A quote from the National Institute of Mental Health's website:
"By now, everyone knows that medication
development for mental disorders has hit a wall, pharmaceutical companies have abandoned the search for new medications,
and there are no promising new medications on the horizon. So it is important to take a moment to consider ketamine, an anesthetic
that has been around for decades. Twenty years ago ketamine achieved notoriety as a recreational drug under the
moniker "Special K." But in the past decade, ketamine has emerged as a potential antidepressant.
Recent data suggest that ketamine might be the most important breakthrough in antidepressant
treatment in decades. Three findings are worth noting. First and most important, several studies demonstrate that ketamine
reduces depression within six hours, with effects that are equal to or greater than the effects of six weeks of treatment
with other antidepressant medications. The shift from six weeks to six hours has already transformed what we could and
should expect of antidepressant treatments.
Second, ketamine's effects
have been noted in people with treatment-resistant depression. Most of the studies to date have tested ketamine in people
for whom other treatments were not effective, including both medications and psychotherapy. This promises a new option
for people with some of the most disabling and chronic forms of depression, whether classified as major depressive disorder or bipolar depression.
Third, it appears that one of the earliest effects of the drug is a profound
reduction in suicidal thoughts. Although lithium and clozapine have been reported to reduce suicide risk, we have
not had medications that were specifically anti-suicidal. It is too early to label ketamine as an anti-suicide
medication, but the reduction in suicidal thoughts even prior to the antidepressant effect is promising, especially
given the risk of suicide in people with severe, treatment- resistant depression.
But there is enough potential here that several universities and companies
have launched research and development efforts. Reports of efficacy both obsessive-compulsive disorder and
post-traumatic stress disorder have surfaced in the past year. Recently the Food and Drug Administration awarded breakthrough
therapy designation for the development of intranasal ketamine for treating depression. This is the first time this
special designation, usually reserved for drugs targeting an epidemic or a deadly form of cancer, has been awarded for the development of a medication for a mental disorder. This speaks
not only to the scientific opportunity but the public health need for having a rapid antidepressant.
That need is leading to ketamine clinics using this drug "off-label"
to treat depression. While the science is promising, ketamine is not ready for broad use in the clinic. We just don't
know enough about either efficacy or safety. But with the excitement generated by early results, we will have
more information soon. The doom and gloom surrounding medication development, at least for depression, seems to be rapidly
Usually there is a delay of weeks to months in treatment response
with conventional antidepressants, which is a major drawback that highlights the need to develop faster acting agents. This
is particularly of paramount importance for depressed patients who present with suicidality, a major challenge in Treatment
Resistant Depression (TRD). So far, Ketamine looks promising as a potentially rapid acting antidepressant with a novel
mechanism of action.
Facts about Ketamine Treatments
- Ketamine, an FDA-approved anesthetic, has shown promise in rapidly and effectively treating TRD,
sometimes in as soon as 2 hours
pharmaceutical companies are working to develop Ketamine isomers or metabolites to treat TRD. Janssen Pharmaceutical, for example, has developed a Ketamine enantiomer for intranasal
use, called Esketamine, that is currently in phase II clinical trials with the FDA.
- In August 2016 the FDA put Esketamine on the fast track to official approval for use in treating major depression.
- Duration of benefits following injections varies widely, and more research is needed
to help guide clinicians.
- Reports also
suggest Ketamine may have a role in treating Bipolar depression, severe anxiety, OCD, PTSD, & chronic pain, but more research
is needed in these areas as well.
How Ketamine Works
- Ketamine works primarily as a glutamate receptor (NMDA) antagonist. It suppresses the excitatory
neurotoxicity effects of glutamate, promotes synaptogenesis in key brain areas involved in depression, and rapidly improves
symptoms of TRD, including suicidality. Most
of the approved antidepressant medications primarily target brain monoamine systems (serotonin, norepinephrine, or dopamine)
and, unlike Ketamine which acts ultra-rapidly (usually within two hours of infusion or even quicker), none of these are known
to target the glutamate system, which has been implicated as an important therapeutic target based on recent research in TRD.
- The efficacy of Ketamine in TRD, compared
to other antidepressant medications, stands out in terms of not only its rapidity of effects (within 2–4 hours) but
also its ability to rapidly reverse suicidality in patients with TRD. We are excited to partner with The Georgia Treatment
Resisitant Depression Clinic, becoming one of the few sites in the nation offering this promising new option for
patients with TRD!
What to Expect
- Typically, a patient will receive a series of two intramuscular injections in the deltoid (shoulder) 2-3 days apart.
- Because Ketamine works so rapidly, patients will know whether or not they are responding
after two injections and then can consult with the Psychiatrist regarding the option having three additional injections over
the next 10-12 days or so.
- We have found
that the beneficial effects of a series of 5 injections within a 15-day period may last anywhere between 5-12 weeks.
- After the index course of five treatments, patients may choose the gradual tapering
of a course of maintenance therapy versus taking a "wait and see" approach as to how long benefits will last, resuming
injections only when the beneficial effects wane.
times, injections can rapidly reverse depressive symptoms to the point they can be adequately treated solely with
maintenance antidepressant medications prescribed by your referring physician.
- Treatments are generally well tolerated, with nausea, brief dissociation during the first 15 minutes
or so, and slight blood pressure increases being most common.
- The patient must remain in the office for 60-90 minutes after the injection and must be cleared by
the doctor or nurse prior to being released to drive. it is preferrable to have someone drive you the first visit to see how
you repond prior to driving yourself.
Cost of Injections
- Ketamine's use in Psychiatry, while promising, is not yet FDA approved and therefore NOT covered
by any insurance plans.
- The cost of each injection and clinical monitoring is $160.
Ketamine in the Press
Ketamine: The Future of Depression Treatment?
FDA puts Esketamine on Fast-track for Approval
The last decade has witnessed not only emergence of novel interventions
like Ketamine but also the considerable progress which has been made in examining the utility of the other not-so-new interventions
In this section we present
an overview of the various key aspects of Ketamine, that is, neurobiology of the glutamate system in depression and role of
Ketamine (and its metabolites) in
inducing remission of symptoms of TRD quite rapidly and role of ketamine in neuroplasticity and synaptogenesis that could
possibly explain these rapid effects. One limitation of ketamine is its short lasting effects. The major mechanisms of action
of Ketamine (and its metabolites) in depression are (1) its antagonism of the NMDA subtype of glutamate receptor, (2) its
inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2, also called CaMKIII) thus resulting in increased
synaptic protein synthesis, (3) its action via the mammalian target of rapamycin (mTOR) dependent synapse formation, (4) its
inhibition of the nicotinic acetyl choline receptor (NAR), and (5) its suppression of the glycogen synthase kinase 3 (GSK-3). Ketamine’s effect on GSK-3 provides the rationale to combine ketamine with lithium
(which suppresses GSK-3 as well) for their possible synergistic effect on treatment resistant depression.
Ketamine is primarily known to be an antagonist of the excitatory glutamate receptors:
it directly blocks the NMDA subtype of the glutamate receptor and through this it indirectly affects the AMPA receptors, the
other subtype. The neurobiological mechanisms that implicate the glutamate system in TRD and the role of ketamine in it are
complex and are dependent on many factors including the dose of ketamine and locations of the glutamate receptors not only
in the key brain areas implicated in TRD but also with respect to the synaptic junction, that is, presynaptic versus postsynaptic.
Many researchers have further elaborated upon the possible dysfunction of glutamatergic signaling contributing to depression
by the involvement of D-serine which is a key NMDA receptor coagonist that plays a critical role in long term potentiation
and also NMDA-induced toxicity which has been implicated as one of the neurobiological mechanisms of depression. Glutamate
evokes the release of D-serine from astrocytes and neurons, which then acts at the glycine site on the NR1 subunit of NMDA
receptors that result in excitotoxicity. Ketamine, by its antiglutamate actions, is postulated to reverse this neurotoxicity,
promote rapid proliferation of the dendritic spines in key brain areas, and thus rapidly reverse the symptoms of depression.