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!
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.
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:
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.
Environmental influences: Negative life events such as trauma, negligence, or abuse increase the risk of developing depression.
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).
Traumatic Brain Injury: Definition, Classification, and Management
We hear a lot about traumatic brain injury (TBI) nowadays: among NFL players (as in the movie ‘Concussion’), and as a signature diagnosis among recent combat veterans. What doesn’t get as much press coverage is the impact of TBI on those suffering from addiction. Having an alcohol or other substance use disorder greatly increases the risk of TBI. But what is TBI? How do I diagnose it? How does it manifest? How do I manage it?
Defining TBI Although there is no universally accepted definition for TBI, recently updated guidelines from the Department of Veterans Affairs (VA/DoD Clinical Practice Guideline for the Management of Concussion-mild Traumatic Brain Injury, 2016; https://tinyurl.com/y8e6owdx) state that a TBI is an injury to the brain caused by an external force accompanied by one of several clinical signs following the event). These signs can be an intracranial lesion, loss of consciousness, amnesia, confusion, slowed thinking, muscle weakness, sensory loss, or another neurological deficit. The severity of a TBI (mild, moderate, or severe) is determined by the symptoms immediately following the injury (see the VA TBI severity table below). If the patient meets different ratings for the different criteria, go with the more severe rating. The lay term “concussion” equates to a mild TBI. In addition to the neurological symptoms, patients may experience cognitive problems affecting their attention, memory, processing speed, and executive function. Mental health effects include irritability, impulsivity, depression, and anxiety. However, these symptoms can be an effect of the TBI or part of a comorbid, major depressive disorder, posttraumatic stress disorder (PTSD), or substance use disorder.
Assessment and treatment But what symptoms should I really be concerned about? For any TBI that is associated with progressively declining neurological function or worsening headache, pupil asymmetry, seizures, intractable vomiting, ongoing disorientation or neurological deficit, slurred speech, or new bizarre behavior, you should immediately refer for emergency evaluation.
The good news is that the vast majority of mild TBI cases resolve without any intervention. It’s important for the physician to provide education and reassurance to the patient and family. Any interventions should be tailored to the specific symptoms while reinforcing good sleep hygiene, relaxation techniques, and limiting use of caffeine, tobacco, and alcohol. Return to normal functioning at work or school should be encouraged in a gradual, monitored fashion. Patients with a TBI who report ongoing symptoms need appropriate referral and a comprehensive treatment plan (Silver JM et al, Textbook of Traumatic Brain Injury, American Psychiatric Publishing, Inc; 2nd ed;2011).
Cognitive rehabilitation therapy (CRT) You may have heard of cognitive rehabilitation therapy (CRT) as a treatment for TBI. But what exactly does it involve? And does it work? After a TBI there may be functional deficits that are both physical and mental in nature. CRT is a therapeutic process structured to improve the patient’s functioning in their daily lives. Patients are first guided through recognizing their strengths, weaknesses, and what deficits they want to improve. Then techniques are relearned when possible (solve the problem), or compensatory strategies are identified (work around the problem). The last step is to incorporate these relearned or new skills into daily life. This process can be applied to both physical and cognitive deficits that arise from a TBI.
CRT sessions should be tailored to the individual but most incorporate memory compensation techniques. Such techniques include having the patient write down at each session what was important to them, then reviewing their notes and memory of what was said during the next session. This method not only increases their participation in the therapy sessions but teaches them how to use the memory compensation techniques in their daily lives.
The evidence for CRT after stroke and moderate to severe TBI has long been established, showing improvement in the domains of memory, attention, and communication (Cicerone KD et al, Arch Phys Med Rehabil 2005;86(8):1681-1692). However, for mild TBI, CRT remains more controversial as there isn’t strong evidence for improved functional outcomes. The 2016 VA clinical guidelines recommend short-term CRT for moderate to severe TBI and discourages prolonged treatment courses without measurable improvements.
Sometimes the most concerning symptoms the patient will come to us for are the cognitive deficits and they may press for neuropsychological (NP) testing early. However, NP testing should not be done in the first 30 days. Most cognitive deficits of mild TBI will improve within this time period. And if the problems last longer than 30 days, NP testing may be helpful. Whenever referring for NP testing, be specific in why you are making the request. A targeted referral allows the NP examiner to choose the right tests to provide the most useful information.
Pharmacologic treatment When considering medication treatment for symptoms following a TBI, there are several general guidelines to follow (Silver JM et al, Neurology 2006;67(5):748-755.2011). Again, most symptoms of a mild TBI will abate within a month, so watchful waiting and reassurance are important. Symptom improvement may continue throughout the first year as the brain continues to heal, so be sure to reassess the need for the medication intervention. Many times, the neuropsychiatric symptoms after a TBI can be complicated by concurrent major depressive disorder, PTSD, or a substance use disorder. Untreated depression can be the root cause of cognitive problems, irritability, sleep disturbance, fatigue, and headache. Be sure to perform a thorough psychiatric assessment so that you can tailor the treatment plan accordingly. Target specific symptoms or concurrent conditions with your medication choices. After a TBI the brain can be more susceptible to side effects of medications, underscoring the importance of “starting low, and going slow.”
Here are a few specific medication recommendations to target neuropsychiatric symptoms (Silver JM et al, 2011). For improving processing speed, methylphenidate has the most evidence. Donepezil and rivastigmine also may have some utility for treating memory impairment. When targeting depression and anxiety, SSRIs are first-line and choose a specific SSRI based on side effect profile and limiting medication interactions (sertraline, citalopram, and escitalopram are favorable choices) (Salter DL et al, J Head Trauma Rehabil 2016;31(4):E21-32). Be cautious with bupropion due to increased seizure risk. Caution is also advised with typical antipsychotics as they may inhibit neuronal recovery, and also benzodiazepines due to the memory impairment effects. For controlling mania or irritability, valproate is preferred due to its anti-seizure effect as well as having less cognitive side effects in long term treatment than other mood stabilizers (carbamazepine or lithium). Atypical antipsychotics may also be helpful in controlling irritability especially when combined with psychosis, and are preferred over typical antipsychotics. More recent research shows beneficial effects of amantadine in treating aggression from TBI even 6 months post-injury and more studies are evaluating its use in the acute phase after a severe TBI (Hammond FM et al, J Head Trauma Rehabil. 2017;32(5):308-318).
CATR Verdict: When treating patients with TBI, always remember that the brain has a great capacity for plasticity and recovery. Encourage patients to see their treatment as a process and journey. Take care to evaluate for comorbid mental health disorders, and handle accordingly. Those with substance use disorders, whether existing pre-TBI or newly occurring, should be encouraged to enter into treatment promptly. With the right combination of cognitive rehabilitation, pharmacotherapy, and a good therapeutic alliance, your patients can make great strides in recovery after a TBI.
Alcohol use and TBI are closely related. Up to two-thirds of people with TBI have a history of alcohol abuse or risky drinking. Between 30-50% of people with TBI were injured while they were drunk and about one-third were under the influence of other drugs. Around half of those who have a TBI cut down on their drinking or stop altogether after injury, but some people with TBI continue to drink heavily, which increases their risk of having negative outcomes.
After TBI, many people notice their brains are more sensitive to alcohol. Drinking increases your chances of getting injured again, makes cognitive (thinking) problems worse, and increases your chances of having emotional problems such as depression. In addition, drinking can reduce brain injury recovery. For these reasons, staying away from alcohol is strongly recommended to avoid further injury to the brain and to promote as much healing as possible.
Facts about TBI and alcohol
Alcohol and brain injury recovery
Recovery from brain injury continues for much longer than we used to think possible. Many people notice improvements for many years after injury.
Alcohol slows down or stops brain injury recovery.
Not drinking is one way to give the brain the best chance to heal.
People’s lives often continue to improve many years after brain injury. Not drinking will increase the chance of improvement.
Alcohol, brain injury and seizures
Traumatic brain injury puts survivors at risk for developing seizures (epilepsy).
Alcohol lowers the seizure threshold and may trigger seizures.
Not drinking can reduce the risk of developing seizures.
Alcohol and the risk of having another brain injury
After a brain injury, survivors are at higher risk (3 to 8 times higher) of having another brain injury.
Drinking alcohol puts survivors at an even higher risk of having a second brain injury. This may be because both brain injury and alcohol can affect coordination and balance.
Not drinking can reduce the risk of having another brain injury.
Alcohol and mental functioning
Alcohol and brain injury have similar negative effects on mental abilities like memory and thinking flexibility.
Alcohol magnifies some of the cognitive problems caused by brain injury.
Alcohol may affect brain injury survivors more than it did before their injury.
The negative mental effects of alcohol can last from days to weeks after drinking stops.
Not drinking is one way to keep your mental abilities at their best and stay sharp and focused.
Alcohol and mood
Depression is about 8 times more common in the first year after TBI than in the general population.
Alcohol is a “depressant” drug, and using alcohol can cause or worsen depression.
Alcohol can reduce the effectiveness of anti-depressant medications. People who are taking antidepressants should not drink alcohol.
One way to improve problems with sadness or depression after TBI is to stop or cut down on the use of alcohol.
Alcohol and sexuality
Lowered desire is the most common effect of TBI on sexuality.
Alcohol reduces testosterone production in males.
Alcohol reduces sexual performance (erection and ejaculation) in men.
Alcohol reduces sexual satisfaction in men and women.
Avoiding alcohol improves sexual ability and activity in men and women.
How much alcohol is “safe” after TBI?
After TBI the brain is more sensitive to alcohol. This means that even one or two drinks may not be safe, especially when you need to do things that require balance, coordination and quick reactions, such as walking on uneven surfaces, riding a bicycle or driving a car. The fact is, there is no safe level of alcohol use after TBI.
Alcohol and medications
Alcohol is especially dangerous after TBI if you are taking certain prescription medications. Alcohol can make some medicines less effective and can greatly increase the effects of others, potentially leading to overdose and death. Using alcohol along with anti-anxiety medications or pain medications can be highly dangerous because of the possible multiplying effect.
What about using other drugs?
Alcohol is a drug. Almost everything mentioned above about alcohol applies equally to other drugs. If your drug of choice is something other than alcohol-such as marijuana, cocaine, methamphetamine or prescription drugs, anti-anxiety medications (benzodiazepines such as Ativan, Valium, or Xanax), or pain medication (opioids like Percocet, Oxycodone or Oxycontin)-many of the same principles apply. In addition, use of illegal drugs or misuse of prescription drugs can lead to legal problems.
If you use multiple drugs like alcohol and marijuana, or alcohol and pain pills, there is a higher risk of addiction and overdose. Using alcohol and pain medications together, or alcohol and anti-anxiety medications, has killed many people. Contact your doctor if you are drinking and using prescription drugs.
What should you do?
The stakes are higher when people choose to use alcohol after having a TBI. Some people continue drinking after a TBI and don’t have any desire to change that behavior. Others know they probably should stop or reduce alcohol use, but don’t know how or have tried in the past and not been successful.
There are many ways to stop using alcohol or other drugs and many ways to reduce the potential for harm. The great majority of people who have stopped having alcohol problems did it on their own. They got no professional help or counseling and did not use Alcoholics Anonymous (AA). Don’t underestimate your ability to change if you want to.
There are many ways to change, cut down or stop drinking
The key ingredients to changing your drinking are: (1) find people who will support your efforts to change your drinking; (2) set a specific goal; (3) make clear how you will meet your goal; (4) identify situations or emotions that can trigger drinking, and figure out ways to cope with those triggers ahead of time; and (5) find ways to reward yourself for sticking to your plan and meeting your goals.
If you have questions or concerns about your drinking, there are many ways to get information or help:
Substance Abuse and Mental Health Services Administration (SAMHSA) is a federal program that can help you find a treatment facility wherever you live (http://findtreatment.samhsa.gov/; 800-662-4357).
Private treatment: look in the Yellow Pages under substance abuse, chemical dependency counselor, or addiction treatment.
Reduce the harm from drinking
For those who don’t want to stop drinking, it is still possible to reduce some harm from drinking:
Eat food and drink water before you drink alcohol. This will help reduce the sharp spike in blood alcohol level that can cause nausea, vomiting, falls, blackouts and alcohol poisoning.
Plan your transportation so you don’t drink and drive: have a non-drinking designated driver; plan to spend the night where you are doing your drinking; or drink only at home.
To avoid dangerous peaks in blood alcohol concentrations, drink beer rather than hard liquor, or mix hard liquor with water instead of with sweet, carbonated beverages.
Sip your drinks slowly (no more than one per hour). Drinking too fast can make the pleasant feelings of alcohol go away.
Drinking in bars slows some people down because of the expense. However, be sure you do not drive after drinking.
Take vitamins B1 (thiamine), B12 and folate to reduce the chances of alcohol-related brain damage.
Keep your drinking to no more than two drinks per day. Or cut back on certain days of the week, such as weeknights.
Take a drinking “holiday” (days or weeks when you decide not to drink at all). This can remind you of some of the benefits of being sober.
How family members can help
No one can force another person to stop using alcohol or drugs, but you can have an influence. Attending Al Anon meetings can be a good source of support for a friend or family member of someone who abuses alcohol or drugs, and it can help promote change. Planning an “intervention” where family and friends confront the person may help.
A program called Community Reinforcement and Family Training (CRAFT) has been found to work best. CRAFT takes a more positive, motivational approach that helps loved ones make not drinking more rewarding for the person with the alcohol problem. Research has shown that alcoholics are more likely to go into treatment if their loved ones follow the CRAFT method. To learn about CRAFT, see the book Get Your Loved One Sober in the Resources section below, or find a counselor familiar with this approach.
Bombardier, C.H. & Turner, A. (2009). Alcohol and traumatic disability. In R. Frank & T. Elliott (Eds.), The Handbook of Rehabilitation Psychology, Second Edition (pp. 241-258). Washington, DC: American Psychological Association Press.
Corrigan, J., & Lamb-Hart, G. (2004). Alcohol, Other Drugs, and Brain Injury. Columbus, Ohio: Ohio Valley Center for Brain Injury Prevention and Rehabilitation, Ohio State University Dept. of Physical Medicine and Rehabilitation. (Available from the Brain Injury Association, http://www.biausa.org/LiteratureRetrieve.aspx?ID=43235. )
Meyers, R.J., & Wolfe, B.L. (2004). Get Your Loved One Sober: Alternatives to Nagging, Pleading, and Threatening. Center City, MN: Hazelden Publications.
On Tuesday (March 5), the U.S. Food and Drug Administration (FDA) approved a ketamine-like nasal spray for patients with depression who haven’t responded to other treatments.
But what makes this newly approved treatment so different?
The drug, called Spravato and made by Janssen Pharmaceuticals, contains the active ingredient esketamine. This substance has the same molecular formula as ketamine but a different chemical structure. (In other words, it contains the same type and number of elements but in a different configuration.) Ketamine is typically used as an anesthetic, but it’s also been used as an illicit party drug.
One reason experts are excited about the nasal spray is that its effects can be seen within several hours to days. Other antidepressants, meanwhile, can take weeks to start working
Antidepressants work by regrowing brain cells and the connections between them, and ketamine appears to have the same effects, said David Olson, an assistant professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. But, these effects likely start much sooner than with other antidepressants, he said.
Still, it’s not entirely clear how the drug works.
Ketamine-like drugs are “dirty”, meaning they likely hit a variety of targets in the brain, Olson told Live Science. “There are a lot of very interesting hypotheses out there, [and] many of them are probably partially valid.”
One idea is that ketamine treats depression by blocking a neurotransmitter called glutamate from binding to the NMDA receptor, and stopping signals from cascading across the brain, Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, told Live Science.
Glutamate is a chemical that brain cells use to send signals to other brain cells. But high levels of it can cause over-excitement in the brain, which can, in turn, damage brain cells.
A more controversial idea is that ketamine binds to opioid receptors, causing a release of naturally occurring opioids in the body. Schatzberg and his team published a small study on this last summer in which they gave patients with depression ketamine twice — once after receiving an opioid-blocking drug, and once after receiving a placebo in place of the opioid blocker. The two treatments took place about a month apart, and neither the participants nor the researchers knew whether patients received the opioid blocker or the placebo. The study found that the patients responded well to the ketamine treatment if they didn’t receive the opioid-blocking drug, but ketamine had no effect on those that did, suggesting an opioid-like role.
“My concern about this compound is that it is a disguised form of opiates,” said Dr. Mark George, a distinguished professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. While George said he is “overjoyed” for the prospect of a new treatment option, “I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.”
If this is the mechanism that ketamine acts through to treat depression, its effects won’t last and people might develop a tolerance to the drug, possibly even becoming addicted, George told Live Science. But if its antidepressant effects come from other mechanisms, such as blocking the NMDA receptor, then “that’s good,” he said.
Olson, however, said that he is less convinced by the opioid hypothesis and thinks more work needs to be done before ringing the alarm bells.
What’s more, the new drug will see limited use. The medication comes with a risk of sedation and dissociation, such as difficulty with judgment, attention and thinking. Because of that, the nasal spray was approved to be used only under a “restricted distribution system,” according to a statement from the FDA.
This means that only patients with severe depression who haven’t responded to at least two antidepressant treatments can receive the drug. In addition, the treatment is administered only in doctor’s offices, and patients must stay in the office and be monitored for several hours after receiving the treatment.
Ultimately, despite some potential problems with the newly approved drug, experts are hopeful it will come through strong.
“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases,” Olson said. “Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”
A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.
The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.
Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.
The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.
“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”
Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.
Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.
Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.
About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.
But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.
“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.
“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.
Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.
“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”
Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.
In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.
Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.
“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”
The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.
She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.
Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.
Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.
“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”
The fast-acting drug offers a new way to treat depression and fathom its origins. Recent approval of a nasal spray promises to expand access, but much remains unknown about long-term use and the potential for abuse.
t 32, Raquel Bennett was looking for a reason to live. She’d struggled with severe depression for more than a decade, trying multiple antidepressants and years of talk therapy. The treatment helped, but not enough to make it seem worth living with a debilitating mental illness, she says. “I was desperate.”
In 2002, following a friend’s suggestion, Bennett received an injection of ketamine, an anesthetic and psychedelic party drug also known as Special K. During her first ketamine trip, Bennett hallucinated that God inserted a giant golden key into her ear, turning on her brain. “It was as if I was living in a dark house and suddenly the lights came on,” she says. “Suddenly everything seemed illuminated.”
The drug lifted Bennett’s depression and dispelled her thoughts of suicide within minutes. The effect lasted for several months, and, she says, the respite saved her life. She was fascinated by the drug’s rapid effects and went on to earn a doctoral degree in psychology, writing her dissertation about ketamine. Today, she works at a clinic in Berkeley, California, that specializes in using ketamine to treat depression. “This medicine works differently and better than any other medication I’ve tried,” she says.
When Bennett experimented with ketamine, the notion of using a psychedelic rave drug for depression was still decidedly fringe. Since the first clinical trials in the early 2000s, however, dozens of studies have shown that a low dose of ketamine delivered via IV can relieve the symptoms of depression, including thoughts of suicide, within hours.
Even a low dose can have intense side effects, such as the sensation of being outside one’s body, vivid hallucinations, confusion and nausea. The antidepressant effects of ketamine typically don’t last more than a week or two. But the drug appears to work where no others have — in the roughly 30 percent of people with major depression who, like Bennett, don’t respond to other treatments. It also works fast, a major advantage for suicidal patients who can’t wait weeks for traditional antidepressants to kick in.
“When you prescribe Prozac, you have to convince people that it’s worth taking a medication for several weeks,” says John Krystal, a psychiatrist and neuroscientist at Yale University in New Haven, Connecticut. “With ketamine, patients may feel better that day, or by the next morning.”
The buzz around ketamine can drown out just how little is known about the drug. In the April 2017 JAMA Psychiatry, the American Psychiatric Association published an analysis of the evidence for ketamine treatment noting that there are few published data on the safety of repeated use, although studies of ketamine abusers — who typically use much higher doses — show that the drug can cause memory loss and bladder damage. Most clinical trials of the low dose used for depression have looked at only a single dose, following up on patients for just a week or two, so scientists don’t know if it’s safe to take the drug repeatedly over long periods. But that’s exactly what might be necessary to keep depression at bay.
The analysis also warned about ketamine’s well-established potential for abuse. Used recreationally, large doses of the drug are known to be addictive — there’s some evidence that ketamine can bind to opioid receptors, raising alarms that even low doses could lead to dependence.
Bennett has now been receiving regular ketamine injections for 17 years, with few negative side effects, she says. She doesn’t consider herself addicted to ketamine because she feels no desire to take it between scheduled appointments. But she does feel dependent on the drug, in the same way that a person with high blood pressure takes medication for hypertension, she says.
Still, she acknowledges what most clinicians and researchers contend: There simply aren’t enough data to know what the optimal dose for depression is, who is most likely to benefit from ketamine treatment and what long-term treatment should look like. “There’s a lot that we don’t know about how to use this tool,” Bennett says. “What’s the best dose? What’s the best route of administration? How frequently do you give ketamine treatment? What does maintenance look like? Is it OK to use this in an ongoing way?”
Despite the unknowns, pharmaceutical companies have been racing to bring the first ketamine-based antidepressant to market. In March, the US Food and Drug Administration approved a ketamine-derived nasal spray, esketamine, developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. Only two of Janssen’s five phase III trials had shown a benefit greater than taking a placebo. Still, in February an independent panel recommended FDA approval. That makes ketamine the first novel depression drug to hit the market in more than 50 years, notes Carlos Zarate Jr, a psychiatrist who studies mood disorder therapies at the National Institute of Mental Health.
Thousands of people are already flocking to private clinics like Bennett’s, which provide intravenous ketamine infusions. Because the drug was approved in the 1970s as an anesthetic, physicians can legally provide the drug as an “off-label” depression treatment. Many ketamine clinics have long waiting lists or are so swamped that they aren’t accepting new patients, and Janssen’s nasal spray could rapidly expand access to treatment.
But some researchers worry that the nasal spray won’t solve many of ketamine’s problems and could create new ones. Although the FDA is requiring that the nasal spray be administered only in a certified doctor’s office or clinic, esketamine is “every bit as habit forming as regular ketamine,” and will be difficult to keep out of the hands of abusers, says Scott Thompson, a neuroscientist at the University of Maryland and a coauthor with Zarate of a 2019 review on fast-acting antidepressants in the Annual Review of Pharmacology and Toxicology. A nasal spray can’t deliver as precise a dose as an IV infusion, Thompson notes. “If someone has got a cold, they’re not going to get the same dose.”
Scott Thompson of the University of Maryland discusses how ketamine is changing the landscape of the psychiatric treatment of severe depression.
CREDIT: VIDEO PRODUCED BY HUNNI MEDIA FOR KNOWABLE
In Thompson’s view, esketamine holds few advantages over generic ketamine, which costs less than a dollar per dose, although the IV infusions in private clinics often cost hundreds of dollars per visit. Janssen has indicated that each esketamine treatment will range from $590 to $885, not including the costs of administration and observation.
Zarate and others are still thrilled to see big pharma investing in ketamine, after decades of stalled efforts to find new psychiatric drugs. “As esketamine hits the market, venture capitalists will come up with better versions and move the field forward,” Zarate says. Several drug companies are now testing other ketamine-like compounds in hopes of developing drugs that have its potent antidepressant potential without its psychedelic and dissociative side effects.
Depression, fast and slow
In 2001, writer Andrew Solomon published a haunting description of the depression that derailed his early 30s: “If one imagines a soul of iron that weathers with grief and rusts with mild depression, then major depression is the startling collapse of a whole structure,” he wrote.
When Solomon first fell ill, in the 1990s, many clinicians and researchers presumed that the pathological brain changes underlying depression were inherently slow to repair. This mind-set was rooted in the modest but controversial success of a class of slow-acting drugs that includes Prozac.
Developed in the 1950s, the drugs were first inspired by the chance observation that a hypertension drug called reserpine – an extract of the plant Rauwolfia serpentina, or devil pepper — made people intensely depressed. After discovering that reserpine depletes monoamine neurotransmitters in the brain, including serotonin and norepinephrine, scientists hypothesized that low neurotransmitter levels causedepression. They went on to develop monoaminergic antidepressants, drugs designed to increase circulating levels of these chemicals in the brain.
Today, monoaminergic antidepressants include selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Lexapro and Zoloft, as well as the older and less commonly prescribed monoamine oxidase inhibitors (MAOIs) and tricyclic and tetracyclic antidepressants. Scientists have long debated whether the drugs work at all, but the most comprehensive study to date — published in The Lancet in 2018 — suggests that they do lower depression symptoms in about 60 percent of depressed people, albeit only modestly more than taking a placebo.
The benefits start to show up only after several weeks of treatment, however, and roughly a third of people with major depression disorder – called treatment-resistant patients — don’t respond to at least two types of monoaminergic antidepressant.
By the early 2000s, the monoamine hypothesis had unraveled. This was partly due to the antidepressants’ mediocre performance in patients, and partly to experiments which showed that depleting neurotransmitter levels in healthy people does not make people depressed. Scientists now believe that drugs like Prozac do not directly treat depression’s root cause. Instead, they think the drugs work via an indirect mechanism to subtly boost the growth of synapses and the birth of new neurons, and that this somehow relieves symptoms.
Solomon’s bleak metaphor of corrosion was at least partly grounded in science. Many scientists now agree that depression slowly eats away at the neural pathways underlying our sense of worth and well-being, our desire to go to the movies or get out of bed. But research into ketamine holds out new hope that — unlike rusted iron — the depressed brain can be restored, by repairing and strengthening the neural circuits that regulate mood. —Emily Underwood
Some researchers are also testing whether ketamine works for conditions beyond depression, such as obsessive-compulsive disorder, as well as in specific subsets of patients, such as severely depressed teenagers. Other scientists are using ketamine to help untangle one of the biggest mysteries in neuroscience: What causes depression? (See sidebar.)
Seeking answers in neural wiring
Thirty years ago, the prevailing thought was that low levels of certain brain chemicals, such as serotonin, caused depression. Boosting those could remove symptoms.
“I felt that depression needed months or weeks of treatment — that the plastic changes involved in the healing process would require weeks to reset themselves,” says Todd Gould, a neuropharmacologist at the University of Maryland and a coauthor of the recent review paper. But ketamine’s speed of action casts doubt on that idea.
Newer evidence suggests that depression is caused by problems in the neural circuits that regulate mood, Gould notes. Much of the evidence for this faulty-wiring hypothesis comes from rodents. Starting in the 1990s, scientists began to discover intriguing abnormalities in the brains of mice and rats that had been exposed to certain stressors, such as bullying by a big, aggressive male.
Stress and trauma are strong predictors of depression in people, but scientists can’t ask rats or mice if they are depressed. Instead, they use behavioral tests for classic depression symptoms such as anhedonia, the inability to take joy in pleasurable activities, Thompson says. Depressed animals “give up easily” in experiments that test their willingness to work for rewards like sugar water, or their interest in the intoxicating scent of a potential mate’s urine. “They can’t be bothered to cross the cage,” he says.
Thompson and others have found that there are fewer connections, or synapses, between neurons that communicate reward signals in the brain in depressed animals. Other labs have found shriveled connections in neuronal circuits key to decision-making, attention and memory. Brain imaging studies in people with depression have also revealed abnormal activity in neural circuits that regulate emotion, suggesting that the findings in rodents may also apply to humans.
If faulty neural connections are to blame for depression, the next question is, “How do we get atrophied neural pathways to regrow?” Krystal says.
The answer, many scientists now believe, is the brain’s most abundant neurotransmitter, glutamate.
Glutamate is the workhorse of the brain. It relays fleeting thoughts and feelings, and enables the formation of memories by strengthening synaptic connections. Glutamate is the reason you can still ride a bike years after you learned, even if you never practiced.
Not all glutamate activity is good. Too much can cause the equivalent of an electrical storm in the brain — a seizure — and chronically high levels may lead to dementia. Abnormalities in glutamate receptors — specialized proteins on the surface of brain cells where glutamate can dock and bind — are linked to a wide array of psychiatric diseases, including depression and schizophrenia.
To maintain balance, cells called inhibitory interneurons act like brakes, releasing a neurotransmitter called GABA that quiets brain activity. Most mind-altering drugs work by changing the balance between GABA and glutamate — amphetamines and PCP enhance glutamate signaling, for example, while alcohol inhibits glutamate and boosts GABA.
By the 1990s, scientists had discovered that ketamine triggers a gush of glutamate in the brain’s prefrontal cortex. This region governs attention and plays an important role in emotional regulation. The out-of-body sensations that some people experience when they take ketamine may occur because this rapid release of glutamate “excites the heck out of a whole bunch of neurons” in the prefrontal cortex, says Bita Moghaddam, a neuroscientist at Oregon Health & Science University who discovered the drug’s glutamate-revving effect on rats while studying schizophrenia.
Scientists aren’t sure yet how ketamine forms stronger neural circuits. But the hypothesis goes roughly like this: When ketamine enters the brain, it causes a short-term burst of neuronal activity that triggers a series of biochemical reactions that create stronger, more plentiful synaptic connections between brain cells.
At first, many researchers thought ketamine’s antidepressant effects relied on a structure located on the surface of neurons, called the NMDA receptor. Like a key that fits into different locks, ketamine can bind to several types of NMDA receptor, making neurons release the excitatory glutamate neurotransmitter.
This hypothesis suffered a blow, however, when several drugs designed to bind to the NMDA receptor (as ketamine does) failed in clinical trials for depression.
Esketamine also complicates the story. Ketamine is made up of two molecules that form mirror images of each other, R- and S-ketamine. Esketamine is made up of just the S form and binds roughly four times as effectively as R-ketamine to the NMDA receptor. Despite acting much more powerfully on the NMDA receptor, studies in rodents suggest that S-ketamine is a less potent antidepressant than R-ketamine, although it’s not yet clear whether or not R-ketamine could work better in humans.
Zarate and others now believe ketamine may work through a different receptor that binds glutamate, called AMPA. By pinpointing which receptor ketamine acts on, researchers hope to develop a similar drug with fewer side effects. One hot lead is a compound called hydroxynorketamine (HNK) — a metabolic byproduct of ketamine that does not affect NMDA receptors but still produces rapid antidepressant effects in rodents. The drug appears to lack ketamine’s disorienting side effects, and Zarate and Gould plan to launch the first small clinical trials to establish HNK’s safety in humans this year, likely in around 70 people. “I think we have a very good drug candidate,” Gould says. (Zarate and Gould, among others, have disclosed that they are listed on patents for HNK, so they stand to share in any future royalties received by their employers.)
Plastic synaptic remodelers
To alter how the brain processes mood, scientists believe ketamine must ultimately change synapses. In experiments in rodents, Ron Duman of Yale University has shown that both ketamine and HNK can harness one of the brain’s most important tools for synaptic remodeling: brain-derived neurotrophic factor, or BDNF.
BDNF is a protein intimately involved in shaping synapses during brain development and throughout the lifespan. Healthy brain function depends on having just the right amount of BDNF in the right place at the right time. Many mental illnesses, including depression, are associated with low or abnormal amounts of the protein. For example, samples of brain tissue from people who have died by suicide often contain abnormally low amounts of BDNF.
Duman and colleagues have found that both ketamine and HNK cause a sharp uptick in the amount of BDNF that is released from neurons. This increase is required for the drugs’ antidepressant effects, and for the increase in dendritic spines — the stubby protrusions that form synaptic connections with other neurons. Both ketamine and HNK also seem to reduce inflammation, which has been linked repeatedly to the stress-induced loss of synapses.
Ketamine is not the only compound that can induce rapid synaptic plasticity: Other psychedelics, such as ecstasy (MDMA), acid (LSD), and DMT also trigger similar structural changes in neurons and rapid antidepressant effects in rodents, researchers at the University of California at Davis recently found. The effects don’t hinge on getting high, the team reported in March in ACS Chemical Neuroscience. Even very small doses — too low to cause perceptual distortions — can increase synapse density and lift depression.
Traditional antidepressants such as Prozac also increase BDNF levels in the brain, but not nearly as fast as ketamine does, Duman says. That is why most antidepressants take so long to remodel synapses and relieve depression symptoms, he says.
Beyond promising new treatments, Zarate and other researchers see ketamine as a powerful tool for probing depression’s tangled neurobiology. Studies in mice and rats are a good start, but scientists need to study the drug in people to truly understand how ketamine affects the brain. Unlike traditional, slower-acting antidepressants, ketamine lends itself to short-term lab experiments.
Zarate is using neuroimaging tools such as fMRI to study the human brain on ketamine. Past studies have shown that in people with depression, communication among several key brain networks is disrupted. One network, called the default-mode network (DMN), is involved in self-referential thoughts such as ruminating about one’s problems or flaws. This network tends to be hyperactive in people with depression, and less connected to more outwardly attuned brain networks such as the salience network, which helps the brain notice and respond to its surroundings.
In one recent study, Zarate and his colleagues found that after receiving an IV dose of ketamine, people with depression had more normal activity in the default mode network, and that it was better connected to the salience network. At least temporarily, the drug seems to help people get unstuck from patterns of brain activity associated with repetitive, negative thoughts. Zarate does caution that the study results need to be replicated.
The team has also used brain imaging to study how ketamine affects suicidal thoughts. About four hours after an infusion of ketamine, a chunk of the prefrontal cortex that is hyperactive in people with depression had calmed down, researchers found, which correlated with people reporting fewer thoughts of suicide.
Ketamine also seems to tune other brain regions that are key to effective treatment. Last year, scientists published a study in mice showing that ketamine quiets abnormal activity in the lateral habenula, a small nodule wedged deep under the cortex. Some researchers have described the lateral habenula as the brain’s “disappointment center.” The region is responsible for learning from negative experiences, and is hyperactive in people with depression, as if “broadcasting negative feelings and thoughts,” Thompson says.
Such studies remain exploratory. As to why ketamine works — and just as important, why its effects are transient — scientists are still speculating. “I think ketamine is resetting neural circuits in a way that improves the symptoms of depression, but the risk factors — whether genetic, environmental or other risk factors — are still present,” Gould says. “It seems to help reset things temporarily, but the underlying cause is not necessarily resolved.”
Helen Mayberg, a neurologist at Mount Sinai Hospital in New York who specializes in using an experimental procedure called deep brain stimulation to treat depression, suggests that ketamine may be like using a defibrillator on someone experiencing cardiac arrhythmia. “I am not addressing the fact that you have underlying heart disease, but now that your arrhythmia is gone, I can concentrate on other treatments.”
It’s important to put the potential risks of ketamine into perspective, particularly for people contemplating suicide, researchers emphasize. Most people are willing to tolerate severe side effects for other life-saving treatments, such as cancer drugs, Mayberg points out. “If you can interrupt an extreme suicidal plan and ideation, I’ll take that.”
Ketamine in teens?
For Krystal, weighing ketamine’s still largely uncharted risks and potential rewards ultimately comes down to a deeply personal question: “What would we want for ourselves? For our families? Do we want them to have to go through several failed trials over several months, or even a year, before taking a medication that might make their depression better in 24 hours?”
Some of the hardest decisions are likely to involve children and adolescents. Hospitalization for youth suicide attempts and ideation nearly doubled between 2008 and 2015, leaving many clinicians — and parents — desperate for more effective and rapid treatments. Left untreated, depression is “really bad for the brain” and can cause serious, long-term cognitive and developmental problems when it starts young, Zarate says. “The question is, is that going to be better than the long-term side effects of ketamine?”
Untreated depression is really bad for the brain, especially in the young. The question is, is that going to be better than the long-term side effects of ketamine?
Scientists don’t yet know. Ketamine has been deemed safe to use as an anesthetic in children, but there aren’t yet sufficient clinical data to show how low, repeated doses of ketamine used for depression could affect the developing brain.
On a more fundamental level, scientists don’t fully understand the neurobiology of adolescent depression, notes psychiatrist Kathryn Cullen of the University of Minnesota. It may involve abnormalities in brain development, such as the way the prefrontal cortex connects to brain regions that process emotion, but “we don’t know if the brain connection abnormalities emerge because of toxic stress induced by depression, or if these abnormalities predispose people to develop depression, or if depression itself reflects abnormal development,” Cullen says. “It’s critical to figure out how to alleviate the biological changes that are associated with [teen] depression so that the brain can get back on a healthy trajectory.”
Two recent clinical trials — one at Yale and another at Minnesota run by Cullen — have found that ketamine can lower symptoms in severely depressed teenagers, but neither study was set up to follow the teenagers long-term, says Cullen. Janssen is currently running a trial of its esketamine nasal spray with 145 youths who are suicidal, but the results of that study have not been published yet. Cullen thinks ketamine has potential for use in teens, particularly to avoid suicide, but “there are still a lot of unknowns.”
Not just a quick fix
Worldwide, depression afflicts more than 300 million people, making it the leading global cause of disability. When contemplating such overwhelming misery, the vision of a world in which depression can be cured with a single injection or squirt of nasal spray holds obvious appeal.
But — despite the hype — that is not what ketamine offers, Bennett says. Based on her own experience as a patient, and her clinical work, she is troubled by the framing of ketamine as a “rapid” depression treatment if that precludes the slower, more effortful process of psychotherapy. Without psychotherapy, she says, “you’re not giving patients any tools to help themselves, just making them dependent on a molecule that has temporary effects. When the effect wears off, they have to go back for more medicine. This is going to be lucrative for the pharmaceutical company but probably not in the patient’s best interest.”
In Bennett’s clinic, ketamine is administered only alongside talk therapy, which she uses to prepare patients before they take ketamine, and afterward to help them process the experience. “I think this is the only ethical way” to administer a drug that can trigger disorienting psychedelic experiences, she says. “This isn’t a ‘take two and call me in the morning’ situation.”
There’s growing scientific interest in whether ketamine can enhance the effectiveness of therapy by increasing the brain’s ability to remodel circuits through experience, Krystal notes. And in 2017 a small Yale study found that providing cognitive behavioral therapy in tandem with ketamine can extend the drug’s antidepressant effects.
Unlike some researchers and pharmaceutical companies, which consider ketamine’s and esketamine’s hallucinogenic side effects inherently negative, Bennett thinks that for some people the visions can be positive — particularly in the context of therapy. There’s scant scientific evidence to support the idea that such hallucinations are therapeutic, and they can be deeply disturbing for some people. (If people who experience hallucinations do better, it may simply be because they have received a higher dose of ketamine, Krystal points out.)
Still, Bennett thinks researchers and clinicians need to stay open-minded about why ketamine is helping people — and be more attentive to the settings in which ketamine and esketamine are administered. “People consistently report that they experience the presence of God, or their own sacredness,” she says. “When someone comes to my office wanting to kill themselves, ready to die — and then they have a transformational moment where they believe their life is sacred — it’s indescribable how exciting that is as a clinician.”
An hour before we spoke, Darragh O’Carroll, an emergency room physician from Hawaii, had just given an elderly patient a sedating shot of ketamine. The man had pneumonia and was acting confused and fidgety, making him hard to treat.
“Not only it was a pain control for him when I was putting needles into his neck, but it also kept him still,” O’Carroll says. “And with very minimal risk of lowering his blood pressure.”
Ketamine’s use as an anesthetic — and not as a party drug — is widespread, though not commonly known. In fact, the World Health Organizationestimates ketamine is the most widely used anesthetic in the world and keeps it on their list of essential medicines, a category of drugs that all developed countries should have on hand.
O’Carroll has described ketamine as his “favorite medicine of all time” in an article for Tonic, not only because the anesthetic is incredibly safe and effective, but also because of its versatility. It’s most widely used in surgery, but could also help treat severe asthma, chronic pain, and may even possess anti-tumor properties. In the last two decades, ketamine has also emerged as a potent antidepressant, able to treat symptoms of some mental illnesses in less than 72 hours.
“I think the more research that goes into ketamine, the more uses that we find for it,” O’Carroll says.
From PCP to Painkiller
Ketamine’s story begins with a drug called PCP. Yes, that PCP — phencyclidine or so-called “angel dust,” a drug that when smoked can cause a trance-like state, agitation and out-of-body hallucinations. After it was first synthesized by medicinal chemist Victor Maddox in 1956, the drug was briefly approved as an anesthetic by the FDA for its sedative properties. In tests with a wild rhesus monkey, for example, researchers put their fingers in the previously aggressive animal’s mouth and watched its jaw remain slack.
But while it was safe and effective for pain relief, the side effects of PCP soon became too obvious to ignore.
Some patients under the influence of PCP would feel like they lost their arms or legs or that they were floating in space. It could also cause seizures and delirium. Scientists began seeking a shorter-acting anesthetic without convulsant properties. In 1962, chemistry professor Calvin Stevens discovered a PCP analogue that fit the bill: ketamine.
Ketamine is a potent, sedating painkiller that can cause amnesia and is mostly used in surgery and veterinary medicine. During the Vietnam Invasion, ketamine saw widespread use in the U.S. military because it has several advantages over opioids. First, unlike morphine, ketamine doesn’t suppress blood pressure or breathing. It also doesn’t need to be refrigerated, making it useful in the field or in rural areas that don’t have access to electricity.
Ketamine’s benefits extend beyond use as an anesthetic, though — in some cases it can serve as a balm for the mind as well. A 2008 analysis found that burn victims who were given ketamine were less likely to develop symptoms of post-traumatic stress disorder, even if their injuries were more severe. Those findings have been replicated, such as a 2014 clinical trial of 41 patients, who saw their PTSD symptoms diminish within 24 hours, an effect that lasted for two weeks.
“When somebody gets one of their limbs dramatically blown off or is shot in the face, it’s a very traumatic event,” O’Carroll says. In such a situation, giving ketamine not only provides instant pain relief, it could prevent long-lasting trauma.
Because its chemical structure is so similar to PCP, ketamine can still give lucid hallucinations, such as feeling that your mind has separated from the body — a dissociative state users sometimes call a “K-hole.” One recent study based on users’ written reports even indicated that this kind of experience might be a close analogue to a near-death experience. However, these dissociative states only happen at high doses — the amount of ketamine used to for surgery and to treat depression is typically much lower.
But ketamine’s side effects are less common and easier to manage than PCP. In fact, ketamine is one of the safest drugs used in medicine today and can even be given to young children. For example, ketamine was used to sedatethe boys’ soccer team trapped in a cave in Thailand last year. Putting the kids in a tranquilized state made it easier to rescue them, and ketamine is safer than the opioids or benzodiazepines that are also commonly used as sedatives.
Ketamine as Antidepressant
But it wasn’t until the 1990s that what could turn out to be ketamine’s most important function was discovered. A team from Yale University School of Medicine was examining the role of glutamate, a common neurotransmitter, in depression, and discovered something remarkable: ketamine could rapidly relieve depression symptoms.
“To our surprise, the patients started saying, they were better in a few hours,” Dennis Charney, one of the researchers, told Bloomberg. This rapid relief was unheard of in psychiatry.
Glutamate is associated with neural plasticity, our brain’s ability to adapt and change at the level of the neuron. Ketamine blocks certain glutamate receptors, but not others, and the end effect could be to promote the growth of new neurons while protecting old ones. This could explain how ketamine can help reset the brain, though the theory hasn’t yet been definitively proven.
The prescription meds currently on the market for depression have some major drawbacks. Drugs like Prozac or Wellbutrin can take a few weeks or months to kick in while worsening symptoms in the short term — not a good combination, especially for someone who is extremely depressed, or even suicidal.
It took around a decade for mainstream science to take notice of these early ketamine-depression studies. But once it did, ketamine clinics began popping up all across North America, offering fast relief for depression, anxiety and other mental illnesses. Patients are given an infusion — an IV drip that lasts about an hour — and many people, but not everyone, have seen rapid relief of their symptoms.
Suddenly, ketamine infusions became trendy, though the science to back up some of the medical claims is still inconclusive, according to STAT. However, ketamine infusions are rarely covered by insurance, although that is changing. A typical session can run $700, with many patients taking six sessions or more. But many of these patients have so-called treatment-resistant depression. They’ve tried other medications or therapies without success and some see ketamine as a last resort.
Steven Mandel, a clinical psychologist and anesthesiologist, has used ketamine on patients since it first came on the market around 50 years ago. In 2014, he began using it for patients with depression and opened Ketamine Clinics of Los Angeles, one of the oldest and largest clinics in the country. They’ve done over 8,000 infusions so far.
“Our success rate is better than 83 percent,” Mandel says. For his clinic, success means a 50 percent improvement of depression symptoms for longer than three months.
Ketamine’s success as an antidepressant couldn’t help but attract the attention of major pharmaceutical companies as well. In 2009, Johnson & Johnson began developing their own version of the drug they called esketamine. Rather than an infusion through a vein, it’s dispensed through a nasal spray. The FDA approved their formulation in early March. It was thefirst drug in 35 years to fight depression using a different approach than traditional drugs.
“Esketamine is a giant step forward,” Mandel says. “It means we’re not going to be demonizing mind-altering substances used for therapeutic purposes. It opens the door to research on LSD, on psilocybin, on MDMA and many other agents that could possibly relieve a great deal of suffering.”
But many clinicians have raised concerns about long-term side effects, such as heart and bladder toxicity. Others have been critical of esketamine, saying there isn’t enough data yet to suggest the drug is safe or effective. Husseini Manji, a neuroscientist who helped develop the drug for Johnson & Johnson at their subsidiary Janssen, has pushed back against these claims.
“When you line up the totality of the studies, it was really an overwhelming amount of data that was all in the same direction,” Manji says in a call. Though just two of the five late-state clinical trials showed significant results, the changes in mood in the three that fell short were “almost identical in magnitude” to the others, Manji says. It was enough for the drug to meet standards for FDA approval.
We can probably expect other ketamine-related drugs to come to market soon. ATAI Life Sciences, a company funding research on the use of magic mushrooms for depression, is developing their own ketamine depression drug. The pharmaceutical company Allergan also developed rapastinel, another ketamine-like drug, though it failed to show any real benefits for patients in later trials. Manji says this is unfortunate for people who could be helped by these kinds of drugs.
“From a patient standpoint, we were hoping it would work,” he says, even though he was not involved in rapastinel’s development. “But sometimes if you really haven’t got the mechanism right and you haven’t really threaded the needle, then sometimes you don’t see these results.”
Drug of Abuse?
Even though ketamine’s medical uses are well-established, most people have only heard of ketamine in the context of a party drug. Because of this bad reputation — and what’s perceived as growing misuse of the drug — several countries, such as China and the UK, have tried to place greater restrictions on ketamine. This would make it harder to study and more expensive in clinical use.
“If it was to ever be rescheduled, places that would be first affected would be you know places that need it most,” O’Carroll says. The WHO has asked at least four times for countries to keep access to ketamine open. “The medical benefits of ketamine far outweigh potential harm from recreational use,” Marie-Paule Kieny, assistant director general for Health Systems and Innovation at WHO, said in 2015.
So far, no countries have put greater restrictions on ketamine, and that’s probably a good thing. Ketamine has a rich history, but its future is still being written.
Ketamine was originally approved by the US Food and Drug Administration (FDA) as an anesthetic, but is increasingly being used to treat mood disorders, such as treatment-resistant depression, anxiety disorders, and post-traumatic stress disorder (PTSD).1,2 Several studies have also found it to be effective for treating suicidal ideation.3,4
“Ketamine can play an important role in the treatment of anxiety disorders,” according to Prakash Masand, MD, co-founder, chairman, and CEO of Centers of Psychiatric Excellence (COPE) (https://www.copepsychiatry.com) and adjunct professor at the Academic Medicine Education Institute, Duke-National University of Singapore Medical School (Duke-NUS).
“Nowadays, people with anxiety disorders are treated either with a generic antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), an SNRI (selective norepinephrine reuptake inhibitor), or a benzodiazepine and if they don’t respond to one of these, they get a trial of another or several more,” Dr Masand said.
However, between 30% and 40% of these patients will not achieve remission, despite 3 or 4 different traditional agents, and even with evidence-based nonpharmacologic therapies, such as cognitive behavioral therapy (CBT) or mentalization-based therapy (MBT), he noted.
“No good current strategies are available for these non-responders, so novel agents are being studied — including ketamine, which is accumulating an evidence base as [being] rapidly effective for an array of anxiety disorders, including social anxiety disorder (SAD) and PTSD,” he said.
How Does Ketamine Work?
A growing body of evidence points to the role of glutamate, a widely distributed excitatory neurotransmitter, in mediating response to stress and the formation of traumatic memories.2 Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist. Its antidepressant and anti-anxiety effects are presumed to occur through activating synaptic plasticity by increasing brain-derived neutrophic factor translation and secretion and also by inhibiting glycogen synthase kinase-3 and activating mammalian target of rapamycin signaling.5
Brain-derived neutrophic factor plays a role in behavioral responses to classical antidepressants, but the impact on synaptic plasticity may take several weeks to manifest. In contrast, ketamine-mediated synaptic plasticity changes appear to occur within a matter of hours after ketamine administration.5
“The current thinking is that eventually, 6 to 12 weeks after initiating treatment with traditional antidepressants, dendritic growth and increased synaptic connections occur but with ketamine, these can occur within 24 hours of the infusion,” Dr Masand said.
Ketamine and Anxiety: An Increasing Evidence Base
“Ketamine has been studied and shown [to be] effective with an array of anxiety disorders, including SAD, general anxiety disorder (GAD), and PTSD, although the data on its effectiveness in obsessive compulsive disorder (OCD) are more mixed,” Dr Masand observed.
A small study of patients with GAD and/or SAD (n=12) compared 3 ascending ketamine doses to midazolam. Each was given at 1-week intervals, with midazolam counterbalanced in dosing position across patients. Ketamine was found to dose-dependently improve scores on the Fear Questionnaire. Moreover, it’s impact on decreasing theta frequency in the right frontal sites assessed via electroencelphalogram (EEG) was comparable to that of conventional anxiolytics.6
Glue et al evaluated the efficacy and safety of ketamine in 12 patients with refractory GAD and/or SAD who were not currently depressed using an ascending single-dose at weekly intervals study design. Within 1 hour of dosing, patients reported reduced anxiety, which persisted for up to 7 days.7
A continuation of that study evaluated the impact of maintenance treatment ketamine in patients with GAD and/or SAD (n=20) and found that 18 of the 20 patients reported ongoing improvements in social functioning and/or work functioning during maintenance treatment. The researchers concluded that maintenance therapy ”may be a therapeutic alternative for patients with treatment-refractory GAD/SAD.”8
“What is interesting about this study is that the impact of just one infusion lasted for 14 weeks, suggesting that patient[s] with anxiety disorders might have longer maintenance of response than patients with major depression, where the response has been maintained for only one week,” Dr Masand commented.
A study of patients with anxious and non-anxious bipolar depression (n=21 for both groups) found that both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group.9 “Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest the need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.,” the investigators concluded.9
An open-label trial of ketamine in 10 patients with treatment-refractory OCD found that ketamine’s effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.10
On the other hand, another randomized controlled trial (RCT) of 15 patients with OCD found that anti-OCD effects from a single intravenous dose of ketamine persisted for more than 1 week in some patients with OCD with constant intrusive thoughts, demonstrating that “a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an [SSRI].”11
In PTSD, there is “mounting evidence for a role of the excitatory neurotransmitter glutamate in stress responsiveness, the formation of traumatic memories, and the pathophysiology of PTSD, raising the possibility of identifying novel glutamatergic interventions for this disorder.”12
One double-blind study demonstrated that infusion of ketamine rapidly and significantly reduces symptom severity in patients with PTSD compared with midazolam.2
Another study found that administration of ketamine immediately after witnessing a traumatic event has been shown to prevent the enhancement of passive avoidance learning in mice.13Ketamine may thus target the mechanisms involved in the consolidation of traumatic memory and may enable the brain to reconsolidate memory and release trauma.14
A case study of a child with PTSD reported remission from behavioral dysregulation after receiving procedural ketamine.15
Drawbacks and Potential Adverse Effects
The main concern regarding the use of ketamine for anxiety disorders is the lack of a road map regarding maintenance, Dr Masand noted.
“At COPE, we have found that roughly 30% to 40% of our patients being treated with ketamine require maintenance infusions, and we highly personalize this approach so that patients can identify early signs of recurrence or relapse and we can devise a treatment schedule to prevent them,” he said.
Some patients continue treatment with pharmacotherapy, including standard antidepressants, benzodiazepines, or a mood stabilizer such as valproate and some patients become more receptive to psychotherapies such as CBT,” he stated.
However, “there is very little data regarding what happens long-term in this patient population.”
“Most side effects are mild and transient,” Dr Masand reported. “Patients must be monitored because of potential increases in blood pressure and pulse.”
Additional adverse events include nausea or vomiting, which are also mild and transient. Patients may be pre-treated with prophylactic anti-nausea medication, such as ondansetron, to pre-empt these symptoms, he said.
Some patients experience dissociation, or an out-of-body experience, which is also usually transient but seen by some patients as “annoying,” he noted. “Dissociative experiences are sometimes seen as a biomarker for insufficient response and suggest that the dose should be increased.”
Providers should be aware that cystitis and lower urinary tract pathologies (eg, detrusor over-activity) have been reported in long-term ketamine users, but typically only at high doses.16
Ketamine’s psychedelic effects make it a” popular recreational drug.”16 At lower doses, the predominant effects are stimulating, and users experience mild dissociation with hallucinations and a distortion of time and space. However, higher doses can induce more severe, schizophrenia-like symptoms and perceptions.16 Although these effects resolve rapidly, long-term use “can cause more pronounced and persistent neuropsychiatric symptoms. For this reason, ketamine should be “used cautiously with other drugs that alter mood and perception, including alcohol, opioids, benzodiazepines and cannabis.”16
“Ketamine for treatment-resistant depression has a robust evidence base and a rapidly-growing evidence base for its use in anxiety disorders,” Dr Masand said.
“Given the gaps in current treatment, this promising agent is occupying a more promising role in treatment of anxiety disorders, such as PTSD. Considering how common PTSD is, ketamine can make an important difference for a large number of people who suffer from this debilitating condition,” he concluded.
First Person Account of Ketamine Therapy: An Interview with Kimberly Palmer
To gain insight into the experience of ketamine treatment in a person with depression and anxiety, Psychiatry Advisor interviewed Kimberly Palmer of Los Angeles, California. Ms Palmer received treatment at the Ketamine Clinics of Los Angeles (https://www.ketamineclinics.com). Ms Palmer works as a program manager for a consulting company where she organizes and runs corporate events for small groups.
Psychiatry Advisor:What made you decide to pursue ketamine treatment?
Ms Palmer:I was raised in an abusive home, and as an adult I had severe major depression, as well as anxiety. I was treated with medications, such as antidepressants, but they had many adverse events and they ended up making me feel like a zombie, so I discontinued them. I managed okay for a while, but then I had another major depressive episode.
I was receiving psychotherapy at the time and it was only moderately helpful — not enough to stop the episode. Fortunately, I knew someone who works at a ketamine clinic. She told me how many patients had been helped by ketamine and I was interested, mostly because the adverse events of ketamine seemed mild and are not long-term.
Psychiatry Advisor: What were your experiences during your infusion?
Ms Palmer: I felt incredible during the infusion. The best way I can describe it is by referring to the movie Avatar, specifically the scene in which the protagonist is walking through a jungle at night for the first time and touching all the plants, which light up with pretty colors—very vivid, colorful, and not linear. There was the sensation of being on a sort of roller coaster, riding through different scenes.
At one point, it felt as though my chair was on a cloud. Then suddenly, the chair disappeared and I was floating on the cloud. It was a wonderful experience.
Psychiatry Advisor: How did the ketamine treatment affect you afterwards?
Ms Palmer: After only one treatment, it was as if a switch had flipped in my brain that allowed me to digest things and move beyond my trauma. Before the infusion, a lot of what was going on with me had to do with self-esteem issues and negative self-talk. These were behaviors learned over many years. After the infusion, the negative self-talk immediately disappeared. All of those thoughts — such as telling myself I am not good enough — that were preventing me from working through emotional issues, were resolved. I was able to start looking at things more objectively rather than taking them personally, and not take on responsibility for other people’s emotions and reactions.
I am currently working with a therapist and a life coach to help me feel more comfortable with communication because I was raised not to ask for things and to put up with anything I’m asked to do. As a result, I have developed a much more positive outlook of myself and the world.
Psychiatry Advisor: How many ketamine treatments have you had?
Ms Palmer: Over a 6-month period I had 6 treatments, which were all very helpful. Then, 6 months after the conclusion of this first series of treatments, some new issues came up, so I received 2 more — one regular 60-minute treatment and one extended 90-minute treatment.
Recently, with the holidays coming up, I decided to pre-empt the effect of some stressors and have another treatment. My most recent infusion took place the day after my father passed away. I noticed that during the infusion, I was able to steer myself away from negative thoughts about that issue. Although I cannot control what visions or experiences I might have, I do have some control over the direction of my thoughts and the after-effects have been positive and helpful.
Psychiatry Advisor: Did you have any adverse events from the treatments?
Ms Palmer: I had no negative physical effects. I had one mild bad reaction, when I came to the treatment session in an agitated state because I had gotten into a fight with someone right before. I was sad and crying by the time I finished the infusion. But I was in a bad headspace before I even walked into the room. And my experience was not scary, only sad.
Psychiatry Advisor: What impact has your treatment had on your day-to-day life?
Ms Palmer: My depression had interrupted my schooling. I was in school for 3 and a half years and then I hit a roadblock. After the treatments, I was able to complete my studies and graduated with a BA in business administration and management.
My job is stressful. I counterbalance the stress with hobbies like surfing and photography. But there are still stressors, and I have a dog who is reaching the end of life, which is affecting me. The ketamine treatments have helped me to manage those stressors.
The newest FDA-approved medication to treat severe depression, a nasal spray based on the anesthetic (and misused hallucinogenic party drug) ketamine, will soon be available to veterans treated within the Department of Veterans Affairs.
In a move that may help thousands of former service members with depression that has not improved with other treatments, VA officials announced Tuesday that the department’s doctors are now authorized to prescribe Spravato, the brand name for esketamine, a molecular variation of ketamine.
The decision to offer a drug hailed by many as a breakthrough in treatment for its speedy results — often relieving symptoms in hours and days, not weeks — shows the VA’s “commitment to seek new ways to provide the best health care available for our nation’s veterans,” Secretary Robert Wilkie said in a release.
“We’re pleased to be able to expand options for Veterans with depression who have not responded to other treatments,” Wilkie added.
The treatment will be available to veterans based on a physician’s assessment and only will be administered to patients who have tried at least two antidepressant medications and continue to have symptoms of major depressive disorder.
An estimated 16 million Americans have had at least one major episode of depression, and of those, 1 in 3 are considered treatment-resistant. In the veteran population of 20 million, the estimated diagnosis rate of depression is 14 percent — up to 2.8 million veterans. Between one-third and half of those veterans may be treatment-resistant.
The lack of effective medications for difficult-to-treat patients prompted the Food and Drug Administration to place esketamine on a fast track, expediting its review of the drug to ensure that it went to patent as soon as safely possible, according to administration officials.
“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process, including a robust discussion with our external advisory committees, were important in our decision to approve this treatment,” said Dr. Tiffany Farchione, acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products, in a release.
As with any other medication, there are risks. Spravato carries a boxed warning for side effects that include misuse, the reason it is administered under a doctor’s supervision. The list of side effects includes sedation and blood pressure spikes and disassociation, such as feelings of physical paralysis and out-of-body experiences. It also can cause suicidal thoughts and behaviors.
Acknowledging the dangers, FDA made esketamine available only through a restricted distribution system.
A veteran prescribed Spravato would inhale the nasal spray at a medical facility while under supervision of a medical provider, and would be monitored for at least two hours after receiving the dose. A typical prescription includes twice-weekly doses the first month, followed by a single dose weekly or biweekly as needed. Spravato cannot be dispensed for home use.
Spravato is made by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first major antidepressant medication to hit the market in 30 years.
A nasal spray version of the drug ketamine has shown promise as an antidepressant, even if its properties still aren’t well understood.
Of the 16 million American adults who live with depression, as many as one-quarter gain little or no benefit from available treatments, whether drugs or talk therapy. They represent perhaps the greatest unmet need in psychiatry. On Tuesday, the Food and Drug Administration approved a prescription treatment intended to help them, a fast-acting drug derived from an old and widely used anesthetic, ketamine.
The move heralds a shift from the Prozac era of antidepressant drugs. The newly approved treatment, called esketamine, is a nasal spray developed by Janssen Pharmaceuticals Inc., a branch of Johnson & Johnson, that will be marketed under the name Spravato. It contains an active portion of the ketamine molecule, whose antidepressant properties are not well understood yet.
“Thank goodness we now have something with a different mechanism of action than previous antidepressants,” said Dr. Erick Turner, a former F.D.A. reviewer and an associate professor of psychiatry at Oregon Health & Science University. “But I’m skeptical of the hype, because in this world it’s like Lucy holding the football for Charlie Brown: Each time we get our hopes up, the football gets pulled away.”
The generic anesthetic is already increasingly available for depression, at hundreds of clinics around the country that provide a course of intravenous treatments, and studies suggest it can help treatment-resistant people. It often causes out-of-body and hallucinogenic sensations when administered; in the 1980s and 1990s it was popular as a club drug, Special K.
The cost for these treatments typically is out of pocket, as the generic anesthetic is not approved by the F.D.A. for depression. In contrast, esketamine likely would be covered under many insurance plans, and its side effects, though similar to those of generic ketamine, are thought to be less dramatic.
The recommended course of the newly approved drug is twice a week, for four weeks, with boosters as needed, along with one of the commonly used oral antidepressants. F.D.A. approval requires that doses be taken in a doctor’s office or clinic, with patients monitored for at least two hours, and their experience entered in a registry; patients should not drive on the day of treatment.
Esketamine, like ketamine, has the potential for abuse, and both drugs can induce psychotic episodes in people who are at high risk for them. The safety monitoring will require doctors to find space for treated patients, which could present a logistical challenge, some psychiatrists said.
The cost for a one-month course of treatment will be between $4,720 and $6,785, said Janssen, and experts said it will give the company a foothold in the $12 billion global antidepressant market, where most drugs now are generic.[L
The approval of esketamine marks a new approach to treating serious mood problems, experts said. Prozac and similar drugs enhance the activity of brain messengers such as serotonin; they are mildly effective, but they take weeks or months for their effects to be felt, and for many patients they provide little or no relief from depression. In contrast, the ketamine-based compounds — several others are being developed — work within hours or days, and are effective in some people who are considered “treatment resistant,” meaning they have not benefited from other antidepressants.
“These are exciting times, for sure,” said Dr. Todd Gould, an associate professor of psychiatry in the University of Maryland School of Medicine. “We have drugs that work rapidly to treat a very severe illness.” Dr. Gould was not involved in the Janssen study but has identified a metabolite, or ketamine breakdown product, that could be developed into another drug.
Experts with long experience in treating depression were encouraged by the news, but also chary. The effectiveness of the previous class of antidepressants such as Prozac and Paxil was vastly exaggerated when they came on the market. And the results of esketamine trials, which were paid for and carried out by Janssen, were mixed.
In each trial submitted, all patients were started on a new antidepressant drug, and given a course of esketamine treatment or a placebo. In one monthlong study, those on esketamine performed better statistically than those on placebo, reducing scores on a standard, 60-point depression scale by 21 points, compared to 17 points for placebo. But in two others trials, the drug did not statistically outperform placebo treatment. Historically, the F.D.A. has required that a drug succeed in two short-term trials before it is approved; the agency loosened its criteria for esketamine, opting instead to study relapse in people who did well on the drug.
In that trial, Janssen reported that only about one-quarter of subjects relapsed, compared to 45 percent of subjects who received the placebo spray. All the subjects had been given a diagnosis of treatment-resistant depression, or T.R.D., having previously failed multiple courses of drug treatment.
“We’ve had nothing new in 30 years,” said Steven Hollon, a professor of psychiatry and behavior sciences at Vanderbilt University. “So if this drug is an effective way to get a more rapid response in people who are treatment resistant, and we can use it safely, then it could be a godsend.”
Desperate for relief
One question that will need to be answered is how well esketamine performs in comparison to intravenous ketamine.
Theresa, 57, an adjunct professor of English in New York, who asked that her last name be omitted to protect her privacy, has lived much of her life with deep depression. She tried a course of I.V. generic ketamine last summer, at a local clinic, which typically entails a half-dozen infusions, given over a couple of weeks, for about $500 apiece, with follow-up “booster” treatments as needed.
“I remember floating, I was really high,” she said. “I was tripping on sounds, textures and shapes, that was very much a part of it.”
The first infusion provided no relief, she said. But after the third or fourth, she noticed a satisfying “shift” in her underlying mood. “It’s a hard thing to describe. I was still anxious, but I felt somehow more solid, like something gelled within me, and my husband has noticed it, too.”
Dr. Glen Brooks, the founder and medical director of NY Ketamine Infusions, a clinic in downtown Manhattan, said he has treated some 2,300 people, of all ages, with intravenous ketamine, the generic anesthetic. His clients had received a variety of diagnoses, including post-traumatic stress, anxiety, and obsessive-compulsive disorder, as well as depression.
“What they all have in common is that other medications have failed,” Dr. Brooks, an anesthesiologist, said. “They’re hopeless, and they think, ‘Nothing else has worked, why should this?’” He said that, in his experience, the infusions quickly reduced symptoms for teenagers and young adults, but seemed to be less effective for people over 50.
The data that Janssen presented to the F.D.A. likewise suggested that esketamine was less effective in people aged 65 and older, barely better than placebo treatment.
Ketamine was developed more than five decades ago as a safer alternative to the anesthetic phencyclidine, or PCP, and is used worldwide, in operating rooms, on the battlefield and in pediatric clinics. The World Health Organization has listed ketamine as one of its essential medicines since 1985.
By the 1990s, interest turned to the drug’s potential to combat depression, when a government scientist named Phil Skolnick argued that targeting glutamate pathways — the primary “excitatory,” or neuroactivating, brain processes — could produce antidepressant effects. In 2000, a team of researchers at Yale University and the Connecticut Mental Health Center, led by Dr. Robert M. Berman, reported that doses of ketamine provided quick relief to seven people with depression.
The field took off in 2006, when a team at the National Institute of Mental Health led by Dr. Carlos Zarate Jr. reported that 18 treatment-resistant people who received the drug intravenously reported that their despair lifted within hours.
“What seems remarkable is that the drug also seems to help domains other than depression, like anxiety, suicidal thinking, and anhedonia” — the inability to feel pleasure — said Dr. Zarate, chief of the N.I.M.H.’s experimental therapeutics and pathophysiology branch. “It seems to have more broad effects, on many areas of mood.”
The apparent ability of ketamine to blunt suicidal thinking is particularly compelling, and Janssen is pursuing this indication for esketamine. In jails and psychiatry wards, suicide is an acute risk for people in crisis, and a fast-acting drug could save many lives, doctors said.
For now, no one knows whether esketamine, or any of the other ketamine-based compounds being studied, are any more effective than the generic anesthetic itself — or, for that matter, whether the out-of-body and hallucinatory “side effects” are in fact integral to its antidepressant properties.
“For that, we will need head-to-head studies,” Dr. Zarate said. “And we don’t have those yet.”
The US Food and Drug Administration approved Janssen Pharmaceuticals Inc.’s esketamine on Tuesday for treatment-resistant depression; the drug is the chemical cousin of ketamine, the powerful anesthetic that has been used illegally as the club drug Special K.It will be sold as Spravato. More specifically, it’s for patients who have tried at least two other medications without success, and it should be taken with an oral antidepressant.”There has been a longstanding need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition,” Dr. Tiffany Farchione, acting director of the Division of Psychiatry Products at the FDA’s Center for Drug Evaluation and Research, said in a news release announcing the approval.Spravato is a nasal spray administered by an approved health care provider in a doctor’s office or a medical clinic. It may also be self-administered but only under the supervision of a care provider and cannot be taken home. “Because of [safety] concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient,” Farchione said.Depending on the severity of the patient’s depression, it is given either once a week or once every other week.
Esketamine is an option for patients with treatment-resistant depression.The drug is rapidly acting, so it starts working faster than other antidepressants, according to Janssen. It works by restoring brain cells in patients with treatment-resistant depression.Currently available treatments for major depression are ineffective in 30% to 40% of patients. According to the FDA, there is one other approved medication for treatment-resistant depression, Symbyax, which was approved in 2009.Side effects of Spravato include dizziness, nausea, vertigo, anxiety, lethargy, increased blood pressure, vomiting, feeling drunk, decreased sensitivity, sedation and dissociation, a feeling of being temporarily “disconnected” from your body and your mind.The drug label will contain a “boxed warning” to alert patients to the risk of “sedation, and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug,” the agency said in its announcement.Because of these risks, patients must be monitored for at least two hours after being given the drug.Get CNN Health’s weekly newsletterIn clinical trials, six patients who were taking the drug died, three from suicide, but FDA background materials reviewed by the advisory committee that recommended approval last monthsaid, “It is difficult to consider these deaths as drug-related.”Because of the drug’s close relationship to ketamine, experts have raised concerns about its potential for misuse and abuse, but clinical trials found those risks to be unfounded.Concerns have also been raised about a lack of long-term data on possible health effects, most notably cognitive ones.The drug was designated as a breakthrough therapy in 2013, a status intended to “expedite the development and review of drugs for serious or life-threatening conditions,” the FDA said at the time.Greg Panico, a spokesman for Janssen, a division of Johnson & Johnson, did not say when Spravato will be available. He wrote in an email, “We are working quickly to educate and certify treatment centers on the unique administration requirements of SPRAVATO™ to ensure patients can access this important medicine.”As for the cost, it will be “generally comparable with other specialty mental health drugs,” Panico said: about $590 to $885 per treatment session, based on the dosage and not accounting for mandatory discounts or negotiated rebates.
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