Flavanols, which are found in small amounts in raw cocoa, tea leaves, fruits, and vegetables, may be able to improve age-related memory loss. The normal process by which chocolate is made removes all flavanols from cocoa, but the Mars Inc. company recently developed a process to isolate flavanol in powder form.
In a 2014 study by Scott Small et al. in Nature Neuroscience, of 37 participants between the ages of 50 and 69, those who were randomized to a high-flavanol diet (900mg per day, from drinking the powder mixed with water or milk) over a three-month period showed more improvement on a memory test than those participants who were randomized to a low-flavanol diet (10mg per day). The high-flavanol group both scored higher than the other group at the end of the study and showed more improvement relative to their own abilities at the start of the study. Small said that after three months of taking the flavanols, someone who began with a typical memory for a 60-year-old developed a memory more like a 30- or 40-year-old. The high-flavanol group also showed improvement in function in a part of the hippocampus called the dentate gyrus.
Three articles in the September 2014 issue of the journal Psychiatric Annals (Volume 44 Issue 9) discussed differentiating pediatric bipolar disorder from attention deficit hyperactivity disorder (ADHD). The first article, by Regina Sala et al., said that reasons to suspect bipolar disorder in a child with ADHD include:
- The ADHD symptoms appear for the first time after age 12.
- The ADHD symptoms appear abruptly in an otherwise healthy child.
- The ADHD symptoms initially responded to stimulnts and then did not.
- The ADHD symptoms come and go and occur with mood changes.
- A child with ADHD begins to have periods of exaggerated elation, grandiosity, depression, decreased need for sleep, or inappropriate sexual behaviors.
- A child with ADHD has recurring severe mood swings, temper outbursts, or rages.
- A child with ADHD has hallucinations or delusions.
- A child with ADHD has a strong family history of bipolar disorder in his or her family, particularly if the child does not respond to appropriate ADHD treatments.
The second article, by this editor Robert Post, Robert Findling, and David Luckenbaugh, emphasized the greater severity and number of symptoms in childhood onset bipolar disorder versus ADHD. Children who would later develop bipolar disorder had brief and extended periods of mood elevation and decreased sleep in the early years of their lives. These, along with pressured speech, racing thoughts, bizarre behavior, and grandiose or delusional symptoms emerged differentially from age three onward. In contrast, the typical symptoms of ADHD such as hyperactivity, impulsivity, and decreased attention were equal in both diagnoses.
In the third article, Mai Uchida et al. emphasized the utility of a family history of bipolar disorder as a risk factor. Moreover, a child with depression plus ADHD is at increased risk for a switch into mania on antidepressants if there is a family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania symptoms, or psychosis.
The differential diagnosis of ADHD versus bipolar disorder (with or without comorbid ADHD) is critical, as drug treatment of these disorders is completely different.
Bipolar disorder is treated with atypical antipyschotics; anticonvulsant mood stabilizers, such as valproate, carbamazepine, or lamotrigine; and lithium. Only once mood is stabilized should small doses of stimulants be added to treat residual ADHD symptoms.
ADHD, conversely, is treated with short- or long-acting stimulants such as amphetamine or methylphenidate from the onset, and these may be augmented by the noradrenergic alpha-2 agonists guanfacine or clonidine. The selective noradrenergic re-uptake inhibitor atomoxetine is also approved by the Federal Drug Administration (FDA) for the treatment of ADHD, and the dopamine-active drug bupropion has mild anti-ADHD effects, as do the anti-narcolepsy drugs modafinil and armodafinil.
A 5mg dose of the antidepressant vortioxetine (Brintellix) was previously reported to have positive cognitive effects in elderly depressed patients. In a 2014 article in the International Journal of Neuropsychopharmacology, researcher Roger S. McIntyre et al. presented data from FOCUS, a study of cognition in depressed patients. The eight-week double-blind study included 18- to 65-year-olds (who were not selected for having cognitive problems per se).
McIntyre and colleagues used two tests of cognition, the Digit Symbol Substitution Test (DSST), which measures attention, psychomotor speed, and executive function, and the Rey Auditory Verbal Learning Test (RAVLT), which measures memory and acute and delayed recall. The researchers found that both the 195 patients taking 10mg/day of vortioxetine and the 207 patients taking 20mg/day of vortioxetine had better performance on both tests than the 196 patients who received placebo.
Response rates (meaning a patient achieved a 50% improvement on a scale of depression) were 47.7% on 10mg of vortioxetine, and 58.8% on 20mg of vortioxetine, compared to 29.4% on placebo. Remission rates were 29.5% on 10mg of vortioxetine and 38.2% on 20mg of vortioxetine versus 17% on placebo. McIntyre suggested that the drug worked both directly and indirectly, improving depression in some, but also improving cognition even in those whose depression did not improve.
The mechanism that could account for vortioxetine’s cognitive effects has not yet been identified. Like other selective serotonin reuptake inhibitor (SSRI) antidepressants, vortioxetine is a potent blocker of serotonin (5HT) reuptake, which it does by inhibiting the serotonin transporter (5HT-T). Unlike other SSRIs, vortioxetine is also a blocker of 5HT3 and 5HT7 receptors, an agonist at 5HT1A and 5HT1B and a partial agonist at 5HT1D receptors. It could be considered a polymodal 5HT active drug in contrast to the more selectively active 5HT-T–inhibiting SSRIs.
A new technology is making it possible to view the mammalian brain’s structure and connectivity for the first time. Karl Deisseroth discussed the technology, called CLARITY, at a plenary lecture at the 2014 meeting of the International College of Neuropsychopharmacology.
The way CLARITY works is by replacing lipids in the brain with a hydrogel substance. This preserves the structure of the brain’s neural networks, leaves proteins and nucleic acids intact, but allows for observation by rendering the brain transparent. This can be done in a system as large as the entire adult mouse brain. Early attempts took a whole day, but Deisseroth eventually found a way to render a mouse’s brain transparent in a matter of minutes.
The pictures are truly amazing, allowing for the visualization of previously microscropic neurons, dendrites, axons and connections in life-sized images. Pictures and details are available at www.clarityresourcecenter.org.
Deisseroth and colleagues have used CLARITY imaging to determine where neurons fire during different social activities. By placing photosensitive fibers in selected neurons using a virally based gene insertion technique, Deisseroth and colleagues were able to selectively fire dopamine neurons in the ventral tegmental area, part of the brain’s reward system, and thus increase or decrease the social interaction of mice by increasing or decreasing firing. The effects were selective to social interaction; the firing did not affect locomotor activity or exploration of an inanimate object.
The ventral tegmental area contains neurons that project to several locations in the brain, and Deisseroth and colleagues hoped to observe which were important to social interaction. Stimulating the ventral tegmental area to drive the medial prefrontal cortex caused anxiety in the mice and made them averse to social interaction. However, when the ventral tegmental area was used to selectively drive the nucleus accumbens, another part of the brain’s reward system, social interaction increased.
Deisseroth wanted to know if the nucleus accumbens was also involved in normal spontaneous social interactions. The researchers used a virus to insert an opsin-sensitive calcium gene that could give an ongoing readout of neural activity. (Opsin is a light-sensitive receptor found in cells in the retina.) The team found that the nucleus accumbens was implicated in social interaction with another mouse, but not in exploration of a novel object. Based on CLARITY imaging of the structure of ion channels (which are so small they cannot even be seen with an electron microscope), Deisseroth was able to selectively alter ion fluxes and turn neuronal firing on or off at will.
In the last 50 years, the brain and its billions of neurons and hundreds of trillions of synapses have gone from complete inaccessibility toward increasing clarity.
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.
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. Read more
Saffron, the expensive yellow spice derived from the plant Crocus sativus, was the subject of a recent meta-analysis in the journal Human Psychopharmacology. The meta-analysis included six studies of a total of 230 adult outpatients with major depressive disorder. In two of these studies, 30mg/day of saffron extract was as effective as 20mg/day of the antidepressant fluoxetine and 100mg/day imipramine for the treatment of mild to moderate depression had been in other studies.
Saffron is suggested to have anticancer, anti-inflammatory, antioxidant, and antiplatelet effects, and current clinical trials are exploring whether it could prevent and treat Alzheimer’s disease.
The current study was an effort to systematically analyze clinical trials on saffron to establish treatment parameters such as dosage in addition to safety information.
In the past there has been some concern that selective serotonin reuptake inhibitor (SSRI) antidepressants taken during pregnancy could increase an infant’s risk of cardiac problems. There was particular concern that the SSRI paroxetine could lead to right ventricular outflow tract obstruction, and sertraline could lead to ventricular septal defects. A 2014 study by KF Huybrechts et al. in the New England Journal of Medicine analyzed data from 949,504 women in a Medicaid system from three months before pregnancy until one month after delivery during the years 2000-2007.
Infants born to mothers who had taken antidepressants during their first trimester were compared to infants whose mothers had not taken antidepressants. In total, 6.8% or 64,389 women had used antidepressants in their first trimester.
While the rate of cardiac defects in newborns was greater among those mothers who had taken antidepressants (90.1 infants per 10,000 infants who had been exposed to antidepressants versus 72.3 infants per 10,000 infants who had not been exposed to antidepressants), this relationship diminished as confounding variables were removed. The relative risk of any cardiac defect after taking SSRIs was 1.25, but this decreased to 1.12 when restricted to only those mothers who were diagnosed with depression, and to 1.06 when the researchers controlled for things like depression severity. (All relative risk numbers were calculated with a 95% confidence interval.)
The researchers concluded that there is no substantial risk of increased cardiac defects in children born to mothers who took antidepressants during their first trimester.
Deep brain stimulation is a treatment in which electrodes are implanted in the brain to treat movement or affective disorders. At the 2014 meeting of the International College of Neuropsychopharmacology, Thomas Schlaepfer reviewed the current status of studies of deep brain stimulation for depression. The bad news is that two double-blind randomized controlled studies are no longer recruiting patients because interim analysis failed to show a benefit to the deep brain stimulation over a sham stimulation. The studies targeted two of the most promising parts of the brain for deep brain stimulation—the subgenual anterior cingulate (important for motivation) and the anterior limb of the internal capsule (which contains nerve fibers going to and from the cerebral cortex), so their failure is a big disappointment.
The better news is that Schlaepfer repositioned the electrodes to target a site in the medial forebrain bundle nearer to the ventral tegmental area. After this shift he observed rapid onset of antidepressant response (within two days) in seven of the first eight patients studied, and these responses persisted over many months of follow up. This response was achieved at 2.8 microamps, a lower stimulation current than was used in other studies of deep brain stimulation.
Editor’s Note: Since patients started to feel better when they were still on the operating table, this may offer an opportunity to more rapidly assess effectiveness, do a double-blind study, and see if the findings can be replicated as another mode of achieving rapid-acting and long-lasting antidepressant effects in treatment-resistant patients. Intravenous ketamine has rapid-onset antidepressant effects, but its effects are short-lived.
Researcher Tony Pitts presented a study at the 2014 meeting of the International College of Neuropsychopharmacology (CINP) that described the neurobiology of an animal model of depression in rodents. In animal models, researchers provoke depression-like symptoms in animals with the hopes of finding neurobiological clues to human depression. Pitts’ studies explored the effects of acute stressors as well as more chronic long-term stressors such as learned helplessness.
In the rodents, acute stressors caused increased cell firing in the hippocampus, which caused increases in burst firing and an increase in the number of cells firing in the ventral tegmental area, which then led to increased activity in the nucleus accumbens (the brain’s reward center). However, after the stressor was over, there was an opponent process that resulted in a much more prolonged period of inhibition in the nucleus accumbens, with associated decreases in psychomotor activity and reward seeking. The rodents lost their preference for sucrose and engaged in less intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. These and other effects suggest an analogy to anhedonia (loss of pleasure in activities that were previously enjoyed), which is a key component of human depression.
In related studies, after experiencing periods of inescapable shocks, rodents developed learned helplessness, failing to avoid the area where shocks were delivered even when an exit was readily available. Rodents who had learned helplessness showed inhibited firing of cells in the ventral tegmental area, less activity in the nucleus accumbens, and apparent anhedonia. This inhibition was mediated via messages from the infralimbic prefrontal cortex (the equivalent to the subgenual cingulate cortex in humans, important for motivation) to the amygdala and then the GABAergic ventral pallidum, which decreased the number of dopaminergic cells firing in the ventral tegmental area. Blocking the amygdala input to this inhibitory pathway reversed the low dopamine firing and the anhedonia-like behaviors.
The anesthetic ketamine (which has rapid-acting antidepressant effects in humans) produces an immediate reversal of the learned helpless behavior in the rodents and increases the number of dopamine cells firing in the ventral tegmental area. Ketamine administered directly into the nucleus accumbens induces long-term potentiation (enhanced synaptic responsivity) and reverses helpless behavior and the long-term depression of neural firing that is associated with it.
Thus, when an acute stressor is over and the opponent process emerges, or following long-term chronic stressors such as learned helplessness, the excitatory path to the ventral tegmental area is absent, while the inhibitory path to the ventral tegmental area (via the infralimbic prefrontal cortex, amygdala, and ventral pallidum) predominates. Ketamine is able to re-activate the activating pathway and increase activity in the ventral tegmental area and the nucleus accumbens, changes that are associated with the reversal of learned helplessness and anhedonia.
Editor’s Note: In the previous BNN, we reported researcher Scott Russo’s findings that input from the intralaminar nucleus of the thalamus was critical to the depression-like behaviors seen in a different animal model of depression, social defeat stress, where repeated exposure to defeat by a larger, more aggressive animal produces behaviors that resemble human depression. Here in Pitts’ research, learned helplessness is induced by inescapable shocks. Both models share the finding that firing decreases in the reward area of the brain (the nucleus accumbens). However, the key part of the brain driving the low levels of activity in the nucleus accumbens and the associated depression-like behavior appear to be different in these two different models. The intralaminar nucleus of the thalamus plays a key role in the social defeat stress model, while the infralimbic cortex and the amygdala play key roles in the learned helplessness model. These data together suggest that part of the reason depression differs from person to person may be because the illness can be driven by different brain areas as a result of different kinds of stressors.
To study depression in humans, researchers look to rodents to learn more about behavior. Rodents who are repeatedly defeated by more aggressive animals often begin to exhibit behavior that resembles depression. At the 2014 meeting of the International College of Neuropsychopharmacology (CINP), researcher Andre Der-Avakian reported that in a recent study, repeated experiences of social defeat led to depressive behavior in a subgroup of animals (which he calls susceptible), but not in others (which he calls resilient). Among many biological differences, the resilient animals showed increases in neurogenesis in the dentate gyrus of the hippocampus.
Chronic treatment of the susceptible animals with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine or the tricyclic antidepressant desipramine, which both increase neurogenesis, also reversed the depressive behavior in about half of the animals. A single injection of the anesthetic ketamine (which has rapid-acting antidepressant effects in humans) reversed social avoidance behavior in about 25% of the animals. One depression-like symptom was anhedonia (loss of pleasure from previously enjoyed activities), which researchers measured by observing to what extent the animals engaged in intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. The effectiveness of the drugs in inducing resilient behavior was related to the degree of anhedonia seen in the animals. The drugs worked less well in the more anhedonic animals (those who gave up the intracranial stimulation more easily, indicating that they experienced less reward from it.)