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The Brain on Fire: Depression and Inflammation

According to the World Health Organization, depression is the leading cause of disability. Unfortunately, 30 to 60 percent of patients are not responsive to available antidepressant treatments (Krishnan & Nestler, 2008). In other words, 40 to 70 percent of patients are not helped by existing treatments. One area of research might shed some light on why a sizable portion of patients are not helped by current antidepressants.

There is growing evidence that inflammation can exacerbate or even give rise to depressive symptoms. The inflammatory response is a key component of our immune system. When our bodies are invaded by bacteria, viruses, toxins, or parasites, the immune system recruits cells, proteins, and tissues, including the brain, to attack these invaders. The main strategy is to mark the injured body parts, so we can pay more attention to them. Local inflammation makes the injured parts red, swollen, and hot. When the injury is not localized, then the system becomes inflamed. These pro-inflammatory factors give rise to “sickness behaviors.” These include physical, cognitive and behavioral changes. Typically, the sick person experiences sleepiness, fatigue, slow reaction time, cognitive impairments, and loss of appetite. This constellation of changes that take place when we are sick is adaptive. It compels us to get more sleep to heal and remain isolated so as not to spread infections.

However, a prolonged inflammatory response can wreak havoc in our bodies and can put us at risk of depression and other illnesses. There is plenty of evidence solidifying the link between inflammation and depression. For example, markers of inflammation are elevated in people who suffer from depression compared to non-depressed ones (Happakoski et al., 2015). Also, indicators of inflammation can predict the severity of depressive symptoms. A study that examined twins who share 100 percent of the same genes found that the twin who had a higher CRP concentration (a measure of inflammation) was more likely to develop depression five years later.  

Doctors noticed that their cancer and Hepatitis C patients treated with IFN-alpha therapy (increases inflammatory response) also suffered from depression. This treatment increased the release of pro-inflammatory cytokines, which gave rise to a loss of appetite, sleep disturbance, anhedonia (loss of pleasure), cognitive impairment, and suicidal ideation (Lotrich et al., 2007). The prevalence of depression in these patients was high. These results add credence to the inflammation story of depression.

Subsequent careful studies showed that the increase in the prevalence of depression in patients treated with IFN-alpha was not only because they were sick. Using a simple method of injecting healthy subjects with immune system invaders, researchers found higher rates of depressive symptoms in the ones who were exposed compared to the placebo group. The subjects who were induced to have an inflammatory response complained of symptoms such as negative mood, anhedonia, sleep disturbances, social withdrawal, and cognitive impairments.

The link between inflammation and depression is even more solid for patients who don’t respond to current antidepressants. Studies have shown that treatment-resistant patients tend to have elevated inflammatory factors circulating at baseline than the responsive ones. This is clinically important; a clinician can utilize a measure like CRP levels, which are part of a routine physical, to predict the therapeutic response to antidepressants. In one study, they found that increased levels of an inflammation molecule prior to treatment predicted poor response to antidepressants (O’Brien et al., 2007).

There are environmental factors that cause inflammation and therefore elevate risk for depression: stress, low socioeconomic status, or a troubled childhood. Also, an elevated inflammatory response leads to increased sensitivity to stress. The effect has been reported in multiple studies in mice. For example, mice that have gone under chronic unpredictable stress have higher levels of inflammation markers (Tianzhu et al., 2014). Interestingly, there are individual differences that make some mice more resistant to stress, therefore initiating a calmer immune response (Hodes et al., 2014).

Depression is a heterogeneous disorder. Each patient’s struggle is unique given their childhood, genetics, the sensitivity of their immune system, other existing bodily illnesses, and their current status in society. Being on the disadvantageous end of these dimensions irritates our immune system and causes chronic inflammation. The brain is very responsive to these circulating inflammatory markers and initiates “sickness behavior.” When the inflammation is prolonged by stressors or other vulnerabilities, the sickness behavior becomes depression.

If you are a professional working with patients suffering from depression, I urge you to consider the health of your patients’ immune systems. If you are a patient suffering from an exaggerated immune disorder (e.g., arthritis), do not ignore the depressive symptoms that you might be experiencing. If you are suffering from depression, avoid anything that might exacerbate your immune response. This is another example of the beautiful dance between mind and body!

References

Haapakoski,R.,Mathieu,J.,Ebmeier,K.P.,Alenius,H.,Kivimäki,M., 2015. Cumulative meta-analysisofinterleukins6 and 1β,tumournecrosisfactorα and C-reactive protein in patients with major depressive disorder. Brain Behav.Immun. 49,206.

Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D et al (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 111: 16136–16141.

Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature 455: 894–902.

Lotrich,F.E.,Rabinovitz,M.,Gironda,P.,Pollock,B.G., 2007. Depression following pe-gylated interferon-alpha:characteristics and vulnerability.J.Psychosom.Res.63, 131–135.https://doi.org/10.1016/j.jpsychores.2007.05.013.

O’Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., Dinan, T.G., 2007a. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326e331.

Tianzhu, Z., Shihai, Y., Juan, D., 2014. Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evid. Based Complement. Altern. Med. 2014, 438506.

The Serotonin Transporter Gene and Depression

A new large-scale study casts doubt on a widely reported association.

Why some people develop major depressive disorder and others do not is a complex and not well-understood process. Several factors have been discussed to contribute to depression, among them:

cialis generico spedizione gratuita Genetic variation: Individuals carrying one or two copies of a specific risk allele on one or more “depression gene/s” have a higher risk of developing depression.

anyone bought accutane without prescription Environmental influences: Negative life events such as trauma, negligence, or abuse increase the risk of developing depression.

prezzo levitra generico 2017 Gene-by-environment interactions: Negative life events only lead to depression in individuals with a specific genetic set-up that makes them risk-prone to develop depression.

The gene most commonly associated with depression is the serotonin transporter gene SLC6A4 (Bleys et al., 2018). Serotonin is a neurotransmitter affecting multiple physiological processes and cognitivebrain functions, among them mood and emotions, which is why it has been linked to mood disorders such as depression. Indeed, low serotonin levels have been associated with depressed mood (Jenkins et al., 2016), and selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. SSRIs block the reuptake of serotonin during cellular communication in the brain, making more serotonin available, and thus in theory helping to reduce depression.

Along these lines, the idea that the serotonin transporter gene could affect depression risk or severity intuitively made sense. Specifically, many scientists focused on the so-called 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene to research the effects of this gene on depression. Genetic polymorphism means that at a specific location in the genome, different people might have slight variations in their DNA which could affect how well the protein that the gene produces could do its job. In the case of the 5-HTTLPR polymorphism, there is a short allele (s) and a long allele (l). Already back in the 1990s, researchers showed that people with two or one short alleles have a higher chance of developing depression than those with two long alleles, as the short allele leads to reduced expression of the serotonin transporter (Collier et al., 1996).

This initial study sparked interest in the 5-HTTLPR polymorphism, but not all empirical works could find a clear association. In 2003, a surprising finding seemingly resolved this controversy. In a widely cited study, Caspi and colleagues were able to show that the effects of 5-HTTLPR polymorphism genotype on depression were moderated by a so-called gene-by-environment interaction (Caspi et al., 2003). This means that the genotype would only have an effect if individuals were also subjected to specific environmental conditions. Specifically, the scientists found that individuals reacted differently to highly stressful life events, depending on the 5-HTTLPR genotype. People with at least one short allele on the 5-HTTLPR polymorphism developed more depressive symptoms if they experienced a highly stressful life event than people with two long alleles. However, without a stressful life event, the genotype did not have an effect on the probability to develop depression.

This study further increased the interest in the 5-HTTLPR polymorphism and its relation to depression, leading to more studies on this topic. However, a problem of many of these studies was that their sample sizes were comparably small for genetic studies, potentially leading to erroneous results and overblown effects.

Almost a decade ago, Risch and co-workers (Risch et al., 2009) conducted a so-called meta-analysis, a statistical integration of empirical studies. They analyzed 14 studies on the 5-HTTLPR polymorphism and its relation to depression and on whether this relation was influenced by stressful life events as had been suggested by Caspi et al. (2003). Their result was clear: While more stressful life events led to a higher risk of depression, there was no effect of the 5-HTTLPR genotype on depression and no gene-by-environment interaction effect between genotype and stressful life events.

Despite this finding, hundreds of studies on the 5-HTTLPR polymorphism and depression have been published since 2009 (the scientific search engine PubMed lists more than 800 hits for the search term “5-HTTLPR depression” as of early May 2019). A new study recently published by Richard Border and colleagues in The American Journal of Psychiatry(Border et al., 2019) aimed to resolve the controversy about whether or not the 5-HTTLPR genotype affects depression and whether there is a gene-by-environment interaction between this genotype and stressful life events once and for all. To avoid the statistical problems of previous studies, they obtained data from several large genetic datasets available to researchers, leading to a sample size of several hundred thousand individuals. The results of the analysis were clear as well: There was no statistical evidence for a relation between the 5-HTTLPR polymorphism and depression, and there was also no evidence that traumatic life events or adverse socioeconomic conditions might show a gene-by-environment interaction with this genotype.

This, of course, does not mean that there is no relationship between serotonin and depression (there clearly is, as shown by the treatment success of SSRIs), but it lends further support to an emerging insight in psychiatry genetics: Mental illness is a highly complex process that is likely influenced by a large number of genetic and non-genetic effects. As such, it is unlikely that single genetic variations such as the 5-HTTLPR polymorphism have a huge impact on whether or not an individual develops depression or any other form of mental illness. Future psychiatry genetic studies will need to take this complexity into account by analyzing genetic variation across the whole genome and epigenome and relating it to mental illness (Meier & Deckert, 2019).



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Ketamine Study Reveals How to Make It an Even Better Depression Treatment

In early March, the FDA approved a nasal spray for depression based on ketamine, a substance once known only as a rave drug. Despite its reputation, ketamine is so promising as an anti-depressant that it will soon be available in licensed clinics throughout the country. A study published in Science on Thursday proposes the new treatment can be made even better.

In their paper, a team of scientists at Weill Cornell’s Medicine’s Feil Family Brain and Mind Research Institute show that ketamine can help the brain reform synapses, crucial connections between neurons, that can alleviate depressive symptoms. Ketamine is already famous for working quickly to relieve depressive symptoms — within days or hours — co-author Conor Liston, Ph.D., tells Inverse, but maintaining those crucial connections is key to extending its effects.

“Our study shows that the formation of new connections (synapses) between brain cells is required for sustaining ketamine’s antidepressant effects in the days after treatment,” says Liston, also professor of neuroscience at Weill Cornell. “Ketamine is an exciting new treatment for depression that differs from drugs like SSRIs in that it relieves symptoms rapidly. However, those effects are not always sustained.”

upset, depressed
Ketamine-based nasal spray is a new FDA-licensed drug for treatment-resistant depression.

Growing Back Dendritic Spines

In a mouse model, Liston and his co-authors demonstrated that doses of ketamine helped mouse brains regrow dendritic spines, small protrusions on neurons that help them pick up signals rom other cells that, crucially, degrade during exposure to chronic stress. These dendritic spines are a key part of synapse formation.

The degradation of these spines is not a perfect analog to human depression, but humans have them as well, and Liston points out that some of the most important features of depression in humans are also present in chronically stressed mice.

To create depression-like conditions, the team degraded the dendritic spines in their mice using stress hormones. Then, they gave one group a dose of ketamine, which they expected to have anti-depressive effects.

dendritic spine
A dendritic spine helps form a synapse — a connection to another neuron.

The dose of ketamine not only changed the mice’s behavior — they tried harder to escape their cages — it also helped reform the dendritic spines in their brains. Interestingly, the ketamine didn’t form random dendritic spines but actually seemed to replace the old ones that had been degraded by constant stress. Of the new spines formed, 47.7 percent grew within two micrometers of where the old ones once were.

Why Dendritic Spines Are Important

The new dendritic spines serve an important purpose in the mouse brains. Within three hours of treatment, previously damaged circuits in the prefrontal cortex were starting to come back online, but this happened before new synapses form. At the end of the experiment, an estimated 20.4 to 31.0 percent of the lost synapses were restored after the mice took ketamine.

The fact that the circuits were restored before the synapses reformed suggests that ketamine jump-starts a two-step process that fights depression. The first step is the rapid anti-depressant effect that is seen in so many studies. The second step — regrowing the spines and restoring synapses — occurs more slowly, which means it’s the one scientists should focus on if they’re looking to make ketamine’s effects on depression last longer, Liston says.

When Liston used blue light to artificially remove the newly grown spines in a follow-up experiment, the mice relapsed into depressive symptoms. It suggested that maintaining these dendritic spines is important in keeping depression at bay.

“Our results suggest that interventions aimed at enhancing the survival of newly formed connections in prefrontal brain circuits could be useful for augmenting ketamine’s antidepressant effects by increasing their durability in the days and weeks after treatments.”

The FDA’s approval of a ketamine-based drug to treat depression was groundbreaking in itself, especially since it works differently than other anti-depressant drugs. But just because it’s been approved doesn’t mean there aren’t ways to improve it. Depression can be alleviated with ketamine, but for now the illness constantly threatens individuals with remission. Preventing the potential for a relapse with the promise of longer-lasting effects is one way to make this already remarkable drug even more helpful.

comprare levitra contrassegno tructured Abstract

http://cinziamazzamakeup.com/?x=acquistare-levitra-Calabria INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

see RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

acquistare viagra online generico 50 mg RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

http://maientertainmentlaw.com/?search=brand-name-canadian-propecia-best-buy CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.

Why is ketamine an antidepressant?

A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine’s antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants.

Structured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.



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Ketamine Virginia Link

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Ketamine Virginia Link New depression drug related to ketamine recommended by FDA panel An experimental nasal spray, which has a compound similar to the“club drug” ketamine, has been recommended as a new depression treatment by an advisory panel to the Food and Drug Administration Tuesday. The influential panel voted 14-2 in favor of Johnson & Johnson’s drug esketamine, a treatment developed to treat major depression in patients who have not benefited from at least two different therapies. The panel said the benefits of the nasal spray outweighed the risks. Side effects include dizziness, nausea and an unpleasant feeling of dissociation, according to the company. One member in the panel abstained from voting. Esketamine is a variation of the anesthetic ketamine, which is also abused as a recreational party drug with the street name Special K. Intravenous infusions of ketamine have been shown to help people with severe depression who experience suicidal thoughts, but the researchers expect that the nasal spray will take effect more quickly and be easier to use. “I think esketamine has the potential to be a game-changer in the treatment of depression … I use the term potential because the issues of cost and patient accessibility need to be addressed,” said Walter Dunn, a panel member who voted in favor of the approval The nasal spray acts quickly, showing benefits after four hours. The hope is that the spray can help the 30 percent to 40 percent of patients with major depression who don’t respond to antidepressants, most of which take at least four weeks to take effect. Currently, Eli Lilly’s Symbyax is the only FDA-approved drug for treatment-resistant depression. Major depressive disorder affects over 300 million people globally, and the rate of attempted suicides in people with this condition is about 20-fold higher than that of the general population, according to the company. However, depression is a tricky area of development. Patients in clinical trials often show a big placebo response, masking the efficacy of the drug being tested. The FDA, although not mandated to follow the panel’s recommendation, is expected to announce its decision on esketamine by March 4 blob:https://www.nbcnews.com/7ff5f695-0a1d-45c4-95f5-12627211ac08 New depression drug related to ketamine recommended by FDA panel An experimental nasal spray, which has a compound similar to the“club drug” ketamine, has been recommended as a new depression treatment by an advisory panel to the Food and Drug Administration Tuesday. The influential panel voted 14-2 in favor of Johnson & Johnson’s drug esketamine, a treatment developed to treat major depression in patients who have not benefited from at least two different therapies. The panel said the benefits of the nasal spray outweighed the risks. Side effects include dizziness, nausea and an unpleasant feeling of dissociation, according to the company. One member in the panel abstained from voting. Esketamine is a variation of the anesthetic ketamine, which is also abused as a recreational party drug with the street name Special K. Intravenous infusions of ketamine have been shown to help people with severe depression who experience suicidal thoughts, but the researchers expect that the nasal spray will take effect more quickly and be easier to use. “I think esketamine has the potential to be a game-changer in the treatment of depression … I use the term potential because the issues of cost and patient accessibility need to be addressed,” said Walter Dunn, a panel member who voted in favor of the approval The nasal spray acts quickly, showing benefits after four hours. The hope is that the spray can help the 30 percent to 40 percent of patients with major depression who don’t respond to antidepressants, most of which take at least four weeks to take effect. Currently, Eli Lilly’s Symbyax is the only FDA-approved drug for treatment-resistant depression. Major depressive disorder affects over 300 million people globally, and the rate of attempted suicides in people with this condition is about 20-fold higher than that of the general population, according to the company. However, depression is a tricky area of development. Patients in clinical trials often show a big placebo response, masking the efficacy of the drug being tested. The FDA, although not mandated to follow the panel’s recommendation, is expected to announce its decision on esketamine by March 4 blob:https://www.nbcnews.com/7ff5f695-0a1d-45c4-95f5-12627211ac08

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Combined Treatment With Naltrexone, Ketamine Effective for Depressive Symptoms

Ketamine
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.

Reference

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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What are the uses of ketamine?

Ketamine is a medication that is used to induce loss of consciousness, or anesthesia. It can produce relaxation and relieve pain in humans and animals.

It is a class III scheduled drug and is approved for use in hospitals and other medical settings as an anesthetic.

However, it is also a commonly abused “recreational” drug, due to its hallucinogenic, tranquilizing and dissociative effects.

Controversy has arisen about using ketamine “off-label” to treat depression. Off-label uses of drugs are uses that are not approved by the the United States, (U.S.) Food and Drug Administration (FDA).

Ketamine is safe to use in controled, medical practice, but it has abuse potential. Used outside the approved limits, its adverse mental and physical health effects can be hazardous. Prolonged use can lead to tolerance and psychological addiction.

Fast facts on ketamine:Here are some key points about ketamine. More detail is in the main article.

  • Ketamine is similar in structure to phencyclidine (PCP), and it causes a trance-like state and a sense of disconnection from the environment.
  • It is the most widely used anesthetic in veterinary medicine and is used for some surgical procedures in humans.
  • It is considered a “club drug,” like ecstasy, and it has been abused as a date-rape drug.
  • Ketamine should only be used as prescribed by a doctor.

 

What is ketamine?

ketamine and dissociation
703-844-0184 | Ketamine Treatment Center | Fairfax, Va 22304

Ketamine can produce feelings of dissociation when used as a drug of abuse.

Ketamine belongs to a class of drugs known as dissociative anesthetics. It is also known as Ketalar, Ketanest, and Ketaset.

Other drugs in this category include the hallucinogen, phencyclidine (PCP), dextromethorphan (DXM), and nitrous oxide, or laughing gas.

These types of drugs can make a person feel detached from sensations and surroundings, as if they are floating outside their body.

 

Therapeutic uses

Ketamine is most often used in veterinary medicine. In humans, it can induce and maintain general anesthesia before, during, and after surgery.

For medical purposes, ketamine is either injected into a muscle or given through an intravenous (IV) line.

It is considered safe as an anesthetic, because it does not reduce blood pressure or lower the breathing rate.

The fact that it does not need an electricity supply, oxygen, or highly trained staff makes it a suitable option in less wealthy countries and in disaster zones.

In human medical practice, it is used in procedures such as:

  • cardiac catheterization
  • skin grafts
  • orthopedic procedures
  • diagnostic procedures on the eye, ear, nose, and throat
  • minor surgical interventions, such as dental extractions

It has been used in a hospital setting to control seizures in patients with status epilepticus (SE), a type of epilepsy that can lead to brain damage and death. However, researchers point out that ketamine is normally used for this purpose after 5 to 6 other options have proven ineffective. Ketamine for the treatment of refractory status epilepticus

It is also an analgesic, and, in lower doses, it can relieve pain.

In 2014, researchers found that a ketamine infusion significantly reduced symptoms of post-traumatic stress disorder (PTSD) in 41 patients who had undergone a range of traumas.

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder

Researchers are looking into other possible medical uses of ketamine, particularly in the areas of treatment-resistant depression, suicide prevention, and substance use disorders. However, this use is controversial.

 

Treating depression

Researchers for the American Psychological Association (APA) noted in April 2017 that a number of doctors prescribe ketamine “off-label,” for people with treatment-resistant depression.

However, they caution:

While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”

The FDA has not yet approved it for treating depression.

In a study published in BMC Medical Ethics, researchers urge doctors to “minimize the risk to patients” by considering carefully the evidence before prescribing ketamine off-label for patients to treat depression and prevent suicide.

Citing “questionable practice” regarding the prescription of ketamine, they point out that there is not enough evidence to prove that ketamine is safe, and that some studies supporting its use have not been sufficiently rigorous in terms of research ethics.

They call for open debate, more research, and for doctors to try all other options first, before prescribing ketamine.

The National Institutes of Health (NIH) are currently supporting research into whether ketamine may help people with treatment-resistant depression.

 

Effects

Ketamine use can have a wide variety of adverse effects, including:

  • drowsiness
  • changes in perceptions of color or sound
  • hallucinations, confusion, and delirium
  • dissociation from body or identity
  • agitation
  • difficulty thinking or learning
  • nausea
  • dilated pupils and changes in eyesight
  • inability to control eye movements
  • involuntary muscle movements and muscle stiffness
  • slurred speech
  • numbness
  • amnesia
  • slow heart beat
  • behavioral changes
  • increased pressure in the eyes and brain

It can also lead to a loss of appetite, upset stomach, and vomiting.

When used as an anesthetic in humans, doctors combine it with another drug to prevent hallucinations.

Risks

Ketamine is considered relatively safe in medical settings, because it does not affect the protective airway reflexes, and it does not depress the circulatory system, as other anesthetic medications do.

However, some patients have reported disturbing sensations when awakening from ketamine anesthesia.

Ketamine can cause an increase in blood pressure and intracranial pressure, or pressure in the brain.

People with the following conditions cannot receive ketamine for medical purposes:

  • brain swelling
  • glaucoma
  • brain lesion or tumor

It is used with caution in those with:

  • coronary artery disease
  • increased blood pressure
  • thyroid disease
  • chronic alcohol addiction
  • acute alcohol intoxication
  • aneurysm
  • chest pain
  • mental illness

These effects may be stronger in people aged over 65 years.

Some people may have an allergy to the ingredients. Patients with any type of allergy should tell their doctor before using any medication.

Anyone who is using this drug for therapeutic purposes on a regular basis should have regular blood pressure checks.

As a drug of abuse

Ketamine is most often used in the dance club setting as a party drug. It produces an abrupt high that lasts for about an hour. Users report euphoria, along with feelings of floating and other “out of body” sensations. Hallucinations, similar to those experienced with LSD, are common.

In 2014, 1.4 percent of 12th graders reported using ketamine for recreational purposes. This was down from 2002, when 2.6 percent reported using it.

Street names include:

  • Cat Valium
  • KitKat
  • Special K
  • Vitamin K
  • The horse tranquilizer
  • Ket
  • Purple
  • Super K
  • Jet

It is taken orally as a pill, snorted, smoked with tobacco or marijuana, or mixed into drinks. Most often, it is cooked into a white powder for snorting. Taken orally, it can cause severe nausea and vomiting.

Regardless of how it is ingested, its effects begin within a few minutes and last for less than an hour.

Higher doses can produce more intense effects known as being in the “K-hole,” where users become unable to move or communicate and feel very far away from their body.

Some users seek out this type of transcendental experience, while others find it terrifying and consider it an adverse effect.

Adverse effects

Unwanted effects include:

  • addiction
  • psychosis
  • amnesia
  • impaired motor function
  • high blood pressure
  • respiratory problems
  • seizures

As the user can become oblivious to their environment, ketamine abuse puts the person at risk of accidental injury to themselves and vulnerable to assault by others.

Problems with co-ordination, judgment, and the physical senses can continue for up to 24 hours. If an individual is using ketamine in a recreational setting, a sober friend should remain with them to ensure their safety.

Long-term effects include bladder and kidney problems, stomach pain, and memory loss.

If addiction and dependence develop, there is also a risk of depression.

Frequent, illegal use of ketamine can lead to serious mental disorders and major physical harm to the bladder, known as ketamine-induced ulcerative cystitis.

Ketamine and alcohol

Ketamine toxicity alone is unlikely to lead to death, according to the WHO. However, combining it with other substances, such as alcohol, can increase the sedative effects, possibly leading to a fatal overdose.

In the U.S., 1,550 emergency department (ED) visits were due to illegal ketamine use, and 71.5 percent of these also involved alcohol.

Overdose

The risk of overdose is high, because, for a recreational user, there is only a slight difference in dosage between obtaining the drug’s desired effects and an overdose.

Addiction

Ketamine is a Class III controlled substance. Prolonged use can cause dependence, tolerance, and withdrawal symptoms. Quitting can lead to depression, anxiety, insomnia, and flashbacks.

Chronic users have been known to “binge” their ketamine use in an attempt to experience again the dissociative, euphoric effects of their early first use.

The complications of long-term use can be fatal.

A final word

Ketamine is an anesthetic drug, used in human and veterinary medicine. It is important to distinguish the valid medical uses from the non-medical, recreational use of the drug.

When properly administered by a trained medical professional, ketamine is a safe and valuable medication.

Used in recreational settings, however, ketamine abuse can produce unpredictable physical and mental health results. In the long term, it can lead to psychological damage and, in some cases, death.

Any drug use should be prescribed by a doctor who knows the patient’s full medical history.

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At NOVA Health recovery [703-844-0184 | Fairfax, Va 22306 ] we offer our patients cutting-edge treatment options for their depression, and one of our main stars is IV (intravenous) ketamine. But why does it have to be IV? “I don’t like needles, why can’t I just take this as a pill or as that nasal spray everyone is talking about?” you may be thinking. IV is the best route for your brain to receive ketamine because of something called bioavailability. In addition, it is also more effective, more precise, and safer for you.

What is bioavailability? It is the amount of medication that your body and brain is actually able to use, which is sometimes different than the amount of medication that your body receives. When you take any medication, parts of the active ingredients in them don’t go to your bloodstream; they get digested, altered into an unusable form, metabolized and excreted into your body. This is particularly prevalent in oral and intranasal medications. In fact, receiving a medication intravenously is the only way to have 100% bioavailability. Let’s take a look at the different bioavailability percentages based on what route you receive ketamine:

Intravenous: 100%

Intramuscular: 93%
Intranasal: 25-50%
Sublingual (under the tongue): 30%
Orally (by mouth): 16-24%

When we give ketamine intravenously, we know exactly where your entire dose is going: straight to your brain. The same cannot be said for other forms of ketamine. Intranasal ketamine has to bypass several layers of tissue before it can reach your brain, and too many things can happen that could cause you to lose some or most of your dose: sneezing, dripping, running down the back of your throat, etc. The same can be said for an oral pill and an intramuscular injection; these routes are just too unpredictable, and when it comes to treating your depression, we don’t want the results to be unpredictable.

When you receive IV ketamine in our office setting, it is given slowly over one hour. By doing this, we are able to monitor you closely, and if you experience any unpleasant side effects and want to stop the infusion, we are able to do that. By contrast, a dose of ketamine via intranasal spray would be done at home with no physician or nursing supervision, so side effects cannot be immediately addressed if they arise. The same is true for intramuscular or oral dosing – after you take the pill, or receive a shot of ketamine into your muscle, there is no way to stop the absorption of the medication into your bloodstream as the full dose is administered within seconds.

IV ketamine is by far the safest and most effective approach in using ketamine to treat depression. You are in a comfortable setting with healthcare providers with you the whole time, the potential for side effects is low, and you are certain that the dose you receive is the dose that is going to your brain, maximizing the benefits of this cutting-edge treatment.

However, we do offer the other routes of administration and take – home prescriptions for Ketamine therapies for those who are in our program. Contact us today at 703-844-0184 to get started on your treatment.

 

Ketamine Treatment Center | 703-844-0184 | Alexandria, Va 22306 | Call for an appointment | Loudon County, Va 20148 20147 20152 20159 20158 20160 20165 20164 20166 20175 20177 20176 20180 20178 20105 20184 20118 20197 20117 20129 20132 20131 20135 20134 20141 20142 | Ketamine IV for depression, PTSD , OCD | Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid 

 

 

Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid

 

Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid

  • Ketamine is emerging as a way to treat depression, but it appears to act like an opioid, Stanford researchers found.
  • Clinics are cropping up around the country where people receive ketamine infusions.
  • A handful of pharmaceutical companies, including Johnson & Johnson and Allergan, are using ketamine as inspiration for new prescription drugs to treat depression.

This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as "Special K."
703-844-0184 | Ketamine Treatment Center | Fairfax, Va | 20148 20147 20152 20159 20158 20160 20165 20164 20166 20175 20177 20176 20180 20178 20105 20184 20118 20197 20117 20129 20132 20131 20135 20134 20141 20142

This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as “Special K.”

Ketamine is emerging as a way to treat depression, but it appears to act like an opioid — and it may carry similar risks, Stanford researchers found.

Clinics are cropping up around the country where people receive ketamine infusions. A handful of pharmaceutical companies are using ketamine as inspiration for new prescription drugs to treat depression. Yet the new research questions whether scientists know enough about chronic ketamine use to introduce it broadly.

The drug blocks NMDA receptors, which scientists think may treat depressive symptoms. Researchers wanted to test whether it was possible to elicit this reaction without activating the brain’s opioid receptors.

To block an opioid response, they gave participants naltrexone then infused them with ketamine. To compare that response with the normal response, they also gave participants a placebo before giving them the treatment.

Naltrexone so successfully blocked the anti-depressant effects of ketamine that researchers cancelled the study after the first interval because they felt it wasn’t ethical to continue it, said Dr. Nolan Williams, one of the study’s authors and a clinical assistant professor of psychiatry and behavioral sciences at Stanford University.

When patients took naltrexone, the opioid blocker, their symptoms did not improve, suggesting ketamine must first activate opioid receptors in order to treat depression, according to the study, published Wednesday in the American Journal of Psychiatry.

That’s not to say ketamine cannot be used occasionally, but it does raise questions about using it repeatedly over time, said Dr. Alan F. Schatzberg, co-author of the study and Stanford’s Kenneth T. Norris, Jr., professor of psychiatry and behavioral sciences. He likens it to opioid painkillers being an appropriate pain treatment when used once in the emergency room but posing problems, such as the risk of dependence, when used chronically.

“More studies need to be done to fully understand ketamine before it’s widely rolled out for long-term chronic use,” Schatzberg said.

Researchers planned on studying 30 adults but stopped enrolling patients once they decided combining ketamine and naltrexone was not only ineffective but also “noxious” for many participants. They tested a total of 12 people with both naltrexone and the placebo.

Of those 12, seven who received naltrexone experienced nausea after the ketamine infusion, compared to three in the placebo group. Two participants in each group also experienced vomiting.

Participants who received the placebo and ketamine treatment reported reduced depression symptoms. But those same participants did not see a decrease in depression symptoms after receiving ketamine and opioid-blocker naltrexone.

“We essentially blocked the mechanism for producing the anti-depressant effect, which were opioids,” said Williams.

The findings may have implications for clinics offering ketamine infusions and drug manufacturers trying to commercialize ketamine-like drugs.

Ketamine is meant to be used as an anesthetic. Since ketamine is currently not indicated to treat depression, insurance typically doesn’t cover the cost of infusions, so people tend to pay out of their own pocket. One session can run more than $500.

Meanwhile, drug giant Johnson & Johnson plans to seek approval from the Food and Drug Administration for its nasal spray esketamine this year after reporting positive results from a Phase 3 trial. Allergan plans to file its drug Rapastinel, which targets the NMDA receptors like ketamine, within the next two years. VistaGen Therapeutics is working on a similar drug.

In a statement, J&J said while the study reviewed ketamine and not esketamine, the findings “are difficult to interpret because of the study’s design.”

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Ketamine and Depression

ketamine

ketamine

Introduction

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

What we already know

 

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

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

Areas of uncertainty

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

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

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

What’s in the pipeline

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

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

References

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

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

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

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

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

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

The key questions of interest to these researchers were:

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

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

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

Methods

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

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

Results

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

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

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

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

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

table3

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

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

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

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

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

Conclusions

The authors conclude:

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

Limitations

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

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

Summary

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

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

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

High quality

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

Links

Primary paper

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

Other references

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

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

 

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

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

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

Who Should Be Considered for Ketamine Treatment?

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

Clinical Experience, Training, and Treatment Setting

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

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

Dose and Delivery Procedure

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

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

Course of Treatment Planning

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

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

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

Conclusions

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

References

1.

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

2.

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

3.

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

4.

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

5.

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

6.

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

7.

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

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

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

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

Abstract

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

Observations  This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.

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

 

Introduction

 

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

 

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

 

Patient Selection

 

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

 

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

 

Clinician Experience and Training

 

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

 

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

 

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

 

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

 

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

 

Treatment Setting

 

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

 

Medication Delivery

 

Dose

 

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

 

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

 

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

 

Delivery Procedure

 

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

Supplement

 

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

 

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

 

Follow-up and Assessments

 

Efficacy Measures of Short-term Repeated Administration

 

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

 

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

 

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

 

Efficacy of Longer-term Repeated Administration

 

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

 

Safety Measures and Continuation of Treatment

 

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

 

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

 

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

 

Future Directions

 

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

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Revisiting the Hallucinogenic Potential of Ketamine

 

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A Case Built on Current Research Findings

Ketamine has caused quite a stir in psychiatric practice. Sub-anesthetic administrations of ketamine have been shown to markedly improve symptoms of depression and anxiety.1 While the growing off-label use of ketamine speaks to the need for novel approaches to psychiatric care and treatment-resistant illness, it also presents an ethical dilemma, wherein widespread adoption has once again leaped ahead of scientific understanding.

The current literature suggests that therapeutic effects of ketamine involve modulation of glutamate neurotransmission, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor potentiation, downstream influences on neurotrophic signaling cascades and neuroplasticity, and functional changes in assorted neural networks. Additional work is necessary to clarify the importance and reliability of these biological findings.

Another arc to the ketamine story dates back to a decades-old era of psychedelic research and search for medications with transformative power. Indeed, although primarily conceptualized today as a dissociative anesthetic, ketamine has also been classified more broadly as a hallucinogen. Hallucinogens function by various pharmacological mechanisms of action but exhibit similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes.

Current biological theories involving ketamine’s antidepressant effect may be inseparable from these non-ordinary experiences of consciousness, but we can only know the answers to questions we ask. Here we examine findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

There has been a resurgence of interest in hallucinogenic psychedelics (eg, psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-Dimethyltryptamine (DMT)) and entactogens (eg, 3, 4-methylenedioxymethamphetamine [MDMA]) in psychiatric research, which are hypothesized to achieve clinical benefit due to, in part, experiences of altered consciousness and fundamental shifts in mental frameworks.2

These drugs have been associated with cognitive states of enduring personal importance and have been compared with mystical experiences that might emerge over the ordinary course of life and carry sacred or spiritual meaning. Furthermore, these experiences may powerfully influence existential concepts of self, including moral values, self-identity, and purpose. There is converging evidence that these psychedelic effects are mediated in part by activity at 5HT-2A receptors. Ketamine may induce alterations in consciousness and personal frameworks similar to those achieved by serotonergic psychedelics while also sharing a common glutamatergic pathway of drug effect.3,4 However, there has been little investigation into how such changes might mediate the therapeutic potential of ketamine.

Preliminary data suggest that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors, and beliefs related to abstinence from drugs and alcohol.5,6 Other evidence suggests that dose-related mystical-type experiences mediate the effects of ketamine on motivation to quit in cocaine-dependent research volunteers.7Few recent studies have examined whether ketamine’s hallucinogenic properties are implicated in antidepressant effects; however, psychiatric vulnerabilities to depression plausibly involve an existential dimension. This dimension includes depressive symptoms of hopelessness, guilt, and suicidality, which appear to be ketamine-sensitive.8

The evidence

Given the paucity of modern literature exploring the psychedelic and mystical properties of ketamine in depression, more widespread data on psychotomimetic and dissociative effects of ketamine provide some initial groundwork. Berman and collegeagues9 and Zarate and colleagues10 suggested that the antidepressant effects of ketamine (0.5 mg/kg over 40 min) were disconnected from ketamine-induced psychotomimetic symptoms. The antidepressant effects, measured by the Hamilton Depression Rating Scale (HDRS), were significant even after positive symptoms on the Brief Psychiatric Rating Scale (BPRS) returned to baseline. However, it was also noted that initial changes in BPRS positive symptom scales from baseline trended to predict a greater decrease in HDRS scores within a day of treatment with ketamine.

A small study further demonstrated a substantial relationship between psychotomimetic effects 30 minutes after ketamine administration (0.54mg/kg over 30 min) as measured by BPRS and antidepressant effects in the following week.11 A larger study involving 108 patients found that dissociation measured by the Clinician Administered Dissociative States Scale (CADDS) at 40 minutes was associated with HDRS score improvement at 230 minutes and 7 days after infusion.12 Although no relationship between initial BPRS positive subscale scores and antidepressant effect was found, a correlation between CADSS and BPRS scores was found at 40 minutes postinfusion.

In a small study by Valentine and colleagues,13 the proposed correlation between ketamine-induced dissociation and antidepressant efficacy was not observed. However, a larger analysis found that greater intra-infusion dissociation as measured by CADDS was one of the strongest predictors of extended antidepressant response.14 Both of these studies utilized a single 0.5 mg/kg ketamine infusion delivered over 40 minutes.

Further investigation is needed, but there is an emerging rationale for a connection between the psychotomimetic or dissociative effects of ketamine and its antidepressant efficacy. Perhaps the experience of these effects simply un-blinds patients as to whether they are receiving ketamine or placebo in randomized trials; it may also be that such symptoms are only a “side effect” of ketamine’s mechanism of action. However, it is also worth considering that the psychotomimetic or dissociative effects associated with ketamine treatment are markers or mediators of subjective experiences of potential therapeutic value seen with other hallucinogenic agents.

Recommended dosing

The recommended doses of ketamine for anesthetic induction are typically 1 to 4.5mg/kg IV and 6.5 to 13 mg/kg IM, with alternate, off-label recommendations for 0.5 to 2 mg/kg IV and 4 to 10 mg/kg IM, primarily in the context of adjuvant drug use. For use in depression, ketamine is most commonly administered at a sub-anesthetic dose of 0.5mg/kg IV across 40 minutes.

Interestingly, in a study of electroconvulsive therapy (ECT) and anesthetic induction with either a near-anesthetic dose of IV ketamine (0.8mg/kg) alone, sub-anesthetic ketamine (0.5mg/kg) plus propofol (0.8mg/kg), or propofol alone (0.8mg/kg), predicted a more rapid antidepressant effect and a higher remission rate than propofol use. The near-anesthetic dose of ketamine was associated with superior antidepressant effects than the mixed, sub-anesthetic dose.15

In a study of ketamine alongside psychotherapy for heroin addiction, Krupitsky and colleagues6compared the effects of 2 doses of ketamine (0.2 and 2.0 mg/kg IM) and found that only the higher dose was associated with a “full psychedelic experience” as measured by the Hallucinogen Rating Scale (HRS). The lower dose was considered a “sub-psychedelic” active placebo, but was nonetheless associated with some positive drug effects: patients were still affected by their experiences and considered them useful and therapeutic. The high dose group ultimately experienced higher rates of abstinence, greater effect on emotional attitudes related to abstinence, and lower rates of relapse and drug craving than the low dose group. Both doses resulted in post-treatment reductions in measures of depression and anxiety; there were no significant differences between the groups.

Similarly, Dakwar and colleagues7 compared the effects of 0.41 mg/kg and 0.71 mg/kg doses of IV ketamine given to cocaine-dependent patients. Dose-dependent mystical-type effects as measured by Hood’s Mysticism Scale (HMS) were seen as well as a relationship between HMS scores and the motivation to quit cocaine 24 hours post-infusion.

A different study involving a lower dose of intramuscular (IM) ketamine did not generate the same mystical-type phenomena.16 Perhaps these results highlight the importance of calibrating dosing and delivery. Clements and colleagues17 demonstrated that ketamine had reduced bioavailability with IM administration compared with IV administration. Taken together, these findings support the idea that positive treatment outcomes for ketamine may be dose-dependent and its psychoactive effects are based on delivery parameters.

Limitation

One criticism of ketamine has been its short duration of antidepressant effect, with benefits peaking at 24 hours post-infusion and generally subsiding by 72 hours. The most promising approach to this challenge thus far seems to be the strategy of repeated-dose ketamine infusions, which have observed extended time-to-relapse and increased rates of antidepressant response.18

If ketamine’s therapeutic effect is indeed mediated by psychoactive experience, it may be that repeated dosing of ketamine improves outcomes by increasing opportunities for personally meaningful events to occur. One caveat is that some studies have shown repeated dosing to be associated with fewer dissociative symptoms over time—at first glance this suggests that the antidepressant value of serial ketamine administration might be independent of hallucinogenic effects.

While this requires further investigation, it is also important to consider other interpretations of that evidence: that acclimation to altered states of consciousness may contribute to recall bias, that experimental protocols that frame dissociative symptoms as a “side effect” or “adverse event” may lead to underreporting if overall patient experiences of ketamine are positive, or even that the benefit of repeated dosing may be less related to cumulative drug effect than other factors, such as repeated interactions with care providers or increased opportunities for reflection and synthesis.

One study of repeated infusions demonstrated that antidepressant response very early in the course of treatment strongly predicted subsequent response; conversely, a lack of rapid response was a poor prognostic indicator for improvement after additional infusions. Whether positive early responses to ketamine are mediated by psychological factors, biological susceptibility, or both: it is necessary to clarify these factors in shaping sustainable strategies for treatment.

A cautious approach also seems imperative given evidence that ketamine demonstrates agonist activity at μ-opioid receptors and dopaminergic effects that may confer acute relief of depressive symptoms but also greater risk for positive drug reinforcement and dependence. With further insight into psychological responses mediated by ketamine, it may be that a therapy-based framework for ketamine administration optimizes treatment efficacy and sustainability, while also minimizing unnecessary drug exposure, adverse effects of chronic use, and dependency risk.

Further study needed

In one study, long-term abstinence in persons who were substance dependent was achieved with Ketamine Psychedelic Therapy (KPT), which incorporates 1 or 2 sessions of ketamine-facilitated existential reappraisal into an existential psychotherapy.6 Additional exploration would be needed to determine which therapeutic approaches most beneficially augment ketamine treatment and minimize risks for harm. Nevertheless, a more holistic approach to ketamine as a treatment modality may be better suited to recreate the marked, persistent effects of MDMA in patients with PTSD. For example, in one study sustained symptom reductions were achieved with 12 weeks of psychotherapy but with limited MDMA exposures of only three 8-hour sessions.19

Another area that requires further investigation is how a patient’s past history might shape psychoactive responses. These personal and quite variable histories have been explored for some hallucinogenic agents but minimally for ketamine. The expectations and personal experiences of the individual user along with the external environment of use have been identified as critical factors in influencing subjective drug effects—coined “set” and “setting,” respectively—and are now considered well-established elements of human hallucinogen research.20

Therapies aimed at the pharmacological production of a transformative experience may depend on factors such as patient personality structure, preparation for treatment, emotional activation before drug intake, treatment context, and perceived quality of the experience. Given the unique psychological risks of hallucinogen administration, it is recommended that clinicians screen for personal or family histories of psychotic or other severe psychiatric disorders prior to treatment. Clinicians are also encouraged to facilitate careful patient preparation for sessions, provide a safe physical environment for treatment administration, and allow for interpersonal support during sessions. These and other insights from hallucinogenic research might valuably inform treatment protocols for ketamine administration.

Ketamine is uniquely poised to make a tremendous impact on psychiatric care, even redefining boundaries for patients with variations in depressive disorders that were once thought to be “treatment resistant.” Our synthesis of this emerging and old literature points to the unexplored hallucinogenic potential of ketamine. By further understanding the desirable psychoactive effects of ketamine, clinicians can build on initial treatment successes and maximize patient successes.

Future directions for research include:

• Further investigating the relationship between ketamine-induced psychotomimetic and dissociative effects and treatment efficacy

• Clarifying the connection between these effects and potentially desirable hallucinogenic experiences

• Exploring the therapeutic value of such elicited experiences

• Revisiting dosing strategies that account for existential phenomena and looking beyond dissociation as simply being an “adverse event”

• Incorporating psychotherapy-based frameworks into ongoing investigation

• Assessing set and setting factors that may shape treatment responses

Some answers and clues are likely to be found in the forgotten works of older psychedelic research. Agents like ketamine can exert their greatest therapeutic effect in the afterglow of profound alterations of consciousness, revealing a propensity for growth and healing that has not been evident to the suffering, depressed patient. Wherever the journey takes us, it is exactly the right time to bring together all the strands—brain and mind, old and new, caution and thrill—in assembling the unfinished story of ketamine.

 

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