Oxytocin May Reduce PTSD Symptoms
The hormone oxytocin, best known for creating feelings of love and bonding, may help treat post-traumatic stress disorder, since it also reduces anxiety. A study by Saskia B.J. Koch and colleagues that will soon be published in the journal Neuropsychopharmacology reports that a single intranasal administration of oxytocin (at a dose of 40 IU) reduced anxiety and nervousness more than did placebo among police officers with PTSD.
Oxytocin also improved abnormalities in connectivity of the amygdala. Male participants with PTSD showed reduced connectivity between the right centromedial amygdala and the left ventromedial prefrontal cortex compared to other male participants who had also experienced trauma but did not have PTSD. This deficit was corrected in the men with PTSD after they received a dose of oxytocin. Female participants with PTSD showed greater connectivity between the right basolateral amygdala and the bilateral dorsal anterior cingulate cortex than female participants who had experienced trauma but did not have PTSD. This was also restored to normal following a dose of oxytocin.
These findings suggest that oxytocin can not only reduce subjective feelings of anxiety in people with PTSD, but may also normalize the way fear is expressed in the amygdala.
Marijuana Use Worsens PTSD Symptoms in Veterans
A 2015 study by Samuel T. Wilkinson and colleagues in the Journal of Clinical Psychiatry reports that among war veterans who completed a special treatment program for post-traumatic stress disorder, those who continued or began using marijuana after treatment had more severe PTSD symptoms, were more violent, and used drugs and alcohol more often. Those who stopped using marijuana or never used it had the lowest levels of PTSD symptoms in the study.
Editor’s Note: Scientific information about marijuana is almost never reported in the media. Evidence of the adverse effects of heavy marijuana use are robust and consistent.
Some of these include:
- A doubling of the risk of psychosis compared to non-users. People with a common variation in the enzyme COMT, which metabolizes dopamine, have an even higher rate of psychosis.
- An increased risk of bipolar disorder onset.
- A worse course of bipolar disorder.
- An increased risk of schizophrenia.
- Memory deficits that remain even after marijuana use has ceased.
- Loss of motivation (exactly what someone with depression doesn’t need).
- Anatomical changes in brain structures.
- A worse course of PTSD and increased violence in those with PTSD.
Bottom line: Those who say marijuana is benign may be ill-informed. People with mood disorders, proneness to paranoia, or PTSD should stay away from marijuana.
Another Expert Opinion on PTSD Treatment: Prazosin, SSRIs, and Mirtazapine
Researcher Albert Sattin has had extensive experience treating veterans with post-traumatic stress disorder (PTSD) in the U.S. Department of Veteran’s Affairs medical system. He believes that what is known as “treatment resistance” is really under-treatment, and he described his recommended regimen for thorough treatment of PTSD to this editor (Robert M. Post) at the 2015 meeting of the Society of Biological Psychiatry in May.
One of the key elements in the regimens he prescribes for patients with PTSD is prazosin, an alpha-1 antagonist drug used to treat hypertension. Extensive placebo-controlled data by another researcher, Murray Raskind, and colleagues supports the use of prazosin in PTSD. It is typically used to prevent nightmares, but Raskind, Sattin, and others find it has a broad range of positive effects in most domains of PTSD.
Sattin’s key insight is that prazosin should be administered three times a day because of its short half-life. This allows for the treatment of daytime as well as sleep-related PTSD symptoms. Sattin has patients choose from three schedules: 6am, 2pm, 10pm; 7am, 3pm, 11pm; or 8am, 4pm, 12am. Prazosin comes in 1mg, 2mg, and 5mg tablets, but patients must begin by taking the 1mg doses to reduce the risk of orthostatic hypotension (low blood pressure upon standing up), slowly increasing the dose as tolerated and if needed for symptom improvement.
Raskind reported in a poster at the same meeting that in a study of active duty combat soldiers, elevated blood pressure at baseline predicted that a patient would respond well to prazosin, so for patients with elevated blood pressure, Sattin starts with prazosin.
For other patients, Sattin begins by prescribing one of the two selective serotonin reuptake inhibitors (SSRIs) approved by the Federal Drug Administration for use in PTSD—sertraline (Zoloft) or paroxetine (Paxil)—and then adds the antidepressant mirtazapine (Remeron) if necessary. If the patient still remains symptomatic, Sattin then adds prazosin to the regimen with the added warning to take time sitting up or standing up to avoid potential dizziness from low blood pressure. Read more
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.
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.”
Acute Steroid Injection May Ward Off PTSD
Low cortisol after a trauma is a risk factor for developing chronic post-traumatic stress disorder (PTSD). Researcher Joseph Zohar studied has been researching the effects of steroids on the development of PTSD and presented some findings at the 2014 meeting of the International College of Neuropsychopharmacology.
Twenty-five patients who experienced a traumatic event and showed acute stress symptoms were given either a single high-dose injection of hydrocortisone (100–140 mg) or a placebo within six hours of the trauma. Follow-up evaluation took place after two weeks, one month, and three months. Those who received this single high dose of hydrocortisone had lowered stress symptoms and less subsequent PTSD compared to those who received placebo.
A Re-Kindling Process Produces Late-Onset PTSD
Not everyone who experiences trauma develops post-traumatic stress disorder (PTSD) immediately. Researchers are discovering that some people go on to develop symptoms like flashbacks or intrusive thoughts, anxiety, and withdrawal, sometimes after long periods of being asymptomatic. Two studies provide hints about the mechanism of this late-onset (or delayed-type) PTSD.
In an article by Danny Horesh et al. published in the journal Psychiatry Research in 2013, a reported 16.5% of 675 Israeli veterans of the 1982 conflict with Lebanon developed late-onset PTSD after a completely non-symptomatic period. The number of deployments soldiers were sent on and the number of terror incidents they experienced within Israel after the war were correlates of the late-onset PTSD, while continuous post-war employment was a protective factor reducing late-onset PTSD.
In a study of 260 older adults (above age 60) who survived the destruction around Galveston Bay, Texas by Hurricane Ike in 2008, Robert H. Pietrzak et al. reported in the Journal of Psychiatry Research in 2013 that 5.3% developed late-onset PTSD. In this case as well, a greater number of subsequent traumatic and stressful life events (and in particular financial difficulties) was associated with late onset of PTSD. The majority of participants in Pietrzak’s study (78.7 %) had no to few PTSD symptoms, while 16.0% had chronic PTSD symptoms from the outset persisting through assessments at three months and 15 months.
Editor’s Note: These two studies reveal that upon prospective follow-up, a small but substantial group of patients (5–16%) develop a late-onset type of PTSD. Acute onset PTSD has been closely linked to new trauma in adulthood, especially following the occurrence of previous (childhood) traumas. The late-occurring variety of PTSD seems to appear after an incubation period, and appears to be closely associated with the occurrence of new traumatic events during the well interval. These new events may result in a kindling-like effect, where repetition of subthreshold stimuli come to evoke a full-blown episode. PTSD appearing after repeated traumatic experiences may operate in a similar fashion to seizures that gradually emerge following repeated electrical stimulation of the amygdala (i.e. amygdala kindling). Read more
Ketamine for Chronic PTSD
We reported in BNN Volume 17, Issue 6 in 2013 on researchers’ efforts to treat symptoms of post-traumatic stress disorder using the drug ketamine. This research by Adriana Feder et al. has now been published in the journal JAMA Psychiatry.
In the study of 41 patients with post-traumatic stress disorder, patients showed a greater reduction in symptoms 24 hours after receiving intravenous (IV) ketamine than after taking IV midazolam, a benzodiazepine used as an active placebo control because it produces anti-anxiety and sedating effects similar to ketamine’s. The patients ranged in age from 18 to 55 years of age and were free of other medication for two weeks before the study. Ketamine was also associated with reduction in depressive symptoms and with general clinical improvement, and side effects were minimal.