Meta-Analysis Shows Effectiveness of Ketamine for Bipolar and Unipolar Depression
Ketamine, an anesthetic sometimes used intravenously in the treatment of depression, can bring about rapid onset of antidepressant effects. A new meta-analysis by researcher Michael Bloch and colleagues presented at a recent conference showed that ketamine’s maximum antidepressant effects occur within one day of administration, and its effects remain significant (compared to control conditions) one week following infusion. Ketamine’s effects were diminished in patients taking other medications. There was a trend for better response in patients with bipolar disorder than with unipolar disorder.
Bloch and colleagues analyzed eight earlier studies including a total of 180 participants. In each study, ketamine had been compared to a control condition, either an infusion of saline solution or of midazolam, which mimics ketamine’s sensory effects but does not have antidepressant effects. The researchers are calling for more meta-analyses of ketamine studies to determine which patients respond best to ketamine and how to sustain ketamine’s effects.
Editor’s Note: In another poster presented at the same conference, James Murrough reported that patients with slower processing speed responded best to ketamine. Other findings have shown that those with a history of alcohol abuse and a common genetic variant of brain-derived neurotrophic factor (BDNF), the val-66-val allele of proBDNF, are more likely to respond to ketamine.
High Blood Pressure is a Marker of Good Response to Prazosin in PTSD
Prazosin, an alpha-1 adrenoreceptor antagonist, has been found to be effective at reducing symptoms of post-traumatic stress disorder (PTSD), including nightmares. Researchers led by Murray Raskind hypothesized that there may be a link between blood pressure and response to prazosin, since resting blood pressure can be used to measure alpha-1 adrenoreceptor responsiveness. In a study of active duty combat soldiers with PTSD, higher resting blood pressure and smaller drop in blood pressure when going from lying down to standing up predicted a better response to prazosin.
The researchers believe that blood pressure can be used to estimate the central nervous systems’s responsiveness to norepinephrine, which prazosin blocks. In patients with PTSD who received placebo instead of prazosin, blood pressure did not predict improvement. Raskind and colleagues hope to be better able to predict response to prazosin in PTSD by measuring patients’ baseline blood pressure.
Ziprasidone Added to Escitalopram Improved Unipolar Depression
In a new study of patients with major depressive disorder who did not improve after eight weeks of the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram, the addition of the atypical antipsychotic ziprasidone improved their depression more than did placebo. Patients took the combination of escitalopram (20mg/day on average) and ziprasidone twice a day at doses of 20–80 mg.
This was the first randomized, double-blind placebo controlled trial of ziprasidone as an adjunct treatment for unipolar depression. While ziprasidone was more efficacious than placebo, discontinuation of the study due to intolerance was higher among the patients who received ziprasidone.
Editor’s Note: Two atypical antipsychotics (quetiapine and aripiprazole) have been approved by the Federal Drug Administration for augmentation of antidepressants in unipolar depression. Now there have also been placebo-controlled positive trials of two others (ziprasidone and cariprazine).
These findings are of particular interest as the studies of ziprasidone monotherapy in bipolar depression not only failed, but response to ziprasidone and placebo was virtually identical (and negligible).
More Evidence for Cariprazine’s Efficacy in Bipolar Depression
In an eight-week study of the drug cariprazine for bipolar depression by Joe Calabrese and colleagues, patients who received 1.5mg/day doses of the drug showed more improvement in their illness and higher remission rates after six weeks than patients who received placebo. Side effects were rare, with mild or moderate akithisia (restless legs) being most common. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors.
Transcranial Direct Current Stimulation May Improve Cognition in Schizophrenia
A recent study by Robert Smith and colleagues studied the use of transcranial direct current stimulation (tDCS) in patients with schizophrenia. TDCS is very low level current that has a positive (anode) or negative (cathode) electrode. Anodal stimulation of the cortex is usually associated with positive effects on mood and cognition. Patients received either five sessions of active tDCS for 20 minutes (at 2 milli Amps) or a sham stimulation for the same period. Then, one day after the final session, the patients were measured on a variety of scales for cognition and illness. Patients who received the active tDCS showed more improvements in working memory and attention than patients who received the sham treatment.
There was no difference in the two groups’ schizophrenic symptoms, including hallucinations. Smith and colleagues suggest that the improvements in cognition may result from changes to brain connectivity networks, since abnormalities in these networks have been identified in patients with schizophrenia and bipolar disorder.
Replications of this type of study are needed to clarify the effect of tDCS on cognition in schizophrenia, but given the safety and convenience of the procedure, the findings are promising.
Exercise Improves Fitness, May Help Reduce Cocaine Use
In studies of rodents, running on a wheel reduces cocaine self-administration. A recent study by Richard de la Garza and colleagues investigated whether running or walking on a treadmill can reduce cocaine cravings and use in humans. In the study of 24 participants who had been using cocaine an average of 19.7 years, participants were randomized to run, walk, or sit for 30 minutes three times per week for four consecutive weeks. After exercising, the participants reported having less craving for cocaine. Fitness measures such as body weight and resting heart rate improved in both walkers and runners. While not statistically significant, by the end of the study there was a trend indicating that exercise improved abstinence from cocaine and decreased daily craving for cocaine.
Editor’s Note: Exercise Increases brain-derived neurotrophic factor (BDNF) and neurogenesis. In rodents, cocaine is associated with decreases in BDNF in the frontal cortex, and injecting BDNF there decreases cocaine seeking. Whether this BDNF effect or the general effects of exercise on mood and conditioning account for these positive cocaine effects remains to be ascertained.
Exposure to Stress Hormone Leads to Poor Decision-Making
Adolescence may be a period of particular vulnerability to the effects of stress. New research by Shannon Gourley indicates a possible mechanism for this vulnerability. When Gourley exposed adolescent mice to low levels of the stress hormone corticosterone (the equivalent to human cortisol), they developed habit-based rather than goal-oriented decision-making, leading to behaviors that resembled human depression, which lasted into adulthood. Adult mice that were exposed to the low levels of corticosterone were not affected by it.
Gourley also used an alternative method of producing these stress responses a second time by silencing the trkB receptor for brain-derived neurotrophic factor (BDNF) in the amygdala and hippocampus of the mice. The depression-like behaviors that resulted, such as lack of motivation, were able to be reversed by treating the mice with 7,8-dihydroxyflavone, a drug that activated the trkB receptor. In the adolescent mice, this treatment had antidepressant effects that lasted into adulthood, even though the treatment stopped earlier.
Short Telomeres in a Rat Model of Depression, Lithium Reverses Abnormality
telomere
Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect them during cell replication. Telomeres get shorter with aging and with stressors or psychiatric illnesses. Researcher Alexandre Mathe and colleagues recently found that in a line of rats bred to be more susceptible to stress and depression-like behavior, hippocampal telomeres were shorter than in normal rats or rats bred to be less susceptible. The susceptible rats also had lower levels of enzymes that maintain telomere length. Both telomerase activity and Tert (telomerase reverse transcriptase) expression were reduced in the susceptible rat compared to the other rats. However, lithium reversed the low levels of telomerase activity and Tert expression.
Editor’s Note: Lithium increases hippocampal volume in people, and also increases human telomerase. Researcher Lina Martinsson reported in 2013 that lithium increases telomere length in white cells. Now lithium has increased hippocampal telomerase in a rat model of depression. Short telomeres are associated with aging and increased vulnerability to a wide range of medical and psychiatric disorders. Since people with bipolar disorder are prone to memory problems, medical problems, and short telomeres, they might want to talk to their physician about including lithium in their treatment regimen, if they are not already taking it.
Gene CACNA1C is Associated with Early-Onset Bipolar Disorder
Several genes have previously been implicated in bipolar illness. In a recent study, researchers at the Mayo Clinic, led by Paul Croarkin, compared variations in three genes (CACNA1C, ANK3, and ODZN) across 69 children aged 6–15 with mania, a 776-person control group from the Mayo Biobank database, and 732 adults with bipolar disorder (some with onset in childhood and adolescence and some with onset in adulthood, also from the Biobank). All participants were Caucasian, to minimize confounding by population stratification. The researchers found that the minor allele of rs10848632 in CACNA1C was associated with childhood onset of bipolar disorder. The haplotype (or sequence of nucleotides) T-G-G-T was the one associated with risk. Genetic risk scores were also associated with early onset of illness.
Editor’s Note: In research by Michael McCarthy and colleagues, CACNA1C has been linked to abnormal circadian rhythms in bipolar disorder and to responsiveness to lithium treatment. Together, these data suggest the importance of studying the calcium channel blocker nimodipine (which blocks calcium influx through CACNA1C) in childhood-onset bipolar disorder. A 1999 case report by Pablo A. Davanzo and colleagues described a teenager with ultra rapid cycling bipolar disorder (multiple mood switches/day) that did not respond to a host of conventional medications, who improved dramatically on nimodipine, reaching remission. This author (Robert M. Post) has also seen confirmed responsivity in adults with rapid cycling bipolar disorder (reported in the 2008 book Treatment of Bipolar Illness: A Casebook for Clinicians and Patients, by Post and Gabriele S. Leverich).
Calcium Channel May Be Responsible for Circadian Rhythm Abnormalities in Bipolar Disorder
Genetic variation in L-type calcium channel genes have been linked to bipolar disorder. Since calcium plays an important role in circadian rhythms, abnormalities in the calcium channel in bipolar disorder could explain some of the circadian rhythm disturbances patients with bipolar disorder exhibit. New research by Michael McCarthy and colleagues shows that calcium channels in general, and the gene CACNA1C in particular, affect signaling pathways that regulate circadian rhythms in both human and animal cells. The researchers also found that calcium channels affected how lithium changes circadian rhythms, suggesting a mechanism by which the treatment may work. They suggest that drugs that affect the L-type calcium channel may be promising treatments for bipolar disorder.
Editor’s Note: The L-type calcium channel blocker nimodipine has had antidepressant, antimanic, and anticycling effects in some patients with bipolar disorder in small studies both by Peggy Pazzaglia and colleagues (including this author Robert Post) and a larger randomized study by Haroon R. Chaudhry.
The clinical effects of nimodipine results thus align with studies linking the CACNA1C gene to bipolar illness and its early onset, increased expression of the gene in the brain of bipolar patients in autopsy studies, increased levels of calcium in white cells of bipolar patients, and a variety of other neurobiological phenomena observed in normal controls carrying the risk gene.
The new link found between CACNA1C and circadian rhythms further links the L-type calcium channel abnormality and bipolar disorder, as well as the therapeutic effects of the L-type calcium channel blocker nimodipine. This drug deserves further study, especially in those with the genetic variation in CACNA1C that has been linked to bipolar disorder.
