenous (IV) ketamine currently represents perhaps the most dramatic and innovative antidepressant pharmacotherapy to emerge in decades.4,5 It is pharmacodynamically unique in its rapid onset (hours rather than days to weeks) and its potential ability to reduce suicidal ideation after a single dose, independent of its antidepressant properties.6 (While both lithium and clozapine have been shown to reduce suicidal behaviors, neither has been shown to reduce ideation, much less in the same day after a single dose.) Meta-analyses suggest that 0.5 mg/kg IV ketamine produces nearly a 10-fold greater likelihood of response than placebo at day 1 and a 4- to 5-fold likelihood of sustained response after one week.7

The exact psychotropic mechanism of action of ketamine remains elusive. Initial work focused on blockade of ionotropic N-methyl-D-aspartate (NMDA) receptors as accounting broadly for its antidepressant effects. However, subsequent negative randomized trials with other NMDA receptor antagonists (such as riluzole8) redirected interest toward ketamine’s other, non-NMDA receptor-related mechanisms, such as sigma receptor agonism, mu opioid receptor antagonism, or midbrain monoaminergic inhibition. Other authors have suggested that at low doses, ketamine’s antidepressant effects may derive from an increase in glutamate transmission with increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression, leading to increased release of brain-derived neurotrophic factor (BDNF).9Murrough and colleagues10 recently observed the necessity of AMPA receptor activation for the antidepressant effects of ketamine. They reported that “directly targeting the NMDA [receptor] may not be required.” As noted by the American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments,11 future advances will depend on a better understanding of the many mechanisms of action relative to the antidepressant properties of ketamine.

Ketamine is currently not approved by the FDA as a treatment for depression. Uncertainty remains as to whether repeated dosing is safe, effective, and necessary to avoid relapse and, if so, when, at what frequency, and for how long. The aforementioned APA Council on Research Consensus Statement on ketamine treatment for depression11 stated that while some clinics already offer 2- to 3-week courses of ketamine delivered 2 to 3 times per week, “there remain no published data that clearly supports this practice, and . . . the relative benefit of each ketamine infusion [should] be considered in light of the potential risks associated with longer term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration.” 11 Thus far, studies of other pharmacotherapies to sustain an initial ketamine response (such as riluzole or lithium) have proven no better than placebo.

Enantiomeric esketamine remains investigational as a possible easier-to-administer intranasal (IN) antidepressant, although IN bioavailability is only about half that of IV ketamine’s 100%. Two randomized multi-site trials of IN esketamine added to antidepressants showed dose-related better efficacy than placebo: Daly and colleagues12 found that 28 mg to 84 mg of IN ketamine twice weekly over two weeks produced significant improvement in depressive symptoms as compared to placebo beginning after 1 week and continuing through week 9 for the majority of responders. A study by Canuso and colleagues13 demonstrated a significant reduction in depressive symptoms within 4 hours of administration (56 mg to 84 mg insufflated over 15 minutes) and a medium to large effect size, sustained after 25 days; suicidal ideation reduced significantly at 4 hours but not beyond that time. Another recent randomized pilot trial of IN racemic ketamine (the mixture of S- and R-ketamine) was prematurely discontinued due to poor tolerability (including cardiovascular and neurological adverse effects) and highly variable absorption across subjects.14

Modulation of the endogenous opioid system has long been a target of interest in the treatment of mood disorders, but it is limited by safety risks, tolerance, and addiction potential. Recent work has focused on a proprietary combination of the μ-opioid partial agonist/kappa antagonist buprenorphine plus the μ-opioid receptor antagonist samidorphan (ALKS 5461). The potent blockade of μ-opioid receptors in samidorphan, which prevents buprenorphine access to these receptors, effectively renders buprenorphine a selective kappa opiate receptor (KOR) antagonist, which is its putative antidepressant mechanism. After initial favorable Phase II trials, in 2013 the FDA granted ALKS 5461 fast track status for accelerated regulatory review as an antidepressant adjunct. Subsequent randomized trials in treatment-resistant major depression revealed statistically significant differences from placebo on some, but not all, depressive symptom outcome measures and at some, but not all, doses studied.15,16 The FDA initially refused to review the new drug application for ALKS 5461 as an adjunctive therapy for depression because of concerns about bioavailability and lack of evidence, but then reversed its position. ALKS 5461 is currently under regulatory review and a decision regarding its possible approval is expected by early 2019.

Antiinflammatories and immunomodulators

There has been growing recognition of complex interrelationships between depression and inflammation. Some but not all patients with clinically significant depression appear to have elevated serum markers of systemic inflammation, such as high sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines. While causal relationships between depression and inflammation are poorly understood and questions remain whether depression causes inflammation or vice versa, randomized trial data suggest potential antidepressant value of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the COX-2 inhibitor celecoxib. A pooled meta-analysis of 5447 participants from 10 NSAID trials and 4 cytokine inhibitors (as mono- or add-on therapy for depression) revealed statistically significant advantages over placebo, with small to medium effect sizes, for response (odds ratio = 6.6; 95% confidence interval=2.2-19.4) or remission (odds ratio = 7.9; 95% confidence interval=2.9-21.1)17It has not been established whether adding celecoxib or other NSAIDs to an antidepressant may be more useful only in the setting of elevated serum markers of inflammation. Elsewhere, preliminary studies reveal that inflammatory depressive subtypes (ie, high baseline hs-CRP) may respond better to a tricyclic than SSRI,18 adjunctive L-methylfolate,19 or the tumor necrosis factor (TNF) antagonist infliximab (admnistered IV at 5 mg/kg over 3 doses).20

The antimicrobial minocycline exerts anti-inflammatory and anti-oxidative properties and has been preliminarily studied mostly in small or open/nonrandomized trials. A meta-analysis of 3 randomized controlled trials found an overall significantly greater effect than placebo with a medium to large effect size and good tolerability, although the small number of well-designed studies and samples sizes (total N = 158) limits their generalizability.21

Anticholinergic muscarinic agents

Harkening back to the 1970s hypothesis that depression could reflect cholinergic-adrenergic dysregulation, interest has turned to the possible antidepressant effects of the muscarinic cholinergic antagonist scopolamine. Preliminary studies of intravenous scopolamine dosed at 4 µg/kg in both unipolar and bipolar depression have produced remission rates from 45% to 56% (Cohen’s d ranged from 1.2-3.4) typically within several days of administration, with persistence for 10 to 14 days.22Antimuscarinic adverse effects such as sedation, dry mouth, and blurry vision are common but transient. Neurocognitive measures reaction time during selective attention tasks reveal no significant delays following IV scopolamine infusion.23 Analogous to IV ketamine, questions remain about the optimal number of infusions to minimize relapse as well as the use of nonparenteral formulations.

Brexanolone (SAGE-547), also known as allopregnanolone, is a positive allosteric modulator of GABA-A receptors. It is a progesterone metabolite that exerts neuroprotective, pro-cognitive, and possible antidepressant/anxiolytic properties. Precipitous drops in progesterone and allopregnanolone after childbirth prompted interest in the use of allopregnanolone specifically in postpartum depression. A small (N = 21) initial trial of brexanolone (administered intravenously because of its short half-life and poor oral bioavailability) or placebo for severe postpartum depression yielded a substantial reduction in depressive symptom severity within 60 hours (effect size = 1.2).24 Further data remain pending. SAGE-217 is reformulated brexanolone that has good oral bioavailability, allowing for oral administration, as well as a longer half-life allowing once-a-day dosing. It is currently being studied as an adjunctive agent for treatment resistant depression.

PPAR-γ agonists and incretins

Thiazolidinediones are insulin sensitizers that also demonstrate antidepressant properties in animal studies and appear to possess anti-inflammatory, neuroprotective, antioxidant and anti-excitatory properties. Pioglitazone, a PPAR-γ agonist thiazolidinedione, has been studied versus placebo or metformin in major depression, both as monotherapy and in combination with antidepressants or lithium. A meta-analysis of 4 trials revealed significantly higher remission rates than controls (27% versus 10%, respectively; odds ratio of remission in major depression = 5.9 (95% confidence interval=1.6-22.4), p = .009), with an NNT = 6.25 Even though PPAR-γ agonists can decrease insulin resistance, weight gain can be an undesired adverse effect that is possibly a result of a combination of fat cell proliferation, fluid retention, and increased appetite. Pioglitazone also carries serious adverse risks for congestive heart failure and bladder cancer.

Glucagon-like peptide 1

Another class of antidiabetic drugs known as glucagon-like peptide 1 (GLP-1) agonists mimic the action of insulin (so-called incretins) and are of interest as a potential target for depression. GLP-1 agonists such as liraglutide possess neuroprotective and antiapoptotic properties, and animal studies suggest it has antidepressant and pro-cognitive effects, particularly involving reward and motivation. Human studies have thus far focused more on weight-reducing and possible cognitive benefits of liraglutide more than its potential antidepressant efficacy, but its mechanism represents a promising direction for further study.

Future directions

This brief overview has focused on emerging novel pharmacotherapies for depression. While the provisional nature of proof-of-concept studies may be encouraging, they are far from definitive. The aforementioned findings are largely preliminary and meant more to prompt larger randomized trials to establish efficacy, safety, and generalizability rather than inspire premature immediate uptake into clinical practice.

Given the focus on neuroprotection and enhanced neuroplasticity as proposed targets of treatment, it would seem remiss not to at least mention the neurobiological impact of depression-specific psychotherapies, mindfulness meditation, and related psychosocial interventions. Psychotherapy is, among other things, a behavioral learning paradigm, presumably rendering alterations in cognitive functions (memory, attention, and decision-making), fear extinction, and emotional processing. Evidence-based psychotherapies for depression have been shown to produce changes in brain network connectivity26 (recapitulating the idea of Hebbian synapses, where “neurons that fire together wire together”) and upregulation of intracellular transcription factors involved in neuronal plasticity.27Enhanced neuroplasticity may represent a common denominator target for effective biological or psychosocial treatments for depression.

Increasingly, drugs we call antidepressants are diversifying to include broader classes of molecules. A more neuroscience-based nomenclature for psychotropic drugs has already been proposed28 and will no doubt invoke more novel drug mechanisms, supplanting older concepts about depression as a chemical imbalance as perspectives continue to evolve about how antidepressants impact neuronal viability and brain microarchitecture.

References:

1. Cipriani A, Furukawa TA, Salanti G,et al.Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; S0140-6736:32802-7. [Epub ahead of print]

2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.

3. Cartwright C, Gibson K, Read J, et al. Long-term antidepressant use: patient perspectives of benefits and adverse effects. Patient Prefer Adher. 2016;10:1401-1407.

4. Zarate CA Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.

5. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134-1142.

6. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150-158.

7. Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172:950-966.

8. Mathew SJ, Gueorguieva R, Brandt C, et al. A randomized, double-blind, placebo-controlled, sequential parallel comparison design trial of adjunctive riluzole for treatment-resistant major depressive disorder. Neuropsychopharmacol 2017;42: 2567-2574.

9. Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacol. 2012;62:35-41.

10. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16:472-486.

11. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74:399-405.

12. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:139-148.

13. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. April 2018; Epub ahead of print.

14. Gálvez V, Li A, Huggins C, et al. Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial. J Clin Psychopharmacol. 2018;32:397-407.

15. Ehrich E, Turncliff R, Du Y, et al. Evaluation of opioid modulation in major depressive disorder. Neuropsychopharmacol. 2015;40:1448-1455.

16. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173:499-508.

17. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71:1381-1391.

18. Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171:1278-1286.

19. Papakostas GI, Shelton RC, Zajecka JM, et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014;75:855-863.

20. Raison CL, Rutheford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.

21. Rosenblat JD, McIntyre RS. Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. J Affect Disord. 2018;227:219-225.

22. Drevets WC, Zarate CA Jr, Furey ML. Antidepressant effects of the muscarinic cholinergic antagonist scopolamine: a review. Biol Psychiatry. 2013;73:1156-1163.

23. Furey ML Pietrini P, Haxby JV, et al. Selective effects of cholinergic modulation on task performance during selective attention. Neuropsychopharmacol 2008; 33:913-923.

24. Kanes S, Colquohoun H, Grunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390:480-489.

25. Colle R, de Larminat D, Rotenberg S, et al. Pioglitazone could induce remission in major depression: a meta-analysis. Neuropsychiatr Dis Treat 2016;13: 9-16.

26.Yang CC, Barrós-Loscertales A, Pinazo D, et al. State and training effects of mindfulness meditation on brain networks reflect neuronal mechanisms of its antidepressant effect. Neural Plast. 2016;2016:9504642.

27. Koch JM, Hinze-Selch D, Stingele K, et al. Changes in CREB phosphorylation and BDNF plasma levels during psychotherapy of depression. Psychother Psychosom. 2009;78:187-192.

28. ECNP Neuroscience Applied. Neuroscience-based Nomenclature. https://www.ecnp.eu/research-innovation/nomenclature.aspx. Accessed June 6, 2018.


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Ketamine

The drug Ketamine is considered a breakthrough treatment for depression and some other neuropsychiatric conditions. Below are excerpts from recent articles discussing this revolutionary treatment and the links to the full articles.

Ketamine For Depression: the Highs and Lows.

The Lancet Psychiatry. VOLUME 2, ISSUE 9, P783–784, SEPTEMBER 2015

Long used as an anaesthetic and analgesic, most people familiar with ketamine know of it for this purpose. Others know it as a party drug that can give users an out-of-body experience, leaving them completely disconnected from reality. Less well known is its growing off-label use in the USA for depression, in many cases when other options have been exhausted.

David Feifel, a professor of psychiatry at the University of California, San Diego, was one of the first clinicians to use ketamine off-label to treat depression at UCDS’s Center for Advanced Treatment of Mood and Anxiety Disorders, which he recently founded. “Currently approved medications for depression all have about the same, very limited efficacy. A large percentage of patients with depression do not get an adequate level of relief from these antidepressants even when they have tried several different ones and even when other drugs known to augment their effects are added to them”, Feifel tells The Lancet Psychiatry. “The stagnation in current antidepressant medication on the one hand, and the tremendous number of treatment-resistant patients, has propelled me to explore truly novel treatments like ketamine.”

Compelling published study results and case reports exist of patients’ depression—in some cases deeply entrenched depression that has lasted months or even years—alleviating within hours of use of ketamine. However, critics have warned that the drug has not been studied sufficiently (at least outside clinical trials), and also emphasized the cost. Patients can pay more than $1000 per session for treatment that must usually be repeated several times. That cost is rarely covered by the patient’s medical insurance.

Advocates of ketamine use in depression are excited because it has a different mechanism of action to standard antidepressants, which affect signalling by monoamine neurotransmitters such as serotonin, noradrenaline, or dopamine. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain, which interact with the amino acid neurotransmitter glutamate.

Feifel states that he has patients who have been receiving ketamine treatments every 2–4 weeks for long periods, some for around 3 years, and has not yet seen any safety issues arise.

Pharmaceutical companies are entering this exciting arena by attempting to develop new drugs based on ketamine without similar side-effects. Feifel dismisses the notion that the dissociative so-called trip induced by ketamine is actually an important negative side-effect. “Although I have had a couple patients have unpleasant ‘trips’, it’s exceedingly rare, usually dose related, and very transitory due to ketamine’s rapid metabolism.” Feifel says that, more often than not, patients find the trip to be positive, or even spiritual, and believe it is an important component of the antidepressant effect they experience afterwards. “There is no doubt the dissociative effect represents a logistical issue, requiring monitoring—and this should be addressed in any approval given for ketamine”, he adds.

Feifel says that it is not for him, but for his patients to decide where the balance of risks and benefits lies in trying ketamine to treat their depression”One could make a compelling argument that it’s unethical to withhold ketamine treatments from someone who has chronic, severe treatment resistant depression. But I know this from the patients who tell me they would not be in this world right now if it were not for the ketamine.”

Feifel concludes that it is straightforward to talk to TRD patients about ketamine. “I tell them all the relevant information. The efficacy rates, time to onset of benefits, duration limitations, alternatives, lack of insurance coverage, and other information. My job is to make sure they understand the parameters of the treatment, not to decide whether they should do it.”

Full article: The Lancet

Ketamine for depression the highs and lows b

Onetime Party Drug Hailed as Miracle for Treating Severe Depression

Washington Post, Feb 2, 2016

Ketamine, popularly known as the psychedelic club drug Special K, has been around since the early 1960s. It is a staple anesthetic in emergency rooms, regularly used for children when they come in with broken bones and dislocated shoulders. It’s an important tool in burn centers and veterinary medicine, as well as a notorious date-rape drug, known for its power to quickly numb and render someone immobile. Since 2006, dozens of studies have reported that it can also reverse the kind of severe depression that traditional antidepressants often don’t touch.

Experts are calling it the most significant advance in mental health in more than half a century. They point to studies showing ketamine not only produces a rapid and robust antidepressant effect; it also puts a quick end to suicidal thinking.  “This is the next big thing in psychiatry,” says L. Alison McInnes, a San Francisco psychiatrist who over the past year has enrolled 58 severely depressed patients in Kaiser’s San Francisco clinic. The excitement stems from the fact that it’s working for patients who have spent years cycling through antidepressants, mood stabilizers and various therapies. “Psychiatry has run out of gas” in trying to help depressed patients for whom nothing has worked, she says. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

Ketamine does, however, have one major limitation: Its relief is temporary. Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.

A study published in the journal Science in 2010 suggested that ketamine restores brain function through a process called synaptogenesis. Scientists at Yale University found that ketamine not only improved depression-like behavior in rats but also promoted the growth of new synaptic connections between neurons in the brain.

Patients often describe a kind of lucid dreaming or dissociative state in which they lose track of time and feel separated from their bodies. Many enjoy it; some don’t. But studies at NIMH and elsewhere suggest that the psychedelic experience may play a small but significant role in the drug’s efficacy.

As a drug once known almost exclusively to anesthesiologists, ketamine now falls into a gray zone. As the use of ketamine looks likely to grow, many psychiatrists say that use of ketamine for depression should be left to them. “The bottom line is you’re treating depression,” says psychiatrist David Feifel, director of the Center for Advanced Treatment of Mood and Anxiety Disorders at the University of California at San Diego. “And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients.”

Full article: The Washington Post

Onetime party drug hailed as miracle for treating severe depression


A Ketamine intravenous drip being prepared. (Amarett Jans/Courtesy of Enrique Abreu)

February 1, 2016

It was November 2012 when Dennis Hartman, a Seattle business executive, managed to pull himself out of bed, force himself to shower for the first time in days and board a plane that would carry him across the country to a clinical trial at the National Institute of Mental Health (NIMH) in Bethesda.

After a lifetime of profound depression, 25 years of therapy and cycling through 18 antidepressants and mood stabilizers, Hartman, then 46, had settled on a date and a plan to end it all. The clinical trial would be his last attempt at salvation.

For 40 minutes, he sat in a hospital room as an IV drip delivered ketamine through his system. Several more hours passed before it occurred to him that all his thoughts of suicide had evaporated.

“My life will always be divided into the time before that first infusion and the time after,” Hartman says today. “That sense of suffering and pain draining away. I was bewildered by the absence of pain.”

Ketamine could be speedy depression treatment

Ketamine is being used by researchers at The National Institutes of Health as a treatment for major depression. 

Ketamine, popularly known as the psychedelic club drug Special K, has been around since the early 1960s. It is a staple anesthetic in emergency rooms, regularly used for children when they come in with broken bones and dislocated shoulders. It’s an important tool in burn centers and veterinary medicine, as well as a notorious date-rape drug, known for its power to quickly numb and render someone immobile.

Since 2006, dozens of studies have reported that it can also reverse the kind of severe depression that traditional antidepressants often don’t touch. The momentum behind the drug has now reached the American Psychiatric Association, which, according to members of a ketamine task force, seems headed toward a tacit endorsement of the drug for treatment-resistant depression.

Experts are calling it the most significant advance in mental health in more than half a century. They point to studies showing ketamine not only produces a rapid and robust antidepressant effect; it also puts a quick end to suicidal thinking.

Traditional antidepressants and mood stabilizers, by comparison, can take weeks or months to work. In 2010, a major study published in JAMA, the journal of the American Medical Association, reported that drugs in a leading class of antidepressants were no better than placebos for most depression.

A growing number of academic medical centers, including Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic, have begun offering ketamine treatments off-label for severe depression, as has Kaiser Permanente in Northern California.

The ‘next big thing’

“This is the next big thing in psychiatry,” says L. Alison McInnes, a San Francisco psychiatrist who over the past year has enrolled 58 severely depressed patients in Kaiser’s San Francisco clinic. She says her long-term success rate of 60 percent for people with treatment-resistant depression who try the drug has persuaded Kaiser to expand treatment to two other clinics in the Bay Area. The excitement stems from the fact that it’s working for patients who have spent years cycling through antidepressants, mood stabilizers and various therapies.

“Psychiatry has run out of gas” in trying to help depressed patients for whom nothing has worked, she says. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

McInnes is a member of the APA’s ketamine task force, assigned to codify the protocol for how and when the drug will be given. She says she expects the APA to support the use of ketamine treatment early this year.

The guidelines, which follow the protocol used in the NIMH clinical trial involving Hartman, call for six IV drips over a two-week period. The dosage is very low, about a tenth of the amount used in anesthesia. And when it works, it does so within minutes or hours.

“It’s not subtle,” says Enrique Abreu, a Portland, Ore., anesthesiologist who began treating depressed patients with it in 2012. “It’s really obvious if it’s going to be effective.

“And the response rate is unbelievable. This drug is 75 percent effective, which means that three-quarters of my patients do well. Nothing in medicine has those kind of numbers.”

So far, there is no evidence of addiction at the low dose in which infusions are delivered. Ketamine does, however, have one major limitation: Its relief is temporary. Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.

Ketamine works differently from traditional antidepressants, which target the brain’s serotonin and noradrenalin systems. It blocks N-methyl-D-aspartate (NMDA), a receptor in the brain that is activated by glutamate, a neurotransmitter.

In excessive quantities, glutamate becomes an excitotoxin, meaning that it overstimulates brain cells.

“Ketamine almost certainly modifies the function of synapses and circuits, turning certain circuits on and off,” explains Carlos Zarate Jr., NIMH’s chief of neurobiology and treatment of mood disorders, who has led the research on ketamine. “The result is a rapid antidepressant effect.”

Rapid effect

study published in the journal Science in 2010 suggested that ketamine restores brain function through a process called synaptogenesis. Scientists at Yale University found that ketamine not only improved depression-like behavior in rats but also promoted the growth of new synaptic connections between neurons in the brain.

mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.

Psychedelic-Assisted Psychotherapy A Paradigm Shift in Psychiatric Research and Development

Psychedelics Promote Structural and Functional Neural Plasticity.

Even a low-dose infusion can cause intense hallucinations. Patients often describe a kind of lucid dreaming or dissociative state in which they lose track of time and feel separated from their bodies. Many enjoy it; some don’t. But studies at NIMH and elsewhere suggest that the psychedelic experience may play a small but significant role in the drug’s efficacy.

“It’s one of the things that’s really striking,” says Steven Levine, a Princeton, N.J., psychiatrist who estimates that he has treated 500 patients with ketamine since 2011. “With depression, people often feel very isolated and disconnected. Ketamine seems to leave something indelible behind. People use remarkably similar language to describe their experience: ‘a sense of connection to other people,’ ‘a greater sense of connection to the universe.’ ”

Although bladder problems and cognitive deficits have been reported among long-term ketamine abusers, none of these effects have been observed in low-dose clinical trials. In addition to depression, the drug is being studied for its effectiveness in treating obsessive-compulsive disorder, post-traumatic stress disorder, extreme anxiety and Rett syndrome, a rare developmental disorder on the autism spectrum.

Booster treatments

The drug’s fleeting remission effect has led many patients to seek booster infusions. Hartman, for one, began his search before he even left his hospital room in Bethesda.

Four years ago, he couldn’t find a doctor in the Pacific Northwest willing to administer ketamine. “At the time, psychiatrists hovered between willful ignorance and outright opposition to it,” says Hartman, whose depression began creeping back a few weeks after his return to Seattle.

It took nine months before he found an anesthesiologist in New York who was treating patients with ketamine. Soon, he was flying back and forth across the country for bimonthly infusions.

Upon his request, he received the same dosage and routine he’d received in Bethesda: six infusions over two weeks. And with each return to New York, his relief seemed to last a little longer. These days, he says that his periods of remission between infusions often stretch to six months. He says he no longer takes any medication for depression besides ketamine.

“I don’t consider myself permanently cured, but now it’s something I can manage,” Hartman says, “like diabetes or arthritis. Before, it was completely unmanageable. It dominated my life and prevented me from functioning.”

In 2012 he helped found the Ketamine Advocacy Network, a group that vets ketamine clinics, advocates for insurance coverage and spreads the word about the drug.

And word has indeed spread. Ketamine clinics, typically operated by psychiatrists or anesthesiologists, are popping up in major cities around the country.

Levine, for one, is about to expand from New Jersey to Denver and Baltimore. Portland’s Abreu recently opened a second clinic in Seattle.

Depression is big business. An estimated 15.7 million adults in the United States experienced at least one major depressive episode in 2014, according to the NIMH.

“There’s a great unmet need in depression,” says Gerard Sanacora, director of the Yale Depression Research Program. “We think this is an extremely important treatment. The concern comes if people start using ketamine before CBT [cognitive behavioral therapy] or Prozac. Maybe someday it will be a first-line treatment. But we’re not there yet.”

Many unknowns

Sanacora says a lot more research is required. “It’s a medication that can have big changes in heart rate and blood pressure. There are so many unknowns, I’m not sure it should be used more widely till we understand its long-term benefits and risks.”

While a single dose of ketamine is cheaper than a $2 bottle of water, the cost to the consumer varies wildly, running anywhere between $500 and $1,500 per treatment. The drug itself is easily available in any pharmacy, and doctors are free to prescribe it — as with any medication approved by the Food and Drug Administration — for off-label use. Practitioners attribute the expense to medical monitoring of patients and IV equipment required during an infusion.

There is no registry for tracking the number of patients being treated with ketamine for depression, the frequency of those treatments, dosage levels, follow-up care and adverse effects.

“We clearly need more standardization in its use,” Zarate says. “We still don’t know what the proper dose should be. We need to do more studies. It still, in my opinion, should be used predominantly in a research setting or highly specialized clinic.”

As a drug once known almost exclusively to anesthesiologists, ketamine now falls into a gray zone.

“Most anesthesiologists don’t do mental health, and there’s no way a psychiatrist feels comfortable putting an IV in someone’s arm,” Abreu says.

It’s a drug, in other words, that practically demands collaboration. Instead, it has set off a turf war. As the use of ketamine looks likely to grow, many psychiatrists say that use of ketamine for depression should be left to them.

“The bottom line is you’re treating depression,” says psychiatrist David Feifel, director of the Center for Advanced Treatment of Mood and Anxiety Disorders at the University of California at San Diego. “And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients. Many of them have bipolar disorder and are in danger of becoming manic. My question [to anesthesiologists] is: ‘Do you feel comfortable that you can pick up mania?’ ”

But ketamine has flourished from the ground up and with little or no advertising. The demand has come primarily from patients and their families; Zarate, for instance, says he receives “at least 100 emails a day” from patients.

Nearly every one of them wants to know where they can get it.