At a recent scientific meeting, researcher John Geddes and colleagues reported that compared to adding placebo to the treatment of bipolar depressed patients already receiving the atypical antipsychotic quetiapine, adding the mood stabilizing drug lamotrigine led to significant improvements in their illness. Lamotrigine was slowly titrated to doses of 200mg/day. (Slowly increasing dosage is important because a serious rash is a possible side effect of lamotrigine, occuring in about one in 5,000 individuals exposed.)
Researcher Charles Bowden found in 2000 that adding lamotrigine to valproate improved its effectiveness, as Marc van der Loos found in 2008 with lamotrigine and lithium. Thus it appears that adding lamotrigine to a mood stabilizer or to an atypical antipsychotic like quetiapine is a good second-line option in the treatment of bipolar depression. While lamotrigine is not FDA-approved for the acute treatment of depression, this approach is worthy of consideration, and could be of immediate clinical use. It provides an alternative to adding a unimodal antidepressant, which recent meta-analyses have indicated is not effective and which can increase switches into mania, cycle acceleration, or even treatment resistance in patients with bipolar disorder.
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Robert Findling reported on a double blind, placebo controlled 36-week study of lamotrigine for children and adolescents with bipolar I disorder. The doses designed for maintenance treatment averaged about 225 mg/day, achieved by very slow increases over time in order to reduce the risk of a serious rash.
Findling found that lamotrigine was more effective than placebo in extending the time until a patient required an intervention for a new mood episode among the older children in the study (aged 13 to 17). Among the younger children in the study (aged 10 to 12), lamotrigine’s effects were not statistically significant compared to placebo. Findling and colleagues concluded that lamotrigine appeared effective in delaying time to onset of a new episode in adolescents with bipolar I disorder.
Lamotrigine is approved by the Federal Drug Administration (FDA) for bipolar disorder in adults only.
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Adelaine Robb reported that in 81 children with mania (aged 7-17), lithium was superior to placebo in reducing the severity of mania measured on the Young Mania Rating Scale. There had been some debate about the efficacy of lithium in young children with mania, but this study clearly indicates lithium’s effectiveness. The drug is approved by the Federal Drug Administration (FDA) for use in patients with bipolar disorder aged 12 and up.
Another researcher, Vivian Kafrantaris, found that in children who averaged 14.5 years of age, lithium increased the volume of the corpus callosum, a bundle of neural fibers that connects the brain’s right and left hemispheres. Lithium also normalized white matter integrity in other neural fiber tracts—the cingulum bundle and the superior longitudinal fasciculus. The authors concluded that lithium may “facilitate microstructural remodeling of white matter tracts involved in emotional regulation.”
Editor’s Note: There is much research showing that in adults, lithium has positive effects on the brain, including increases in hippocampal and cortical grey matter volume. Now it appears that lithium can improve white matter integrity in the developing brain as well.
Researcher Charles Popper gave a talk at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry on the benefits of nutritional supplements designed to provide multiple vitamins and minerals to children with bipolar disorder and other dyscontrol syndromes, such as attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder. Popper reviewed the literature on the substantial incidence of vitamin and mineral deficiencies among these children.
A modicum of data support the effectiveness of supplements for children with these disorders. One of these supplements is called EMPowerPlus and is sold online. It is moderately expensive and must be given under the supervision of a knowledgeable treating physician. While it is relatively safe in medication-free children, Popper says it can exacerbate withdrawal reactions from some psychotropic medications.
In addition, EMPowerPlus greatly increases lithium-related side effects, in patients taking lithium, the dose must be reduced to about one-tenth of a normal dose for those who are adding EMPowerPlus.
Popper and another researcher, Mary Fristad, have both seen excellent responses to this type of supplementation in children with bipolar disorder who have been unresponsive to more traditional drugs.
In another study by Rita Aouad et al., 72.3% of 980 children with a variety of psychiatric diagnoses had insufficient vitamin D levels (values < 30 nanograms/ml) and 26.7% had vitamin D deficiency (values < 20 nanograms/ml). These data support the rationale for vitamin D supplementation, especially in those who have low levels to start with.
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.
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.
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 disappointment. However, Helen Mayberg, one of the lead researchers studying the subgenual anterior cingulate, will continue to study this target for deep brain stimulation.
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.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Rieva et al. reported that 60% of bipolar patients with comorbid alcohol abuse have attempted suicide, and 48% of bipolar patients with cocaine abuse have attempted suicide. Thus, both of these comorbidities deserve specific attention and treatment. Unfortunately there are currently no Federal Drug Administration–approved drugs for bipolar patients with these comorbidities. The most promising treatments, based on data in patients with primary addictions, are the nutritional supplement N-acetylcysteine and topiramate, which have both performed better than placebo in studies of alcohol and cocaine abuse disorders.
In an earlier BNN we mistakenly attributed the protocol developed by David Bakish, a renowned Canadian psychopharmacologist, to another doctor named Vaishali P. Bakshi. Our apologies to both individuals.
Dr. David Bakish is Medical Director at the Ottawa Psychopharmacology Clinic and a Former Professor of Psychiatry at the University of Ottawa in Ottawa, Ontario. He shared with this editor his novel treatment strategy for patients with exceptionally profound degrees of post-traumatic stress disorder (PTSD), which, particularly among military veterans, can be compounded by traumatic brain injury. He has had a distinguished academic career with an extensive CV and credentials including membership in the International College of Neuropsychopharmacology (CINP), the Royal College of Physicians and Surgeons of Canada, and the Canadian and European Colleges of Neuropsychopharmacology. Most importantly he has had great success in treating large numbers of patients with severe PTSD. Treatment options based on placebo-controlled clinical trials are sometimes insufficient for the treatment of seriously ill patients. FDA-approved treatment for PTSD consists of serotonin-selective antidepressants, while exposure therapies (in which the patient is gradually exposed to more of the stimuli that triggered symptoms) are the recommended psychotherapy, but these methods often leave patients highly disabled. We relay Dr. Bakish’s treatment strategy with several caveats.
Most of Bakish’s suggestions are “off-label” treatments for the treatment of PTSD or traumatic brain injury, i.e. treatments that are not FDA-approved for these purposes. In some of these instances, there is no controlled research to support the use of these drugs in patients with PTSD. Thus the ideas noted here are anecdotal, based on his personal experience, and have not been tested in controlled clinical trials. Accordingly, patients with their physicians must make their own decisions about any of the strategies reported in this or other issues of the BNN.
Bakish’s typical treatment algorithm goes well beyond the usual treatment guidelines to find solutions for hard-to-treat patients. Bakish first addresses sleep disturbance, which is almost universal in PTSD. He suggests the anticonvulsant levetiracetam (Keppra), for the hyperarousal and sleep disorder. He uses starting at doses of 125mg per night and increases by 125mg every three weeks. Read more