David Baxter PhD
Late Founder
Ketamine Boosts Hope for Depression Therapy
By MICHELE G. SULLIVAN, Clinical Psychiatry News
08/09/12
In the near future, the anesthetic agent ketamine could play an important role in the treatment of patients who are depressed ? and even suicidal.
Several recent studies support the drug?s almost immediate and long-lasting effects. Animal trials suggest that ketamine might work by stimulating brain-derived neurotrophic factors (BDNFs), which spur neuronal growth. They also hint that variations in the genes that code for BDNF might confer resistance to ketamine; humans with this allele might be less likely to respond to ketamine?s effects.
"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," said Dr. Carlos A. Zarate, a primary investigator in some of the studies. "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."
The National Institutes of Health funded all of the ketamine studies, which were published in several journals between December 2011 and June 2012.
A study of 30 patients with treatment-resistant major depressive disorder concluded that ketamine infusions were associated with significant increases in serum BDNF, accompanied by changes in slow-wave activity on electroencephalograms. Dr. Wallace C. Duncan Jr., of the National Institute of Mental Health, found that the changes were directly related to response: Patients who experienced significant improvements in depression had the highest level of change (Int. J. Neuropsychopharmacol. 2012 June 7 [doi: 10.1017/S1461145712000545]).
"The induction of neurotrophic factors may therefore partially underlie the antidepressant effects of ketamine, given that major depressive disorder is associated with low levels of BDNF and that chronic treatment with antidepressants elevates BDNF levels," he said.
BDNF also is important in facilitating synaptic potentiation, he added.
A mouse study, published in the June issue of Biological Psychiatry, shed some additional light on how the drug might work, and in whom. Dr. George Aghajanian of Yale University, Boston, and his colleagues examined mice specifically bred to express two copies of a gene that impairs BDNF signaling ? an allele configuration expressed in about 30% of humans (Biol. Psychiatry 2012;71:996-1005).
The researchers compared the brains of these mice to those of mice with a single copy of the gene, and to those that lacked the risk allele completely. The homozygous mice displayed significantly less dendritic complexity in their brain neural networks. The density of individual dendritic spines also was much reduced.
Some of the mice received injections of ketamine. When their brains were examined 24 hours later, the heterozygous and wild-type mice showed significantly more dendritic complexity. The mice that were homozygous for the risk gene, however, had fewer improvements in neural health, showing that the gene blunts ketamine?s neural benefits.
A study in humans supports that idea. Dr. Gonzalo Laje of the National Institute of Mental Health has reported on a series of 62 patients with major depressive disorder who were genotyped for the risk allele and treated with ketamine. The presence of a double copy of the gene accounted for 28% of the difference in patients? response to the drug (Biol. Psychiatry 2012 July 9 [doi: 10.1016/j.biopsych.2012.05.031]).
Two recent clinical trials of ketamine show the drug?s potential in major depression. Dr. Zarate reported on a series of 15 patients with bipolar I or II depression stabilized on lithium or valproate who received infusions of ketamine or placebo in a crossover design. The investigators rated depressive symptoms at 40, 80, 110, and 230 minutes after the infusions, and also on days 1, 2, 3, 7, 10, and 14 after each phase of treatment (Biol. Psychiatry 2012;71:939-46).
Depressive symptoms significantly decreased in the active group, compared with the placebo group. The difference between groups remained significant through the third day.
The investigators also examined the drug?s effect on suicidal ideation. On two scales, suicidal thoughts decreased significantly by 40 minutes after the infusion and remained significantly decreased for up to 10 days.
"The most intriguing finding ... may be that ketamine exerted measurable, rapid, and continued anti-suicidal effects," the authors said. "To our knowledge, no controlled study of patients with bipolar depression has yet demonstrated this rapidity of onset, robustness of effect, and continued effect on suicidal ideation resulting from a single administration of any intervention."
Dr. Zarate and co-investigators also published a meta-analysis of ketamine studies, which found strong evidence that the drug offers a rapid, sustained improvement in depressive symptoms. Thus far, 163 patients have been treated in open-label or placebo-controlled trials; response rates have varied from 25% to 85% at 24 hours post infusion, and from 14% to 70% 72 hours afterward. Two open-label and seven randomized controlled trials are currently ongoing (Biol. Psychiatry 2012 June 18 [doi: 10.1016/j.biopsych.2012.05.003]).
Despite encouraging results, questions remain, Dr. Zarate and his coauthors said. "It?s unclear why many patients showing a response at 24 hours relapse less than 48 hours later," they wrote. "It?s also unclear why some patients maintain their response for several weeks."
Although the drug?s adverse event profile is largely acceptable, "there are disadvantages to continuing patients on thrice-weekly or even weekly [intravenous] ketamine infusions."
One option might be to start patients getting a single ketamine dose on an approved monoaminergic antidepressant or mood stabilizer, Dr. Zarate and his colleagues suggested. "Even though patients may have previously not responded to this medication, it might still help maintain an acute response to ketamine."
However, they concluded, "this type of approach, although practical, remains speculative at this point, and future studies are clearly needed."
Dr. Zarate has a patent application for the use of ketamine in major depression. He has assigned his rights to the U.S. government, but will still receive a share of any royalties that might be produced. Dr. Duncan, Dr. Aghajanian, and Dr. Laje declared they had no financial conflicts of interest.
By MICHELE G. SULLIVAN, Clinical Psychiatry News
08/09/12
In the near future, the anesthetic agent ketamine could play an important role in the treatment of patients who are depressed ? and even suicidal.
Several recent studies support the drug?s almost immediate and long-lasting effects. Animal trials suggest that ketamine might work by stimulating brain-derived neurotrophic factors (BDNFs), which spur neuronal growth. They also hint that variations in the genes that code for BDNF might confer resistance to ketamine; humans with this allele might be less likely to respond to ketamine?s effects.
"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," said Dr. Carlos A. Zarate, a primary investigator in some of the studies. "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."
The National Institutes of Health funded all of the ketamine studies, which were published in several journals between December 2011 and June 2012.
A study of 30 patients with treatment-resistant major depressive disorder concluded that ketamine infusions were associated with significant increases in serum BDNF, accompanied by changes in slow-wave activity on electroencephalograms. Dr. Wallace C. Duncan Jr., of the National Institute of Mental Health, found that the changes were directly related to response: Patients who experienced significant improvements in depression had the highest level of change (Int. J. Neuropsychopharmacol. 2012 June 7 [doi: 10.1017/S1461145712000545]).
"The induction of neurotrophic factors may therefore partially underlie the antidepressant effects of ketamine, given that major depressive disorder is associated with low levels of BDNF and that chronic treatment with antidepressants elevates BDNF levels," he said.
BDNF also is important in facilitating synaptic potentiation, he added.
A mouse study, published in the June issue of Biological Psychiatry, shed some additional light on how the drug might work, and in whom. Dr. George Aghajanian of Yale University, Boston, and his colleagues examined mice specifically bred to express two copies of a gene that impairs BDNF signaling ? an allele configuration expressed in about 30% of humans (Biol. Psychiatry 2012;71:996-1005).
The researchers compared the brains of these mice to those of mice with a single copy of the gene, and to those that lacked the risk allele completely. The homozygous mice displayed significantly less dendritic complexity in their brain neural networks. The density of individual dendritic spines also was much reduced.
Some of the mice received injections of ketamine. When their brains were examined 24 hours later, the heterozygous and wild-type mice showed significantly more dendritic complexity. The mice that were homozygous for the risk gene, however, had fewer improvements in neural health, showing that the gene blunts ketamine?s neural benefits.
A study in humans supports that idea. Dr. Gonzalo Laje of the National Institute of Mental Health has reported on a series of 62 patients with major depressive disorder who were genotyped for the risk allele and treated with ketamine. The presence of a double copy of the gene accounted for 28% of the difference in patients? response to the drug (Biol. Psychiatry 2012 July 9 [doi: 10.1016/j.biopsych.2012.05.031]).
Two recent clinical trials of ketamine show the drug?s potential in major depression. Dr. Zarate reported on a series of 15 patients with bipolar I or II depression stabilized on lithium or valproate who received infusions of ketamine or placebo in a crossover design. The investigators rated depressive symptoms at 40, 80, 110, and 230 minutes after the infusions, and also on days 1, 2, 3, 7, 10, and 14 after each phase of treatment (Biol. Psychiatry 2012;71:939-46).
Depressive symptoms significantly decreased in the active group, compared with the placebo group. The difference between groups remained significant through the third day.
The investigators also examined the drug?s effect on suicidal ideation. On two scales, suicidal thoughts decreased significantly by 40 minutes after the infusion and remained significantly decreased for up to 10 days.
"The most intriguing finding ... may be that ketamine exerted measurable, rapid, and continued anti-suicidal effects," the authors said. "To our knowledge, no controlled study of patients with bipolar depression has yet demonstrated this rapidity of onset, robustness of effect, and continued effect on suicidal ideation resulting from a single administration of any intervention."
Dr. Zarate and co-investigators also published a meta-analysis of ketamine studies, which found strong evidence that the drug offers a rapid, sustained improvement in depressive symptoms. Thus far, 163 patients have been treated in open-label or placebo-controlled trials; response rates have varied from 25% to 85% at 24 hours post infusion, and from 14% to 70% 72 hours afterward. Two open-label and seven randomized controlled trials are currently ongoing (Biol. Psychiatry 2012 June 18 [doi: 10.1016/j.biopsych.2012.05.003]).
Despite encouraging results, questions remain, Dr. Zarate and his coauthors said. "It?s unclear why many patients showing a response at 24 hours relapse less than 48 hours later," they wrote. "It?s also unclear why some patients maintain their response for several weeks."
Although the drug?s adverse event profile is largely acceptable, "there are disadvantages to continuing patients on thrice-weekly or even weekly [intravenous] ketamine infusions."
One option might be to start patients getting a single ketamine dose on an approved monoaminergic antidepressant or mood stabilizer, Dr. Zarate and his colleagues suggested. "Even though patients may have previously not responded to this medication, it might still help maintain an acute response to ketamine."
However, they concluded, "this type of approach, although practical, remains speculative at this point, and future studies are clearly needed."
Dr. Zarate has a patent application for the use of ketamine in major depression. He has assigned his rights to the U.S. government, but will still receive a share of any royalties that might be produced. Dr. Duncan, Dr. Aghajanian, and Dr. Laje declared they had no financial conflicts of interest.
