“I could watch the sunset over the ocean, or notice a rainbow
after a warm summer rain, but never feel moved or awed by
its beauty or wonder. Drinking or getting high is the only thing
that allows me to feel anything good anymore—but only lasts
a short while. So most nights I go to bed hoping that I won’t
wake up in the morning.”
~Sarah, 33, San Diego, Ca.
Like addiction, Major Depressive Disorder (MDD) is a life threatening brain disease characterized by persistent depressed mood with overwhelming sadness, loss of pleasure (anhedonia), isolation, despair and hopelessness (DSM V, 2013). MDD is not having a bad day or week or feeling blue for a few days, like most of us will experience for brief periods during our lives. Rather, depressed persons feel as if they have sunk into a deep, dark hole with no way out —and with little belief that things will ever improve. Like addictive disease, MDD is not well understood and difficult to treat. Persons with these disorders are prone to relapse and without optimal treatment of adequate intensity and duration, these disorders can result in premature death or disability.
Treatment Resistant Depression (TRD)
Treatment resistant depression is diagnosed when a patient fails to respond to at least two courses of traditional antidepressant therapy, usually coupled with individual psychotherapy. At present, the most commonly prescribed antidepressant medications are Selective Serotonin Re-Uptake Inhibitors (SSRI’s) and their first cousins, Selective Serotonin Norepinephrine Re-Uptake Inhibitors (SSRNI’s). While effective in many patients, SSRI’s), such as Zoloft, Prozac, Paxil,…and SSNRI’s such as Effexor and Cymbalta, can take up to 6 weeks to be effective. As a result, adherence to these medications, especially among young depressed persons is very low. Whether they were addicted and now depressed or just depressed, they want to feel normal now—and many know how to do so by using illicit intoxicants or alcohol. Self-medication with powerful addictive substances can provide immediate, but temporary relief that wears off quickly, and over time, actually makes depression worse.
To be sure, SSRI’s and SSNRI’s have been life savers for millions of people suffering from MDD, largely because of their impressive safety profile, limited side effects and documented efficacy. Although many patients respond to SSRI’s or SSNRI’s, many have only a partial response and never return to their pre morbid state. For those with TRD, waiting weeks or months for relief can seem like an eternity. Often they can’t stand feeling empty, losing hope and wondering if life is worth living. Who can blame them? These non-responders often suffer through numerous trial and error with different medications, doctors, combinations of SSRI’s / SSRNI’s, sometimes combined with mood stabilizers and antiseizure medications. To make matters worse, psychiatrists have no way, other than trial and error and their clinical experience to predict which medications might work and which will not. This is not surprising as most of the currently available medications are based on a circa 1960’s, catecholaminergic view of
depression, anxiety and addiction. Yet, those with TRD remain treatment resistant, often desperately going from doctor to doctor seeking relief until they either give up, drop out of treatment, start self-medicating or start thinking of suicide.
These data confirm what I first wrote about in the 80’s. Namely that we are far away from understanding the genesis of major depression. Moreover, our current arsenal of medications, may in fact be working on secondary brain systems rather than the root neurobiological cause.
What is Ketamine?
Ketamine is an N-Methyl D-Aspartame (NMDA) receptor antagonist with dissociative properties. NMDA receptors (NMDARs) possess high calcium permeability which allows Ketamine to pass through the blood brain barrier and reach its target very quickly. Illicitly, Ketamine is still a drug of abuse in the US, but it is primarily used in Asia, especially in Hong Kong where it is commonly abused as a “club drug”.
Ketamine has been FDA approved in the US as an anesthetic for nearly 50 years. It is used safely, primarily by anesthesiologists, in both hospital and surgical settings.
Recently several small but well-controlled studies have found that Ketamine can dramatically relieve and even eliminate depressive states and suicidality in a matter of hours, even among the most severely depressed persons and non-responders, when administered intravenously, in sub anesthetic doses. These small studies have been replicated by researchers at the National Institute of Mental Health (NIMH), Yale University, Mt Sinai, Washington University, and at Stanford. Because Ketamine also reverses suicidal thinking, it may ultimately provide ED physicians a way to quickly stabilize suicidal patients and facilitate referral to the appropriate psychiatric or dual disorders provider.
Researchers, like me, view Ketamine as a major advance in our understanding of the etiology of depression, primarily due to the nearly immediate effectiveness and short duration of Ketamine. These data suggests to me, and others, that we are on the verge of a new and novel understanding of depression and the development of a new class of antidepressant treatment. Ketamine unlocks a key in the brain that clearly provides immediate relief to some TRD patients. There is no reason to settle for the “wait 4-6 weeks and see” approach used today in treating TRD. Some physicians have already begun to offer Ketamine, as an “off label” treatment for severely depressed, non-responders, who exhibit symptoms of suicidality (JAMA Psychiatry. March 2017).
Why We Can’t Wait for a Cure
Today, Major Depressive Disorder (MDD) also called unipolar depression, affects more than 14 million Americans annually. Depression is now the leading cause of disability in US, and the mortality rate (suicide) for adults with untreated or under-treated depression is between 15-20%. Recent surveys by the CDC and others indicate that as many as 1 in 5 high school students in the US have seriously considered, or attempted suicide. The American Academy of Child & Adolescent Psychiatry (2013) reports that suicide is now the third leading cause of death for 15-to-24-year-olds, and the sixth leading cause of death for 5-to- 14-year-olds—and growing. No, it’s not a typo, 5 year old children are committing suicide. It’s absolutely shocking to realize that with the elimination of the diseases that shortened lives of young people 100 years ago, depression and drugs have slowly and steadily moved up to become number one public health concerns. Depression in any age is crippling. But young children can feel so
overwhelmed, sad, or lonely that the only solution they can think of is to end their life. I suspect that prenatal and early life exposure to alcohol, drugs, second and third hand smoke play a role. Academics may argue over the chicken or the egg, but SUDs cause depression which can last long after detox, when the chemicals have cleared from the body.
The Conundrum of Addiction and Depression
Fact: Addicts are depressed
Fact: Depressed people often become addicts
Depression and addiction share common neurocircuitry in striatum and forebrain. Thus, the concordance rate of addiction and depression is between 45-60%. Clearly they are related. Moreover, this relationship is bi-directional, meaning that one doesn’t necessarily cause the other. In other words, they simply “co-occur” and should be treated as such. If a child had strep throat and severe diarrhea, we would treat both aggressively and wouldn’t waste a second arguing about which came first. The same principle applies to addiction and depression. It doesn’t matter which came first, they must both be treated. Why? Because the cost of failure is very high. The best addiction treatment centers know this, have Psychiatrists, counselors, and addiction experts so that they can aggressively address depression and other co-occurring disorders.
All drugs of abuse initially produce euphoria, but over time, what goes up, must come down, and soon depression, anhedonia and boredom become reasons for continued and harmful drug use, which is addiction. In the 80s, we showed that cocaine did this by increasing dopamine to cause pleasure and then using up the dopamine and causing depression even while cocaine use continued. The cocaine crash looks and feels like major depression. The pathophysiology of addictive disease usurps the brain’s reward center, via numerous mechanisms that cause disruption of the dopamine circuitry making it nearly impossible for the addicted individual to experience good feelings without intoxicants. Other important neurotransmitters are also involved in the neurobiological “cascade” that produces and sustains both depression and addiction. Like alcohol, Ketamine inhibits the release GABA, a neurotransmitter which hinders the release of dopamine (which results in increased stratal dopamine) and glutamate, an abundant and vitally
important neurotransmitter that is linked to the pathophysiology of numerous disorders including depression and addiction. By inhibiting GABA, ketamine increases dopamine and releases a bolus dose of glutamate causing neurogenesis and synaptic rebuilding in the brain’s reward system.
The Good News: Ketamine
The effects of Ketamine on TRD is an exciting finding because of its potential to change the way we think about depression and its treatment. It could become the mother of novel and powerful new therapies—which are desperately needed. At present, Electro Convulsive Therapy (ECT) and most recently Transcranial Magnetic Stimulation (TMS), have been the only other FDA approved treatments for severe and treatment resistant, life threatening depression and acute suicidality. Both are effective, but neither is convenient. Ketamine may successfully treat different types of patients than either ECT or TMS. Time will tell. Understanding more about how Ketamine effects mood will change our understanding of the pathophysiology of depression and addictive disease, as well as our approach to relapse and suicidal thinking. To prepare graduates for this new Psychiatry, Yale University has recently started a new one year training program for Psychiatrists in an exciting new field called “Interventional Psychiatry.”
Treating Depression with Ketamine
At present, Ketamine is delivered as a low dose intravenous infusion of 0.5mg/kg over forty minutes. The early results indicate more than 70 percent of patients with TRD have experienced significant relief with ketamine infusion therapy. Because Ketamine is a powerful anesthetic which can be associated with dissociative symptoms, cardiovascular, respiratory and other medical emergencies, a thorough pre-anesthesia like work up prior to infusion is indicated. Such a work up provides valuable information regarding medical risks, dosage and treatment frequency in order to maximize response and minimize adverse events. Patients undergoing ketamine infusion require monitoring of their respiratory function, CO2 levels, along with vital signs. Accordingly, an anesthesiologist and/or specially trained interventional psychiatrist with advanced life support training are recommended.
As reports have spread from the research and medical literature to the lay press, some Psychiatrists and physicians have started ketamine infusion centers. For this reason, The American Psychiatric Association (APA) has recently issued guidelines for clinicians who wish to use ketamine as an off label treatment for TRD and suicidality.
APA Guidelines for Ketamine Use
1. A comprehensive diagnostic assessment should be completed
to establish current diagnosis and evaluate history of substance
use and psychotic disorders.
2. Assessment of baseline symptom severity should be
completed to allow later assessments of clinical change
3. A thorough history of antidepressant treatment should
be collected and documented to confirm previous adequate trials
of antidepressant treatments.
4. A thorough review of systems should be performed
to evaluate potential risk factors associated with
5. Decisions on the specific physical examination and
laboratory screening assessments should be made according
to established guidelines and advisories issued by the American
College of Cardiology Foundation/American Heart Association
and the American Society of Anesthesiologists and should be
based on a patient’s individual clinical characteristics.
6. A careful review of past medical and psychiatric records and/
or corroboration of the past history by family members are
strongly encouraged; all current medications and allergies should
be reviewed, including histories of opiate and benzodiazepine
use; the use of a baseline urine toxicology screen is
strongly encouraged to ensure the accuracy of the reported
substance use and medication record.
7. An informed consent process, including discussion of
the risks associated with the treatment, the limits of the
available information pertaining to the potential benefits of the
treatment, the fact that this is an off-label use of ketamine, and a
discussion of alternative treatment options should be completed;
this discussion should be complemented with written materials,
and the patient should provide written informed consent
before initiating treatment.
As I previously mentioned, a number of Addiction Medicine physicians are also Board Certified in Anesthesiology and have administered ketamine to countless patients. Many addiction medicine doctors and addiction psychiatrists have also worked in pain medicine. For licensed medical professionals the APA guidelines are a good reference if Ketamine is being considered. Certainly more studies are needed and professionals will require new skills with specific training in Psychiatry, Addiction Medicine, TRD, TMS and Ketamine therapy, especially when treating patients with co-occurring depression and addictive disease.
It is not surprising that a drug of abuse, like Ketamine, can play an important role in medicine—not unlike opioids, that are both FDA approved medications— and also drugs of abuse. Similarly, coca leaves (cocaine) are consumed like we drink coffee, by those who live in the Andes Mountain regions of South America, while pure cocaine hydrochloride is still used by ENT doctors as a local anesthetic during nasal surgery.
So, is Ketamine a panacea for depression? Unlikely, or maybe it’s just too early to know for sure. At present, the IV delivery system for Ketamine therapy is neither convenient, simple, or without risk. Although the remarkable and fast acting effects of Ketamine is short lived, the fact that it works at all and exerts its effect via the NMDA system is a potential game-changer. Further, this research may shed some light on why a disproportionally high percent of motivated and treatment adherent recovering people struggle with debilitating depression long-after they have stopped using intoxicants. Although they remain sober, many struggle with sleep problems, anhedonia, boredom, and mood swings, all of which are well documented risk factors for relapse. Our research and work with impaired health professionals have found that 12-Step programs, Caduceus Fellowship, continuous drug and alcohol testing, ongoing professional and peer support have produced unprecedented success, e.g., Over 80% of MD’s in these
• Have never tested positive for drugs or alcohol during 5 years of monitoring.
• Nearly all returned to work in their chosen field without restrictions.
• Nearly all report having a high quality of life.
We know and accept that many of our addicted patients experience co-occurring depression. Accordingly, recovery counseling, tailored psychotherapy modalities, and, when needed, antidepressant therapy can help. If not, TMS, ECT and now, perhaps Ketamine may provide relief and prevent relapse, overdose, loss of hope, and even suicide.
In summary, addictive drugs change the brain. These changes include depression and may persist for months and even years into recovery. Yet we continue seeking to improve because the cost of failure for TRD and addictive disease is simply too high. So we will keep an eye open, and an open mind regarding Ketamine and the research that will certainly follow.
Mark S. Gold, MD, Chairman of the RiverMend Health Scientific
Advisory Boards, is an award-winning expert on the effects of
opiates, cocaine, food and addiction on the brain. His work over
the past 40 years has led to new treatments for addiction and
obesity which are still in widespread use today. He has authored
over 1000 medical articles, chapters, abstracts, journals, and
twelve professional books on a wide variety of psychiatric research
subjects, including psychiatric comorbidity, detox and addiction
treatment practice guidelines.