A Paradigm for Treatment of Severe PTSD developed by Dr. David Bakish
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
Prazosin Effective for Nightmares and Other PTSD Symptoms
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.”
Agomelatine in an Animal Model of PTSD
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.”
Anti-Coagulants May Treat Psychosis
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
