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

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

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

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



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Ketamine-like depression treatment on track for FDA approval


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

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

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

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


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

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

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

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

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

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


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A Randomized Controlled Trial of Intranasal Ketamine in Major
Depressive Disorder

A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

Background—The N-methyl-d-aspartate glutamate receptor antagonist ketamine, delivered via
an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant
depression. The current study was designed to test the safety, tolerability and efficacy of intranasal
ketamine in patients with depression who had failed at least one prior antidepressant trial.
Methods—Twenty patients with major depression were randomized and 18 completed two
treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution in a randomized,
double-blind, crossover study. The primary efficacy outcome measure was change in depression
severity 24 hours following ketamine or placebo, measured using the Montgomery-Asberg
Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in selfreports of depression, changes in anxiety, and proportion of responders. Potential
psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with
ketamine were also measured.

Results—Patients showed significant improvement in depressive symptoms at 24 hours
following ketamine compared to placebo [t=4.39, p<0.001; estimated mean MADRS score
difference of 7.6 ± 3.7 (95% CI: 3.9 – 11.3)]. Eight of 18 patients (44%) met response criteria 24
hours following ketamine administration, compared to 1 of 18 (6%) following placebo (p=0.033).
Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and
was not associated with clinically significant changes in hemodynamic parameters.

Conclusions—This study provides the first controlled evidence for the rapid antidepressant
effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If
replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients
with major depression

Intranasal ketamine has shown safety and efficacy as an anesthetic and analgesic agent (16–
20). In particular, intranasal ketamine has been successfully used in the treatment of
headache and pain in ambulatory patients (21–23). In one study, 50 mg of ketamine
administered intranasally was well tolerated and led to symptomatic improvement in chronic
pain (23). The objective of the current proof of concept clinical trial was to test the rapid
antidepressant effect of a single 50 mg administration of ketamine via an intranasal route in
patients with major depression who had failed to respond to at least one prior antidepressant
trial. Based on accumulating evidence supporting the efficacy and tolerability of ketamine
administered IV in depression, and prior research examining intranasal ketamine in pain, we
hypothesized that a dose of 50 mg, administered via an intranasal route, would be safe, well
tolerated and lead to a rapid reduction in depressive symptoms.

In the current study we found that a single dose of 50 mg of ketamine administered via
intranasal route was associated with a rapid antidepressant response in patients with major
depression who had failed at least one prior antidepressant trial. A significant antidepressant
effect of ketamine was detected as early as 40 min following administration and there was a
large difference in depression severity between the treatment conditions at the 24-hour
primary outcome (mean difference in MADRS score of 7.6 ± 3.7). In aggregate, there was
significant antidepressant benefit following ketamine compared to placebo over the full 7-
day assessment period, although when comparing individual time points the treatment
conditions no longer separated at 72 hours or 7 days. Ketamine was associated with
significant improvement in anxiety symptoms and self-reports of depressive symptoms at 24
hours. Intranasal ketamine was well tolerated with only very minimal increases in
dissociation, psychosis-like symptoms or hemodynamic parameters. This study provides the
first randomized, controlled evidence that intranasal ketamine is safe, well tolerated, and
effective for rapid reduction of depressive symptoms in patients with MDD and at least mild
treatment resistance.
In comparison with prior studies of ketamine administered IV (at a dose of 0.5 mg/kg) in
depression, our observed magnitude of antidepressant effect with intranasal administration
may be somewhat reduced. Murrough et al. reported a mean ketamine-placebo difference of
7.95 points (95% CI: 3.20–12.71) on the MADRS 24 hours following a single IV infusion
and a response rate of 64% (15). Response rates as high as 70% following IV administration
have been reported in some studies (11, 15), though other studies have reported response
rates from 50% to as low as 30% following IV ketamine (28, 29). Our mean drug-placebo
difference is in line with what has been previously reported (7.6 ± 3.7 points on the
MADRS), although the proportion of responders in our study may be somewhat lower at
44%. This lower proportion of treatment responders may be consistent with the lower blood
ketamine levels achieved in our study compared to levels previously reported following IV
administration. In our sample, the mean ketamine blood level was 72 ng/mL at 20 min and
84 ng/mL at 40 min. In contrast, mean ketamine levels reported following IV infusion
(0.5mg/kg) are approximately 150 ng/mL at 30 min and 200 ng/mL at 40 min. (27, 30, 31).
It is currently not known if efficacy equivalent to IV administration can be obtained by
intranasal administration in the case that comparable blood levels can be achieved.

We report a significant improvement in anxiety symptoms at 24 hours, assessed with the
HAM-A. Two studies of IV ketamine for bipolar depression reported a significant
improvement in anxiety symptoms measured with the HAM-A and a visual analog scale(27,
32). However, previous studies of patients with unipolar TRD have not described effects of
IV ketamine on anxiety, with the exception of an early RCT (11) and an open label study
(33) reporting significant improvement in psychic anxiety measured as an individual
symptom on the Hamilton Depression Rating Scale, and another open-label study reporting
significant decrease in anxiety symptoms on the HAM-A at +230 minutes (34).
Previous studies of IV ketamine in depression have reported elevations in measures of
psychotomimetic, dissociative and hemodynamic parameters (11, 13, 35). In our study, the
ketamine group experienced a very limited increase in dissociation at +40 min as measured
by the CADSS (mean 1.4 points; scale range 0–92). In comparison, Murrough et al. reported
a larger dissociative effect 40 min following ketamine administered IV [mean CADSS score
of 14.7 points (95% CI: 10.6–18.8)] (15). A similar pattern was observed for psychotic-like
effects measured using the BPRS+ (11, 15). We also observed comparatively small changes
in hemodynamic parameters. No patient met protocol criteria for interventions. Studies of IV
ketamine in depression have reported relatively greater changes in hemodynamic parameters
(mean systolic BP increase of 19.0 versus our 7.6 mmHg at +40mins relative to baseline)
(15). The reduced magnitude of acute behavioral and hemodynamic changes observed in the
current study may be consistent with the lower blood levels achieved compared to prior
studies with ketamine administered IV, as discussed above.
The bioavailability of ketamine administered via an intranasal route has been reported to be
between 25–50% (36). A study in healthy volunteers comparing administration methods
found intranasal ketamine bioavailability of 45%, higher than subligual, oral, or rectal
administration and found no significant differences in pharmacokinetics between
preparations, including injection (37). Additionally, this study found conversion to
norketamine was more similar between intranasal and injection than the other administration
methods, suggesting that first-pass metabolism is relatively absent with intranasal
administration. The area under the ketamine and norketamine plasma concentration-time
curves in that study was lowest for intranasal administration but was found to increase
almost linearly with doses from 25 to 50mg (37). In previous studies of IV ketamine in
depression, peak norketamine blood levels of approximately 20–50 ng/mL have been
reported (30, 31). In line with these findings, the mean norketamine level in our study was
46 ng/mL at 40 min.
We selected our dose of 50 mg largely based on a previous study using a similar design and
the same dose in patients with a chronic pain disorder (23). Based on an expected
bioavailability of intranasal ketamine between 25–50% (36), our dose may be approximately
equivalent to 0.15 – 0.34 mg/kg administered IV. Although this is lower than the standard
0.5 mg/kg IV frequently used in ketamine depression studies, we reasoned that this dose was
appropriate from a safety perspective given that the administration period in the current
study is relatively short (20 min versus 40 min or longer in IV studies). Clearly, much more
research is required in order to determine the optimal dose, duration, frequency and route of
administration of ketamine for depression

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Combined Treatment With Naltrexone, Ketamine Effective for Depressive Symptoms

Participants who received the naltrexone and ketamine regimen reported an improvement in depressive symptoms.

The effectiveness of ketamine as an antidepressant has been mitigated by concerns of possible abuse and suggestions that the antidepressant effects might be dependent on opiate receptor stimulation. However, results from a case series published in JAMA Psychiatry support the efficacy of combined naltrexone and ketamine treatment for depressive symptoms.

Investigators conducted an 8-week open-label pilot study of 5 patients with current major depressive disorder and alcohol use disorder. Patients received a single dose of injectable naltrexone (380 mg) 2 to 6 days prior to the first ketamine treatment, followed by 4 weeks of ketamine infusions (0.5 mg/kg once a week). Patients were assessed at baseline and at 4 hours after each infusion with the Montgomery Åsberg Depression Rating Scale. The primary outcome measure was a 50% or higher improvement from baseline Montgomery Åsberg Depression Rating Scale score. All patients were abstinent from alcohol for 5 days or longer prior to the initial ketamine infusion.

Combined treatment with naltrexone and ketamine was associated with a significant reduction in depressive symptoms. Three of 5 patients (60%) met response criteria following initial ketamine dose, and 5 of 5 patients (100%) met response criteria by the fourth dose, although 1 patient left the trial following 2 ketamine infusions. Symptoms improved by 57% to 92%, depending on the patient. In addition, 4 of 5 patients (80%) reported a reduction in alcohol craving and consumption per the Obsessive Compulsive Drinking Scale. Combined treatment was safe and well tolerated. No serious adverse events were reported in the trial.

These results challenge existing data that pretreatment with naltrexone may interfere with the antidepressant properties of ketamine. Research with a larger cohort is necessary to further investigate the efficacy of combination treatment with naltrexone and ketamine for depression.


Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder [published online January 9, 2019]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2018.3990

Association of Combined Naltrexone and Ketamine with depressive symptoms in a case series of patients with depression and AUD

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Allergan and Lundbeck await depression and mania data

Allergan needs a win with rapastinel, while Lundbeck’s chief exec faces her second clinical challenge.

Calendar pin 14th

Welcome to your weekly digest of approaching regulatory and clinical readouts. After a tough 2018 Allergan needs some good news, and it will soon find out if its depression project rapastinel will provide it. Three phase III trials of the project are due to yield topline data in the first half of this year.

Rapastinel targets the NMDA receptor, making it similar to Johnson & Johnson’s ketamine enantiomer esketamine. The J&J candidate is under US review with a PDUFA date of May 2019, though continuing US government shutdown could put approval in doubt.

Although the two projects are often mentioned in the same breath they act differently: rapastinel is a partial agonist of the NMDA receptor, while esketamine blocks it. This way, Allergan hopes, its project might not have the same psychomimetic effects as ketamine and, to a lesser extent, esketamine.

Dissociation – becoming less aware of one’s surroundings – has been seen with the J&J project. Allergan will want to show a safety edge with rapastinel, but stronger efficacy versus esketamine would not go amiss either. Still, Bernstein analysts only give rapastinel a 50% chance of success.

The three phase III trials of rapastinel test the project on top of standard antidepressants in patients with a partial response to the existing drugs. The primary endpoint of all three is change in Montgomery-Asberg depression rating scale (MADRS) at three weeks.

Esketamine itself had mixed results in its pivotal programme: the Transform-2 trial met its primary endpoint, but Transform-3 and Transform-1 did not. Across the three studies, which tested esketamine on top of an oral antidepressant, the reduction in MADRS score at four weeks was 3.2-4.1 points.

Allergan is also developing an oral NMDA modulator, AGN-241751, but this has only just entered phase II. The company, which faced calls for a break-up last year, needs a nearer-term boost, and with 2024 sales forecasts of $505m rapastinel is its biggest pipeline hope.

Selected upcoming rapastinel phase III readouts
NameSetting Trial ID Primary completion
RAP-MD-01Adjunctive therapy NCT02932943Nov 2018
RAP-MD-02Adjunctive therapy NCT02943564Nov 2018
RAP-MD-03Adjunctive therapy NCT02943577Nov 2018
RAP-MD-06 Long-term safety study, adjunctive therapyNCT03002077Nov 2018
RAP-MD-04 Adjunctive therapy, relapse preventionNCT02951988Sep 2019
RAP-MD-32MonotherapyNCT03560518Feb 2020
RAP-MD-30 MonotherapyNCT03675776Dec 2020
RAP-MD-99 Adjunctive or monotherapyNCT03668600Feb 2021
RAP-MD-33 Monotherapy, relapse preventionNCT03614156Jul 2021
Source: EvaluatePharma,

Second test

The two upcoming phase III readouts for Lundbeck’s antipsychotic Rexulti in bipolar mania might not be game changing: there are already approved drugs for this indication, and existing off-label use of antipsychotics is being fuelled by increasing genericisation.

Still, the data will be interesting as they represent the second clinical stock catalyst for Lundbeck’s new chief executive, Deborah Dunsire. The first was the failure of Lu AF35700 in treatment-resistant schizophrenia, and drove shares down almost 30%.

Some analysts do not think that success in bipolar mania will add materially to Rexulti sales, but the downside risk of a second negative trial readout is substantially greater given the lack of other catalysts.

The two bipolar trials have enrolled 322 and 333 patients, the active cohorts given 2-4mg of Rexulti for 21 days, with a six-month follow-up. The primary endpoint is change in the Young-mania rating scale, and a key secondary endpoint is clinical global impression-bipolar (CGI BP) severity-of-illness score in mania.

Even if there is improvement in severity of illness, success in bipolar mania will at best be a nice-to-have addition to Rexulti’s current uses in schizophrenia and major depressive disorder, according to analysts at Leerink.

A more exciting event for Lundbeck will be whether Rexulti can have an impact on agitation in Alzheimer’s disease, where Bernstein analysts reckon success could add $1bn of sales. However, previous data have been mixed.

For now, if Rexulti does not deliver the goods in the more immediate bipolar indication, the market could seize it as an opportunity to punish the stock further.

Selected upcoming Rexulti phase III readouts
SettingTrial IDData due
Bipolar manic episodesNCT03259555Q1 2019
Bipolar manic episodesNCT03257865Q1 2019
Alzheimer’s agitationNCT035485842020
Alzheimer’s agitationNCT035941232021
Alzheimer’s agitationNCT037249422021
Source: EvaluatePharma,


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“The biggest breakthrough in depression treatment since Prozac”

  • 6 FEBRUARY 2019
New variation of ketamine to be approved by FDA for treatment of depression

Back in July of 2017, the world’s first ketamine trial for depression proved to be “incredibly effective” in curing elderly patients. The drug, often referred to as Special K, is a popular substance found clubland culture, but recent breakthrough studies and the development of chemical variations of ketamine has shown that the drug is a powerful tool that can help save lives and allow people to live life to the fullest potential.

According to Bloomberg, the Food and Drug Administration (FDA) has cleared the way for the first drug based on ketamine, from Johnson & Johnson, to gain approval as soon as March 2019. The ketamine variant, called esketamine, may very well become the first-ever rapid-acting antidepressant for suicidal patients and “treatment-resistant depression”. While physicians are still unsure about the long term effects of the drug and more trials need to be conducted in order to get to the root of its effectiveness, many doctors think esketamine may be “the biggest breakthrough in depression treatment since Prozac”.

The long-form story published in Bloomberg tells the stories of multiple people who have benefited from ketamine treatment and how the rapid development of this new miracle drug is being used to combat the skyrocketing rate of suicide in the United States (up 33 per cent in the last 20 years).

The drug esketamine provides “a quick molecular reset button for brains impaired by stress or depression”. Initially developed as an intravenous drug, Johnson & Johnson has developed a nasal solution that has the same effect. The initial study of the drug involved 68 people at high risk that were all antidepressants and other treatment – no placebos were used on actively suicidal patients. Of those who were given esketamine, 40 per cent were deemed “no longer at risk of killing themselves within 24 hours”.

As physicians and investors race to find out more about this supposed miracle drug, concerns remain that a new abuse crisis – similar to that of the current opioid crisis – may arise following federal approval of the substance.

Check out the captivating story behind these successful studies here

Learn more about ketamine’s colorful clubland history here.

Find out how we survived an unconventional, silly, hilarious and definitely brilliant musical about ketamine here.


Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

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Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

A version of the club drug is expected to be approved for depression in March. Researchers think it could help treat suicidal thinking.

Joe Wright has no doubt that ketamine saved his life. A 34-year-old high school teacher who writes poetry every day on a typewriter, Wright was plagued by suicidal impulses for years. The thoughts started coming on when he was a high schooler himself, on Staten Island, N.Y., and intensified during his first year of college. “It was an internal monologue, emphatic on how pointless it is to exist,” he says. “It’s like being ambushed by your own brain.”

He first tried to kill himself by swallowing a bottle of sleeping pills the summer after his sophomore year. Years of treatment with Prozac, Zoloft, Wellbutrin, and other antidepressants followed, but the desire for an end was never fully resolved. He started cutting himself on his arms and legs with a pencil-sharpener blade. Sometimes he’d burn himself with cigarettes. He remembers few details about his second and third suicide attempts. They were halfhearted; he drank himself into a stupor and once added Xanax into the mix.

Wright decided to try again in 2016, this time using a cocktail of drugs he’d ground into a powder. As he tells the story now, he was preparing to mix the powder into water and drink it when his dog jumped onto his lap. Suddenly he had a moment of clarity that shocked him into action. He started doing research and came upon a Columbia University study of a pharmaceutical treatment for severe depression and suicidality. It involved an infusion of ketamine, a decades-old anesthetic that’s also an infamous party drug. He immediately volunteered.

His first—and only—ketamine infusion made him feel dreamlike, goofy, and euphoric. He almost immediately started feeling more hopeful about life. He was more receptive to therapy. Less than a year later, he married. Today he says his dark moods are remote and manageable. Suicidal thoughts are largely gone. “If they had told me how much it would affect me, I wouldn’t have believed it,” Wright says. “It is unconscionable that it is not already approved for suicidal patients.”

The reasons it isn’t aren’t strictly medical. Over the past three decades, pharmaceutical companies have conducted hundreds of trials for at least 10 antidepressants to treat severe PMS, social anxiety disorder, and any number of conditions. What they’ve almost never done is test their drugs on the sickest people, those on the verge of suicide. There are ethical considerations: Doctors don’t want to give a placebo to a person who’s about to kill himself. And reputational concerns: A suicide in a drug trial could hurt a medication’s sales prospects.

The risk-benefit calculation has changed amid the suicide epidemic in the U.S. From 1999 to 2016, the rate of suicides increased by 30 percent. It’s now the second-leading cause of death for 10- to 34-year-olds, behind accidents. (Globally the opposite is true: Suicide is decreasing.) Growing economic disparity, returning veterans traumatized by war, the opioid crisis, easy access to guns—these have all been cited as reasons for the rise in America. There’s been no breakthrough in easing any of these circumstances.

But there is, finally, a serious quest for a suicide cure. Ketamine is at the center, and crucially the pharmaceutical industry now sees a path. The first ketamine-based drug, from Johnson & Johnson, could be approved for treatment-resistant depression by March and suicidal thinking within two years. Allergan Plc is not far behind in developing its own fast-acting antidepressant that could help suicidal patients. How this happened is one of the most hopeful tales of scientific research in recent memory.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

Dennis Charney, dean of the Icahn School of Medicine at Mount Sinai in New York, works from an office filled with family pictures, diplomas, and awards from a long career in research. One thing on the wall is different from the rest: a patent for the use of a nasal-spray form of ketamine as a treatment for suicidal patients. The story of the drug is in some ways the story of Charney’s career.

In the 1990s he was a psychiatry professor, mentoring then associate professor John Krystal at Yale and trying to figure out how a deficit of serotonin played into depression. Back then, depression research was all about serotonin. The 1987 approval of Prozac, the first selective serotonin reuptake inhibitor, or SSRI, ushered in an era of what people in the industry call me-too drug development, research that seeks to improve on existing medicines rather than exploring new approaches. Within this narrow range, pharmaceutical companies churned out blockbuster after blockbuster. One in eight Americans age 12 and older reported using antidepressants within the past month, according to a survey conducted from 2011 to 2014 by the U.S. Centers for Disease Control and Prevention.

Charney was a depression guy; Krystal was interested in schizophrenia. Their curiosity led them to the same place: the glutamate system, what Krystal calls the “main information highway of the higher brain.” (Glutamate is an excitatory neurotransmitter, which helps brain cells communicate. It’s considered crucial in learning and memory formation.) They had already used ketamine to temporarily produce schizophrenia-like symptoms, to better understand glutamate’s role in that condition. In the mid-1990s they decided to conduct a single-dose study of ketamine on nine patients (two ultimately dropped out) at the Yale-affiliated VA Connecticut Healthcare System in West Haven to see how depressed people would react to the drug.

“If we had done the typical thing … we would have completely missed the antidepressant effect”

Outside the field of anesthesiology, ketamine is known, if it’s known at all, for its abuse potential. Street users sometimes take doses large enough to enter what’s known as a “K hole,” a state in which they’re unable to interact with the world around them. Over the course of a day, those recreational doses can be as much as 100 times greater than the tiny amount Charney and Krystal were planning to give to patients. Nonetheless, they decided to monitor patients for 72 hours—well beyond the two hours that ketamine produces obvious behavioral effects—just to be careful not to miss any negative effects that might crop up. “If we had done the typical thing that we do with these drug tests,” Krystal says, “we would have completely missed the antidepressant effect of ketamine.”

Checking on patients four hours after the drug had been administered, the researchers saw something unexpected. “To our surprise,” Charney says, “the patients started saying they were better, they were better in a few hours.” This was unheard of. Antidepressants are known for taking weeks or months to work, and about a third of patients aren’t sufficiently helped by the drugs. “We were shocked,” says Krystal, who now chairs the Yale psychiatry department. “We didn’t submit the results for publication for several years.”

When Charney and Krystal did publish their findings, in 2000, they attracted almost no notice. Perhaps that was because the trial was so small and the results were almost too good to be true. Or maybe it was ketamine’s reputation as an illicit drug. Or the side effects, which have always been problematic: Ketamine can cause patients to disassociate, meaning they enter a state in which they feel as if their mind and body aren’t connected.

But probably none of these factors mattered as much as the bald economic reality. The pharmaceutical industry is not in the business of spending hundreds of millions of dollars to do large-scale studies of an old, cheap drug like ketamine. Originally developed as a safer alternative to the anesthetic phencyclidine, better known as PCP or angel dust, ketamine has been approved since 1970. There’s rarely profit in developing a medication that’s been off patent a long time, even if scientists find an entirely new use for it.

Somehow, even with all of this baggage, research into ketamine inched forward. The small study that almost wasn’t published has now been cited more than 2,000 times.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
John Mann in his office at Columbia’s New York State Psychiatric Institute. 

Suicide is described in medicine as resulting from a range of mental disorders and hardships—a tragedy with many possible roots. Conditions such as severe depression, bipolar disorder, and schizophrenia are known risk factors. Childhood trauma or abuse may also be a contributor, and there may be genetic risk factors as well.

From these facts, John Mann, an Australian-born psychiatrist with a doctorate in neurochemistry, made a leap. If suicide has many causes, he hypothesized, then all suicidal brains might have certain characteristics in common. He’s since done some of the most high-profile work to illuminate what researchers call the biology of suicide. The phrase itself represents a bold idea—that there’s an underlying physiological susceptibility to suicide, apart from depression or another psychiatric disorder.

Mann moved to New York in 1978, and in 1982, at Cornell University, he started collecting the brains of people who’d killed themselves. He recruited Victoria Arango, now a leading expert in the field of suicide biology. The practice of studying postmortem brain tissue had largely fallen out of favor, and Mann wanted to reboot it. “He was very proud to take me to the freezer,” Arango says of the day Mann introduced her to the brain collection, which then numbered about 15. “I said, ‘What am I supposed to do with this?’ ”

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Some of Mann’s brain collection. 

They took the work, and the brains, first to the University of Pittsburgh, and then, in 1994, to Columbia. They’ve now amassed a collection of some 1,000 human brains—some from suicide victims, the others, control brains—filed neatly in freezers kept at –112F. The small Balkan country of Macedonia contributes the newest brains, thanks to a Columbia faculty member from there who helped arrange it. The Macedonian brains are frozen immediately after being removed and flown in trunks, chaperoned, some 4,700 miles to end up in shoe-box-size, QR-coded black boxes. Inside are dissected sections of pink tissue in plastic bags notated with markers: right side, left side, date of collection.

In the early 1990s, Mann and Arango discovered that depressed patients who killed themselves have subtle alterations in serotonin in certain regions of the brain. Mann remembers sitting with Arango and neurophysiologist Mark Underwood, her husband and longtime research partner, and analyzing the parts of the brain affected by the deficit. They struggled to make sense of it, until it dawned on them that these were the same brain regions described in a famous psychiatric case study. In 1848, Phineas Gage, an American railroad worker, was impaled through the skull by a 43-inch-long tamping iron when the explosives he was working with went off prematurely. He survived, but his personality was permanently altered. In a paper titled “Recovery From the Passage of an Iron Bar Through the Head,” his doctor wrote that Gage’s “animal propensities” had emerged and described him as using the “grossest profanity.” Modern research has shown that the tamping iron destroyed key areas of the brain involved in inhibition—the same areas that were altered in the depressed patients who’d committed suicide. For the group, this was a clue that the differences in the brain of suicidal patients were anatomically important.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Columbia’s Victoria Arango. 

“Most people inhibit suicide. They find a reason not to do it,” Underwood says. Thanks to subtle changes in the part of the brain that might normally control inhibition and top-down control, people who kill themselves “don’t find a reason not to do it,” he says.

About eight years ago, Mann saw ketamine research taking off in other corners of the scientific world and added the drug to his own work. In one trial, his group found that ketamine treatment could ease suicidal thoughts in 24 hours more effectively than a control drug. Crucially, they found that the antisuicidal effects of ketamine were to some extent independent of the antidepressant effect of the drug, which helped support their thesis that suicidal impulses aren’t necessarily just a byproduct of depression. It was this study, led by Michael Grunebaum, a colleague of Mann’s, that made a believer of Joe Wright.

“It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off”

In 2000, the National Institutes of Health hired Charney to run both mood disorder and experimental drug research. It was the perfect place for him to forge ahead with ketamine. There he did the work to replicate what he and his colleagues at Yale had discovered. In a study published in 2006, led by researcher Carlos Zarate Jr., who now oversees NIH studies of ketamine and suicidality, an NIH team found that patients had “robust and rapid antidepressant effects” from a single dose of the drug within two hours. “We could not believe it. In the first few subjects we were like, ‘Oh, you can always find one patient or two who gets better,’ ” Zarate recalls.

In a 2009 study done at Mount Sinai, patients suffering from treatment-resistant depression showed rapid improvement in suicidal thinking within 24 hours. The next year, Zarate’s group demonstrated antisuicidal effects within 40 minutes. “That you could replicate the findings, the rapid findings, was quite eerie,” Zarate says.

Finally ketamine crossed back into commercial drug development. In 2009, Johnson & Johnson lured away Husseini Manji, a prominent NIH researcher who’d worked on the drug, to run its neuroscience division. J&J didn’t hire him explicitly to develop ketamine into a new pharmaceutical, but a few years into his tenure, Manji decided to look into it. This time it would come in a nasal-spray form of esketamine, a close chemical cousin. That would allow for patent protection. Further, the nasal spray removes some of the challenges that an IV form of the drug would present. Psychiatrists, for one thing, aren’t typically equipped to administer IV drugs in their offices.

While these wheels were slowly turning, some doctors—mostly psychiatrists and anesthesiologists—took action. Around 2012 they started opening ketamine clinics. Dozens have now popped up in major metropolitan areas. Insurance typically won’t touch it, but at these centers people can pay about $500 for an infusion of the drug. It was at one time a cultural phenomenon—a 2015 Bloomberg Businessweek story called it “the club drug cure.” Since then, the sense of novelty has dissipated. In September the American Society of Ketamine Physicians convened its first medical meeting about the unconventional use of the drug.

“You are literally saving lives,” Steven Mandel, an anesthesiologist-turned-ketamine provider, told a room of about 100 people, mostly doctors and nurse practitioners, who gathered in Austin to hear him and other early adopters talk about how they use the drug. Sporadic cheers interrupted the speakers as they presented anecdotes about its effectiveness.

There were also issues to address. A consensus statementin JAMA Psychiatry published in 2017 said there was an “urgent need for some guidance” on ketamine use. The authors were particularly concerned with the lack of data about the safety of prolonged use of the drug in people with mood disorders, citing “major gaps” in the medical community’s knowledge about its long-term impact.

The context for the off-label use of ketamine is a shrinking landscape for psychiatry treatment. An effort to deinstitutionalize the U.S. mental health system, which took hold in the 1960s, has almost resulted in the disappearance of psychiatric hospitals and even psychiatric beds within general hospitals. There were 37,679 psychiatric beds in state hospitals in 2016, down from 558,922 in 1955, according to the Treatment Advocacy Center. Today a person is often discharged from a hospital within days of a suicide attempt, setting up a risky situation in which someone who may not have fully recovered ends up at home with a bunch of antidepressants that could take weeks to lift his mood, if they work at all.

A ketamine clinic can be the way out of this scenario—for people with access and means. For Dana Manning, a 53-year-old Maine resident who suffers from bipolar disorder, $500 is out of reach. “I want to die every day,” she says.

After trying to end her life in 2003 by overdosing on a cocktail of drugs including Xanax and Percocet, Manning tried virtually every drug approved for bipolar disorder. None stopped the mood swings. In 2010 the depression came back so intensely that she could barely get out of bed and had to quit her job as a medical records specialist. Electroconvulsive therapy, the last-ditch treatment for depressed patients who don’t respond to drugs, didn’t help.

Her psychiatrist went deep into the medical literature to find options and finally suggested ketamine. He was even able to get the state Medicaid program to cover it, she says. She received a total of four weekly infusions before she moved to Pennsylvania, where there were more family members nearby to care for her.

The first several weeks following her ketamine regimen were “the only time I can say I have felt normal” in 15 years, she says. “It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off.”

She’s now back in Maine, and the depression has returned. Her current Medicare insurance won’t cover ketamine. She lives on $1,300 a month in disability income. “Knowing it is there and I can’t have it is beyond frustrating,” she says.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Mark Underwood at the New York State Psychiatric Institute. 

Ketamine is considered a “dirty” drug by scientists—it affects so many pathways and systems in the brain at the same time that it’s hard to single out the exact reason it works in the patients it does help. That’s one reason researchers continue to look for better versions of the drug. Another, of course, is that new versions are patentable. Should Johnson & Johnson’s esketamine hit the market, the ketamine pioneers and their research institutions stand to benefit. Yale’s Krystal, NIH’s Zarate, and Sinai’s Charney, all of whom are on the patent on Charney’s wall, will collect royalties based on the drug’s sales. J&J hasn’t said anything about potential pricing, but there’s every reason to believe the biggest breakthrough in depression treatment since Prozac will be expensive.

The company’s initial esketamine study in suicidal patients involved 68 people at high risk. To avoid concerns about using placebos on actively suicidal subjects, everyone received antidepressants and other standard treatments. About 40 percent of those who received esketamine were deemed no longer at risk of killing themselves within 24 hours. Two much larger trials are under way.

When Johnson & Johnson unveiled data from its esketamine study in treatment-resistant depression at the American Psychiatric Association meeting in May, the presentation was jammed. Esketamine could become the first-ever rapid-acting antidepressant, and physicians and investors are clamoring for any information about how it works. The results in suicidal patients should come later this year and could pave the way for a Food and Drug Administration filing for use in suicidal depressed patients in 2020. Allergan expects to have results from its suicide study next year, too.

“The truth is, what everybody cares about is, do they decrease suicide attempts?” says Gregory Simon, a psychiatrist and mental health researcher at Kaiser Permanente Washington Health Research Institute. “That is an incredibly important question that we hope to be able to answer, and we are planning for when these treatments become available.”

Exactly how ketamine and its cousin esketamine work is still the subject of intense debate. In essence, the drugs appear to provide a quick molecular reset button for brains impaired by stress or depression. Both ketamine and esketamine release a burst of glutamate. This, in turn, may trigger the growth of synapses, or neural connections, in brain areas that may play a role in mood and the ability to feel pleasure. It’s possible the drug works to prevent suicide by boosting those circuits while also reestablishing some of the inhibition needed to prevent a person from killing himself. “We certainly think that esketamine is working exactly on the circuitry of depression,” Manji says. “Are we homing in exactly on where suicidal ideation resides?” His former colleagues at NIH are trying to find that spot in the brain as well. Using polysomnography—sleep tests in which patients have nodes connected to various parts of their head to monitor brain activity—as well as MRIs and positron emission tomography, or PET scans, researchers can see how a patient’s brain responds to ketamine, to better understand exactly what it’s doing to quash suicidal thinking.

Concerns about the side effects of ketamine-style drugs linger. Some patients taking esketamine have reported experiencing disassociation symptoms. Johnson & Johnson calls the effects manageable and says they cropped up within an hour of the treatment, a period in which a person on the drug would likely be kept in the doctor’s office for monitoring. Some patients also experienced modest spikes in blood pressure within the same timeframe.

Nasal-spray dosing brings other issues. The Black Dog Institute in Australia and the University of New South Wales in Sydney, which teamed up to study a nasal-spray form of ketamine, published their findings last March in the Journal of Psychopharmacology. The researchers found that absorption rates were variable among patients. J&J says its own studies with esketamine contradict these findings.

But in the wake of the opioid crisis, perhaps the biggest worry is that loosening the reins too much on the use of ketamine and similar drugs could lead to a new abuse crisis. That’s why Wall Street analysts are particularly excited by Allergan’s rapid-acting antidepressant, rapastinel, which is about a year behind esketamine in testing. Researchers say it likely acts on the same target in the brain as ketamine, the NMDA receptor, but in a more subtle way that may avoid the disassociation side effects and abuse potential. Studies in lab animals show the drug doesn’t lead creatures to seek more of it, as they sometimes do with ketamine, says Allergan Vice President Armin Szegedi. Allergan’s medicine is an IV drug, but the company is developing an oral drug.

For its suicide study, Allergan is working hard to enroll veterans, one of the populations most affected by the recent spike in suicides, and has included several U.S. Department of Veterans Affairs medical centers as sites in the trial. More than 6,000 veterans died by suicide each year from 2008 to 2016, a rate that’s 50 percent higher than in the general population even after adjusting for demographics, according to VA data.

“How the brain mediates what makes us who we are is still a mystery, and maybe we will never fully understand it,” Szegedi says. “What really changed the landscape here is you had clinical data showing ‘This really does the trick.’ Once you find something in the darkness, you really have to figure out: Can you do something better, faster, safer?”

If you or someone you know is having suicidal thoughts, the National Suicide Prevention hotline is 1 (800) 273 8255.

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Depression Therapy With Party-Drug Roots Faces FDA Panel Review

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Potential for abuse and strategies for containing any risks from an experimental depression treatment from Johnson & Johnson will be in focus at an Food and Drug Administration panel next week.

J&J’s nasal spray, esketamine, a close cousin of the party drug ketamine, will be considered by an FDA advisory panel on Feb. 12. While agency staff seemed satisfied that the likelihood of abuse is low, they raised questions about safety issues connected to a dreamlike sensation the medication can create in some users.

“Ketamine abuse is relatively uncommon in the general population,” agency staff said in a report ahead of next week’s meeting. Just 1.3 percent of people over age 12 abuse the drug, lower than abuse rates for other hallucinogens like ecstasy and LSD.

At the same time, reviewers worried that patients could get into accidents or otherwise be harmed if they leave a doctor’s office while still experiencing disassociation, a known side effect of ketamine — and a sought-after experience for casual users who have dubbed the spacey feeling the “K-hole.”

It takes roughly 90 minutes for disassociation symptoms from esketamine to resolve, according to the report. FDA staff also cited elevated blood pressure as a safety concern.

Esketamine is a key part of J&J’s pharmaceutical pipeline, as the company faces flagging sales this year weighed down by drug pricing scrutiny and looming generic competition. Its shares, which rose 2.3 percent this year through Thursday’s close, were were little changed in early trading on Friday.

In addition to weighing in on the drug’s safety and a proposed risk-evaluation and mitigation strategy, FDA staff will ask advisers to vote on whether esketamine effectively treated the depression of patients who weren’t helped by other therapies. They’ll also discuss whether additional studies are needed before or after the drug is potentially approved.

The staff report noted there were six deaths among patients taking the J&J drug, of which three were suicide in the esketamine depression program, but they didn’t see a clear link to the drug itself.

“Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug related,” staff reviewers noted.

A decision on whether to allow the drug on the market is expected by March 4. Esketamine has the FDA’s breakthrough-therapy designation in treatment-resistant depression as well as for depressed people at risk of suicide. Results from a study in suicidal patients are expected this year. Allergan is also testing a fast-acting antidepressant, rapastinel, which is about a year behind esketamine in testing.

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BDNF-VEGF interplay key to rapid antidepressant actions A study in Biological Psychiatry investigates the mechanisms of fast-acting antidepressants E-MAIL

Philadelphia, January 31, 2019 — A study by researchers at Yale University reveals a complex interplay of two different growth factors in the rapid and long-lasting antidepressant effects of ketamine. The study, published in Biological Psychiatry, reports that the antidepressant-like actions of brain-derived neurotrophic factor (BDNF) require the release of vascular endothelial growth factor (VEGF).

“Surprisingly, the reciprocal relationship was also observed, indicating that BDNF-VEGF interdependence plays a crucial role in the actions of rapid-acting antidepressants,” said senior author Ronald Duman, PhD.

Ketamine requires the release of both BDNF and VEGF to produce its rapid antidepressant effects, but the connection between the two growth factors–which have different functions and act through different mechanisms–was unknown.

Using mice to model behaviors of depression, the researchers investigated the interaction of BDNF and VEGF. Administering BDNF or VEGF to a brain region implicated in depression, the medial prefrontal cortex (mPFC), produces rapid and long-lasting antidepressant-like actions similar to those of ketamine. In the study, Dr. Duman and colleagues found that removing VEGF from the mPFC prevented the antidepressant-like effects of BDNF in mice. When they performed similar experiments but instead blocked BDNF, the antidepressant-like effects of VEGF were prevented.

Deeper analysis using neuron cultures to examine how the two factors depend on each other revealed that BDNF signaling stimulates VEGF release in neurons and requires VEGF to produce its neurotrophic effects. Conversely, VEGF stimulates the release of BDNF and requires BDNF signaling to produce its neurotrophic effects.

“This observation may have important clinical implications. VEGF inhibitors are widely used to treat various cancers and can be associated with increased risk for depression and cognitive impairments sometimes called the ‘fog of chemotherapy’.

“Since most antidepressant effects are mediated by BDNF, and therefore VEGF, how should we treat these forms of depression and cognitive impairments? The answer to this question may draw us to BDNF-independent effects of antidepressants and new insights into the biology and treatment of depression,” said John Krystal, MD, Editor of Biological Psychiatry.

The results provide the first evidence that reciprocal interdependence of BDNF and VEGF plays a crucial role in their rapid antidepressant-like effects, revealing key mechanisms of ketamine, which requires both BDNF and VEGF. The findings also highlight avenues of research to better understand how each of the factors may affect a person’s risk of depression or their response to antidepressant drugs.

Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor  < Article

Major depressive disorder is a widespread debilitating illness, affecting approximately 17% of the population in the United States and causing enormous personal and socioeconomic burden (12) . Conventional antidepressants, notably monoamine reuptake inhibitors, take weeks to months to produce a therapeutic response and have limited efficacy, as approximately one third of patients with depression fail to respond to typical antidepressants and are considered treatment resistant (3) . Recent studies demonstrate that a single subanesthetic dose of ketamine, an N -methyl-D-aspartate receptor (NMDAR) antagonist, produces rapid (within hours) and sustained (up to a week) antidepressant actions even in patients with treatment-resistant depression(45) ; similar rapid and long-lasting effects are observed in rodent models (67) .

Although the mechanisms underlying the pathophysiology of major depressive disorder and the therapeutic actions of ketamine remain unclear, growing evidence supports a neurotrophic hypothesis of depression and antidepressant response 8910 . This hypothesis is based on evidence that reduced neurotrophic factor levels, notably brain-derived neurotrophic factor (BDNF) and/or vascular endothelial growth factor (VEGF), are tightly linked with neuronal atrophy in brain regions implicated in major depressive disorder, including the prefrontal cortex (PFC) and hippocampus 8910 . BDNF and VEGF are two completely different pleiotropic growth factors that bind to and activate different tyrosine kinase receptors, neurotrophic receptor tyrosine kinase 2 (TRKB) and fetal liver kinase 1 (FLK1) (also known as VEGF receptor 2), respectively, that have unique as well as overlapping signaling pathways 111213 . In support of this hypothesis, neuroimaging studies have consistently reported decreased volume of the PFC and hippocampus in patients with depression (1415) ; neuronal atrophy and glial loss have also been reported in postmortem studies of depressive subjects and rodent chronic stress models (1016) . Postmortem studies of subjects with depression and studies of rodent chronic stress also report decreased levels of BDNF and VEGF, as well as their receptors, TRKB and FLK1, respectively, in the PFC and hippocampus(91718192021 ; the VEGF level is also decreased in the cerebrospinal fluid of persons who had attempted suicide (22) .

Conversely, preclinical studies reveal that ketamine and other rapid-acting antidepressants act at least in part by producing the opposite effects, increasing BDNF and/or VEGF release and signaling in the PFC and hippocampus (1023242526 . Ketamine blockade of NMDARs located on gamma-aminobutyric acidergic interneurons leads to disinhibition and a rapid and transient glutamate burst that activates postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, resulting in stimulation of calcium ion (Ca 2+ ) influx through voltage-dependent calcium channels that activates BDNF release (10) ; this increases and reverses the synaptic deficits in the PFC caused by chronic stress (67) , and it is required for the antidepressant-like behavioral actions of ketamine (2327) . The actions of conventional antidepressants are also linked to BDNF and VEGF, although these monoaminergic agents increase trophic factor levels only after long-term treatment and increase only expression but not release of BDNF and VEGF (928293031323334 .

We have recently reported that neuronal VEGF-FLK1 signaling in the medial PFC (mPFC) is also required for the neurotrophic and antidepressant-like behavioral actions of ketamine (24) . Since BDNF is reported to stimulate VEGF expression and release in neuroblastoma cells (35) , we hypothesized that VEGF signaling acts downstream of BDNF to produce the neurotrophic and antidepressant-like actions. The current study addresses this hypothesis as well as the interdependence between BDNF and VEGF signaling.


The current results demonstrate several important points. First, a single intra-mPFC infusion of BDNF produces rapid and sustained antidepressant-like actions similar to those of ketamine and intra-mPFC VEGF infusion, consistent with our recent findings (2438) . Second, the antidepressant-like actions of BDNF in three different behavioral paradigms require neuronal-derived extracellular VEGF. Third, BDNF-TRKB signaling stimulates VEGF release in primary cortical neurons, consistent with a previous report showing BDNF-induced VEGF release in a neuroblastoma cell line (35) . Fourth, BDNF-induced neurotrophic actions on dendrite complexity require VEGF-FLK1 signaling in primary cortical neurons. Fifth, the results also demonstrate a reciprocal interdependence, showing that the antidepressant-like and neurotrophic actions of VEGF require BDNF and that VEGF stimulates BDNF release in primary cortical neurons. These results provide the first evidence of a crucial role for interplay between BDNF and VEGF signaling in the neurotrophic and rapid and/or sustained antidepressant-like responses of these factors. Because these studies were conducted in male mice, further studies are needed to determine whether similar effects are observed in female mice.

Previous studies showed that the rapid antidepressant-like actions of ketamine are blocked by the infusion of a BDNF nAb into the mPFC (23) and are blocked in mice with a knockin of the BDNF Val66Met polymorphism (valine at position 66 replaced by methionine), which blocks activity-dependent BDNF release (27) . The behavioral actions of two other rapid-acting antidepressants, rapastinel (an NMDAR modulator) and scopolamine (a nonselective muscarinic acetylcholine receptor antagonist), are also blocked by intra-mPFC infusion of a BDNF nAb and are blocked in Val66Met knockin mice (3846) . These effects differ from those of typical monoaminergic antidepressants, which increase the expression but not the release of BDNF, and they indicate that BDNF release accounts for the rapid actions of ketamine and other rapid-acting agents (910) . In addition, we have recently demonstrated that VEGF release in the mPFC is also required for the rapid antidepressant-like actions of ketamine (24) .

The results of the current study demonstrate that infusion of a VEGF nAb into the mPFC is sufficient to block the antidepressant-like effects of BDNF. The dependence on VEGF was observed in three different antidepressant behavioral paradigms, including models of behavioral despair (FST), motivation and reward (FUST), and anxiety (NSF). While future studies will be needed to test this BDNF–VEGF interaction in chronic stress models, such as chronic unpredictable stress or social defeat (747) , the current results indicate a broad effect across these different behavioral paradigms. Together, the results demonstrate that the antidepressant-like behavioral actions of BDNF are dependent on release of VEGF from excitatory neurons in the mPFC. The results of immunoblot analysis demonstrate that the VEGF nAb does not cross-react with recombinant BDNF, but further studies are needed to demonstrate the lack of cross-reactivity under physiological conditions. In any case, the results of the nAb approach were confirmed with an independent approach, neuronal deletion of VEGF ( CaMKIIα-Crerecombinase line crossed with a Vegfa flox/flox ) (24) . Here we show that the antidepressant-like behavioral actions of BDNF in all three behavioral paradigms are also blocked in the neuronal VEGF–deletion mutants. Since VEGF is expressed by multiple cell types, including neurons, astrocytes, and endothelial cells (33) , we cannot rule out the possibility that VEGF derived from one or more of the other cell types contributes to the BDNF response. However, the results indicate an essential role for VEGF derived from neurons.

Analysis of VEGF release in vivo is technically difficult, so we utilized a primary cortical neuron cell culture system to demonstrate that ketamine stimulates BDNF release (2334) . Here we show that incubation with BDNF increases the release of VEGF in primary cortical neurons, and that coincubation with a selective TRKB inhibitor blocks both BDNF-induced and basal VEGF release. The mechanisms underlying BDNF-TRKB–stimulated VEGF release are unclear, but they could involve effects on neuronal activity or signaling pathways linked with neurotrophic factor release. Evidence for an activity-dependent mechanism is provided by previous studies reporting that infusion of BDNF into the mPFC (48) or hippocampus induces c-Fos expression (49) . Induction of c-Fos is coupled with neuronal activity, although stimulation of intracellular signaling pathways independent of neuronal activity can also increase this immediate early gene. More direct evidence is provided by electrophysiological studies demonstrating that BDNF potentiates glutamatergic transmission by increasing the probability of presynaptic release in hippocampal primary neurons or slices 50515253 and in visual cortex slices(54) . BDNF stimulates the release of Ca 2+ from intracellular stores via activation of phospholipase Cγ (13) , which could stimulate VEGF release ( Figure 6 ). These findings are consistent with the possibility that BDNF-enhancement of glutamatergic transmission stimulates activity-dependent VEGF release. There is also evidence that BDNF stimulates VEGF expression and release via the mechanistic target of rapamycin complex 1 pathway and induction of hypoxia-inducible factor-1α in a neuroblastoma cell line (35) . These reports raise the possibility that activity-dependent, as well as intracellular, signaling could be involved in VEGF release, and further studies are needed to determine the exact pathways. 

Figure 6

Ketamine rapidly increases the number and function of spine synapses on layer V pyramidal neurons in the mPFC, and these synaptic effects require activity-dependent BDNF and VEGF release (6102427) . Similar to ketamine, rapastinel and scopolamine also increase the number and function of spine synapses in the mPFC (38465556) . All of these rapid-acting antidepressants produce neurotrophic actions in primary cortical neurons, including increased BDNF release and increased dendrite complexity (23243446) . We have also reported that ketamine, as well as VEGF induction of dendrite complexity, is completely blocked by a selective FLK1 inhibitor(24) . The current study demonstrates that BDNF increases dendrite complexity in primary neurons and that these neurotrophic effects are completely blocked by incubation with a selective FLK1 inhibitor. These findings provide further evidence that VEGF is required for the neurotrophic actions of BDNF on dendrite complexity.

The results clearly demonstrate a requirement for VEGF in the antidepressant-like and neurotrophic actions of BDNF, but we also examined reciprocal interactions between these two factors. Somewhat surprisingly, we found that the antidepressant-like and neurotrophic effects of VEGF required BDNF release and TRKB signaling. Using similar experimental approaches, the results show that coinfusion of a BDNF nAb into the mPFC blocks the antidepressant-like behavioral responses of VEGF in the three behavioral paradigms tested. The neutralizing antibody used for these studies was specific to BDNF as there was no cross-reactivity with VEGF examined by immunoblot analysis. We also found that incubation of primary cortical neurons with VEGF stimulates the release of BDNF into the culture media, and that this effect is blocked by a selective FLK1 antagonist. In addition, the results show that VEGF stimulation of dendrite complexity is blocked by incubation with a selective TRKB receptor antagonist. The mechanisms underlying VEGF stimulation of BDNF release are unclear but could also involve activity-dependent effects. VEGF increases presynaptic glutamate release probability, leading to enhanced glutamatergic transmission in primary hippocampal slices (57) , and it also increases excitatory transmission via postsynaptic NMDARs (58) . VEGF also stimulates the release of Ca 2+ from intracellular stores via activation of phospholipase Cγ (11) , which could stimulate BDNF release ( Figure 6 ).


In conclusion, the current results in combination with our recent findings (232427343846) demonstrate a key interdependence between BDNF and VEGF signaling in the mPFC and suggest that this reciprocal dependence plays a crucial role in the neurotrophic and antidepressant-like effects of rapid-acting antidepressants. This is particularly clear for the antidepressant-like actions of ketamine, which are blocked by inhibition of either BDNF or VEGF (232427) . Although the requirement for VEGF in the actions of other agents, notably rapastinel and scopolamine, have not been tested and the role of VEGF in patients with depression remains unclear, the prediction is that there is also a requirement for VEGF. These findings raise several interesting possibilities regarding the consequences of this interdependence. For example, previous studies demonstrate that deletion of either BDNF or VEGF in mice is insufficient to produce depressive behaviors, possibly because of the antidepressant-like and neurotrophic actions of the remaining factor (242728) , and it would be interesting to determine whether dual-deletion mutants display depressive-like behaviors. A related consequence is whether a functional polymorphism of one factor would increase vulnerability but is insufficient alone to produce depression, which appears to be the case for the BDNF Val66Met polymorphism (275960) . In contrast, the antidepressant actions of ketamine and other rapid-acting agents could be attenuated by a functional polymorphism of one factor, as reported for the ketamine response in carriers of the BDNF Met allele (27384661) , although this effect also appears to be race specific (62) . The present results provide new insights on the complex interdependence of these two critical neurotrophic factors that could have important consequences for understanding the pathophysiology and treatment of depression.


Antidepressant Efficacy of Ketamine in Treatment resistant depression

The VAL66MET polymporphism may predict response to Ketamine and suggest additional therapies to add on to those who do not respond:

Our results suggest that MDD patients with the Val/Val BDNF allele at rs6265 are more likely to exhibit increased antidepressant response to ketamine than Met carriers. Liu and colleagues
(8) alluded to the possibility that the weakened antidepressant response to ketamine infusion typically seen in approximately
30% of patients might be related to the Val66Met polymorphism. Our finding is consistent with their hypothesis that rs6265 genotypes could help separate ketamine responders from nonresponders. They also suggested that it may be possible to administer BDNF-enhancing compounds to Met allele-carrying patients before administering ketamine. Standard antidepressants, electroconvulsive therapy, and brain stimulation techniques such as transcranial magnetic stimulation all increase BDNF levels (11,12); exercise also has BDNF secretion-enhancing effects (13).
In contrast, a previous report that included the large STAR*D cohort found no association between traditional antidepressants and rs6265 (14). This suggests that the Val66Met variant
may play a different role in patients treated with traditional antidepressants as opposed to those treated with rapid-acting antidepressants such as ketamine.

Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene,
a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with
alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We
generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in
humans with the variant allele. BDNFMet was expressed in brain at normal levels, but its secretion
from neurons was defective. When placed in stressful settings, BDNFMet/Met mice exhibited increased
anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant
BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.Human Biomarkers of Rapid Antidepressant EffectsMood disorders such as major depressive disorder and bipolar disorder—and their consequent effects on the individual and
society—are among the most disabling and costly of all medical illnesses. Although a number of antidepressant treatments are available
in clinical practice, many patients still undergo multiple and lengthy medication trials before experiencing relief of symptoms. Therefore
a tremendous need exists to improve current treatment options and to facilitate more rapid, successful treatment in patients suffering
from the deleterious neurobiological effects of ongoing depression. Toward that end, ongoing research is exploring the identification of
biomarkers that might be involved in prevention, diagnosis, treatment response, severity, or prognosis of depression. Biomarkers
evaluating treatment response will be the focus of this review, given the importance of providing relief to patients in a more expedient
and systematic manner. A novel approach to developing such biomarkers of response would incorporate interventions with a rapid
onset of action—such as sleep deprivation or intravenous drugs (e.g., ketamine or scopolamine). This alternative translational model for
new treatments in psychiatry would facilitate shorter studies, improve feasibility, and increase higher compound throughput testing for
these devastating disorders.________________________________________________________________________Predictors of Response to Ketamine in Treatment Resistant Depression and Bipolar DisorderAbstract: Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects
in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD)
and bipolar disorder (BD). The identification of depressed sub-populations that are more likely
to benefit from ketamine treatment remains a priority. In keeping with this view, the present
narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as
part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE,,
and Scopus were searched for relevant articles from inception to January 2018. The search term
ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder,
predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of
response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family
history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels),
polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate
ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF
allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of
alcohol use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression
more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding,
metabolic-inflammatory alterations are emerging as possible pretreatment response predictors
of depressive symptom improvement, most notably being cognitive impairment. Sophisticated
data-driven computational methods that are iterative and agnostic are more likely to provide
actionable baseline pretreatment predictive information.In addition to pretreatment pro-inflammatory cytokines potentially moderating response to
ketamine, preliminary evidence indicates that circulating vitamin B12 levels may affect the treatment
outcomes with ketamine [34]. Previous reports indicate that higher levels of circulating vitamin B12
are associated with a greater probability of response to conventional antidepressants [35].To contextualize the foregoing results, a single small study with 20 subjects identified vitamin
B12 levels were cross-sectionally associated with bipolar depression. Specifically, ketamine treatment
“responders” had higher levels of circulating vitamin B12 when compared to “non-responders”,
where “responders” were subjects with a 50% or greater reduction of HDRS, as compared to baseline,
on the seventh day after infusion. This result is consistent with studies showing that higher levels of
vitamin B12 are positively correlated with the conventional antidepressant response [21,35].3.5. Neurochemistry Variables
Abnormalities in amino acid neurotransmitter systems are postulated to play a critical role in the
pathoetiology of MDD [38]. Stress-induced depression and cognitive impairment have been found
to be associated with the reduced expression of the gamma-aminobutyric acid (GABA) receptors in
the brain [39].
Using proton magnetic resonance spectroscopy (1H-MRS), Salvadore et al. (2012) measured levels
of the amino acid neurotransmitters gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate
(a surrogate marker of glutamine), in the ventromedial and the dorsomedial/dorsal anterolateral
prefrontal cortex before and after IV ketamine treatment in subjects with MDD (n = 14). Following
ketamine infusion, depressive symptoms significantly improved after 230 min, as assessed by the
changes in the mean MADRS score. The authors reported that while pretreatment GABA and glutamate
did not correlate with an improvement of depressive symptoms, pretreatment Glx/glutamate
ratio was found to be significantly and inversely correlated with the symptomatic improvement
with ketamine [23].

Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusionSymptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion


  • Some subjects display antidepressant response to ketamine two weeks post-infusion.

  • Two-week post-infusion data from multiple ketamine trials (MDD & BD) were combined.

  • Smoking history & family history of alcohol use were linked to response at two weeks.

  • Less sadness, anhedonia & trouble concentrating at day 1 predicted greater response.

  • Sleep quality was not significantly improved in responders at two weeks.
  • ________________________________________________________________________________________

rs6265 – Val66Met – the Ketamine SNP   < LINK

rs6265, also known as Val66Met, is a SNP in brain-derived neurotrophic factor BDNF gene. The more common G allele encodes the Val, while the A allele encodes Met.

The A allele may also be protective against depression when subjected to repeated defeat [PMID 17956738g2b2mh blog


On a driving-based motor learning task subjects with this genotype showed greater error during short-term learning and poorer retention over 4 days, relative to subjects without the polymorphism. The presence of this BDNF polymorphism is associated with differences in brain motor system function, altered short-term plasticity, and greater error in short-term motor learning. [PMID 19745020]

A 2017 study of 1,000 Alzheimer’s disease patients, a third of whom were rs6265(A) carriers, concluded that over the ~7 year study such carriers lost memory and thinking skills somewhat more rapidly than non-carriers.10.​1212/​WNL.​0000000000003980


Of interest regarding this SNP:


Next time you get cut off by a another driver, consider giving the offender a break: One-third of Americans might be genetically predisposed to crappy driving.

No, really, it’s not just your imagination.

In a new study of college undergraduates, those with a common genetic variation scored 20 percent worse in a driving simulator than their counterparts.

“The people who had this genetic variation performed more poorly from the get-go and learned more slowly as they went along,” said Steven Cramer, a University of California, Irvine neurologist, who works on helping stroke victims recover. “Then, when we brought them back four days later, they had more forgetting.”

The single nucleotide polymorphism, or SNP, is just one of millions of single-letter variations between humans’ genetic codes. This one occurs in a gene that produces a protein called brain-derived neurotrophic factor, which helps regulate the formation of new synapses, and the maintenance of old ones. BDNF plays a very important role in what’s called neuroplasticity, or the brain’s ability to rewire itself on the fly.

As described in a paper published in the journal Cerebral Cortex, study participants were asked to drive 16 laps in a driving simulator that was essentially a screen with a steering wheel. As they drove around the course, they attempted to keep their cars on a black strip in the center of the road. The software grades their ability to complete that task quantitatively. And, of a small sample of 29 students, people with that single genetic difference, called Val66Met, performed more poorly than their demographically similar counterparts.

“It’s a very nice study, well designed, and the questions they ask are good,” said Clifford Nass, a co-founder of Stanford’s CarLab, an interdisciplinary research institute. He was not part of the study.

Cramer considers the simulation a good proxy not just for driving, but for other complex motor skills tasks. Because it’s not controlling a motor vehicle, per se, that he’s interested in, but how the brain learns, or relearns complex tasks.

When people have a stroke, and a portion of their brain dies, they have to relearn tasks using different parts of their brains. Individual genes are only part of the symphony of influences that determine individual behavior, but the Val66Met variation appears to have an unusually strong influence on the brain’s activity.

“There is mounting evidence that the one in three people who have this variation have less plasticity than the two-thirds of people who lack that genetic variation,” Cramer said.

Results from a separate study reported earlier this year in Scientific American also found that genetic variation in BDNF helped determined people’s skill at a simple computer game.

The effect is so pronounced, in fact, that Cramer said he could imagine future stroke patient routing within hospitals based on the SNP.

“I wonder if there aren’t going to be treatments, when they have traumatic brain injury and you’re in the rehab ward, where they test the gene and say, ‘Send them to the BDNF ward,'” he said.

So, if the presence of the gene makes you a worse driver, a slower stroke-victim recoverer and possibly has other negative effects, why is the variant still present?

“Variations can stick around just for the fact that they are not that bad for you,” said Bruce Teter, a geneticist who studies the brain at UCLA. “They don’t kill you before you reproduce, in which case, there is no selective advantage or disadvantage.”

But it also turns out that people with the Val66Met variant could be less susceptible to degenerative neurological disorders like Parkinson’s and Huntington’s.

“Originally people thought plasticity had to be good, as it’s related to the ability of the brain to adapt and learn and things like that,” Teter said. “But neuroplasticity can also be bad for you in situations where the kinds of changes that are seen are deleterious.”

But if you want to stay out of car accidents, it’s better to have the dominant BDNF variant, Cramer’s study suggests. And if further work continues to support that idea, the question is, can or should we do anything with that information?

“Let’s pretend that the one in three people are more prone to car accidents,” Cramer said. “It’s up to society to say, how do we deal with that fact?”

SNPwatch: The Bad Driving Gene?

New research suggests that your skills behind the wheel may be affected by your genes.

To better understand the effects of a variant in the BDNF gene on motor skills learning, Steven Cramer and colleagues at UC Irvine tested 29 subjects in a driving simulator. Their results, published in the journal Cerebral Cortex, might make you think twice about whom you go on your next road trip with.

Subjects sat in front of a screen with their hands firmly planted at “10 and 2” on a steering wheel and guided their “car” around a track, attempting to stay centered over a black line. The steering was tuned so that subjects had to begin turning before the screen actually changed.

Over the course of 15 trials, all of the study subjects got better at the driving task. But the seven people who had a T improved less than those with two Cs. When subjects returned to the lab four days later for a final lap, everyone had forgotten how to drive the simulator a little bit, but those with a T did worse.

“These people [with a T at ] make more errors from the get-go, and they forget more of what they learned after time away,” Cramer said in a press release.

The BDNF protein helps to regulate how nerve cells make new connections and maintain old ones. The T version of the variant, also known as the Val66Met, reduces the amount of BDNF available in the brain and has been linked to impaired learning and memory. Studies have shown that stroke victims with this variant don’t recover as well as those who lack it.

But there may be an upside: the variant seems to have a beneficial effect on cognition in people with Parkinson’s disease, Huntington’s disease, lupus and multiple sclerosis.

“It’s as if nature is trying to determine the best approach,” Cramer said. “If you want to learn a new skill or have had a stroke and need to regenerate brain cells, there’s evidence that having the variant is not good. But if you’ve got a disease that affects cognitive function, there’s evidence it can act in your favor. The variant brings a different balance between flexibility and stability.”

Can nurture save you from your own genes? Genes, environment and depression

Welcome to Mind Matterswhere top researchers in neuroscience, psychology, and psychiatry explain and discuss the findings and theories driving their fields. Readers can join them. We hope you will. This week: Genes, Environment, and Depression:How Nurture Can Save You from Your Own Genes _____________________ Introductionby David DobbsEditor, Mind MattersAmong biology’s more riveting inquiries is the investigation of gene-environment interactions — the demonstration that a person’s genes constantly react to experience in a way that changes behavior, which in turn shapes environment, which in turn alters gene expression and so on. As David Olds described a few weeks ago, this new subdiscipline is yielding startling insights about how nature and nurture mix to help determine one’s health and character. This week reviewer Charles Glatt reviews a study that takes this investigation a level deeper, examining how two different gene variants show their power — or not — depending on whether a child is abused, nurtured, or both. As Glatt describes, this study, despite its grim subject, suggests promising things about the power of nurture to magnify nature’s gifts or lift its burdens. _____________________ Gene-Environment Interactions:When Nurture Wears a White Hat Charles GlattWeill Cornell Medical College, New York, NY For centuries, philosophers, theologians and biologists have debated the relative roles of inborn traits versus environmentally defined experiences in determining what and who we are. This nature-nurture debate carries fundamental implications for our understanding of self-determination, or free will. Indeed, as research has begun to identify genetic risk factors for certain behavioral traits, these risk factors have already been used in court (see here and here)to argue that punishment should be lessened for convicted felons — the presumption being that their genes made them inherently more likely to misbehave.The importance and challenge of the nature-nurture debate in behavior has recently spawned a new area of research that looks at the interaction between genetic risk factors and experience in the development of psychopathology. A study led by Joan Kaufman and Joel Gelernter, both of Yale, and published in Biological Psychiatry, has demonstrated what many of us have intuitively concluded, which is that both nature and nurture contribute to who we are. In this particular study, genetic and environmental factors interact to determine risk for depression. In their study, “Brain-Derived Neurotrophic Factor-5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children,” Kaufman, Gelernter and colleagues found distinct gene-environment interactions in the risk for depressive symptoms. Other studies have found similar interactions, but looked mainly at interactions between single genetic and single environmental risk factors. This study ups the ante by examining various interactions among two genetic and two environmental factors, including a four-way interaction with two genetic and two environmental variables. Where the Money Is Kaufman and colleagues took the approach of bank robber Willie Sutton who, when asked why he robbed banks, is said to have replied, “Because that’s where the money is.” Kaufman and colleagues focused on the most well known and accepted genetic and environmental risk factors for depression to see how they interacted with one another to alter risk. On the nature side, they focused on polymorphisms — genetic differences between individuals — that have been implicated in depression through a variety of methods. The first polymorphism is in the regulatory region of the gene for the serotonin transporter. This polymorphism is the 5-HTTLPR, which stands for the serotonin (5-hydroxytryptamine, 5-HT) transporter linked polymorphism. The 5-HTTLPR has received much research attention because it appears to alter the expression of the serotonin transporter molecule, which is the target of the commonly prescribed serotonin-selective reuptake inhibitor (SSRI) class of antidepressants and is itself implicated in depression. Caspi and Moffit and other research groups have repeatedly found this polymorphism to be associated with depression in the presence of stressful life events. The second polymorphism Kaufman studied is the gene for brain-derived neurotrophic factor, or BDNF. BDNF is a molecule that seems to encourage the growth of new neurons; it appears to be central to brain growth and learning. This polymorphism in the BNDF gene alters the efficiency of secretion of this molecule. Recent studies in animals and humans have shown that BDNF levels are decreased during stress and depression and that SSRIs act at least in part by normalizing the levels of BDNF. (BNDF levels have been shown to rise in response to successful SSRI treatment, as well as in response to successful psychotherapy and, for that matter, exercise. An earlier Mind Matters by Francis Lee and Larry Tecott reviewed a rare paper finding a downside to BNDF. ) Thus it is not hard to imagine that polymorphisms (that is, certain variants) of the BDNF gene might interact with other factors to contribute to depression risk. BNDF and 5-HTTLPR, then, were the “nature” factors Kaufman and colleagues examined. From the “nurture,” or environment/experience, side they added two epidemiologically established modifiers of risk for depression — childhood abuse/maltreatment on one hand and, on the other, positive social support.Please Interact Amongst Yourselves The researchers studied 109 children who had been removed from their parents’ care due to reports of abuse or neglect and 87 control children with no reports of abuse or maltreatment. They scored all the children for depressive symptoms such as irritability, crying and reluctance to see friends. High scores on this scale indicate greater depression. They then compared the distribution of these scores in children with different combinations of the 5-HTTLPR and BDNF polymorphisms described above. They found that children with the “bad” form of 5-HTTLPR had higher depressive symptom scores — but only if they had a history of maltreatment. Bad 5-HTTLPR made it more likely (but not certain) that an abused child would develop depression. But it created no effect on depression scores in children without a history of maltreatment. It was like a seed that had to be watered by abuse. This replicates similar findings in studies by Caspi and Moffit and other groups. Kaufman and colleagues then looked at how the different forms of BDNF might affect this picture. They found that a certain version (or allele) of the BDNF gene amplified the effects of the 5-HTTLPR gene, making it even more likely that a given child would develop depression — but again, only if the child had suffered abuse. Finally, Kaufman and colleagues looked at the effects of social support. They asked the children about people in their lives whom they could talk to about personal things, count on to buy them things they needed and other, similar signs of supportive relationships, and from the answers derived a social support score. Children were then characterized as having high or low support. The researchers found that high levels of such nurturing counteracted the effects of the genetic risk factors almost completely.Balance of Power As with any behavioral genetic study, one must be careful not to overinterpret these findings, because virtually no study in behavioral genetics is consistently or completely replicated. Nonetheless, some additional points about this paper can help inform us on the nature-nurture debate. First, depression scores and categorical diagnoses of depression were significantly higher in children with a history of maltreatment versus controls even before any genetic analysis was factored in. In a similar vein, the highest average depression score of any genotype category in the unabused control children was lower than the average depression score for any genotype category in the maltreated children; genes alone weren’t likely to make the child depressed, but maltreatment alone could. These findings suggest that, at least regarding these specific polymorphisms, nurture beats nature. This conclusion will come as a relief to believers in human free will. It also argues strongly for the identification of children at risk for maltreatment and strong actions to reverse the negative effects of this experience.

Oral Scopolamine Augmentation in Moderate to Severe Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Study

Objective:To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram.

Method:In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18–55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n=20) or placebo (n=20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥50% decrease in HDRS score; remission, as HDRS score ≤7.

Results: Augmentation with scopolamine was significantly more effective than placebo (F1,38=5.831, P=.021). Patients receiving scopolamine showed higher rates of response (65%, 13/20 at week 4) and remission (65%, 13/20 at week 6) than the placebo group (30%, 6/20 and 20%, 4/20, respectively; P=.027, P=.004, respectively). Patients in the scopolamine group showed higher rates of dry mouth, blurred vision, and dizziness than the placebo group.

Conclusions: Oral scopolamine is a safe and effective adjunct for treatment of patients with moderate to severe major depressive disorder.

Exploratory genome-wide association analysis of response to ketamine and a polygenic analysis of response to scopolamine in depression.

Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine a review.

Pulsed Intravenous Administration of Scopolamine Produces Rapid Antidepressant Effects and Modest Side Effects

SNP watch link

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A Vaccine for Depression?

Ketamine’s remarkable effect bolsters a new theory of mental illness.

A Vaccine for Depression?

Ketamine’s remarkable effect bolsters a new theory of mental illness.


One sunny day this fall, I caught a glimpse of the new psychiatry. At a mental hospital near Yale University, a depressed patient was being injected with ketamine. For 40 minutes, the drug flowed into her arm, bound for cells in her brain. If it acts as expected, ketamine will become the first drug to quickly stop suicidal drive, with the potential to save many lives. Other studies of ketamine are evaluating its effect as a vaccination against depression and post-traumatic stress. Between them, the goal is nothing less than to redefine our understanding of mental illness itself.

Depression is the most common mental illness in the United States, affecting 30 percent of Americans at some point in their lives. But despite half a century of research, ubiquitous advertising, and blockbuster sales, antidepressant drugs just don’t work very well. They treat depression as if it were caused by a chemical imbalance: Pump in more of one key ingredient, or sop up another, and you will have fixed the problem.

PREPARED: One day, soldiers heading into combat could be treated to reduce the chance of getting PTSD.Co Rentmeester/Getty Images

But the correspondence between these chemicals (like serotonin) and depression is relatively weak. An emerging competitive theory, inspired in part by ketamine’s effectiveness, has it that psychiatric disease is less about chemical imbalance than structural changes in the brain—and that a main cause of these changes is psychological stress. “I really do think stress is to mental illness as cigarettes are to heart disease,” says Gerard Sanacora, the psychiatry professor running the ketamine trial at Yale.

The theory describes stress grinding down individual neurons gradually, as storms do roof shingles. This, in turn, changes the nature of their connections to one another and the structure of the brain. Ketamine, along with some similar molecules, acts to strengthen the neuron against that damage, affecting not just the chemistry of the brain but also its structure.

Mental hospitals don’t usually see patients until they break: a brain shaped by vulnerable genes, wrecked by the stress of loss or trauma. This isn’t how it works with other sicknesses: heart disease, cancer, AIDS. Detected early, these conditions can often be managed. Crises averted.



If Sanacora and like-minded researchers are right, we may be on the cusp of a sea change that allows for a similar approach to mental health. The new approaches may prevent mental illness before it hits, by delivering a vaccination for the mind.

The need for progress could hardly be more urgent: Of all illnesses, neuropsychiatric diseases are estimated to put the heaviest burden on society. Nearly half of Americans are affected by some sort of mental disorder at some point in life. Suicides, 90 percent of them among the mentally ill, take 40,000 Americans every year—more than murder or car crashes. Since 2005, the suicide rate among U.S. war veterans has nearly doubled; in the first half of 2012, more service members died by suicide than in combat. Few medical failures are more flagrant than psychiatry’s impotence to save these people.

At the same time, treatment can be woefully ineffective. Less than a third of depression patients respond to a drug within 14 weeks, according to the 2006 STAR*D trial, the largest clinical test of antidepressants. After six months and multiple drugs, only half of patients recovered. Thirty-three percent don’t respond to any drug at all. When the pills do work, they are slow—a deadly risk, given that people with mood disorders kill themselves more often than anyone else.

Our treatments work so poorly in part because we don’t really understand what they do. Serotonin, the most common target for current antidepressants, is a neurotransmitter, a chemical that carries messages in the brain. But it was first found, in 1935, in the gut. Serotonin’s name comes from blood serum, where Cleveland Clinic scientists discovered it in 1948, noting that the chemical helps with clotting.

When Betty Twarog, a 25-year-old Ph.D. student at Harvard, later found serotonin in neurons, she wasn’t taken seriously. At that time, brain signals were thought to be purely electrical impulses that leapt between cells. Twarog called this old idea “sheer intellectual idiocy,” as Gary Greenberg reports in his book Manufacturing Depression. Working at the Cleveland Clinic in 1953, she found serotonin in the brains of rats, dogs, and monkeys.

K: One obstacle to the therapeutic use of ketamine is its reputation as a recreational drug.Wikipedia

Twarog didn’t know yet what serotonin was doing there, but a clue came soon from D.W. Woolley, a biochemist at Rockefeller University, in New York. In 1954 Woolley pointed out in a paper that lysergic acid diethylamide, or LSD, is chemically similar to serotonin and is processed similarly in the brain. Since LSD “calls forth in man mental disturbances resembling those of schizophrenia,” he wrote, another drug affecting serotonin might be used to treat schizophrenia. Twarog’s original paper would take years to percolate through the male-dominated field, but her work and Woolley’s would become accepted as evidence of how important chemicals like serotonin could be to brain signaling. The discovery was a breakthrough for neuroscience—but it also birthed a misleading, long-lived belief about mental illness. “The thesis of this paper,” Woolley wrote, “is that … serotonin has an important role to play in mental processes and that the suppression of its action results in a mental disorder. In other words, it is the lack of serotonin which is the cause of the disorder.”

Around the same time, other researchers stumbled on the first antidepressants, iproniazid and imipramine. Intended to treat tuberculosis and schizophrenia, respectively, these drugs also happened to make some patients “inappropriately happy.” Researchers found that the drugs elevated levels of serotonin, along with related neurotransmitters.1 This began a huge search to find chemically similar drugs that worked better as antidepressants.

Drug companies often say mood disorder is caused by a “chemical imbalance.” But the evidence for this story is slim.

Iproniazid was the first of a class of medicines that block an enzyme from breaking down serotonin, as well as dopamine and norepinephrine, two other neurotransmitters. The chief downside of these drugs, called monoamine oxidase inhibitors (MAOIs), is that they require a strict diet: no aged cheeses, wine, beer, or cured meats. Combined with these foods, the drugs can cause deadly spikes in blood pressure, a hassle that often inclines patients to ditch them. (The novelist David Foster Wallace took an MAOI for decades; in part to escape the food restrictions, he got off the drug months before his suicide.) On the other hand, tricyclic antidepressants, like imipramine, work by blocking the re-absorption of serotonin and norepinephrine. The cost is a host of side effects, from dry mouth to weight gain to erectile dysfunction and loss of libido.

The next generation of drugs focused on fine-tuning the same mechanisms, and had somewhat improved side effects. A new class of drugs known as selective serotonin reuptake inhibitors, or SSRIs, arrived in the ’80s, bringing huge commercial successes like Prozac, Zoloft, and Paxil. Since SSRIs are more specifically focused on serotonin, they were heralded as cleaner options; but they are not much more effective at lifting mood than the older drugs. We often take for granted the diabetes analogy for depression: If you are depressed, it is because you need serotonin, just as a diabetic person needs insulin. Drug companies often say that mood disorder is caused by a “chemical imbalance” in serotonin or a signal like it. One ad for Zoloft, the blockbuster antidepressant, featured a sad white circle crawling cutely beneath a gray cloud; the voice-over boasted that depression may be “related to an imbalance of natural chemicals in the brain. Zoloft works to correct this imbalance.”

But the evidence for this story is slim. Prozac raises serotonin levels within hours yet doesn’t change mood for weeks. When scientists deplete serotonin in healthy people, it does not make them sad. And when doctors measure serotonin levels in the cerebrospinal fluid of depressed people, they do not find a consistent deficiency; one 2008 study even found increased levels of serotonin in depressed people’s brains. The drug tianeptine, discovered in the late ‘80s, decreases serotonin levels yet relieves depression. And studies have shown that people falling in love show lower, not higher, levels of serotonin.

Serotonin is clearly not just a feel-good chemical. If a serotonin-based drug like Zoloft makes you happier, it works in some other, indirect way. As psychiatrist Ronald Pies, editor of Psychiatric Times, put it in 2011, “The ‘chemical imbalance’ notion was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.”

Meanwhile, as serotonin falls far short of explaining depression, a more likely candidate is emerging.

Stress in moderation is not harmful, but motivating. Cortisol, a stress hormone, cycles daily; synchronizing with sunlight, it helps arouse us for the day. In health, the hormone spikes when we need to pay attention: a test, a job interview, a date. Studies on rodents and humans confirm that brief, mild increases in stress are good for the brain, particularly for memory. During these spikes, neurons are born and expand in the hippocampus, the seahorse-shaped finger of tissue responsible for forming new memories and understanding three-dimensional space, and rodents learn better. The student who gets stressed while studying is more alert and remembers more than the one who feels no urgency—up to a point. The problem comes when stress is either too intense at one moment, as in a rape or violent attack, or too sustained, as in long-term poverty, neglect, or abuse.

ACCENTUATING THE NEGATIVE …: Under prolonged stress, neurons in the amygdala, the brain’s fear center, expand like overgrown shrubbery and become hyperactive.Image from “Nature Reviews Neuroscience”*

Stress changes brain architecture differently, depending on how long it lasts. After chronic stress, like childhood trauma, the effect of hormones on brain cells inverts: Neurons in the hippocampus and the prefrontal cortex, which is responsible for mood and impulse control, start to shrink, while those in the amygdala, the almond-shaped seat of fear and anxiety, expand like overgrown shrubbery. But people are differently vulnerable, depending on genes and on prior life experience. “If you take two people and subject them to the same stressful event, for one of them it will be harmful and for the other, no,” says Maurizio Popoli, a professor of pharmacology at the University of Milan. “It is because they perceive the stress differently.”

… AND ELIMINATING THE POSITIVE: In the prefrontal cortex and hippocampus, regions responsible for memory, attention, and self-control, chronic stress shrinks the branches of neurons.Image from “Nature Reviews Neuroscience”*

Stress hormones’ most important effect is to flood parts of the brain with glutamate, the brain’s “go” signal. Used by 80 percent of neurons in the cortex, this key neurotransmitter drives mental processes from memory to mood. Glutamate triggers neurons to generate sudden bursts of electricity that release more glutamate, which can in turn trigger electrical bursts in nearby neurons.

This cellular signaling is called excitation and is fundamental to how information is processed in the brain. Like sexual excitability, it ebbs and flows; a “refractory period” follows each neural firing, or spike, during which the neuron cannot be excited. Other neurotransmitters, like serotonin, are called “modulatory,” because they change the sensitivity of neurons that secrete glutamate (among others). Less than 1 percent of neurons in the cortex signal with these modulators. As Popoli puts it, these modulators are “very important for fine-tuning the machine. But the machine itself is an excitatory machine,” driven by glutamate.

Glutamate moves like a ship between neurons. The sea it sails is called the synapse, the shore it departs from is the presynaptic neuron, and the destination, on the synapse’s far side, is the postsynaptic neuron. Another component, called a glial cell, works to remove glutamate ships from the synapse and recycle them. The glutamate system is affected at each of these points by stress hormones: They push the first neuron to send more ships, interfere with the glial cell’s recycling, and block the docks on the distant shore. All of these changes increase the number of glutamate ships left in the synapse, flooding the cell with aberrant signals. Indeed, depressed people’s brains, or at least animal models of depression, show all three of these problems, leading to long-lasting excesses of glutamate in key portions of the brain.

This superabundance of glutamate makes a neuron fire sooner than it should and triggers a cascade of signals inside the cell, damaging its structure. Glutamate binds to the neuron and allows in a flood of positively charged particles, including calcium, which are vital to making a neuron fire. But in excess, calcium activates enzymes that break down the neuron. Each neuron has tree-like branches, called dendrites, which are used to communicate with other neurons. When overdosed in glutamate, this canopy of branches shrinks, like a plant doused with herbicide. First the “twigs,” called spines, disappear. After prolonged stress, whole branches recede.

This harmful process, called excitotoxicity, is thought to be involved in bipolar disorder, depression, epilepsy, and neurodegenerative diseases like Alzheimer’s, Huntington’s, and Parkinson’s. In depressed brains, many areas are shrunken and underactive, including part of the prefrontal cortex and the hippocampus. The brain changes that cause mood disorders, Sanacora and his colleagues believe, come in part from chronic stress overexciting neurons with glutamate.

Ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.

We usually think of our brains’ adaptability as a good thing. Just as neurons grow during development, the wiring in the adult brain can change. After strokes or other brain injuries, neural signals re-route themselves around damage, allowing even very old people to re-learn lost skills. Psychotherapy and meditation can change patterns of brain activity in ways that persist after treatment.2

But the neuroplasticity hypothesis of mental disorder highlights the drawback of such neural liberalism: The human brain’s flexibility allows regeneration, but also renders it vulnerable to being altered by stress. Subjected to the trauma of war, a bad breakup, or a bout of homelessness, a person with a genetic predisposition may find his mind stuck in a loop of chronic fear or depression.

The mood drugs in wide use now focus on modulatory neurotransmitters like serotonin. Ketamine, however, works directly on glutamate signaling. If ketamine is tapping into the root of the problem, this might explain why it works faster, better, and more often than more popular antidepressants.

Not everybody accepts the idea that glutamate and stress are central to depression. Some experts see the effects of stress as downstream effects, not the root cause of mood disorder. “The mechanism of action of a good treatment does not have to be the inverse of a disease mechanism,” says Eric Nestler, an expert on addiction and depression at Mt. Sinai Hospital. Serotonin drugs and ketamine may affect depression indirectly, without a serotonin or glutamate abnormality at the root of depression. Nestler also points out that depression probably includes a diversity of subtypes, without any single cause. He treats depression not as a unified disease, but a constellation of symptoms, each with discrete neural roots.

Even so, we do know that ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.

If ketamine turns out to be a psychiatric savior, it will be one with a surprising history. Since 1962 it has been a go-to anesthetic for children in emergency rooms, because it kills pain, muffles consciousness, and rarely causes breathing or heart problems. Children given ketamine enter “a trance like state of sensory isolation” free of pain, memory, and awareness, as one review put it. Emergency room doctors rely on ketamine to make sure kids have no awareness or memory of, say, the trauma of having a shattered arm set back into place.

On the other hand, ketamine is a well-known recreational drug with potential for abuse. The dissociative trip caused by a moderate dose of ketamine has made it popular in clubs and raves since the 1970s, especially in Asian cities like Hong Kong. Its sedative effect made “special K” a date-rape drug. Doctors, patients, and the government agencies that fund research are often suspicious of a drug known to cause hallucinations, as they have been of psychedelics like psilocybin and ecstasy, despite their potential for treating depression or anxiety. Each tends to show fast results after a single dose, like ketamine.

In 1999, the same year ketamine was declared a controlled substance in the United States, Yale researchers happened upon its antidepressant power. A team co-led by Dennis Charney, now dean of the Icahn School of Medicine at Mt. Sinai, in Manhattan, and John Krystal, now chair of the department of psychiatry at Yale, used ketamine to study glutamate: Since ketamine was known to block glutamate receptors, it might show what role the excitatory neurotransmitter plays in the depressed brain. To their surprise, they found that the drug made patients feel better, often within hours. A single dose, much smaller than what’s used for anesthesia, tended to last for weeks.

Since 1999, a dozen studies have replicated the results, often on patients who failed to respond to other drugs. Ketamine also works for bipolar people in depressive phases, without triggering mania, as classic antidepressants sometimes do. The majority of depressed people studied have responded to ketamine. For patients who are often suicidal, this fast response can be lifesaving. Some 50 doctors in the U.S. now offer ketamine infusions for depression.

The first evidence in humans that ketamine might work to prevent mood disorder came from the battlefield.

Many leaders in the field see the emergence of ketamine, and future fast antidepressants based on glutamate, as a great leap forward for the field. “In my mind,” Sanacora told NPR recently, “it is the most exciting development in mood-disorder treatment in the last 50 years.”

Ketamine and the old antidepressants both result in fuller neural “trees,” but by different routes, at different speeds. Prozac and other serotonin-based drugs take four to six weeks to kick in. A landmark 2003 Science study by Columbia University’s René Hen and Ronald Duman, now at Yale, found that serotonin-based antidepressants only work if they spur birth of new neurons in the hippocampus.3 These new neurons take four to six weeks to mature, roughly the same amount of time that conventional antidepressants take to lift a depressed person’s spirits. A 2010 paper argued that SSRIs like Prozac may work by dampening glutamate release in response to stress. So even old-school antidepressants, when they work, may act on the glutamate system.

Ketamine, on the other hand, seems to act directly on mature neurons, fertilizing them to grow branches more robustly, or protecting them against damage. Ketamine’s key effect is to block glutamate receptors of one type. This causes less calcium to flow into the neuron, reducing the risk of the neuron shrinking or self-destructing.

Today ketamine is offered by psychiatrists and anesthesiologists, at prices ranging from $300 to $1,000 per dose, for people who are morbidly depressed or have chronic pain. Insurance doesn’t usually cover the cost of an infusion, because even though it is FDA approved as an anesthetic, it has not been approved as an antidepressant. Each new use of a drug requires multiphase clinical trials for FDA approval, usually funded by pharmaceutical companies, which have little incentive to invest in a drug they can’t monetize. Ketamine got its original patent in 1966, and that expired long ago. So even if drug companies steered ketamine through the expensive approval process as an antidepressant, doctors could still prescribe the cheap, generic versions already available for anesthesia instead of pricier, patented versions intended for depression. This is an old story. Lithium carbonate, which also acts on glutamate receptors, is still one of the most reliable drugs for treating bipolar disorder. But lithium, which is an element, can’t be patented. So, despite their effectiveness, these generic pills do not attract many corporate dollars.


One tough truth about mood disorder is that not all forms may ever be curable. Brain-imaging studies have shown structural differences between the white matter in healthy versus bipolar brains. Differences in personality and sleep patterns also persist in bipolar people, even between manic or depressed episodes. The structural changes likely have genetic roots, and once they arise, are difficult or impossible to reverse.

Nevertheless, if a drug prevents a mood disorder from manifesting, it might prevent harmful anatomical changes from ever taking place. Just as a vaccine triggers the body to arm itself against a particular virus, a drug like ketamine, given before the crisis that triggers a breakdown, might protect the brain against the effects of stress. Like a vaccine, the drug might only need to be given once for lasting resilience.

The first evidence in humans that ketamine might work to prevent mood disorder, not just treat it, came from the battlefield. U.S. soldiers injured in Iraq were treated with various anesthetics, including ketamine. Since ketamine can cause hallucinations, surgeons worried that it might make trauma worse: Scary combat-related hallucinations could put soldiers at higher risk of mental illness.

But they found the opposite. Out of 25,000 service members wounded in Iraq between 2002 and 2007, the data showed, veterans treated with ketamine for burns had lower rates of post-traumatic stress disorder. Among civilians and soldiers hospitalized for burns, as many as 45 percent end up with PTSD. But soldiers treated with ketamine on the battlefield got PTSD about half as often—even though they had more severe burns requiring more surgeries and longer hospital stays.

Mental hospitals don’t usually see patients until they break: This isn’t how it works with other sicknesses.

Rebecca Brachman, a neuroscientist and recent doctoral graduate from Columbia University, and her supervisor, Christine Denny, tried giving ketamine to mice and then exposing them to stressors.4 The researchers tested several types of stress, including one in which subject mice are “bullied” by more aggressive mice for two weeks. After this daily hazing, mice ordinarily develop the rodent equivalent of PTSD and depression: freezing in a new space, refusing to interact with other mice, and not moving in a forced swim test. But the mice “vaccinated” before the bullying fared far better: They didn’t act depressed afterward. Brachman and Denny found that the protection from a single dose lasted for weeks, even though ketamine only stays in the body for a few hours. Though they haven’t tested it yet, it is possible that, like a vaccine, this protection could last for much longer. Their rodent research suggests ketamine may work even better as a prophylactic than as an antidepressant.

Denny says that we may eventually routinely use ketamine to prevent PTSD in combat veterans, rape victims, or survivors of car crashes or mass shootings. Ketamine seems to be most strongly protective in mice when given before stressful events, Brachman says. Since we can’t predict most traumatic life events, this would limit the drug’s utility. But if injected after a trauma yet before the psychological damage sets in—as with the burned soldiers—ketamine may still be protective. Denny is investigating this possibility now.

And in some situations, violent shock is predictable. “You don’t know when an earthquake will happen,” Brachman says, “but we do know when we’re about to send U.N. workers into an area devastated by a disaster.” When people know they are going into an acutely traumatic situation, she imagines, a preventive drug given ahead of time might protect their brains from the long-lasting effects of stress. Think of earthquake aid workers, fire fighters, or rescue workers in Syria, dragging mangled people from rubble.

The idea that a single injection could prevent mood disorders is a radical departure from current psychiatric thinking. But there are some precedents: Talk therapy and mindfulness meditation have long focused on building resilience to stress. Bipolar patients take “neuroprotective” drugs like lithium not to treat current symptoms, but as a protection against future breakdowns, for instance.

Not everyone is confident that ketamine is a safe bet, to be sure. Ketamine’s long-term safety is not known, says Nestler. No lasting ill effects are seen in anesthesia patients, who take much larger doses, but they haven’t received routine treatments, the way it is administered as an antidepressant.

Plus, ketamine’s reputation as a street drug is tough to shake. Many doctors consider the hallucinogenic an unacceptable risk for patients, who they fear may develop a taste for the high. Yale’s Sanacora points out that patients in his trial, who are screened for drug or alcohol abuse, often find the trip feeling unpleasant or disturbing. The psychedelic experience is surreal, he points out, not the mellowing pleasure of a drug like alcohol, Xanax, or heroin. Extreme ketamine trips, referred to as falling in a “K-hole,” are often compared to near-death or unsettling out-of-body experiences; they hardly sound like fun to most people.

But since the antidepressant dose is far lower than the one taken to get high, many patients don’t even notice. Drug companies are also competing to develop a less trippy alternative. Johnson & Johnson is testing a nasal spray form of esketamine, a version of ketamine with less psychoactive impact. A company called Naurex has finished phase II trials of Rapastinel, an injected drug that partially blocks the same glutamate receptors as ketamine, but is not psychedelic.

The ketamine pioneers emphasize that their prevention research is the beginning of a new road, raising hopes, rather than offering an immediate cure. Brachman and Denny stress that ketamine may not be the drug that ultimately makes it into widespread use; like the anti-tubercular drugs in the 1950s that spawned the antidepressant era, it is the first to trail-blaze this new class of psychiatric prophylactics. “What this work shows us is that we can intervene beforehand and create some sort of self-reinforcing stress resilience,” Brachman says. “We didn’t know that before; that’s what’s important. Everything else—should we use it, how should we use it—that all comes later.”

Taylor Beck is a journalist based in Brooklyn. Before writing, he worked in brain imaging labs studying memory, aging, and dreams.


1. Maxwell, R.A. & Eckhardt, S.B. Drug Discovery Humana Press, New York, NY (1990).

2. Kennedy, S.H., et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. American Journal of Psychiatry 164, 778-788 (2007).

3. Vogel, G. Depression drugs’ powers may rest on new neurons. Science 301, 757 (2003).

4. Brachman, R.A., et al. Ketamine as a prophylactic against stress-induced depressive-like behavior.Biological Psychiatry (2015). Retrieved from DOI:

*Images reprinted from Popoli, M., Yan, Z., McEwen, B., & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nature Reviews Neuroscience 13, 22-37 (2011).

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