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Old Club Drug Is Repurposed Into Depression Treatment
A North Texas woman said a popular club drug and animal tranquilizer saved her from a life of depression and suicidal thoughts.
You may have heard of the drug before, as Special K on the street. it was designed as a horse tranquilizer, but Ketamine is gaining popularity as a treatment for depression.
Some doctors believe the controversial drug will become a game-changer in slowing the nation’s suicide epidemic.
Tiffany McCombie, a 40-year-old mother of one, knows what depression feels like in its darkest moments.
“I definitely was feeling what I would consider suicidal, not really wanting to live, not really wanting to die, just numb. That’s not a healthy place for me,” McCombie said.
She said she has lived with depression and Bipolar disorder for 30 years, has tried dozens of medications and supplements to combat it, but nothing, she said, has worked as well as the Ketamine infusions she gets at Rise Wellness Center.
She’s had six of them in ten months.”I had the right attitude and wanted to be healed and believing that it was going to happen for me and my brain. It happened. It cut down the mood stabilizers and antidepressants I had been on for years. I don’t take them at all,” she said.
More studies,like this one, are finding that Ketamine may be more effective and work faster than traditional antidepressants.
A local team of anesthesiologists had used the drug before, as an anaesthetic inside the operating room, but after seeing its potential to treat depression, they opened Rise Wellness Center, which specializes in Ketamine infusions.
“We get people that are so far down and so dark that we need this to get them out, to get them up, to get them moving. No drug does that like Ketamine,” said Dr. Renaud Rodrigue, a pain management physician at Rise Wellness Center.
Experts say Ketamine can be dangerous, even deadly, if abused or taken in large doses.
Even though it’s not FDA-approved to treat depression, Dr. Rodrigue said, when given in small doses and in a clinical setting, 90 percent of his patients with severe depression reported long-term benefits.
Researchers at the University of Illinois published this study about how Ketamine may trigger a depression-fighting protein in the brain.
“This protein changed the game for us. We know now there’s something that is created just by the drug itself, which is staying in the central nervous system and is exerting this affect way beyond the duration of the drug,” said Dr. Rodrigue.
McCombie said Ketamine saved her life.
Could Ketamine conquer Treatment resistant depression?
Transcript
{Video opens with music and pictures of UTSW patient Megan Joyce along with her mother and with her husband.}
Megan Joyce: Everything in my life seems great.
Narrator: Megan Joyce’s life may look picture perfect.
Megan: I graduated college. I got married. He’s an amazing person. He is incredibly supportive.
Narrator: But what these happy photos hide is a relentless inner struggle.
Megan: This is not something that I love to admit, but I fight for my life every single day.
Narrator: The 27-year-old has spent more than a decade battling severe depression. It triggers for no obvious reason.
Megan: They have defined my bipolar illness as treatment resistant.
Narrator: She says she tried every medication in the books … as well as checking into inpatient and outpatient treatment centers. Nothing worked. Until doctors at UT Southwestern Medical Center tried something bold. Ketamine infusion therapy.
Megan: I don’t know if I would be here without the Ketamine treatment. I drive from Austin every 10 days, and I come for treatment, and I’m in the hospital for about 5 hours, and then I go home the same day.
Narrator: Several studies show ketamine can quickly stabilize severely depressed patients. But it does come with risks.
Dr. Madhukar Trivedi: There is a risk for addiction so that if people start taking Ketamine on their own on the black market, then that can be very dangerous. There are toxic effects in the brain if you overdose. On the other hand, for patients who do well on this and are getting the right dose under the guidance of a physician, it can be life saving.
Megan: When I have the IV in, it’s for 40 minutes, and then I stay for 2 hours after because it is an anesthetic so they want to make sure you don’t have adverse side effects.
Narrator: Dr. Madukhar Trivedi is closely monitoring Joyce … as well as the work his colleagues are doing at the bench.
Dr. Trivedi: At UT Southwestern, we have the whole breadth of work being done. There are people working like Dr. Monteggia in basic research. Understanding the exact mechanism of how Ketamine changes molecularly and changes the mechanism of action.
Dr. Lisa Monteggia: We got involved with how Ketamine triggers an anti-depressant effect because of the real need. Some of the recent clinical data has really shown that about a third of all patients don’t respond to anti-depressants. So, what do you do for treatment for those individuals?
Narrator: UT Southwestern’s Dr. Lisa Monteggia is a neuroscientist whose lab pinpointed a key protein that helps tigger Ketamine’s rapid antidepressent effects in the brain. Whereas traditional antidepressents can take up to 8 weeks to work, the effects of ketamine are seen within 60 to 90 minutes.
Dr. Monteggia: The idea of trying to understand how you generate a rapid anti-depressant response in patients … it’s really the first time we’ve been able to study it.
Narrator: Her study, published in the prestigious journal Nature, shows that ketamine blocks a protein responsible for a range of normal brain functions.
Dr. Monteggia: How we think Ketamine triggers an anti-depressant effect, this blocking the NMDA receptor, we think may also be causing the side effects associated with Ketamine. One of the things we’re working on is to try and see if we can identify compounds, slight derivatives perhaps, that may have the beneficial effects of Ketamine, in terms of triggering anti-depressant effects, without the side effects.
Narrator: In the meantime, Joyce remains optimistic for her future and the millions of others trying to defeat depression.
Megan: That’s why I really sought out Ketamine is I really wanted to give back and just have a chance at a semi-normal life.
Depression Patients Turning to Local Doctor’s Ketamine Therapy
The deaths of designer Kate Spade on Tuesday and TV Chef Anthony Bourdain Friday morning are bringing new attention to depression and suicide.
A new Center for Disease Control and Prevention report reveals suicide rates have risen 30 percent across much of the country since 1999.
But right here in San Diego, there is hope for a category of patients some doctors call “the untreatable.”
This patient, we’ll call Lisa, is composing a letter to the editor about her 20-year fight to stay alive.
“I know how tall the bridge is. I know how many seconds it takes to land,” Lisa said.
Lisa is an attorney with severe depression. Conventional medicines could not suppress her suicidal thoughts.
“It’s awful,” she said. “The day starts with waking up thinking ‘Can I even get out of bed?’ You just fight it to exhaustion every single day.”
She was referred to Dr. David Feifel who NBC 7 first also spoke to three years ago. Patients travel from as far away as Canada to undergo his Ketamine therapy.
“Sort of a psychedelic experience. It’s also been termed dissociative experience because it is sort of an out-of-body feeling,” Dr. Feifel said of his therapy.
Dr. Feifel says low doses of Ketamine have an almost immediate effect on his patients, unlike conventional anti-depressants that can take weeks to build up a therapeutic level.
While Ketamine doesn’t stay in the body more than a day, its effects can last for months.
“It seems to be able to vaporize people’s sense of wanting to take their life.” Dr. Feifel said.
Lisa has received some 35 treatments over the last four months.
“I walk in here crappy, I’ll leave happy. It is a remarkable, remarkable experience that in 20 years nothing has ever come close” Lisa said.
Her goal is to need fewer treatments and experience longer-lasting effects.
Lisa’s hope for the so-called “untreatable community” of depressed people is they find help.
Ketamine-Associated Brain Changes – A Review of the Neuroimaging Literature
KEY POINTS:
Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature
Subanesthetic doses of ketamine have rapid (within hours), robust (across a variety of symptoms), and relatively sustained (typically up to one week) antidepressant effects—even in patients with TRD (treatment resistant depression). Clinical studies show that about 50% of patients with TRD have a significant decrease in symptoms within 24 hours of a single intravenous subanesthetic ketamine dose.
Animal models show that ketamine’s antidepressant effects are likely mediated by its antagonism of N-methyl-D-aspartate (NMDA) receptors through increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA)–mediated glutamatergic signaling. This triggers activation of intracellular synaptogenic pathways, most notably in the mechanistic target of rapamycin (mTOR)–signaling pathway, which also has implications in many other psychiatric disorders.
With regard to MDD patients, decreased glutamate has been noted in various prefrontal regions, including the dorsolateral prefrontal cortex (dlPFC), dorsomedial PFC (dmPFC), and anterior cingulate cortex (ACC), when compared to controls.8–10 This shortage of glutamate makes ketamine an ideal treatment for MDD; by creating a surge in glutamate levels in regions of the brain that suffer from a glutamate deficit, ketamine may provide some normalization of glutamate levels in patients with MDD. This “glutamate surge” hypothesis has dominated as the primary theory of ketamine’s antidepressant mechanism.
Ketamine may work through additional receptors, as it is known to have effects on several opioid receptors, adrenergic receptors, and several serotonin and norepinephrine transporters.17–19 It is also possible that acute dissociative side effects of ketamine may be mediating antidepressant response.
One salient biological metric that may provide insight into ketamine’s mechanism of action is related to dissociation. Dissociative side effects begin from infusion, reach a peak typically within an hour of infusion, and are completely diminished 230 minutes after infusion.20 The same study has shown that increased dissociation and psychotomimetic symptoms immediately following infusion may predict antidepressant response. (Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 2014;159:56–61Do the dissociative side effects of ketamine mediate its antidepressant effects.)
Certain themes have emerged with Ketamine. First are our findings of convergent brain regions implicated in MDD and how ketamine modulates those areas. Specifically, the subgenual ACC has been a region of interest in many previous studies. In relation to emotion and cognition, ketamine appears to reduce brain activation in regions associated with self-monitoring, to increase neural regions associated with emotional blunting, and to increase neural activity in reward processing.
Overall, ketamine’s effects were most notably found in the subgenual ACC, PCC, PFC, and hippocampus. Abnormalities in overlapping regions (specifically, the dorsal and subgenual ACC, amygdala, hippocampus, and ventral striatum) have been implicated, via a growing body of neuroimaging literature, in the pathophysiology of depression. The subgenual ACC, in particular, has been a frequently studied area of interest concerning ketamine and MDD.
FMRI found significant reductions in subgenual ACC coupling with hippocampus, retrosplenial cortex, and thalamus. Immediate reductions in subgenual ACC blood flow and focal reductions in OFC blood flow strongly predicted dissociation.
NIMH studies using PET 120 minutes postinfusion found that increased metabolism in the subgenual ACC was positively correlated with improvements in depression scores post-ketamine. (Neural correlates of rapid antidepressant response to ketamine in bipolar disorder..)
Analysis of resting-state scans in healthy volunteers further suggests that dissociation may be responsible for ketamine’s antidepressant effects because it may disconnect the “excessive effects of an aversive visceromotor state on cognition and the self”—a hallmark of depression.40(p 163) Related, one study found that ketamine may dampen brain regions involved in rumination (the repetitive focusing of attention on negative feelings and thoughts in response to negative mood) by reducing the functional connectivity between the pregenual ACC and the dorsal PCC, and decreasing connectivity between the left and right executive-control networks. (. Lehmann M, Seifritz E, Henning A, et al. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. Soc Cogn Affect Neurosci 2016;11:1227–35 .Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network.)
Taken together, these studies suggest that 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. (Scheidegger M, Henning A, Walter M, et al. Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation. Hum Brain Mapp 2016;37:1941–52.Ketamine administration reduces amygdalo‐hippocampal reactivity to emotional stimulation)
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.
Perhaps most interesting are ketamine’s effects on brain connectivity as it relates to self-monitoring behaviors. Reduced connectivity between the pregenual ACC and dorsal PCC was associated with increased dissociation during infusion, and reduced activation in the left superior temporalcortex was associated with impaired self-monitoring56,65—which is disruptive to patients with psychotic illness—especially those with chronic symptoms of psychosis. By contrast, the transient dissociation experienced by depressed patients during a ketamine infusion may have the effect of dampening what the hyperactive self-monitoring associated with depressive illness (Lehmann M, Seifritz E, Henning A, et al. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. Soc Cogn Affect Neurosci 2016;11:1227–35. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. b)
During ketamine administration, subjects experience emotional blunting, which may be associated with reduced limbic responses to emotional stimuli.54,55 It is possible that by decreasing the activity of deep limbic structures (thought to be involved in the pathophysiology of depression, such as the amygdala), ketamine acutely disables the emotional resources required to perpetuate the symptoms of depression. (Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine and fMRI BOLD signal: distinguishing between effects mediated by change in blood flow versus change in cognitive state. Hum Brain Mapp 2003;18:135–45. Ketamine and fMRI BOLD signal Distinguishing between effects mediated by change in blood flow versus change in cognitive state|||| Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport 2003;14:387–91 Ketamine alters neural processing of facial emotion recognition in healthy men an fMRI study.)
Ketamine may play a role in reactivating reward areas of the brain in patients with MDD. This reactivation may be especially important, as reward areas in MDD have been characterized by decreased subcortical and limbic activity and by an increased cortical response to reward paradigms. (Zhang WN, Chang SH, Guo LY, Zhang KL, Wang J. The neural correlates of reward-related processing in major depressive disorder: a meta-analysis of functional magnetic resonance imaging studies. J Affect Disord 2013;151:531–9.)
In resting-state scans, BOLD activation in the cingulate gyrus, hippocampus, insula, thalamus, and midbrain increased after ketamine.( Stone J, Kotoula V, Dietrich C, De Simoni S, Krystal JH, Mehta MA. Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. J Psychopharmacol 2015;29:1025–8.Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe)
In addition, ketamine increases neural activation in the bilateral MCC, ACC, and insula, as well as the right thalamus. Activation of these areas is consistent with activation of reward-processing areas, suggesting that ketamine may play a role in activating reward neurocircuitry. (Hoflich A, Hahn A, Kublbock M, et al. Ketamine-dependent neuronal activation in healthy volunteers. Brain Struct Funct 2017;222:1533–42.)
Though no single brain area has been singled out as the locus of depression, ketamine affects different areas of the brain in various ways, which may contribute to overall mood improvements. For example, at baseline, patients with MDD, compared to healthy volunteers, had reduced global connectivity in the PFC and increased connectivity in the posterior cingulate, precuneus, lingual gyrus, and cerebellum; postketamine, responders had increased connectivity in the lateral PFC, caudate, and insula. (Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology 2017;42:1210–9.Ketamine Treatment and Global Brain Connectivity in Major Depression.)
These 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. Similarly, TRD patients, compared to healthy volunteers, had reduced insula and caudate responses to positive emotions at baseline, which normalized in the caudate post-ketamine. (Murrough JW, Collins KA, Fields J, et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry 2015;5:e509 Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.)
Improvements are correlated with increased metabolism in the hippocampus, dorsal ACC, and decreased metabolism in the OFC. (Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol 2015;29:596–607 Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.)
Specifically, based on this review, future studies should likely focus on ketamine’s action in the subgenual ACC, PCC, PFC, and hippocampus. Another promising direction for research builds on the view that depression is the product of underactive prefrontal and limbic mood-regulation networks and overreactive subcortical limbic networks, which are involved in emotional and visceral responses. (Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213:93–118 Brain structural and functional abnormalities in mood disorders.)
Ketamine’s potential use in both research and treatment is promising indeed.
Mechanisms of Ketamine Action as an Antidepressant
Ketamine and Ketamine Metabolite Pharmacology Insights into Therapeutic Mechanisms.
THE NEUROBIOLOGY OF ketamine and addiction
Psychedelic-Assisted Psychotherapy – A Paradigm Shift in Psychiatric Research and Development
Ketamine for the treatment of addiction Evidence and potential mechanisms <<<<<<<<<<<<<<<<<<<<<<<<<<<
REVIEW OF KETAMINE ABUSE AND DIVERSION
Rapid-Acting Antidepressants Mechanistic Insights and Future Directions.
Ketamine and rapid-acting antidepressants a new era in the battle against depression and suicide.
Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine
New Targets for Rapid Antidepressant Action
Role of copper in depression. Relationship with ketamine treatment
Ketamine normalizes brain activity during emotionally valenced attentional processing in depression.
Recognizing Depression from the Microbiota⁻Gut⁻Brain Axis. b
Psychobiotics and the gut–brain axis in the pursuit of happines
S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life
S-Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders.
Ketamine for Depression, 2 Diagnostic and Contextual Indications.
The role of adipokines in the rapid antidepressant effects of ketamine.
response to ketamine and prediction of treatment outcome
Medical comorbidity in bipolar disorder The link with metabolic-inflammatory systems.
Role of neuro-immunological factors in the pathophysiology of mood disorders.
Immune-based strategies for mood disorders facts and challenges
Metabolic syndrome in psychiatric patients implications
Case–control association study of 14 variants of CREB1, CREBBP and CREM on MDD and bipolar
Metabolic syndrome in psychiatric patients overview, mechanisms, and implications.
Peripheral inflammation, Physical Activity and Cognition in Bipolar Disorder
Bipolar Disorder and Inflammation.
Pharmacologic implications of inflammatory comorbidity in bipolar disorder.
Minding the brain- the role of pharmacotherapy in substance-use disorder treatment
Molecular and Cellular Effects of Traumatic Stress Implications for PTSD