illustration of roads showing off label and on label use of ketamine

Ketamine FDA Approval & Off-label Use

Ketamine as an Anesthetic

In 1962, ketamine was first synthesized. By 1964, it was being trialed on humans. It was found to produce a state that was described as “dissociative anesthesia”. Following these trials, it was approved as an anesthetic by the Food and Drug Administration (FDA) in 1970.

 

S-ketamine for Treatment-resistant Depression

At the turn of the millennium, ketamine was found to have profound and fast-acting antidepressant effects [1]. Subsequent studies found it helped many people with depression so severe that the condition did not respond to any other treatment modality. 60 to 70% of participants showed an antidepressant response [2-6].

The drug was also found to be very fast acting. Effects were observed within a matter of hours after administration. This is compared with the several weeks that traditional antidepressants can take to have an effect. In 2019, the FDA approved s-ketamine, for use in treatment-resistant depression.

 

Off-label Use of Ketamine

The use of ketamine is considered “on-label” when it is used for the medical purposes that the FDA has approved it for.  This includes:

When it is used for other conditions that are not covered by the FDA designation then the use is considered “off-label”. Ketamine has been found to help with a variety of mental health issues such as depression, bipolar, anxiety and PTSD. It is now being used off-label to treat these conditions.

 

Common Disorders That Ketamine Can Treat Off-label

 

1. Depression

Although s-ketamine is approved to treat depression, r-ketamine is still in clinical trials to treat depression on-label.

 

How does ketamine work as an antidepressant?

Ketamine acts on one of the brain’s main neurotransmitter systems, the glutamate system. It does so by activating NMDA receptors, the main receptor in the brain involved in learning and memory. NMDA receptor activation results in changes in brain circuitry, known as neuroplasticity.

Ketamine may also work as an antidepressant by producing a strong stimulus to the glutamatergic system. This temporarily shifts the brain out of its habitual ruts and allows it to settle into a healthier equilibrium.

As ketamine acts on these receptors, it promotes neuroplasticity. This allows the brain to adapt and function in a more flexible way. Depression is typically characterized by a sense of being stuck in a particular psychological mode. Flexibility through neuroplasticity may represent a powerful way out of depression if coupled with therapy to identify new ways of responding to old situations.

Ketamine also activates opioid receptors. This mediates its pain-relieving effect as an anesthetic. The same circuitry in the brain mediates the sense of physical and emotional pain. (A word of caution, this may also contribute to the addictive potential of ketamine when misused in a recreational setting.)

 

2. Bipolar

Bipolar disorder is characterized by dramatic fluctuations in mood, from depressive to manic. Ketamine therapy is typically used to help with the depressive episodes of bipolar, given its powerful antidepressant effects. While research on bipolar is less common than for depression, several studies have found ketamine to be an effective therapy for this condition.

The first randomized, double-blind, placebo-controlled study of a single-dose ketamine infusion therapy for bipolar found an antidepressant effect when administered alongside mood stabilizers [10]. Since this study, these findings have been replicated by other studies [11-15]. They have been confirmed by meta-analyses of this research, in which the totality of the evidence is integrated and considered [17-18].

 

How does ketamine treat bipolar?

The treatment of bipolar with ketamine is thought to be similar to that of depression: acting on plasticity via the glutamate system. Studies have found that a high Body Mass Index (BMI) and lower levels of adiponectin (a hormone released by fat tissue that affects insulin sensitivity) were predictive of how well ketamine will work for bipolar and depression [19-20]. This raises the possibility that metabolism may play a mediating role in the effects of ketamine therapy in these conditions.

Since ketamine is being used for the treatment of depressive symptoms of bipolar disorder, it is important to monitor for worsening of the symptoms of mania following successful treatment of the depression. It is suggested that one continues seeing their therapist throughout the duration of the treatment.

 

3. Anxiety

Anxiety is a feeling of unease, worry or fear. It is a symptom that is common to many mental health issues such as:

  • Post-Traumatic Stress Disorder (PTSD)
  • Phobias
  • Social Anxiety Disorder (SAD)
  • Panic disorder

When anxiety is severe and present across different situations, one may be diagnosed with Generalized Anxiety Disorder (GAD).

 

How does ketamine treat anxiety?

Ketamine has been found to have anxiolytic or “anxiety reducing” effects in people suffering from GAD and SAD. One study investigated the efficacy and safety of ketamine individuals with refractory versions of these disorders. These individuals had not responded successfully to other treatments, and were not suffering from depression at the time of the study. Participants reported reduced anxiety within an hour of the ketamine being administered. This effect persisted for up to 1 week [21].

The anxiolytic effects of ketamine may be achieved by a similar mechanism to the antidepressant effects. Anxiety and depression are both states of disordered mood and are related, often occurring together. The major difference between these mental health challenges is that in depression one is typically in a largely deactivated state of hopelessness while in anxiety one is typically in an activated, fearful state.

Ketamine may be able to help the brain by promoting plasticity and stimulating the glutamate pathways that mediate information processing in the brain. The therapy supporting this treatment can help identify new ways of processing information, allowing the brain to respond differently. The anesthetic properties of ketamine may also serve to reduce symptoms of anxiety in the short term.

 

4. PTSD

Post-Traumatic Stress Disorder (PTSD) refers to a state of being following a traumatic experience where the person is unable to process the fear associated with the past event and this manifests as anxiety, sleep issues, intrusive thoughts and flashbacks after the event.

 

How does ketamine treat PTSD?

Research comparing ketamine to the anti-anxiety drug midazolam in patients with PTSD found that ketamine rapidly reduced the severity of their symptoms [22]. One case study of a child with PTSD found that their symptoms went into remission after being treated with ketamine [23].

Beyond treating symptoms, ketamine may also be able to work as a preventative medicine. One study in mice found that the administration of ketamine immediately after a traumatic event resulted in an impairment of the storage of the fear memory [24].

Memory storage occurs in the brain when the synapses between glutamatergic neurons become strengthened as a result of NMDA receptor activation. Since ketamine acts on these precise receptors in these specific neurons, it holds much hope as a treatment for PTSD.

By boosting plasticity in these pathways it may be possible for individuals to unlearn the fear memories that give rise to their symptoms and to replace them with memories of safety. Early ketamine treatment may also provide a way to disrupt the consolidation of these memories, the process by which they are transferred into long term storage.

Since its approval for use by the FDA in 1970, ketamine has been found to help multiple conditions. From its original approved uses in anesthesia and pain relief to the treatment of depression, bipolar, anxiety, and PTSD ketamine has helped countless people through both its on-label and off-label use. As research continues, we’re hopeful to see this list of conditions that ketamine can treat expand in the future.

 

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References

[1] Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354. 

[2] Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170: 1134–1142. 

[3] Zarate CAJ, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856–864. 

[4] Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67: 793–802.

[5] Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol 2015; 30: 152–163. [PubMed] 

[6] Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry 2018; 175: 150–158.

[10] Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793–802. 

[11] Zarate CA Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939–946.

[12] Grunebaum MF, Ellis SP, Keip JG, et al. Ketamine versus midazolam in bipolar depression with suicidal thoughts: a pilot midazolam-controlled randomized clinical trial. Bipolar Disord. 2017;19(3):176–183. doi:10.1038/s41386-019-0317-8

[13] Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA Jr. A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar Disord. 2015;17:438–443.

[14] Permoda-Osip A, Skibinska M, Bartkowska-Sniatkowska A, Kliwicki S, Chlopocka-Wozniak M, Rybakowski JK. Factors connected with efficacy of single ketamine infusion in bipolar depression. Psychiatr Pol. 2014;48:35–47. 

[15] Rybakowski JK, Permoda-Osip A, Bartkowska-Sniatkowska A. Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression. Int J Psychiatry Clin Pract. 2017;21:99–103.

[17] Kishimoto T, Chawia JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46:1459–1472. 

[18] Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150–158.

[19] Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Clinical predictors of ketamine response in treatment-resistant major depression. J Clin Psychiatry. 2014;75:e417–e423. 

[20] Machado-Vieira R, Gold PW, Luckenbaugh DA, et al. The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry. 2017;22:127–133. doi:10.1038/mp.2016.3621. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing

[21] Glue P, Medlicott NJ, Harland S, et al. Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017;31(10):1302-1305.

[21] Shadli SM, Kawe T, Martin D, McNaughton N, Neehoff S, Glue P. Ketamine effects on EEG during therapy of treatment-resistant generalized anxiety and social anxiety [published online April 24,2018]. Int J Neuropsychopharmacology. doi:10.1093/ijnp/pyy032

[22] Feder A, Parides M, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681-688.

[23] Donoghue AC, Roback MG, Cullen KR. Remission from behavioral dysregulation in a child with PTSD after receiving procedural ketamine. Pediatrics. 2015;136(3):e694-e696.

[24] Ito W, Erisir A, Morozov A. Observation of distressed conspecific as a model of emotional trauma generates silent synapses in the prefrontal-amygdala pathway and enhances fear learning, but ketamine abolishes those effects. Neuropsychopharmacology. 2015; 40(11):2536-2545.

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