Mixed Findings for Intranasal Ketamine
The drug ketamine can rapidly and temporarily improve depression when delivered intravenously. Researchers have been working on extending ketamine’s effects and finding easier ways of delivering the medication. One new delivery method under investigation is nasal spray, which could be used repeatedly to extend ketamine’s effects.
Unfortunately, researcher Colleen Loo reported in the Journal of Psychopharmacology in 2018 that a pilot study of self-administered intranasal ketamine for severe depression was suspended when 5 of the 10 participants had side effects that included high blood pressure, psychotic symptoms, and motor incoordination that made them unable to keep using the spray. Early in the four-week study, dosage was adjusted to leave more time between sprays, but this was not enough to prevent the problems with side effects.
Loo said that the nasal spray version of ketamine has complications including variations in absorption among different people and on different days, depending on factors like mucus in the nose and exact application techniques. Its rapid absorption into the bloodstream could lead to high peak levels in certain people.
Loo and colleagues had previously found that elderly patients receiving injections of ketamine under the skin required highly individualized dosing to avoid side effects. This may also be the case with nasal spray.
While Loo’s study found intranasal ketamine infeasible for the moment, Janssen Research and Development, a pharmaceutical company owned by Johnson & Johnson, reported positive results in phase 3 clinical trials of intranasal esketamine (a component of ketamine) at the annual meeting of the American Psychiatric Association in May. Researchers for Janssen reported that intranasal esketamine was highly effective for depression and well-tolerated both in acute treatment and over a year-long period. Janssen is now pursing approval for the drug from the US Food and Drug Administration.
Intranasal Ketamine for Bipolar Disorder
An in-press article due out in January 2018 by Demitri F. Papolos and colleagues in the Journal of Affective Disorders reports that intranasal ketamine delivered every three to four days reduced symptoms of bipolar disorder in 45 teens (aged 16 years on average). The teens treated in one private practice had the ‘fear-of-harm’ subtype, which in addition to bipolar symptoms is characterized by treatment resistance, separation anxiety, aggressive obsessions, disordered sleep, and poor temperature regulation.
The repeated administration of ketamine produced long-lasting positive results, improving bipolar symptoms as well as social function and academic performance. Many participants reported via survey that they were much or very much improved after being treated for durations ranging from 3 months to 6.5 years. Side effects were minimal and included sensory problems, urination problems, torso acne, dizziness, and wobbly gait.
The ketamine was delivered to alternating nostrils via 0.1 ml sprays that included 50–200 mg/ml of ketamine in 0.01% benzalkonium chloride. Patients were instructed to increase the dosage just up until it became intolerable and then repeat the last tolerable dose every three to four days. Final doses ranged from 20–360 mg. The mean dose was 165 mg (plus or minus 75 mg) delivered every 3 days.
Papolos and colleagues called for placebo-controlled clinical trials based on the positive results from this open study.
Intranasal Oxytocin Soon After a Trauma May Prevent Worsening PTSD
Oxytocin, a hormone that promotes emotional bonding, also benefits people having trouble dealing with stress. A new study suggests that giving oxytocin for a week shortly following a traumatic experience reduces the risk that the recipient will develop post-traumatic stress disorder (PTSD).
In the study by researcher Mirjam van Zuiden and colleagues, people who visited an emergency room following some kind of trauma were randomized to receive either a placebo nasal spray or intranasal oxytocin twice daily for 7.5 days beginning within 12 days after the trauma. The dosage was 40 IU twice daily.
For those participants with severe PTSD symptoms at baseline, repeated oxytocin administration prevented worsening PTSD. The research was presented at the 2016 meeting of the Society of Biological Psychiatry.
Intranasal Ketamine Produces Long-Lasting Antidepressant Effects
It has been known for years that ketamine, an anesthetic at higher doses, can quickly produce anti-depressant effects when delivered intravenously. However, these effects typically last only a few days. New research is exploring how to extend the antidepressant effects of ketamine.
Researcher Ella Daly and colleagues recently compared a form of ketamine called esketamine, this time delivered intranasally, to placebo in people with tough-to-treat depression that had resisted other treatments. Daly and colleagues randomized participants to receive one of three different doses of intranasal esketamine (28mg, 56mg, or 84mg) or placebo twice a week.
All of the doses of intranasal esketamine improved participants’ depression compared to placebo, with higher doses producing more sustained improvement. After the 2-week double-blind study, participants could choose to continue (or begin) taking esketamine for another nine weeks, tapering dosage slowly from twice a week to once every other week by the end. The participants were then monitored for another eight weeks. The intranasal esketamine doses they received led to sustained improvements in depression that lasted, in some cases, through the eight weeks following their final dose.
Side effects were not severe. Ketamine can produce dissociative sensations, but these tended to dissipate with two hours of administration.
Johnson and Johnson Pharmaceuticals funded this research, which was presented at a scientific meeting in 2015, and they plan to continue researching intranasal esketamine in the hopes of getting Food and Drug Administration approval for the drug.
Intranasal Ketamine May Be an Alternative to IV in Refractory Depression
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Kyle Lapidus of Mount Sinai Hospital reviewed the literature from controlled studies on the efficacy of intravenous (IV) ketamine at a dosage of 0.5 mg/kg over a 40-minute infusion for adults with treatment-resistant depression (with consistent response rates of 50% or more), and suggested that intranasal ketamine may also be effective.
Ketamine is a strong blocker of the glutamate NMDA receptor. At high doses (6 to 12 mg/kg) it is an anesthetic, at slightly lower doses (3 to 4 mg/kg) it is psychotomimetic (causing psychotic symptoms) and is sometimes used as a drug of abuse, and at very low doses it is a rapidly acting antidepressant, often bringing about results within 2 hours. Antidepressant effects typically last 3 to 5 days, so the question of how to sustain these effects is a major one for the field.
Murrough et al. reported in Biological Psychiatry in 2012 that five subsequent infusions of ketamine sustained the initial antidepressant response and appeared to be well tolerated by the patients. Another NMDA antagonist, riluzole (used for the treatment of ALS or Lou Gehrig’s disease), did not sustain the acute effects of ketamine, and now lithium is being studied as a possible strategy for doing so.
The bioavailability of ketamine in the body depends on the way it is administered. Compared to IV administration, intramuscular (IM) administration is painful but results in 93% of the bioavailability of IV ketamine. Intranasal (IN) administration results in 25-50% of the bioavailability of IV administration, while oral administration results in only 16-20% of the bioavailability of IV administration, so Lapidus chose to study the IN route. He compared intranasal ketamine at doses of 50mg (administered in a mist ) to 0.5 ml of intranasal saline. Both were given in two infusions seven days apart. Lapidus observed good antidepressant effects and good tolerability. Papolos et al. had reported earlier that intranasal ketamine had good effects in a small open trial in treatment-resistant childhood onset bipolar disorder.
Editor’s Note: Further studies of the efficacy and tolerability of intranasal ketamine are eagerly awaited.
Intranasal Ketamine Helps Some Kids with Bipolar Disorder
The anesthetic ketamine given intranasally may help children with a certain type of bipolar disorder. In an article published in the Journal of Affective Disorders in 2013, Demetri Papolos et al. reported seeing marked improvement in a subgroup of 12 children aged 6 to 19 years of age who were nonresponsive to the usual treatment regimens of lithium, mood stabilizers, and antipsychotics. Papolos has described these children as having the “fear of harm (FOH) subtype.” In addition to having typical mood swings, these children also have a fear of aggression, separation anxiety, sleep and circadian rhythm disorders, nightmares, thermoregulatory problems, and carbohydrate craving.
Ketamine was given as an intranasal spray using an inhaler in 10mg doses. Doses were increased until the targeted symptoms remitted. Average doses ranged from 30mg to 120mg, given every 3 to 7 days. All symptom areas including depression and mania improved markedly, usually within a few hours, and this improvement lasted 3 to 4 days. Four types of aggression (measured on the Overt Aggression Scale) decreased significantly.
There were some dissociative side effects that were usually mild to moderate, but occasionally severe. They resolved spontaneously, usually within the first hour after treatment, and there appeared to be tolerance to them following repeated administration.
The authors urged caution until findings from these cases are confirmed by more controlled studies, but they concluded that the magnitude and rapidity of effects in these children with treatment resistant bipolar disorder suggested effectiveness and safety.
