Successful Trial of N-Acetylcysteine for Veterans with PTSD and Substance Abuse
The antioxidant N-acetylcysteine (NAC) can improve a number of habit-related conditions, such as substance use disorders, gambling, and compulsive hair-pulling. It also aids in the treatment of depression and obsessive-compulsive disorder (OCD). A 2016 study by Susie E. Back and colleagues in the Journal of Clinical Psychiatry found that NAC can also improve symptoms of post-traumatic stress disorder (PTSD) in veterans who also had substance use disorders.
In the pilot study of 35 veterans, participants were randomized to receive an 8-week course of NAC (2,400 mg/day) or placebo, plus cognitive-behavioral therapy targeting their substance use disorder. PTSD and substance use disorders have some overlapping neurobiological features, such as impaired prefrontal cortex regulation of basal ganglia circuitry.
At the end of the 8-week trial, those veterans who received NAC showed improvement in PTSD symptoms, substance cravings, and depression compared to those who received placebo. Substance use was similar and low among both groups. Side effects were minimal.
While these results were preliminary, they suggest that NAC could treat both PTSD and substance use disorders, which often occur together. Larger studies are expected to follow.
Editor’s Note: These preliminary data add to the evidence that NAC has remarkably wide utility in addictions (cocaine, alcohol, nicotine, and marijuana), habits (including OCD, trichotillomania/hair-pulling, nail biting, skin-picking, and cutting), depression and anxiety in bipolar disorder and negative symptoms in schizophrenia.
Different Types of Trauma Affect Brain Volume Differently
Post-traumatic stress disorder (PTSD) has been associated with decreased volume of gray matter in the cortex. Research by Linghui Meng and colleagues has revealed that the specific types of trauma that precede PTSD affect gray matter volume differently.
At the 2016 meeting of the Society for Neuroscience, Meng reported that PTSD from accidents, natural disasters, and combat led to different patterns of gray matter loss. PTSD from accidents was associated with gray matter reductions in the bilateral anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC). PTSD from natural disasters was linked to gray matter reductions in the mPFC and ACC, plus the amygdala and left hippocampus. PTSD from combat reduced gray matter volume in the left striatum, the left insula, and the left middle temporal gyrus.
Meng and colleagues also found that severity of PTSD was linked to the severity of gray matter reductions in the bilateral ACC and the mPFC.
In a 2016 article in the journal Scientific Reports, Meng and colleagues reported that single-incident traumas were associated with gray matter loss in the bilateral mPFC, the ACC, insula, striatum, left hippocampus, and the amygdala, while prolonged or recurrent traumas were linked to gray matter loss in the left insula, striatum, amygdala, and middle temporal gyrus.
Steroid Dexamethasone Facilitates Fear Extinction
A 2017 article by Vasiliki Michopoulos and colleagues in the journal Psychoendocrinology reports that the potent steroid dexamethasone reduced the fear-potentiated startle response in patients with post-traumatic stress disorder (PTSD) but not in healthy controls. Dexamethasone acts on glucocorticoid receptors to suppress the body’s secretion of cortisol.
In the study, participants both with and without PTSD were taught to associate a picture of a blue square or a purple triangle with an uncomfortable short blast of air to the larynx (voicebox) and a loud burst of broadband noise in the participants’ headphones.
Some participants were given a placebo the night before the study, while others received a 0.5 mg dose of dexamethasone. Those who received dexamethasone the night before the study acquired a startle response to the blue square or purple triangle as much as other participants.
People without PTSD were easily able to eliminate their fear of the visual symbol when it was no longer linked to the noise and the blast of air, regardless of whether they had taken dexamethasone. However, among those with PTSD, only those who received dexamethasone were able to eliminate this fear-potentiated startle response and properly discriminate between safe and unsafe signals. People with PTSD who received the placebo maintained the fearful response to the blue square or purple triangle and startled in response to safe symbols.
People with PTSD may have difficulty learning to inhibit their fearful responses to stimuli that are no longer dangerous. In this study, the patients with PTSD continued to startle even after repeated presentations of the visual symbol without any accompanying air blast, while the controls showed excellent extinction of the response. After dexamethasone, but not placebo, patients with PTSD were just as successful in extinguishing the fear potentiated startle response as the controls. The authors conclude that dexamethasone could help facilitate extinction-based interventions used in PTSD, such as exposure therapy delivered during cognitive behavioral therapy or virtual reality exposure therapy.
Antibiotic Doxycycline May Block PTSD Symptoms
A 2017 proof-of-concept study suggests that the antibiotic doxycycline can block the formation of negative thoughts and fear memories, perhaps offering a new way to treat or prevent post-traumatic stress disorder (PTSD).
In the study by Dominik R. Bach in the journal Molecular Psychiatry, healthy adults who received doxycycline had a lower fear response to fearful stimuli compared to healthy adults who received a placebo. The 76 participants received either doxycycline or placebo and then were taught to associate a color with an electric shock. Later, they were exposed to the color accompanied by a loud sound (but no shock), and their startle response was measured by tracking eye blinks, an instinctive response to sudden threats. Bach and colleagues found that the fear response was 60% lower in those participants who received doxycycline, suggesting that the antibiotic disrupted the fear memory linking the color to a threat.
The theory is based on evidence that doxycycline can inhibit metalloproteinase enzymes, which are involved in memory formation.
While in the study doxycycline was delivered before the fearful event occurred, there is hope that the antibiotic could also do some good after the fact. There is growing evidence that actively recalling a traumatic event can open a ‘memory reconsolidation window’ during which emotions associated with that event are open to change. Bach and colleagues hope to follow up with studies involving this reconsolidation window.
Another line of research is exploring how pain medications may reduce the emotional power of traumatic memories, because intense pain strengthens memory consolidation.
Three Experts’ Different Approaches to Treating PTSD in Veterans
In the BNN we have previously described some experts’ preferred treatment algorithms for patients with treatment-resistant post-traumatic stress disorder (PTSD), which is often complicated by traumatic brain injury (TBI). In this article, we update and expand upon these expert views.
David Bakish has worked as Medical Director at the Ottawa Psychopharmacology Clinic and is a former professor of psychiatry at the University of Ottawa in Ottawa, Ontario. In addition, he works with the Canadian military seeing patients with PTSD, substance abuse, and traumatic brain injuries. He uses a symptom-driven approach to PTSD, including 6 to 7 targeted medications added in sequence.
Albert Sattin is a professor of psychiatry and biobehavioral sciences at UCLA, belongs to their Brain Research Institute, and is affiliated with both the Ronald Reagan UCLA Medical Center and the Veterans Affairs Greater Los Angeles Healthcare System. He prefers to treat PTSD with a three-part combination of the blood pressure–lowering drug prazosin, a selective serotonin reuptake inhibitor (SSRI) antidepressant, and the atypical antidepressant mirtazapine.
Murray Raskind pioneered placebo-controlled studies of prazosin for PTSD and served as director of the Veterans Affairs Puget Sound Health Care System Mental Health Service, in addition to serving in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine. Raskind’s approach to PTSD includes prazosin, the tricyclic antidepressant amitriptyline, and if needed for sleep, the sedative zolpidem.
Only SSRIs are approved by the US Food and Drug Administration (FDA) for the treatment of PTSD, but these on their own are rarely sufficient to handle the insomnia and other symptoms that accompany PTSD. Exposure therapy, in which patients are gradually led to approach trauma-related memories, feelings, and situations they previously avoided, is the most recommended type of therapy, but it too is often insufficient to treat all the complexities of the illness. Read on for more on each doctor’s approach to treating PTSD. Read more
Intranasal Oxytocin Soon After a Trauma May Prevent Worsening PTSD
Oxytocin, a hormone that promotes emotional bonding, also benefits people having trouble dealing with stress. A new study suggests that giving oxytocin for a week shortly following a traumatic experience reduces the risk that the recipient will develop post-traumatic stress disorder (PTSD).
In the study by researcher Mirjam van Zuiden and colleagues, people who visited an emergency room following some kind of trauma were randomized to receive either a placebo nasal spray or intranasal oxytocin twice daily for 7.5 days beginning within 12 days after the trauma. The dosage was 40 IU twice daily.
For those participants with severe PTSD symptoms at baseline, repeated oxytocin administration prevented worsening PTSD. The research was presented at the 2016 meeting of the Society of Biological Psychiatry.
Cognitive Behavioral Therapy Improves Depression, PTSD by Improving Brain Connectivity
A recent study clarified how cognitive behavioral therapy improves symptoms of depression and post-traumatic stress disorder (PTSD). The participants were 62 adult women. One group had depression, one had PTSD, and the third was made up of healthy volunteers. None were taking medication at the time of the study. The researchers, led by Yvette Shelive, used functional magnetic resonance imaging (fMRI) to analyze participants’ amygdala connectivity.
At the start of the study, participants with depression or PTSD showed diminished connectivity between the amygdala and brain areas related to cognitive control, the process by which the brain can vary behavior and how it processes information in the moment based on current goals. The lack of connectivity reflected the severity of the participants’ depression. Twelve weeks of cognitive behavioral therapy improved mood and connectivity between the amygdala and these control regions, including the dorsolateral prefrontal cortex and the inferior frontal cortex. These regions also allow for executive functioning, which includes planning, implementation, and focus.
Mice Who Witness Another Being Attacked Show Depression-Like Behaviors
Stress is a risk factor for depression and other mental health disorders. Researchers are currently working to clarify how stress leads to depression, anxiety, and post-traumatic stress disorder, and why trauma early in life has lasting consequences.
Two recent studies in mice examined whether just witnessing a stressful event leads to depression-like behaviors. In one, adult female mice watched a male mouse as it was repeatedly attacked by a larger mouse. After ten days of this, the female mice were socially withdrawn, had lost interest in drinking sucrose, and gave up more easily during a physical challenge. They also lost weight and showed higher levels of the stress hormone corticosterone in their blood. The researchers, led by Sergio Iniguez, believe their study clarifies how witnessing traumatic events can lead to stress-induced mood disorders.
In the other study, by Carlos Bolanos-Guzman, adolescent male mice witnessed another mouse being attacked. Both the mice that went through the physical stress of being attacked and the mice that went through the emotional stress of watching the attacks occur showed similar depressive behaviors to the mice in the previous study—social withdrawal, loss of interest in sucrose, decreased food intake and exploration of the environment, and decreased motivation in physical challenges. These behaviors persisted into adulthood. Both groups of mice also had increased levels of corticosterone and reduced expression of a particular protein in the ventral tegmental area, a part of the brain linked to stress response. Bolanos-Guzman suggests that both physical and emotional stress have lifelong consequences in mice.
The studies were presented at a scientific meeting in December.
Inflammation Plays a Role in Fear Memories
People with post-traumatic stress disorder (PTSD) often experience fearful memories of the trauma they witnessed. Researchers are working to determine the neurobiological basis for these persistent fear memories in order to better treat PTSD. Current treatments mainly target the central nervous system. Because many people with PTSD have elevated levels of pro-inflammatory immune molecules in their blood, there has been a recent push to determine whether targeting that inflammation may be another way of treating PTSD.
A recent study by researchers Matthew Young and Leonard Howell used an animal model to learn more about the link between trauma, inflammation, and fear memories. The researchers exposed mice to a trauma that produced both a persistent fear response and an increase in inflammatory molecules in the blood. Some of the mice were also given antibodies to neutralize the inflammatory immune response. When the mice were exposed to a cue meant to remind them of the trauma, levels of the inflammatory molecule IL-6 spiked again. When the mice were given antibodies to neutralize IL-6 just before being exposed to the cue, they produced less of a fear reaction.
The researchers, who presented their work at a scientific meeting in December, concluded that traumatic experiences produce not only persistent fearful memories, but also an immune reaction. They believe that the spike in IL-6 following trauma plays a role in the persistence of those memories, and that elevated IL-6 in the blood may explain symptoms of PTSD and other disorders that involve fear learning (such as phobias).
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.
