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.
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
Researcher Murray Raskind has conducted a series of controlled studies, all with the same conclusion—the alpha-1 antagonist prazosin, used to treat high blood pressure, works for post-traumatic stress disorder (PTSD), especially in preventing nightmares. In his latest study, 67 soldiers were randomly assigned to either prazosin or placebo for 15 weeks. Doses were slowly titrated (to avoid low blood pressure and dizziness) to a possible maximum dose of 5mg at midmorning and 20mg at bedtime for men and 2mg at midmorning and 10mg at bedtime for women over a period of 6 weeks, based on whether the patients continued to experience nightmares.
Raskind found that prazosin was effective for trauma nightmares, sleep quality, global functioning, total score on a scale of PTSD symptoms, and hyperarousal. Side effects were minimal. Raskin concluded that prazosin “is effective for combat-related PTSD with trauma nightmares in active-duty soldiers, and benefits are clinically meaningful.”
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Joseph Zohar presented a poster on the effects of early post-stressor intervention with the drug agomelatine in animals who showed behavioral and molecular responses to stress that served as a model of post-traumatic stress disorder (PTSD).
Agomelatine is available clinically as an antidepressant in Canada and Europe (but not in the US), and can also reduce anxiety and re-synchronize circadian rhythms. Agomelatine is a melatonin (MT1/MT2) receptor agonist and a serotonin 5HT2C antagonist (increasing dopamine and norepinephrine in the frontal cortex).
Long-term behavioral, molecular and structural effects of the drug were assessed in animals. Adult male Sprague-Dawley rats were exposed to the scent of a predator for 10 minutes, and one hour later they were treated acutely for this stress with agomelatine (50mg/kg i.p.) or placebo.
Agomelatine decreased the prevalence of extreme, PTSD-like behavioral and molecular responses to the stressor, such as freezing in place and increased corticosterone. Agomelatine also normalized decreases in brain-derived neurotrophic factor (BDNF) observed in the dentate gyrus of the hippocampus, the cortex (layer III), and the basolateral amygdala. In line with this, agomelatine-treated stressed animals displayed significantly increased number and length of dendrites at glutamate synapses in the hippocampus (including the dentate gyrus and CA1) and reversed the hippocampal neuronal retraction observed in the rats who were given the placebo.
Agomelatine also affected the expression of clock genes in the rats, which regulate biorhythms. These genes lead to the production of the major clock gene proteins Per1 and Per2. Agomelatine normalized Per1 increases in three parts of the brain: the CA3, another glutamate synapse near the dentate gyrus; the suprachiasmatic nucleus over the optic chiasm, important for circadian rhythms; and the basolateral amygdala. Per2, a protein that also drives circadian rhythms, increased in the CA1 synapse of the hippocampus, the suprachiasmatic nucleus and the basolateral amygdala of the stressed rats.
The researchers concluded that the data provide “initial evidence that a single dose of agomelatine administered in the acute aftermath of stress promotes recovery while promoting enhanced neuronal and synaptic plasticity and connectivity in the secondary prevention of PTSD in this model.”
Schizophrenia is generally associated with a reduction in volume of the hippocampus. It is thought that the illness results from a predisposition that is triggered by an event such as a trauma or drug use that causes the release of chemicals that damage neurons. Recently, following the finding that five patients with schizophrenia and recurrent deep vein thrombosis (a blood clotting disorder) achieved remission of their psychosis after being treated with the anticoagulant warfarin (Coumadin) and have been able to go years with antipsychotic treatment, researchers Silvia Hoirisch-Clapauch and Antonio Egidio Nardi searched the existing literature for any connection between blood clotting and hippocampal neurogenesis, hoping to find a protein that could encourage neuronal growth in the hippocampus.
They found tissue-plasminogen activator (tPA), which facilitates the conversion of plasminogen to plasmin (the major enzyme responsible for breaking down blood clots) and plays a role in the repair of hippocampal neurons after stress. Low tPA activity is associated with clotting disorders and psychotic events. The drug warfarin reduces blood clotting, and also increases tPA activity, which may explain its effectiveness in treating the five patients who had both schizophrenia and deep vein thrombosis.
Abnormalities in schizophrenia that could be related to low tPA include deficient dopamine transmission at D1 receptors in the prefrontal cortex, impaired cleavage of the precursor to brain-derived neurotrophic factor (pro-BDNF, which can kill cells) to mature BDNF (which helps cells survive), abnormal NMDA receptor-mediated signaling, reduced Akt phosphorylation, and abnormal activation of reelin. The researchers found that all five patients had more than one tPA-related vulnerability to deep vein thrombosis, including high fasting blood insulin, high homocysteine, altered prothrombin activity, and anti-phospho-antibodies.
The same investigators have also examined whether plasmin plays a role in schizophrenia. Read more
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Lakshmi Latham presented a poster on three studies of the atypical atypical antipsychotic caripazine, a treatment that has not yet been approved by the Federal Drug Administration. We call it an atypical atypical because it is a partial agonist at dopamine D2 and D3 receptors, meaning it stimulates the receptors a little, but in the presence of high levels of dopamine it blocks excess activity by sitting on the receptor and preventing the actions of the excess dopamine. Aripiprazole is also a partial agonist at dopamine and serotonin 5HT1a receptors, but caripazine differs in that it has a particular affinity for the D3 receptor.
Previous analyses had revealed that cariprazine has good acute antimanic efficacy. All three studies described by Latham were randomized, double-blind, placebo-controlled three-week studies in patients with bipolar mania. In total the studies included 1065 patients, 442 of whom received placebo and 623 of whom received cariprazine.
Cariprazine doses from three studies were pooled, and ranged from 3-12 mg/day. Additional analyses evaluated the 3-6 and 9-12 mg/day groups specifically.
Approximately 70% of patients completed the study. The most common side effects included akathisia or restless legs (placebo, 5%; cariprazine, 20%), extrapyramidal disorder characterized by abnormal motor symptoms (5%, 13%), restlessness (2%, 6%) and vomiting (4%, 9%). The incidence of serious side effects was similar across the placebo and the treatment groups. Side effects that led to discontinuation of participation in the study occurred in 7% of placebo patients and 12% of cariprazine patients. Suicidal ideation was an infrequent side effect (placebo, 4; cariprazine, 2), and there were no suicide attempts.
Mean changes in weight were small (averaging 0.17kg in patients taking placebo and 0.54kg in those taking cariprazine), and the proportion of patients with 7% or higher increase in weight were similar across the two groups (both 2%). Mean changes in blood pressure and pulse were slightly greater with cariprazine and were related to dosage. Cariprazine was not associated with mean increases in electrocardiogram (EKG) parameters except for a slight increase in ventricular heart rate versus placebo (5.0 and 0.9 bpm, respectively). Mean changes in lipids and glucose were generally small and similar between groups. Levels of the hormone prolactin decreased in both groups.
Latham concluded that cariprazine treatment for three weeks was safe and well-tolerated.
Low levels of folate, also known as folic acid or vitamin B9, have been associated with depressive symptoms in the general population. A 2014 article by A.L. Sharpley et al. in the Journal of Affective Disorders explored whether folate has protective effects. Teens and young adults (ages 14–24) at high risk for mood disorders due to a family history of these illnesses were randomly assigned to receive either folate supplements (2.5 mg daily) or placebo for up to three months. While there were no significant differences in the percentage of young people in each group who went on to be diagnosed with a mood disorder, in the folate group there was a delayed onset of illness in those who went on to become unwell.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher N. Miyake described the effects of the nutritional supplement n-acetylcysteine (NAC) on clinical symptoms in subjects with subthreshold symptoms of psychosis.
N-acetylcysteine, a glutathione precursor, has neuroprotective effects. In this case series, four patients with subthreshold psychosis were given 2000mg/day of NAC for 12 weeks. The patients’ symptoms improved to the point that three of the four were no longer considered at risk for psychosis.
Editor’s Note: These promising anecdotal observations deserve careful follow up using a control group. Omega-3 fatty acids have been show to slow conversion to full psychosis and performed better than placebo in a controlled study. Both n-acetylcysteine and omega-3 fatty acids should definitely be studied for those with emerging symptoms of bipolar disorder.
C-reactive protein, or CRP, is a protein found in blood plasma, the levels of which rise in response to inflammation. In a recent study, levels of CRP were able to predict which of two antidepressants a patient was more likely to respond to.
The 2014 article by Rudolph Uher et al. in the American Journal of Psychiatry reported that low levels of CRP (<1 mg/L) predicted a good response to the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) while higher levels of CRP predicted a good response to the tricyclic antidepressant nortriptyline, a blocker of norepinephrine reuptake.
The research was part of the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured in the blood of 241 adult men and women with major depressive disorder. In the article the researchers say that CRP and its interaction with medication explained more than 10% of the individual variance in response to the two antidepressants.
If these findings can be replicated with these and similarly acting drugs, it would be a very large step in the direction of personalized medicine and the ability to predict individual response to medications.