Rapid-Onset Antidepressant Treatments
At the International College of Neuropsychopharmacology (CINP) World Congress of Neuropsychopharmacology in 2014, several presentations and posters discussed treatments that bring about rapid-onset antidepressant effects, including ketamine, isoflurane, sleep deprivation, and scopolamine.
Ketamine’s Effects
Multiple studies, now including more than 23 according to researcher William “Biff” Bunney, continue to show the rapid-onset antidepressant efficacy of intravenous ketamine, usually at doses of 0.5 mg/kg over 40 minutes. Response rates are usually in the range of 50–70%, and effects are seen within two hours and last several days to one week. Even more remarkable are the six studies (two double-blind) reporting rapid onset of antisuicidal effects, often within 40 minutes and lasting a week or more. These have used the same doses or lower doses of 0.1 to 0.2mg/kg over a shorter time period.
Attempts to sustain the initial antidepressant effects include repeated ketamine infusions every other day up to a total of six infusions, a regimen in which typically there is no loss of effectiveness. Researcher Ronald Duman is running a trial of co-treatment with ketamine and lithium, since both drugs block the effects of GSK-3, a kinase enzyme that regulates an array of cellular functions, and in animals the two drugs show additive antidepressant effects. In addition, lithium has been shown to extend the acute antidepressant effects of one night of sleep deprivation, which are otherwise reversed by a night of recovery sleep.
Ketamine’s effects are related to the neurotransmitter glutamate, for which there are several types of receptors, including NMDA and AMPA. Ketamine causes a large burst of glutamate presumably because it blocks NMDA glutamate receptors on inhibitory interneurons that use the neurotransmitter GABA, causing glutamatergic cells to lose their inhibitory input and fire faster. While ketamine blocks the effects of this glutamate release at NMDA receptors, actions at AMPA receptors are not blocked, and AMPA activity actually increases. This increases brain-derived neurotrophic factor (BDNF), which is also required for the antidepressant effects of ketamine. Ketamine also increases the effects of mTOR, a kinase enzyme that regulates cell growth and survival, and if these are blocked with the antibiotic rapamycin, antidepressant effects do not occur.
In animal studies, ketamine increases dendritic spine growth and rapidly reverses the effects of chronic mild unpredictable stressors on the spines (restoring their mature mushroom shape and increasing their numbers), effects that occur within two hours in association with its rapid effects on behaviors that resemble human depression.
About 50–70% of treatment-resistant depressed patients respond to ketamine. However, about one-third of the population has a common genetic variation of BDNF in which one or both valine amino acids that make up the typical val-66-val allele are replaced with methionine (producing val-66-met proBDNF or met-66-met proBDNF). The methionine variations result in the BDNF being transported less easily within the cell. Patients with these poorly functioning alleles of BDNF are less likely to get good antidepressant effects from treatment with ketamine.
Ketamine in Animal Studies
Researcher Pierre Blier reviewed the effects of ketamine on the neurotransmitters serotonin, norepinephrine, and dopamine. In rodents, a swim stress test is used to measure depression-like behavior. Researchers record how quickly the rodents give up trying to get out of water and begin to float instead. Blier found that ketamine’s effects on swim stress were dependent on all three neurotransmitters. For dopamine, ketamine’s effects were dependent on increases in the number of dopamine cells firing, not on the firing rate, and for norepinephrine, ketamine’s effects were dependent on increases in burst firing patterns. Each of these effects was dependent on glutamate activity at AMPA receptors. Given these effects, Blier believes that using ketamine as an adjunct to conventional antidepressants that tend to increase these neurotransmitters may add to its clinical effectiveness.
Important Anecdotal Clinical Notes
Blier reported having given about 300 ketamine infusions to 25 patients, finding that two-thirds of these patients responded, including one-third who recovered completely, while one-third did not respond to the treatment. Patients received an average of 12 infusions, not on a set schedule, but according to when they began to lose response to the last ketamine infusion. If a patient had only a partial response, Blier gave the next ketamine treatment at a faster rate of infusion and was able to achieve a better response. These clinical observations are among the first to show that more than six ketamine infusions may be effective and well tolerated.
In a personal communication, researcher Robert Kowatch indicated that he is also using intravenous ketamine at doses of 0.5mg/kg over a 20-minute period in adolescents (age 13 to 17) with treatment-resistant depression, with some success.
Ketamine’s Effects on Human Brain Activity
Austrian researcher Rupert Lanzenberger used imaging techniques to study the effects of ketamine on different parts of the brain. He observed increases in serotonin and dopamine. Glucose metabolism increased in the thalamus and the frontal and parietal cortices, and decreased in the right habenula and insula. Increases in metabolism in the subgenual cingulate cortex were related to the degree of clinical antidepressant response to ketamine. Measuring blood flow, Lanzenberger saw increases in activity in the anterior cingulate cortex and the medial and inferior frontal cortices, but decreases in the cerebellum.
Editor’s Note: Ketamine reverses (or normalizes) typical regional neurophysiological signs of depression, including frontal lobe underactivity and overactivity in the habenula and cerebellum.
Isoflurane: Rapid Onset Antidepressant Effects
The anesthetic isoflurane may also produce rapid onset antidepressant effects (some but not all studies have been positive), and does not appear to work by increasing BDNF or inducing synaptic spine effects as ketamine does. Isoflurane rather appears to cause shrinkage and loss of dendritic spines in the hippocampus. It is conceivable that isoflurane could work in ketamine non-responders, as its mechanism of action is different and it does not require BDNF increases or spine alterations, which ketamine does. However, a recent study indicated that isoflurane’s effects were mediated by TrkB, the receptor for BDNF, so BDNF activity at its receptor may still be important.
Sleep Deprivation: Overnight Antidepressant Effects
At the Congress, Bunney reviewed the extensive and consistent literature on the acute antidepressant effects of one night of sleep deprivation. These antidepressant effects can be extended beyond one day by co-treatment with lithium or with the use of bright light (10,00 Lux) in the morning along with a phase advance (going to sleep from 6pm to 2am the following night, 7pm to 3am the next, and 8pm to 4am the next, and so on until a normal sleep schedule occurs). This alters circadian rhythms and the expression of CLOCK genes, which control these rhythms. Bunney believes that this alteration in CLOCK gene expression could be responsible for the antidepressant effects.
Researcher Francesco Benedetti reported that a series of three nights of sleep deprivation (every other night) while patients took lithium and received light therapy resulted in positive and extended antidepressant effects. Most intriguingly, he reported that even non-responders to sleep deprivation showed improvement in suicidal ideation with this regimen. There are normal variations in CLOCK genes in the general population, and Benedetti linked the presence of the CC allele (as opposed to the TT allele) of the gene to both insomnia and suicidal ideation.
Rapid Onset Antidepressant Effects with Scopolamine
Scopolamine is another drug that can be used intravenously to bring about rapid onset of antidepressant effects at doses of 4 micrograms/kg. Scopolamine blocks acetylcholine muscarinic receptors. Researcher Ronald Duman suggests that scopolamine blocks these receptors on inhibitory GABA interneurons synapsing on glutamatergic cell bodies, thus causing a rapid increase in glutamate similar to that brought about by ketamine. Scopolamine also increases BDNF and mTOR, and rapidly increases synaptic spines in the prefrontal cortex, as ketamine does.
Editor’s Note: Since chronic oral scopolamine also augments the effects of antidepressant drugs over a period of several weeks, the acute short-lived antidepressants effects of intravenous ketamine could theoretically be extended with oral scopolamine, but this possibility has not yet been studied.
