Ketamine: Key Predictor of Treatment Response for MDD Identified
I am going to link into a few articles that discuss a phenomena that I have observed in the office setting at NOVA Health Recovery (Alexandria, Va 703-844-0184) for our Ketamine infusions in depressed and PTSD patients. The best long term results seem to occur when the individual has a slightly more dissociative experience during the infusion. A lot of times I will give an initial boost to the medication at the start to get that state of mind going. Studies below have hinted that the slight dissociation actually improves outcomes:
Ketamine: Key Predictor of Treatment Response for MDD Identified
Nancy A. Melville
April 12, 2018
WASHINGTON — More intense dissociative symptoms exhibited during ketamine infusion for severe depression, particularly depersonalization, may be key predictors of treatment response. In addition, new safety and efficacy data for off-label use of the drug are encouraging.
Mark Niciu, MD, PhD, of the National Institute of Mental Health (NIMH), and colleagues analyzed three studies involving 126 patients with treatment-resistant depression. They found a significant association between dissociative symptoms experienced during infusion and reductions in depressive symptoms, as reflected in some, but not all, dissociation subscale measures.
“The findings suggest that mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded,” Niciu told delegates attending the Anxiety and Depression Association of America (ADAA) Conference 2018.
The results were also published in the May issue of the Journal of Affective Disorders.
In another presentation at the ADAA conference, Samuel Wilkinson, MD, assistant director of the Depression Research Program at Yale University, New Haven, Connecticut, reported details from his institution’s experience with the use of ketamine during a period of more than 30 months in patients with severe and treatment-resistant mood disorders.
Among 50 patients who received one to four treatments, the response rate, defined as a 50% improvement in symptoms, was approximately 50%; the remission rate was 27.3%.
In a subset of 14 patients who received 12 to 45 total treatments during a period of 14 to 126 weeks, there was no evidence of cognitive decline or delusions, as measured with the CogState cognitive assessment tool, Wilkinson reported.
Because conventional antidepressants can take weeks if not months to reach full effect and are completely ineffective in many patients, interest in ketamine, an N-methyl-d-aspartate receptor antagonist, as a rapid-acting treatment for severe mood disorders has soared in recent years, noted Niciu.
Previous studies have reported significant improvements in depression following a single ketamine infusion, with improvements lasting from several days to a week. However, not everyone responds to ketamine.
In the new study, 84 of the 126 participants had major depressive disorder, and 42 had bipolar depression. All were treated with the standard ketamine treatment for depression, consisting of a single subanesthetic dose (0.5 mg/kg) delivered by infusion over 40 minutes.
Patients were followed for at least 1 week post infusion and, in one of the three studies that were assessed, for up to 28 days.
In one of the studies, dissociative effects, measured using the Clinician-Administered Dissociative States Scale (CADSS) at baseline and at the end of infusion, were associated with symptoms of depression, as measured with the Hamilton Depression Rating Scale (HDRS-17), at day 7 following the infusion (P = .04).
Scores on the depersonalization subscale of the CADSS were related to percentage change in HDRS-17 score in all three studies and at all time points (P = .04).
Scores on the subscale of derealization were associated with percentage change in HDRS score on day 7 post infusion in one study (P = .01).
No association was observed between amnesia symptoms during infusion and reduction in depression, as reflected in percentage change in HDRS score.
“What really jumped out at us was the depersonalization subscale,” Niciu said.
He speculated that depersonalization in particular may relate to some of the deeper aspects of depression, more so than derealization, which involves detachment from reality, or amnesia.
“There might be mechanistic similarities between depersonalization and an antidepressant response,” Niciu explained.
“These are people with a highly introspective disorder and are often focused on their inner self. If you can detach them from that for a period of time and disconnect them from the subjective sensations, then that may result in a better antidepressant response, but that’s a hypothesis,” he said.
The findings suggest that the use of the depersonalization scale could represent a relatively easy way to assess the possibility of the patient’s responding to ketamine.
“In the clinical setting, if someone is administering ketamine and doesn’t have much time and just wants to get a sense of how a patient might respond, the CADSS depersonalization subscale is something they might want to administer,” Niciu said.
“It is easy to administer — it’s only five items, and those who tend to score higher on that subscale may be more likely to be responders,” he added.
The study was an extension of earlier research from the investigators linking the degree of dissociative symptoms with ketamine’s antidepressant effects.
On the basis of those findings, some clinicians already try to achieve the effects in order to evoke a better response, said Sanjay Mathew, MD, professor of psychiatry and behavioral sciences, Baylor College of Medicine and the Michael E. Debakey VA Medical Center, Houston, Texas, while commenting on the study at the meeting.
“Often, anesthesiologists and psychiatrists at ketamine clinics will start at 0.5 mg/kg and titrate the dose to mild dissociation,” said Matthew. “They often want the patient to feel buzzed, because that’s when they feel confident that they’ve hit the ‘sweet spot’ of NMDA modulation.”
He noted that another NIMH study of 99 patients, which is currently under review, showed that the best outcomes, as reflected in scores on depression scales, were achieved with the standard 0.5 mg/kg dose in comparison with the 1.0 mg/kg dose and the very low dose of 0.1 mg/kg, which were associated with a high degree of dissociation.
“Clearly, the message from that study is that you don’t need to dissociate to get better,” he said.
Nevertheless, “the issue is fascinating, with high clinical relevance in terms of how clinicians are using ketamine in the community,” Mathew said.
However, Wilkinson noted that he has not seen similar patterns in his patients who were treated with ketamine, and he questioned the use of the CADSS tool for determining dissociation symptoms in the study.
“We have not observed that the level of dissociation and depersonalization predict response,” he told Medscape Medical News.
“I am skeptical of this finding, as the CADSS instrument was not designed for use in ketamine studies and in my opinion does not do a great job at capturing this phenomenon related to ketamine,” he added.
Wilkinson noted that the dissociative symptoms that can occur with ketamine treatment do not appear to subside after multiple infusion sessions.
“In my experience treating patients, there seem to be a group of patients who always develop fairly significant symptoms, even though they have been treated 20 times or more with ketamine,” he said.
During the presentation of his own study, Wilkinson reported that 21 participants (38%) were men and 96% were being treated with concomitant medications during the acute course. These medications included antidepressants (72.2%), antipsychotics (53.7%), mood stabilizers (37%), lithium (18.5%), and sedatives/hypnotics (50%).
Patients were initially treated intravenously with a single or double infusion of 0.5 mg/kg over 40 minutes. However, patients were later transitioned to a four-dose protocol administered twice per week over 2 weeks.
The response rate was about 50%, and the remission rate was 27.3% among 50 patients who received one to four treatments.
Although there was no evidence of cognitive decline or delusions, one person discontinued infusion because of intolerability, one discontinued because of hypertension, one experienced relapse of cannabis use disorder, and three required rehospitalization for suicidal ideation or suicide attempts.
There were two completed suicides, one occurring 10 months after last contact with the program, and one 4 months after last contact.
Wilkinson noted that the 50% response rate is somewhat lower than rates reported in clinical trials, which may reflect a real-world setting.
“This is sometimes called the ‘efficacy-effectiveness gap’ and is not really surprising, because clinical trials are usually done in ideal conditions, whereas community practice represents real-world conditions and the patients are generally sicker and have comorbidities,” he told Medscape Medical News.
He added that once patients have responded to several weeks of ketamine treatments, efforts are made to help them shift to other forms of management.
“For those patients who do well following a series of four to six ketamine infusions, we initially try and keep them well using a strategy that does not involve repeated use of ketamine,” said Wilkinson.
Despite the encouraging improvements in depression that have been reported, the increased popularity of ketamine without long-term safety or efficacy data has raised considerable concerns, as reflected in aconsensus statement issued by an American Psychiatric Association Task Force in 2017.
Wilkinson said he shares the task force’s concerns.
“Ketamine has tremendous potential, but this needs to be tempered with the potential risks. There needs to be a higher level of regulation than currently exists,” he said.
“Ketamine is very safe in the short term, but we need better long-term data, because the risks of long-term adverse effects with repeated use are not theoretical,” Wilkinson added.
“We know that too much ketamine is not good for the brain or bladder. We just don’t know how much is too much,” he said.
Dr Niciu has disclosed no relevant financial relationships. The senior author of the study is a coinventor on a patent for the use of ketamine and its metabolites in the treatment of major depression. Although he assigned his rights in the patent to the US Government, he will share a percentage of any royalties that may be received. Wilkinson has received funding, administered through Yale University, from Janssen to conduct clinical trials with esketamine. He has also received consulting fees of less than $5000 from Janssen.
Anxiety and Depression Association of America (ADAA) Conference 2018. Session 341R, presented April 7, 2018.
Cite this article: Ketamine: Key Predictor of Treatment Response for MDD Identified – Medscape – Apr 12, 2018.
CADSS-test-for-PTSD <<Clinician-Administered Dissociative States Scale (CADSS) A test to see how dissociated an individual is – the more the better!
The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.
Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7.
Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r=−0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.
Secondary data analysis, combined diagnostic groups, potential unblinding.
Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.
•Intra-infusion dissociation is associated with antidepressant response to ketamine.
•Antidepressant response may be uniquely related to dissociative symptom clusters.
•Depersonalization was globally associated with antidepressant response.
•Derealization was discriminately associated with antidepressant response.
Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters.
Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response.
Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change.
Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine’s antidepressant efficacy; the possibility of Type I errors in secondary analyses.
From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.
Anne Stallings says she has been battling severe depression for most of her life. She tried anti-depressants and even electroconvulsive therapy, but nothing worked until she went to a Ketamine clinic and tried ketamine, reports CBS News correspondent Paula Reid. “It was like the fifth treatment in and I had come home from the grocery store and I was putting away the groceries and I was like, ‘Wow, this is how you don’t feel depressed.’ It was like from turning on a black and white TV to a color TV,” Stallings said. Ketamine was approved by the FDA in the 1970s to sedate patients during medical procedures. It is more commonly known as an animal tranquilizer and in powder form as “Special K,” a club drug used to get high. Today, ketamine is being provided legally off-label to treat depression at an estimated 250 clinics across the U.S.
Dr. Steve Levine offers intravenous ketamine infusions at several clinics around the country as an alternative to common anti-depressants. He says he treats about 70-80 patients across all the offices on any given day.
“Everything for the past 50 years has been based on the chemical imbalance theory of depression which has never held water,” Levine said. “So all these medicines, while they do help a lot of people, are based upon a flawed theory. And that is probably one of the reasons why they do take so long to work. They all take weeks to months to work so here is a medicine that people can take infrequently that is based upon a theory of the brain that makes a lot more sense and it works almost immediately.” Stallings didn’t have time to wait. She had an especially hard time over the holidays and when her father got sick, she thought about taking her own life. “I actually had suicidal ideations and the one thing about ketamine was that I was able to get in here emergently because I knew what was going on and when I left here my suicidal thoughts were gone,” Stallings said. That is in line with what Columbia University discovered in one of the largest studies yet on ketamine. Researchers found the drug was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients. The effects lasted up to six weeks. Twenty-two-year-old Marc Nelson ditched his antidepressants for ketamine and talk therapy. He says he now feels more like himself, but it came at a cost. He has spent more than $10,000 on treatments. “So many different drugs that I am now off of all of them, which you know, the side effects were just not tolerable to me. They make me a zombie. I was not happy,” Nelson said. But these infusions can have their own pitfalls. Ketamine can cause people to feel detached from their bodies.
“The 45-minute period of very floatiness, I sometimes get nauseous,” Nelson said. “It’s a very interesting process. … I just lost my train of thought.” Once the treatment was finished, Nelson said he felt “clear, cognizant” and “definitely able to pronounce” his words again. Asked to address critics who say he’s making money by giving people the opportunity to get high, Levine said, “I would say that if you ask any of our patients none of them feel that they are getting high.”
“People tend to focus on the party use of ketamine, because it is more exciting, it’s sexier in some way. It does it a disservice because that’s a very small fraction of its use,” Levine added. “And as far as the money making aspect of this, if you were doing things in the right way you’re not gonna make a lot of money.”
Ketamine has piqued the interest of some major pharmaceutical companies. There are half a dozen drugs in development that mimic the way ketamine works, with some undergoing FDA clinical trials for approval as antidepressants.
For decades, Dr. Gerry Sanacora has been studying ketamine at Yale.
“What we’re trying to understand is what does it change in the brain that allows that sustained anti-depressant like response?” Sanacora said. He says the drug is not addictive in the way opioids are, but could still be harmful in the long run. “There is at least evidence in animal models that these type of medications can actually cause some structural damage in the brain. That’s usually at higher doses, that’s usually at longer term exposure but we don’t know where that level is,” Sanacora said. Dr. Levine said he monitors patients closely.
“In our population even people who have been having ketamine on a maintenance basis for up to six years now we haven’t seen any sign of that,” Levine said.
But for Anne Stallings, despite the unknowns, she’s content with a chance to feel normal. “If I can live a quality, happy life, and be productive, be able to go to work, to be able to have my family, to enjoy life – not walk through life but enjoy life – then it’s worth it.”
In major depression with clinically significant suicidal ideation,
a single subanesthetic ketamine infusion, adjunctive to ongoing
pharmacotherapy, was associated with a greater reduction
in suicidal thoughts at day 1, the primary outcome measure,
compared with midazolam control infusion. The adjusted
mean difference of 4.96 points on the clinician-rated SSI, a
Cohen’s d of 0.75, and a number needed to treat of 4 for
response represent a medium-sized effect. Adverse effects—
mainly blood pressure increase and dissociative symptoms—
were similar to those reported in other ketamine studies (37)
and were mostly mild to moderate, and transient, typically
resolving within minutes to hours after infusion. Improvement
in suicidal ideation largely persisted during the 6-week period of uncontrolled observation, during which
standard pharmacological treatments were also optimized.
To our knowledge, there is no established definition of a
clinically meaningful reduction in score on a standard suicidal
ideation scale. A prospective study (N=6,891) of patients
with depressive disorders (23) found that a baseline SSI
score .2 predicted suicide during up to 20 years of follow-up.
In a prospective study of 562 inpatients (64% with a mood
disorder) who endorsed suicidal thoughts (38), those who
experienced a 50% reduction within 24 hours from a severe
level (suicidal ideation “most of the time”) had one-third the
risk of subsequent self-harm events during a mean length of
stay of 24 days, compared with those whose suicidal thoughts
remained elevated. Given concerns about ketamine’s 1- to 2-week antidepressant
effect in previous studies (11), it is notable that the
improvement in suicidal ideation in this trial was largely
maintained through the 6-week follow-up ratings. This may
be partly explained by the fact that patients continued prior
psychotropic medication, which was optimized after completion
of day 1 postinfusion ratings. Our result is consistent
with the Hu et al. trial (41), in which patients with major depression
who were randomly assigned to receive a single
ketamineinfusion onday 1 of escitalopram therapy experienced
a faster response compared with patients who received a saline
control infusion, and the benefits were maintained for 4 weeks.
We found greater reductions in overall mood disturbance,
depression, and fatigue, assessed with the POMS, on day 1 after
ketamine compared with midazolam.A
secondary analysis of adjunctive ketamine (N=14) found
a reduction in suicidal ideation even when depression did
not remit (17)Ketamine is mechanistically distinct from
currently approved antidepressants, its therapeutic effects
possiblyinvolving rapid synapse formation (44)
In summary, in this randomized trial in suicidal depressed patients, a single adjunctive subanesthetic ketamine infusion was associated with a clinically significant reduction in suicidal ideation at day 1 that was greater than with the midazolam control infusion. In the context of standard, optimized treatment after the ketamine infusion, this improvement appeared to persist for at least 6 weeks. The clinical applicability of our findings was improved with infusion administration by a psychiatrist and without a medication washout, as has been done in some studies
I sifted through the article and took out several points in the discussion of the article below.:
By taking the focus off “oneself” and placing it on other stimuli,
it is possible that ketamine decreases awareness of negative
experiences and consequently improves mood.
The transient dissociation experienced by depressed patients
during a ketamine infusion may have the effect of dampening
what the hyperactive self-monitoring associated with
Radiology findings may reflect ketamine’s ability to reclaim frontal control over deeper limbic structures, thus strengthening the cognitive control of emotions and decreasing depressive symptoms.
Ketamine may cause a “disconnect”
in several circuits related to affective processing, perhaps
by shifting focus of attention away from the internal
states of anxiety, depression, and somatization, and more toward
the perceptual changes (e.g., hallucinations, visual distortions,
derealization) induced by ketamine. Similarly,
during an emotion task, ketamine attenuated responses to
negative pictures, suggesting that the processing of negative
information is specifically altered in response to ketamine.57
By taking the focus off “oneself” and placing it on other stimuli,
it is possible that ketamine decreases awareness of negative
experiences and consequently improves mood
Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine’s mechanism may be elucidated in humans. Here, we review 47 articles of ketamine’s effects as revealed by neuroimaging studies. Some important brain areas emerge, especially the subgenual anterior cingulate cortex.
Ketamine could offer a fast and effective treatment for people with depression, even those who have failed to respond to current therapy options. A new medical reviewpublished this month adds to the growing evidence that the drug could be used in a clinical setting.
The review, published in the Harvard Review of Psychiatry, analyzed 47 studies on ketamine as a treatment for depression. The paper outlined specific ways in which ketamine affected the brains of depression patients.
Ketamine is a drug that can relieve pain and cause feelings of relaxation. It is generally used as an anesthetic in medical setting, but it is also abused as a party drug. Recreational users typically seek a sensation described as being similar to an out-of-body experience.
Despite its popularity at parties, ketamine has been the subject of numerous clinical studies for its potential to treat depression. Data have been mounting in its favor, and now a team at Harvard Medical School has reviewed the evidence thus far.
The authors found that many patients given ketamine displayed measurable positive changes in brain activity in areas associated with the ability to process and control emotions, Business Insider reported.
Those changes include activation of the subgenual anterior cingulate cortex—connected to both emotions and cognition—as observed by neuroimaging. The activation was directly associated with improvement of depression symptoms in as little as 24 hours after patients received a single intravenous subanesthetic ketamine dose.
The drug also enhanced how the brain responded to positive emotions, a change indicated by increased connectivity in the right-hemisphere caudate. That enhancement helped relieve symptoms of depression, possibly because of this region’s connection to the brain’s reward system.
Although the review did not describe exactly how ketamine produces its antidepressant effect, the authors noted that the effect may be indirect. Past research found that ketamine affects several receptors in the brain, such as opioid receptors, adrenegic receptors and serotinin receptors. The review concluded that the side effects of ketamine’s effect on those receptors may be the root cause of its antidepressant response. However, more research is needed to confirm this.
Each year, 13 to 14 million people in America suffer from major depression. Of those numbers who seek treatment, about 30-40% don’t get any better or recover through using the standard depression medications prescribed by healthcare professionals.
Untreated depression puts someone at a greater risk of alcohol and drug abuse, hospitalization and attempted suicide. However, there’s a growing body of research which shows there is a new reason to hope, and it’s the anesthesia drug ketamine.
Ketamine is a popular illicit party drug because it provides the user with hallucinogenic effects. The medication is used in only a handful of clinics around the United States, people who weren’t helped by standard psychiatric treatments are receiving a series of ketamine infusions to help ease the effects of their depression. Ketamine has also been used in emergency rooms to help curb suicidal thoughts, which means the drug is a potential lifesaver.
Ketamine is a fast-acting drug, the effects peak, often within hours, and healthcare providers who give it to a patient at a therapeutic dose say its side effects are brief and mild in most people. The drug hasn’t been studied for long-term safety and effectiveness and the Food and Drug Administration hasn’t approved it to treat depression.
Medical experts do not yet fully understand all the ways ketamine works, but it does work differently than antidepressants such as Zoloft, Prozac and Effexor. The way the drug works might explain why people who don’t respond to traditional treatment methods respond so well to ketamine.
It’s important to remember that no matter how successful cialis generico miglior prezzo ketamine may prove to be, one single treatment isn’t enough to cure depression. To successfully treat depression, a medical professional will need to address all aspects of a person’s disease from the biological, psychological to social and environmental angles.
go site A Brief History of Ketamine
Ketamine is an anesthetic that has been used on both humans and animals for over 52 years. Unlike other anesthetics, it doesn’t depress patients’ breathing or circulatory systems and it is very fast-acting.
source How Is Ketamine Used
Because of its effectiveness and safety when delivered appropriately, ketamine is being used more in the following ways: treating depression and other mood disorders and pain conditions including Complex Regional Pain Syndrome (CPRS/RSD). Leading institutions such as Yale University, The National Institute of Mental Health, and Massachusetts General Hospital have completed research that demonstrates the efficacy and safety of ketamine infusion treatments for these conditions.
here The Visit
The medicine is given very slowly over 40 minutes. Most people can expect to be with us for about 90 minutes. You will leave treatment without side effects and you should not experience side effects between treatments.
go to site In As Little As One Treatment
Ketamine treatments may free you from depression, OCD, PTSD, anxiety, CRPS/RSD, fibromyalgia & other chronic pain conditions.
watch Ketamine Infusion for Depression, Bipolar Disorder or PTSD?
Ketamine could be the bridge for somebody who is suicidal because if they are given the drug and it’s effective for 3 days, the person could be hooked up with outpatient resources, other medications and psychotherapy.
Not all cases of suicidal thoughts are linked to depression, post-traumatic stress disorder, borderline personality disorder and alcohol and other substance abuse issues can also account for some suicides. Further research is needed to determine how ketamine can be utilized for treatment of depression and other psychiatric disorders.
Approximately one-third to one-half of all people with Social Anxiety Disorder (SAD) do not experience adequate clinical benefits from using the current treatment methods for SAD. These treatments include conventional approaches like selective serotonin reuptake inhibitors or SSRIs or cognitive behavioral therapy. Failing to relieve anxiety in patients with social anxiety disorder is a source of distress, substantial morbidity and it decreases the quality of a person’s life over the long term.
Feeling shy or uncomfortable in certain public situations isn’t an indication of a social anxiety disorder, particularly if these emotions are present in young children. A person’s comfort level in social situations will vary and depend on the individual’s personality and life experiences. Some people are naturally reserved and other people are outgoing, some are a mixture of both. In contrast to everyday nervousness, social anxiety disorder includes distress, avoidance and unease that interferes with one’s daily life, routine, work, school and other activities.
There’s been new evidence from neuroimaging and pharmacological studies which support the importance of glutamate abnormalities in the pathogenesis of social anxiety disorder. In a previous clinical study, an elevate glutamate to creatinine ratio was found in the anterior cortex of social anxiety disorder patients when compared with healthy control subjects.
Ketamine is a potent agonist of the N-methyl-D-aspartate receptor is a major glutamate receptor in the brain. The drug is normally used as an anesthetic because of its dissociative properties. In a multitude of controlled clinical studies, ketamine has proven to be an effective treatment for reducing symptoms of depression and anxiety. Ketamine has produced a rapid antidepressant effect in unipolar and bipolar depression and the effects peak 1-3 days following infusion and is observed long after the drug has been metabolized and excreted by the body.
The results of several studies involving ketamine infusion show the medication may have significant anxiolytic effects. For patients with major depressive disorders or social anxiety disorder, the drug has shown strong and significant reductions in co-morbid anxiety symptoms. If you want to find out more information about how ketamine infusion may work for you, please contact us at 703-844-0184 – NOVA Health Recovery
Ketamine is a drug that was developed more than 50 years ago to be used as anesthesia during surgery, and it has also been used as an illicit street drug. Recently, ketamine has been found to be a valuable and extremely effective treatment for depression, anxiety, PTSD, OCD and certain pain disorders, like fibromyalgia.
Our Ketamine treatment center in Bowie MD offer infusions on an outpatient basis and following a consultation with medical staff it can be determined if the medication is appropriate and safe for a person. A patient using ketamine infusion therapy is monitored during the process by a clinical coordinator to ensure a smooth, supportive and successful treatment process.
Because the effects of a ketamine infusion are short-lived, patients will usually receive a series of infusions over a series of 2-3 weeks. Ketamine infusions for PTSD is an off-label use and it means the Food and Drug Administration has not approved the drug for this particular use. However, the drug’s safety and effectiveness have been demonstrated in multiple research studies and off-label prescribing is a common and necessary practice in the medical world.
Unlike most of the common antidepressant medications that may take weeks or months before a patient and doctor can even determine if it works, ketamine infusions yield positive results within hours or days. Many patients will know within the first few hours or days if ketamine is working for them or not. The most common experience when using ketamine infusions is no side effects between treatments, so it is a good option for those with treatment-resistant depression or those who have troublesome side effects from other medications commonly prescribed.
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Ketamine for resistant depression: Outstanding promise, outstanding issues.
Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it’s powerful antidepressant properties (Berman et al 2000; Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.
Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.
The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).
To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.
An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it’s beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).
Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.
Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.
However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).
Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.
In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.
Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.
The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.
A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.
The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.
Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines)receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be ‘absorbed’ back into the dendritic tree.
Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are ‘pruned’ back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer’s and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.
REGULATION OF THE SPINE:
The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).
Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.
There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHOfamily. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.
Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to ‘coalesce’ at dendritic spines.
The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.
Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it’s complexity (and beauty).
Glutamate & GABA for psychiatrists
Rapid Dissemination of Information
Glutamate and GABA are the archetypal ‘fast’ transmitters. If a neuron in the brain ‘wishes’ to communicate rapidly with another cell, the chances are that it will utilise glutamate or GABA. Of course, glutamate neurons exert an excitatory influence on the cells they contact, whereas GABA, at least on first glance, is inhibitory.
Fast transmitters bind to receptors on membrane-spanning ion channels. An ion-channel is in constant flux between various conformations: e.g. open, closed, desensitised. Binding of fast transmitter ‘causes’ the ion channel to snap open for brief periods, and ions rush down their concentration gradients causing an abrupt, short-lived, change in the local membrane potential of the post-synaptic cell (Figure 1). From start to finish the whole process is over within tens of milliseconds, and constitutes a discrete electrical signal (termed an excitatory or inhibitory post-synaptic potential; EPSP, IPSP).
Figure 1. The NMDA Receptor mediates an EPSP.
Neurotransmission v neuromodulation
Fast transmission, as a concept, pre-supposes slow transmission. The classical slow transmitters are the monoamines, e.g. noradrenaline and dopamine. These substances are used as transmitters by neurons within specific brainstem nuclei, whose axons project to numerous subcortical structures and large areas of cortex. There are relatively few monoamine neurons (tens of thousands), but their projections show massive arborisation within the ‘higher centres’ and the limbic system. Anatomically, glutamate and GABA signalling is characterised by point-to-point communication between narrowly separated (and tethered) pre-synaptic and post-synaptic elements, whereas for monoamine systems, the release sites (boutons) and post-synaptic receptors are not necessarily in close proximity. In contrast to glutamate and GABA, which convey a fast, discrete, short-lived electrical signal, monoamines evoke slower-onset, diffuse, longer-duration biochemical changes in their target neurons. Monoamine systems are not optimised for the rapid dissemination of specific information, but instead for modulating those neurons that are.
Ensemble formation and Gestalts
Pyramidal neurons (the principal output neuron of the hippocampus and cortex) use glutamate as a transmitter to communicate rapidly with neurons in ‘lower centres’ such as the striatum, thalamus, pontine nuclei and the cord although most communication is with other pyramidal neurons. Pyramidal neurons organise themselves into ensembles. This process, in which pyramidal neurons fire in synchrony for brief periods of time is thought to be essential for object perception and for movement, speech and thinking.
Consider a pyramidal neuron ‘sitting’ at resting-membrane-potential (-70mV). It receives tens of thousands of excitatory (glutamate) inputs on its dendritic spines, (dynamic structures that are moulded by experience over a lifetime). A single excitatory input (by itself) has little overall impact on the pyramidal neuron. But when numerous EPSP’s from a multitude of inputs arrive ‘synchronously’, the depolarisation may be sufficient for the pyramidal neuron to fire an action potential (AP). In short, the pyramidal neuron is recruited (by the ensemble) into joining the ensemble.
It can be grasped that for AP firing to occur in a pyramidal neuron, there has to be a convergence of excitatory information from numerous sources. Excitatory inputs come from various thalamic nuclei and from stellate cells (in primary sensory cortices), although the overwhelming majority come from other pyramidal neurons. Regardless of the source, timing is key. In order to generate enough depolarisation to trigger an AP, inputs must arrive (and summate) within the same narrow time window (of the order of milliseconds).
Precise Timing and cortical dynamics
The output of a pyramidal neuron (AP spiking) is finely controlled. Precise timing is so fundamental for cortical processing that various auxiliary neurons appear to be tasked with a pacemaker role. These neurons utilise GABA as a transmitter. Classical neuroscience conceptualised GABA containing neurons as nothing more than inhibitory interneurons – this is no longer tenable. There are various populations of GABA containing neuron, which have been classified according to their morphology, their location in the cortex, which proteins they use to sequester calcium, and their electrophysiological properties. Some are even excitatory. For simplicity, we shall restrict ourselves to a simple classification based upon where the GABA neuron contacts the pyramidal neuron (Figure 2).
Figure 2. A pyramidal neuron receives inhibitory GABA-ergic input to its dendrites. GABA pacemakers synapse on the soma and axon initial segment.
Contacts formed with the dendrites of pyramidal neurons function as inhibitory interneurons in the classical sense (i.e. they oppose excitatory drive), whereas GABA neurons targeting the soma or the proximal axon (of the pyramidal neuron) function as pacemakers. We can consider how these GABA pacemaker neurons are optimised for their task. Firstly they have very fast dynamics, swifter for example than the pyramidal neurons that they make contact with. Secondly, they provide a very strong and reliable signal to the pyramidal neuron by engulfing the soma or the proximal axon with numerous terminals. A strong, brief, recurrent signal to the soma and proximal axon creates a series of time windows, which determine precisely when the pyramidal neuron fires. Thirdly, individual pacemaker neurons make contact with numerous local pyramidal neurons. And finally, groups of pacemaker neurons are connected by electrical synapses (gap junctions) so that they can function as an interconnected single entity, a syncytium. For completion, pyramidal neurons make strong, reliable synapses (excitatory) with pacemaker neurons.
It is readily apparent that the interconnectivity of pyramidal neurons and GABA interneurons favours the emergence of oscillations, with successive, precisely timed periods of integration followed by periods of AP discharge. Experiments have shown that the population of neurons in an active ensemble generate the rhythm, whilst the rhythm puts precise constraints upon when an individual neuron can fire.
Systems and levels
For slow, diffuse modulators such as noradrenaline, it makes sense to talk of a system. To recap, noradrenaline [NA] is synthesized by no more than tens of thousands of neurons, confined to discrete nuclei within the brainstem, and is ‘sprayed’ from en-passant boutons over large territories of CNS tissue, in a hormone-like manner. Crucially, the release patterns of noradrenaline [and other neuromodulators] can be clearly mapped onto distinct behavioural states, the most marked differences arising in the sleep-state [noradrenaline – ‘off’] versus the waking-state [noradrenaline – ‘on’]. Since the extracellular concentrations of noradrenaline [and other neuromodulators] can inform directly about higher brain/mind levels, the idea of a noradrenergic system has utility.
Glutamate and GABA are too ubiquitous as fast point-to-point transmitters for the term ‘system’ to be applicable in the same way. Particular patterns of behaviour cannot be mapped onto the release of GABA or glutamate at a specific locus. All we can say is that neurons in an ensemble use glutamate and GABA to communicate with each other. Whereas transient fluctuations in the extracellular concentrations of GABA/glutamate do not reveal anything about behaviour, the dynamics of neuronal ensembles correspond with distinct behavioural states. Again the sleep wake-cycle is illustrative. Oscillatory activity generated by the ensemble can be mapped unambiguously onto the sleep-state and the waking-state.
Learning & Memory
In the 1970s it became clear that excitatory connections onto pyramidal neurons could be made stronger, if they were subjected to particular patterns of input. This was the first experimental support for an idea that can be traced back to Ramon y Cajal – the idea that synapses are modifiable (plastic) and that such plasticity might serve as the physical basis of memory.
There are various forms of plasticity, but the most widely studied is NMDA-dependent long-term potentiation (LTP). In the early 1980’s, researchers based in Bristol showed that NMDA receptor antagonists could block the initiation of LTP [and subsequent behavioural experiments, (most famously, by Richard Morris in Edinburgh) showed that such drugs could inhibit new learning].
NMDA receptor channels are found at the heads of dendritic spines, adjacent to the glutamate terminal. AMPA receptor channels are found in the same locale. When activated, both receptor channels produce an excitatory-post-synaptic-potential (EPSP). In the case of the AMPA receptor, the EPSP is mediated by sodium ions flowing into the spine. For NMDA receptors, the EPSP is mediated by a combination of sodium and calcium ions. [It is the calcium signal that initiates LTP (Figure 3). Early-phase LTP is mediated by phosphorylation of AMPA receptors (increasing their conductance) and by insertion of new AMPA receptors into the post-synaptic membrane].
Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.
AMPA and NMDA receptor channels differ in one other key property. The NMDA channel is voltage-dependent. At membrane potentials less than -50mV, the NMDA channel remains closed, even if glutamate is bound to the receptor. For the NMDA channel to snap open, the membrane potential must be already depolarised to at least -30mV. So two conditions are necessary for NMDA conductance; binding of glutamate and membrane depolarisation. For this reason, the NMDA receptor is said to be a coincidence detector (or in engineering terms, an AND gate).
Sufficient post-synaptic depolarisation can occur from backward-propagating action potentials (APs) or from temporally or spatially summated excitatory input to a dendritic branch. Research in the last decade has revealed that the timing of pre-synaptic activity (glutamate release) and of post-synaptic activity (post-synaptic-depolarisation) is critical in determining whether synaptic strength will be altered. Pre and post synaptic ‘events’ must occur within approximately 20 milliseconds, otherwise synaptic strength remains unchanged. This form of plasticity, known as Spike-Timing-Dependent-Plasticity (SDTP), is likely to become increasingly relevant as we begin to conceptualise ‘micro-circuit’ abnormalities in major neurodevelopmental disorders. Two final points about SDTP will be made here. Plasticity is bidirectional (potentiation or depression) depending on the order of pre and post-synaptic events. And conventional modulators such as dopamine can impact upon the timing rules and alter the direction of the plasticity, (LTP or LTD).
Some Psychiatry: The K-Hole and beyond
Ketamine, a drug that has attracted the attention of psychiatrists in the past few decades, ‘blocks’ the NMDA channel. It has been used as a model psychosis, and latterly has been demonstrated to have acute anti-depressant properties. (It certainly impairs new learning, as would be expected).
Downstream of NMDA blockade, there is no clear consensus as to how ketamine produces a psychosis. Counter-intuitively (for a glutamate antagonist), ketamine increases the excitability (spiking) of pyramidal neurons. Ketamine also increases the power of gamma band (~40 Hz oscillations) and some have proposed that ‘kernels’ of ‘abnormal’ gamma underlie the psychotic-like effect.
But the behavioural pharmacology of ketamine is far from straightforward. Rating-scales used in schizophrenia research, are probably not ideal for capturing the nuances of the drug. Those who have taken a more phenomenological approach [in the sense of ‘bracketing-out’ existing assumptions, whilst focussing on clear descriptions] have identified a much richer and more complex behavioural psychopharmacology, which includes euphoria, near-death experiences, the cessation of time, the dissolution of the ego, and the experience of being immersed in fractal geometries or boundless oneness (Jansen K, Ketamine: Dreams & Realities 2000).
Close observation reveals the dose-dependent emergence of an oneroid (dream-like) state, and other catatonic features (ambitendency, posturing) but not a classic paranoid psychosis. Researchers have also tended to assume that ketamine can ‘cause’ negative symptoms, but reports of euphoria, terror and awe are inconsistent with this categorisation. Motor output (which includes speech of course) is certainly restricted following ketamine, but because the concurrent inner world is a kaleidoscope of strange, mystical and fantastic experiences with extremes of emotion, the overall picture is far removed from the negative syndrome.
Nevertheless, ketamine is frequently championed as the most convincing drug-model of schizophrenia because it can induce negative symptoms, on a rating scale. The irony perhaps is that the ketamine experience might actually be more schizophrenia-like than many of its proponents have suggested. Ketamine elicits phenomena, which are now very rarely encountered in psychiatric clinics, given the modern-day domination of the softer, paranoid form of the illness.
Paul Janssen’s genius was in predicting that a drug which blocked the effects of amphetamine in animals, would be an effective treatment for those cases of schizophrenia that resembled an amphetamine psychosis (characterised by agitation, hallucinations and delusions)[link]. That drug was haloperidol, and that class of drug (D2 dopamine receptor antagonists) changed the landscape of psychiatry.
Janssen’s logic would also suggest that a drug which inhibited the effects of ketamine in animals, would be an effective treatment for those cases of schizophrenia which resemble ketamine-elicited psychopathology (characterised by bizarre, inaccessible dream-like states, and psychotic motor phenomena. i.e. cases where ECT becomes a sensible option). A pharmacological antagonist of ketamine (in animals) proved to be ineffective against human paranoid schizophrenia. Perhaps this could have been predicted, by closer attention to the phenomenology of ketamine. The question now is whether ‘The Lilly compound‘ has efficacy against non-paranoid schizophrenia?
Natural antidepressants & new brain cells
New Brain Cells
In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.
The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.
Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.
There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.
Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.
A new paper from researchers at King’s College London provides an excellent summary of work in this area. The full paper can be read here.
Here is a knock off of the article from Ascend Ketamine in Houston:
There is an undeniable connection between depression and chronic pain. While depression is a clinical mental health disorder, it manifests with inexplicable psychical ailments: migraine headaches, back pain, etc. And while chronic pain is a clinically physical condition, it manifests with inexplicable mental ailments: elevated stress levels, poor quality of sleep, low self-esteem, etc. And the worst part: these mental and physical conditions perpetuate each other. Chronic pain exacerbates depressive symptoms. Depressive symptoms result in heightened levels of pain. And so on…
Breaking the Pain-Depression Cycle
Being proactive is the most important step an individual can take in an effort to break the pain-depression cycle. Acute pain can easily become chronic pain if left unaddressed. Advocate for yourself and speak to a physician if you notice any of these symptoms, even if you don’t think they are anything to be concerned about:
Depression, sadness or anxiety
Poor quality sleep or trouble falling asleep
Loss of hope
Loss of interest in enjoyable activities
Changes to your appetite
Inability to become motivated
Be mindful of—and avoid—stressful situations, as stress can result in heightened pain levels. And don’t assume that depressive symptoms will be resolved when your pain is minimized. It’s better to talk about what you’re experiencing now than it is to spend months or years suffering in the future.
Ketamine Infusions for Chronic Pain & Depression
Ketamine treatments are proven to reduce chronic pain and alleviate the symptoms of depression in up to 70% of patients. If chronic pain and depression are negatively impacting your life, ketamine infusions may be an option for you. Taking a multi-disciplinary approach to treating chronic pain, depression, and other psychiatric disorders, however, is a more high yield approach than any one therapy. Other treatment options to consider include:
Psychotherapy or counseling
Exercise, meditation, journaling, and other mind-body solutions
Medicinal or pharmacological solutions
Ketamine infusions coupled with any of the above treatments will likely yield the most promising results, minimizing chronic pain and effectively reducing depressive symptoms before they become untreatable.
CBS News Features Dr. Ashraf Hanna Discussing How IV Ketamine is Successfully Treating Lyme Disease
TAMPA, Fla., Feb. 22, 2016 /PRNewswire/ — CBS news just broadcast a featured story on Lyme disease and itsfar-reaching complications. There are over 400,000 new cases of the disease diagnosed each year, and the rate has been increasing dramatically.
Dr. Ashraf Hanna, a board certified physician and director of pain management at the Florida Spine Institute in Clearwater, FL discusses this tragic disease: “Lyme disease is a infectious disease caused by bacteria which is transmitted by ticks. The symptoms include rash, fatigue, arthritis of the joints, joint pain, muscle aches, and headaches, numbness, tingling and pain. 70-80% of patients get relief from antibiotics within a few weeks by their primary care or infectious disease physician, but 20-30% may continue with chronic pain symptoms.”
“For the remaining 20-30%, it is not a simple infection anymore; it is a complex, multi-system disease. We have to treat the different types of co-existing infections, autonomic dysfunction, hormonal deficiency, food allergies, etc. But the major contributing factor with persistence of those symptoms after antibiotic treatment is neuro-inflammation and immune-mediated reactions,” stated Dr. Hanna.
IV Ketamine appears to be the best treatment for late stage Lyme disease, after failed antibiotic treatments, and other therapies. Many Lyme patients are reporting remarkable success after treatments with IV Ketamine.
One of the Lyme Patients being treated by Dr. Hanna was Krysten Fernandez: “A few weeks after my tick bite, my symptoms began getting worse, I had extreme pain and was becoming lethargic and weak. I visited over 40 doctors, and after having being misdiagnosed and trying many failed remedies and treatments that were actually worse for my condition, I was finally diagnosed with Late Stage Lyme Disease. At this point I could not work or even walk. I used to be independent and active, was a yoga instructor and had a successful Internet business. Everyday was a struggle to do the simplest tasks.”
“After years of suffering and depression, I found Dr. Ashraf Hanna at the Florida Spine Institute and he recommended IV Ketamine for the treatment of my late stage Lyme disease. After only a few treatments, I had incredible results! My pain levels were reduced, and I felt better than I have felt in years! I am so thankful that Dr. Hanna was able to treat me with IV Ketamine. I can now walk again, have increased function in my limbs and I am getting back to a normal life and feeling great!” said Krysten.
“IV Ketamine Infusion simply blocks receptors in the brain that are responsible for releasing chemicals that cause inflammation of the nervous system that in turn can cause painful symptoms. What makes our program different is that we incorporate physical therapy so that we not only improve pain, but also improve function, and we have seen amazing results. We want patients to get their life back and live productive, fulfilling lives,” Said Dr. Hanna.
EFFECTS OF INTRAVENOUS KETAMINE IN A PATIENT WITH POST-TREATMENT LYME DISEASE SYNDROME:
Discussion and conclusion
A recent double-blind, randomized, placebo-controlled
clinical trial was conducted to evaluate the efficacy of IV
ketamine in patients with treatment-resistant depression.15
These investigators reported that IV ketamine was effective at
reducing depressive symptoms in this patient population. The
results of our case report and evidence from similar studies
and preceding case reports substantiate the antidepressant
efficacy of ketamine.4,16–18 To our knowledge, there have
been no other reports in the literature that have assessed the
effects of IV ketamine in a patient with PTLDS until now.
In this patient with whole-body chronic pain associated
with PTLDS, IV ketamine drastically reduced pain levels
(Figure 1). The patient’s depression and suicidal ideations
were also eliminated post-ketamine infusion. Although we19,20
and others21,22 have reported the efficacy of IV ketamine for
the treatment of chronic pain, this patient’s results were not
typical. In this case, the drastic reductions in pain levels (VAS
reduced from 7 to 2) were followed by an eventual return to
baseline. However, when the patient’s pain did return, shorter
booster infusions were sufficient to maintain analgesia for
months at a time. This is in contrast to, for example, our
previous documentation of a patient with fibromyalgia who
achieved complete remission for more than a year postinfusion
without additional treatment.19
The current PTLDS patient’s pain levels were adequately
controlled using IV ketamine infusions for a duration of
~1–2 months from the last infusion session. Given that the
elimination half-life of IV ketamine is only 2.5 hours,23,24
this means that the duration of analgesia produced in this
case did not require the sustained pharmacological action
of ketamine, since it would have been eliminated within
the first day following the last infusion. This observation
supports theories that chronic pain associated with PTLDS
may be neuropathic in nature25 and that ketamine’s analgesic
efficacy is centrally mediated.
“Central sensitization” has been coined to describe
numerous neuropathic pain conditions resulting from a
nociceptive insult that triggers a prolonged but reversible
increase in the excitability and synaptic efficacy of neurons
in central nociceptive pathways.26 Ketamine is thought to
de-sensitize centrally mediated pain via repeated NMDA
receptor blockade.27 However, it is likely that ketamine acts
via multiple mechanisms to produce analgesia in neuropathic
pain conditions. Neuropathic pain has been associated with
increased glial activation and subsequent release of proinflammatory
cytokines. Interestingly, ketamine produces
pharmacological effects that reduce cell excitotoxicity via
NMDA antagonism and reduce inflammation by suppressing
the hyperactivation of microglia.28 Moreover, ketamine
produces immunomodulatory actions that may also be
uniquely beneficial to conditions that may have an autoimmune
component, such as PTLDS. Thus, ketamine appears
to produce a robust polypharmacological “entourage effect”
that is highly effective in treating neuropathic pain conditions
– which are notoriously difficult to treat with more
conventional analgesic drugs.
In conclusion, the pain relief (~71% decrease) described
in this case report was achieved without the use of increasing
doses of opioid analgesics and, in fact, afforded the
patient’s fentanyl dosage to be reduced from 125 µg to 75 µg
(40% decrease) every 48 hours. Opioid-sparing therapies,
such as ketamine, should be used more frequently for the
management of chronic pain. This is especially important
given the frequency of opioid dependence and abuse, which
has reached such severity to be widely regarded as an “epidemic”.29
Future studies should be conducted to optimize
ketamine for the management of chronic pain conditions
without the use of opioids, where appropriate.
CLEARWATER, Fla., Dec. 22, 2017 /PRNewswire/ — Chronic pain, inflammation and depression are major components of many conditions such as CRPS, RSD, Fibromyalgia, treatment-resistant depression, PTSD and Chronic Lyme Disease. IV Ketamine Infusions have successfully helped thousands of patients for which conventional treatments had failed. In the past, most insurance companies did not cover Ketamine treatments limiting many patient’s access to the drug. Now, many insurance companies have recognized the significant effectiveness of Ketamine and are beginning to cover many treatments.
Dr. Ashraf Hanna, a board certified physician and director of pain management at the Florida Spine Institute in Clearwater, FL discusses this breakthrough treatment: “IV Ketamine Infusions offer hope to my patients and give them relief from their pain and suffering. We are happy to announce that many insurance companies are now covering Ketamine treatments!”
“The insurance companies can no longer ignore the overwhelming research studies by top universities and hospitals regarding the use of Ketamine for numerous difficult-to-treat medical conditions. We use IV Ketamine Infusions for chronic pain as well as treatment-resistant depression, PTSD, OCD, anxiety and many more,” stated Dr. Hanna. “The fact that insurance is now accepted has really opened up the possibility of this treatment for many patients from around the world.”
IV Ketamine has been a safe and effective FDA-approved drug for nearly 50 years. At a molecular level, Ketamine blocks the NMDA receptor. The NMDA receptor is responsible for the body’s underlying neural network (similar to a computer network) and it’s ability to process pain signals to the central nervous system. Over-activation of this receptor can result in excitotoxicity, resulting in a myriad of pain disorders. Ketamine is thought to correct this over-activation by blocking the NMDA receptor. However, the therapeutic effects of ketamine far outlast the actual drug levels in the body leading many to hypothesize that ketamine induces secondary changes that produce long-lasting therapeutic effects in a myriad of disease states.
“While not all insurance companies cover every Ketamine treatment, we hope to continue to add new Ketamine-compliant insurance companies in 2018. Our goal is to help as many patients as possible with this amazing treatment. I have provided over 8,000 Ketamine infusions and have seen so many incredible successes over the past 5 years. Some of my patients were unable to move a limb or walk and now have complete mobility and can walk unaided,” stated Dr. Hanna.
Title: Ketamine for chronic pain: risks and benefits.
Authors: Niesters, M., Martini, C. and Dahan, A.
Journal: Journal of Clinical Pharmacology
Abstract: The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (4–14 days) show long-term analgesic effects up to 3 months following infusion. The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain. Link to Full Text
Title: Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study
Authors: M. Niesters, L. Aarts, E. Sarton and A. Dahan
Journal: British Journal of Anesthesia
Abstract: Background Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients.
Methods CPM responses were obtained in 10 adult neuropathic pain subjects (two men/eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg–1 h–1 for 1 h) and morphine (0.065 mg kg−1 h−1 for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm.
Results Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P<0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief.
Conclusions The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment. Link to Full Text
Title: The Dose-Dependent Effect of S(+)-Ketamine on Cardiac Output in Healthy Volunteers and Complex Regional Pain Syndrome Type 1 Chronic Pain Patients
Authors: Olofsen, Erik MSc; Sigtermans, Marnix MD, PhD; Noppers, Ingeborg MD, PhD; Niesters, Marieke MD, Msc; Mooren, Rene MSc; Bauer, Martin MD; Aarts, Leon MD, PhD; Sarton, Elise MD, PhD; Dahan, Albert MD, PhD
Journal: Anesthesia & Analgesia
Abstract: BACKGROUND: Ketamine is used as an analgesic for treatment of acute and chronic pain. While ketamine has a stimulatory effect on the cardiovascular system, little is known about the concentration–effect relationship. We examined the effect of S(+)-ketamine on cardiac output in healthy volunteers and chronic pain patients using a pharmacokinetic–pharmacodynamic modeling approach.
METHODS: In 10 chronic pain patients (diagnosed with complex regional pain syndrome type 1 [CRPS1] with a mean age 43.2 ± 13 years, disease duration 8.4 years, range 1.1 to 21.7 years) and 12 healthy volunteers (21.3 ± 1.6 years), 7 increasing IV doses of S(+)-ketamine were given over 5 minutes at 20-minute intervals starting with 1.5 mg with 1.5-mg increments. Cardiac output (CO) was calculated from the arterial pressure curve obtained from an arterial catheter in the radial artery. Ketamine and norketamine plasma concentrations were measured. A novel pharmacokinetic–pharmacodynamic model was constructed to quantify the direct stimulatory effect of ketamine on CO and the following adaptation/inhibition.
RESULTS: Significant differences in pharmacokinetic estimates were observed between study groups with 15% and 40% larger S(+)-ketamine S(+)-norketamine concentrations in healthy volunteers compared to CRPS1 patients. S(+)-ketamine had a dose-dependent stimulatory effect on CO in patients and volunteers. After infusion an inhibitory effect on CO was observed. Pharmacodynamic model parameters did not differ between CRPS1 patients and healthy volunteers. The concentration of S(+)-ketamine causing a 1 L/min increase in CO was 243 ± 54 ng/mL with an onset/offset half-life of 1.3 ± 0.21 minutes. The inhibitory component was slow (time constant of 67.2 ± 17.0 minutes).
CONCLUSIONS: S(+)-ketamine pharmacokinetics but not pharmacodynamics differed between study populations, related to differences in disease state (CRPS1 or not) or age. The dose-dependent effect of S(+)-ketamine on CO was well described by the biphasic dynamic model. The effect of S(+)-ketamine on CO was similar between study groups with respect to its stimulatory and inhibitory components, despite group differences in age and health. Link to Full Text
Title: Intravenous Infusions in Chronic Pain Management
Authors: Boleslav Kosharskyy, MD, Wilson Almonte, MD, Naum Shaparin, MD, Marco Pappagallo, MD, and Howard Smith, MD
Journal: Pain Physician
Abstract: In the United States, millions of Americans are affected by chronic pain, which adds heavily to national rates of morbidity, mortality, and disability, with an ever-increasing prevalence. According to a 2011 report titled Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research by the Institute of Medicine of the National Academies, pain not only exacts its toll on people’s lives but also on the economy with an estimated annual economic cost of at least $560 – 635 billion in health care costs and the cost of lost productivity attributed to chronic pain. Intravenous infusions of certain pharmacologic agents have been known to provide substantial pain relief in patients with various chronic painful conditions. Some of these infusions are better, and although not necessarily the first therapeutic choice, have been widely used and extensively studied. The others show promise, however are in need of further investigations. This article will focus on non-opiate intravenous infusions that have been utilized for chronic painful disorders such as fibromyalgia, neuropathic pain, phantom limb pain, post-herpetic neuralgia, complex regional pain syndromes (CRPS), diabetic neuropathy, and central pain related to stroke or spinal cord injuries. The management of patients with chronic pain conditions is challenging and continues to evolve as new treatment modalities are explored and tested. The following intravenous infusions used to treat the aforementioned chronic pain conditions will be reviewed: lidocaine, ketamine, phentolamine, dexmedetomidine, and bisphosphonates. This overview is intended to familiarize the practitioner with the variety of infusions for patients with chronic pain. It will not, however, be able to provide guidelines for their use due to the lack of sufficient evidence. Link to Full Text
Title: The Use of Ketamine in Neuropathic Pain
Authors: Sarah Lee O’Brien • Sanjog Pangarkar • Joshua Prager
Journal: Curr Phys Med Rehabil Rep
Abstract: Hyperactivity of N-methyl-D-aspartate (NMDA) receptors may be one of the factors in the genesis of neuropathic pain (NP). Ketamine is a dissociative anesthetic and analgesic that is the most potent NMDA receptor antagonist currently available for human use. There is a growing body of literature for three decades suggesting efficacy of subanaesthetic doses of ketamine in the treatment of NP, particularly the pain in complex regional pain syndromes. The primary limitations of ketamine use are secondary to psychotomimetic and, to a lesser extent, sympathetic activation. The purpose of this article is to review the history, pharmacology, pharmacodynamics, clinical benefits, and limitations of ketamine for treatment of NP. Methods of administration and management of adverse effects are highlighted based on the clinical experience of the authors. Link to Full Text
Title: Ketamine: a growing global health-care need
Authors: T. T. Dong, J. Mellin-Olsen and A. W. Gelb
Journal: British Journal of Anesthesia
Abstract: Ketamine was first synthesized in 1962, patented in Belgium in 1963, and approved for human use by the US Food and Drug Administration in 1970. Unlike inhalation anaesthetics, ketamine provides analgesia, preserves airway reflexes, offers haemodynamic stability, and maintains respiratory drive, which gives ketamine an excellent safety profile. It is therefore a favoured choice for trauma triage, use in man-made and natural disasters, and for many other patients with compromized haemodynamic stability. However, side-effects, such as agitation, hallucinations, and panic attacks, have limited its clinical use as an anaesthetic in affluent countries. Lately, ketamine has found new uses in clinical medicine in addition to renewed threats to its availability. Link to Full Text
Title: Ketamine-induced affective switch in a patient with treatment-resistant depression
Authors: Girish Banwari, Prutha Desai, and Prahlad Patidar
Journal: Indian Journal of Pharmacology
Abstract: There is growing evidence to support the rapid, albeit short-lived antidepressant effect of subanesthetic dose of ketamine, a noncompetitive glutamate N-methyl-D-aspartate receptor antagonist in treatment-resistant unipolar and bipolar depression. Ketamine is known to cause transient mood elevation or euphoria, psychotomimetic effects, and dissociative symptoms, but its use in unipolar or bipolar depression has not been reported to induce an affective switch amounting to persistent or prolonged hypomania/mania or manic-like syndrome. We report the case of a 52-year-old male with first episode, continuous, nonpsychotic, treatment-resistant, unipolar major depression of 10 years duration, who manifested a switch from depression to mania while being treated with subanesthetic dose of ketamine, given intramuscularly. This case suggests that polarity switch should be considered as a potential side effect while using ketamine for treatment-resistant depression. Link to Full Text
Title: Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
Authors: James W. Murrough, , M.D., Dan V. Iosifescu, , M.D., Lee C. Chang, , M.D., Rayan K. Al Jurdi, , M.D., Charles E. Green, , Ph.D., Andrew M. Perez, , M.D., Syed Iqbal, , M.D., Sarah Pillemer, , B.A., Alexandra Foulkes, , M.S., Asim Shah, , M.D., Dennis S. Charney, , M.D., Sanjay J. Mathew, , M.D.
Journal: American Journal of Psychiatry
Abstract:Intravenous ketamine demonstrated rapid antidepressant effects in an optimized study design, improving depression severity in 64% of treatment-resistant patients 24 hours after a single dose. The double-blind trial provides evidence for the role of the N-methyl-d-aspartate glutamate receptor in depression, a receptor not currently activated by existing antidepressant drugs.
Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.
This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.
Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice. Link to Full Text
Title: Intravenous Therapies in the Management of Neuropathic Pain: A Review on the Use of Ketamine and Lidocaine in Chronic Pain Management
Authors: Harsha Shanthanna
Journal: Neuropathic Pain
Abstract: Neuropathic Pain is a term referred to “pain arising as a direct consequence of a lesion affecting the somatosensory system”. As a first line option, oral medications are mostly used, as they are easily available, relatively safe, and do not need much resources. They include antidepressants in the form of tricyclics, newer selective reuptake inhibitors of serotonin and norepinephrine, gabapentin, pregabalin etc. Although neuropathic pain conditions do share some common clinical features, they are quite diverse when considered individually according to their etiology and pathogenesis. Hence not all patients and not all types of neuropathic pain respond to such oral therapy. In practice patients are given a form of such neuropathic pain medication along with or without an opioid, depending upon the extent of pain that the patient suffers. Opioids are potent analgesics but are not a good choice for neuropathic pain conditions. With time the clinician is left with fewer alternatives and furthermore, with the the increasing knowledge that escalation of opioid therapy will perhaps lead to hyperalgesia and tolerance, it becomes necessary to explore other options. Among the other options one can always consider to explore treatment with intravenous medication such as Ketamine, Lidocaine, and Magnesium etc. This chapter would highlight the use of ketamine and lidocaine in the form of drug profile, the pharmacological basis behind its use, strategies to use, important side effects and limitations and available evidence base, including a review of randomised controlled studies. Both are considered separately in two different parts. References for both the parts are given at the end, in separate sections. Link to Full Text
Post-Treatment Lyme Syndrome
Title: Post-Treatment Lyme Syndrome and Central Sensitization
Authors: Shweta Batheja, , M.B, B.S., Jenifer A. Nields, , M.D., Alla Landa, , Ph.D., Brian A. Fallon, , M.D., M.P.H.
Journal: Journal of Neuropsychiatry
Abstract: The authors of this clinically important article describe the process whereby chronic Lyme disease and its CNS sequelae can result in various treatment-resistant pain and anxiety disorders that are characterized by hypersensitivity to noxious and non-noxious stimuli. These may include skin reactions, fatigue, muscle weakness, extreme sensitivity to sound or smell, and, also, mood and cognitive symptoms. The article reviews several treatment approaches beyond antibiotics, including antidepressants and anti-epileptic drugs.
Central sensitization is a process that links a variety of chronic pain disorders that are characterized by hypersensitivity to noxious stimuli and pain in response to non-noxious stimuli. Among these disorders, treatments that act centrally may have greater efficacy than treatments acting peripherally. Because many individuals with post-treatment Lyme syndrome (PTLS) have a similar symptom cluster, central sensitization may be a process mediating or exacerbating their sensory processing. This article reviews central sensitization, reports new data on sensory hyperarousal in PTLS, explores the potential role of central sensitization in symptom chronicity, and suggests new directions for neurophysiologic and treatment research. Link to Full Text
Title: Review of pharmacological therapies in fibromyalgia syndrome
Authors: Winfried Häuser, Brian Walitt, Mary-Ann Fitzcharles and Claudia Sommer
Journal: Arthritis Research & Therapy
Abstract: This review addresses the current status of drug therapy for the management of fibromyalgia syndrome (FMS) and is based on interdisciplinary FMS management guidelines, meta-analyses of drug trial data, and observational studies. In the absence of a single gold-standard medication, patients are treated with a variety of drugs from different categories, often with limited evidence. Drug therapy is not mandatory for the management of FMS. Pregabalin, duloxetine, milnacipran, and amitriptyline are the current first-line prescribed agents but have had a mostly modest effect. With only a minority of patients expected to experience substantial benefit, most will discontinue therapy because of either a lack of efficacy or tolerability problems. Many drug treatments have undergone limited study and have had negative results. It is unlikely that these failed pilot trials will undergo future study. However, medications, though imperfect, will continue to be a component of treatment strategy for these patients. Both the potential for medication therapy to relieve symptoms and the potential to cause harm should be carefully considered in their administration. Link to Full Text
Title: Effects of Intravenous Ketamine Infusions in a Neuropathic Pain Patient with Lichen Sclerosus et Atrophicus
Authors: Ashraf F. Hanna, Josh S. Armstrong, Adam J. Smith
Journal: Karger Open Access
Abstract: A patient reported to the Florida Spine Institute (Clearwater, Fla., USA) with severe lichen sclerosus of the anogenital region and legs. The patient’s pain presentation was neuropathic with hypersensitivity, allodynia, swelling, and weakness. The patient had failed multiple pain management modalities including opioid therapy, anticonvulsants, and antidepressants. The patient completed a standard intravenous ketamine infusion regimen developed at the Florida Spine Institute and reported complete abolishment of her pain syndrome. For the first time, we report that ketamine infusions also dramatically improved a patient’s lichen sclerosus. That ketamine is known to have immunomodulatory properties, and given the clinical observations described in this case report,suggests that ketamine should be explored as a possible new therapeutic option for managing lichen sclerosus, especially in cases that are refractory to conventional therapies.
Title: Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews
Authors: Neil E O’Connell, Benedict M Wand, James McAuley, Louise Marston, G Lorimer Moseley
Journal: Cochrane Database of Systematic Reviews
Abstract: Complex regional pain syndrome (CRPS) is characterised by persistent pain, usually in the hands or feet, that is not proportionate inseverity to any underlying injury. It often involves a variety of other symptoms such as swelling, discolouration, stiffness, weakness and changes to the skin. This over view sought to summarise and report all of the available evidence arising from systematic reviews for all treatments for this condition regarding how well they work and any potential harm that they might cause. We identiﬁed six Cochrane reviews and 13 non-Cochrane systematic reviews that included evidence relating to a broad range of treatments, from drugs to surgical procedures, rehabilitation and alternative therapies. For most treatments there were only a small number of published trials and the quality of these trials was mixed. As such, most of the evidence for most treatments is of low or very low quality and can not be regarded as reliable.We found low quality evidence that a daily course of the drug ketamine delivered intravenously may effectively reduce pain, although it is also associated with a variety of side effects. We found low quality evidence that the bisphosphonate class of drugs, calcitonin and programmes of graded motor imagery may be effective for CRPS, and that mirror therapy may be effective in people who develop CRPS after suffering a stroke. Low quality evidence suggested that physiotherapy and occupational therapy did not lead to clinically important beneﬁts at one year follow up, and that blocking sympathetic nerves with local anaesthetic is not effective. There is moderate quality evidence that an intravenous regional blockade using the drug guanethidine is not effective and may be associated with complications.For a range of other interventions we found only very low quality evidence or no evidence at all. No conclusions should be drawn regarding the value of these interventions based on this level of evidence.Based on the existing evidence it is difﬁcult to draw ﬁrm conclusions as to which therapies should be offered to patients with CRPS.Better quality research is vital to reduce uncertainty in this area and is necessary before conﬁdent recommendations can be made. Link to Full Text
Title: Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds
Authors: Mark J. Niciu, Ioline D. Henter, David A. Luckenbaugh, Carlos A. Zarate Jr., and Dennis S. Charney
Journal: Annu Rev Pharmacol Toxicol.
Abstract: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine’s antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine’s antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine’s antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine’s adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine’s antidepressant effects. Link to Full Text
Highlight: Ketamine: A New (and Faster) Path to Treating Depression
Left: Change in the 21-item Hamilton Depression Rating Scale (HDRS) following ketamine or placebo treatment. Right: Proportion of responders showing a 50 percent improvement on the HDRS following ketamine or placebo treatment.34
Source: Carlos Zarate, M.D., Experimental Therapeutics and Pathophysiology Branch, NIMH
The most commonly used antidepressants are largely variations on a theme; they increase the supply within synapses of a class of neurotransmitters believed to play a role in depression. While these drugs relieve depression for some, there is a weeks-long delay before they take effect, and some people with “treatment-resistant” depression do not respond at all.
The delay in effectiveness has suggested to scientists that the medication-induced changes in neurotransmitters are several steps away from processes more central to the root cause of depression. One possibility for a more proximal mechanism is glutamate, the primary excitatory, or activating, neurotransmitter in the brain. Preliminary studies suggested that inhibitors of glutamate could have antidepressant-like effects, and in a seminal clinical trial, the drug ketamine—which dampens glutamate signaling—lifted depression in as little as 2 hours in people with treatment-resistant depression.34
The discovery of rapidly acting antidepressants has transformed our expectations—we now look for treatments that will work in 6 hours rather than 6 weeks. But ketamine has some disadvantages; it has to be administered intravenously, the effects are transient, and it has side effects that require careful monitoring. However, results from clinical studies have confirmed the potential of the glutamate pathway as a target for the development of new antidepressants. Continuing research with ketamine has provided information on biomarkers that could be used to predict who will respond to treatment.35Clinical studies are also testing analogs of ketamine in an effort to develop glutamate inhibitors without ketamine’s side effects that can then be used in the clinic.36 Ketamine may also have potential for treating other mental illnesses; for example, a preliminary clinical trial reported that ketamine reduced the severity of symptoms in patients with PTSD.37 Investigation of the role of glutamate signaling in other illnesses may provide the impetus to develop novel therapies based on this pathway.
One of the imperatives of clinical research going forward will be to demonstrate whether the ability of a compound to interact with a specific brain target is related to some measurable change in brain or behavioral activity that, in turn, can be associated with relief of symptoms. In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities—which lasted up to 14 days.38 Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain. This approach is consistent with the NIMH’s RDoC project, which calls for the study of functions—such as the ability to seek out and experience rewards—and their related brain systems that may identify subgroups of patients with common underlying dysfunctions that cut across traditional diagnostic categories.
The ketamine story shows that in some instances, a strong and repeatable clinical outcome stemming from a hypothesis about a specific molecular target (e.g., a glutamate receptor) can open up new arenas for basic research to explain the mechanisms of treatment response; basic studies can, in turn, provide data leading to improved treatments directed at that mechanism. A continuing focus on specific mechanisms will not only provide information on the potential of test compounds as depression medications, but will also help us understand which targets in the brain are worth aiming at in the quest for new therapies.
PET scans revealed that ketamine rapidly restored bipolar depressed patients’ ability to anticipate pleasurable experiences by boosting activity in the dorsal anterior cingulate cortex (yellow) and related circuitry. Picture shows PET scan data superimposed on anatomical MRI.38
I also threw in a reprint of the article from NIH regarding strategic principle #2 to find biomarkers of mental health disorders:
Highlight: GPS for the Brain? BrainSpan Atlas Offers Clues to Mental Illnesses
The recently created BrainSpan Atlas of the Developing Human Brain incorporates gene activity or expression (left) along with anatomical reference atlases (right) and neuroimaging data (not shown) of the mid-gestational human brain. In this figure, the location and expression level of the gene TGIF1 is shown in a brain from 21 weeks postconception.
Source: Allen Institute for Brain Science
Technologies have come a long way in mapping the trajectory of mental illnesses. Early efforts provided information on anatomical changes that occur over the course of development. In a step that has been hailed as providing a “GPS for the brain,” the BrainSpan Atlas of the Developing Brain, a partnership among the Allen Institute for Brain Science, Yale University, the University of Southern California, and NIMH—has created a comprehensive 3-D brain blueprint.25 The Atlas details not only the anatomy of the brain’s underlying structures, but also exactly where and when particular genes are turned on and off during mid-pregnancy—a time during fetal brain development when slight variations can have significant long-term consequences, including heightened risk for autism or schizophrenia.26 Knowledge of the location and time when a particular gene is turned on can help us understand how genes are disrupted in mental illnesses, providing important clues to future treatment targets and early interventions. The Atlas resources are freely available to the public on the Allen Brain Atlas data portal. Already, the BrainSpan Atlas has been used to identify genetic networks relevant to autism and schizophrenia.27,28 In both of these studies, the fetal pattern of gene expression revealed relationships that could not be detected by studying gene expression in the adult brain. As most mental illnesses are neurodevelopmental, mapping where and when genes are expressed in the brain provides a fundamental atlas for charting risk.
NOVA Health Recovery <<< Ketamine infusion center in Fairfax, Virginia 22306 – ketamine for depression, pain, addiction
Call 703-844-0184 for immediate evaluation!
I am posting a Ketamine article I published in “Your Health Magazine” below. There is excellent studies demonstrating the efficacy of Ketmine in multiple disorders, especially depression, PTSD, post-partum depression, suicidality, Obsessive-compulsive disorder, and severl other mental health problems. Likewise, Ketamine is effective in numerous painful conditions, including CRPS, neuropathy, fibromyalgia, post-herpetic neuralgia, phantom-limb pain, and others. I will discuss articles on each in the ensuing months.
I have used Ketamine over the past 20 years with excellent results in multiple settings. I have always been impressed by it’s safety, especially when it comes to respiratory and cardiac situations.
More and more information is coming about Ketamine’s versatility. Even Time magazine had a recent posting regarding it’s use in depression:
Ketamine has been safely used for over 45 years, serving as an effective anesthetic agent that has also been shown to have benefits in the treatment of a wide variety of painful conditions as well as mood-related disorders. Treatment-resistant depression is an example of a life-threatening disorder that can be improved through the use of specific protocols that involve the infusion of Ketamine. Depression causes tremendous suffering in both quality of life as well as medical problems that result from the stress it produces. Many individuals have tried numerous therapies that have had little to no impact on their depression, leaving them feeling hopeless over their condition. It turns out that for properly selected individuals, Ketamine can provide acute relief within hours to days. Unlike typical antidepressants, Ketamine interacts with certain brain-derived factors that encourage nerve cells to make meaningful connections that can diminish depression within a much shorter time than a standard depression medication. It is a ‘brain reset’ of sorts, allowing underlying medications to be adjusted while your mood is rapidly elevated through genuine changes of brain circuitry.
Ketamine also provides potentially effective treatment in cases of painful conditions, such as RSD/CRPS, trigeminal neuralgia, post-herpetic neuralgia, and several other nerve conditions. Ketamine can be used in an office-based intravenous protocol and then continued in a topical treatment for those who respond well.
Although Ketamine is FDA approved for anesthetic use, it has not been sent to the FDA for approval of any other medical states. However, the evidence for Ketamine’s ability to provide relief in conditions such as PTSD, anxiety disorders, depression, suicidality, post-herpetic neuralgia, CRPS, trigeminal neuralgia, and multiple other conditions has accumulated over 45 years of use in multiple studies. Ketamine is also being evaluated for drug addictions as well as alcohol use disorder. More recently, Ketamine was featured in Time magazine (August 2017) and in JAMA (November 2017) due to the positive effects it has had in difficult-to-treat depression.
More and more clinics are offering this treatment, which creates new possibilities for improving conditions that formerly had so few options. With proper patient selection and appropriate monitoring, Ketamine can be safely and comfortably used in an office setting. With a standard slow infusion, most people do not even notice any significant side effects. If you have suffered from any of these conditions then ask your specialist if Ketamine may be a solution for you.
“Addiction is a devastating disease that affects an individual physically and psychologically. Counseling may help the psychological component but medications can be much more effective for the physical changes that result from alcohol and opioid abuse.” – Christopher Sendi MD • Link in bio #alcoholaddiction #addiction #opioidaddiction #counseling #medication #recovery#addiction#medication#recovery#counseling#opioidaddiction#alcoholaddiction
Depression afflicts 16 million Americans.
One third don’t respond to treatment
A surprising new drug may change that”
The drug in question is ketamine. Will ketamine stop suicidal thoughts better than traditional antidepressants?
When someone is suicidal seconds count!
Q. Is ketamine infusion safe for the elderly? My son’s mother-in-law (age 69) has been diagnosed with major depression. She has made two suicide attempts.
I am not sure what she is taking now, but she seems apathetic, worries about everything and interacts inappropriately with family. She is almost completely unresponsive to her grandchildren. This is a total change from her personality five years ago, when she was devoted to her family and engaged with the world.
A. Major depression takes a terrible toll on the individual, family and friends. Suicide attempts are a clear signal that your son’s mother-in-law is desperate and requires expert medical intervention.
Ketamine (Ketalar) is a fascinating drug that has been used since 1962 as a general anesthetic. Over the last several years researchers have discovered that this medication has profound antidepressant activity that kicks in within hours instead of the usual weeks of standard drugs. When someone is suicidal it is dangerous to wait weeks for an antidepressant drug to work.
“These cases demonstrate that low doses of sublingual ketamine repeated over a span of hours can induce rapid remission of suicidality in unipolar or bipolar depression.
“Chronic use of oral or sublingual ketamine has been helpful in the past 4 years for many of my patients with mild depressive symptoms.
“Sublingual ketamine may be a practical option for managing suicidality in outpatients as an adjunct to traditional antidepressants and mood stabilizers and could shorten the hospital stay of psychiatric inpatients. Sublingual ketamine is worthy of systematic study as a treatment to provide rapid relief of suicidal ideation.”
…”the evidence to date supporting the clinical use of ketamine as antisuicidal treatment is extremely preliminary, and on the basis of the article by Ionescu et al, conclusions concerning the effects of ketamine on suicidal ideation should be drawn with caution.”
“Cancer patients experience increased risk and incidence of suicide and other psychiatric disorders.
“In the past 10 years, evidence has emerged showing that sub-anesthetic doses of ketamine (0.5 mg/kg) induce fast-acting antidepressant effects on depressed patients. Antidepressant effects of ketamine were observed as soon as 40 min after infusion and typically lasted at most for 7 days, with some patients experiencing more prolonged mood improvement.
” Collectively, this study provides novel information about the rapid antidepressant effect of ketamine on acute depression and suicidal ideation in newly-diagnosed cancer patients.”
“Ketamine for Treatment of Suicidal Ideation and Reduction of Risk for Suicidal Behavior”
“Our review concludes that ketamine treatment can be seen as a double-edged sword, clinically to help provide treatment for acutely suicidal patients and experimentally to explore the neurobiological nature of suicidal ideation and suicidal behavior.”
Ketamine and Your Mother-In-Law:
There is inadequate research on ketamine infusion in older patients (Expert Opinion on Pharmacotherapy, April 2017). Since this medication may alter blood pressure and heart rate, the latest recommendations from the American Psychiatric Association call for monitoring so that immediate care may be provided if necessary (JAMA Psychiatry, April 1, 2017).
More articles from The People’s Pharmacy about whether Ketamine can stop suicidal thoughts are available at these links:
Dr. Sendi graduated from Georgetown University Medical School and trained at Pitt County Memorial Hospital, East Carolina University, Greenville, N.C. for his Board Certification in Internal Medicine. He is also ABPSUS Board Certified in Emergency Medicine and Board Certified in Obesity Medicine with the American Board of Obesity Medicine.
NOVA Health Recovery was founded to provide the optimal care to patients suffering from life-altering, preventable illnesses such as Obesity, Addiction, and Pain. We provide progressive therapies for challenging cases of depression, PTSD, neuropathy, CRPS/RSD, and other painful conditions using Ketamine infusions in a comfortable and safely monitored setting. We also use state-of-the-art interventions for addictions of multiple types, providing the tools and support to allow one to move forward in a healthy, successful manner. There is no need to suffer from treatable conditions in which progressive medication assisted therapies, behavioral support, wellness plans, and general health screening can allow you to improve your quality of life. We also use telemedicine to make it easy for you to see your physician from the comfort of your own home.
American College of Physicians, American Society of Addiction Medicine, American Society for Nutrition, The Obesity Society.
Dr. Sendi has 21 years experience in the medical field. Included experiences are Addiction and Pain Management, Obesity and weight management, lipidology, and wellness. Dr. Sendi is Board Certified in Internal Medicine, Emergency Medicine, and Obesity Medicine. His additional interests include wellness, aging, and health-risk mitigation.
Have you Tried all options for depression and pain?
At NOVA Health Recovery, we understand how painful conditions, such as CRPS, post-herpetic neuralgia, and neuropathies rob your life of comfort and quality. We also recognize the suffering that mental health problems, such as anxiety, depression, and PTSD inflict on people and destroy the ability to enjoy even their best years. Many have exhausted multiple therapies and feel hopeless about any treatment at all. NOVA Health Recovery offers Ketamine treatments to appropriate patients who suffer such conditions. In conjunction with other regimens, Ketamine infusion, offered in a monitored, comfortable setting, may provide improvement. This option may just be what you need to pick up your mood and decrease you pain while your regular medications take effect.
Want to learn more? Schedule a consultation today by calling 703-844-0184.